2014 Payers' Guide to New FDA Approvals by Dalia Buffery

march 2014

Volume 7 I Special Feature

THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN™

For Payers, Purchasers, Policymakers, and Other Healthcare Stakeholders

™

Fifth Annual Payers’ Guide to New FDA Approvals Foreword The Fifth Annual Payers’ Guide to FDA Approvals Introduction New FDA Drug Approvals in 2013 FDA Approvals of Brand-Name Prescription Drugs in 2013 Specialty Drugs Top the Trends in the 2014 Pipeline Product Profiles of Select Drugs Approved in 2013

Special Feature

SARY

Stimulating

*Soluble Guanylate Cyclase

It means different things to different people.

INDICATIONS • Adempas (riociguat) tablets are indicated for the treatment of adults with persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH), (WHO Group 4) after surgical treatment, or inoperable CTEPH, to improve exercise capacity and WHO functional class. • Adempas is indicated for the treatment of adults with pulmonary arterial hypertension (PAH), (WHO Group 1), to improve exercise capacity, WHO functional class and to delay clinical worsening.† Efficacy was shown in patients on Adempas monotherapy or in combination with endothelin receptor antagonists or prostanoids. Studies establishing effectiveness included predominantly patients with WHO functional class II–III and etiologies of idiopathic or heritable PAH (61%) or PAH associated with connective tissue diseases (25%). † Time to clinical worsening was a combined endpoint defined as death (all-cause mortality), heart/lung transplantation, atrial septostomy, hospitalization due to persistent worsening of pulmonary hypertension, start of new PAH-specific treatment, persistent decrease in 6MWD and persistent worsening of WHO functional class.

IMPORTANT SAFETY INFORMATION WARNING: EMBRYO-FETAL TOXICITY Do not administer Adempas (riociguat) tablets to a pregnant female because it may cause fetal harm. Females of reproductive potential: Exclude pregnancy before the start of treatment, monthly during treatment, and 1 month after stopping treatment. Prevent pregnancy during treatment and for one month after stopping treatment by using acceptable methods of contraception. For all female patients, Adempas is available only through a restricted program called the Adempas Risk Evaluation and Mitigation Strategy (REMS) Program.

Please see additional Important Safety Information, including Boxed Warning, throughout and Brief Summary of Prescribing Information at end of advertisement.

For Mary, it means going from the garage to the garden Proven in PAH (WHO Group 1):

36m

improvement in 6-minute walk distance (6MWD) over placebo at Week 12 (95% Confidence Interval (CI): 20m-52m; p<0.0001)

6MWD over 12 weeks (mean change) with results from Week 2 onward.

Change from baseline to last visit in 6MWD (m)

40 PATENT-1: 443 PAH patients were studied (Adempas 2.5 mg n=254; 1.5 mg n=63, placebo n=126).

Adempas

Baseline characteristics:

Placebo

– PAH defined as: pulmonary vascular resistance (PVR) >300 dyn·sec·cm-5, pulmonary arterial pressure (PAP) mean >25 mm Hg.

– Mean age: 51 years (approximately 80% female). – PAH etiologies: idiopathic (61%), familial (2%), associated with connective tissue disease (25%), congenital heart disease (8%), portal hypertension (3%), or anorexigen or amphetamine use (1%).

– Mean 6MWD was 363 m. – Concomitant medications included oral anticoagulants, diuretics, digitalis, calcium channel blockers, and oxygen were allowed.

0 Baseline

6 Weeks

Patient population was: 50% treatment-naïve, 44% pretreated with an endothelin receptor antagonist (ERA), and 6% pretreated with a prostacyclin analogue (PCA). The majority of patents had WHO Functional Class (FC) II (42%) or III (54%) at baseline. Patients with systolic blood pressure (SBP) <95 mm Hg were excluded.

Contraindications Adempas is contraindicated in: • Pregnancy. Adempas may cause fetal harm when administered to a pregnant woman. Adempas was consistently shown to have teratogenic effects when administered to animals. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus • Co-administration with nitrates or nitric oxide donors (such as amyl nitrite) in any form. • Concomitant administration with phosphodiesterase (PDE) inhibitors, including specific PDE-5 inhibitors (such as sildenafil, tadalafil, or vardenafil) or nonspecific PDE inhibitors (such as dipyridamole or theophylline).

Warnings and Precautions Embryo-Fetal Toxicity. Adempas may cause fetal harm when administered during pregnancy and is contraindicated for use in women who are pregnant. In females of reproductive potential, exclude pregnancy prior to initiation of therapy, advise use of acceptable contraception and obtain monthly pregnancy tests. For females, Adempas is only available through a restricted program under the Adempas REMS Program.

Please see additional Important Safety Information, including Boxed Warning, throughout and Brief Summary of Prescribing Information at end of advertisement.

See where you can take your patients Proven in CTEPH* (WHO Group 4):

46m

improvement in 6MWD over placebo at Week 16 (95% CI: 25m-67m; p<0.0001)

6MWD over 16 weeks (mean change) with results from Week 2 onward.

Change from baseline to last visit in 6MWD (m)

CHEST-1: 261 CTEPH patients were studied (Adempas n=173, placebo n=88).

Adempas

Baseline characteristics:

Placebo

* Inoperable and recurrent/persistent CTEPH after surgery. – Mean age: 59 years (range:18-80). – Mean 6MWD was 347m.

– Concomitant medications: Stable dosages of oral anticoagulants, diuretics, digitalis, calcium channel blockers, and oxygen were allowed, but not NO donors, ERAs, PCAs, specific PDE-5 inhibitors (such as sildenafil, tadalafil, or vardenafil), and nonspecific PDE inhibitors (for example, dipyridamole or theophylline), or nonspecific PDE inhibitors (for example, dipyridamole or theophylline).

0 Baseline

8 Weeks

Patient population was: 72% inoperable by pulmonary endarterectomy (PEA) (pulmonary vascular resistance [PVR] >300 dyn·sec·cm-5 and PAP mean >25 mm Hg measured at least 90 days after the start of full anticoagulation); 28% recurrent or persisting PH following PEA (PVR >300 dyn·sec·cm-5 measured at least 180 days following PEA). The majority of patients were WHO FC II (31%) or III (64%) at baseline. Patients with SBP <95 mm Hg were excluded.

Warnings and Precautions Adempas REMS Program. Females can only receive Adempas through the Adempas REMS Program, a restricted distribution program. Important requirements of the Adempas REMS program include the following: • Prescribers must be certified with the program by enrolling and completing training. • All females, regardless of reproductive potential, must enroll in the Adempas REMS Program prior to initiating Adempas. Male patients are not enrolled in the Adempas REMS Program. • Female patients of reproductive potential must comply with the pregnancy testing and contraception requirements. • Pharmacies must be certified with the program and must only dispense to patients who are authorized to receive Adempas. Further information, including a list of certified pharmacies, is available at www.AdempasREMS.com or 1-855-4ADEMPAS.

First-in-class sGC stimulator Adempas targets sGC via a dual mode of action, regardless of nitric oxide (NO) level.

It sensitizes sGC to endogenous NO by stabilizing NO-sGC binding. Adempas also directly stimulates sGC via a different binding site, independently of NO.

The first drug proven in both PAH and CTEPH • For PAH: 50% more patients improved WHO Functional Class (21% Adempas vs 14% placebo at 12 weeks) • For CTEPH: More than twice as many patients improved WHO Functional Class (33% Adempas vs 15% placebo at 16 weeks) • Adempas is indicated to treat adults with PAH (WHO Group I) and persistent/recurrent CTEPH (WHO Group 4) after surgery, or inoperable CTEPH. In studies establishing effectiveness, most patients were in WHO Functional Class II and III

Warnings and Precautions Hypotension. Adempas reduces blood pressure. Consider the potential for symptomatic hypotension or ischemia in patients with hypovolemia, severe left ventricular outflow obstruction, resting hypotension, autonomic dysfunction, or concomitant treatment with antihypertensives or strong CYP and P-gp/BCRP inhibitors. Consider a dose reduction if patient develops signs or symptoms of hypotension. Bleeding. In the placebo-controlled clinical trials program, serious bleeding occurred in 2.4% of patients taking Adempas compared to 0% of placebo patients. Serious hemoptysis occurred in 5 (1%) patients taking Adempas compared to 0 placebo patients, including one event with fatal outcome. Serious hemorrhagic events also included 2 patients with vaginal hemorrhage, 2 with catheter site hemorrhage, and 1 each with subdural hematoma, hematemesis, and intra-abdominal hemorrhage. Pulmonary Veno-Occlusive Disease. Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno-occlusive disease (PVOD). Therefore, administration of Adempas to such patients is not recommended. Should signs of pulmonary edema occur, the possibility of associated PVOD should be considered and if confirmed, discontinue treatment with Adempas. BAYER, the Bayer Cross, and Adempas are registered trademarks of Bayer. Bayer HealthCare LLC 100 Bayer Boulevard, Whippany, NJ 07981 USA ©2014 Bayer HealthCare Inc. 400-10-0003-13 March 2014

Stimulating

For PAH. For CTEPH. For people like Mary.

Most Common Adverse Reactions • The most common adverse reactions occurring more frequently (≥3%) on Adempas than placebo were headache (27% vs 18%), dyspepsia/gastritis (21% vs. 8%), dizziness (20% vs 13%), nausea (14% vs 11%), diarrhea (12% vs 8%), hypotension (10% vs 4%), vomiting (10% vs 7%), anemia (7% vs 2%), gastroesophageal reflux disease (5% vs 2%), and constipation (5% vs 1%). • Other events that were seen more frequently in Adempas compared to placebo and potentially related to treatment were: palpitations, nasal congestion, epistaxis, dysphagia, abdominal distension and peripheral edema. For important risk and use information, please see the Brief Summary of the full Prescribing Information, including Boxed Warning, on the next page.

Adempas (riociguat) tablets, for oral use Initial U.S. Approval: 2013 BRIEF SUMMARY of prescribing information CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION WARNING: EMBRYO-FETAL TOXICITY Do not administer Adempas to a pregnant female because it may cause fetal harm [see Contraindications (4) and Use in Specific Populations (8.1)]. Females of reproductive potential: Exclude pregnancy before the start of treatment, monthly during treatment, and 1 month after stopping treatment. Prevent pregnancy during treatment and for one month after stopping treatment by using acceptable methods of contraception [see use in Special Populations (8.6)]. For all female patients, Adempas is available only through a restricted program called the Adempas Risk Evaluation and Mitigation Strategy (REMS) Program [see Warnings and Precautions (5.2)]. 1 INDICATIONS AND USAGE 1.1 Chronic-Thromboembolic Pulmonary Hypertension Adempas is indicated for the treatment of adults with persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH), (WHO Group 4) after surgical treatment, or inoperable CTEPH, to improve exercise capacity and WHO functional class [see Clinical Studies (14.1)]. 1.2 Pulmonary Arterial Hypertension Adempas is indicated for the treatment of adults with pulmonary arterial hypertension (PAH), (WHO Group 1), to improve exercise capacity, WHO functional class and to delay clinical worsening. Efficacy was shown in patients on Adempas monotherapy or in combination with endothelin receptor antagonists or prostanoids. Studies establishing effectiveness included predominately patients with WHO functional class II–III and etiologies of idiopathic or heritable PAH (61%) or PAH associated with connective tissue diseases (25%) [see Clinical Studies (14.2)]. 4 CONTRAINDICATIONS 4.1 Pregnancy Adempas may cause fetal harm when administered to a pregnant woman. Adempas is contraindicated in females who are pregnant. Adempas was consistently shown to have teratogenic effects when administered to animals. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1)]. 4.2 Nitrates and Nitric Oxide Donors Co-administration of Adempas with nitrates or nitric oxide donors (such as amyl nitrite) in any form is contraindicated [see Drug Interactions (7.1), Clinical Pharmacology (12.2)]. 4.3 Phosphodiesterase Inhibitors Concomitant administration of Adempas with phosphodiesterase (PDE) inhibitors, including specific PDE-5 inhibitors (such as sildenafil, tadalafil, or vardenafil) or nonspecific PDE inhibitors (such as dipyridamole or theophylline) is contraindicated [see Drug Interactions (7.1), Clinical Pharmacology (12.2)]. 5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Toxicity Adempas may cause fetal harm when administered during pregnancy and is contraindicated for use in women who are pregnant. In females of reproductive potential, exclude pregnancy prior to initiation of therapy, advise use of acceptable contraception and obtain monthly pregnancy tests. For females, Adempas is only available through a restricted program under the Adempas REMS Program [see Dosage and Administration (2.3), Warnings and Precautions (5.2) and Use in Specific Populations (8.1, 8.6)]. 5.2 Adempas REMS Program Females can only receive Adempas through the Adempas REMS Program, a restricted distribution program [see Warnings and Precautions (5.1)]. Important requirements of the Adempas REMS Program include the following: • Prescribers must be certified with the program by enrolling and completing training. • All females, regardless of reproductive potential, must enroll in the Adempas REMS Program prior to initiating Adempas. Male patients are not enrolled in the Adempas REMS Program. • Female patients of reproductive potential must comply with the pregnancy testing and contraception requirements [see Use in Specific Populations (8.6)]. • Pharmacies must be certified with the program and must only dispense to patients who are authorized to receive Adempas. Further information, including a list of certified pharmacies, is available at www.AdempasREMS.com or 1-855-4 ADEMPAS. 5.3 Hypotension Adempas reduces blood pressure. Consider the potential for symptomatic hypotension or ischemia in patients with hypovolemia, severe left ventricular outflow obstruction, resting hypotension, autonomic dysfunction, or concomitant treatment with antihypertensives or strong CYP and P-gp/BCRP

inhibitors [see Drug Interactions (7.2), Clinical Pharmacology (12.3)]. Consider a dose reduction if patient develops signs or symptoms of hypotension. 5.4 Bleeding In the placebo-controlled clinical trials program, serious bleeding occurred in 2.4% of patients taking Adempas compared to 0% of placebo patients. Serious hemoptysis occurred in 5 (1%) patients taking Adempas compared to 0 placebo patients, including one event with fatal outcome. Serious hemorrhagic events also included 2 patients with vaginal hemorrhage, 2 with catheter site hemorrhage, and 1 each with subdural hematoma, hematemesis, and intra-abdominal hemorrhage. 5.5 Pulmonary Veno-Occlusive Disease Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno-occlusive disease (PVOD). Therefore, administration of Adempas to such patients is not recommended. Should signs of pulmonary edema occur, the possibility of associated PVOD should be considered and, if confirmed, discontinue treatment with Adempas. 6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: • Embryo-Fetal Toxicity [see Warnings and Precautions (5.1)] • Hypotension [see Warnings and Precautions (5.3)] • Bleeding [see Warnings and Precautions (5.4)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety data described below reflect exposure to Adempas in two, randomized, double blind, placebo-controlled trials in patients with inoperable or recurrent/persistent CTEPH (CHEST-1) and treatment naive or pre-treated PAH patients (PATENT-1). The population (Adempas: n = 490; Placebo: n = 214) was between the age of 18 and 80 years [See Clinical Studies (14.1, 14.2)]. The safety profile of Adempas in patients with inoperable or recurrent/ persistent CTEPH (CHEST 1) and treatment naive or pre-treated PAH (PATENT 1) were similar. Therefore, adverse drug reactions (ADRs) identified from the 12 and 16 week placebo-controlled trials for PAH and CTEPH respectively were pooled, and those occurring more frequently on Adempas than placebo (≥3%) are displayed in Table 1 below. Most adverse events in Table 1 can be ascribed to the vasodilatory mechanism of action of Adempas. The overall rates of discontinuation due to an adverse event in the pivotal placebo-controlled trials were 2.9% for Adempas and 5.1% for placebo (pooled data). Table 1: Adverse Reactions Occurring More Frequently (≥3%) on Adempas than Placebo (Pooled from CHEST 1 and PATENT 1) Adverse Reactions Adempas % Placebo % (n=490) (n=214) Headache 27 18 Dyspepsia and Gastritis 21 8 Dizziness 20 13 Nausea 14 11 Diarrhea 12 8 Hypotension 10 4 Vomiting 10 7 Anemia (including laboratory parameters) 7 2 Gastroesophageal reflux disease 5 2 Constipation 5 1 Other events that were seen more frequently in riociguat compared to placebo and potentially related to treatment were: palpitations, nasal congestion, epistaxis, dysphagia, abdominal distension and peripheral edema. With longer observation in uncontrolled long-term extension studies the safety profile was similar to that observed in the placebo controlled phase 3 trials. 7 DRUG INTERACTIONS 7.1 Pharmacodynamic Interactions with Adempas Nitrates: Co-administration of Adempas with nitrates or nitric oxide donors (such as amyl nitrite) in any form is contraindicated because of hypotension [see Contraindications (4.1), Clinical Pharmacology (12.2)]. PDE Inhibitors: Co-administration of Adempas with phosphodiesterase (PDE) inhibitors, including specific PDE-5 inhibitors (such as sildenafil, tadalafil, or vardenafil) and nonspecific PDE inhibitors (such as dipyridamole or theophylline), is contraindicated because of hypotension [see Contraindications (4.3), Clinical Pharmacology (12.2)]. 7.2 Pharmacokinetic Interactions with Adempas Smoking: Plasma concentrations in smokers are reduced by 50-60% compared to nonsmokers. Based on pharmacokinetic modeling, for patients

who are smokers, doses higher than 2.5 mg three times a day may be considered in order to match exposure seen in nonsmoking patients. Safety and effectiveness of Adempas doses higher than 2.5 mg three times a day have not been established. A dose reduction should be considered in patients who stop smoking [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)]. Strong CYP and P-gp/BCRP inhibitors: Concomitant use of riociguat with strong cytochrome CYP inhibitors and P-gp/BCRP inhibitors such as azole antimycotics (for example, ketoconazole, itraconazole) or HIV protease inhibitors (such as ritonavir) increase riociguat exposure and may result in hypotension. Consider a starting dose of 0.5 mg 3 times a day when initiating Adempas in patients receiving strong CYP and P-gp/BCRP inhibitors. Monitor for signs and symptoms of hypotension on initiation and on treatment with strong CYP and P-gp/BCRP inhibitors. A dose reduction should be considered in patients who may not tolerate the hypotensive effect of riociguat [see Dosage and Administration (2.5), Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)]. Strong CYP3A inducers: Strong inducers of CYP3A (for example, rifampin, phenytoin, carbamazepine, phenobarbital or St. John’s Wort) may significantly reduce riociguat exposure. Data are not available to guide dosing of riociguat when strong CYP3A inducers are co-administered [see Clinical Pharmacology (12.3)]. Antacids: Antacids such as aluminum hydroxide/magnesium hydroxide decrease riociguat absorption and should not be taken within 1 hour of taking Adempas [see Clinical Pharmacology (12.3)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category X Risk Summary Adempas may cause fetal harm when administered to a pregnant woman and is contraindicated during pregnancy. Adempas was teratogenic and embryotoxic in rats at doses with exposures approximately 3 times the human exposure. In rabbits, riociguat led to abortions at 5 times the human exposure and fetal toxicity at doses with exposures approximately 15 times the human exposure. If Adempas is used in pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus [see Contraindications (4.1)]. Animal Data In rats administered riociguat orally (1, 5, 25 mg/kg/day) throughout organogenesis, an increased rate of cardiac ventricular-septal defect was observed at the highest dose tested. The highest dose produced evidence of maternal toxicity (reduced body weight). Post-implantation loss was statistically significantly increased from the mid-dose of 5 mg/kg/day. Plasma exposure at the lowest dose is approximately 0.15 times that in humans at the maximally recommended human dose (MRHD) of 2.5 mg three times a day based on area under the time-concentration curve (AUC). Plasma exposure at the highest dose is approximately 3 times that in humans at the MRHD while exposure at the mid-dose is approximately 0.5 times that in humans at the MRHD. In rabbits given doses of 0.5, 1.5 and 5 mg/kg/day, an increase in spontaneous abortions was observed starting at the middle dose of 1.5 mg/kg, and an increase in resorptions was observed at 5 mg/kg/day. Plasma exposures at these doses were 5 times and 15 times the human dose at MRHD respectively. 8.3 Nursing Mothers It is not known if Adempas is present in human milk. Riociguat or its metabolites were present in the milk of rats. Because many drugs are present in human milk and because of the potential for serious adverse reactions in nursing infants from riociguat, discontinue nursing or Adempas. 8.4 Pediatric Use Safety and effectiveness of Adempas in pediatric patients have not been established. 8.5 Geriatric Use Of the total number of subjects in clinical studies of Adempas, 23% were 65 and over, and 6% were 75 and over [see Clinical Studies (14)]. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Elderly patients showed a higher exposure to Adempas [see Clinical Pharmacology (12.3)]. 8.6 Females and Males of Reproductive Potential Pregnancy Testing: Female patients of reproductive potential must have a negative pregnancy test prior to starting treatment with Adempas, monthly during treatment, and one month after discontinuation of treatment with Adempas. Advise patients to contact their health care provider if they become pregnant or suspect they may be pregnant. Counsel patients on the risk to the fetus [see Boxed Warning and Dosage and Administration (2.2)]. Contraception: Female patients of reproductive potential must use acceptable methods of contraception during treatment with Adempas and for 1 month after treatment with Adempas. Patients may choose one highly effective form

of contraception (intrauterine devices [IUD], contraceptive implants or tubal sterilization) or a combination of methods (hormone method with a barrier method or two barrier methods). If a partner’s vasectomy is the chosen method of contraception, a hormone or barrier method must be used along with this method. Counsel patients on pregnancy planning and prevention, including emergency contraception, or designate counseling by another healthcare provider trained in contraceptive counseling [See Boxed Warning]. 8.7 Renal Impairment Safety and efficacy have not been demonstrated in patients with creatinine clearance <15 mL/min or on dialysis [see Clinical Pharmacology (12.3).] 8.8 Hepatic Impairment Safety and efficacy have not been demonstrated in patients with severe hepatic impairment (Child Pugh C) [see Clinical Pharmacology (12.3)]. 10 OVERDOSAGE In cases of overdose, blood pressure should be closely monitored and supported as appropriate. Based on extensive plasma protein binding, riociguat is not expected to be dialyzable. 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide). Embryo-Fetal Toxicity Instruct patients on the risk of fetal harm when Adempas is used during pregnancy [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)]. Instruct females of reproductive potential to use effective contraception and to contact her physician immediately if they suspect they may be pregnant. Female patients must enroll in the Adempas REMS Program. Adempas REMS Program For female patients, Adempas is available only through a restricted program called the Adempas REMS Program [see Warnings and Precautions (5.2)]. Male patients are not enrolled in the Adempas REMS Program. Inform female patients (and their guardians, if applicable) of the following important requirements: • All female patients must sign an enrollment form. • Advise female patients of reproductive potential that she must comply with the pregnancy testing and contraception requirements [see Use in Specific Populations (8.6)]. • Educate and counsel females of reproductive potential on the use of emergency contraception in the event of unprotected sex or contraceptive failure. • Advise pre-pubertal females to report any changes in their reproductive status immediately to her prescriber. Review the Medication Guide and REMS educational materials with female patients. Other Risks Associated with Adempas • Inform patients of the contraindication of Adempas with nitrates or nitric oxide donors or PDE-5 inhibitors. • Advise patients about the potential risks/signs of hemoptysis and to report any potential signs of hemoptysis to their physicians. • Instruct patients on the dosing, titration, and maintenance of Adempas. • Advise patients regarding activities that may impact the pharmacology of Adempas (strong multi pathway CYP inhibitors and P-gp/BCRP inhibitors and smoking). Patients should report all current medications and new medications to their physician. • Advise patients that antacids should not be taken within 1 hour of taking Adempas. • Inform patients that Adempas can cause dizziness, which can affect the ability to drive and use machines [see Adverse Reactions (6.1)]. They should be aware of how they react to Adempas, before driving or operating machinery and if needed, consult their physician.

Manufactured for:

editorial board Editor-in-Chief

David B. Nash, MD, MBA Dean, the Dr Raymond C. and Doris N. Grandon Professor, Jefferson School of Population Health Philadelphia, PA Deputy Editors

Joseph D. Jackson, PhD Program Director, Applied Health Economics and Outcomes Research, Jefferson University School of Population Health, Philadelphia Laura T. Pizzi, PharmD, MPH, RPh Associate Professor, Dept. of Pharmacy Practice, Jefferson School of Pharmacy, Philadelphia Aging and Wellness

Eric G. Tangalos, MD, FACP, AGSF, CMD Professor of Medicine Mayo Clinic, Rochester, MN CANCER RESEARCH

Al B. Benson, III, MD, FACP, FASCO Professor of Medicine, Associate Director for Clinical Investigations Robert H. Lurie Comprehensive Cancer Center Northwestern University, IL Past Chair, NCCN Board of Directors Samuel M. Silver, MD, PhD, FASCO Professor of Internal Medicine, Hematology/Oncology Assistant Dean for Research, Associate Director, Faculty Group Practice, University of Michigan Medical School EMPLOYERS

Arthur F. Shinn, PharmD, FASCP President, Managed Pharmacy Consultants, LLC, Lake Worth, FL F. Randy Vogenberg, RPh, PhD Principal, Institute for Integrated Healthcare Greenville, SC ENDOCRINOLOGY

James V. Felicetta, MD Chairman, Dept. of Medicine Carl T. Hayden Veterans Affairs Medical Center, Phoenix, AZ Quang Nguyen, DO, FACP, FACE Medical Director, Las Vegas Endocrinology Adjunct Associate Professor Endocrinology Touro University Nevada EPIDEMIOLOGY Research

Joshua N. Liberman, PhD Executive Director, Research, Development & Dissemination, Sutter Health, Concord, CA

health & value promotion

Craig Deligdish, MD Hematologist/Oncologist Oncology Resource Networks, Orlando, FL Thomas G. McCarter, MD, FACP Chief Clinical Officer Executive Health Resources, PA Albert Tzeel, MD, MHSA, FACPE Regional Medical Director Medicare Operations, North Florida Humana, Jacksonville MANAGED MARKETS

GOVERNMENT

Kevin B. “Kip” Piper, MA, FACHE President, Health Results Group, LLC Washington, DC

Jeffrey A. Bourret, PharmD, MS, RPh, FASHP Senior Director, North America Medical Affairs Medical Lead, Specialty Payer & Channel Customer Strategy, Pfizer Inc. Richard B. Weininger, MD Chairman, CareCore National, LLC Bluffton, SC

HEALTH INFORMATION TECHNOLOGY

PATIENT ADVOCACY

Kelly Huang, PhD Operating Partner, Spindletop Capital Austin, TX Victor J. Strecher, PhD, MPH Professor and Director for Innovation and Social Entrepreneurship, University of Michigan School of Public Health and Medicine HEALTH OUTCOMES RESEARCH

Russell Basser, MBBS, MD, FRACP Senior Vice President Global Clinical Research and Development CSL Behring, King of Prussia, PA Diana Brixner, RPh, PhD Professor & Chair, Dept. of Pharmacotherapy Executive Director, Outcomes Research Center, Director of Outcomes, Personalized Health Care Program, University of Utah, Salt Lake City Joseph E. Couto, PharmD, MBA Clinical Program Manager Cigna Corporation, Bloomfield, CT

Steven Miff, PhD Senior Vice President VHA, Inc., Irving, TX Terri S. Moore, PhD, RPh, MBA Senior Manager, Product Development URAC, Washington, DC Kavita V. Nair, PhD Professor and Director, Graduate Program Track in Pharmaceutical Outcomes Research Skaggs School of Pharmacy and Pharmaceutical Sciences University of Colorado, Aurora Gary M. Owens, MD President, Gary Owens Associates Ocean View, DE Andrew M. Peterson, PharmD, PhD Dean, Mayes School of Healthcare Business and Policy, Associate Professor, University of the Sciences, Philadelphia Sarah A. Priddy, PhD Director, Competitive Health Analytics Humana, Louisville, KY Timothy S. Regan, BPharm, RPh, CPh Executive Director, Strategic Accounts Xcenda, Palm Harbor, FL Vincent J. Willey, PharmD Associate Professor, School of Pharmacy, University of the Sciences, Philadelphia Paul Wilson Senior VP, Health Consumer Insights and Analytics, Blue Bell, PA David W. Wright, MPH President, Institute for Interactive Patient Care Bethesda, MD

American Health & Drug Benefits

Mike Pucci Sr VP, Commercial Operations and Business Development, PhytoChem Pharmaceuticals Lake Gaston, NC

Grant D. Lawless, RPh, MD, FACP Assoc. Prof. and Director, Healthcare Decision Analysis, Dept. of Clinical Pharmacy Univ. of Southern California, Los Angeles PHARMACY BENEFIT DESIGN

Joel V. Brill, MD, AGAF, CHCQM Chief Medical Officer, Predictive Health, Phoenix, AZ Teresa DeLuca, MD, MBA Chief Medical Officer–Pharmacy Magellan Health Services Leslie S. Fish, PharmD Vice President of Clinical Programs Fallon Community Health Plan, MA John Hornberger, MD, MS Cedar Associates, LLC CHP/PCOR Adjunct Associate, Menlo Park, CA Michael S. Jacobs, RPh MSJ Associates, Sandy Springs, GA Matthew Mitchell, PharmD, MBA Director, Pharmacy Services SelectHealth, Murray, UT Paul Anthony Polansky, BSPharm, MBA PAPRx, LLC Gulph Mills, PA Christina A. Stasiuk, DO, FACOI Senior Medical Director Cigna, Philadelphia, PA POLICY & PUBLIC HEALTH

Joseph R. Antos, PhD Wilson H. Taylor Scholar in Health Care Retirement Policy, American Enterprise Institute Washington, DC Robert W. Dubois, MD, PhD Chief Science Officer National Pharmaceutical Council, Washington, DC Jack E. Fincham, PhD, RPh Professor of Pharmacy, School of Pharmacy University of Missouri, Kansas City, MO Walid F. Gellad, MD, MPH Assistant Professor of Medicine, University of Pittsburgh, Staff Physician, Pittsburgh VA Medical Center, Adjunct Scientist, RAND Health Paul Pomerantz, MBA CEO, American Society of Anesthesiologists Park Ridge, IL J. Warren Salmon, PhD Professor of Health Policy & Administration School of Public Health University of Illinois at Chicago Raymond L. Singer, MD, MMM, CPE, FACS Chief, Division of Cardiothoracic Surgery Vice Chair, Department of Surgery for Quality & Patient Safety and Outreach Lehigh Valley Health Network, PA RESEARCH & DEVELOPMENT

Amalia M. Issa, PhD, MPH Director, Program in Personalized Medicine & Targeted Therapeutics, University of the Sciences, Philadelphia

Christopher (Chris) P. Molineaux President, Pennsylvania BIO Malvern, PA Michael F. Murphy, MD, PhD Chief Medical Officer and Scientific Officer Worldwide Clinical Trials King of Prussia, PA

PHARMACOECONOMICs

SPECIALTY PHARMACY

Personalized medicine

Josh Feldstein President & CEO, CAVA, The Center for Applied Value Analysis, Inc., Norwalk, CT Jeff Jianfei Guo, BPharm, MS, PhD Professor of Pharmacoeconomics & Pharmacoepidemiology, College of Pharmacy, Univ. of Cincinnati Medical Center, OH

www.AHDBonline.com

Atheer A. Kaddis, PharmD Senior Vice President Sales and Business Development Diplomat Specialty Pharmacy, Flint, MI James T. Kenney, Jr, RPh, MBA Pharmacy Operations Manager, Harvard Pilgrim Health Care, Wellesley, MA Michael Kleinrock Director, Research Development IMS Institute for Healthcare Informatics

March 2014

Vol 7

Special Feature

Volume 7 I Special Feature

march 2014

The Peer-Reviewed Forum for REAL-World Evidence in Benefit Design ™

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Publishing Staff Senior Vice President/Group Publisher Nicholas Englezos nenglezos@the-lynx-group.com Directors, Client Services Joe Beck jbeck@the-lynx-group.com Zach Ceretelle zceretelle@the-lynx-group.com Ron Gordon rgordon@the-lynx-group.com Editorial Director Dalia Buffery dbuffery@the-lynx-group.com Senior Associate Editor Lilly Ostrovsky Associate Editor Lara J. Lorton Editorial Assistants Jennifer Brandt Cara Guglielmon Senior Production Manager Lynn Hamilton Founding Editor-in-Chief Robert E. Henry

Table of Contents 12

Foreword The Fifth Annual Payers’ Guide to New FDA Approvals

Introduction New FDA Drug Approvals in 2013 Gary M. Owens, MD

16 FDA Approvals of Brand-Name Prescription Drugs in 2013 33 Specialty Drugs Top the Trends in the 2014 Pipeline Dalia Buffery, MA, ABD 41 Abraxane (nab-Paclitaxel) Receives a New Indication for the Treatment of Patients with Metastatic Pancreatic Cancer 45 Adempas (Riociguat): A Novel, First-in-Class Therapy Approved for the Treatment of 2 Types of Pulmonary Hypertension 50 Amitiza (Lubiprostone): The First Oral Treatment Approved by the FDA for OpioidInduced Constipation 54 Anoro Ellipta (Umeclidinium/Vilanterol): First Dual Long-Acting Inhaler for Long-Term Maintenance Treatment of COPD 63 Botox (OnabotulinumtoxinA) Now FDA Approved for Overactive Bladder 67 Breo Ellipta (Fluticasone Furoate/Vilanterol): Fixed-Dose Combination Oral Inhaler Receives FDA Approval for Long-Term Maintenance Treatment of COPD

Continued on page 10

Mission Statement American Health & Drug Benefits is founded on the concept that health and drug benefits have undergone a transformation: the econometric value of a drug is of equal importance to clinical outcomes as it is to serving as the basis for securing coverage in formularies and benefit designs. Because benefit designs are greatly affected by clinical, business, and policy conditions, this journal offers a forum for stakeholder integration and collaboration toward the improvement of healthcare. This publication further provides benefit design decision makers the integrated industry information they require to devise formularies and benefit designs that stand up to today’s special healthcare delivery and business needs.

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Table of Contents

(Continued)

71 Brintellix Tablets (Vortioxetine) Approved by the FDA for the Treatment of Major Depressive Disorder 76 Gazyva (Obinutuzumab) for Chronic Lymphocytic Leukemia: First FDA-Approved Breakthrough Therapy in Oncology 84 Fetzima Extended-Release (Levomilnacipran) Receives FDA Approval for the Treatment of Major Depressive Disorder in Adults 88 Gilotrif (Afatinib): Second-Generation Tyrosine Kinase Inhibitor Indicated for the FirstLine Treatment of Patients with Non–Small-Cell Lung Cancer and EGFR Mutation 93 Ilaris (Canakinumab) Receives a New Indication for the Treatment of Systemic Juvenile Idiopathic Arthritis 97 Imbruvica (Ibrutinib) for Mantle-Cell Lymphoma: First Bruton’s Tyrosine Kinase Inhibitor Approved for Use in a Hematologic Malignancy 101 Injectafer (Ferric Carboxymaltose Injection) Receives FDA Approval for the Treatment of Iron-Deficiency Anemia 105 Invokana (Canagliflozin): First-in-Class SGLT2 Inhibitor Approved for the Treatment of Type 2 Diabetes

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American Health & Drug Benefits, ISSN 1942-2962 (print); ISSN 1942-2970 (online), is published 9 times a year by Engage Healthcare Communications, LLC, 1249 South River Rd, Suite 202A, Cranbury, NJ 08512. Copyright © 2014 by Engage Healthcare Communications, LLC. All rights reserved. American Health & Drug Benefits and The Peer-Reviewed Forum for Real-World Evidence in Benefit Design are trademarks of Engage Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the Publisher. Printed in the United States of America. Address all editorial correspondence to: editorial@engagehc.com Telephone: 732-992-1892 Fax: 732-992-1881 American Health & Drug Benefits 1249 South River Rd, Suite 202A Cranbury, NJ 08512 The ideas and opinions expressed in American Health & Drug Benefits do not necessarily reflect those of the Editorial Board, the Editors, or the Publisher. Publication of an advertisement or other product mentioned in American Health & Drug Benefits should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturers about any features or limitations of products mentioned. Neither the Editors nor the Publisher assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material mentioned in this publication. For permission to reuse material from American Health & Drug Benefits (ISSN 1942-2962), please access www. copyright.com <http://www.copyright. com/> or contact the Copyright Clearance Center, Inc. (CCC), 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400.

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Table of Contents

(Continued)

110 Kadcyla (Ado-Trastuzumab Emtansine): First Antibody-Drug Conjugate Approved for the Treatment of HER2-Positive Metastatic Breast Cancer 120 Mirvaso (Brimonidine): First Topical Gel Approved by the FDA for the Treatment of Facial Erythema of Rosacea 123 Latuda (Lurasidone HCl) Receives 2 New Indications for Use in Bipolar Depression as Monotherapy and as Adjunctive Therapy with Lithium or Valproate 127 Nesina, Kazano, and Oseni: Three Alogliptin-Based Agents Approved for the Treatment of Type 2 Diabetes 134 Otrexup (Methotrexate) Injection: Novel Methotrexate Delivery System for Patients with Rheumatoid Arthritis 139 Pomalyst (Pomalidomide): A New Third-Generation Immunomodulatory Drug for Relapsed and/or Refractory Multiple Myeloma 142 Revlimid (Lenalidomide) Receives a New Indication for the Treatment of Patients with Relapsed or Progressing Mantle-Cell Lymphoma 151 Simbrinza (Brinzolamide/Brimonidine Tartrate) Receives FDA Approval for the Treatment of Open-Angle Glaucoma or Ocular Hypertension 156 Simponi (Golimumab) Receives New FDA Indication as the First Subcutaneous Anti-TNF Therapy for Ulcerative Colitis 160 Simponi Aria (Golimumab): A New Intravenous TNF Inhibitor for the Treatment of Patients with Moderate-to-Severe Rheumatoid Arthritis 164 Stelara (Ustekinumab) Receives New FDA Indication for the Treatment of Patients with Active Psoriatic Arthritis 177 Tafinlar (Dabrafenib) and Mekinist (Trametinib): Two Oral Targeted Kinase Inhibitors for the Treatment of Patients with Metastatic Melanoma and BRAF Mutations 184 Tecfidera (Dimethyl Fumarate), a New Oral Therapy Approved by the FDA for the Treatment of Relapsing Forms of Multiple Sclerosis 191 Xiaflex (Collagenase Clostridium Histolyticum), First Drug Approved by the FDA for Peyronie’s Disease 195 Xofigo (Radium Ra 223 Dichloride): The First Alpha Particle–Emitting Radioactive Agent for the Treatment of Castration-Resistant Prostate Cancer with Symptomatic Bone Metastases

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Foreword

The Fifth Annual Payers’ Guide to New FDA Approvals A Payers’ Guide to New FDA Approvals is published annually by American Health & Drug Benefits to offer payers and other healthcare stakeholders a detailed analysis of new drugs approved by the US Food and Drug Administration (FDA) in the previous year, as well as an overview of the key drugs in the pharmaceutical pipeline. The 2014 edition represents the fifth year of publication of this Guide by American Health & Drug Benefits. This special feature was first published in 2010. This year’s Guide includes in-depth updates on many of the new drugs that have either recently been launched or are soon to be launched, including new molecular entities (NMEs), new biologics, and important new or expanded indications, providing a practical, detailed resource for medical and pharmacy directors to guide their benefit design decision-making process. Each edition has expanded the scope of the drug updates coverage, as well as the review of new FDA approvals. The 2014 edition includes in-depth updates on 29 of the drugs that had received FDA approval in 2013. This edition also includes a detailed introduction, “New FDA Drug Approvals in 2013” (page 13), reflecting on some of the key trends that were

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evident in the FDA approval process in 2013, and which may carry into 2014. Also included is a comprehensive review of all NMEs and biologic license applications approved in 2013, as well as the new combinations, formulations, and indications added to the therapeutic options in 2013 “FDA Approvals of Brand-Name Prescription Drugs in 2013” (page 16). A pipeline article titled “Specialty Drugs Top the Trends in the 2014 Pipeline” (page 33) features key players in the current pharmaceutical pipeline, highlighting the major clinical categories in drug development and key trends in pharmaceutical research and development. The role of specialty drugs and the number of orphan drugs approved by the FDA remain 2 of the main trends that continue to dominate the market. American Health & Drug Benefits will continue to provide this Guide in the coming years to offer healthcare stakeholders a tool for applying up-to-date information on new pharmaceuticals into their benefit design decisions. We welcome your feedback and suggestions. Send any comments to editorial@engagehc. com. This Guide is also available online at www.AHDBonline.com.

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New FDA Drug Approvals in 2013 By Gary M. Owens, MD President, Gary Owens Associates, Ocean View, DE

n 2013, there were 27 new molecular entities (NMEs) approved by the US Food and Drug Administration (FDA), of which more than 50% were specialty pharmaceuticals.1 However, compared with 2012, when 39 NMEs were approved, the number of new FDA-approved drugs fell by more than 30% in 2013.1 Of the 27 NMEs approved last year, 16 were specialty drugs and almost 33% of the approvals were for rare diseases, continuing a multiyear trend favoring specialty and orphan drugs.1 Despite the decline in total NMEs approved last year, the total approved innovative medications is in line with the historical trend of the FDA, which has, on average, approved 28 NMEs annually over the past 5 years.1 According to experts, the decline in NMEs approved is a result of fewer drug applications submitted to the agency. The FDA received at least 32 applications for innovative medicines in 2013, down from 41 in 2012, according to a recent presentation by FDA representative John K. Jenkins, MD, Director of the Office of New Drugs at the FDA’s Center for Drug Evaluation and Research.2 Among the new FDA NME approvals for 2013 were1: • 10 drugs (37%) targeting novel mechanisms of action • 4 drugs (15%) that received accelerated approval • 8 drugs (30%) for cancer • 5 approvals (19%) for anti-infective drugs, including 4 antivirals • 3 approvals for drugs designated as breakthrough therapies.

Specialty Drugs Continued to Dominate 2013 Approvals As was the case in 2012, new drug approvals in 2013 continued the trend of growth for new specialty drugs. The Table lists the new agents approved in 2013 that are generally considered to be specialty agents. Among the newly approved drugs last year, 16 agents may be classified as specialty agents (Table). Of those 16 specialty drugs, 50% are indicated for the treatment of various cancers, which is again a continuation of a multiyear trend. However, there were also approvals for 2 new agents for hepatitis C virus (HCV) infection, 2 new agents for pulmonary hypertension, and 1 oral agent for the treatment of multiple sclerosis (MS).

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The emphasis on specialty drug development is here to stay, and it will likely remain the major focus of pharmacy innovation in 2014 and beyond.

Breakthrough Therapies Emerge in 2013 On July 9, 2012, the Food and Drug Administration Safety and Innovation Act (FDASIA) was signed.2 FDASIA Section 902 provided a new designation for breakthrough therapies. A breakthrough therapy is a designation given for a drug that is intended to be used alone or in combination with 1 or more other drugs for the treatment of a serious or life-threatening disease or condition. Furthermore, preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on 1 or more clinically significant end points, such as substantial beneficial clinical effects observed early in a drug’s clinical development.3 If a drug is designated as a breakthrough therapy, the FDA is required to expedite the development and review of that drug.3 The classification was designed to speed up the development of promising drugs by providing companies with extra meetings and earlier communication with scientists at the FDA. In January 2013, Vertex was the first company to disclose that their therapies for cystic fibrosis had been granted this status by the FDA.4 Less than 1 year later, 3 therapies that were granted a breakthrough therapy designation by the FDA received approval last year. These include obinutuzumab (Gazyva; Genentech) for the treatment of previously untreated chronic lymphocytic leukemia (CLL), ibrutinib (Imbruvica; Pharmacyclics) for the treatment of mantle-cell lymphoma, and sofosbuvir (Sovaldi; Gilead Sciences) for the treatment of chronic HCV infection. Cancer Drugs Continued to Dominate the Therapeutic Categories For the third consecutive year, drugs for the treatment of cancer dominated the new drug approvals. The FDA approved 8 new agents for cancer (Table). Although this is a decrease from 2012, it is identical to the number of drugs for cancer that were approved in 2011.

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Introduction

Table FDA Approvals of Specialty Drugs in 2013 Brand (generic) Manufacturer name Indication Actelion

Opsumit (macitentan)

Pulmonary arterial hypertension

Bayer HealthCare

Xofigo (radium Ra 223 dichloride)

Castration-resistant prostate cancer

Bayer HealthCare

Adempas (riociguat)

Chronic thromboembolic pulmonary hypertension

Biogen Idec

Tecfidera (dimethyl fumarate)

Relapsing forms of multiple sclerosis

Boehringer Ingelheim

Gilotrif (afatinib)

Non–small-cell lung cancer

Celgene

Pomalyst (pomalidomide)

Multiple myeloma

Genentech

Kadcyla (ado-trastuzumab emtansine)

Metastatic breast cancer

Genentech

Gazyva (obinutuzumab)

Chronic lymphocytic leukemia

Genzyme

Kynamro Homozygous familial (mipomersen sodium) hypercholesterolemia

Gilead Sciences

Sovaldi (sofosbuvir)

Hepatitis C

GlaxoSmithKline

Tafinlar (dabrafenib)

Unresectable or metastatic melanoma

GlaxoSmithKline

Mekinist (trametinib)

Unresectable or metastatic melanoma

Hyperion Therapeutics

Ravicti (glycerol phenylbutyrate)

Urea cycle disorders

Janssen Biotech

Olysio (simeprevir)

Hepatitis C

Pharmacyclics

Imbruvica (ibrutinib)

Mantle-cell lymphoma

Raptor

Procysbi Cystinosis (cysteamine bitartrate)

Malignant Melanoma Therapies The FDA approved 2 targeted oral therapies for patients with melanoma at the same time in 2013. Trametinib (Mekinist) was approved for the treatment of patients with metastatic or unresectable melanoma with the BRAF V600E or BRAF V600K mutation who have not been previously treated with BRAF inhibitor therapy. Dabrafenib (Tafinlar) was approved for the treatment of patients with unresectable or metastatic melanoma with the BRAF V600E mutation. Both drugs were approved concurrently with the FDA approval of a com-

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panion diagnostic assay for the detection of BRAF V600E and BRAF V600K mutations. Subsequently, in 2014 these drugs were approved by the FDA as the first combination therapy indicated for the treatment of patients with advanced or metastatic melanoma.

Hematologic Malignancies Two important new agents were approved in 2013 to treat hematologic malignancies. As noted earlier, ibrutinib was approved in November 2013 for the treatment of patients with mantle-cell lymphoma. This agent inhibits the function of the Bruton’s tyrosine kinase (BTK). The BTK is a key signaling molecule of the B-cell receptor– signaling complex that plays an important role in the survival of malignant B-cells.5 Of note, the FDA subsequently approved ibrutinib for the treatment of patients with CLL in early 2014. With its approval in November 2013, obinutuzumab became the first agent to be approved under the breakthrough therapy designation. Obinutuzumab is a humanized anti-CD20 monoclonal antibody of the immunoglobulin G1 subclass. It recognizes a specific epitope of the CD20 molecule found on B-cells.6 Obinutuzumab is specifically indicated for use in combination with chlorambucil for the treatment of patients with previously untreated CLL. Solid-Organ Tumors The year 2013 also had important approvals for the treatment of solid-organ tumors. Radium Ra 223 dichloride (Xofigo; Bayer HealthCare) was approved by the FDA in May 2013 for symptomatic metastatic castration-resistant prostate cancer that affects bones but not other organs (ie, with no known visceral metastatic disease). The active ingredient of this drug, radium Ra 223 dichloride, is an alpha particle–emitting radioactive therapeutic agent that mimics calcium and forms complexes with the bone mineral hydroxyapatite at areas of increased bone turnover, such as bone metastases. Afatinib (Gilotrif) tablets were approved by the FDA in mid-2013 as a first-line oral treatment for non–smallcell lung cancer with epidermal growth factor receptor (EGFR) mutations. The FDA approved afatinib concurrently with the companion diagnostic (EGFR RGQ PCR Kit), which helps determine if a patient’s lung cancer cells express the EGFR mutations. Therefore, afatinib joins a growing group of anticancer drugs that have been launched with companion diagnostics to appropriately target this drug for the treatment of patients who are most likely to benefit from it—a growing trend in oncology therapies. Hepatitis C Treatments in the Spotlight in 2013 In the United States, there are approximately 3.2

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million persons who have chronic HCV infection, many of whom will develop chronic liver disease, cirrhosis, and liver cancer if left untreated. The first of 2 new HCV treatments, simeprevir (Olysio; Janssen Biotech) was approved in November 2013. This drug is an oral capsule that is intended to be used as part of a combination regimen for the treatment of chronic HCV infection in adults, including patients with compensated cirrhosis or other stable liver disease. Simeprevir is indicated, in combination with peginterferon alfa and ribavirin, for the treatment of infections caused by HCV genotype 1, according to the drug’s labeling.7 The addition of simeprevir to the treatment regimen resulted in up to 80% of clinical trial participants with genotype 1 HCV infection becoming free of infection after completing their treatment. Genotype 1 infections are more difficult to treat than some other genotypes of HCV infection, and the results of the clinical trials were considered a significant advance.7 The second agent to be approved for HCV infection was sofosbuvir (Sovaldi; Gilead Sciences). Sofosbuvir oral tablets are used as part of a regimen for the treatment of chronic HCV infection caused by viruses of genotypes 1, 2, 3, or 4. According to the FDA, sofosbuvir is the first drug that can be used without an interferon agent to treat certain types of chronic HCV infection.8 These 2 new agents are just the beginning of a new era in HCV infection treatment that will ultimately result in better cure rates and all-oral treatments for the majority of patients with this type of infection.

Significant Advances in Other Therapeutic Categories Many other important approvals or expanded indications for existing drugs occurred in 2013. Dimethyl fumarate (Tecfidera; Biogen Idec) became the third oral agent approved for adults with relapsing forms of MS. Additions to the arsenal of agents to treat pulmonary arterial hypertension (PAH) included macitentan (Opsumit; Actelion), an oral endothelin receptor antagonist, and riociguat (Adempas; Bayer HealthCare), which represents a new class of therapies for PAH. Riociguat belongs to a class of drugs called soluble guanylate cyclase stimulators that help arteries relax to increase blood flow and decrease blood pressure. Not all significant new therapies approved in 2013 were specialty agents. It is beyond the scope of this introduction to mention all the newly released agents; significant small-molecule agents approved by the FDA in 2013 include: • Canagliflozin (Invokana; Janssen Pharmaceuticals), the first treatment for diabetes approved in a new class of drugs known as sodium-glucose cotransporter 2 inhibitors. This new agent works by blocking the reab-

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sorption of glucose by the kidney, increasing glucose excretion, and lowering blood glucose levels in diabetic patients who have elevated blood glucose levels • Levomilnacipran extended-release capsules (Fetzima; Forest Laboratories), a serotonin and norepinephrine reuptake inhibitor, received a new FDA indication for the treatment of major depressive disorders in adults • The combination of fluticasone furoate and vilanterol— an inhaled corticosteroid and a long-acting beta2- adrenergic agonist (Breo Ellipta; GlaxoSmithKline)— was approved as an inhaled long-term, once-daily maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema. It is also indicated to reduce exacerbations of COPD in patients with a history of exacerbations.

Looking Forward For the drug industry, and for all healthcare stakeholders, 2013 included the release of many new and innovative therapies. Although the approvals of new drugs did not match the 15-year high seen in 2012, there were many approvals for novel agents that offer first-in-class treatments for patients with serious diseases. As we enter 2014, the pipeline of new agents, particularly specialty agents and therapies for cancer, is robust, and we will likely see another year of significant growth for the drug industry and for patients. n Author Disclosure Statement Dr Owens is a consultant to Allergan, Biogen Idec, Boston Scientific, CardioDx, Crescendo Bioscience, Eli Lilly, Johnson & Johnson, and Millennium Pharmaceuticals.

References

1. US Food and Drug Administration. Center for Drug Evaluation and Research. Approved drugs 2013. January 2014. www.fda.gov/downloads/drugs/development approvalprocess/druginnovation/ucm381803.pdf. Accessed February 28, 2014. 2. Specialty drugs account for more than half of approved drugs in 2013. Specialty PharmaJournal.com. Updated January 3, 2014. www.specialtypharmajournal.com/ index.php?option=com_content&view=article&id=4655:specialty-drugs-accountfor-more-than-half-of-approved-drugs-in-2013&catid=403:business-news& Itemid=841. Accessed January 5, 2014. 3. US Food and Drug Administration. Fact sheet: breakthrough therapies. Updated August 21, 2013. www.fda.gov/regulatoryinformation/legislation/federalfooddrugand cosmeticactfdcact/significantamendmentstothefdcact/fdasia/ucm329491.htm. Accessed February 28, 2014. 4. Vertex. Vertex outlines corporate strategy and defines key 2013 business priorities. January 6, 2013. http://investors.vrtx.com/releasedetail.cfm?ReleaseID=731630. Accessed February 28, 2014. 5. Carroll J. J&J, Pharmacyclics win early approval for ‘breakthrough’ cancer drug ibrutinib. FierceBiotech. November 13, 2013. www.fiercebiotech.com/story/jj-pharma cyclics-win-early-approval-breakthrough-cancer-drug-ibrutinib/2013-11-13. Accessed February 27, 2014. 6. CenterWatch. Gazyva (obinutuzumab). www.centerwatch.com/drug-information/ fda-approved-drugs/drug/1292/gazyva-obinutuzumab. Accessed February 27, 2014. 7. Traynor K. Simeprevir approved for hepatitis C virus infection. November 25, 2013. www.ashp.org/menu/News/PharmacyNews/NewsArticle.aspx?id=3988. Accessed February 23, 2014. 8. Traynor K. Sofosbuvir approved for chronic hepatitis C infection. December 9, 2013. www.ashp.org/menu/News/PharmacyNews/NewsArticle.aspx?id=3993. Accessed February 23, 2014.

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FDA Approvals of Brand-Name Prescription Drugs in 2013 I. New Pharmaceuticals: New Molecular Entities (NMEs) and Biologic License Applications (BLAs) Approved Adempas (NME) (Riociguat; Bayer HealthCare) Class/route: Soluble guanylate cyclase stimulator; oral Indications: For adults with chronic thromboembolic pulmonary hypertension (CTEPH) after surgery or patients with inoperable CTEPH to improve exercise capacity and World Health Organization (WHO) functional class; and patients with pulmonary arterial hypertension to improve their exercise capacity, improve their WHO functional class, and to delay clinical worsening Approval considerations: Priority review, orphan, risk evaluation and mitigation strategy (REMS) Anoro Ellipta (NME) (Umeclidinium and vilanterol inhalation powder; GlaxoSmithKline) Class/route: Anticholinergic and long-acting β2adrenergic agonist combination; inhalation Indication: For the long-term, once-daily maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD); not for the relief of acute bronchospasm or for the treatment of asthma Aptiom (NME) (Eslicarbazepine acetate; Sunovion Pharmaceuticals) Class/route: Antiepileptic; oral Indication: For partial-onset seizures as an add-on medication Breo Ellipta (NME) (Fluticasone furoate and vilanterol inhalation powder; GlaxoSmithKline) Class/route: Corticosteroid and a long-acting β2-adrenergic agonist combination; inhalation Indications: For the long-term, once-daily maintenance of airflow obstruction in patients with COPD, and to reduce exacerbations in patients with COPD; not for relief of acute bronchospasm or for the treatment of asthma

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Brintellix (NME) (Vortioxetine; Takeda Pharmaceuticals) Class/route: Serotonergic antidepressant; immediate release; oral Indication: For the treatment of major depressive disorder Dotarem (NME) (Gadoterate meglumine; Guerbet) Class/route: Magnetic resonance imaging contrast media; intravenous Indication: For use in magnetic resonance imaging of the brain, spine, and associated tissues of patients aged ≥2 years to detect and to visualize the area with disruption of the blood–brain barrier and/or normal vascularity Approval consideration: Priority review Duavee (NME) (Conjugated estrogens/bazedoxifene; Pfizer) Class/route: Sex hormone combination; oral Indications: For women with a uterus and moderateto-severe hot flashes associated with menopause, and to prevent osteoporosis after menopause Flublok (BLA) (Influenza vaccine, recombinant hemagglutinin; Protein Sciences Corporation) Class/route: Vaccine; intramuscular injection Indication: For active immunization against disease caused by influenza virus subtypes A and type B contained in the vaccine in persons aged 18 through 49 years Gazyva (NME) (Obinutuzumab; Genentech) Class/route: CD20-directed cytolytic monoclonal antibody; intravenous Indication: For patients with previously untreated chronic lymphocytic leukemia (CLL) in combination with chlorambucil chemotherapy Approval considerations: Priority review, breakthrough therapy, orphan drug

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Gilotrif (NME) (Afatinib; Boehringer Ingelheim) Class/route: Kinase inhibitor; oral Indication: For the first-line treatment of patients with metastatic non–small-cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test Approval considerations: Priority review, orphan drug, fast track

non–high-density lipoprotein cholesterol Approval considerations: Orphan drug, REMS

Imbruvica (NME) (Ibrutinib; Pharmacyclics) Class/route: Kinase inhibitor; oral Indications: Treatment of patients with mantle-cell lymphoma who have received at least 1 previous therapy, and patients with CLL who had at least 1 previous therapy Approval considerations: Priority review, breakthrough therapy, accelerated approval, fast track, orphan drug

Lymphoseek (NME) (Technetium Tc99m tilmanocept; Navidea Biopharmaceuticals) Class/routes: Radioactive diagnostic agent; subcutaneous, intradermal, or peritumoral injection Indication: For lymphatic mapping with a handheld gamma counter to assist in the localization of lymph nodes draining a primary tumor site in patients with breast cancer or melanoma

Invokana (NME) (Canagliflozin; Janssen) Class/route: Sodium-glucose cotransporter-2 inhibitor; oral Indication: For patients with type 2 diabetes in conjunction with diet and exercise to improve glycemic control Kadcyla (NME) (Ado-trastuzumab emtansine; Genentech) Class/route: Antineoplastic agent; intravenous Indication: Treatment of people with human EGFR 2– positive metastatic breast cancer who have received previous treatment with trastuzumab and a taxane, separately or in combination Approval considerations: Priority review, fast track Kcentra (BLA) (Prothrombin complex concentrate, human; CSL Behring GmbH) Class/route: Blood coagulation factor replacement; intravenous Indication: For the urgent reversal of acquired coagulation factor deficiency induced by vitamin K antagonist (eg, warfarin) therapy in adult patients with acute major bleeding Kynamro (NME) (Mipomersen sodium; Genzyme/Sanofi) Class/route: Antihyperlipidemic agent; subcutaneous injection Indication: For patients with homozygous familial hypercholesterolemia as an adjunct to lipid-lowering medications and diet to reduce low-density lipoprotein cholesterol, apolipoprotein B, total cholesterol, and Vol 7

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Luzu (NME) (Luliconazole; Medicis Pharmaceutical) Class/route: Antifungal; topical Indications: For the topical treatment of interdigital tinea pedis, tinea cruris, and tinea corporis caused by Trichophyton rubrum and Epidermophyton floccosum in patients aged ≥18 years

Mekinist (NME) (Trametinib; GlaxoSmithKline) Class/route: Kinase inhibitor; oral Indication: As a single agent and in combination with dabrafenib, for patients with unresectable or metastatic melanoma with BRAF V600E or BRAF V600K mutations as detected by an FDA-approved test Approval considerations: Priority review, fast track, orphan drug Nesina (NME) (Alogliptin; Takeda Pharmaceuticals) Class/route: Dipeptidyl peptidase-4 inhibitor; oral Indication: For adults with type 2 diabetes in conjunction with diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus NovoEight (BLA) (Antihemophilic factor, recombinant; Novo Nordisk) Class/route: rFactor VIII; intravenous Indication: For adults and children with hemophilia A for the control and prevention of bleeding episodes, perioperative management, and routine prophylaxis to prevent/reduce bleeding episodes; not indicated for von Willebrand disease Octaplas (BLA) (Solvent/detergent treated, pooled human plasma; Octapharma USA) Class/route: Blood modifier; intravenous infusion Indications: Replacement of multiple coagulation factors in patients with acquired deficiencies resulting

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from liver disease and in patients undergoing cardiac surgery or liver transplant, and for plasma exchange in patients with thrombotic thrombocytopenic purpura

prevent bleeding episodes; perioperative management; and routine prophylaxis to prevent/reduce bleeding episodes

Olysio (NME) (Simeprevir; Janssen Biotech) Class/route: Protease inhibitor; oral Indication: For the treatment of chronic hepatitis C infection as a component of a combination antiviral treatment regimen Approval considerations: Priority review, fast track

Sovaldi (NME) (Sofosbuvir; Gilead Sciences) Class/route: Nucleotide analog inhibitor; oral Indication: For the treatment of chronic hepatitis C infection as a component of a combination antiviral treatment regimen Approval considerations: Priority review, breakthrough therapy, fast track

Opsumit (NME) (Macitentan; Actelion Pharmaceuticals) Class/route: Endothelin receptor antagonist; oral Indication: For the treatment of patients with pulmonary arterial hypertension to delay disease progression Approval considerations: Orphan drug, REMS Osphena (NME) (Ospemifene; Shionogi) Class/route: Estrogen agonist/antagonist; oral Indication: To treat women experiencing moderateto-severe dyspareunia due to menopause Pomalyst (NME) (Pomalidomide; Celgene) Class/route: Antineoplastic and immunosuppressant; oral Indication: Treatment of patients with multiple myeloma who received at least 2 previous therapies, including lenalidomide and bortezomib, and have demonstrated disease progression on or within 60 days of completion of the last therapy Approval considerations: Accelerated approval, orphan drug, REMS Ravicti (BLA) (Glycerol phenylbutyrate; Hyperion Therapeutics) Class/route: Urea cycle disorder agent; oral liquid Indication: For use as a nitrogen-binding agent for the chronic management of patients aged ≥2 years with urea cycle disorders who cannot be managed by dietary protein restriction and/or amino acid supplementation alone; must be used with dietary protein restriction and, in some cases, dietary supplements Approval considerations: Priority review, orphan drug Rixubis (BLA) (Coagulation factor IX, recombinant; Baxter Healthcare) Class/route: Coagulation modifier; intravenous Indication: For adults with hemophilia B to control/

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Tafinlar (NME) (Dabrafenib; GlaxoSmithKline) Class/route: Multikinase inhibitor; oral Indication: For patients with unresectable or metastatic melanoma with the BRAF V600E mutation as detected by an FDA-approved test; not indicated for the treatment of patients with wild-type BRAF melanoma Approval considerations: Fast track, orphan drug Tecfidera (NME) (Dimethyl fumarate; Biogen Idec) Class/route: Selective immunosuppressant; oral Indication: For patients with relapsing forms of multiple sclerosis Tivicay (NME) (Dolutegravir; ViiV Healthcare) Class/route: Integrase strand transfer inhibitor; oral Indication: For the treatment of HIV-1 infection in adults and children aged ≥12 years, weighing ≥40 kg, in combination with other antiretroviral agents Approval considerations: Priority review, fast track TOBI Podhaler (BLA) (Tobramycin inhalation powder; Novartis) Class/route: Aminoglycoside antibiotic; inhalation Indication: For the management of cystic fibrosis patients with Pseudomonas aeruginosa Tretten (BLA) (Coagulation factor XIII A-subunit, recombinant; Novo Nordisk) Class/route: Anticoagulation factor; intravenous Indication: For routine prophylaxis of bleeding in patients with congenital factor XIII A-subunit deficiency; not for use in patients with congenital factor XII B-subunit Approval consideration: Orphan drug

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Velphoro (BLA) (Sucroferric oxyhydroxide; Vifor Pharma) Class/route: Iron-based, calcium-free phosphate binder; oral (chewable) tablet Indication: For control of hyperphosphatemia in patients with chronic kidney disease Vizamyl (NME) (Flutemetamol F 18; GE Healthcare) Class/route: Radioactive diagnostic agent; intravenous Indication: For positron emission tomography imaging of the brain to estimate β-amyloid neuritic plaque density

in adults with cognitive impairment who are being evaluated for Alzheimer’s disease and other causes of cognitive decline Xofigo (NME) (Radium Ra 223 dichloride; Bayer HealthCare) Class/route: Diagnostic radiopharmaceutical; intravenous Indication: For patients with symptomatic metastatic castration-resistant prostate cancer, symptomatic bone metastases, and no known visceral metastatic disease Approval considerations: Priority review, fast track

II. New Combinations, Formulations, Indications Abilify Maintena (new formulation) (Aripiprazole; Otsuka Pharmaceutical) Class/route: Atypical antipsychotic; intramuscular injection New formulation: Extended-release injectable suspension for intramuscular injection; already available in oral form Indications: For the treatment of schizophrenia; acute treatment of manic or mixed episodes associated with bipolar I disorder as monotherapy and as an adjunct to lithium or valproate; maintenance treatment of bipolar I disorder, both as monotherapy and as an adjunct to lithium or valproate; adjunctive treatment of major depressive disorder; treatment of irritability associated with autistic disorder; acute treatment of agitation associated with schizophrenia or bipolar I disorder

Aciphex Sprinkle (new indication) (Rabeprazole sodium; Eisai) Class/route: Proton pump inhibitor; oral New indication: For the treatment of gastroesophageal reflux disease (GERD) in pediatric patients aged 1 to 11 years; already indicated for erosive or ulcerative GERD, maintenance of healing of erosive or ulcerative GERD, treatment of symptomatic GERD, healing of duodenal ulcers, Helicobacter pylori eradication to reduce the risk of duodenal ulcer recurrence, treatment of pathologic hypersecretory conditions (including Zollinger-Ellison syndrome), and in adolescents aged ≥12 years for short-term treatment of symptomatic GERD Approval consideration: Priority review

Abraxane (new indication) (Paclitaxel protein-bound particles for injectable suspension [albumin bound]; Celgene) Class/route: Antineoplastic agent; intravenous infusion New indication: First-line treatment of patients with metastatic adenocarcinoma of the pancreas, in combination with gemcitabine; already indicated for metastatic breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy, and for locally advanced or metastatic non– small-cell lung cancer (NSCLC) as first-line treatment in combination with carboplatin in patients who are not candidates for curative surgery or radiation therapy Approval considerations: Priority review, orphan drug

Actemra (new formulation, new indication) (Tocilizumab; Genentech) Class/route: Humanized antihuman interleukin-6 receptor antagonist monoclonal antibody; subcutaneous New formulation: Subcutaneous injection; already available as intravenous New indication: For the treatment of patients aged ≥2 years with active polyarticular juvenile idiopathic arthritis Indications: For the treatment of adults with moderately to severely active rheumatoid arthritis (RA) who have used ≥1 disease-modifying antirheumatic drugs, and patients aged ≥2 years with active systemic juvenile idiopathic arthritis

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Amitiza (new indication) (Lubiprostone; Sucampo Pharma Americas) Class/route: Chloride channel activator; oral New indication: For the treatment of opioid-induced constipation in adults with chronic noncancer pain; already indicated for the treatment of chronic idiopathic constipation in adults and of irritable bowel syndrome with constipation in women aged ≥18 years Approval consideration: Priority review Astagraf XL (new formulation) (Tacrolimus extended-release capsules; Astellas Pharma US) Class/route: Calcineurin inhibitor immunosuppressant; oral New formulation: Extended-release capsules Indication: For the prophylaxis of organ rejection in patients receiving a kidney transplant with mycophenolate mofetil and corticosteroids, with or without basiliximab induction Botox (new indication) (OnabotulinumtoxinA; Allergan) Class/routes: Acetylcholine release inhibitor and neuromuscular blocking agent; intramuscular, intradetrusor, and intradermal New indications: Treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency, in adults who have an inadequate response to or are intolerant of an anticholinergic medication; and treatment of urinary incontinence resulting from detrusor overactivity associated with a neurologic condition in adults who have an inadequate response to or are intolerant of an anticholinergic medication; already indicated for the prophylaxis of headaches in adults with chronic migraine, upper limb spasticity in adults, cervical dystonia in adults to reduce the severity of abnormal head position and neck pain, severe axillary hyperhidrosis that is inadequately managed by topical agents in adults, blepharospasm associated with dystonia in patients aged ≥12 years, and strabismus in patients aged ≥12 years Botox Cosmetic (new indication) (OnabotulinumtoxinA; Allergan) Class/route: Acetylcholine release inhibitor and neuromuscular blocking agent; intramuscular injection New indication: Temporary improvement in the appearance of moderate-to-severe lateral canthal lines associated with orbicularis oculi activity in adults; already indicated for the temporary improvement in the appearance of moderate-to-severe glabellar lines associated with corrugator and/or procerus muscle activity in adults

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Brisdelle (new formulation) (Paroxetine; Noven Therapeutics) Class/route: Selective serotonin reuptake inhibitor; oral New formulation: Once-daily 7.5-mg capsules for oral use Indication: For the treatment of moderate-to-severe vasomotor symptoms associated with menopause Cimzia (new indication) (Certolizumab pegol; UCB) Class/route: Tumor necrosis factor blocker; subcutaneous New indication: For the treatment of adults with active psoriatic arthritis and for adults with active ankylosing spondylitis; previously indicated for reducing the signs and symptoms of Crohn’s disease and maintaining clinical response in adults with moderately to severely active disease who have had an inadequate response to conventional therapy, and for the treatment of adults with moderately to severely active RA Delzicol (new formulation) (Mesalamine; Warner Chilcott) Class/route: Aminosalicylate; oral New formulation: Delayed-release capsule Indication: For the treatment of mildly to moderately active ulcerative colitis and for the maintenance of remission of ulcerative colitis Diclegis (new formulation) (Doxylamine succinate and pyridoxine hydrochloride; Duchesnay USA) Class/route: Combination of an antihistamine and a vitamin B6 analog; oral New formulation: Fixed-dose combination in a delayedrelease tablet Indication: For the treatment of nausea and vomiting in pregnancy in women who do not respond to conservative management Epiduo (new indication) (Adapalene and benzoyl peroxide; Galderma Laboratories) Class/route: Retinoid/oxidizing agent; topical New indication: For the treatment of acne vulgaris in patients aged ≥9 years Exelon Patch (new indication) (Rivastigmine; Novartis) Class/route: Acetylcholinesterase inhibitor; transdermal patch New indication: For the treatment of patients with severe Alzheimer’s disease; already indicated for the treatment of mild-to-moderate dementia of the Alzheimer’s type and mild-to-moderate dementia associated with Parkinson’s disease

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Exjade (new indication) (Deferasirox; Novartis) Class/route: Iron chelator; oral New indication: For the treatment of chronic iron overload in patients aged ≥10 years with non–transfusion-dependent thalassemia syndromes and with a liver iron concentration of ≥5 mg of iron per gram of dry weight and a serum ferritin >300 mcg/L; previously indicated for the treatment of chronic iron overload resulting from blood transfusions in patients aged ≥2 years Fetzima (new enantiomer) (Levomilnacipran, a new enantiomer of milnacipran; Forest Laboratories) Class/route: Serotonin and norepinephrine reuptake inhibitor; extended-release capsules, oral Indication: Major depressive disorder in adults Gleevec (new indication) (Imatinib mesylate; Novartis) Class/route: Kinase inhibitor; oral New indication: Pediatric patients with newly diagnosed Philadelphia chromosome–positive acute lymphoblastic leukemia in combination with chemotherapy Ilaris (new indication) (Canakinumab; Novartis) Class/route: Interleukin-1β blocker; subcutaneous injection New indication: To treat active systemic juvenile idopathic arthritis in patients aged ≥2 years; already indicated for the treatment of cryopyrin-associated periodic syndromes, including familial cold autoinflammatory syndrome and Muckle-Wells syndrome Injectafer (new formulation) (Ferric carboxymaltose injection; American Regent) Class/route: Iron replacement; intravenous New formulation: High-dose nondextran intravenous iron Indication: For the treatment of iron-deficiency anemia in adults who have intolerance to oral iron or who have had an unsatisfactory response to oral iron, and adults who have nondialysis-dependent chronic kidney disease Karbinal ER (new formulation) (Carbinoxamine maleate; Tris Pharma) Class/route: Histamine receptor blocker; oral New formulation: Sustained-release oral suspension Indications: For the symptomatic treatment of seasonal and perennial allergic rhinitis, vasomotor rhinitis, allergic conjunctivitis resulting from inhalant allergens and foods, mild uncomplicated allergic skin manifestations of urticaria and angioedema, and dermatographism; as therapy for anaphylactic reactions adjunctive to epinephrine Vol 7

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and other standard measures after the acute manifestations have been controlled; and for the amelioration of the severity of allergic reactions to blood or plasma Kazano (new combination) (Alogliptin and metformin hydrochloride; Takeda Pharmaceuticals) Class/route: Dipeptidyl peptidase-4 inhibitor and a biguanide; oral Indication: For adults with type 2 diabetes mellitus as an adjunct to diet and exercise to improve glycemic control Khedezla (new formulation) (Desvenlafaxine; Osmotica Pharmaceutical) Class/route: Serotonin and norepinephrine reuptake inhibitor; oral New formulation: Extended-release tablets Indication: For the treatment of major depressive disorder Latuda (new indications) (Lurasidone hydrochloride; Sunovion Pharmaceuticals) Class/route: Atypical antipsychotic; oral New indications: Depressive episodes associated with bipolar I disorder as monotherapy and as adjunctive therapy with lithium or valproate; already indicated for schizophrenia Liptruzet (new combination) (Ezetimibe and atorvastatin; Merck) Class/route: Cholesterol absorption inhibitor and an HMG-CoA reductase inhibitor; oral Indications: As adjunctive therapy to diet to reduce elevated total cholesterol, low-density lipoprotein cholesterol, apolipoprotein B, triglycerides, and non– high-density lipoprotein cholesterol (HDL-C), and to increase HDL-C in patients with primary (heterozygous familial and nonfamilial) hyperlipidemia or mixed hyperlipidemia; to reduce elevated total cholesterol and low-density lipoprotein cholesterol in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering treatments Mirvaso (new dosage form) (Brimonidine; Galderma Laboratories) Class/route: Alpha-adrenergic agonist; topical New dosage form: Topical gel 0.33% Indication: For the topical treatment of persistent (nontransient) facial erythema of rosacea in adults aged ≥18 years Mycamine (new indication) (Micafungin sodium; Astellas Pharma US) Class/route: Echinocandin antifungal agent; intravenous infusion

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New indication: For adults and pediatric patients aged ≥4 months to treat candidemia, acute disseminated candidiasis, Candida peritonitis and abscesses; patients with esophageal candidiasis; prophylaxis of Candida infections in patients undergoing hematopoietic stemcell transplantation (HSCT)

Oseni (new combination) (Alogliptin and pioglitazone; Takeda Pharmaceuticals) Class/route: Dipeptidyl peptidase-4 inhibitor and thiazolidinedione; oral Indication: As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus

Nexavar (new indication) (Sorafenib; Bayer HealthCare) Class/route: Kinase inhibitor; oral New indication: For patients with locally recurrent or metastatic, progressive, differentiated thyroid carcinoma refractory to radioactive iodine treatment; already indicated for patients with unresectable hepatocellular carcinoma and patients with advanced renal-cell carcinoma and liver cancer Approval consideration: Priority review, orphan drug

Otrexup (new formulation) (Methotrexate; Antares Pharma) Class/new route: Folate analog metabolic inhibitor; subcutaneous Indications: For the management of patients with severe, active RA and polyarticular juvenile idiopathic arthritis who are intolerant of or had an inadequate response to first-line therapy, and for the symptomatic control of severe, recalcitrant, disabling psoriasis in adults who are not adequately responsive to other forms of therapy

Noxafil (new formulation) (Posaconazole; Merck) Class/route: Azole antifungal agent; oral New formulation: Delayed-release tablets; already available as an oral suspension Indications: For the prophylaxis of invasive Aspergillus and Candida infections in patients aged ≥13 years who are at high risk of developing these infections as a result of being severely immunocompromised, such as HSCT recipients with graft-versus-host disease or those with hematologic malignancies with prolonged neutropenia from chemotherapy

Perjeta (new indication) (Pertuzumab; Genentech) Class/route: HER2/neu receptor antagonist; intravenous injection New indication: Use in combination with trastuzumab and docetaxel as neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early-stage breast cancer (either >2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer; already indicated for use in combination with trastuzumab and docetaxel for treatment of patients with HER2-positive metastatic breast cancer who have not received previous anti-HER2 therapy or chemotherapy for metastatic disease Approval consideration: Priority review

Nymalize (new formulation) (Nimodipine; Arbor Pharmaceuticals) Class/route: Dihydropyridine calcium channel blocker; oral New formulation: Oral solution; already available in capsules Indication: For the improvement of neurologic outcome by reducing the incidence and severity of ischemic deficits in adults with subarachnoid hemorrhage from ruptured intracranial berry aneurysms regardless of their postictus neurologic condition (ie, Hunt and Hess Grades I-V) Orenitram (new formulation) (Treprostinil; United Therapeutics) Class/route: Prostacyclin vasodilator; oral New formulation: Extended-release oral tablets; already available as subcutaneous or intravenous solution and as an inhaled solution Indication: For the treatment of pulmonary arterial hypertension (WHO Group 1) to improve exercise capacity

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Prevnar 13 (new indication) (Pneumococcal 13-valent conjugate vaccine [diphtheria CRM197 protein]; Pfizer) Class/route: Vaccine; intramuscular injection New indication: In children aged 6 years through 17 years (before the 18th birthday), for active immunization for the prevention of invasive disease caused by Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F; already indicated for children aged 6 weeks through 5 years (before the 6th birthday), for the active immunization for the prevention of invasive disease caused by S pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F; for active immunization for the prevention of otitis media caused by S pneumoniae serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F; in adults aged ≥50 years, for active immunization for the prevention of pneumonia and invasive disease caused by S pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F

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Procysbi (new formulation) (Cysteamine bitartrate; Raptor Pharmaceuticals) Class/route: Cystine-depleting agent; oral New formulation: Delayed-release capsules Indication: For the management of nephropathic cystinosis in adults and children aged ≥6 years Approval consideration: Orphan drug

New indication: Moderate-to-severe ulcerative colitis with an inadequate response or intolerant to previous treatment or requiring continuous steroid therapy; already indicated for moderately to severely active RA in combination with methotrexate, active psoriatic arthritis alone or in combination with methotrexate, and active ankylosing spondylitis

Prolensa (new formulation) (Bromfenac ophthalmic solution; Bausch & Lomb) Class/route: Nonsteroidal anti-inflammatory drug; topical ophthalmic solution New formulation: Once-daily bromfenac 0.07% topical ophthalmic solution Indications: For the treatment of postoperative inflammation and for the reduction of ocular pain in patients who have undergone cataract surgery

Simponi Aria (new formulation) (Golimumab; Janssen Biotech) Class/route: Tumor necrosis factor blocker; intravenous New formulation: Intravenous infusion; already available as subcutaneous injection Indication: For the treatment of adults with moderately to severely active RA in combination with methotrexate

Quartette (new formulation) (Levonorgestrel/ethinyl estradiol and ethinyl estradiol; Teva Pharmaceuticals) Class/route: Estrogen/progestin combined oral contraceptive; oral New formulation: 91-day oral tablet regimen Indication: For use by women to prevent pregnancy Revlimid (new indication) (Lenalidomide; Celgene) Class/route: Thalidomide analog; oral New indication: For patients with mantle-cell lymphoma whose disease has relapsed or progressed after 2 prior therapies; already indicated for multiple myeloma, in combination with dexamethasone, in patients who have received at least1 prior therapy; transfusion-dependent anemia due to low- or intermediate-1–risk myelodysplastic syndromes associated with a deletion 5q abnormality with or without additional cytogenetic abnormalities Simbrinza (new combination) (Brinzolamide/brimonidine tartrate; Alcon Laboratories) Class/route: Fixed-dose combination of a carbonic anhydrase inhibitor and an alpha-2 adrenergic receptor agonist; ophthalmic suspension; the only beta blocker– free treatment for intraocular pressure Indication: For the reduction of elevated intraocular pressure in patients with primary open-angle glaucoma or ocular hypertension Simponi (new indication) (Golimumab; Janssen Biotech) Class/route: Tumor necrosis factor blocker; subcutaneous injection Vol 7

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Sitavig (new formulation) (Acyclovir; BioAlliance Pharma) Class/route: Synthetic purine nucleoside analog; oral New formulation: Buccal tablets Indication: For the treatment of recurrent herpes labialis (cold sores) in immunocompetent adults Skyla (new formulation) (Levonorgestrel-releasing intrauterine system; Bayer HealthCare) Class/route: Progestin-containing intrauterine system; intrauterine New formulation: Intrauterine device that releases 13.5 mg of levonorgestrel slowly for up to 3 years Indication: For the prevention of pregnancy for up to 3 years Stelara (new indication) (Ustekinumab; Janssen Biotech) Class/route: Human interleukin-12 and interleukin-23 antagonist; subcutaneous New indication: For adults with active psoriatic arthritis, alone or in combination with methotrexate; already indicated for adults with moderate-to-severe plaque psoriasis who are candidates for phototherapy or systemic therapy Stivarga (new indication) (Regorafenib; Bayer HealthCare) Class/route: Kinase inhibitor; oral New indication: Locally advanced unresectable or metastatic gastrointestinal stromal tumor previously treated with imatinib mesylate and sunitinib malate; already indicated for metastatic colorectal cancer previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an antivascular endothelial growth factor therapy, and, if KRAS

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wild-type, an anti–epidermal growth factor receptor (EGFR) therapy Approval considerations: Priority review, orphan drug Sustiva (new indication) (Efavirenz; Bristol-Myers Squibb) Class/route: Nonnucleoside reverse transcriptase inhibitor; oral New indication: In combination with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 infection in adults and in pediatric patients aged ≥3 months and weighing ≥3.5 kg using a “capsule sprinkle” method of administration (contents of the open capsule sprinkled into a small amount of food or formula) Tarceva (new indication) (Erlotinib; Astellas Pharma/Genentech) Class/route: Kinase inhibitor; oral New indication: First-line treatment of patients with metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by a US Food and Drug Administration– approved test; already indicated for maintenance treatment of patients with locally advanced or metastatic NSCLC whose disease has not progressed after 4 cycles of platinum-based first-line chemotherapy; the treatment of locally advanced or metastatic NSCLC after failure of at least 1 previous chemotherapy regimen; the first-line treatment of patients with locally advanced, unresectable or metastatic pancreatic cancer in combination with gemcitabine; and in combination with gemcitabine for the first-line treatment of patients with locally advanced unresectable or metastatic pancreatic cancer Topicort (new formulation) (Desoximetasone; Taro Pharmaceutical Industries) Class/route: Corticosteroid; topical New formulation: Topical spray, 0.25%; already available as a cream, gel, and ointment Indication: For the treatment of plaque psoriasis in patients aged ≥18 years Trokendi XR (new formulation) (Topiramate; Supernus Pharmaceuticals) Class/route: Antiepileptic; oral New formulation: Once-daily extended-release capsules Indications: For initial monotherapy in patients aged ≥10 years with partial-onset or primary generalized tonic-clonic seizures, as adjunctive therapy in patients aged ≥6 years with partial-onset or primary generalized tonic-clonic seizures, and for adjunctive therapy in patients aged ≥6 years with seizures associated with Lennox-Gastaut syndrome

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Uceris (new formulation) (Budesonide; Santarus) Class/route: Glucocorticosteroid; oral New formulation: 9-mg extended-release tablets Indication: For the induction of remission in patients with active, mild-to-moderate ulcerative colitis Valchlor (new formulation) (Mechlorethamine; Actilion) Class/route: Alkylating drug; topical New formulation: Topical gel, 0.016% Indication: For the topical treatment of Stage IA and IB mycosis fungoides–type cutaneous T-cell lymphoma in patients who have received previous skin-directed therapy Approval consideration: Orphan drug Varithena (new formulation) (Polidocanol; BTG) Class/route: Sclerosing agent; intravenous New formulation: Injectable foam for intravenous use under ultrasound guidance Indications: For the treatment of incompetent great saphenous veins, accessory saphenous veins, and visible varicosities of the great saphenous vein system above and below the knee; improves the symptoms of superficial venous incompetence and the appearance of visible varicosities Vibativ (new indication) (Telavancin; Theravance) Class/route: Lipoglycopeptide antibacterial; intravenous New indication: Hospital-acquired and ventilatorassociated bacterial pneumonia caused by susceptible isolates of Staphylococcus aureus when alternative treatment is not suitable; already indicated for complicated skin and skin structure infections Vituz (new formulation) (Hydrocodone bitartrate and chlorpheniramine maleate; Hawthorn Pharmaceuticals) Class/route: A combination of an antitussive and a histamine-1 receptor antagonist; oral New formulation: Oral solution Indications: For the relief of cough and symptoms associated with upper respiratory allergies or a common cold in adults aged ≥18 years Xgeva (new indication) (Denosumab; Amgen) Class/route: Ligand inhibitor; subcutaneous New indication: For the treatment of adults and skeletally mature adolescents with giant-cell tumor of bone that is unresectable or where surgical resection is

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likely to result in severe morbidity; already indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors Approval consideration: Priority review, orphan drug Xiaflex (new indication) (Collagenase clostridium histolyticum; Auxilium Pharmaceuticals) Class/route: Bacterial collagenase; intralesional injection New indication: For the treatment of adult men with Peyronie’s disease with a palpable plaque and curvature deformity of at least 30 degrees at the start of therapy; already indicated for adults with Dupuytren’s contracture with a palpable cord Zecuity (new formulation) (Sumatriptan iontophoretic transdermal system; NuPathe) Class/route: Serotonin 1b/1d receptor agonist; transdermal New formulation: Single-use, battery-powered patch

Indication: For the acute treatment of migraine with or without aura in adults Zohydro ER (new formulation) (Hydrocodone bitartrate; Zogenix) Class/route: Opioid agonist; oral New formulation: Extended-release capsules Indication: For the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate Zubsolv (new formulation) (Buprenorphine and naloxone; Orexo AB) Class/route: Partial opioid agonist; sublingual New formulation: Sublingual tablet Indication: For the maintenance treatment of opioid dependence Approval consideration: Risk evaluation and mitigation strategy

Lupus Conference Reports from ACR NOW AVAILABLE

an e-newsletter brought to you by the publishers of THE PEER-REVIEWED FORUM FOR REAL-WORLD EVIDENCE IN BENEFIT DESIGN™

FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

TOPICS INCLUDE:

Information for payers and healthcare providers treating patients with lupus • On-site coverage from ACR/ARHP 2013 Annual Meeting • Review of currently approved and future therapies for lupus •

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POMALYST® (pomalidomide) is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

Help give your patients a chance for response Overall response rate (ORR) of 29.2% was achieved with all-oral POMALYST + low-dose dex ORR (≥PR) 100%

Patients, %

80%

95% CI for ORR: POMALYST: 3.3% to 14.1% POMALYST + low-dose dex: 21.0% to 38.5%

60% 40% 20%

ORR 7.4% (n=8)

PR 7.4% (n=8) CR 0% (n=0)

ORR 29.2% (n=33)

PR 28.3% (n=32) CR 0.9% (n=1)

POMALYST (N=108)

POMALYST + low-dose dex (N=113)

Study design: A Phase II, Stud multicenter, randomized open-label study in patients who were refractory to their last myeloma therapy and had received lenalidomide and bortezomib. The safety and efficacy of POMALYST 4 mg 21/28 days until disease progression was evaluated alone and in combination with low-dose dex: 40 mg per day (patients ≤75 years) or 20 mg per day (patients >75 years) only on Days 1, 8, 15, and 22 for each 28-day cycle. Patients in the POMALYST alone arm were allowed to add low-dose dex upon disease progression.

CI, confidence interval; CR, complete response; Dex, dexamethasone; PR, partial response. Endpoint based on responses assessed by IRAC, based on EBMT criteria.

7.4-month median duration of response (n=33; 95% CI, 5.1 to 9.2) vs NE for POMALYST + low-dose dex and POMALYST, respectively NE, not established (the median has not yet been reached).

ORR did not differ based on type of prior anti-myeloma therapy

For more information visit www.pomalyst.com or use your smartphone to scan this code.

WARNING: EMBRYO-FETAL TOXICITY and VENOUS THROMBOEMBOLISM See full prescribing information for complete boxed warning EMBRYO-FETAL TOXICITY • POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe life-threatening birth defects • For females of reproductive potential: Exclude pregnancy before start of treatment. Prevent pregnancy during treatment by the use of two reliable methods of contraception POMALYST is available only through a restricted program called the POMALYST REMS program. VENOUS THROMBOEMBOLISM • Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE) occur in patients with multiple myeloma treated with POMALYST

CONTRAINDICATIONS Pregnancy POMALYST can cause fetal harm when administered to a pregnant female. POMALYST is contraindicated in females who are pregnant. Pomalidomide is a thalidomide analogue, and is teratogenic in both rats and rabbits when administered during the period of organogenesis. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. POMALYST is only available under a restricted distribution program, POMALYST REMS™. Please see brief summary of full Prescribing Information, including Boxed WARNINGS, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS, and Important Safety Information on following pages.

Important Safety Information WARNING: EMBRYO-FETAL TOXICITY and VENOUS THROMBOEMBOLISM Embryo-Fetal Toxicity • POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting POMALYST treatment • Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after stopping POMALYST treatment POMALYST is only available through a restricted distribution program called POMALYST REMS™. Venous Thromboembolism • Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE) occur in patients with multiple myeloma treated with POMALYST. Prophylactic anti-thrombotic measures were employed in the clinical trial. Consider prophylactic measures after assessing an individual patient’s underlying risk factors

CONTRAINDICATIONS: Pregnancy

• POMALYST can cause fetal harm and is contraindicated in females who are pregnant. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus • Pomalidomide is a thalidomide analogue and is teratogenic in both rats and rabbits when administered during the period of organogenesis

WARNINGS AND PRECAUTIONS Embryo-Fetal Toxicity

• Females of Reproductive Potential: Must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. Must commit either to abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control, beginning 4 weeks prior to initiating treatment with POMALYST, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of POMALYST therapy. Must obtain 2 negative pregnancy tests prior to initiating therapy • Males: Pomalidomide is present in the semen of patients receiving the drug. Males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Males must not donate sperm • Blood Donation: Patients must not donate blood during treatment with POMALYST and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to POMALYST

POMALYST REMS Program

Because of the embryo-fetal risk, POMALYST is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called “POMALYST REMS.” Prescribers and pharmacists must be certified with the program; patients must sign an agreement form and comply with the requirements. Further information about the POMALYST REMS program is available at [celgeneriskmanagement.com] or by telephone at 1-888-423-5436.

Venous Thromboembolism: Patients receiving POMALYST have developed venous thromboembolic events reported as serious adverse reactions. In the trial, all patients were required to receive prophylaxis or antithrombotic treatment. The rate of DVT or PE was 3%. Consider anticoagulation prophylaxis after an assessment of each patient’s underlying risk factors. Hematologic Toxicity: Neutropenia of any grade was reported in 50% of patients and was the most frequently reported Grade 3/4 adverse event, followed by anemia and thrombocytopenia. Monitor patients for hematologic toxicities, especially neutropenia, with complete blood counts weekly for the first 8 weeks and monthly thereafter. Treatment is continued or modified for Grade 3 or 4 hematologic toxicities based upon clinical and laboratory findings. Dosing interruptions and/or modifications are recommended to manage neutropenia and thrombocytopenia. Hypersensitivity Reactions: Patients with a prior history of serious hypersensitivity associated with thalidomide or lenalidomide were excluded from studies and may be at higher risk of hypersensitivity.

WARNINGS AND PRECAUTIONS (continued) Dizziness and Confusional State: 18% of patients experienced dizziness and 12% of patients experienced a confusional state;

1% of patients experienced grade 3/4 dizziness, and 3% of patients experienced grade 3/4 confusional state. Instruct patients to avoid situations where dizziness or confusion may be a problem and not to take other medications that may cause dizziness or confusion without adequate medical advice. Neuropathy: 18% of patients experienced neuropathy (approximately 9% peripheral neuropathy). There were no cases of grade 3 or higher neuropathy adverse reactions reported. Risk of Second Primary Malignancies: Cases of acute myelogenous leukemia have been reported in patients receiving POMALYST as an investigational therapy outside of multiple myeloma.

ADVERSE REACTIONS

In the clinical trial of 219 patients who received POMALYST alone (n=107) or POMALYST + low-dose dexamethasone (low-dose dex) (n=112), all patients had at least one treatment-emergent adverse reaction. • In the POMALYST alone versus POMALYST + low dose dexamethasone arms, respectively, most common adverse reactions (≥30%) included fatigue and asthenia (55%, 63%), neutropenia (52%, 47%), anemia (38%, 39%), constipation (36%, 35%), nausea (36%, 22%), diarrhea (34%, 33%), dyspnea (34%, 45%), upper respiratory tract infection (32%, 25%), back pain (32%, 30%), and pyrexia (19%, 30%) • 90% of patients treated with POMALYST alone and 88% of patients treated with POMALYST + low-dose dex had at least one treatment-emergent NCI CTC Grade 3 or 4 adverse reaction • In the POMALYST alone versus POMALYST + low dose dexamethasone arms, respectively, most common Grade 3/4 adverse reactions (≥15%) included neutropenia (47%, 38%), anemia (22%, 21%), thrombocytopenia (22%, 19%), and pneumonia (16%, 23%). For other Grade 3 or 4 toxicities besides neutropenia and thrombocytopenia, hold treatment and restart treatment at 1 mg less than the previous dose when toxicity has resolved to less than or equal to Grade 2 at the physician’s discretion • 67% of patients treated with POMALYST and 62% of patients treated with POMALYST + low-dose dex had at least one treatment-emergent serious adverse reaction • In the POMALYST alone versus POMALYST + low dose dexamethasone arms, respectively, most common serious adverse reactions (≥5%) were pneumonia (14%, 19%), renal failure (8%, 6%), dyspnea (5%, 6%), sepsis (6%, 3%), pyrexia (3%, 5%) dehydration (5%, 3%), hypercalcemia (5%, 2%), urinary tract infection (0%, 5%), and febrile neutropenia (5%, 1%)

DRUG INTERACTIONS

No formal drug interaction studies have been conducted with POMALYST. Pomalidomide is primarily metabolized by CYP1A2 and CYP3A. Pomalidomide is also a substrate for P-glycoprotein (P-gp). Coadministration of POMALYST with drugs that are strong inhibitors or inducers of CYP1A2, CYP3A, or P-gp should be avoided. Cigarette smoking may reduce pomalidomide exposure due to CYP1A2 induction. Patients should be advised that smoking may reduce the efficacy of pomalidomide.

USE IN SPECIFIC POPULATIONS

Pregnancy: If pregnancy does occur during treatment, immediately discontinue the drug and refer patient to an obstetrician/

gynecologist experienced in reproductive toxicity for further evaluation and counseling. Report any suspected fetal exposure to POMALYST to the FDA via the MedWatch program at 1-800-332-1088 and also to Celgene Corporation at 1-888-423-5436. Nursing Mothers: It is not known if pomalidomide is excreted in human milk. Pomalidomide was excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from POMALYST, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: Safety and effectiveness of POMALYST in patients under the age of 18 have not been established. Geriatric Use: No dosage adjustment is required for POMALYST based on age. Patients greater than or equal to 65 years of age were more likely than patients less than or equal to 65 years of age to experience pneumonia. Renal and Hepatic Impairment: Pomalidomide is metabolized in the liver. Pomalidomide and its metabolites are primarily excreted by the kidneys. The influence of renal and hepatic impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Avoid POMALYST in patients with a serum creatinine >3.0 mg/dL. Avoid POMALYST in patients with serum bilirubin >2.0 mg/dL and AST/ALT >3.0 x ULN.

Please see full Prescribing Information, including Boxed WARNINGS, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS. POMALYST® is a registered trademark of Celgene Corporation. POMALYST REMS™ is a trademark of Celgene Corporation. © 2013 Celgene Corporation 04/13 US-POM120033

This brief summary does not include all the information needed to use POMALYST® (pomalidomide) safely and effectively. See full prescribing information for POMALYST. WARNING: EMBRYO-FETAL TOXICITY and VENOUS THROMBOEMBOLISM Embryo-Fetal Toxicity • POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting POMALYST treatment. • Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after stopping POMALYST treatment [see Contraindications (4), Warnings and Precautions (5.1), and Use in Specific Populations (8.1, 8.6)]. POMALYST is only available through a restricted distribution program called POMALYST REMS [see Warnings and Precautions (5.2)]. Venous Thromboembolism • Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE) occur in patients with multiple myeloma treated with POMALYST. Prophylactic anti-thrombotic measures were employed in the clinical trial. Consider prophylactic measures after assessing an individual patient’s underlying risk factors [see Warnings and Precautions (5.3)]. 1 INDICATIONS AND USAGE 1.1 Multiple Myeloma POMALYST is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate [see Clinical Studies (14.1)]. Clinical benefit, such as improvement in survival or symptoms, has not been verified. 2 DOSAGE AND ADMINISTRATION 2.1 Multiple Myeloma Females of reproductive potential must have negative pregnancy testing and use contraception methods before initiating POMALYST [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. The recommended starting dose of POMALYST is 4 mg once daily orally on Days 1-21 of repeated 28-day cycles until disease progression. POMALYST may be given in combination with dexamethasone [see Clinical Studies (14.1)]. POMALYST may be taken with water. Inform patients not to break, chew or open the capsules. POMALYST should be taken without food (at least 2 hours before or 2 hours after a meal). 2.2 Dose Adjustments for Toxicity Table 1: Dose Modification Instructions for POMALYST for Hematologic Toxicities Toxicity

Dose Modification

Neutropenia • ANC* < 500 per mcL Interrupt POMALYST or Febrile neutropenia treatment, follow CBC (fever more than or weekly. equal to 38.5°C and ANC < 1,000 per mcL) • ANC return to more than or equal to 500 per mcL

Resume POMALYST at 3 mg daily.

• For each subsequent drop < 500 per mcL

Interrupt POMALYST treatment

• Return to more than or equal to 500 per mcL

Resume POMALYST at 1 mg less than the previous dose

Toxicity

Dose Modification

Thrombocytopenia • Platelets < 25,000 per Interrupt POMALYST mcL treatment, follow CBC weekly • Platelets return to > 50,000 per mcL

Resume POMALYST treatment at 3 mg daily

• For each subsequent drop < 25,000 per mcL

Interrupt POMALYST treatment

• Return to more than Resume POMALYST at or equal to 50,000 per 1 mg less than previous mcL dose. *Note: ANC = Absolute Neutrophil Count For other Grade 3 or 4 toxicities hold treatment and restart treatment at 1 mg less than the previous dose when toxicity has resolved to less than or equal to Grade 2 at the physician’s discretion. To initiate a new cycle of POMALYST, the neutrophil count must be at least 500 per mcL, the platelet count must be at least 50,000 per mcL. If toxicities occur after dose reductions to 1 mg, then discontinue POMALYST. 4 CONTRAINDICATIONS Pregnancy POMALYST can cause fetal harm when administered to a pregnant female [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)]. POMALYST is contraindicated in females who are pregnant. Pomalidomide is a thalidomide analogue, and is teratogenic in both rats and rabbits when administered during the period of organogenesis. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. 5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Toxicity POMALYST is a thalidomide analogue and is contraindicated for use during pregnancy. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death [see Use in Specific Populations (8.1)]. POMALYST is only available through the POMALYST REMS program [see Warnings and Precautions (5.2)].Females of Reproductive Potential Females of reproductive potential must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. Females must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control, beginning 4 weeks prior to initiating treatment with POMALYST, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of POMALYST therapy. Two negative pregnancy tests must be obtained prior to initiating therapy. The first test should be performed within 10-14 days and the second test within 24 hours prior to prescribing POMALYST therapy and then weekly during the first month, then monthly thereafter in women with regular menstrual cycles or every 2 weeks in women with irregular menstrual cycles [see Use in Specific Populations (8.6)].Males Pomalidomide is present in the semen of patients receiving the drug. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Male patients taking POMALYST must not donate sperm [see Use in Specific Populations (8.6)]. Blood Donation Patients must not donate blood during treatment with POMALYST and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to POMALYST. 5.2 POMALYST REMS ™ Program Because of the embryo-fetal risk [see Warnings and Precautions

(5.1)], POMALYST is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called “POMALYST REMS.” Required components of the POMALYST REMS program include the following: • Prescribers must be certified with the POMALYST REMS program by enrolling and complying with the REMS requirements. • Patients must sign a Patient-Prescriber agreement form and comply with the REMS requirements. In particular, female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements [see Use in Specific Populations (8.6)] and males must comply with contraception requirements [see Use in Specific Populations (8.6)]. • Pharmacies must be certified with the POMALYST REMS program, must only dispense to patients who are authorized to receive POMALYST and comply with REMS requirements. Further information about the POMALYST REMS program is available at [celgeneriskmanagement.com] or by telephone at 1-888-423-5436. 5.3 Venous Thromboembolism Patients receiving POMALYST have developed venous thromboembolic events (Venous Thromboembolism [VTEs]) reported as serious adverse reactions. In the trial, all patients were required to receive prophylaxis or anti-thrombotic treatment; 81% used aspirin, 16% warfarin, 21% heparin, and 3% clopidogrel. The rate of deep vein thrombosis or pulmonary embolism was 3%. Consider anti-coagulation prophylaxis after an assessment of each patient’s underlying risk factors. 5.4 Hematologic Toxicity Neutropenia was the most frequently reported Grade 3/4 adverse event (AE), followed by anemia and thrombocytopenia. Neutropenia of any grade was reported in 50% of patients in the trial. The rate of Grade 3/4 neutropenia was 43%. The rate of febrile neutropenia was 3%. Monitor patients for hematologic toxicities, especially neutropenia. Monitor complete blood counts weekly for the first 8 weeks and monthly thereafter. Patients may require dose interruption and/or modification [see Dosage and Administration (2.2)]. 5.5 Hypersensitivity Reactions. Patients with a prior history of serious hypersensitivity associated with thalidomide or lenalidomide were excluded from studies and may be at higher risk of hypersensitivity. 5.6 Dizziness and Confusional State. In the trial, 18% of patients experienced dizziness and 12% of patients experienced a confusional state; 1% of patients experienced grade 3/4 dizziness, and 3% of patients experienced grade 3/4 confusional state. Instruct patients to avoid situations where dizziness or confusion may be a problem and not to take other medications that may cause dizziness or confusion without adequate medical advice. 5.7 Neuropathy In the trial, 18% of patients experienced neuropathy, with approximately 9% of the patients experiencing peripheral neuropathy. There were no cases of grade 3 or higher neuropathy adverse reactions reported. 5.8 Risk of Second Primary Malignancies Cases of acute myelogenous leukemia have been reported in patients receiving POMALYST as an investigational therapy outside of multiple myeloma. 6 ADVERSE REACTIONS The following adverse reactions are described in detail in other labeling sections: • Fetal Risk [see Boxed Warnings, Warnings and Precautions (5.1, 5.2)] • Venous Thromboembolism [see Boxed Warnings, Warnings and Precautions (5.3)] • Hematologic Toxicity [see Warnings and Precautions (5.4)] • Hypersensitivity Reactions [see Warnings and Precautions (5.5)]

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• Dizziness and Confusional State [see Warnings and Precautions (5.6)] • Neuropathy [see Warnings and Precautions (5.7)] • Risk of Second Primary Malignancies [see Warnings and Precautions (5.8)] 6.1 Clinical Trials Experience in Multiple Myeloma Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In clinical trial 1, data were evaluated from 219 patients (safety population) who received treatment with POMALYST + Low Dose Dexamethasone (Low dose Dex) (112 patients) or POMALYST alone (107 patients). Median number of treatment cycles was 5. Sixty three percent of patients in the study had a dose interruption of either drug due to adverse reactions. Thirty seven percent of patients in the study had a dose reduction of either drug due to adverse reactions. The discontinuation rate due to treatment-related adverse reaction was 3%. Tables 2, 3 and 4 summarize all treatment-emergent adverse reactions reported for POMALYST + Low dose Dex and POMALYST alone groups regardless of attribution of relatedness to pomalidomide. In the absence of a randomized comparator arm, it is often not possible to distinguish adverse events that are drug-related and those that reflect the patient’s underlying disease. In the clinical trial of 219 patients who received POMALYST alonea (n=107) or POMALYST + Lowdose Dex (n=112), all patients had at least one treatment-emergent adverse reaction. Adverse reactions ≥10% in either arm, respectively, included: General disorders and administration site conditions: Fatigue and asthenia (55%, 63%), Pyrexia (19%, 30%), Edema peripheral (23%, 16%), Chills (9%, 11%), Pain (6%, 5%); Blood and lymphatic system disorders: Neutropenia (52%, 47%), Anemia (38%, 39%), Thrombocytopenia (25%, 23%), Leukopenia (11%, 18%), Lymphopenia (4%, 15%); Gastrointestinal disorders: Constipation (36%, 35%), Diarrhea (34%, 33%), Nausea (36%, 22%), Vomiting (14%, 13%); Infections and infestations: Pneumonia (23%, 29%), Upper respiratory tract infection (32%, 25%), Urinary tract infection (8%, 16%); Musculoskeletal and connective tissue disorders: Back pain (32%, 30%), Musculoskeletal chest pain (22%, 20%), Muscle spasms (19%, 19%), Arthralgia (16%, 15%), Musculoskeletal pain (11%, 15%), Pain in extremity (5%, 14%), Muscular weakness (12%, 12%), Bone pain (12%, 5%); Respiratory, thoracic and mediastinal disorders: Dyspnea (34%, 45%), Cough (14%, 21%), Epistaxis (15%, 11%); Metabolism and nutritional disorders: Decreased appetite (22%, 18%), Hyperglycemia (12%, 15%), Hyponatremia (10%, 13%), Hypercalcemia (21%, 12%), Hypocalcemia (6%, 12%), Hypokalemia (10%, 11%); Skin and subcutaneous tissue disorders: Hyperhidrosis (6%, 16%), Rash (22%, 16%), Night sweats (5%, 13%), Dry skin (9%, 11%), Pruritus (15%, 11%); Nervous system disorders: Dizziness (20%, 17%), Tremor (9%, 13%), Headache (13%, 8%), Neuropathy peripheral (10%, 7%); Investigations: Blood creatinine increased (15%, 11%), Weight increased (1%, 11%), Weight decreased (14%, 8%); Psychiatric disorders: Insomnia (7%, 14%), Confusional state (10%, 13%), Anxiety (11%, 7%); Renal and urinary disorders: Renal failure (15%, 10%). Grade 3/4 adverse reactions reported in 90% of patients treated with POMALYSTa alone (96/107) and 88% with POMALYST + Low dose Dex (99/112). Grade 3/4 Adverse Reactions ≥ 5% in either arm, respectively, included: Blood and lymphatic system disorders: Neutropenia (47%, 38%), Anemia (22%, 21%), Thrombocytopenia (22%, 19%), Leukopenia

(6%, 10%), Lymphopenia (2%, 7%); Infections and infestations: Pneumonia (16%, 23%), Urinary tract infection (2%, 8%), Sepsis (6%, 3%); Metabolism and nutritional disorders: Hypercalcemia (9%, 1%); General disorders and administration site conditions: Fatigue and asthenia (11%, 13%); Investigations: Blood creatinine increased (6%, 3%); Respiratory, thoracic and mediastinal disorders: Dyspnea (7%, 13%); Musculoskeletal and connective tissue disorders: Back pain (12%, 9%), Muscular weakness (6%, 4%); Renal and urinary disorders: Renal failure (9%, 6%). Serious adverse events were reported in 67% of patients treated with POMALYSTa (72/107) and 62% with POMALYST + Low dose Dex (69/112). Serious Adverse Reactions in 2 or more patients in either arm, respectively, included: Infections and infestations: Pneumonia (14%, 19%), Urinary tract infection (0%, 5%), Sepsis (6%, 3%); Respiratory, Thoracic and mediastinal disorders: Dyspnea (5%, 6%); General disorders and administration site conditions: Pyrexia (3%, 5%); General physical health deterioration (0%, 2%); Cardiac Disorders: Atrial fibrillation (2%, 3%), Cardiac failure congestive (0%, 3%); Renal and urinary disorders: Renal failure (8%, 6%), Gastrointestinal disorders: constipation (1%, 3%); Blood and Lymphatic system disorders: Febrile neutropenia (5%, 1%); Metabolism and nutrition disorders: Dehydration (5%, 3%), Hypercalcemia (5%, 2%); Musculoskeletal and connective tissue disorders: Back pain (4%, 2%) aPOMALYST alone arm includes all patients randomized to the POMALYST alone arm who took study drug; 61 of the 107 patients had dexamethasone added during the treatment period. Other Adverse Reactions Other adverse reactions of POMALYST in patients with multiple myeloma, not described above, and considered important: Ear and Labyrinth Disorders: Vertigo; Hepatobiliary Disorders: Hyperbilirubinemia; Infections and Infestations: Pneumocystis jiroveci pneumonia, Respiratory syncytial virus infection, Neutropenic sepsis; Investigations: Alanine aminotransferase increased; Metabolism and Nutritional Disorders: Hyperkalemia; Renal and Urinary Disorders: Urinary retention; Reproductive System and Breast Disorders: Pelvic Pain; Respiratory, Thoracic and Mediastinal Disorders: Interstitial Lung Disease 7 DRUG INTERACTIONS No formal drug interaction studies have been conducted with POMALYST. Pomalidomide is primarily metabolized by CYP1A2 and CYP3A. Pomalidomide is also a substrate for P-glycoprotein (P-gp). 7.1 Drugs That May Increase Pomalidomide Plasma Concentrations CYP3A, CYP1A2 or P-gp inhibitors: Co-administration of POMALYST with drugs that are strong inhibitors of CYP1A2, CYP3A (e.g. ketoconazole) or P-gp could increase exposure and should be avoided. 7.2 Drugs That May Decrease Pomalidomide Plasma Concentrations CYP3A, CYP1A2 or P-gp inducers: Co-administration of POMALYST with drugs that are strong inducers of CYP1A2, CYP3A (e.g. rifampin) or P-gp could decrease exposure and should be avoided. Smoking: Cigarette smoking may reduce pomalidomide exposure due to CYP1A2 induction. Patients should be advised that smoking may reduce the efficacy of pomalidomide. Dexamethasone: Co-administration of multiple doses of 4 mg POMALYST with 20 mg to 40 mg dexamethasone (a weak inducer of CYP3A) to patients with multiple myeloma had no effect on the pharmacokinetics of pomalidomide compared with pomalidomide administered alone. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category X [see Boxed Warnings and Contraindications (4)]

Risk Summary POMALYST can cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a human teratogen, inducing a high frequency of severe and life-threatening birth defects such as amelia (absence of limbs), phocomelia (short limbs), hypoplasticity of the bones, absence of bones, external ear abnormalities (including anotia, micropinna, small or absent external auditory canals), facial palsy, eye abnormalities (anophthalmos, microphthalmos), and congenital heart defects. Alimentary tract, urinary tract, and genital malformations have also been documented and mortality at or shortly after birth has been reported in about 40% of infants. Pomalidomide was teratogenic in both rats and rabbits when administered during the period of organogenesis. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. If pregnancy does occur during treatment, immediately discontinue the drug. Under these conditions, refer patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. Report any suspected fetal exposure to POMALYST to the FDA via the MedWatch program at 1-800-332-1088 and also to Celgene Corporation at 1-888-423-5436. Animal Data Pomalidomide was teratogenic in both rats and rabbits in the embryofetal developmental studies, when administered during the period of organogenesis. In rats, pomalidomide was administered orally to pregnant animals at doses of 25 to 1000 mg per kg per day. Malformations of absence of urinary bladder, absence of thyroid gland, and fusion and misalignment of lumbar and thoracic vertebral elements (vertebral, central and/or neural arches) were observed at all dose levels. There was no maternal toxicity observed in this study. The lowest dose in rats resulted in an exposure (AUC) approximately 85-fold of the human exposure at the recommended dose of 4 mg per day. Other embryofetal toxicities included increased resorptions leading to decreased number of viable fetuses. In rabbits, pomalidomide was administered orally to pregnant animals at doses of 10 to 250 mg per kg per day. Increased cardiac malformations such as interventricular septal defect were seen at all doses with significant increases at 250 mg per kg per day. Additional malformations observed at 250 mg per kg per day included anomalies in limbs (flexed and/or rotated fore- and/or hindlimbs, unattached or absent digit) and associated skeletal malformations (not ossified metacarpal, misaligned phalanx and metacarpal, absent digit, not ossified phalanx, and short not ossified or bent tibia), moderate dilation of the lateral ventricle in the brain, abnormal placement of the right subclavian artery, absent intermediate lobe in the lungs, low-set kidney, altered liver morphology, incompletely or not ossified pelvis, an increased average for supernumerary thoracic ribs and a reduced average for ossified tarsals. No maternal toxicity was observed at the low dose (10 mg per kg per day) that resulted in cardiac anomalies in fetuses; this dose resulted in an exposure (AUC) approximately equal to that reported in humans at the recommended dose of 4 mg per day. Additional embryofetal toxicity included increased resorption. 8.3 Nursing mothers It is not known if pomalidomide is excreted in human milk. Pomalidomide was excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from POMALYST, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric use Safety and effectiveness of POMALYST in patients below the age of 18 have not been established.

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8.5 Geriatric use No dosage adjustment is required for POMALYST based on age. Of the total number of patients in clinical studies of POMALYST, 41 percent were 65 and over, while 12 percent were 75 and over. No overall differences in effectiveness were observed between these patients and younger patients. In this study, patients greater than or equal to 65 years of age were more likely than patients less than or equal to 65 years of age to experience pneumonia. 8.6 Females of Reproductive Potential and Males POMALYST can cause fetal harm when administered during pregnancy [see Use in Specific Populations (8.1)]. Females of reproductive potential must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. Females Females of reproductive potential must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control simultaneously (one highly effective form of contraception – tubal ligation, IUD, hormonal (birth control pills, injections, hormonal patches, vaginal rings or implants) or partner’s vasectomy and one additional effective contraceptive method – male latex or synthetic condom, diaphragm or cervical cap. Contraception must begin 4 weeks prior to initiating treatment with POMALYST, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of POMALYST therapy. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy. Females of reproductive potential should be referred to a qualified provider of contraceptive methods, if needed. Females of reproductive potential must have 2 negative pregnancy tests before initiating POMALYST. The first test should be performed within 10-14 days, and the second test within 24 hours prior to prescribing POMALYST. Once treatment has started and during dose interruptions, pregnancy testing for females of reproductive potential should occur weekly during the first 4 weeks of use, then pregnancy testing should be repeated every 4 weeks in females with regular menstrual cycles. If menstrual cycles are irregular, the pregnancy testing should occur every 2 weeks. Pregnancy testing and counseling should be performed if a patient misses her period or if there is any abnormality in her menstrual bleeding. POMALYST treatment must be discontinued during this evaluation. Males Pomalidomide is present in the semen of males who take POMALYST. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Male patients taking POMALYST must not donate sperm. 8.7 Renal Impairment Pomalidomide and its metabolites are primarily excreted by the kidneys [see Clinical Pharmacology (12.3)]. The influence of renal impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Patients with serum creatinine greater than 3.0 mg/dL were excluded in clinical studies. Avoid POMALYST in patients with a serum creatinine greater than 3.0 mg/dL. 8.8 Hepatic Impairment Pomalidomide is metabolized in the liver [see Clinical Pharmacology (12.3)]. The influence of hepatic impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Patients with serum bilirubin greater than 2.0 mg/dL and AST/ALT greater than 3.0 x upper limit normal (ULN) were excluded in clinical studies. Avoid POMALYST in patients with serum bilirubin greater than 2.0 mg/dL and AST/ALT greater than 3.0 x ULN. 10 OVERDOSAGE No specific information is available on the treatment of overdose with pomalidomide, and it is unknown whether pomalidomide or its metabolites are dialyzable.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Studies examining the carcinogenic potential of pomalidomide have not been conducted. One of twelve monkeys dosed with 1 mg/kg of pomalidomide (an exposure approximately 15-fold of the exposure in patients at the recommended dose of 4 mg/per day) developed acute myeloid leukemia in a 9-month repeat-dose toxicology study. Pomalidomide was not mutagenic or clastogenic in a battery of tests, including the bacteria reverse mutation assay (Ames test), the in vitro assay using human peripheral blood lymphocytes and the micronucleus test in orally treated rats administered doses up to 2000 mg/kg/day. In a fertility and early embryonic development study in rats, drug-treated males were mated with untreated or treated females. Pomalidomide was administered to males and females at doses of 25 to 1000 mg/kg/day. When treated males were mated with treated females, there was an increase in post-implantation loss and a decrease in mean number of viable embryos at all dose levels. There were no other effects on reproductive functions or the number of pregnancies. The lowest dose tested in animals resulted in an exposure (AUC) approximately 100-fold of the exposure in patients at the recommended dose of 4 mg/day. When treated males on this study were mated with untreated females, all uterine parameters were comparable to the controls. Based on these results, the observed effects were attributed to the treatment of females. 17 PATIENT COUNSELING INFORMATION See FDA- approved Patient labeling (Medication Guide). Embryo-Fetal Toxicity Advise patients that POMALYST is contraindicated in pregnancy [see Contraindicatons (4)]. POMALYST is a thalidomide analog and may cause serious birth defects or death to a developing baby. [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)]. • Advise females of reproductive potential that they must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. • Initiate POMALYST treatment in females of reproductive potential only following a negative pregnancy test. • Advise females of reproductive potential of the importance of monthly pregnancy tests and the need to use two different forms of contraception including at least one highly effective form simultaneously during POMALYST therapy, during therapy interruption and for 4 weeks after she has completely finished taking POMALYST. Highly effective forms of contraception other than tubal ligation include IUD and hormonal (birth control pills, injections, patch or implants) and a partner’s vasectomy. Additional effective contraceptive methods include latex or synthetic condom, diaphragm and cervical cap. • Instruct patient to immediately stop taking POMALYST and contact her doctor if she becomes pregnant while taking this drug, if she misses her menstrual period, or experiences unusual menstrual bleeding, if she stops taking birth control, or if she thinks FOR ANY REASON that she may be pregnant. • Advise patient that if her doctor is not available, she can call 1-888-668-2528 for information on emergency contraception [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. • Advise males to always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. • Advise male patients taking POMALYST that they must not donate sperm [see Warnings and

Precautions (5.1) and Use in Specific Populations (8.6)]. • All patients must be instructed to not donate blood while taking POMALYST and for 1 month following discontinuation of POMALYST [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. POMALYST REMS Program Because of the risk of embryo-fetal toxicity, POMALYST is only available through a restricted program call POMALYST REMS [see Warnings and Precautions (5.2)]. • Patients must sign a Patient-Prescriber agreement form and comply with the requirements to receive POMALYST. In particular, females of reproductive potential must comply with the pregnancy testing, contraception requirements and participate in monthly telephone surveys. Males must comply with the contraception requirements [see Use in Specific Populations (8.6)]. • POMALYST is available only from pharmacies that are certified in POMALYST REMS program. Provide patients with the telephone number and website for information on how to obtain the product. Venous Thromboembolism Inform patients of the potential risk of developing venous thromboembolic events and discuss the need for appropriate prophylactic treatment. Hematologic Toxicities Inform patients on the risks of developing neutropenia, thrombocytopenia and anemia and the need to report signs and symptoms associated with these events to their health care provider for further evaluation. Hypersensitivity Inform patients of the potential for a severe hypersensitivity reaction to POMALYST if they have had such a reaction in the past to either THALOMID® or REVLIMID®. Dizziness and Confusional State Inform patients of the potential risk of dizziness and confusion with the drug and to avoid situations where dizziness or confusion may be a problem and not to take other medications that may cause dizziness or confusion without adequate medical advice. Neuropathy Inform patients of the risk of neuropathy and report the signs and symptoms associated with these events to their health care provider for further evaluation. Second Primary Malignancies Inform the patient that the potential risk of developing acute myelogenous leukemia during treatment with POMALYST is unknown. Dosing Instructions Inform patients on how to take POMALYST [see Dosage and Administration (2.1)] • POMALYST should be taken once daily at about the same time each day • POMALYST should be taken without food (at least 2 hours before or 2 hours after a meal). • The capsules should not be opened, broken, or chewed. POMALYST should be swallowed whole with water. • Instruct patients that if they miss a dose of POMALYST, they may still take it up to 12 hours after the time they would normally take it. If more than 12 hours have elapsed, they should be instructed to skip the dose for that day. The next day, they should take POMALYST at the usual time. Warn patients not to take 2 doses to make up for the one that they missed. Other Information Advise patients who smoke to stop because smoking may reduce the efficacy of pomalidomide [see Drug Interactions (7.2)]. Manufactured for: Celgene Corporation Summit, NJ 07901 POMALYST®, REVLIMID® and THALOMID® are registered trademarks of Celgene Corporation. POMALYST REMS™ is a trademark of Celgene Corporation. U.S. Pat. Nos. 5,635,517; 6,045,501; 6,315,720; 6,316,471; 6,476,052; 6,561,976; 6,561,977; 6,755,784; 6,908,432; 8,158,653; 8,198,262; 8,204,763; 8,315,886 ©2005-2013Celgene Corporation, All Rights Reserved. POMBSv.001a 02/13

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Specialty Drugs Top the Trends in the 2014 Pipeline By Dalia Buffery, MA, ABD Editorial Director of American Health & Drug Benefits

rug development is fraught with significant risks for failure and astronomical expenditures, but its successes are rewarded by many lives saved and high monetary compensations. According to the Pharmaceutical Research and Manufacturers of America (PhRMA), for every 5000 to 10,000 compounds in the pipeline, only 1 compound makes the full development route through the US Food and Drug Administration (FDA) approval process.1 This miniscule ratio explains why, on average, it costs $1.2 billion to get 1 drug to market––a cost that includes the expenditures for the failed compounds for the specific company.1 Furthermore, the investment in time could discourage many companies from entering the business of developing medicines: according to PhRMA, it takes 3 to 6 years to get a drug through the discovery phase and another 6 to 7 years to get a drug to the FDA review phase.1 Even the recently expanded priority and accelerated reviews by the FDA do not cut the time by more than a few months, which pales in the face of the total 9 to 13 years of drug development. The recent introduction of breakthrough therapy designation is significant, because it can cut the development process by several years, allowing the FDA to introduce important medicines to the market based on very promising phase 2 rather than phase 3 clinical trial results. With all these challenges facing drug manufacturers, perhaps it is not surprising that the rate of new molecular entities approved by the FDA in 2013 was lower than the total approved in 2012, which was a record year for FDA approvals of new molecular entities. However, the number of new drugs that have already been approved in the first quarter of 2014 (Table 1) indicates that the FDA remains steady in its efforts to expedite the approval of innovative drugs, and 2014 may yet be another record year for new molecules entering the market.

Biotechnology Innovation Continuing the trend seen in the past few years, reinforced by the ongoing advancements of technological innovations, specialty pharmaceuticals dominate the current drug pipeline, even though the number of patients benefiting from these drugs remains very small compared with traditional drugs. Of the total of 27 new

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molecular entities approved by the FDA in 2013, approximately 60% were specialty drugs.2,3 This trend is more than likely to continue in 2014, based on the continuing growth of specialty drugs in the pharmaceutical pipeline. Not surprisingly, the share of specialty medications managed under the pharmacy benefit continues to grow. By the end of the decade, suggests one expert, more than 50% of the drugs covered under the pharmacy benefit will be specialty drugs.4 The role of biotechnology in the development of new drugs is especially apparent in the specialty drugs arena in tandem with the growing focus on targeted drugs; the role of genetics in various disease states; and the identification of biomarkers in the search for new drugs combined with “companion” diagnostics used to identify the subpopulation of patients who would benefit from those very specialized drugs and will justify their use, even with their high price tag. The cost of specialty drugs, though, remains a challenge. Despite the growing competition in the specialty drug arena, there is no sign that increased competition is lowering the cost of these medications.4 In addition, biosimilars, which are expected to reduce the cost of specialty drugs by approximately 20%––a not-so-dramatic reduction compared with the 80% to 90% reduction with generic drugs––are yet to be approved by the FDA. Although the FDA has issued various guidance statements to help manufacturers in the development of biosimilars, it will likely take another 1 or 2 years before the first biosimilar is approved in the United States (unlike in Europe, where several biosimilars have already been approved). By 2018, overall spending on specialty drugs by patients and by payers is expected to exceed the total spending on traditional, small-molecule drugs, even though these agents are used by a very small percentage of the total patient population in the United States.3 Nevertheless, traditional medicines, perhaps to the surprise of some healthcare stakeholders, are being developed in large numbers. The traditional pharmaceutical lines of development still boast a large number of new drugs for many clinical categories, with cardiometabolic diseases, especially diabetes, leading the way (Table 2); there are currently 180 drugs in development for diabetes alone.1

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Table 1 New FDA-Approved Drugs in First Quarter of 2014, as of March 7 Drug (brand) name Manufacturer Indication/class/route

Approval date

Dapagliflozin (Farxiga)

Bristol-Myers Squibb/ AstraZeneca

SGLT-2 inhibitor for type 2 diabetes; oral

1/8/2014

Glatiramer acetate (Copaxone)

Teva Pharmaceuticals

New 40-mg/mL dosing for relapsing forms of multiple sclerosis; immunomodulator; orphan drug; oral

1/29/2014

Tasimelteon (Hetlioz)

Vanda Pharmaceuticals

Melatonin receptor agonist for non–24-hour sleep-wake disorder in the totally blind; orphan drug; oral

1/31/2014

Ibrutinib (Imbruvica)

Pharmacyclics

BTK inhibitor for chronic lymphocytic leukemia; oral

2/12/2014

Elosulfase alfa (Vimizim)

BioMarin Pharmaceuticals

Recombinant human N-acetylgalactosamine-6sulfatase for Morquio A syndrome; orphan drug; IV

2/14/2014

Droxidopa (Northera)

Chelsea Therapeutics

Synthetic precursor of norepinephrine for neurogenic orthostatic hypotension; orphan drug; oral

2/18/2014

Indomethacin (Tivorbex)

Iroko Pharmaceuticals

COX inhibitor for acute pain; oral

2/24/2014

Metreleptin for injection (Myalept)

Amylin Pharmaceuticals Replacement therapy for leptin deficiency in patients with congenital/acquired generalized lipodystrophy; orphan drug; SC

Testosterone undecanoate Endo Pharmaceuticals (Aveed)

Testosterone replacement for hypogonadism

2/25/2014

3/7/2014

BTK indicates Bruton’s tyrosine kinase; COX, cyclooxygenase; IV, intravenous; SC, subcutaneous; SGLT-2, sodium-glucose cotransporter 2.

Orphan Drugs Orphan drugs remain strong in the current pipeline. In 2013, the FDA made full use of its priority review and accelerated approval pathways to expedite patients’ access to drugs that demonstrated evidence for significant clinical benefit, and this trend is especially evident in the orphan drugs arena. Approximately 25 million people in the United States have rare diseases, which justifies the development of such drugs, although individually, each drug would benefit only 200,000 people or fewer (according to the definition of an orphan drug).3 The overall spending on orphan drugs in the United States amounts to 6% of the total drug spending, and approximately 30% of these drugs are considered “blockbusters,”3 even though the price of 1 orphan drug can be in the thousands of dollars monthly. Overall, the growth of orphan drugs is more than 20% annually compared with only 20% for nonorphan drugs.3 In 2014, already 4 orphan drugs received FDA approval (Table 1), and many more are in the pipeline; at least 9 new orphan drugs are expected to be reviewed by the FDA between 2014 and 2016, and several new drugs for pulmonary arterial hypertension (PAH) are expected to be approved between 2014 and 2017 (Table 3), in addition to the 3 new drugs that were approved in 2013 for PAH. Other key orphan drugs in late-stage development are for cystic fibrosis and for bleeding disorders.

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Specialty Drugs: Oral and Subcutaneous Administration As the competition in the specialty drug arena is growing, the number of therapeutic options in the pipeline is also expanding within certain therapeutic categories, including diabetes, certain types of cancer, inflammatory conditions, and certain neurologic disorders, especially multiple sclerosis (MS). Last year’s report from PhRMA suggested that the drug pipeline is booming with specialty drugs, with thousands of clinical trials being conducted for novel therapies and novel mechanisms of action, targeting more than 100 different disease states, including many novel therapies for rare diseases.5 The gradual but consistent move toward oral and subcutaneous medications in specialty pharmaceuticals is a trend evident in numerous clinical categories, including cancer. Oral or subcutaneous medications, unlike infused drugs, can curb the provider’s time for direct involvement in the administration of the drug. However, although this trend may eventually save costs, it can also exacerbate concerns for nonadherence, by putting the patient in charge of taking the oral or subcutaneous medication. Promising Drugs in Late-Stage Development The top clinical categories in specialty drug develop-

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Table 2 Traditional Medicines in the Cardiometabolic Pipeline in Late-Stage Development Development stage/ Drug name Manufacturer Therapeutic category/route/class comments Lipid disorders Anacetrapib

Merck

CETP inhibitor for dyslipidemia; oral

Phase 3 trials

EPA + DHA (Epanova)

AstraZeneca/Omthera

Omega-3 free fatty acids for hypertriglyceridemia; oral

PDUFA: 5/5/2014

Evacetrapib (LY2484595)

Lilly

CETP inhibitor for high-risk vascular disease; oral

Phase 3 trials

Inhaled insulin (Afrezza)

MannKind

Insulin for type 1 and type 2 diabetes; inhalation

PDUFA: 4/1/2014

Insulin degludec (Tresiba)

Novo Nordisk

Insulin for type 1 and type 2 diabetes; SC

FDA requested more information: 2/8/2013

Insulin degludec/liraglutide (IDegLira)

Novo Nordisk

Long-acting basal insulin and GLP-1 agonist for type 2 diabetes; SC

Under regulatory review in the European Union

Insulin glargine (LY2963016)

Boehringer Ingelheim/ Lilly

Insulin for type 1 and type 2 diabetes; SC

NDA accepted: 12/20/2013

Insulin glargine (U300)

Sanofi

Insulin for type 1 and type 2 diabetes; SC

Phase 3 trials

Insulin lispro (LY2605541)

Lilly

Insulin for type 1 and type 2 diabetes; SC

Phase 3 trials

Empagliflozin

Boehringer Ingelheim/ Lilly

SGLT-2 inhibitor for type 2 diabetes; oral

FDA requested more information: 3/5/2014

Ertugliflozin

Merck/Pfizer

SGLT-2 inhibitor for type 2 diabetes; oral

Phase 3 trials

LX4211

Lexicon

SGLT-2 inhibitor for type 1 diabetes; oral

Completed phase 2 trials

Albiglutide (Syncria)

GlaxoSmithKline

GLP-1 agonist for type 2 diabetes; SC

PDUFA: 4/15/2014

Dulaglutide

Lilly

GLP-1 agonist for type 2 diabetes; SC

Phase 3 trials PDUFA: 9/26/2014

Lixisenatide (Lyxumia)

Sanofi

GLP-1 agonist for type 2 diabetes; SC

Plans to resubmit NDA in 2015; European Commission approval: 2/1/2013

Semaglutide

Novo Nordisk

GLP-1 agonist for type 2 diabetes; SC

Phase 3 trials

Omarigliptin (MK-3102)

Merck

DPP-4 inhibitor for type 2 diabetes; oral

Phase 3 trials

Trelagliptin (SYR-472)

Takeda Pharmaceuticals

DPP-4 inhibitor for type 2 diabetes; oral

Phase 3 trials

Diabetes Insulins

SGLT-2 inhibitors

GLP-1 agonists

DPP-4 inhibitors

CETP indicates cholesteryl ester transfer protein; DHA, docosahexaenoic acid; DPP-4, dipeptidyl peptidase-4; EPA, eicosapentaenoic acid; FDA, US Food and Drug Administration; GLP-1, glucagon-like peptide-1; NDA, New Drug Application; PDUFA, Prescription Drug User Fee Act; SC, subcutaneous; SGLT-2, sodium-glucose cotransporter 2.

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ment in 2014 include inflammatory conditions, MS, cancer, HIV/AIDS, and hepatitis C virus (HCV) infection. Table 3 lists some of the key agents in the specialty drug pipeline for cardiometabolic disorders (which remain the number 1 combined clinical category in terms of morbidity and mortality in the United States), inflammatory conditions, and MS; these drugs are expected to receive FDA approval between 2014 and 2016.

Cardiometabolic Disorders The traditional cardiometabolic pipeline continues to flourish, featuring many of the familiar glucose-lowering classes in late-stage development (Table 2), including 2 of the oral DPP (dipeptidyl peptidase)-4 inhibitors, omarigliptin and trelagliptin, and 4 GLP (glucagon-like peptide)-1 agonists, dulaglutide, lixisenatide (Lyxumia), semaglutide, and albiglutide (Syncria). However, a new drug class was launched in 2013, when canagliflozin (Invokana) became the first-in-class of SGLT (sodium-glucose cotransporter)-2 inhibitors to receive FDA approval for patients with diabetes. Several new SGLT-2 inhibitors are in the drug pipeline and may join canagliflozin in 2014 or 2015 for the management of patients with diabetes. In the specialty drugs pipeline, a new class of drugs for lipid disorders, the PCSK9 (proprotein convertase subtilisin/kexin type 9) protein inhibitors, is emerging (Table 3), reflecting the continuing need for improved mechanisms to control metabolic disorders for the ever-growing number of patients who are obese, and patients with heart disease and/or diabetes. Despite the many drugs currently available for patients with type 1 and type 2 diabetes, as noted earlier, there are now 180 drugs being developed specifically for this patient population.5 Pulmonary Arterial Hypertension Last year, 2 new molecular entities were approved for PAH—macitentan (Opsumit) and riociguat (Adempas) ––in addition to 1 new, extended-release formulation of treprostinil (Orenitram). Currently, 2 more specialty drugs are in late-stage development for PAH, including selexipag, which is in phase 3 clinical trials and is expected to be reviewed by the FDA in 2015, and beraprost-314d, which is in earlier stage development and may not be reviewed by the FDA until 2017 (Table 3). Inflammatory Disorders The monoclonal antibodies (ie, interleukin inhibitors) and the anti-tumor necrosis factor (TNF) agents are currently dominating the market for inflammatory and autoimmune diseases, such as rheumatoid arthritis and psoriatic arthritis. As mentioned earlier, drug development is moving toward subcutaneous administration, and drugs

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that were first available for intravenous administration are now being redeveloped for subcutaneous administration. Several of these agents are close to FDA approval, with apremilast (for psoriatic arthritis) being first in line in this clinical category, with a March 2014 PDUFA (Prescription Drug User Fee Act) date (Table 3). Furthermore, developers of the anti-TNF factor agents and the monoclonal antibodies are often seeking more than 1 indication; for example, secukinumab for psoriasis and rheumatoid arthritis and vedolizumab for ulcerative colitis and Crohn’s disease, with a May 2014 PDUFA date for the latter. Other specialty drugs in late-stage development for inflammatory/rheumatic disorders include rigerimod (Lupuzor) for lupus, rilonacept (Arcalyst) for gout, baricitinib and sarilu mab for rheumatoid arthritis, and brodalumab for psoriasis (Table 3).

Multiple Sclerosis Specialty drugs continue to rule the MS drug arena. Currently, 6 biologics are either in late-stage clinical trials or have already filed with the FDA; 3 of these biologics are monoclonal antibodies, with alemtuzumab (Lemtrada) still waiting for final approval after the FDA requested additional information from the manufacturer in December 2013. Dimethyl fumarate (Tecfidera), which received FDA approval for relapsing forms of MS in 2013, is the latest addition to the current therapies for this condition. In addition, a biologics license application was filed with the FDA last year for peginterferon beta-1a (Plegridy). The other MS specialty drugs in latestage development include laquinimod, masitinib, ocrelizumab, and daclizumab (Zenapax; Table 3). Infectious Diseases The key specialty medicines for infectious diseases in 2014, similar to last year, are new direct-acting oral antiviral and interferon-free oral regimens that are expected to be approved in 2014 and 2015 for HCV infection; these include the oral drugs faldaprevir, asunaprevir, and vaniprevir, as well as an all-oral regimen that combines daclatasvir and asunepravir and can be used without ribavirim. This regimen was granted a breakthrough therapy status on February 24, 2014 (Table 3). New HIV medications are being added to the current classes. The HIV pipeline includes combination therapies, new single-tablet regimens, and injectable therapies (Table 3). Cystic Fibrosis Cystic fibrosis is a rare disease, and therefore the drugs approved for this condition are categorized as orphan drugs. There are currently 8 agents in the pipeline for

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Table 3 Late-Phase Specialty Drugs in the Pipeline: Key Clinical Categories, Excluding Cancer Development stage/ Drug name Manufacturer Therapeutic category/route/class comments Lipid disorders Alirocumab

Regeneron/Sanofi

PCSK9 protein inhibitor for hypercholesterolemia; IV/SC

Phase 3 trials; approval expected 2016+

Evolocumab (AMG 145)

Amgen/Astellas

PCSK9 protein inhibitor for hyperlipidemia; SC

Phase 3 trials; approval expected 2016+

RN316

Pfizer

PCSK9 protein inhibitor for hyperlipidemia; SC

Phase 3 trials; approval expected 2016+

Alemtuzumab (Lemtrada)

Genzyme/Bayer

Humanized monoclonal antibody for MS; IV

FDA requested more information: 12/30/2013

Daclizumab (Zenapax)

Biogen Idec

Humanized monoclonal antibody for relapsing remitting; SC

Phase 3 trials; approval expected 2015

Laquinimod (Nerventa)

Active Biotech/ Teva

Immunomodulator for MS; oral

Phase 3 trials; approval expected 2016

Masitinib

AB Science

Tyrosine kinase inhibitor for MS; oral

Phase 3 trials; approval expected 2016

Ocrelizumab

Genentech/Roche

Humanized monoclonal antibody for MS; IV

Phase 3 trials; approval expected 2016

Peginterferon beta-1a (Plegridy)

Biogen Idec

Pegylated compound for relapsing remitting MS; SC

BLA filed: 5/2013 PDUFA: 5/19/2014

Multiple sclerosis

Inflammatory/rheumatic diseases Apremilast

Celgene

PDE4 inhibitor for psoriatic arthritis; oral

PDUFA: 3/21/2014

Baricitinib

Incyte/Lilly

JAK inhibitor for RA; oral

Phase 3 trials; approval expected 2014

Belimumab (Benlysta)

GlaxoSmithKline

Human monoclonal antibody for lupus; SC

Phase 3 trials; approval expected 2015

Briakinumab (Ozespa)

Abbott

Human monoclonal antibody for psoriasis; SC

Completed phase 3 trials; approval expected 2015

Brodalumab

Amgen

Human monoclonal antibody for psoriasis; SC

Phase 3 trials; approval expected 2015

Rigerimod (Lupuzor)

ImmuPharma

Polypeptide for lupus; SC

Phase 3 trials; approval expected 2015

Rilonacept (Arcalyst)

Regeneron

IL-1 blocker for gout flares; oral

Phase 3 trials; approval expected 2014

Sarilumab

Regeneron/Sanofi

Human monoclonal antibody for RA; SC

Phase 3 trials; approval expected 2014

Secukinumab

Novartis

IL-17A inhibitor for psoriasis and RA; SC

Phase 3 trials; approval expected 2015

Tofacitinib (Xeljanz)

Pfizer

JAK inhibitor for psoriatic arthritis; oral

Phase 3 trials; approval expected 2015

Vedolizumab

Takeda Pharmaceuticals

Monoclonal antibody for ulcerative colitis and Crohnâ&#x20AC;&#x2122;s disease; IV

PDUFA: 5/20/2014

Phase 3 trials; approval expected 2017

Pulmonary arterial hypertension Beraprost-314d

United Therapeutics

Pulmonary arterial hypertension; oral

Selexipag

Actelion

Prostacyclin receptor agonist for pulmonary Phase 3 trials; approval arterial hypertension; oral expected 2015

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Table 3 Late-Phase Specialty Drugs in the Pipeline: Key Clinical Categories, Excluding Cancer (Continued) Development stage/ Drug name Manufacturer Therapeutic category/route/class comments Infectious diseases HIV Atazanavir + cobicistat

Bristol-Myers Squibb/Gilead

Protease inhibitor/booster for HIV; oral

Phase 3 trials; approval expected 2015

Dolutegravir/abacavir/ lamivudine

ViiV

Integrase inhibitor/NRTI single-tablet regimen for HIV; oral

NDA filed: 10/22/2013; approval expected 2014

Prezista/TAF/emtriva/ cobicistat

Tibotec/Gilead

Protease inhibitor/NRTI/NRTI/booster single-tablet regimen for HIV; oral

Expected approval 2014

ABT-450

AbbVie/Enanta

Protease inhibitor for HCV; oral

Phase 3 trials; approval expected 2015

Asunaprevir

Bristol-Myers Squibb

Protease inhibitor for HCV; oral

Phase 3 trials; approval expected 2015

Daclatasavir + asunaprevir combination

Bristol-Myers Squibb

Replication complex inhibitor + Proteasome inhibitor for HCV; oral

Breakthrough therapy: 2/24/2014; all-oral regimen

Faldaprevir

Boehringer Ingelheim

Protease inhibitor for HCV; oral

Phase 3 trials; approval expected 2014

Vaniprevir

Merck

Protease inhibitor for HCV; oral

Phase 3 trials; approval expected 2016

Conestat alfa (Ruconest)

Pharming/ Santarus

Recombinant human C1 inhibitor for hereditary angioedema; IV

PDUFA: 4/16/2014

Siltuximab

Janssen

Anti–IL-6 monoclonal antibody for multicentric Castleman disease; IV

BLA filed: 9/3/2013

Hepatitis C

Miscellaneous orphan drugs

BLA indicates Biologic License Application; FDA, US Food and Drug Administration; HCV, hepatitis C virus; IL, interleukin; IV, intravenous; JAK, Janus kinase; MS, multiple sclerosis; NDA, New Drug Application; NRTI, nucleoside reverse transcriptase inhibitor; PCSK9, proprotein convertase subtilisin kexin 9; PDE-4, phosphodiesterase 4; PDUFA, Prescription Drug User Fee Act; RA, rheumatoid arthritis; SC, subcutaneous.

this condition that are expected to be approved between 2014 and 2016, in addition to the new expanded use for the oral therapy ivacaftor (Kalydeco), which is expected to receive FDA approval at the end of March 2014. Ivacaftor was the first drug to receive 2 breakthrough therapy designations in January 2013, soon after the FDA enacted the new law. It was the first drug that showed benefit in treating the underlying disease in some patients with cystic fibrosis. The current cystic fibrosis pipeline includes 3 new oral therapies—ataluren, lumacaftor, and VX-661; 2 nebulizers for inhalation, levofloxacin (Aeroquin) and amikacin (Arikace); 2 dry powder inhalers, vancomycin (AeroVanc) and mannitol (Bronchitol); and 1 nasal inhalation solution, sinapultide (Aerosurf).

Cancer Continuing the trend of the past few years, cancer

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remains the top clinical category in the specialty pharmaceutical pipeline in 2014. Table 4 lists the key specialty drugs for solid tumors and for hematologic malignancies currently in late stages of development. Furthermore, many of the recently approved specialty cancer drugs are being submitted to the FDA again for new indications. The most recent example of this is ibrutinib (Imbruvica), which was approved for the treatment of patients with mantle-cell leukemia in late 2013 and was then approved in January 2014 for the treatment of patients with chronic lymphocytic leukemia. Very promising results have been shown with some of the drugs in the pipeline for cancer, including idela lisib for non-Hodgkin lymphoma; ramucirumab for gastric cancer, which was granted priority review in February 2014; LKD378 for non–small-cell lung cancer, with breakthrough therapy designation; daratumumab for multiple myeloma; lambrolizumab for advanced

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Table 4 Key Specialty Cancer Drugs in Late-Stage Development Development stage/ comments

Drug name

Manufacturer

Therapeutic category/route/class

Algenpantucel-L

NewLink Genetics

Vaccine for pancreatic cancer; intradermal injection

Phase 3 trials

Belinostat

Spectrum Pharmaceuticals/ TopoTarget

Histone deacetylase inhibitor for relapsed or refractory peripheral T-cell lymphoma; IV, oral

PDUFA: 8/9/2014

Custirsen

OncoGenex

Second-generation phosphorothioate antisense oligonucleotide for prostate cancer; IV

Phase 3 trials

Daratumumab

Janssen

CD38-targeting monoclonal antibody for refractory multiple myeloma; IV

Phase 3 trials; approval expected 2014

Idelalisib

Gilead

PI3K delta inhibitor for indolent nonHodgkin lymphoma and chronic lymphocytic leukemia; oral

NDA filed: 1/13/2014 PDUFA: 5/11/2014

Lambrolizumab (MK-3475)

Merck

Anti–PD1-antibody (immunotherapy) for advanced melanoma; IV

Breakthrough therapy designation; approval expected 2014

LKD378

Novartis

Selective ALK inhibitor for NSCLC; oral

Breakthrough therapy designation; approval expected 2014

Masitinib

AB Science

Tyrosine-kinase inhibitor for gastrointestinal stromal tumor; oral

Phase 3 trials

NGR-hTNF (Arenegyr)

MolMed

Vascular targeting agent for mesothelioma; IV

Phase 3 trials

Nintedanib

Boehringer Ingelheim

Angiokinase inhibitor for NSCLC; oral

Phase 3 trials

Niraparib

Tesaro

PARP inhibitor for breast cancer; oral

Phase 3 trials

Orteronel

Takeda Pharmaceuticals

CYP17 inhibitor for prostate cancer; oral

Phase 3 trials

Palbociclib

Pfizer

CDK inhibitor for breast cancer; oral

Phase 3 trials; approval expected 2014

Panobinostat

Novartis

Pan-deacetylase inhibitor for multiple myeloma; oral

Phase 3 trials

Rilimogene galvacirepvec/ rilimogene glafolivec (ProstVac)

Bavarian Nordic

Vaccine for prostate cancer; SC

Phase 3 trials

Ramucirumab

Lilly

Monoclonal antibody for gastric cancer; IV

FDA granted priority review in 2014; improved survival in NSCLC

Rindopepimut Vaccine

Celldex

Peptide vaccine for glioblastoma; intradermal injection

Phase 3 trials

Talimogene laherparepvec

Amgen

Oncolytic herpes simplex virus vaccine for malignant melanoma; intralesional injection

Phase 3 trials

Tasquinimod

Active Biotech

Allosteric modulator of histone deacety lase 4 for prostate cancer; oral

Phase 3 trials

ALK indicates anaplastic lymphoma kinase; BLA, Biologic License Application; CDK, cyclin-dependent kinase; CYP17, cytochrome P-450 17; FDA, US Food and Drug Administration; IV, intravenous; NDA, New Drug Application; NSCLC, non– small-cell lung cancer; PARP, poly adenosine diphosphate-ribose polymerase; PDUFA, Prescription Drug User Fee Act; PD1, programmed-death 1; PI3K, phosphoinositide 3-kinase.

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melanoma, which received breakthrough therapy designation; and palbociclib for breast cancer. All of these agents are expected to be approved in 2014. If they do indeed receive FDA approval this year, and if drugs already on the market receive new indications for other types of cancers, 2014 could be a record year for cancer drug approvals. This growth in cancer therapies is likely to continue in the future, even while some cancer therapies are reaching new successes in tumor eradication or near eradication––a feat that was unthinkable not too long ago.

Conclusion Judging by the current drug pipeline, encompassing both traditional and specialty medicines, it is safe to presume that cancer and diabetes will remain top targets for innovation in drug development, as new mechanisms of action, novel delivery systems, and as yet unknown therapeutic classes are being developed and introduced to the market. With the increasing role of genomics and drug sequencing, the 2014 drug pipeline promises improved patient outcomes, accompanied by the ever-greater challenge of how to pay for these lifesaving but expensive medicines. Issues of provider reimbursement and Medicare Part D regulations further complicate the question of value-based utilization of drug therapy. Another challenge in the specialty pharmaceutical pipeline is that while many new, often small biotech-

nology companies enter the specialty drug development arena, large pharmaceutical companies must look for new ways to innovate in the face of such increasing competition, increased economic pressures, and looming patent losses. In the face of greater competition fostered in part by new biotechnologies, innovation continues to hold the golden key for success in the pharmaceutical pipeline. n Acknowledgment I would like to thank Lilly Ostrovsky for her help in creating the tables for this article. Author Disclosure Statement Ms Buffery reported no conflicts of interest.

References

1. Pharmaceutical Research and Manufacturers of America. Medicine in Development for Diabetes. 2014 Report. www.phrma.org/sites/default/files/pdf/diabetes2014. pdf. Accessed March 2, 2014. 2. US Food and Drug Administration. Center for Drug Evaluation and Research. Approved drugs 2013. January 2014. www.fda.gov/downloads/drugs/development approvalprocess/druginnovation/ucm381803.pdf. Accessed February 28, 2014. 3. Specialty Pharma Journal. Specialty drugs account for more than half of approved drugs in 2013. Updated January 3, 2014. www.specialtypharmajournal.com/index. php?option=com_content&view=article&id=4655:specialty-drugs-account-formore-than-half-of-approved-drugs-in-2013&catid=403:business-news&Itemid=841. Accessed February 5, 2014. 4. Tharaldson A. Specialty pharmaceuticals in development. Presented at: Academy of Managed Care Pharmacy 2013 NEXUS Meeting; October 17, 2013; San Antonio, CA. 5. Pharmaceutical Research and Manufacturers of America. Biologics research promises to bolster future of medicine: more than 900 biologic medicines and vaccines in development. March 11, 2013. www.phrma.org/media/releases/biologics-researchpromises-bolster-future-medicine. Accessed February 17, 2014.

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Abraxane (nab-Paclitaxel) Receives a New Indication for the Treatment of Patients with Metastatic Pancreatic Cancer By Lisa A. Raedler, PhD, RPh, Medical Writer

he American Cancer Society has estimated that approximately 45,220 new cases of pancreatic cancer would be diagnosed in the United States in 2013 and approximately 38,460 patients would die of pancreatic cancer in 2013.1 Despite being the tenth most common cancer, pancreatic cancer is the fourth most common cause of cancer deaths, in part because a large majority of patients present with nonresectable advanced disease.2,3 Although adjuvant chemotherapy with gemcitabine or with 5-fluorouracil (5-FU) confers a small survival advantage for patients with early-stage pancreatic cancer, the vast majority will relapse and die from their disease.3 Only approximately 4% of patients with pancreatic cancer will be alive and disease free at 5 years.3 With statistics like these, there is clearly an urgent unmet need for more effective therapies for patients with pancreatic cancer.4 Because pancreatic cancer results in substantial morbidity and mortality, the financial burden associated with patient management can be significant. US researchers recently reported the direct medical costs of pancreatic cancer treatment based on an analysis of a population-based cohort of Medicare beneficiaries.5 Using the 2001 to 2007 Surveillance, Epidemiology, and End Results–Medicare database, more than 15,000 patients (aged ≥66 years) with pancreatic cancer were identified.5 The total mean direct medical cost was $65,500, with greater costs ($134,700) for patients with resectable locoregional pancreatic cancer compared with patients with unresectable locoregional or distant disease ($65,300 and $49,000, respectively).5 Hospitalizations and cancer-directed procedures were the largest cost drivers in this analysis.5 Demographic trends and the increasing use of targeted therapies are likely to affect treatment patterns, as well as increase the costs of managing pancreatic cancer in the future, the investigators suggest.5 Today, the only potentially curative technique for pancreatic cancer is surgical resection.6 Cytotoxic chemotherapy and radiation therapy are relevant options in the neoadjuvant and adjuvant settings, as well as in patients with unresectable and metastatic disease. The

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current National Comprehensive Cancer Network (NCCN) guidelines for patients with metastatic or locally advanced unresectable pancreatic cancer include several category 1 recommendations, including clinical trials, the 4-drug regimen FOLFIRINOX (leucovorin, 5-FU, irinotecan, and oxaliplatin), the combination of gemcitabine and erlotinib, other gemcitabine-based combinations, and gemcitabine monotherapy.6 For patients whose performance status is poor (Eastern Cooperative Oncology Group 2 or higher), the NCCN suggests gemcitabine monotherapy or best supportive care.6

Abraxane a New Treatment Option In September 2013, the US Food and Drug Administration (FDA) approved the cytotoxic agent nab-paclitaxel (paclitaxel protein-bound particles for injectable suspension, albumin-bound; Abraxane; Celgene Corporation) for first-line treatment of patients with metastatic adenocarcinoma of the pancreas in combination with gemcitabine.7 Nab-paclitaxel is also approved for firstline treatment of locally advanced or metastatic non– small-cell lung cancer in combination with carboplatin and for breast cancer after failure with combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy.8 The FDA’s approval of nab-paclitaxel for advanced pancreatic cancer was based on the demonstration of a significant increase in overall survival (OS) in a phase 3 multicenter clinical trial of 861 patients with metastatic pancreatic cancer conducted in more than 150 centers throughout the world.9,10 “This large, randomized, international, phase 3 study showed that the nab-paclitaxel plus gemcitabine led to a significant improvement in survival at all time points,” said Daniel D. Von Hoff, MD, Physician-in-Chief, Translational Genomics Research Institute, Phoenix, AZ, and Chief Scientific Officer, Virginia G. Piper Cancer Center Clinical Trials at Scottsdale Healthcare, AZ. “The rate of survival was significantly higher in the nab-paclitaxel-gemcitabine group than in the gemcita bine group,” he added. Dr Von Hoff served as the principal investigator of the Metastatic Pancreatic Adenocar-

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Figure Kaplan-Meier Curve for Overall Survival (ITT Population) 1.0

Nab-paclitaxel plus gemcitabine Gemcitabine

Proportion of survival, %

0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0

0 3 6 9 12 15 18 21 24 27 30 33 36 39 Patients at risk, N Time, months Nab-paclitaxel plus 431 357 269 169 108 67 40 27 16 gemcitabine

9 4 1 1 0

430 340 220 124 69 40 26 15 7 3 1 0 0 0 Gemcitabine 15

Patients were treated until disease progression. Patients with pancreatic cancer who had received cytotoxic doses of gemcitabine or any other chemotherapy in the adjuvant setting were excluded from study participation.9 The primary end point of this trial was OS duration. Secondary end points included progression-free survival (PFS), overall response rate (ORR), and safety.9 Tumor scans were assessed every 8 weeks by investigators, as well as by independent reviewers.9

Patient Population The median age of patients enrolled in this phase 3 clinical trial was 63 years.9 Of the patients, 10% were aged ≥75 years.9 The majority of the patients were male (58%) and white (87%), with Karnofsky performance scores of 80 to 100 (92%).9 Overall, 46% of the patients had 3 or more metastatic sites, and most patients (84%) had liver metastasis.9 Demographic and clinical characteristics were well balanced between the 2 study arms at baseline.9

REFERENCES

Efficacy ITTDepartment indicates intent-to-treat. of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165. The OS benefit, the study’s primary end point, was REFERENCES Reprinted from Abraxane prescribing information; 2013. REFERENCES 2.occupational OSHA Technical Manual,toTED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to U.S. Hazardous Drugs. OSHA, NIOSH Alert: Preventing exposures antineoplastic and other hazardous drugs in healthcare settings. 2004. 1. NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S.

significant for patients receiving the combination of nabpaclitaxel and gemcitabine. In the intent-to-treat populacinoma Clinical Trial (MPACT), which included sites tion, the median OS was 8.5 months (95% confidence in North America, Europe, and Australia. interval [CI], 7.89-9.53) for the nab-paclitaxel plus gemcitabine group compared with 6.7 months (95% CI, 6.01Mechanism of Action 7.23) for the gemcitabine monotherapy group (hazard HOW SUPPLIED/STORAGE AND HANDLING Nab-paclitaxel is a cytotoxic agent that stabilizes micro16.2 Storage ratio for death, 0.72; 95% CI, 0.62-0.83; P <.001).9 The HOW SUPPLIED/STORAGE AND HANDLING 1 How Supplied Store the vials in original cartons at 20 C to 25 C (68 F to 77 F). Retain in the original package to protect from bright light. 1 How Supplied tubules in cancer cells and protects them from disassembly. Figure illustrates these significant OS advantage findings duct No.: 103450 16.3 Handling and Disposal 103450

Cduct No.:No.: 68817-134-50 100 mgfor of paclitaxel in a single-use vial,ofindividually in abecarton.

handling and disposal anticancer packaged drugs should considered. Several guidelines on this subject have C No.: 68817-134-50 Procedures 100This mg of proper paclitaxel in a single-use vial, individually packaged in a carton.

stability inhibits normal microtubule network in the combination of nab-paclitaxel and gemcitabine been published [see References (15)]. There is no general agreement that all of the procedures recommendedfuncin the guidelines are 2 Storage necessary or appropriate. 8 2 theStorage re vials in original cartons at 20 C to 25 C (68 Fare to 77 essential F). Retain in the original package to protect from bright light. Compared with tions that for cell division. using a Kaplan-Meier curve. Of note, these survival curves re the vials in original cartons at 20 C to 25 C (68 F to 77 F). Retain in the original package to protect from bright light. 3 Handling and Disposal the original formulation of paclitaxel, nab-paclitaxel or separated early, with a median improvement of 1.8 3 Handling and Disposal cedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have for proper handling and disposal shouldthat be all considered. guidelines on this subject have are ncedures published [see References (15)]. There of is anticancer no general drugs agreement of the procedures recommended in the guidelines albumin-bound paclitaxel isSeveral a solvent-free formulation months and an improvement of 3.4 months at the time en published [see References (15)]. There is no general agreement that all of the procedures recommended in the guidelines are essary or appropriate. cessary or appropriate. that utilizes albumin to deliver the taxane, resulting in point 20when 25% of the patients were alive.9 In addition, Reference ID: 3369272 11 survival rates were significantly higher in the nab-pac an advantageous pharmacokinetic profile. litaxel plus gemcitabine group than in the gemcitabine 20 Dosing and Administration monotherapy group at 1 year (35% vs 22%, respectively) 20 3369272 3369272 For patients with newly diagnosed metastatic pancreand 2 years (9% vs 4%, respectively).9 The secondary end points of PFS and ORR were also atic cancer, the recommended dose and schedule for significantly improved in the nab-paclitaxel plus gemci nab-paclitaxel is 125 mg/m2 intravenously over 30 to 40 minutes on days 1, 8, and 15 of each 28-day cycle.8 Gemtabine arm relative to the gemcitabine monotherapy arm. citabine should be administered on days 1, 8, and 15 of The median PFS was 5.5 months in patients receiving the each 28-day cycle immediately after nab-paclitaxel.8 nab-paclitaxel plus gemcitabine combination (95% CI, 4.5-5.9) versus 3.7 months for the patients receiving gemPhase 3 Clinical Trial citabine monotherapy (95% CI, 3.6-4).9 At 1 year, the The multicenter MPACT trial enrolled 861 patients PFS rate was 16% in the group receiving nab-paclitaxel with newly diagnosed advanced pancreatic cancer. Paplus gemcitabine compared with 9% in the group receivtients were randomly assigned to nab-paclitaxel 125 mg/ ing gemcitabine.9 According to independent review, the 2 2 ORR was also significantly improved with nab-paclitaxel m followed by gemcitabine 1000 mg/m on days 1, 8, and 15 every 4 weeks or to gemcitabine monotherapy 1000 combined with gemcitabine relative to gemcitabine mg/m2 weekly for 7 of 8 weeks (cycle 1), and then on days alone (23% vs 7%; P <.001).9 The Table summarizes 1, 8, and 15 every 4 weeks (cycle 2 and subsequent cycles). these data and relevant statistical analyses.

NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugsand in healthcare U.S.for http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html partment of Health and1999. Human Services, Public Health Service, Centers for Disease Control Prevention,settings. National2004. Institute partment Health andHealth, Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for upationalofSafety and DHHS (NIOSH) Publication No. 2004-165. 3. American Society of Health-System Pharmacists. cupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165. (2006) ASHP Guidelines on Handling Hazardous Drugs. Am J Health-Syst Pharm. 2006;63:1172-1193. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 9. http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html 4. Polovich, M., White, J. M., & Kelleher, L.O. (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for 99. http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html practice (2nd. ed.) Pittsburgh, PA: Oncology Nursing Society. merican Society of Health-System Pharmacists. (2006) ASHP Guidelines on Handling Hazardous Drugs. Am J10 Health-Syst American Society of Health-System Pharmacists. (2006) ASHP Guidelines on Handling Hazardous Drugs. Am J Health-Syst rm. 2006;63:1172-1193. 16 HOW SUPPLIED/STORAGE AND HANDLING arm. 2006;63:1172-1193. olovich, M., White, J. M., L.O. (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for 16.1& Kelleher, How Supplied Polovich, White, J. Product M., &PA: Kelleher, L.O.Nursing (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for ctice (2nd.M., ed.) Pittsburgh, Oncology Society. No.: 103450

ctice (2nd. ed.) Pittsburgh, Nursing Society. NDC PA: No.:Oncology 68817-134-50 100 mg of paclitaxel in a single-use vial, individually packaged in a carton.

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Safety and Serious Adverse Events In the nab-paclitaxel plus gemcitabine group, the me dian duration of treatment was 3.9 months (0.1-21.9 months) compared with 2.8 months (0.1-21.5 months) in the gemcitabine group.9 The median relative dose intensity rates, defined as the proportion of the administered cumulative dose relative to the planned cumulative dose, in the group receiving nab-paclitaxel plus gemcitabine were 81% for nab-paclitaxel and 75% for gemcitabine.9 In the gemci tabine monotherapy group, the median relative dose intensity was 85%.9 The most frequently reported nonhematologic adverse events (AEs) related to treatment with the nabpac litaxel plus gemcitabine combination included fatigue (54%), alopecia (50%), and nausea (49%).9 Grade 3 or higher neutropenia, leukopenia, fatigue, and peripheral neuropathy were reported more often in the nab- paclitaxel plus gemcitabine group compared with the gemcitabine monotherapy group.9 The incidence rates of anemia (13% in the nab-paclitaxel plus gemcitabine group vs 12% in the gemcitabine monotherapy group) and thrombocytopenia (13% vs 9%) were similar in the 2 treatment arms.9 Febrile neutropenia was rare in both groups (3% vs 1%).9 Peripheral neuropathy was the most notable difference in AEs between the 2 treatment groups.9 It was cumulative and rapidly reversible in most patients after temporary discontinuation of nab-paclitaxel and subsequent dose reduction. None of the patients experienced grade 4 peripheral neuropathy. The rate of discontinuation of nab-paclitaxel secondary to peripheral neuropathy (all grades) was 8%.9 Overall, 10% of the patients had dose reduction of nab-paclitaxel as a result of peripheral neuropathy.9 In the MPACT trial, 50% of the patients receiving nab-paclitaxel plus gemcitabine and 43% of the gemci tabine recipients experienced serious AEs.9 Fatal events were reported for 4% of the patients in each treatment group.9 Patients in the nab-paclitaxel plus gemcitabine group were more likely to experience pneumonitis (4% vs 1%, respectively), as well as sepsis (5% vs 2%, respectively) compared with the gemcitabine group.9 A limitation of the MPACT study was that quality of life was not assessed.9 Warnings and Precautions Hematologic effects. Bone marrow suppression—primarily neutropenia—is a dose-dependent and dose-limiting toxicity associated with nab-paclitaxel. In the phase 3 trial comparing nab-paclitaxel and gemcitabine with gemcitabine monotherapy in metastatic pancreatic cancer, grade 3 to 4 neutropenia occurred in 38% of patients receiving the combination.8,9

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elected Efficacy Results from the MPACT Study in Patients Table S with Adenocarcinoma of the Pancreas (ITT Population) Nab-paclitaxel 125 mg/m2 and gemcitabine Gemcitabine Efficacy end point (N = 431) (N = 430) Progression-free survival Death or progression, N (%) Median progression-free survival, mo 95% CI HR (95% CI)

277 (64)

265 (62)

5.5

3.7

4.5-5.9

3.6-4.0

0.69 (0.58-0.82)

P value

<.001

Overall response rate Confirmed complete or partial overall response, N (%) 95% CI P value

99 (23)

31 (7)

19%-27%

5%-10% <.001

CI indicates confidence interval; HR, hazard ratio; ITT, intent-totreat; MPACT, Metastatic Pancreatic Adenocarcinoma Clinical Trial. Source: Von Hoff DD, et al. N Engl J Med. 2013;369:1691-1703.

Patients with pancreatic cancer who receive nab-pac litaxel and gemcitabine should undergo frequent complete blood cell counts to monitor for myelotoxicity, including before drug dosing on days 1, 8, and 15.8 The combination of nab-paclitaxel and gemcitabine should not be given to patients with pancreatic cancer whose baseline absolute neutrophil count (ANC) is <500 cells/ mm3 or whose platelets are <50,000 cells/mm3.8 Initiation of the next treatment cycle should be delayed if ANC is <1500 cells/mm3 or if the platelet count is <100,000 cells/mm3 on day 1.8 Treatment can be resumed with appropriate dose reduction if recommended.8 Nervous system. Sensory neuropathy is also a dose- dependent and dose-limiting toxicity associated with nab-paclitaxel. Grade 1 or 2 sensory neuropathy typically does not require dose modification.8 If grade 3 or higher sensory neuropathy develops in a patient with pancreatic cancer, withhold nab-paclitaxel treatment until it resolves to grade 1 or lower.8 The dose of nab-paclitaxel should be reduced in all subsequent treatment courses.8 Sepsis. Sepsis with or without neutropenia occurred in 5% of patients with pancreatic cancer who received nab-paclitaxel in combination with gemcitabine.8,9 Risk factors for severe or fatal sepsis included biliary obstruction and the presence of a biliary stent.8 Patients who become febrile regardless of ANC should receive treatment with broad spectrum antibiotics.8 If febrile neutro-

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penia is detected, nab-paclitaxel and gemcitabine should be withheld until fever resolves and ANC increases to ≥1500 cells/mm3.8 Treatment with nab-paclitaxel can then be resumed at reduced dose levels.8 Pneumonitis. Of patients with pancreatic cancer, 4% receiving nab-paclitaxel in combination with gemci tabine experienced pneumonitis, including some fatal cases.8,9 Patients exhibiting signs and symptoms of pneumonitis should not receive nab-paclitaxel and gemcita bine during evaluation. If an infectious etiology is ruled out and pneumonitis is diagnosed, treatment with nab-paclitaxel and gemcitabine should be permanently discontinued.8

For patients with advanced pancreatic cancer, the combination of nab-paclitaxel and gemcitabine offers clinically and significant efficacy benefits, with an acceptable tolerability profile. Hypersensitivity. Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported with nab-paclitaxel. Patients who experience a severe hypersensitivity reaction to nab- paclitaxel should not be rechallenged.8 Hepatic impairment. Dose adjustments are not necessary for patients with mild hepatic impairment.8 How ever, nab-paclitaxel should be withheld if aspartate aminotransferase is greater than 10 times the upper limit of normal (ULN) or if bilirubin is greater than 5 times the ULN.8 The starting dose of nab-paclitaxel should be reduced in patients with moderate-to-severe hepatic impairment.8 Dose reductions or discontinuation may be appropriate if severe hematologic, neurologic, cutaneous, or gastrointestinal toxicities occur.8 Albumin (human). Because nab-paclitaxel contains

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human albumin, a derivative of human blood, it carries a remote risk for viral disease transmission.8 Use in pregnancy. Based on animal studies, nab-pac litaxel can cause fetal harm when administered to a pregnant woman. Women of childbearing age should avoid becoming pregnant while receiving nab-paclitaxel.8

Conclusion For patients with advanced pancreatic cancer, the combination of nab-paclitaxel and gemcitabine offers clinically and significant efficacy benefits, with an acceptable tolerability profile. Experts suggest that this com bination may represent an alternative to FOLFIRINOX in patients who are unlikely to tolerate the toxicities associated with this regimen.10 Studies are under way to elucidate the optimal dosing schedule of the nab-pac litaxel and gemcitabine combination for pancreatic cancer, as well as the efficacy and safety of triple-drug regimens combining these 2 cytotoxic drugs with novel targeted agents.12 n References

1. American Cancer Society. What are the key statistics about pancreatic cancer? Revised September 6, 2013. www.cancer.org/cancer/pancreaticcancer/detailedguide/pancreatic-can cer-key-statistics. Accessed October 16, 2013. 2. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62:10-29. 3. Vincent A, Herman J, Schulick R, et al. Pancreatic cancer. Lancet. 2011;378:607-620. 4. Rosenberg JD, Sigal D. A path toward pancreatic cancer predictive biomarkers. Per Med Oncol. 2013;2:182-190. 5. O’Neill CB, Atoria CL, O’Reilly EM, et al. Costs and trends in pancreatic cancer treatment. Cancer. 2012;118:5132-5139. 6. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): pancreatic adenocarcinoma. Version 1.2013. April 9, 2013. www. nccn.org/professionals/physician_gls/pdf/pancreatic.pdf. Accessed October 21, 2013. 7. US Food and Drug Administration. Drugs: paclitaxel. Updated September 9, 2013. www.fda. gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm367613.htm. Accessed October 21, 2013. 8. Abraxane (paclitaxel protein-bound particles for injectable suspension) (albumin bound) [prescribing information]. Summit, NJ: Celgene Corporation; September 2013. 9. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369:1691-1703. 10. Translational Genomics Research Institute. Pancreatic cancer patient survival is ‘significantly higher’ with nab-paclitaxel, in study led by TGen and Scottsdale Healthcare. Press release. October 16, 2013. www.tgen.org/news/2013-media-releases/abraxane-improves- survival-of-pancreatic-cancer-patients.aspx#.Ul-8NWTwJ4Y. Accessed October 21, 2013. 11. Yardley DA. nab-Paclitaxel mechanisms of action and delivery. J Control Release. 2013;170:365-372. 12. ClinicalTrials.gov. Nab-paclitaxel pancreatic cancer. Search results. www.clinicaltrials. gov/ct2/results?term=nab-paclitaxel+pancreatic+cancer&Search=Search. Accessed October 21, 2013.

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March 2014

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Adempas (Riociguat): A Novel, First-in-Class

Therapy Approved for the Treatment of 2 Types of Pulmonary Hypertension By Lisa A. Raedler, PhD, RPh, Medical Writer

ulmonary hypertension is a serious and life-threatening condition that is caused by increased pressure on the pulmonary arteries. The World Health Organization (WHO) has divided pulmonary hypertension into 5 subgroups, including pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH), based on the causes and treatment options. PAH occurs when the blood pressure in the pulmonary arteries is high.1 Abnormal constriction of the pulmonary arteries impairs oxygen delivery to the body and exacerbates heart function. Over time, PAH progresses and can become life-threatening.1 PAH is a rare disease affecting 1 in 100,000 to 1 million people of all ages and ethnic backgrounds.1 The condition is more common in women than in men.1 The symptoms of PAH can be nonspecific, similar to those of other heart and lung problems. Common complaints of patients with PAH include chest pain, dizziness, fainting, fatigue, leg swelling, and weakness, as well as light-headedness and shortness of breath during physical activity.1 Although there is no cure for PAH, several treatment options are available, including medications and surgery, as well as lifestyle changes. The primary goals of PAH treatment are to reduce symptoms, slow disease progression, and improve quality of life.1 The medications used to manage PAH include endothelin receptor antagonists (ERAs), phosphodiesterase (PDE)-5 inhibitors, prostacy clins, anticoagulants, calcium channel blockers, diuretics, digoxin, and inhaled oxygen. Treatment decisions are based on multiple factors, including functional status severity, which ranks a patient’s ability to complete everyday tasks and ranges from class I (ie, no limitations) to class IV (ie, inability to perform any physical activity).1 Since their introduction, targeted therapies have improved survival, exercise capacity, functional capacity, and hemodynamics in patients with PAH.2 However, current treatments remain inadequate: mortality continues to be high (approximately 1.5%), and functional and hemodynamic impairment can remain significant for many patients with PAH.2 A recent study regarding the cost burden of PAH

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among privately insured Americans has demonstrated that PAH is a costly condition.3 In this 2011 study, patients with PAH incurred significantly higher costs as a result of their disease and the comorbidities associated with PAH. The average monthly direct costs were more than $2000 in patients with PAH compared with approximately $500 for patients without PAH.3 For patients with PAH, almost half (45%) of their monthly direct costs were associated with inpatient services, 38% were for outpatient and other services, and 15% were for prescription medications.3 CTEPH is a serious condition and is one of the leading causes of severe pulmonary hypertension.4 CTEPH occurs in 2% to 4% of patients who have had an acute pulmonary embolism (PE), and is characterized by mean pulmonary artery pressure of >25 mm Hg that continues for 6 months after a diagnosis of PE.5 Risk factors for CTEPH include thyroid disease, thrombophilia, and genetics.5 In CTEPH, pulmonary endarterectomy is the only option for cure.6 However, some patients are unable to undergo or decline surgery, whereas others are unable to access specialty centers.6

Adempas: A Novel Approach to Managing Pulmonary Hypertension On October 8, 2013, the US Food and Drug Administration (FDA) approved riociguat (Adempas, Bayer HealthCare) for the treatment of (1) adults with persistent and recurrent CTEPH (WHO group 4) after surgical treatment or inoperable CTEPH to improve exercise capacity and WHO functional class, and (2) for patients with PAH (WHO group 1) of unknown causes, inherited PAH, or PAH associated with connective tissue disease, to improve their exercise capacity, improve WHO functional class, and to delay the clinical worsening of PAH.7,8 Riociguat is the first agent approved by the FDA in a drug class known as soluble guanylate cyclase (sGC) stimulators.7 sGC helps arteries relax to increase blood flow and to decrease blood pressure.7 Norman Stockbridge, MD, PhD, Director, Division of Cardiovascular and Renal Drug Products in the FDA’s Center for Drug Evaluation and Research, recently discussed riociguat’s

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novelty, stating, “Adempas is the first in its drug class approved to treat pulmonary hypertension and the first drug of any class to be shown to be effective for patients with CTEPH.”7 The FDA approved riociguat under its priority review, which is an expedited 6-month process to enable access to drugs that may offer major advances in treatment.7 The FDA approval of riociguat for patients with CTEPH or PAH was based on demonstration of safety and efficacy in 2 phase 3 clinical trials known as the Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase–Stimulator Trial 1 (CHEST1) and the Pulmonary Arterial Hypertension Soluble Guanylate Cyclase–Stimulator Trial 1 (PATENT-1).6,7,9 The primary efficacy measure in both studies was change in 6-minute walk distance.6,9 When discussing the PATENT-1 study findings, principal investigator Hossein-Ardeschir Ghofrani, MD, Department of Internal Medicine, University Hospital Giessen and Marburg, Germany, stated, “The six-minute walk test is a key indicator for improved outcomes in patients with PAH and, therefore, the positive results of the PATENT-1 trial are encouraging.”10

Mechanism of Action sGC is an enzyme in the cardiopulmonary system. When nitric oxide (NO) binds to sGC, cyclic guanosine monophosphate (cGMP) is synthesized. In turn, cGMP, a signaling molecule, regulates intracellular processes that affect vascular tone, proliferation, fibrosis, and inflammation.8 Endothelial dysfunction, impaired synthesis of NO, and insufficient stimulation of the NO-sGC-cGMP pathway are associated with pulmonary hypertension.8 Riociguat has a dual mode of action. By stabilizing NO-sGC binding, riociguat sensitizes sGC to endogenous NO. Via a binding site that is independent of NO, riociguat also directly stimulates sGC. By stimulating the NO-sGC-cGMP pathway, riociguat increases the generation of cGMP and vasodilation.8 Dosing and Administration The initial dose of riociguat is 1 mg 3 times daily.8 Patients who cannot tolerate riociguat’s hypotensive effect can be started at a dose of 0.5 mg 3 times daily.8 Riociguat doses can be increased by 0.5 mg at 2-week intervals and up to a maximum dose of 2.5 mg 3 times daily, depending on the blood pressure level.8 Key Clinical Trials PATENT-1: Phase 3 Trial in PAH In this 12-week, phase 3, double-blind, clinical trial, investigators randomly assigned 443 patients with symptomatic PAH to receive placebo, riociguat in individual-

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ly adjusted doses of up to 2.5 mg 3 times daily (2.5-mg maximum group), or riociguat in individually adjusted doses that were capped at 1.5 mg 3 times daily (1.5-mg maximum group).9 Patients eligible for this protocol received no other treatment for PAH or were receiving ERAs or prostanoids at doses that had been stable for at least 90 days. Patients with PAH who were receiving PDE-5 inhibitors were excluded from the study.9 The primary end point of the PATENT-1 trial was change from baseline to the end of week 12 in distance walked in 6 minutes.9 The secondary efficacy end points measured changes from baseline to the end of week 12 in pulmonary vascular resistance, N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, WHO functional class, time to clinical worsening, Borg dyspnea score, quality of life using scores from 2 questionnaires, and safety.9 Patient population. Baseline characteristics of patients enrolled in PATENT-1 were well balanced among the 3 arms of the study. The majority of the patients (median age, 51 years) had idiopathic PAH and were WHO functional class II (42%) or III (53%).9 Overall, 44% of the patients were receiving ERAs, 6% were receiving prostanoid therapy, and 50% were receiving no other treatment for PAH.9 A total of 38 patients withdrew from the study before week 12 for various reasons.9 Efficacy. At the end of week 12, 6-minute walk distance for patients in the riociguat 2.5-mg maximum group increased from baseline by an average of 30 m compared with an average decrease of 6 m in the placebo group.9 This mean improvement of 36 m between the 2 study arms was statistically significant (95% confidence interval, 20-52; P <.001).9 Figure 1 compares the mean changes from baseline in the 6-minute walk distance with riociguat versus placebo in PATENT-1.8 Significant improvements were also observed with riociguat in secondary end points, including pulmonary vascular resistance, NT-proBNP levels, WHO functional class, time to clinical worsening, Borg dyspnea score, and quality-of-life variables.9 Safety. Frequently occurring serious adverse events (AEs) during the PATENT-1 study included syncope (1% of patients in the riociguat 2.5-mg maximum group vs 4% in the placebo group), worsening pulmonary hypertension (<1% vs 2%, respectively), chest pain (1% in both groups), and right ventricular failure (1% in both groups).9 In the riociguat 2.5-mg maximum group, drug-related serious AEs included 3 (1%) episodes of syncope and 1 case each of increased hepatic enzyme levels, dizziness, presyncope, acute renal failure, and hypotension (a total of 0.4% of patients).9 In the placebo group, single cases of diarrhea, presyncope, syncope, dyspnea, and worsen-

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CHEST-1: Phase 3 Clinical Trial in CTEPH In this 16-week, phase 3, multicenter, double-blind, placebo-controlled study, investigators randomly assigned 261 patients with inoperable CTEPH or persistent or recurrent pulmonary hypertension after pulmonary endarterectomy to placebo or to riociguat.6 Patients were excluded from the study if they had received an ERA, prostacyclin analog, PDE-5 inhibitors, or NO donor (such as amyl nitrite) within 3 months before the study.6 Riociguat was titrated over 8 weeks in 0.5-mg increments from 1 mg 3 times daily to a maximum of 2.5 mg 3 times daily. After titration to the appropriate dose, riociguat was maintained at that dose for another 8 weeks.6 At week 16, 77% of patients who remained in the study were taking the maximum (2.5 mg 3 times daily) riociguat dose.6 The primary end point in CHEST-1 was change in distance walked in 6 minutes from baseline to the end of week 16.6 Secondary end points included pulmonary vascular resistance, NT-proBNP levels, WHO functional class, time to clinical worsening, Borg dyspnea score, and scores from 2 quality-of-life questionnaires.6 Patient population. Baseline characteristics were well balanced between the placebo and riociguat groups.6 The median age of patients was 59 years, 66% were female, and 71% were Caucasian.6 The majority of patients were WHO functional class II (31%) or III (64%), and had inoperable CTEPH (72% of total patients).6 A total of 18 patients withdrew from the study before week 16.6 Efficacy. After 16 weeks of treatment, patients re ceiving riociguat demonstrated a significant mean improvement in 6-minute walk distance of 39 m.6 Patients receiving placebo showed a mean decrease in 6-minute

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Riociguat Placebo

Change from baseline to last visit in 6-minute walk distance, m

PATENT-2 Study The results from PATENT-2, a long-term extension study of PATENT-1, further supported the findings of the initial study regarding the efficacy of riociguat for patients with PAH. Among 215 patients who received up to 2.5 mg of riociguat 3 times daily, a mean (± standard deviation [SD]) increase of 53 m (± 62 m) compared with the baseline distance in PATENT-1 was observed after the first 12 weeks of PATENT-2.9

Figure 1 PATENT-1: Mean Change from Baseline in the 6-Minute Walk Distance

0 2 4 6 8 Baseline

Weeks

Source: Adempas (riociguat) tablets prescribing information; 2013.

Figure 2 CHEST-1: Mean Change from Baseline in the 6-Minute Walk Distance Riociguat Placebo

Change from baseline to last visit in 6-minute walk distance, m

ing pulmonary hypertension were reported (a total of 1% of patients).9 A total of 8 (3%) patients in the riociguat 2.5-mg maximum group and 9 (7%) patients in the placebo group withdrew from the study as a result of AEs.9 Of the 5 deaths that occurred during the PATENT-1 study (2 in the riociguat 2.5-mg maximum group, 3 in the placebo group), none were believed to be related to the study drug.9

50 40 30 20 10 0

Baseline 2 4 6 8

Weeks

Source: Adempas (riociguat) tablets prescribing information; 2013.

walk distance of 6 m.6 In addition, riociguat showed significant improvements in secondary end point parameters, including pulmonary vascular resistance, NT-proBNP levels, WHO functional class, and quality of life.6 Figure 2 compares mean changes from baseline in the 6-minute walk distance for the riociguat group with changes seen in the placebo group in CHEST-1.8 A total of 237 patients in CHEST-1 entered a longterm extension study, CHEST-2.6 Study assignments were concealed for the first 8 weeks followed by open- label treatment. Of the 237 patients, 182 received treat-

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Adverse Reactions Occurring More Frequently (≥3%) Table with Riociguat than with Placebo (Pooled from CHEST-1 and PATENT-1) Riociguat, % Placebo, % Adverse reactions (N = 490) (N = 214)

inhibitors sildenafil, tadalafil, and vardenafil, and nonspecific PDE inhibitors, including dipyridamole and theophylline. Riociguat use is also contraindicated concomitant with nitrates (including NO donors, such as amyl nitrite) in any form.8

Headache

Dyspepsia and gastritis

Dizziness

Nausea

Diarrhea

Hypotension

Vomiting

Anemia (including laboratory parameters)

Gastroesophageal reflux disease

Constipation

Warnings and Precautions Boxed warning. Riociguat carries a boxed warning indicating that the drug can harm a developing fetus and should not be used in pregnant women.8 Female patients using riociguat and prescribers of the drug must enroll in the Adempas Risk Evaluation and Mitigation Strategies program.8 Women taking riociguat must comply with pregnancy testing requirements and be counseled regarding the importance of contraception use while taking the medication.8 Pharmacies must be certified to dispense riociguat to eligible patients.8 Hypotension. Because riociguat reduces blood pressure, hypotension and ischemia may occur in patients with hypovolemia, severe left ventricular outflow obstruction, resting hypotension, autonomic dysfunction, and those who take concomitant antihypertensive or strong cytochrome P and P-glycoprotein/breast cancer resistance protein inhibitors.8 Bleeding. During clinical trials of riociguat, serious bleeding occurred in 2.4% of patients in the riociguat group and in none of the patients in the placebo group.8 Serious hemoptysis was observed in 5 (1%) patients taking riociguat and in none of the patients receiving placebo, with 1 event resulting in death.8 Other serious hemorrhagic events included 2 patients with vaginal hemorrhage, 2 patients with catheter-site hemorrhage, and 1 patient each with subdural hematoma, hematemesis, and intra-abdominal hemorrhage.8 Pulmonary veno-occlusive disease. Because vasodilators, including riociguat, can exacerbate symptoms of pulmonary veno-occlusive disease (PVOD), its use is not recommended for patients with this condition. If signs of pulmonary edema are noted and a diagnosis of PVOD is confirmed, treatment with riociguat should be discontinued.8

Source: Adempas (riociguat) tablets prescribing information; 2013.

ment for a median of 336 days.6 Exploratory analysis of the first 12 weeks of CHEST-2 showed additional increases in the 6-minute walk distance among patients who received riociguat in CHEST-1.6 A mean (± SD) increase of 63 m (± 64 m) over the baseline distance in CHEST-1 for these 129 patients was observed at week 12 of CHEST-2.6 Safety. The most frequently occurring serious AEs in CHEST-1 included right ventricular failure (3% of patients in each group), syncope (2% and 3% in the riociguat and placebo groups, respectively), and hemoptysis (2% of patients receiving riociguat).6 Drug-related serious AEs in the riociguat group included syncope in 3 patients, and gastritis, acute renal failure, and hypotension in 1 patient each.6 In the placebo group, syncope and trauma occurred in 1 patient each. Of the 7 patients who discontinued the study as a result of AEs, 5 patients were from the riociguat group and 2 were from the placebo group.6 Overall, 2 patients in the riociguat group died as a result of AEs: acute renal failure (which was deemed related to the study drug) and heart failure.6 In the placebo group, 3 patients died as a result of respiratory insufficiency, circulatory arrest, and cardiac arrest.6 The Table summarizes adverse reactions that occurred more frequently with riociguat compared with placebo using pooled data from CHEST-1 and PATENT-1.8

Contraindications The use of riociguat is contraindicated concomitant with any PDE inhibitors, including the specific PDE-5

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Use in Specific Populations Pregnancy. Riociguat is contraindicated in pregnant women. Patients who are using riociguat during pregnancy or become pregnant while using riociguat should be counseled about the potential risks to the fetus.8 Nursing mothers. Although it is not known whether riociguat is present in human milk, nursing or use of riociguat should be stopped, because of the potential for serious adverse reactions from riociguat in nursing infants.8 Pediatric use. The safety and efficacy of riociguat have not been established in pediatric patients.8

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Geriatric use. Clinical studies have demonstrated that there was no difference between the safety and efficacy of riociguat in patients aged ≥65 years and the safety and efficacy of riociguat in younger patients. However, the possibility of greater sensitivity of some older individuals cannot be dismissed.8 Females and males of reproductive age. Female patients of reproductive age should have a negative pregnancy test before starting treatment with riociguat, monthly during treatment, and 1 month after stopping treatment. Patients should contact their health provider if they become pregnant during treatment or suspect they may be pregnant. In addition, patients should be counseled about the potential hazards to the fetus.8 Female patients of reproductive potential must use contraception during treatment with riociguat and 1 month after treatment. A hormone or barrier method must be used in combination with a partner’s vasectomy. Healthcare providers should discuss pregnancy planning and prevention with their patients.8 Renal and hepatic impairment. The safety and efficacy of riociguat in patients with creatinine clearance of <15 mL/min or in patients on dialysis have not been demonstrated.8 The safety and efficacy of riociguat have not been demonstrated in patients with severe hepatic impairment.8

Conclusion Riociguat is the first in the novel drug class of sGC stimulators to demonstrate efficacy in 2 forms of pulmonary hypertension—CTEPH and PAH. It is the first pharmacologic therapy ever approved by the FDA for CTEPH, for which standard treatment until now has been pulmonary endarterectomy surgery. The FDA approval of riociguat offers a nonsurgical option for patients with CTEPH. In addition, riociguat provides a new oral treatment option, with a new mechanism of action, for patients with PAH. In an editorial discussing the results of PATENT-1 and PATENT-2, Stephen L. Archer, MD, Head of

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Medicine, Queen’s University, Kingston, Ontario, stated, “Riociguat appears to be safe and is a promising addition to the pharmacopeia for [WHO] Group 1

Riociguat is the first in the novel drug class of sGC stimulators to demonstrate efficacy in 2 forms of pulmonary hypertension—CTEPH and PAH. It is the first pharmacologic therapy ever approved by the FDA for CTEPH, for which standard treatment until now has been pulmonary endarterectomy surgery. pulmonary hypertension and potentially the first effective oral therapy for inoperable [WHO] Group 4 pulmonary hypertension.”11 n

References

1. American Lung Association. Pulmonary arterial hypertension. www.lung.org/ lung-disease/pulmonary-arterial-hypertension. Accessed January 28, 2014. 2. Galiè N, Manes A, Negro L, et al. A meta-analysis of randomized controlled trials in pulmonary arterial hypertension. Eur Heart J. 2009;30:394-403. 3. Kirson NY, Birnbaum HG, Ivanova JI, et al. Excess costs associated with patients with pulmonary arterial hypertension in a US privately insured population. Appl Health Econ Health Policy. 2011;9:293-303. 4. Hoeper MM, Mayer E, Simonneau G, Rubin LJ. Chronic thromboembolic pulmonary hypertension. Circulation. 2006;113:2011-2020. 5. Piazza G, Goldhaber SZ. Chronic thromboembolic pulmonary hypertension. N Engl J Med. 2011;364:351-360. 6. Ghofrani HA, D’Armini AM, Grimminger F, et al; for the CHEST-1 Study Group. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med. 2013;369:319-329. 7. US Food and Drug Administration. FDA approves Adempas to treat pulmonary hypertension. Press release. October 8, 2013. Updated October 10, 2013. www.fda. gov/newsevents/newsroom/pressannouncements/ucm370866.htm. Accessed January 28, 2014. 8. Adempas (riociguat) tablets [prescribing information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc; October 2013. 9. Bayer HealthCare. Bayer’s riociguat meets primary endpoint in pivotal phase III study in patients with pulmonary arterial hypertension. Press release. October 22, 2012. www.animalhealth.bayer.com/fileadmin/presslounge/att/2012-0466E.pdf. Accessed January 28, 2014. 10. Ghofrani HA, Galiè N, Grimminger F, et al; for the PATENT-1 Study Group. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013; 369:330-340. 11. Archer SL. Riociguat for pulmonary hypertension—a glass half full. N Engl J Med. 2013;369:386-388.

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Amitiza (Lubiprostone): The First Oral

Treatment Approved by the FDA for Opioid-Induced Constipation By Loretta Fala, Medical Writer

he opioid class of analgesic agents is sometimes used to treat pain in patients with noncancer pain, including chronic nociceptive or neuropathic pain.1 Careful consideration and monitoring are required with long-term opioid therapy, because of the adverse effects associated with these agents, the potential to develop tolerance to the opioid’s analgesic effect, and the potential for abuse or diversion.1 One of the most common adverse effects of long-term opioid therapy is opioid-induced constipation (OIC).2 OIC occurs because the opioids bind to peripheral opioid receptors in the gastrointestinal (GI) tract, causing the absorption of electrolytes (ie, chloride), subsequently reducing the volume of fluid in the small intestine and resulting in abnormal gut motility.2 Constipation may range from discomfort to severe enough to warrant discontinuation of opioid treatment.3 Based on data from the National Health and Wellness Survey of patients receiving opioids, patients with OIC reported significantly more physician visits (mean difference, 3.84 visits; P <.05) than patients without OIC. Moreover, patients with OIC reported more missed time from work, more impairment at work and in daily activities, and a significantly lower health-related quality of life than patients without OIC (P <.05).4 A cost analysis based on 197 patients receiving strong opioids during a 6-month period showed that the total cost per patient per month was significantly higher for patients with severe constipation than for patients with mild, moderate, or no constipation.5 The authors concluded that OIC causes considerable patient discomfort, impacts quality of life, and can limit effective pain treatment.5 In addition to behavioral or lifestyle changes, such as increasing dietary fiber, increasing fluid intake, and increasing physical activity, OIC treatment may require additional medications. These medications may include osmotic laxatives, cathartics (ie, lubricant, bulk, or stimulate), prostaglandins or prokinetic drugs, or others. In some cases, rectal interventions (ie, suppositories, enemas, or colonic irrigation) may be recommended.6 Methylnaltrexone bromide, an opioid receptor antagonist administered subcutaneously, is US Food and Drug

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Administration (FDA)-approved to treat OIC in patients with advanced illness (ie, cancer, chronic obstructive pulmonary disorder, Alzheimer’s disease) who are receiving palliative care when response to laxative therapy is not sufficient.7

First Oral Option for Opioid-Induced Constipation In April 2013, the FDA approved a supplemental indication for lubiprostone (Amitiza; Sucampo Phar maceuticals/Takeda Pharmaceuticals USA), a volumeactivated chloride channel (CIC-2) activator, for the treatment of OIC in adults with chronic noncancer pain. Lubiprostone is the first oral therapy to receive FDA approval for this indication.2 Lubiprostone was first approved by the FDA in 2006 for the treatment of chronic idiopathic constipation.8 In 2008, lubiprostone received FDA approval for another indication—the treatment of irritable bowel syndrome (IBS) with constipation in women aged ≥18 years— making it the first drug available in the United States for IBS with constipation.9 Mechanism of Action Lubiprostone is a locally acting chloride channel activator that enhances a chloride-rich intestinal fluid secretion without altering sodium and potassium concentrations in the serum. Lubiprostone specifically activates CIC-2, a normal constituent of the apical membrane of the human intestine, in a protein kinase A–independent fashion.10 By increasing intestinal fluid secretion, lubiprostone increases motility in the intestine, thereby facilitating the passage of stool and alleviating symptoms associated with chronic idiopathic constipation. Through its activation of apical CIC-2 channels in intestinal epithelial cells, lubiprostone bypasses the antisecretory action of opiates that results from suppression of secretomotor neuron excitability. The activation of CIC-2 by lubiprost one has also been shown to stimulate recovery of mucosal barrier function and reduce intestinal permeability via the restoration of tight junction protein complexes in ex vivo studies of ischemic porcine intestine.10

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Dosing The recommended dose of lubiprostone for the treatment of OIC is 24 mcg taken orally twice daily with food and water. The dosage should be reduced in patients with moderate and severe hepatic impairment.10 Clinical Trials The efficacy of lubiprostone was evaluated in 3 randomized, double-blind, placebo-controlled studies in patients with documented constipation at baseline. Patients received stable opioid therapy for at least 30 days before screening, and the treatment continued throughout the 12-week period. Laxative use was discontinued at the beginning of the screening period and throughout the study. At baseline and monthly during the treatment period, patients were administered the Brief Pain Inventory–Short Form questionnaire to assess pain control.10 Lubiprostone was evaluated in 3 randomized, double- blind, placebo-controlled studies in patients with documented OIC. Lubiprostone achieved the overall efficacy end points in Studies 1 and 2, but not in Study 3.10 Study 1 In Study 1, at baseline, the mean oral morphine equivalent daily doses were 99 mg for the placebo-treated group and 130 mg for the lubiprostone-treated group. The median weekly spontaneous bowel movement frequencies at baseline were 1.5 for the placebo arm and 1.0 for the lubiprostone arm. Except for the 48-hour period before first dose and for at least 72 hours after the first dose, the use of rescue medication was allowed in cases where no bowel movement had occurred over a 3-day period.10 In this study, 431 patients receiving nondiphenylheptane (eg, nonmethadone) opioids were randomized to receive placebo or lubiprostone twice daily for 12 weeks. The primary efficacy analysis was a comparison of the proportion of overall responders in each treatment group. In Study 1, the proportion of overall responders was 8.2% greater with lubiprostone compared with placebo (P = .03) in patients with OIC (Table 1).10 Study 2 In Study 2, the baseline mean oral morphine equivalent daily doses were 237 mg for the placebo-treated group and 265 mg for the lubiprostone-treated group. The median weekly spontaneous bowel movement frequencies at baseline were 1.5 for both treatment groups. With the exception of the 48-hour period before the first dose and for at least 1 week after the first dose, the use of rescue medication was allowed in cases where no bowel movement had occurred in a 3-day period.10 The 418 patients receiving opioids were randomized to receive placebo or lubiprostone twice daily for 12 weeks.

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tudy 1: Lubiprostone versus Placebo; Proportion of Table 1 S Overall Respondersa in Patients with OIC Proportion of overall responders Placebo twice Lubiprostone 24 mcg Treatment daily, % twice daily, % difference, (N = 217) (N = 214) % P value 18.9

27.1

8.2

.03

Patients were considered overall responders if they had ≥1 spontaneous bowel movements (SBMs) over baseline for all treatment weeks for which data were available, and ≥3 SBMs per week were reported for at least 9 of 12 treatment weeks. NOTE: Examination of gender and race subgroups did not identify differences in response to lubiprostone in these subgroups. There were too few patients aged ≥65 years to adequately assess differences in effects in the elderly population. OIC indicates opioid-induced constipation. Source: Amitiza (lubiprostone) capsules prescribing information; 2013. a

tudy 2: Lubiprostone versus Placebo: Mean Change Table 2 S from Baseline in SBM Frequency in Patients with OIC Mean change from baseline in SBM frequency at week 8 Placebo twice Lubiprostone 24 mcg daily twice daily Treatment (N = 208) (N = 210) difference P value 2.4

3.3

0.9

.004

NOTE: Examination of gender and race subgroups did not identify differences in response to lubiprostone in these subgroups. There were too few patients aged ≥65 years to adequately assess differences in effects in the elderly population. OIC indicates opioid-induced constipation; SBM, spontaneous bowel movement. Source: Amitiza (lubiprostone) capsules prescribing information; 2013.

This study did not exclude patients receiving diphenylheptane opioids (eg, methadone). Results for the primary efficacy end point—the mean change from baseline in spontaneous bowel movement frequency at week 8—were a 0.9 greater mean change from baseline (P = .004) with lubiprostone compared with placebo (Table 2).10

Study 3 In Study 3, the baseline mean oral morphine equivalent daily doses were 330 mg for the placebo-treated group and 373 mg for the lubiprostone-treated group. The median weekly spontaneous bowel movement frequencies at baseline were 1.5 for both treatment groups. Except for the 48-hour period before the first dose and for at least 1 week after the first dose, the use of rescue medication was allowed in cases where no bowel movement had occurred in a 3-day period.10

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tudy 3: Lubiprostone versus Placebo: Mean Change Table 3 S from Baseline in SBM Frequency in Patients with OIC Mean change from baseline in SBM frequency at week 8 Placebo twice Lubiprostone 24 mcg daily twice daily Treatment (N = 216) (N = 235) difference P value 2.5

2.7

0.2a

.76

This study did not demonstrate a statistically significant improvement in SBM frequency at week 8. NOTE: Examination of gender and race subgroups did not identify differences in response to lubiprostone in these subgroups. There were too few patients aged ≥65 years to adequately assess differences in effects in the elderly population. OIC indicates opioid-induced constipation; SBM, spontaneous bowel movement. Source: Amitiza (lubiprostone) capsules prescribing information; 2013.

Table 4 Adverse Reactions in Lubiprostone OIC Studies Percentage of patients with adverse reactions Lubiprostone 24 mcg Placebo, % twice daily, % System/adverse reactiona (N = 632) (N = 860) Gastrointestinal disorders Nausea

Diarrhea

Abdominal pain

Flatulence

Abdominal distension

Vomiting

Abdominal discomfort

Nervous system disorders Headache General disorders and site administration conditions Peripheral edema

Includes only those events associated with treatment (possibly, probably, or definitely related, as assessed by the investigator). b This term combines abdominal tenderness, abdominal rigidity, gastrointestinal discomfort, stomach discomfort, and abdominal discomfort. OIC indicates opioid-induced constipation. Source: Amitiza (lubiprostone) capsules prescribing information; 2013. a

Patients receiving opioids (N = 451) were randomized to receive placebo or lubiprostone 24 mcg twice daily for 12 weeks. This study, too, did not exclude patients receiving diphenylheptane opioids (eg, methadone). The

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findings for the primary efficacy end point—the mean change from baseline in spontaneous bowel movement frequency at week 8—were a 0.2 greater mean change from baseline in spontaneous bowel movement frequency in the lubiprostone group (P = .76) compared with placebo (Table 3).10

Safety The most common adverse reactions (incidence >4%) reported in patients receiving lubiprostone for the treatment of OIC are nausea and diarrhea. Adverse reactions that occurred in at least 1% of patients who received lubiprostone 24 mcg twice daily and that occurred more frequently with lubiprostone than with placebo are listed in Table 4.10 Contraindications Lubiprostone is contraindicated in patients with known or suspected mechanical GI obstruction.10 Warnings and Precautions Nausea. Patients taking lubiprostone may experience nausea. Concomitant administration of food may reduce the symptoms of nausea.10 Diarrhea. Lubiprostone should not be prescribed to patients who have severe diarrhea. Patients should be made aware of the potential for diarrhea during treatment, and they should be instructed to discontinue lubiprostone and inform their physician if severe diarrhea occurs.10 Dyspnea. Patients taking lubiprostone may experience dyspnea within 1 hour of the first dose. This symptom generally resolves within 3 hours, but may recur with repeat dosing.10 Bowel obstruction. Patients with symptoms suggestive of mechanical GI obstruction should be evaluated before initiating treatment with lubiprostone.10 Drug interactions. The concomitant use of diphenylheptane opioids (eg, methadone) may interfere with the efficacy of lubiprostone.10 Use in Specific Populations Pregnancy. Lubiprostone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.10 Nursing mothers. Caution should be exercised when administering lubiprostone to a nursing woman.10 Conclusion Lubiprostone, an oral chloride channel activator treatment, became the first oral treatment to treat OIC in adults with chronic, noncancer pain, when it received FDA approval for this supplemental indication in April 2013. This approval provides a new and convenient

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treatment option for patients with OIC who prefer to use an oral rather than a subcutaneous therapy. Two other indications were previously approved by the FDA for

Lubiprostone, an oral chloride channel activator treatment, became the first oral treatment to treat OIC in adults with chronic, noncancer pain, when it received FDA approval for this supplemental indication in April 2013. lubiprostoneâ&#x20AC;&#x201D;for the treatment of chronic idiopathic constipation, and the treatment of IBS with constipation in women aged â&#x2030;Ľ18 years. Lubiprostone was evaluated in 3 randomized, double-blind, placebo-controlled studies in patients with documented OIC. Lubiprostone achieved the overall efficacy end points in Studies 1 and 2, but not in Study 3. The most common adverse reactions (incidence >4%)

reported in patients treated with lubiprostone for OIC are nausea and diarrhea. n

References

1. Moore RA, McQuay HJ. Prevalence of opioid adverse events in chronic non-malignant pain: systematic review of randomised trials of oral opioids. Arthritis Res Ther. 2005;7:R1046-R1051. 2. Jeffrey S. FDA approves Amitiza for opioid-induced constipation. Medscape Medical News. April 23, 2013. www.medscape.com/viewarticle/802953. Accessed September 4, 2013. 3. Benyamin R, Trescot AM, Datta S, et al. Opioid complications and side effects. Pain Physician. 2008;11(2 suppl):S105-S120. 4. Bell T, Annunziata K, Leslie JB. Opioid-induced constipation negatively impacts pain management, productivity, and health-related quality of life: findings from the National Health and Wellness Survey. J Opioid Manag. 2009;5:137-144. 5. Hjalte F, Berggren AC, Begendahl H, Hjortsberg C. The direct and indirect costs of opioid-induced constipation. J Pain Symptom Manage. 2010;40:696-703. 6. Crosta P. All about opioids and opioid-induced constipation (OIC): treatment for OIC. Medical News Today. www.medicalnewstoday.com/info/oic/treatment-for-opioidinduced-constipation.php. Accessed September 4, 2013. 7. Relistor (methylnaltrexone bromide) subcutaneous injection [prescribing information]. Tarrytown, NY: Progenics Pharmaceuticals, Inc; October 2012. 8. CenterWatch. Amitiza (lubiprostone). www.centerwatch.com/drug-information/ fda-approvals/drug-details.aspx?DrugID=894. Accessed August 29, 2013. 9. US Food and Drug Administration. FDA approves Amitiza for IBS-C: only drug available in United States for irritable bowel syndrome with constipation. Press release. April 29, 2008. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2008/ucm 116889.htm. Accessed September 3, 2013. 10. Amitiza (lubiprostone) capsules [prescribing information]. Bethesda, MD: Sucampo Pharma Americas, LLC; and Deerfield, IL: Takeda Pharmaceuticals America, Inc; April 2013.

VISIT OUR ENHANCED USER-FRIENDLY WEBSITE American Health & Drug Benefits is an independent, peer-reviewed journal founded in 2008 Examines drug and other healthcare intervention value for payers, purchasers, providers, patients, manufacturers, regulators, distributors, and evaluators Provides up-to-date information on new drugs approved by the FDA

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Anoro Ellipta (Umeclidinium/Vilanterol): First Dual Long-Acting Inhaler for Long-Term Maintenance Treatment of COPD By Lisa A. Raedler, PhD, RPh, Medical Writer

hronic obstructive pulmonary disease (COPD), which includes chronic bronchitis and emphysema, is a serious and progressive disease characterized by difficulty breathing, productive cough, shortness of breath, and chest tightness.1 The leading causes of COPD are smoking and exposure to secondhand smoke.1,2 Other risk factors for COPD include extended exposure to air pollution, various chemicals, and dust, as well as heredity, a history of childhood respiratory infections, and socioeconomic status.1,3 In the United States, an estimated 12.7 million adults have COPD.4 COPD is the third most common cause of death in the United States.4 The symptoms of COPD significantly limit daily activities and negatively affect the patient’s quality of life.4 Approximately 50% of all patients with COPD are hindered in their ability to work, because of their symptoms.3 In patients with COPD, the pulmonary airflow is poor for multiple reasons, including the airways and air sacs lose their elasticity, the walls between air sacs are destroyed, the airway walls are thick and inflamed, and mucus production is high.1 The diagnosis of COPD is made by spirometry, as well as by the assessment of clinical symptoms and risk factors.1 Therapy for COPD is designed to stabilize the disease and to prevent acute exacerbations.3 Initial pharmacologic treatment is comprised of bronchodilators in the form of either a short-acting beta2-agonist (SABA) or a short-acting muscarinic antagonist. As the disease progresses and the patient experiences more frequent acute exacerbations of COPD, inhaled corticosteroids are used in combination with a long-acting beta2-agonist (LABA) or a long-acting muscarinic antagonist (LAMA).3 Some patients may be candidates for surgical intervention if they have refractory, advanced-stage COPD.3 Nonpharmacologic interventions also play a significant role in reducing symptoms and in improving the quality of life for patients with COPD.3 Patients should also undergo pulmonary rehabilitation, which includes 6 weeks of exercise, nutrition counseling, psychosocial support, disease education, and smoking cessation for those who smoke.3 Although smoking cessation is the single most effective intervention to improve outcomes in COPD, less than 33% of patients maintain

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abstinence.5 Those who do stop smoking often continue to have shortness of breath and other symptoms of limited airflow.5 In addition to therapies approved by the US Food and Drug Administration (FDA), more than 50 new medications are currently in development for the treatment of COPD, including ultra-LABAs, LAMAs, and combination bronchodilator and inhaled corticosteroid therapies, as well as novel agents that target CD8+ T-cells, nuclear factor-κB, chemokine receptors 2 and 3, T-helper 17 cells, and MAP kinase p38.3,6 However, the COPD management approach remains primarily palliative; there is currently no cure for COPD, and none of the currently available therapies can prevent lung function decline or airway destruction.5 In 2010, the cost associated with COPD in the United States was calculated at the staggering amount of approximately $50 billion.3 The mean cost was projected to be more than $4000 per patient annually, and is expected to rise as more patients are diagnosed with COPD.3 Direct healthcare costs account for the majority of COPD-related expenses and include physician office visits, hospitalizations, home care, and medications.3 The cost burden of COPD rises with increasing disease severity. Patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage I COPD spend the lowest amount ($1681 per patient annually), GOLD stage II COPD costs approximately $5000 per patient annually, and GOLD stage III COPD costs more than $10,800 per patient annually.3 Many patients with COPD also have comorbidities, such as cardiovascular disease, lung cancer, and diabetes, which incur additional expenses.3,5

A Novel Combination Therapy for COPD In December 2013, the FDA approved umeclidinium/ vilanterol inhalation powder (Anoro Ellipta; GlaxoSmithKline) for the once-daily long-term maintenance treatment of airflow obstruction in patients with COPD, including chronic bronchitis and/or emphysema.7 Umeclidinium and vilanterol inhalation powder (henceforth, umeclidinium/vilanterol) is the first COPD treatment that contains 2 long-acting bronchodilators —a LAMA and a LABA—in 1 inhaler.7

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Table 1 Efficacy Results of Phase 3 Trial of Umeclidinium 62.5 mcg/Vilanterol 25 mcg Combination Umeclidinium Umeclidinium/ Umeclidinium/ 62.5 mcg/ Umeclidinium Vilanterol vilanterol vilanterol vilanterol 25 mcg 62.5 mcg 25 mcg vs umeclidinium vs vilanterol Efficacy measure vs placebo vs placebo vs placebo alone alone Trough FEV1 at day 169

0.167 L (P <.001)

0.115 L (P <.001)

0.072 L (P <.001)

0.052 L (P = .004)

0.095 L (P <.001)

Increase from baseline 0-6 hr weighted mean FEV1 at day 168

0.242 L (P <.001)

0.15 L (P <.001)

0.122 L (P <.001)

0.092 L (P <.001)

0.12 L (P <.001)

FEV1 indicates forced expiratory volume in 1 second. Source: Donohue JF, et al. Respir Med. 2013;107:1538-1546.

The safety and efficacy of umeclidinium/vilanterol have been evaluated in more than 2400 patients diagnosed with COPD.7 The FDA approval of this new combination therapy was based on the demonstration of safety and improved lung function in a double-blind, placebo-controlled, parallel-group, phase 3 study of more than 1500 patients with COPD, including current and former smokers.8 “Anoro Ellipta works by helping the muscles around the airways of the lungs stay relaxed to increase airflow in patients with COPD,” said Curtis J. Rosebraugh, MD, MPH, Director of the Office of Drug Evaluation II in the FDA’s Center for Drug Evaluation and Research. “The availability of new long-term maintenance medications provides additional treatment options for the millions of Americans who suffer with COPD.”7 The FDA approved this new combination with a patient medication guide that provides instructions for patients on how to use it as well as the potential risks involved in using this inhaled therapy.

Mechanism of Action The active agents—umeclidinium and vilanterol— that are combined in this new inhalation powder involve 2 different mechanisms of action according to the individual components of this medication and have therefore different and combined effects in the lungs. Umeclidinium is a LAMA (anticholinergic) that affects muscarinic receptors M1 through M5.9 In the airways, it causes bronchodilation by inhibiting the M3 receptor at the smooth muscle.9 Vilanterol, a LABA, stimulates intracellular adenyl cyclase, which leads to an increase in cyclic-3’,5’-adenosine monophosphate levels, relaxation of bronchial smooth muscle, and inhibition of inflammatory mediators.9 Dosing and Administration For COPD maintenance, the new inhalation powder, which contains umeclidinium 62.5 mcg and vilanterol

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25 mcg, is administered as 1 inhalation once daily through the mouth.9 Umeclidinium/vilanterol should be used orally at the same time every day and should not exceed 1 oral inhalation every 24 hours.9 No dose adjustment is needed for older patients, patients with renal impairment, or patients with moderate hepatic impairment.9

The active agents—umeclidinium and vilanterol—that are combined in this new inhalation powder involve 2 different mechanisms of action according to the individual components of this medication and have therefore different and combined effects in the lungs. Pivotal Phase 3 Clinical Trial The phase 3 clinical trial that led to the FDA approval was a multicenter, parallel-group study with 1532 patients who were randomly assigned to 24 weeks of 1 of 4 groups: umeclidinium/vilanterol, umeclidinium alone, vilanterol alone, or to placebo.8 The patients (aged ≥40 years) enrolled in this trial were current or former cigarette smokers with a clinically established history of COPD.8 The primary efficacy end point was predose trough forced expiratory volume in 1 second (FEV1) on treatment day 169.8 Secondary end points included the number of patients who responded to umeclidinium/vilanterol, to umeclidinium, or to vilanterol according to FEV1 at day 1, and patients who had a larger change from baseline in 0- to 6-hour weighted mean FEV1 on day 14 with umec lidinium/vilanterol compared with umeclidinium or vilanterol alone. Other outcomes measured were the mean Transition Dyspnea Index focal score, the mean Shortness of Breath with Daily Activities score, rescue

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Table 2 Adverse Events with Umeclidinium/Vilanterol Inhalation Powder with ≥1% Incidence in Patients with COPD Umeclidinium 62.5 mcg/vilanterol Umeclidinium Vilanterol Placebo, % 25 mcg, % 62.5 mcg, % 25 mcg, % Adverse event (N = 555) (N = 842) (N = 418) (N = 1034) Infections/infestations Pharyngitis Sinusitis Lower respiratory tract infection

<1 <1 <1

2 1 1

1 <1 <1

2 1 <1

Gastrointestinal disorders Constipation Diarrhea

<1 1

1 2

<1 <1

<1 2

Musculoskeletal/connective tissue disorders Pain in extremity Muscle spasms Neck pain

1 <1 <1

2 1 1

<1 <1 <1

2 <1 <1

General disorders/administration-site conditions Chest pain

COPD indicates chronic obstructive pulmonary disease. Source: Anoro Ellipta (umeclidinium and vilanterol inhalation powder) prescribing information; 2013.

salbutamol use, the time to first COPD exacerbation, and the St George’s Respiratory Questionnaire (SGRQ) quality-of-life score.8

Patient Population Of 2210 patients with COPD who were screened for the phase 3 trial, 1532 patients were included in the intent-totreat (ITT) analysis of this study.8 A total of 1178 patients with moderate-to-severe COPD completed the study.8 Patient demographics and baseline characteristics were similar among the treatment groups. The median age of participants ranged from 62 to 64 years.8 Approximately 70% of the patients were male, and approximately 50% of the patients were smokers at screening. The large majority of patients were in GOLD stage II or III.8 Efficacy The phase 3 clinical trial demonstrated that the combination of umeclidinium and vilanterol is safe and efficacious in patients with moderate-to-severe COPD. Compared with each of these agents administered as monotherapy, the umeclidinium 62.5-mcg/vilanterol 25 mcg combination demonstrated significant improvements in predose trough FEV1, as well as in 0- to 6-hour weighted mean FEV1 (Table 1).8 In the ITT population, treatment with umeclidinium 62.5 mcg/vilanterol 25 mcg resulted in a significant 0.112-L improvement in FEV1 after 15 minutes (first assessment) compared with placebo. A 0.273-L increase from baseline in peak FEV1 was seen over 6 hours on day 1 for the umeclidinium 62.5-mcg/vilanterol 25-mcg

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combination.8 Improvements in lung function observed with the umeclidinium/vilanterol combination were considered clinically meaningful compared with umeclidinium or vilanterol as monotherapy.8 The results of secondary end point analyses favored the active treatment arms compared with placebo. The 3 active treatments resulted in lower use of rescue inhaler, improvement in SGRQ score, and a lower risk for COPD exacerbation compared with placebo.8

Adverse Effects/Safety The most frequent treatment-emergent adverse effects in the phase 3 study of umeclidinium/vilanterol included headache, nasopharyngitis, upper respiratory tract infection, and cough.8 These reactions were seen with similar frequency in the 3 active treatment groups.8 The adverse effects that led to study withdrawal were infrequent and were related to worsening COPD. A total of 9 patients died of adverse events, including 3 in the umeclidinium 62.5-mcg/vilanterol 25-mcg group, 3 in the vilanterol 25-mcg group, and 3 in the umeclidinium 62.5-mcg group. In addition to the pivotal phase 3 trial, the overall clinical program for umeclidinium/vilanterol included more than 8000 patients with COPD in different clinical trials.9 Table 2 lists the most common adverse reactions associated with the umeclidinium/vilanterol combination that were reported in four 6-month trials: 2 placebo-controlled trials (Trial 1, N = 1532; Trial 2, N = 1489) and 2 active-controlled trials (Trial 3, N = 843; Trial 4, N = 869).8,9

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Contraindications Umeclidinium/vilanterol is contraindicated in patients with severe hypersensitivity to milk proteins or to any of the product’s ingredients.9 Warnings and Precautions Boxed warning. Umeclidinium/vilanterol includes a boxed warning that LABAs, such as vilanterol, increase the risk for asthma-related death. No trial has been conducted to determine if the rate of asthma-related death is increased in patients taking umeclidinium/ vilanterol. This medication is not indicated for the treatment of asthma.9 Disease deterioration. Because it has not been studied in patients during rapidly deteriorating or potentially life-threatening episodes of COPD, umeclidinium and vilanterol inhalation powder should not be used in such patients.9 The oral inhalation powder should not be used for the relief of acute symptoms (ie, as rescue therapy in acute episodes of bronchospasm); there are no studies of umeclidinium/vilanterol in these situations.9 Acute bronchospasm symptoms should be treated with an inhaled SABA.9 Patients who are taking an oral or inhaled SABA on a regular basis (eg, 4 times daily) should discontinue administration in this fashion. SABAs should be used only for the symptomatic relief of acute COPD symptoms.9 If signs of COPD deterioration occur while taking the combination inhalation powder, which include inadequate control of bronchoconstriction symptoms, lowered efficacy of SABA therapy, or higher-than-recommended use of SABAs, physicians should promptly review the patient’s COPD treatment regimen. The daily dose should not be increased beyond the recommended dose in this situation.9 Overuse/use with other LABAs. To prevent overdose, the oral inhalation powder should not be used more often than recommended, at higher doses than recommended, or concomitant with other medications that contain a LABA. The excessive use of inhaled sympatho mimetic drugs can cause cardiovascular adverse effects and fatalities.9 Paradoxical bronchospasm. Like other inhaled medicines, umeclidinium/vilanterol can lead to life-threatening paradoxical bronchospasm. If paradoxical bronchospasm occurs, the patient should use an inhaled, short-acting bronchodilator immediately and umeclidinium/vilanterol should be discontinued.9 Hypersensitivity reactions. The administration of umeclidinium/vilanterol, which contains lactose, can result in hypersensitivity reactions. Anaphylactic reactions have occurred in patients with severe milk protein allergy after the inhalation of other powder products

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containing lactose.9 Patients with severe milk protein allergy should not use this medication.9 Cardiovascular effects. As a beta2-agonist, vilanterol can cause clinically significant cardiovascular adverse effects in some patients. The discontinuation of this treatment should be considered in patients who exhibit such effects. Although the clinical significance is unknown, beta agonists have also been reported to produce electrocardiographic changes, including T-wave flattening, corrected QT interval prolongation, and ST-segment depression. Patients with cardiovascular disorders, particularly coronary insufficiency, arrhythmias, and hypertension, should use umeclidinium/vilanterol with caution.9 Coexisting conditions. Because umeclidinium/vilanterol contains sympathomimetic amines, it should be used with caution in patients with convulsive disorders or thyrotoxicosis, as well as in patients who are unusually responsive to sympathomimetic amines.9 Worsening of narrow-angle glaucoma. Patients with narrow-angle glaucoma should use this medication with caution. Patients should be aware of the signs and symptoms of acute narrow-angle glaucoma and should immediately consult a physician if such problems develop.9 Urinary retention. Umeclidinium/vilanterol should be used with caution in patients with urinary retention, particularly prostatic hyperplasia and bladder-neck obstruction.9 Hypokalemia and hyperglycemia. Some patients who take beta-adrenergic agonists may exhibit significant hypokalemia that can lead to adverse cardiovascular effects. Beta-agonist medications may also result in transient hyperglycemia in some patients. Umeclidinium/ vilanterol did not affect serum glucose or potassium levels in 4 clinical trials that lasted 6 months.9

Use in Specific Populations Umeclidinium/vilanterol has a pregnancy category C. The combination and its individual components have not been studied in well-controlled trials of pregnant women specifically.9 There are also no adequate trials evaluating umeclidinium/vilanterol during labor and delivery. Because beta-agonists can affect uterine contractility, the use of this combination during labor should be considered only if the potential benefit justifies the potential risk.9 Caution should also be exercised when administering umeclidinium/vilanterol to a nursing woman. It is not known whether either drug is excreted in human breast milk.9 The safety and efficacy of umeclidinium/vilanterol in pediatric patients have not been established.9 Clinical trials of umeclidinium/vilanterol for COPD included 2143 patients aged ≥65 years.9 When compar-

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ing older and younger patients, no overall differences in safety or efficacy were observed. No other clinical experience reports have identified differences in responses between elderly and younger patients receiving umeclidinium/vilanterol.9

Umeclidinium/vilanterol inhalation powder is the first FDA-approved once-daily maintenance treatment for COPD that combines 2 long-acting bronchodilators with 2 distinct and complementary mechanisms of action. Conclusion Umeclidinium/vilanterol inhalation powder is the first FDA-approved once-daily maintenance treatment for COPD that combines 2 long-acting bronchodilators with 2 distinct and complementary mechanisms of action. Umeclidinium/vilanterol has been shown effective

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and safe in multiple clinical trials of patients with moderate-to-severe COPD. This new combination therapy offers a convenient treatment option for patients with COPD who require long-term maintenance therapy. n

References

1. National Heart, Lung, and Blood Institute. What is COPD? July 31, 2013. www. nhlbi.nih.gov/health/health-topics/topics/copd/. Accessed January 28, 2014. 2. Gershon AS, Warner L, Cascagnette P, et al. Lifetime risk of developing chronic obstructive pulmonary disease: a longitudinal population study. Lancet. 2011;378: 991-996. 3. Guarascio AJ, Ray SM, Finch CK, Self TH. The clinical and economic burden of chronic obstructive pulmonary disease in the USA. Clinicoecon Outcomes Res. 2013; 5:235-245. 4. American Lung Association. Chronic obstructive pulmonary disease (COPD) fact sheet. August 2013. www.lung.org/lung-disease/copd/resources/facts-figures/COPD-FactSheet.html. Accessed January 28, 2014. 5. Kaplan W, Wirtz VJ, Mantel-Teeuwisse A, et al. Priority Medicines for Europe and the World 2013 Update. www.who.int/medicines/areas/priority_medicines/Master DocJune28_FINAL_Web.pdf. Accessed January 25, 2014. 6. Decramer M, Janssens W, Miravitlles M. Chronic obstructive pulmonary disease. Lancet. 2012;379:1341-1351. 7. US Food and Drug Administration. FDA approves Anoro Ellipta to treat chronic obstructive pulmonary disease. Press release. December 18, 2013. Updated December 19, 2013. www.fda.gov/newsevents/newsroom/pressannouncements/ucm379057.htm. Accessed January 25, 2014. 8. Donohue JF, Maleki-Yazdi MR, Kilbride S, et al. Efficacy and safety of once-daily umeclidinium/vilanterol 62.5/25 mcg in COPD. Respir Med. 2013;107:1538-1546. 9. Anoro Ellipta (umeclidinium and vilanterol inhalation powder) [prescribing information]. Research Triangle Park, NC: GlaxoSmithKline; December 2013.

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1st oral kinase inhibitor for previously treated CLL

NOW APPROVED NEW

INDICATION - IMBRUVICA™ is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy. This indication is based on overall response rate. An improvement in survival or disease-related symptoms has not been established.

1 daily dose

FOR PREVIOUSLY TREATED CLL INDICATION - IMBRUVICA™ is indicated for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. This indication is based on overall response rate. An improvement in survival or disease-related symptoms has not been established.

Learn more at www.IMBRUVICA.com IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS Hemorrhage – Five percent of patients with MCL and 6% of patients with CLL had Grade 3 or higher bleeding events (subdural hematoma, ecchymoses, gastrointestinal bleeding, and hematuria). Overall, bleeding events including bruising of any grade occurred in 48% of patients with MCL treated with 560 mg daily and 63% of patients with CLL treated at 420 mg daily. The mechanism for the bleeding events is not well understood. IMBRUVICA™ may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies. Consider the benefit-risk of withholding IMBRUVICA™ for at least 3 to 7 days pre and post-surgery depending upon the type of surgery and the risk of bleeding. Infections - Fatal and non-fatal infections have occurred with IMBRUVICA™ therapy. At least 25% of patients with MCL and 35% of patients with CLL had infections Grade 3 or greater NCI Common Terminology Criteria for Adverse Events (CTCAE). Monitor patients for fever and infections and evaluate promptly. Myelosuppression - Treatment-emergent Grade 3 or 4 cytopenias were reported in 41% of patients with MCL and 35% of patients with CLL. These included neutropenia (29%), thrombocytopenia (17%) and anemia (9%) in patients with MCL and neutropenia (27%) and thrombocytopenia (10%) in patients with CLL. Monitor complete blood counts monthly. Renal Toxicity - Fatal and serious cases of renal failure have occurred with IMBRUVICA™ therapy. Treatment-emergent increases in creatinine levels up to 1.5 times the upper limit of normal occurred in 67% of patients with MCL and 23% of patients with CLL. Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 9% of patients with MCL and 4% of patients with CLL. Periodically monitor creatinine levels. Maintain hydration.

Please review the Brief Summary of full Prescribing Information on the following page. © Pharmacyclics, Inc. 2014 © Janssen Biotech, Inc. 2014 02/14 PRC-00286

Second Primary Malignancies - Other malignancies have occurred in 5% of patients with MCL and 10% of patients with CLL who have been treated with IMBRUVICA™. Four percent of patients with MCL, had skin cancers, and 1% had other carcinomas. Eight percent of patients with CLL had skin cancers and 2% had other carcinomas. Embryo-Fetal Toxicity - Based on findings in animals, IMBRUVICA™ can cause fetal harm when administered to a pregnant woman. Advise women to avoid becoming pregnant while taking IMBRUVICA™. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. ADVERSE REACTIONS – MCL: The most commonly occurring adverse reactions (≥20%) in the clinical trial were thrombocytopenia*, diarrhea (51%), neutropenia*, anemia*, fatigue (41%), musculoskeletal pain (37%), peripheral edema (35%), upper respiratory tract infection (34%), nausea (31%), bruising (30%), dyspnea (27%), constipation (25%), rash (25%), abdominal pain (24%), vomiting (23%), and decreased appetite (21%). *Treatment-emergent decreases (all grades) of platelets (57%), neutrophils (47%) and hemoglobin (41%) were based on laboratory measurements and adverse reactions. The most common Grade 3 or 4 non-hematological adverse reactions (≥5%) were pneumonia (7%), abdominal pain (5%), atrial fibrillation (5.4%), diarrhea (5%), fatigue (5%), and skin infections (5%). Treatment-emergent Grade 3 or 4 cytopenias were reported in 41% of patients. Ten patients (9%) discontinued treatment due to adverse reactions in the trial (N=111). The most frequent adverse reaction leading to treatment discontinuation was subdural hematoma (1.8%). Adverse reactions leading to dose reduction occurred in 14% of patients.

CLL: The most commonly occurring adverse reactions (≥ 20%) in the clinical trial were thrombocytopenia*, diarrhea (63%), bruising (54%), neutropenia*, anemia*, upper respiratory tract infection (48%), fatigue (31%), musculoskeletal pain (27%), rash (27%), pyrexia (25%), constipation (23%), peripheral edema (23%), arthralgia (23%), nausea (21%), stomatitis (21%), sinusitis (21%), and dizziness (21%). *Treatment-emergent decreases (all grades) of platelets (71%), neutrophils (54%) and hemoglobin (44%) were based on laboratory measurements per IWCLL criteria and adverse reactions. The most common Grade 3 or 4 non-hematological adverse reactions (≥ 5%) were pneumonia (8%), hypertension (8%), atrial fibrillation (6.3%), sinusitis (6%), skin infection (6%), dehydration (6.4%), and musculoskeletal pain (6%). Five patients (10%) discontinued treatment due to adverse reactions in the trial (N=48). These included 3 patients (6%) with infections and 2 patients (4%) with subdural hematomas. Adverse reactions leading to dose reduction occurred in 13% of patients. DRUG INTERACTIONS CYP3A Inhibitors - Avoid concomitant administration with strong or moderate inhibitors of CYP3A. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA™ dose. CYP3A Inducers - Avoid co-administration with strong CYP3A inducers. SPECIAL POPULATIONS - Hepatic Impairment Avoid use in patients with baseline hepatic impairment.

Brief Summary of Prescribing Information for IMBRUVICATM (ibrutinib) IMBRUVICATM (ibrutinib) capsules, for oral use See package insert for Full Prescribing Information INDICATIONS AND USAGE IMBRUVICA is indicated for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. This indication is based on overall response rate. An improvement in survival or disease-related symptoms has not been established [see Clinical Studies (14.1) in full Prescribing Information]. CONTRAINDICATIONS None WARNINGS AND PRECAUTIONS Hemorrhage: Five percent of patients with MCL and 6% of patients with CLL had Grade 3 or higher bleeding events (subdural hematoma, ecchymoses, gastrointestinal bleeding, and hematuria). Overall, bleeding events including bruising of any grade occurred in 48% of patients with MCL treated with 560 mg daily and 63% of patients with CLL treated at 420 mg daily. The mechanism for the bleeding events is not well understood. IMBRUVICA may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies. Consider the benefit-risk of withholding IMBRUVICA for at least 3 to 7 days pre and post-surgery depending upon the type of surgery and the risk of bleeding [see Clinical Studies (14) in full Prescribing Information]. Infections: Fatal and non-fatal infections have occurred with IMBRUVICA therapy. At least 25% of patients with MCL and 35% of patients with CLL had infections Grade 3 or greater NCI Common Terminology Criteria for Adverse Events (CTCAE) [See Adverse Reactions]. Monitor patients for fever and infections and evaluate promptly. Myelosuppression: Treatment-emergent Grade 3 or 4 cytopenias were reported in 41% of patients with MCL and 35% of patients with CLL. These included neutropenia (29%), thrombocytopenia (17%) and anemia (9%) in patients with MCL and neutropenia (27%) and thrombocytopenia (10%) in patients with CLL. Monitor complete blood counts monthly. Renal Toxicity: Fatal and serious cases of renal failure have occurred with IMBRUVICA therapy. Treatment-emergent increases in creatinine levels up to 1.5 times the upper limit of normal occurred in 67% of patients with MCL and 23% of patients with CLL. Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 9% of patients with MCL and 4% of patients with CLL. Periodically monitor creatinine levels. Maintain hydration. Second Primary Malignancies: Other malignancies have occurred in 5% of patients with MCL and 10% of patients with CLL who have been treated with IMBRUVICA. Four percent of patients with MCL, had skin cancers and 1% had other carcinomas. Eight percent of patients with CLL had skin cancers and 2% had other carcinomas. Embryo-Fetal Toxicity: Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. Ibrutinib caused malformations in rats at exposures 14 times those reported in patients with MCL and 20 times those reported in patients with CLL, receiving the ibrutinib dose of 560 mg per day and 420 mg per day, respectively. Reduced fetal weights were observed at lower exposures. Advise women to avoid becoming pregnant while taking IMBRUVICA. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations]. ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: • Hemorrhage [see Warnings and Precautions] • Infections [see Warnings and Precautions] • Myelosuppression [see Warnings and Precautions] • Renal Toxicity [see Warnings and Precautions] • Second Primary Malignancies [see Warnings and Precautions] Because clinical trials are conducted under widely variable conditions, adverse event rates observed in clinical trials of a drug cannot be directly compared with rates of clinical trials of another drug and may not reflect the rates observed in practice. Mantle Cell Lymphoma: The data described below reflect exposure to IMBRUVICA in a clinical trial that included 111 patients with previously treated MCL treated with 560 mg daily with a median treatment duration of 8.3 months.

IMBRUVICATM (ibrutinib) capsules The most commonly occurring adverse reactions (≥ 20%) were thrombocytopenia, diarrhea, neutropenia, anemia, fatigue, musculoskeletal pain, peripheral edema, upper respiratory tract infection, nausea, bruising, dyspnea, constipation, rash, abdominal pain, vomiting and decreased appetite (See Tables 1 and 2). The most common Grade 3 or 4 non-hematological adverse reactions (≥ 5%) were pneumonia, abdominal pain, atrial fibrillation, diarrhea, fatigue, and skin infections. Adverse reactions from the MCL trial (N=111) using single agent IMBRUVICA 560 mg daily occurring at a rate of ≥ 10% are presented in Table 1. Table 1: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with Mantle Cell Lymphoma (N=111) System Organ Class

Preferred Term

Diarrhea Nausea Constipation Abdominal pain Vomiting Stomatitis Dyspepsia Infections and Upper respiratory tract infestations infection Urinary tract infection Pneumonia Skin infections Sinusitis General disorders and Fatigue Peripheral edema administrative site Pyrexia conditions Asthenia Bruising Skin and subcutaneous tissue Rash Petechiae disorders Musculoskeletal and Musculoskeletal pain Muscle spasms connective tissue Arthralgia disorders Respiratory, thoracic Dyspnea Cough and mediastinal Epistaxis disorders Metabolism and Decreased appetite nutrition disorders Dehydration Nervous system Dizziness disorders Headache

Gastrointestinal disorders

All Grades Grade 3 or 4 (%) (%) 5 51 0 31 0 25 5 24 0 23 1 17 0 11 0 3 7 5 1 5 3 1 3 0 3 0 1 0 0 4 0 0 2 4 0 0

34 14 14 14 13 41 35 18 14 30 25 11 37 14 11 27 19 11 21 12 14 13

Table 2: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Patients with MCL (N=111) Percent of Patients (N=111) All Grades (%) Grade 3 or 4 (%) Platelets Decreased

Neutrophils Decreased

Hemoglobin Decreased

* Based on laboratory measurements and adverse reactions Ten patients (9%) discontinued treatment due to adverse reactions in the trial (N=111). The most frequent adverse reaction leading to treatment discontinuation was subdural hematoma (1.8%). Adverse reactions leading to dose reduction occurred in 14% of patients. Patients with MCL who develop lymphocytosis greater than 400,000/mcL have developed intracranial hemorrhage, lethargy, gait instability, and headache. However, some of these cases were in the setting of disease progression. Forty percent of patients had elevated uric acid levels on study including 13% with values above 10 mg/dL. Adverse reaction of hyperuricemia was reported for 15% of patients. Chronic Lymphocytic Leukemia: The data described below reflect exposure to IMBRUVICA in a clinical trial that included 48 patients with previously treated CLL treated with 420 mg daily with a median treatment duration of 15.6 months.

IMBRUVICATM (ibrutinib) capsules

The most commonly occurring adverse reactions (≥ 20%) were thrombocytopenia, diarrhea, bruising, neutropenia, anemia, upper respiratory tract infection, fatigue, musculoskeletal pain, rash, pyrexia, constipation, peripheral edema, arthralgia, nausea, stomatitis, sinusitis, and dizziness (See Tables 3 and 4). The most common Grade 3 or 4 non-hematological adverse reactions (≥ 5%) were pneumonia, hypertension, atrial fibrillation, sinusitis, skin infection, dehydration, and musculoskeletal pain. Adverse reactions from the CLL trial (N=48) using single agent IMBRUVICA 420 mg daily occurring at a rate of ≥ 10% are presented in Table 3.

Five patients (10%) discontinued treatment due to adverse reactions in the trial (N=48). These included 3 patients (6%) with infections and 2 patients (4%) with subdural hematomas. Adverse reactions leading to dose reduction occurred in 13% of patients. Thirty-eight percent of patients had shifts from normal to elevated uric acid levels on study including 4% with values above 10 mg/dL. DRUG INTERACTIONS Ibrutinib is primarily metabolized by cytochrome P450 enzyme 3A. CYP3A Inhibitors: In healthy volunteers, co-administration of ketoconazole, a strong CYP3A inhibitor, increased Cmax and AUC of ibrutinib by 29- and 24-fold, respectively. The highest ibrutinib dose evaluated in clinical trials was 12.5 mg/kg (actual doses of 840 – 1400 mg) given for 28 days with single dose AUC values of 1445 ± 869 ng • hr/mL which is approximately 50% greater than steady state exposures seen at the highest indicated dose (560 mg). Avoid concomitant administration of IMBRUVICA with strong or moderate inhibitors of CYP3A. For strong CYP3A inhibitors used short-term (e.g., antifungals and antibiotics for 7 days or less, e.g., ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin) consider interrupting IMBRUVICA therapy during the duration of inhibitor use. Avoid strong CYP3A inhibitors that are needed chronically. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA dose. Patients taking concomitant strong or moderate CYP3A4 inhibitors should be monitored more closely for signs of IMBRUVICA toxicity [see Dosage and Administration (2.4) in full Prescribing Information]. Avoid grapefruit and Seville oranges during IMBRUVICA treatment, as these contain moderate inhibitors of CYP3A [see Dosage and Administration (2.4), and Clinical Pharmacology (12.3) in full Prescribing Information]. CYP3A Inducers: Administration of IMBRUVICA with strong inducers of CYP3A decrease ibrutinib plasma concentrations by approximately 10-fold. Avoid concomitant use of strong CYP3A inducers (e.g., carbamazepine, rifampin, phenytoin and St. John’s Wort). Consider alternative agents with less CYP3A induction [see Clinical Pharmacology (12.3) in full Prescribing Information].

Table 3: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with Chronic Lymphocytic Leukemia (N=48) All Grades Grade 3 or 4 (%) (%)

System Organ Class

Preferred Term

Gastrointestinal disorders

Diarrhea Constipation Nausea Stomatitis Vomiting Abdominal pain Dyspepsia

63 23 21 21 19 15 13

4 2 2 0 2 0 0

Infections and infestations

Upper respiratory tract infection Sinusitis Skin infection Pneumonia Urinary tract infection

48 21 17 10 10

2 6 6 8 0

General disorders and administrative site conditions

Fatigue Pyrexia Peripheral edema Asthenia Chills

31 25 23 13 13

4 2 0 4 0

Skin and subcutaneous tissue disorders

Bruising Rash Petechiae

54 27 17

2 0 0

Respiratory, thoracic Cough Oropharyngeal pain and mediastinal Dyspnea disorders

19 15 10

0 0 0

Musculoskeletal and Musculoskeletal pain Arthralgia connective tissue Muscle spasms disorders

27 23 19

6 0 2

Nervous system disorders

Dizziness Headache Peripheral neuropathy

21 19 10

0 2 0

Metabolism and nutrition disorders

Decreased appetite

Neoplasms benign, malignant, unspecified

Second malignancies*

10*

Injury, poisoning and procedural complications

Laceration

10 10

0 0

Psychiatric disorders Anxiety Insomnia Vascular disorders

Hypertension

*One patient death due to histiocytic sarcoma. Table 4: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Patients with CLL (N=48) Percent of Patients (N=48) All Grades (%) Grade 3 or 4 (%) Platelets Decreased

Neutrophils Decreased

Hemoglobin Decreased

* Based on laboratory measurements per IWCLL criteria and adverse reactions

USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category D [see Warnings and Precautions]. Risk Summary: Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. If IMBRUVICA is used during pregnancy or if the patient becomes pregnant while taking IMBRUVICA, the patient should be apprised of the potential hazard to the fetus. Animal Data: Ibrutinib was administered orally to pregnant rats during the period of organogenesis at oral doses of 10, 40 and 80 mg/kg/day. Ibrutinib at a dose of 80 mg/kg/day was associated with visceral malformations (heart and major vessels) and increased post-implantation loss. The dose of 80 mg/kg/day in animals is approximately 14 times the exposure (AUC) in patients with MCL and 20 times the exposure in patients with CLL administered the dose of 560 mg daily and 420 mg daily, respectively. Ibrutinib at doses of 40 mg/kg/day or greater was associated with decreased fetal weights. The dose of 40 mg/kg/day in animals is approximately 6 times the exposure (AUC) in patients with MCL administered the dose of 560 mg daily. Nursing Mothers: It is not known whether ibrutinib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from IMBRUVICA, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: The safety and effectiveness of IMBRUVICA in pediatric patients has not been established. Geriatric Use: Of the 111 patients treated for MCL, 63% were 65 years of age or older. No overall differences in effectiveness were observed between these patients and younger patients. Cardiac adverse events (atrial fibrillation and hypertension), infections (pneumonia and cellulitis) and gastrointestinal events (diarrhea and dehydration) occurred more frequently among elderly patients. Of the 48 patients treated for CLL, 52% were 65 years of age or older. No overall differences in effectiveness were observed between these patients and younger patients. A greater number of adverse events were reported in those 65 years of age and older. Grade 3 or higher adverse events occurred more frequently among elderly patients (80% of patients 65 and older versus 61% of younger patients). Renal Impairment: Less than 1% of ibrutinib is excreted renally. Ibrutinib exposure is not altered in patients with Creatinine clearance (CLcr) > 25 mL/min. There are no data in patients with severe renal impairment (CLcr < 25 mL/min) or patients on dialysis [see Clinical Pharmacology (12.3) in full Prescribing Information].

IMBRUVICATM (ibrutinib) capsules Hepatic Impairment: Ibrutinib is metabolized in the liver and significant increases in exposure of ibrutinib are expected in patients with hepatic impairment. Patients with serum aspartate transaminase (AST/SGOT) or alanine transaminase (ALT/SGPT) ≥ 3.0 x upper limit of normal (ULN) were excluded from IMBRUVICA clinical trials. There is insufficient data to recommend a dose of IMBRUVICA in patients with baseline hepatic impairment [see Clinical Pharmacology (12.3) in full Prescribing Information]. Females and Males of Reproductive Potential: Advise women to avoid becoming pregnant while taking IMBRUVICA because IMBRUVICA can cause fetal harm [see Use in Specific Populations]. PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information) • Hemorrhage: Inform patients of the possibility of bleeding, and to report any signs or symptoms (blood in stools or urine, prolonged or uncontrolled bleeding). Inform the patient that IMBRUVICA may need to be interrupted for medical or dental procedures [see Warnings and Precautions]. • Infections: Inform patients of the possibility of serious infection, and to report any signs or symptoms (fever, chills) suggestive of infection [see Warnings and Precautions]. • Renal toxicity: Inform patients of the possibility of renal toxicity. Advise patients to maintain adequate hydration [see Warnings and Precautions]. • Second primary malignancies: Inform patients that other malignancies have occurred in patients who have been treated with IMBRUVICA, including skin cancers and other carcinomas [see Warnings and Precautions]. • Embryo-fetal toxicity: Advise women of the potential hazard to a fetus and to avoid becoming pregnant [see Warnings and Precautions]. • Inform patients to take IMBRUVICA orally once daily according to their physician’s instructions and that the capsules should be swallowed whole with a glass of water without being opened, broken, or chewed at approximately the same time each day [see Dosage and Administration (2.1) in full Prescribing Information]. • Advise patients that in the event of a missed daily dose of IMBRUVICA, it should be taken as soon as possible on the same day with a return to the normal schedule the following day. Patients should not take extra capsules to make up the missed dose [see Dosage and Administration (2.5) in full Prescribing Information]. • Advise patients of the common side effects associated with IMBRUVICA [see Adverse Reactions]. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION. • Advise patients to inform their health care providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Drug Interactions]. • Advise patients that they may experience loose stools or diarrhea, and should contact their doctor if their diarrhea persists. Active ingredient made in China. Distributed and Marketed by: Pharmacyclics, Inc. Sunnyvale, CA USA 94085 and Marketed by: Janssen Biotech, Inc. Horsham, PA USA 19044 Patent http://www.imbruvica.com IMBRUVICA™ is a trademark owned by Pharmacyclics, Inc. ©Pharmacyclics, Inc. 2014 PRC-00320

Issued: February 2014

Botox (OnabotulinumtoxinA) Now FDA Approved for Overactive Bladder By Loretta Fala, Medical Writer

veractive bladder (OAB), a condition characterized by urinary urgency, frequency, nocturia, and urgency incontinence, affects an estimated 33 million people in the United States.1,2 In fact, as many as 30% of US men and 40% of US women experience symptoms of OAB.2 The prevalence of OAB is likely underestimated, given that many individuals suffering from OAB may not seek help because of embarrassment or a lack of knowledge about OAB.2 Many conditions may contribute to the symptoms of OAB, including neurologic disorders (ie, Parkinson’s disease, stroke, multiple sclerosis), elevated urine production (ie, high fluid intake, poor renal function, or diabetes), medications that increase urine production, bladder abnormalities, enlarged prostate, and excess consumption of alcohol or caffeine.3 Although OAB can occur at any age, elderly patients have an increased risk for OAB.3 However, OAB should not be considered a natural and unavoidable consequence of aging.3 Several approaches are currently available to help improve outcomes for patients with OAB. OAB has a considerable impact on a patient’s comorbid conditions, as well as the physical, social, psychological, and other aspects that affect the patient’s quality of life. Overall, patients with OAB may experience major disruptions in their lives, with an increased risk for emotional distress, depression, sleep disturbances, and interrupted sleep cycles.3 OAB is also associated with substantial healthcare costs and quality-of-life sequelae.4 The results of a 2009 study showed that the total annual direct cost for common symptoms of OAB in the United States was $22.3 billion, and the cost for infrequent symptoms of OAB was $33.5 billion.5 Perhaps surprising, the costs were higher in younger adults aged <65 years compared with older adults aged ≥65 years.5 One claims-based analysis showed a nearly 5-fold greater annual cost for patients with OAB than for patients without the condition ($5018 vs $1767, respectively).4,6 The treatment of OAB generally involves a combination of treatment strategies.3 According to the American Urological Association (AUA) 2012 treatment guideline for nonneurogenic OAB, “Successful treatment of OAB symptoms with behavioral approaches, anti-muscarinic medications, neuromodulation therapies, and

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onabotulinumtoxinA, balanced against adverse events, costs and ultimately patient compliance, all have been reported to improve patient quality of life.”1 This AUA guideline recommends that providers review the specific discussion section for each of the treatment types mentioned in the guideline.1 Treating OAB at an early stage may improve patient care and reduce overall healthcare resource utilization; more research is needed on long-term costs, as well as the pathogenesis of OAB-related conditions.7

A New Treatment Option for Patients with OAB On January 18, 2013, the US Food and Drug Administration (FDA) approved an expanded indication for Botox (onabotulinumtoxinA)—an acetylcholine release inhibitor and a neuromuscular blocking agent—for the treatment of OAB with symptoms of urge urinary incontinence, urgency, and frequency in adults who do not tolerate or do not adequately respond to anticholinergic agents.8 The approval of onabotulinumtoxinA was based on 2 clinical trials of 1105 patients who had symptoms of OAB.8 According to Hylton V. Joffe, MD, Director of the Division of Reproductive and Urologic Products at the FDA’s Center for Drug Evaluation and Research, “Clinical studies have demonstrated Botox’s ability to significantly reduce the frequency of urinary incontinence. Today’s approval provides an important additional treatment option for patients with overactive bladder, a condition that affects an estimated 33 million men and women in the United States.”8 OnabotulinumtoxinA was previously approved by the FDA for several other indications in adults, including the treatment of urinary incontinence resulting from detrusor overactivity associated with a neurologic condition, prophylaxis of headaches in patients with chronic migraines, the treatment of upper-limb spasticity, the treatment of cervical dystonia, the treatment of severe axillary hyperhidrosis that is inadequately managed by topical agents, and the treatment of blepharospasm that is associated with dystonia and strabismus in patients aged ≥12 years.9 Mechanism of Action OnabotulinumtoxinA blocks neuromuscular transmission by binding to acceptor sites on motor or sympa-

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Table 1 Study OAB-1: OnabotulinumtoxinA versus Placebo, Changes from Baseline in Key Parameters OnabotulinumtoxinA Placebo Key parameter 100 units (N = 278) (N = 272) Difference

P value

Daily frequency of urinary incontinence episodesa Mean baseline at week 2, N

5.5

5.1

LS mean change at week 2, N

–2.6

–1

–1.6

LS mean changeb at week 6, N

–2.8

–1

–1.8

LS mean change at week 12, N

–2.5

–0.9

–1.6 (95% CI, –2.1 to –1.2)

<.001

11.2

–1.9

–0.9

–1 (95% CI, –1.5 to –0.6)

<.001

156

161

30 (95% CI, 17 to 43)

<.001

Daily frequency of micturition (urination) episodes,d N Mean baseline Mean change at week 12

Volume voided per micturitiond (urination) Mean baseline, mL LS mean change at week 12, mL c

Primary variable. The last-observation-carried-forward values were used to analyze the primary efficacy variable. c Primary time point. d Secondary variable. CI indicates confidence interval; LS, least squared. Source: Botox (onabotulinumtoxinA) for injection prescribing information; 2013. a

thetic nerve terminals, entering the nerve terminals, and inhibiting the release of acetylcholine.9 The injection of onabotulinumtoxinA into the bladder wall (the detrusor muscle) relaxes the bladder, increasing its storage capacity and reducing urinary incontinence episodes.8

Dosing and Administration OnabotulinumtoxinA is available as single-use, sterile 100-unit or 200-unit vacuum-dried powder for reconstitution only with sterile, nonpreserved 0.9% sodium chloride injection USP before injection.9 The recommended total dose for OAB is 100 units, as 0.5-mL (5 units) injections across 20 sites into the detrusor muscle (ie, bladder wall). A total dose of 360 units should not be exceeded in a 3-month interval.9 The injection of onabotulinumtoxinA is administered via a cystoscope procedure that allows visualization of the bladder interior during the injection. A local anesthetic (with or without sedation) may be used before injection. If a local anesthetic instillation is performed, the bladder should be drained and irrigated with sterile saline before injection.9 Patients must not have a urinary tract infection (UTI) at the time of treatment. Prophylactic antibiotics, except aminoglycosides, should be administered 1 to 3 days before treatment, on the treatment day, and 1 to 3

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days after treatment to reduce the risk of procedure-related UTI. Patients receiving antiplatelet therapy should discontinue antiplatelet agents at least 3 days before the administration of onabotulinumtoxinA injection. These patients should also be managed appropriately to decrease the risk of bleeding.9

Clinical Trials The safety and efficacy of onabotulinumtoxinA for OAB were studied in 2 double-blind, placebo-controlled, 24-week trials with patients with OAB and symptoms of urge urinary incontinence, urgency, or frequency (Studies OAB-1 and OAB-2). These patients, whose symptoms were not adequately managed with anticholinergic therapy (ie, inadequate response or intolerable side effects), were randomized to receive either 100 units of onabotulinumtoxinA (N = 557) or placebo (N = 548). All patients received 20 injections of the study drug (5 units of onabotulinumtoxinA) or placebo, spaced approximately 1 cm apart into the detrusor muscle.9 The results of Study OAB-1 are shown in Table 1. At week 12, patients receiving onabotulinumtoxinA experienced urinary incontinence an average of 1.6 fewer episodes daily than patients who received placebo.9 In Study OAB-2 (Table 2), at week 12, patients in the onabotulinumtoxinA group experienced urinary in-

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Table 2 Study OAB-2: OnabotulinumtoxinA versus Placebo, Changes from Baseline in Key Parameters OnabotulinumtoxinA Placebo Key parameter 100 units (N = 275) (N = 269) Difference

P value

Daily frequency of urinary incontinence episodesa Mean baseline at week 2, N

5.5

5.7

LS mean change at week 2, N

–2.7

–1.1

–1.6

LS mean changeb at week 6, N

–3.1

–1.3

–1.8

–3

–1.1

–1.9 (95% CI, –2.5 to –1.4)

<.001

11.8

–2.3

–0.6

–1.7 (95% CI, –2.2 to –1.3)

<.001

144

153

31 (95% CI, 20 to 41)

<.001

LS mean change at week 12, N b

Daily frequency of micturition (urination) episodesd Mean baseline, N LS mean change at week 12, N c

Volume voided per micturitiond (urination) Mean baseline, mL LS mean change at week 12, mL c

continence an average of 1.9 fewer episodes daily than patients in the placebo group.9

Safety The most common adverse reactions reported in clinical trials that were reported in ≥5% of the patients using onabotulinumtoxinA (and occurred more often than with placebo) for OAB include UTI, dysuria (ie, painful urination), and urinary retention.9 However, onabotulinumtoxinA is potentially associated with serious risks and must be used with caution, according to the warnings and precautions noted below. Contraindications OnabotulinumtoxinA is contraindicated in persons who are hypersensitive to any botulinum toxin preparation or to any of the components in the formulation, or in persons who have an infection at the proposed injection site. In individuals receiving intradetrusor injections, onabotulinumtoxinA is contraindicated in persons with a UTI or with urinary retention.9 Boxed Warning OnabotulinumtoxinA was approved by the FDA with a boxed warning about the risk for distant spread of toxin effect, noting that this agent may affect areas away from

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the injection site to produce symptoms consistent with botulinum toxic effects, which have been reported hours to weeks after injection. Swallowing and breathing difficulties associated with this agent can be life-threatening, and there have been reports of death. The risk for symptoms is probably greatest in children treated for spasticity, but symptoms can also occur in adults, particularly in patients who have an underlying condition that would predispose them to these life-threatening symptoms.9

Warnings and Precautions Patients receiving concomitant onabotulinumtoxinA and aminoglycosides or other agents interfering with neuromuscular transmission (eg, curare-like agents), or muscle relaxants, should be observed closely, because the effects of onabotulinumtoxinA may be potentiated. Swallowing and breathing difficulties caused by the spread of toxin effects can lead to death. Immediate medical attention should be sought if respiratory, speech, or swallowing difficulties occur with the use of this agent. The potency units of onabotulinumtoxinA are not interchangeable with other preparations of botulinum toxin products.9 Use in Specific Patient Populations OnabotulinumtoxinA should be used with caution in

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patients with compromised respiratory function. The presence of a concomitant neuromuscular disorder may exacerbate the clinical effects of treatment with onabotulinumtoxinA and should be carefully considered. Because onabotulinumtoxinA increases the incidence of UTI, clinical trials for OAB excluded patients with more than 2 UTIs in the preceding 6 months and patients taking antibiotics chronically for recurrent UTIs. The use of onabotulinumtoxinA for the treatment of OAB in such patients and in patients with multiple recurrent UTIs during treatment should only be considered when the benefit is likely to outweigh the potential risk.

The safety and effectiveness of onabotulinumtoxinA were demonstrated in 2 clinical trials involving more than 1100 patients with symptoms of OAB. At 12 weeks, patients who received onabotulinumtoxinA had an average of 1.6 to 1.9 fewer urinary incontinence episodes daily than patients receiving placebo. Postvoid residual urine volume should be monitored in patients who are receiving treatment for OAB or for detrusor muscle overactivity associated with a neurologic condition who do not catheterize routinely, particularly patients with multiple sclerosis or diabetes mellitus.9

Conclusion Another therapeutic option for OAB became available in 2013 when the FDA approved an expanded indication for onabotulinumtoxinA to treat adults with

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symptoms of urge urinary incontinence, urgency, or frequency, who have an inadequate response to or are intolerant of anticholinergic agents. OnabotulinumtoxinA is administered via injection into the detrusor muscle. The safety and effectiveness of onabotulinumtoxinA were demonstrated in 2 clinical trials involving more than 1100 patients with symptoms of OAB. At 12 weeks, patients who received onabotulinumtoxinA had an average of 1.6 to 1.9 fewer urinary incontinence episodes daily than patients receiving placebo. Moreover, patients in the onabotulinumtoxinA group needed to urinate an average of 1 to 1.7 fewer episodes daily and voided an average of approximately 30 mL more urine than patients in the group receiving placebo. The most common adverse events (â&#x2030;Ľ5% and greater than with placebo) associated with the use of onabotulinumtoxinA in the treatment of OAB were UTI, dysuria, and urinary retention. n

References

1. Gormley EA, Lightner DJ, Burgio KL, et al. American Urological Association (AUA) guideline: diagnosis and treatment of overactive bladder (non-neurogenic) in adults: AUA/SUFU guideline. Approved May 2012. www.auanet.org/common/pdf/ education/clinical-guidance/Overactive-Bladder.pdf. Accessed July 18, 2013. 2. Urology Care Foundation. Overactive bladder (OAB). Updated March 2013. www.urologyhealth.org/urology/index.cfm?article=112. Accessed July 21, 2013. 3. Mayo Clinic staff. Overactive bladder: treatment and drugs. January 16, 2013. www.mayoclinic.com/health/overactive-bladder/DS00827/DSECTION=treatmentsand-drugs. Accessed July 22, 2013. 4. Mullins CD, Subak LL. New perspectives on overactive bladder: quality of life impact, medication persistency, and treatment costs. Am J Manag Care. 2005;11(4 suppl):S101-S102. 5. Onukwugha E, Zuckerman IH, McNally D, et al. The total economic burden of overactive bladder in the United States: a disease-specific approach. Am J Manag Care. 2009;15:S90-S97. 6. Zhou Z, Jensen GA. Insurance claim costs for overactive bladder disorder. Medscape Today News. 2001. www.medscape.com/viewarticle/409985. Accessed July 23, 2013. 7. Hu TW, Wagner TH. Health-related consequences of overactive bladder: an economic perspective. BJU Int. 2005;96(suppl 1):43-45. 8. US Food and Drug Administration. FDA approves Botox to treat overactive bladder. Press release. January 18, 2013. Updated January 22, 2013. www.fda.gov/NewsEvents/ Newsroom/PressAnnouncements/ucm336101.htm. Accessed July 15, 2013. 9. Botox (onabotulinumtoxinA) for injection [prescribing information]. Irvine, CA: Allergan, Inc; January 2013.

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Breo Ellipta (Fluticasone Furoate/ Vilanterol): Fixed-Dose Combination Oral

Inhaler Receives FDA Approval for Long-Term Maintenance Treatment of COPD By Loretta Fala, Medical Writer

hronic obstructive pulmonary disease (COPD) is a common, life-threatening disease characterized by a persistent blockage of airflow from the lungs.1,2 COPD encompasses a range of chronic obstructive lung diseases, including chronic bronchitis and emphysema.1 In 2010, an estimated 14.8 million people were diagnosed with COPD in the United States.3 Yet, as many as 12 million additional people are estimated to have COPD that has not been diagnosed.3 COPD is a major cause of disability and the third leading cause of mortality in the United States, responsible for more than 124,000 deaths annually.4,5 Although COPD can occur in younger people, it has a pronounced impact on the elderly population. Moreover, whereas in the past men were 6 times more likely than women to die of COPD, today more women than men die from COPD annually.1 Deaths attributed to COPD are projected to rise by more than 30% globally over the next decade, unless urgent steps are taken to reduce risk factors, including tobacco use and exposure, and other environmental factors.2 However, it has come to light in recent years that as many as 10% to 20% of patients with COPD have never smoked, indicating that genetic and environmental factors play a larger role than previously thought.1 Recent research also suggests that COPD may have a strong inflammatory and immune component.1 According to recent data from the Centers for Disease Control and Prevention, the prevalence of COPD has increased and now affects >11.6% of people aged â&#x2030;Ľ65 years.6 For elderly patients with COPD, polypharmacy for multiple medical conditions may present challenges for COPD treatment adherence.7 In general, nonadherence to COPD therapy, pharmacologic and nonpharmacologic, is common and may contribute to adverse health outcomes and higher healthcare costs.8 In addition, underuse, overuse, and improper use of treatments contribute to suboptimal adherence to therapy for COPD.9 Adherence to treatments for COPD may be further complicated, given the chronic nature of COPD, the presence of comorbidities (ie,

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hypertension, diabetes, cardiovascular disease, lung cancer, and depression), the use of multiple medications, and periods of symptom remission.9,10 COPD is associated with substantial respiratory-related and total healthcare costs. In 2010, the total annual cost of COPD in the United States was an estimated $49.9 billion, of which $29.5 billion accounted for direct costs, $8 billion for indirect costs for associated morbidity, and $12.4 billion for indirect costs related to COPD mortality.4 COPD is frequently misdiagnosed and may go undetected for years.11 The early diagnosis and appropriate management of COPD are essential, because COPD may worsen over time. Effective management can help control symptoms, reduce the risk of exacerbations and complications, slow disease progression, and, in some cases, can improve a personâ&#x20AC;&#x2122;s ability to lead an active life.11 Therapeutic goals for COPD include preventing and treating exacerbations, reducing hospitalizations and mortality, relieving dyspnea that restricts activity, and increasing exercise tolerance and health-related quality of life.12 Smoking cessation is crucial for smokers with COPD.11 Pharmacologic treatments include bronchodilators (short-acting and long-acting), inhaled steroids, oral steroids, combination inhalers, phosphodiesterase-4 inhibitors, theophylline, and antibiotics. Other therapies include oxygen therapy and lifestyle changes. Surgery may also be an option for some patients with severe disease who do not respond to other treatments.11

Breo Ellipta: A New, Fixed-Dose Combination Inhaler Approved for COPD On May 10, 2013, the US Food and Drug Administration (FDA) approved fluticasone furoate/vilanterol inhalation powder (Breo Ellipta; GlaxoSmithKline) as oral inhalation for the long-term, once-daily, maintenance treatment of airflow obstruction in patients with COPD, including chronic bronchitis and/or emphysema. Fluticasone furoate/vilanterol is also indicated to reduce exacerbations of COPD in patients with a history of exacerbations. Fluticasone furoate/vilanterol is

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not indicated for the relief of acute bronchospasm or for the treatment of asthma, and is not recommended in patients younger than age 18 years.13,14 Curtis J. Rosebraugh, MD, MPH, Director, Office of Drug Evaluation II, Center for Drug Evaluation and Research at the FDA, stated, “The availability of new longterm maintenance medications provides additional treatment options for the millions of Americans who suffer with COPD.”13 The safety and efficacy of fluticasone furoate/vilanterol were evaluated in studies that included 7700 patients with a clinical diagnosis of COPD.13 As part of the approval, the FDA required that fluticasone furoate/vilanterol be accompanied by a patient medication guide with instructions for use and information about the potential risks of taking the drug.13 The prescribing information for fluticasone furoate/ vilanterol includes a Boxed Warning stating that long- acting beta-adrenergic agonists (LABAs), such as vilanterol, one of the ingredients in this combination, are associated with an increased risk of asthma-related death. It also states that the safety and efficacy of fluticasone furoate/vilanterol in patients with asthma have not been established, and that it is not indicated for the treatment of asthma.14

Mechanism of Action Fluticasone furoate/vilanterol contains 2 different classes of drugs—fluticasone furoate, a synthetic trifluorinated corticosteroid, and vilanterol, a LABA. Each of these 2 drugs has a different mechanism of action. Fluticasone Furoate Fluticasone furoate, a synthetic trifluorinated corticosteroid, has anti-inflammatory activity and has been shown in vitro to have a binding affinity for the glucocorticoid receptor that is approximately 29.9 times that of dexamethasone and 1.7 times that of fluticasone propionate. The clinical relevance of these in vitro results is unknown.14 The precise mechanism through which fluticasone furoate affects the symptoms of COPD is not known. Corticosteroids have been shown to have a wide range of actions on multiple cell types and mediators. In vitro and in vivo models have demonstrated specific effects of fluticasone furoate, including activation of the glucocorticoid response element, inhibition of proinflammatory transcription factors (eg, nuclear factor-kappa beta), and inhibition of antigen-induced lung eosinophilia in sensitized rats.14 Vilanterol Inhalation Powder Vilanterol inhalation powder was shown to have a

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functional selectivity similar to salmeterol based on in vitro tests. The clinical relevance of this in vitro finding is unknown. The pharmacologic effects of beta-2 adrenoceptor agonist drugs, including vilanterol, are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of aden osine triphosphate to 3ʹ, 5ʹ-cyclic-adenosine monophosphate (cAMP). Increased cAMP levels cause relaxation of bronchial smooth muscle and inhibition of the release of mediators of immediate hypersensitivity from cells, especially from mast cells.14

Dosing Fluticasone furoate/vilanterol is indicated for oral inhalation only. The recommended dosage for maintenance treatment of COPD is 1 inhalation of fluticasone furoate 100 mcg/vilanterol 25 mcg once daily. The fluticasone furoate/vilanterol inhaler contains 2 double-foil blister strips of powder formulation for oral inhalation: one strip contains fluticasone furoate 100 mcg per blister, and the other contains vilanterol 25 mcg per blister.14 Clinical Studies The FDA approval of fluticasone furoate/vilanterol was based on 4 confirmatory trials (of 6- and 12-months’ duration), 3 active comparator trials (of 12 weeks’ duration), and dose-ranging trials of shorter duration.14 Findings from 2 of the confirmatory trials related to lung function are highlighted below. Of the 2254 patients enrolled in these 2 trials, 70% were male and 84% were Caucasian (mean age, 62 years), with an average smoking history of 44 pack-years; 54% of the patients were identified as current smokers. In these 2 trials, all treatments were administered as 1 inhalation once daily.14 Confirmatory Lung Function Trial 1 Trial 1 was a 24-week, randomized, double-blind, placebo-controlled study that evaluated the efficacy of 2 strengths of fluticasone furoate/vilanterol on lung function in patients with COPD (Table 1). In this study, fluticasone furoate/vilanterol demonstrated rapid and significant sustained improvement in forced expiratory volume in 1 second (FEV1) in patients with moderate-to-severe COPD, which was not influenced by the dose.14,15 Confirmatory Lung Function Trial 2 In trial 2, a 24-week, randomized, double-blind, placebo-controlled study, combination therapy with fluticasone furoate 100 mcg/vilanterol 25 mcg significantly improved the weighted mean FEV1 (173 mL) and trough

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onfirmatory Trial 1: Change from Baselinea in Weighted Mean FEV1 (0-4 Hours) and Table 1 C Trough FEV1 at 6 Months Weighted mean FEV1 (0-4 hours)b

Trough FEV1c

Difference from

Placebo, mL

Fluticasone furoate 100 mcg, mL

Fluticasone furoate 200 mcg, mL

Breo Ellipta (fluticasone furoate 100 mcg/vilanterol 25 mcg) (N = 204)

214 (95% confidence interval, 161-266)

168 (95% confidence interval, 116-220)

—

Fluticasone furoate 200 mcg/vilanterol 25 mcg (N = 205)

209 (95% confidence interval, 157-261)

—

Treatment

Placebo, mL

Vilanterol 25 mcg, mL

144 45 (95% confidence (95% confidence interval, 91-197) interval, –8-97)

168 131 32 (95% confidence (95% confidence (95% confidence interval, 117-219) interval, 80-183) interval, –19-83)

NOTE: Serial spirometric evaluations were performed predose and up to 4 hours after dosing. Least squares mean change. b At day 168. c At day 169. FEV1 indicates forced expiratory volume in 1 second. Source: Breo Ellipta (fluticasone furoate/vilanterol) prescribing information; 2013. a

onfirmatory Trial 2: Change from Baselinea in Weighted Mean FEV1 (0-4 Hours) and Table 2 C Trough FEV1 at 6 Months Trough FEV1c

Difference from

Placebo, mL

Fluticasone furoate 100 mcg, mL

Fluticasone furoate 200 mcg, mL

173 (95% confidence interval, 123-224)

120 (95% confidence interval, 70-170)

—

Treatment Breo Ellipta (fluticasone furoate 100 mcg/vilanterol 25 mcg) (N = 206)

Weighted mean FEV1 (0-4 hours)b

Placebo, mL

Vilanterol 25 mcg, mL

115 48 (95% confidence (95% confidence interval, 60-169) interval, –6-102)

FEV1 (115 mL) versus placebo (P <.001) in patients with moderate-to-severe COPD (Table 2).14,16 All treatments in this study were well-tolerated.16 Overall, fluticasone furoate 100 mcg/vilanterol 25 mcg resulted in a larger increase in the weighted mean FEV1 (from 0 hours to 4 hours) compared with placebo and with fluticasone furoate 100 mcg at day 168. At day 169, trials 1 and 2 showed a significant increase in trough FEV1 for all strengths of fluticasone furoate/vilanterol compared with placebo.14

Adverse Events and Contraindications The most common adverse reactions (incidence, ≥3%) associated with fluticasone furoate/vilanterol are

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nasopharyngitis, upper respiratory tract infection, headache, and oral candidiasis.14 Fluticasone furoate/vilanterol is contraindicated in patients with severe hypersensitivity to milk proteins or those who have demonstrated hypersensitivity to either fluticasone furoate, vilanterol, or any of the excipients.

Warnings and Precautions Fluticasone furoate/vilanterol should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of COPD, or as rescue therapy for the treatment of acute episodes of bronchospasm, which should be treated with an inhaled, short-acting beta-2 agonist.14

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Fluticasone furoate/vilanterol should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medications containing LABAs, because an overdose may result. Oropharyngeal candidiasis has occurred in patients treated with fluticasone furoate/vilanterol. Patients should be monitored periodically and be advised to rinse the mouth without swallowing after inhalation of this agent to help reduce this risk of infection. There is an increased risk for pneumonia in patients with COPD who are taking fluticasone furoate/vilanterol. Patients should be monitored for signs and symptoms of pneumonia.

Fluticasone furoate/vilanterol was shown to improve lung function and reduce exacerbations compared with placebo in several clinical trials. Patients who use corticosteroids are at risk for potential worsening of existing tuberculosis; fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex. A more serious or even fatal course of chickenpox or measles may occur in susceptible patients. There is an increased risk of impaired adrenal function when patients are transferred from systemic corticosteroids. Patients should be tapered slowly from systemic corticosteroids when being transferred to fluticasone furoate/vilanterol. Hypercorticism and adrenal suppression may occur with very high dosages or at the regular dosage of inhaled corticosteroids in susceptible individuals. If such changes occur, fluticasone furoate/vilanterol should be discontinued slowly. Inhaled medications can produce paradoxical bronchospasm, which may be life-threatening. Vilanterol, the LABA in the fluticasone furoate/vilanterol combination, can produce clinically significant cardiovascular effects in some patients. Decreases in bone mineral density have been observed with long-term administration of products containing inhaled corticosteroids, as have glaucoma, increased intraocular pressure, and cataracts. It is recommended that patients be monitored for decreased bone mineral density, glaucoma, and cataracts. Fluticasone furoate/vilanterol should be used with caution in patients with cardiovascular disorders, especially those with coronary insufficiency, cardiac arrhythmias, and hypertension, because of beta-adrenergic stimulation. Caution should be exercised when considering the coadministration of fluticasone furoate/vilanterol with long-term ketoconazole and other known strong

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CYP3A4 inhibitors, because increased systemic corticosteroid and cardiovascular adverse effects may occur. Fluticasone furoate/vilanterol should be used with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, and ketoacidosis. Clinicians should also be alert to hypokalemia and hyperglycemia.

Conclusion A new treatment option for COPD became available in May 2013 when fluticasone furoate/vilanterol received FDA approval for the long-term, once-daily maintenance treatment of airflow obstruction and for reducing exacerbations in patients with COPD. Breo Ellipta is a fixed-dose combination of fluticasone furoate 100 mcg, an inhaled corticosteroid, and vilanterol 25 mcg, a LABA. Fluticasone furoate/vilanterol was shown to improve lung function and reduce exacerbations compared with placebo in several clinical trials that included a total of 7700 patients with a clinical diagnosis of COPD. The most common adverse reactions reported with fluticasone furoate/vilanterol in clinical trials were naso pharyngitis, upper respiratory tract infection, headache, and oral candidiasis. n References

1. National Institutes of Health. Chronic obstructive pulmonary disease (COPD). NIH Research Timeline fact sheet. Updated March 29, 2013. http://report.nih.gov/ NIHfactsheets/ViewFactSheet.aspx?csid=77. Accessed June 19, 2013. 2. World Health Organization. Chronic obstructive pulmonary disease (COPD). Fact sheet. Updated November 2012. www.who.int/mediacentre/factsheets/fs315/en/ index.html. Accessed June 20, 2013. 3. National Heart, Lung, and Blood Institute. Morbidity & Mortality: 2012 Chart Book on Cardiovascular, Lung, and Blood Diseases. February 2012. www.nhlbi.nih. gov/resources/docs/2012_ChartBook.pdf. Accessed June 19, 2013. 4. American Lung Association. Chronic obstructive pulmonary disease (COPD) fact sheet. February 2011. www.lung.org/lung-disease/copd/resources/facts-figures/COPDFact-Sheet.html. Accessed June 20, 2013. 5. National Heart, Lung, and Blood Institute. What is COPD? www.nhlbi.nih.gov/ health/public/lung/copd/what-is-copd/index.htm. Accessed June 20, 2013. 6. Centers for Disease Control and Prevention (CDC). Chronic obstructive pulmonary disease among adults—United States, 2011. MMWR Morb Mortal Wkly Rep. 2012;61:938-943. 7. Hanania NA, Sharma G, Sharafkhaneh A. COPD in the elderly patient. Semin Respir Crit Care Med. 2010;31:596-606. 8. Bourbeau J, Bartlett SJ. Patient adherence in COPD. Thorax. 2008;63:831-838. 9. Restrepo RD, Alvarez MT, Wittnebel LD, et al. Medication adherence issues in patients treated for COPD. Int J Chron Obstruct Pulmon Dis. 2008;3:371-384. 10. Crockett AJ, Price D. Co-morbid disease in COPD—more than a coincidence. Int J Chron Obstruct Pulmon Dis. 2007;2:399-400. 11. Mayo Clinic. COPD. February 1, 2013. www.mayoclinic.com/health/copd/ DS00916. Accessed June 20, 2013. 12. Armstrong C. Practice guidelines: ACP updates guideline on diagnosis and management of stable COPD. Am Fam Physician. 2012;85:204-205. 13. US Food and Drug Administration. FDA approves Breo Ellipta to treat chronic obstructive pulmonary disease. Press release; May 10, 2013. www.fda.gov/News Events/Newsroom/PressAnnouncements/ucm351664.htm. Accessed June 20, 2013. 14. Breo Ellipta (fluticasone furoate and vilanterol inhalation powder) [prescribing information]. Research Triangle Park, NC: GlaxoSmithKline; May 2013. 15. Martinez FJ, Boscia J, Feldman G, et al. Fluticasone furoate/vilanterol (100/25; 200/25 µg) improves lung function in COPD: a randomised trial. Respir Med. 2013; 107:550-559. 16. Kerwin EM, Scott-Wilson C, Sanford L, et al. A randomised trial of fluticasone furoate/vilanterol (50/25 µg; 100/25 µg) on lung function in COPD. Respir Med. 2013;107:560-569.

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Brintellix Tablets (Vortioxetine) Approved by the FDA for the Treatment of Major Depressive Disorder By Loretta Fala, Medical Writer

ajor depressive disorder (MDD) is a common, chronic medical illness that affects 5% to 8% of adults in the United States annually, which amounts to approximately 25 million people.1 Although MDD is treatable in most people, only 50% of patients with MDD ever receive treatment.1,2 Also known as clinical depression, MDD is associated with serious emotional and biological manifestations that impact a person’s thoughts, feelings, mood, behavior, and physical health.3 MDD can disrupt life and health by causing changes in sleep patterns or appetite, poor concentration, loss of energy, low self-esteem, hopelessness, or guilt.2 Overall, MDD occurs 70% more frequently in women than in men.1 In people with chronic diseases (eg, heart disease, diabetes, or cancer), the prevalence of MDD ranges from 10% to 65%.4 MDD can also negatively affect the course of these chronic illnesses.4 Moreover, it is estimated that as many as 30% of drug and alcohol users may have undetected MDD.4 Without appropriate treatment, the severity and frequency of MDD symptoms generally increase over time.1 In fact, without treatment, an MDD episode can last from several months to years.2 Untreated MDD also increases the risk of suicide—the eleventh leading cause of death in the United States.4 More than 15% of Americans with depression take their own lives.4 The average annual cost of MDD in the United States is an estimated $83.0 billion, which includes $26.1 billion in direct medical costs, $5.4 billion in suicide-related mortality costs, and $51.5 billion in workplace-related costs.5 MDD is associated with more employee sick days and more rates of short-term disability than other chronic diseases.4 MDD is managed with pharmacologic therapy, psychotherapy, and electroconvulsive therapy (used for some severe episodes or severe depression with psychosis).2 Other forms of treatment may include transcranial magnetic stimulation, aerobic exercise, and complementary and alternative medicines.2 Antidepressant agents used to treat MDD include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), norepinephrine and dopamine re-

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uptake inhibitors, atypical antidepressants, tricyclic antidepressants, monoamine oxidase inhibitors (MAOIs), or other medication strategies that include appropriate combination and augmentation therapy approaches.3 For most adult patients with MDD, a combination of medication and psychotherapy is the most effective management approach. Early detection, diagnosis, and treatment are crucial to improving outcomes for people with MDD.2

A New Treatment Option for MDD In September 2013, the US Food and Drug Administration (FDA) approved vortioxetine (Brintellix; Takeda Pharmaceuticals) for the treatment of adult patients with MDD.6 Vortioxetine is an immediate-release tablet for oral administration that contains the beta-polymorph of vortioxetine hydrobromide, an antidepressant. This novel agent is thought to act multimodally via several mechanisms of action, including the serotonin (5-hydroxytryptamine [5-HT]) reuptake inhibition, as well as via 5-HT3 receptor antagonism and 5-HT1A receptor agonism.7 According to Mitchell Mathis, MD, Acting Director of the Division of Psychiatry Products in the FDA’s Center for Drug Evaluation and Research, “Major depressive disorder can be disabling and can keep a person from functioning normally.” Commenting on the FDA approval of vortioxetine, Dr Mathis added, “Since medications affect everyone differently, it is important to have a variety of treatment options available for patients who suffer from depression.”6 Dosing Vortioxetine is available as 5-mg, 10-mg, 15-mg, and 20-mg immediate-release tablets. The recommended starting dose of vortioxetine is 10 mg administered orally once daily without regard to meals. The dose should then be increased to 20 mg daily, as tolerated. A 5-mg daily dose should be considered for patients who do not tolerate higher doses. Vortioxetine can be discontinued abruptly; however, it is recommended that doses of 15 mg daily or 20 mg daily be reduced to 10 mg daily for 1 week before full discontinuation, if possible.

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For patients known to be poor metabolizers of the cytochrome (CY) P2D6 enzyme, the maximum recommended dose of vortioxetine is 10 mg daily.

Although the mechanism of action of vortioxetine is not fully understood, it is thought to be related to its enhancement of serotonergic activity in the central nervous system through the inhibition of the reuptake of 5-HT. Vortioxetine has several other activities, including 5-HT3 receptor antagonism and 5-HT1A receptor agonism. Mechanism of Action Although the mechanism of action of vortioxetine is not fully understood, it is thought to be related to its enhancement of serotonergic activity in the central nervous system through the inhibition of the reuptake of 5-HT. Vortioxetine has several other activities, including 5-HT3 receptor antagonism and 5-HT1A receptor agonism. The contribution of these activities to vortioxetine’s antidepressant effect has not been established.7 Vortioxetine is extensively metabolized primarily through oxidation via the CYP450 isozymes CYP2D6, CYP3A4/5, CYP2C19, CYP2C9, CYP2A6, CYP2C8, and CYP2B6, and subsequent glucuronic acid conjugation. CYP2D6 is the primary enzyme catalyzing the metabolism of vortioxetine to its major, pharmacologically inactive, carboxylic acid metabolite, and poor metabolizers of CYP2D6 have approximately twice the vortioxetine plasma concentration of extensive metabolizers.7 Clinical Studies of Vortioxetine The efficacy of vortioxetine was established in 6 randomized, double-blind, placebo-controlled, 6- to 8-week fixed-dose clinical trials, including a study in the elderly and a maintenance study in adult inpatients and outpatients who met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IVTR) criteria for MDD.7 Studies 1-5 In studies 1 through 5 in adults with MDD (aged 18-75 years), patients were randomized to vortioxetine 5 mg, 10 mg, 15 mg, or 20 mg or to placebo once daily. For patients who were randomized to vortioxetine 15 mg daily or 20 mg daily, the final doses were titrated up from 10 mg daily after the first week.7 The primary efficacy measures in these studies in-

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cluded the Hamilton Rating Scale for Depression total score in study 2 and the Montgomery-Åsberg Depression Rating Scale (MADRS) total score in all the other studies. The efficacy results of studies 1 through 5 are shown in Table 1. In each of these studies, at least 1 dose cohort of vortioxetine was superior to placebo in the improvement of depressive symptoms as measured by mean change from baseline to end point visit on the primary efficacy measurement. Moreover, a subgroup analysis by age, sex, or race did not suggest any clear evidence of differential responsiveness. However, 2 studies conducted in the United States with the 5-mg dose (not shown in Table 1) failed to show effectiveness.7

Study 6: Elderly Study The efficacy of vortioxetine for the treatment of patients with MDD was also demonstrated in a randomized, double-blind, placebo-controlled, fixed-dose trial of older patients with MDD aged 64 to 88 years. The patients who met the criteria for recurrent MDD, and with at least 1 previous major depressive episode before the age of 60 years and without comorbid cognitive impairment (based on a Mini-Mental State Examination score of <24), received vortioxetine 5 mg or placebo. The results of study 6 are shown in Table 1.7 Maintenance Study In a non-US maintenance study, 639 patients who met the DSM-IV-TR criteria for MDD received flexible doses of vortioxetine (5 mg or 10 mg) once daily during an initial 12-week, open-label treatment phase. During weeks 8 to 12, the dose of vortioxetine was fixed. In addition, 396 patients, who were in remission after the open-label treatment, were randomly assigned to continuation of a fixed dose of vortioxetine at the final dose they had responded to (approximately 75% of the patients were receiving 10 mg daily) during the open-label phase or to placebo for 24 to 64 weeks. Approximately 61% of randomized patients satisfied the remission criterion (MADRS total score ≤10) for at least 4 weeks (since week 8), and 15% satisfied the remission criterion for at least 8 weeks (since week 4). Patients receiving vortioxetine experienced a significantly longer time to recurrence of depressive episodes than patients receiving placebo. The recurrence of depressive episode was defined as a MADRS total score of ≥22 or a lack of efficacy as judged by the investigator.7 Course of Treatment Response In the 6- to 8-week placebo-controlled studies, an effect of vortioxetine based on the primary efficacy measure was generally observed starting at week 2 and increased in

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Table 1 Vortioxetine: Primary Efficacy Results of 6- to 8-Week Clinical Trials in Patients with MDD Primary Least-squares Placebo-subtracted Study/ measure Treatment group Mean baseline mean change from differencea population instrument (patients) score (SD) baseline (SE) (95% CI) Study 1: Non-US

Study 2: Non-US

Study 3: Non-US

Study 4: US

Study 5: US

Study 6: Elderly; US + non-US

MADRS

HAMD-24

MADRS

MADRS (US study)

MADRS

HAMD-24

Vortioxetine 5 mg dailyb (N = 108)

34.1 (2.6)

–20.4 (1)

–5.9 (–8.6 to –3.2)

Vortioxetine 10 mg dailyb (N = 100)

34 (2.8)

–20.2 (1)

–5.7 (–8.5 to –2.9)

Placebo (N = 105)

33.9 (2.7)

–14.5 (1)

—

Vortioxetine 5 mg daily (N = 139)

32.2 (5)

–15.4 (0.7)

–4.1 (–6.2 to –2.1)

Vortioxetine 10 mg dailyb (N = 139)

33.1 (4.8)

–16.2 (0.8)

–4.9 (–7 to –2.9)

Placebo (N = 139)

32.7 (4.4)

–11.3 (0.7)

—

31.8 (3.4)

–17.2 (0.8)

–5.5 (–7.7 to –3.4)

Vortioxetine 20 mg dailyb (N = 151)

31.2 (3.4)

–18.8 (0.8)

–7.1 (–9.2 to –5)

Placebo (N = 158)

31.5 (3.6)

–11.7 (0.8)

—

Vortioxetine 15 mg daily (N = 145)

31.9 (4.1)

–14.3 (0.9)

–1.5 (–3.9 to 0.9)

Vortioxetine 20 mg dailyb (N = 147)

32 (4.4)

–15.6 (0.9)

–2.8 (–5.1 to –0.4)

Placebo (N = 153)

31.5 (4.2)

–12.8 (0.8)

—

Vortioxetine 10 mg daily (N = 154)

32.2 (4.5)

–13 (0.8)

–2.2 (–4.5 to 0.1)

Vortioxetine 20 mg dailyb (N = 148)

32.5 (4.3)

–14.4 (0.9)

–3.6 (–5.9 to –1.4)

Placebo (N = 155)

32 (4.0)

–10.8 (0.8)

—

29.2 (5)

–13.7 (0.7)

–3.3 (–5.3 to –1.3)

29.4 (5.1)

–10.3 (0.8)

—

Vortioxetine 15 mg daily (N = 149)

Vortioxetine 5 mg daily (N = 155)

Placebo (N = 145)

Difference (drug minus placebo) in least-squares mean change from baseline. Doses that are significantly superior to placebo after adjusting for multiplicity. CI indicates confidence interval; HAMD-24, Hamilton Rating Scale for Depression; MADRS, Montgomery-Åsberg Depression Rating Scale; MDD, major depressive disorder; SD, standard deviation; SE, standard error; US, United States. Source: Brintellix (vortioxetine) tablets prescribing information; 2013. a

subsequent weeks, with the full antidepressant effect of vortioxetine generally not seen until week 4 or later.7

Adverse Events The most common adverse reactions—incidence ≥5% and at least twice the rate of placebo—reported with vortioxetine include nausea, constipation, and vomiting.7 The incidence of common adverse reactions that occurred in ≥2% of patients with MDD in clinical trials who were treated with vortioxetine and at least 2% more frequently than in patients who received placebo

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in the 6- to 8-week placebo-controlled trials included gastrointestinal events, dizziness, abnormal dreams, and pruritus (Table 2).7 Nausea was the most common adverse reaction; its frequency was dose-related.7

Warnings and Precautions Boxed warning. Vortioxetine and other antidepressants have a boxed warning stating that antidepressants can increase the risk of suicidal thoughts and behavior in children, adolescents, and young adults (aged 18-24 years) during initial treatment. These studies did not show an in-

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ommon Adverse Reactions in ≥2% of Patients Receiving Vortioxetine and ≥2% Greater than in Patients Table 2 C Receiving Placebo Vortioxetine Vortioxetine Vortioxetine Vortioxetine System organ class 5 mg daily, % 10 mg daily, % 15 mg daily, % 20 mg daily, % Placebo, % preferred term (N = 1013) (N = 699) (N = 449) (N = 455) (N = 1621) Gastrointestinal disorders Nausea

Diarrhea

Dry mouth

Constipation

Vomiting

Flatulence

Nervous system disorders Dizziness Psychiatric disorders Abnormal dreams Skin and subcutaneous tissue disorders Pruritusa

Includes pruritus generalized. Source: Brintellix (vortioxetine) tablets prescribing information; 2013.

crease in the risk of suicidal thoughts and behavior with the use of antidepressants in patients aged >24 years; there was a trend toward a reduced risk of suicidal thoughts and behavior with antidepressant use in patients aged ≥65 years.7 Contraindication. Vortioxetine is contraindicated in patients who are hypersensitive to vortioxetine or any components of the formulation. Discontinuation. At least 14 days should elapse between the discontinuation of an MAOI intended to treat psychiatric disorders and the initiation of therapy with vortioxetine to avoid the risk of serotonin syndrome. Conversely, at least 21 days should be allowed after stopping vortioxetine before starting an MAOI intended to treat psychiatric disorders. Vortioxetine treatment should not be initiated in patients who are being treated with linezo lid or intravenous methylene blue.7 Serotonin syndrome. Serotonin syndrome has been reported with serotonergic antidepressants (eg, SSRIs, SNRIs), including with vortioxetine, when taken alone, and especially when coadministered with other serotonergic agents (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St John’s wort). If such symptoms occur, vortioxetine should be discontinued and supportive treatment should be initiated. If concomitant use of vortioxetine is clinically warranted, patients should be made aware of a potential increased risk for serotonin

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syndrome, particularly during treatment initiation and dose increases.7 Abnormal bleeding. Treatment with serotonergic antidepressants (eg, SSRIs, SNRIs) may increase the risk of abnormal bleeding. Patients should be cautioned about the increased risk of bleeding when vortioxetine is coadministered with nonsteroidal anti-inflammatory drugs, including aspirin, or other drugs that affect coagulation. Mania and hypomania. The activation of mania and hypomania can occur with antidepressant treatment. Patients should be screened for bipolar disorder before administering vortioxetine. Hyponatremia. This condition can occur in association with the syndrome of inappropriate antidiuretic hormone secretion.7

Drug Interactions The concomitant administration of vortioxetine and strong CYP2D6 inhibitors (eg, bupropion, fluoxetine, paroxetine, or quinidine) may require a 50% reduction in the vortioxetine dose.7 When vortioxetine is coadministered with a strong CYP inducer (eg, rifampin, carbamazepine, or pheny toin) for more than 14 days, an increased vortioxetine dose can be considered. The maximum recommended dose should not exceed 3 times the original dose.7

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Use in Specific Populations Pregnancy. No adequate and well-controlled studies of vortioxetine have been conducted in pregnant women. Vortioxetine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.7 Nursing mothers. It is not known whether vortioxetine is present in human milk. Because many drugs are present in human milk, and because of the potential for serious adverse reactions in nursing infants from vortioxetine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric use. The safety and effectiveness of vortioxetine in the pediatric population have not beenÂ established.7 Geriatric use. No dose adjustment of vortioxetine is recommended on the basis of age. Results from a single-dose pharmacokinetic study in elderly (aged >65 years) patients versus young (aged 24-45 years) patients demonstrated that the pharmacokinetics were generally similar between the 2 age-groups.7 Other populations. No dose adjustment of vortioxetine on the basis of race, sex, ethnicity, or renal function (from mild renal impairment to end-stage renal disease) is necessary. The same dose can be administered in patients with mild-to-moderate hepatic impairment. Vortioxetine has not been studied in patients with severe hepatic impairment, and is therefore not recommended for use in these patients.7 Conclusion MDD is a common and chronic condition with a considerable clinical and economic burden. Although many antidepressants are available, patients respond to each medication differently. The approval of vortioxe-

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tine by the FDA for the treatment of patients with MDD adds a new therapeutic option that is thought to act through multiple mechanisms of action that may benefit patients who do not respond well to current therapies.

The approval of vortioxetine by the FDA for the treatment of patients with MDD adds a new therapeutic option that is thought to act through multiple mechanisms of action that may benefit patients who do not respond well to current therapies. The efficacy of vortioxetine was demonstrated in 6 randomized, double-blind, placebo-controlled fixed-dose studies, including a study in the elderly and a maintenance study in adults with MDD. The most common adverse reactions (incidence â&#x2030;Ľ5% and at least twice the rate of placebo) associated with vortioxetine were nausea, constipation, and vomiting. n

References

1. National Alliance on Mental Illness. What is depression? www.nami.org/Template. cfm?Section=depression. Accessed October 29, 2013. 2. National Alliance on Mental Illness. Major depression fact sheet. Reviewed April 2013. www.nami.org/factsheets/depression_factsheet.pdf. Accessed October 30, 2013. 3. Mayo Clinic staff. Depression (major depression). February 10, 2012. www.mayo clinic.com/health/depression/DS00175/FLUSHCACHE=0&UPDATEAPP=false. Accessed October 30, 2013. 4. National Alliance on Mental Illness Policy Research Institute. The impact and cost of mental illness: the case of depression. www.nami.org/Template.cfm?Section= Policymakers_Toolkit&Template=/ContentManagement/ContentDisplay.cfm& ContentID=19043. Accessed October 30, 2013. 5. Greenberg PE, Kessler RC, Birnbaum HG, et al. The economic burden of depression in the United States: how did it change between 1990 and 2000? J Clin Psychiatry. 2003;64:1465-1475. 6. US Food and Drug Administration. FDA approves new drug to treat major depressive disorder. Press release. September 30, 2013. Updated October 10, 2013. www.fda. gov/NewsEvents/Newsroom/PressAnnouncements/ucm370416.htm. Accessed October 23, 2013. 7. Brintellix (vortioxetine) tablets [prescribing information]. Deerfield, IL: Takeda Pharmaceuticals America, Inc; September 2013.

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Gazyva (Obinutuzumab) for Chronic Lymphocytic Leukemia: First FDA-Approved Breakthrough Therapy in Oncology

By Lisa A. Raedler, PhD, RPh, Medical Writer

hronic lymphocytic leukemia (CLL), a monoclonal disorder characterized by progressive accumulation and proliferation of functionally incompetent B-cells, is the most frequently diagnosed leukemia in the United States.1,2 The American Cancer Society has estimated that 4580 Americans will die from CLL in 2013, which represents approximately 19% of all leukemia deaths.2 Because it can have an insidious onset, CLL is often discovered incidentally after blood work is conducted for another reason.3 Between 25% and 50% of patients with CLL are asymptomatic at the time of presentation.3 Patients with CLL are typically receiving treatment when their disease becomes symptomatic or when the signs of rapid disease progression are detected.3 Drug combinations for patients with CLL who warrant treatment include cytotoxic agents, such as the purine nucleoside analog fludarabine (Fludara), and therapeutic antibodies.3,4 Rituximab (Rituxan), a CD20 antibody, is widely used in patients with previously untreated symptomatic CLL and in salvage regimens.4 Other antibodies with clinical activity in CLL include the anti-CD20 antibody ofatumumab (Arzerra) and the anti-CD52 antibody alemtuzumab (Campath).4 Researchers continue to explore multiple novel strategies for the treatment of patients with CLL, including small molecules and newer- generation monoclonal antibodies, such as RG7356 and veltuzumab.5,6 For patients with CLL who are fit enough to tolerate treatment-related toxicities, including bone marrow suppression, modern chemoimmunotherapy combinations have significantly improved clinical outcomes.7 However, none of these regimens is curative, and a significant number of patients with CLL succumb to their disease. The effective management of elderly patients with CLL represents a particular challenge, in part because older patients with multiple comorbidities have been underrepresented in clinical trials of novel agents and drug combinations.7 Because the majority of patients with CLL are older than 65 years at the time of their diagnosis, reimbursement for the treatment of CLL in the United States is typically provided by Medicare.7,8 An analysis of US

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Medicare data (1999-2007) has demonstrated that the cost burden associated with CLL is substantial.9 This study, which was published in 2012, analyzed the total lifetime cost of treatment for more than 7400 patients with CLL compared with matched controls who did not have cancer. The results demonstrated that patients with CLL incurred average treatment costs of more than $87,000 compared with approximately $47,600 for the matched controls, a very significant difference.9

New Treatment Option for CLL: Obinutuzumab In November 2013, the US Food and Drug Administration (FDA) approved obinutuzumab (Gazyva; Gen entech) for use in combination with chlorambucil in patients with previously untreated CLL.10 The approval was done under the FDA’s priority review. Obinutuzu mab is the first cancer agent with the “breakthrough therapy” designation to receive FDA approval.10,11 The approval of obinutuzumab for the treatment of patients with CLL was based on the demonstration of significant improvement in progression-free survival (PFS) in a randomized, open-label, multicenter trial comparing obinutuzumab in combination with chlor ambucil versus chlorambucil alone.10,12 The study included 356 patients with previously untreated CD20-positive CLL and coexisting medical conditions or reduced renal function.10,12 In this study, known as CLL11, patients received 1 of 3 treatment regimens: chlorambucil alone for 6 cycles, chlorambucil plus obinutuzumab for 6 cycles, or chlorambucil plus rituximab for 6 cycles.12 All cycles were 28 days.12 Data from the first portion of the CLL11 study—the comparison of obinutuzumab plus chlorambucil and chlorambucil alone—were initially presented at the 2013 American Society of Clinical Oncology annual meeting and served as the basis for the FDA’s approval of the drug.12 In an interview regarding the CLL11 study, lead investigator Valentin Goede, MD, of the German CLL Study Group, Department of Internal Medicine, University Hospital Cologne, Germany, stated, “This [significant PFS] finding suggests an 86% reduction in the risk for a progression, relapse, or death in the obinutuz umab arm.”13

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Mechanism of Action Obinutuzumab is a humanized monoclonal antibody directed against CD20.14 On binding to CD20, obinutuz umab mediates B-cell lysis in 3 ways: (1) the engagement of immune effector cells, whose mechanisms include antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis, (2) direct activation of intracellular death signaling pathways, and (3) complement cascade activation.14 Dosing and Administration For patients with newly diagnosed CLL, the dose of obinutuzumab is 100 mg intravenously on day 1 in cycle 1, 900 mg on day 2, and 1000 mg on days 8 and 15; in cycles 2 to 6, the dose is 1000 mg, administered intravenously every 28 days.14 Premedication before infusion with obinutuzumab is recommended to reduce the risk for infusion-related adverse reactions.14 CLL11: Pivotal Phase 3 Clinical Trial In the first portion of the multicenter CLL11 trial, 356 previously untreated patients with CLL were randomly assigned to treatment with obinutuzumab plus chlorambucil or to chlorambucil alone.12 All patients had coexisting medical conditions or reduced renal function as measured by creatinine clearance (CrCl) of <70 mL/min.12 The majority of the patients received 1000 mg of obinutuzumab on days 1, 8, and 15 of the first cycle, followed by treatment on the first day of 5 subsequent cycles (total of 6 cycles, 28 days each). The first dose of obinutuzumab was divided between day 1 (100 mg) and day 2 (900 mg) for 45 patients in the CLL11 trial. Chlorambucil was given orally at 0.5 mg/kg on days 1 and 15 of all treatment cycles (1-6).12 The trial’s primary end point was PFS as assessed by independent review.12 Secondary end points included response rate, complete response rate, duration of response, disease-free survival, overall survival, minimal residual disease, safety, adverse events, patient-reported outcomes, and symptom burden defined by the European Organisation for Research and Treatment of Cancer questionnaire.15 Patient Population In the phase 3 obinutuzumab trial, the patient demographics and clinical characteristics were balanced between the treatment arms.12 The patients’ median age was 73 years, 60% were male, and 95% were Caucasian.12,14 Overall, 68% of the patients had a CrCl of <70 mL/min and 76% had multiple comorbidities.14 The median estimated CrCl was 61 mL/min.12 Of the patients

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Table 1 Phase 3 Clinical Trial CLL11: Efficacy Results Obinutuzumab plus chlorambucil Chlorambucil Efficacy end point (N = 238) (N = 118) PFS Median PFS, months Hazard ratio Stratified log-rank test P value Response rate Overall, % Complete, % Median duration of response, mo

11.1

0.16 (95% CI, 0.11-0.24) <.001 75.9 27.8 15.2

32.1 0.9 3.5

CI indicates confidence interval; PFS, progression-free survival. Source: Gazyva (obinutuzumab) injection prescribing information; 2013.

who received obinutuzumab plus chlorambucil, 81% received all 6 cycles compared with 67% of patients who received chlorambucil alone.14

Efficacy The phase 3 study demonstrated that obinutuzumab is active and safe in patients with newly diagnosed CLL and comorbidities.12 At the time of data cutoff for primary end-point analysis, patients receiving chlorambucil alone and obinutuzumab plus chlorambucil had been followed for a median of 13.6 and 14.5 months, respectively.12 On assessment by independent reviewers, the median PFS was significantly prolonged for patients receiving obinutuzumab plus chlorambucil compared with patients receiving chlorambucil alone (23 months vs 10.9 months, respectively; P <.001).12 This significant difference in median PFS was maintained in a subsequent analysis. After a median observation time of 23 months, the median PFS for patients receiving obinutuzumab plus chlorambucil was 23 months compared with 11.1 months in patients receiving chlorambucil alone (P <.001).14 The PFS and overall response findings from the CLL11 study are summarized in Table 1.14 Safety Of the 240 patients included in the phase 3 trial, approximately 194 (81%) received all 6 cycles (28 days each) of obinutuzumab-based therapy.14 Among the patients who received obinutuzumab, the most common adverse reactions (incidence, ≥10%) were infusion reactions, neutropenia, thrombocytopenia, anemia, pyrexia, cough, and musculoskeletal disorder (Table 2).14 Infusion reactions were noted in 69% of patients undergoing their first infusion of obinutuzumab.14 Severe (grade 3 or 4) infusion reactions were observed in 21% of patients receiving obinutuzumab, and 8% of patients

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Table 2 P hase 3 Clinical Trial CLL11: Adverse Reactions in ≥5% of Patients and ≥2% More in the Obinutuzumab-Treated Arm Obinutuzumab plus chlorambucil (N = 240) Chlorambucil (N = 116) a Adverse reactions All grades, % Grade 3-4, % All grades, % Grade 3-4,a % Injury, poisoning, and procedural complications Infusion-related reactions

Neutropenia

Thrombocytopenia

Anemia

Leukopenia

Blood and lymphatic system disorders

General disorders and administration-site conditions Pyrexia Respiratory, thoracic, and mediastinal disorders Cough

No grade 5 adverse reactions have been observed with a difference of ≥2% between the treatment arms. Clinically significant events. Source: Gazyva (obinutuzumab) injection prescribing information; 2013. a

discontinued therapy.14 The incidence of infusion reactions was significantly lower with subsequent infusions—3% with the second 1000-mg dose of obinutuz umab, and less than 1% thereafter. No severe infusion reactions were reported after the first 1000-mg infusion.14 After this initial experience with infusion reactions in the CLL11 trial, study protocol modifications were made to require premedication with a corticosteroid, an antihistamine, and acetaminophen.14 The first dose of obinutuzumab was also divided into 2 infusions—100 mg on day 1 and 900 mg on day 2. Among the 45 patients for whom these measures were implemented, 21 (47%) had an infusion reaction with the first 1000 mg of obinutuz umab. Less than 2% of patients experienced an infusion reaction with subsequent doses of obinutuzumab.14 HBV infection reactivation. Hepatitis B virus (HBV) reactivation can occur in patients treated with anti-CD20 antibodies, including obinutuzumab. Reactivation of HBV replication is often followed by hepatitis, manifesting as an increase in transaminase levels and, in severe cases, increases in bilirubin level, liver failure, and death.14 In some recipients of obinutuzumab, the reactivation of the HBV resulted in fulminant hepatitis, hepatic failure, and death. HBV reactivation has been reported in patients who are hepatitis B surface antigen (HBsAg) positive, as well as in patients who are HBsAg negative but are anti–hepatitis B core antibody (HBc) positive. Reactivation was also observed in patients who appeared to have

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resolved HBV infection (ie, HBsAg negative, anti-HBc positive, and hepatitis B surface antibody positive).14

Warnings and Precautions Boxed warning. The approval of obinutuzumab includes a boxed warning regarding HBV infection reactivation and progressive multifocal leukoencephalopathy (PML).10 Clinicians should advise patients of these warnings, and should assess patients for HBV and reactivation risk.10 All patients receiving obinutuzumab should be screened for HBV infection by measuring HBsAg and anti-HBc before treatment initiation. Patients who show evidence of HBV infection should consult with physicians experienced in HBV infection to discuss the potential use of HBV antiviral therapy.14 In patients who develop reactivation of the HBV while receiving obinutuzumab, obinutuzumab and any concomitant chemotherapy should be discontinued immediately. Appropriate treatment should be instituted. In patients whose HBV reactivation resolves, resumption of obinutuzumab can be discussed with physicians who are experienced in managing patients with HBV infection. There are insufficient data regarding the safety of resuming obinutuzumab in patients who develop reactivation of the HBV.14 Progressive multifocal leukoencephalopathy. JC virus infection resulting in PML, a potentially fatal condition,

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Table 3 R ecommended Management of Adverse Reactions to Obinutuzumab Infusion, by Disease Severity (Grade) Infusion reaction severity Recommendations Grade 4 reaction (lifethreatening): includes, but not limited to, anaphylaxis, acute life-threatening respiratory symptoms, or other lifethreatening infusion reaction

• Stop the obinutuzumab infusion and permanently discontinue obinutuzumab therapy • Manage symptoms

Grade 3 (severe)

• Interrupt obinutuzumab infusion • Manage symptoms • On resolution of symptoms, consider restarting obinutuzumab infusion at no more than 50% of the previous rate (used at the time that the infusion reaction occurred) • If no further infusion reaction symptoms occur, infusion rate escalation may be resumed at the increments and intervals as appropriate for the treatment cycle dose (see drug labeling) • Permanently discontinue treatment if the patient has a grade 3 infusion-related symptom on rechallenge

Grade 1 or 2 infusion reactions (mild to moderate)

• Interrupt obinutuzumab therapy or reduce the rate of the infusion • Manage symptoms • On resolution of symptoms, continue or resume infusion • If no further infusion reaction symptoms occur, infusion rate escalation may resume at the increments and intervals as appropriate for the treatment cycle dose (see drug labeling)

Source: Gazyva (obinutuzumab) injection prescribing information; 2013.

was observed in patients receiving obinutuzumab. The diagnosis of PML should be considered in any patient presenting with new-onset neurologic manifestations or with changes to preexisting neurologic manifestations. If PML is diagnosed, therapy with obinutuzumab should be discontinued.14 Consider the discontinuation or reduction of concomitant chemotherapy or immunosuppressive therapy in patients who develop PML.14 Infusion reactions. Obinutuzumab can cause severe and life-threatening infusion reactions during initial and subsequent infusions. Symptoms include hypotension, tachycardia, dyspnea, and respiratory symptoms. Other common symptoms include nausea, vomiting, diarrhea, hypertension, flushing, headache, pyrexia, and chills.14 Patients should receive premedication with acetaminophen, an antihistamine, and a glucocorticoid. Patients should be closely monitored during the entire infusion; reactions within 24 hours of receiving obinutuzumab have occurred. If infusion reactions occur, institute medical management with glucocorticoids, epinephrine, bronchodilators, and/or oxygen as needed.14 Table 3 summarizes the recommendations for managing infusion reactions associated with obinutuzumab.14 Because patients with preexisting cardiac or pulmonary conditions may be at greater risk for experiencing more severe infusion reactions, they should be monitored more frequently throughout the obinutuzumab infusion and the postinfusion time frame.14

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Hypotension may occur as part of the obinutuzumab infusion reaction. Consider withholding antihypertensive treatments for 12 hours before the obinutuzumab infusion, during the infusion, and for the first hour after administration until blood pressure is stable. For patients who are at increased risk of hypertensive crisis, the benefits and risks of withholding their hypertensive medication should be deliberated.14 Tumor lysis syndrome. Acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, and/or hyperphosphatemia secondary to tumor lysis syndrome (TLS) can occur 12 to 24 hours after the first infusion of obinutuz umab. Because patients with high tumor burden and/or high circulating lymphocyte count (>25 × 109/L) are at greater risk for TLS, appropriate prophylaxis with antihyperuricemics (eg, allopurinol) and hydration should begin 12 to 24 hours before the infusion.14 Infection. Serious bacterial, fungal, and new or reactivated viral infections can occur during and after obinutuzumab therapy. Obinutuzumab should not be given to patients with active infection. Patients with a history of recurring or chronic infections may be at increased risk of infection while taking obinutuzumab.14 Neutropenia. Neutropenia associated with obinutuz umab can occur more than 28 days after the completion of treatment and can last more than 28 days. Patients with grade 3 or 4 neutropenia while taking obinutuzu mab should be monitored frequently until resolution.

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Any symptoms or signs of infection should be addressed immediately. Patients with neutropenia should receive antimicrobial prophylaxis during the treatment and may consider antiviral and antifungal prophylaxis.14 Thrombocytopenia. In the CLL11 trial, 12% of patients receiving obinutuzumab plus chlorambucil had grade 3 or 4 thrombocytopenia. In 5% of patients, obinutuzumab caused an acute thrombocytopenia within 24 hours after infusion. Platelet counts should be monitored frequently in patients with grade 3 or 4 thrombocytopenia until resolution. Platelet transfusions may be required.14 Immunization. Immunization with live virus vaccines is not recommended until the completion of obinutuzumab treatment and B-cell recovery.14

Obinutuzumab is the first cancer drug with a designated breakthrough therapy to receive FDA approval. This third-generation anti-CD20 monoclonal antibody has demonstrated improved efficacy with manageable side effects compared with chlorambucil alone. Special Populations Obinutuzumab has not been specifically studied in pregnant or nursing women. Women of childbearing age should use an effective contraceptive when receiving this medication and for the 12 months after treatment.14 Nursing women should be carefully evaluated for the benefits of obinutuzumab for the woman versus potential risk for the infant.14 The combination of obinutuzumab and chlorambucil has resulted in serious adverse events in geriatric patients. Among 240 treatment-naïve patients who received obinutuzumab in combination with chlorambucil, 82% were aged ≥65 years and 45% were aged ≥75 years. Of those aged ≥75 years, 45% had serious adverse events and 5% died. Among those aged ≥65 years, adverse event rates were similar in the active treatment and the comparator arms. The efficacy rates were not significantly different among patients of different ages.14 Conclusion Obinutuzumab is the first cancer drug with a designated breakthrough therapy to receive FDA approval. This third-generation anti-CD20 monoclonal antibody,

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which was approved for the initial treatment of patients with CLL in combination with chlorambucil, has demonstrated improved efficacy with manageable side effects compared with chlorambucil alone.11,16 For patients with CLL and coexisting medical conditions and/ or reduced renal function, obinutuzumab plus chlorambucil represents an effective alternative to purine analog–based therapy and to the use of chlorambucil alone. Obinutuzumab may also confer clinical benefit in other cancers that express CD20. Clinical studies are under way to evaluate the use of obinutuzumab combined with cytotoxic agents in indolent and aggressive subtypes of non-Hodgkin lymphoma (NHL), including follicular NHL, diffuse large B-cell lymphoma, and mantle-cell lymphoma.17 n

References

1. Chiorazzi N, Rai KR, Ferrarini M. Chronic lymphocytic leukemia. N Engl J Med. 2005; 352:804-815. 2. American Cancer Society. Cancer facts and figures 2013. 2013. www.cancer.org/ acs/groups/content/@epidemiologysurveilance/documents/document/acspc-036845. pdf. Accessed November 27, 2013. 3. Mir MA, Liu D, Patel SC, Rasool HJ. Chronic lymphocytic leukemia. Medscape. Updated November 11, 2013. http://emedicine.medscape.com/article/199313-overview. Accessed November 27, 2013. 4. Jaglowski SM, Alinari L, Lapalombella R, et al. The clinical application of monoclonal antibodies in chronic lymphocytic leukemia. Blood. 2010;116:3705-3714. 5. Zhang S, Wu CC, Fecteau JF, et al. Targeting chronic lymphocytic leukemia cells with a humanized monoclonal antibody specific for CD44. Proc Natl Acad Sci U S A. 2013;110:6127-6132. 6. OBR. OBR Pipeline Online: chronic lymphocytic leukemia (CLL). http://obr oncology.com/pipeline_online.php. Accessed November 29, 2013. 7. Stephens DM, Byrd JC. Ask the hematologists. Hematologist. 2012;9:4-5. 8. American Cancer Society. What are the key statistics for chronic lymphocytic leukemia? Revised November 14, 2013. www.cancer.org/cancer/leukemia-chroniclymphocyticcll/detailedguide/leukemia-chronic-lymphocytic-key-statistics. Accessed November 28, 2013. 9. Lafeuille MH, Vekeman F, Wang ST, et al. Lifetime costs to Medicare of providing care to patients with chronic lymphocytic leukemia. Leuk Lymphoma. 2012;53:1146-1154. 10. US Food and Drug Administration. Drugs: Gazyva (obinutuzumab). Updated November 1, 2013. www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm373263. htm. Accessed November 29, 2013. 11. US Food and Drug Administration. FDA approves Gazyva for chronic lymphocytic leukemia. Press release. November 1, 2013. www.fda.gov/NewsEvents/Newsroom/ PressAnnouncements/ucm373209.htm. Accessed November 29, 2013. 12. Goede V, Fischer K, Humphrey K, et al. Obinutuzumab (GA101) plus chlorambucil (Clb) or rituximab (R) plus Clb versus Clb alone in patients with chronic lymphocytic leukemia (CLL) and preexisting medical conditions (comorbidities): final stage 1 results of the CLL11 (BO21004) phase III trial. J Clin Oncol. 2013;31(15 suppl). Abstract 7004. 13. McCall B. Obinutuzumab active in elderly chronic lymphocytic leukemia. Medscape Medical News. June 21, 2013. www.medscape.com/viewarticle/806700. Accessed November 29, 2013. 14. Gazyva (obinutuzumab) injection [prescribing information]. South San Francisco, CA: Genentech, Inc; November 2013. 15. ClinicalTrials.gov. CLL11: A Study of RO5072759 (GA101) with Chlorambucil in Patients with Previously Untreated Chronic Lymphocytic Leukemia. http:// clinicaltrials.gov/ct2/show/NCT01010061?term=obinutuzumab&rank=12. Accessed November 29, 2013. 16. Ingram I. FDA approves obinutuzumab (Gazyva) for chronic lymphocytic leukemia. Cancer Network. November 1, 2013. www.cancernetwork.com/news/fda-approvesobinutuzumab-gazyva-chronic-lymphocytic-leukemia. Accessed November 29, 2013. 17. ClinicalTrials.gov. Obinutuzumab. Search results. http://clinicaltrials.gov/ct2/ results?term=obinutuzumab &Search=Search. Accessed November 29, 2013.

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XOFIGO® IS INDICATED

for the treatment of patients with castration-resistant prostate cancer (CRPC), symptomatic bone metastases and no known visceral metastatic disease.1

Prolong life. Treat bone metastases. The first agent to extend overall survival by exerting an antitumor effect on bone metastases in CRPC1,2 • 30% reduction in the risk of death vs placebo (hazard ratio [HR]=0.695)1

• Exploratory updated analysisa: 3.6-month increase in median overall survival vs placebo (HR=0.695; 95% confidence interval [CI]: 0.581-0.832)1

—14.9 months for Xofigo (95% CI: 13.9-16.1) vs 11.3 months for placebo

(95% CI: 10.4-12.8)1

• Prespecified interim analysis: 2.8-month increase in median overall survival vs placebo, P=0.00185 (HR=0.695; 95% CI: 0.552-0.875)1

—14.0 months for Xofigo (95% CI: 12.1-15.8) vs 11.2 months for placebo

(95% CI: 9.0-13.2)1

Not an actual patient. Models used for illustrative purposes only.

To learn more, visit www.xofigo-us.com

• Overall survival benefit supported by delay in time to first symptomatic skeletal event (SSE), favoring Xofigo.b The majority of events consisted of external beam radiation therapy to bone metastases1 • 1-minute intravenous injection every 4 weeks for 6 injections1 An exploratory updated overall survival analysis was performed before patient crossover, incorporating an additional 214 events, resulting in findings consistent with the interim analysis.

SSEs defined as external beam radiation therapy to relieve skeletal symptoms, new symptomatic pathologic bone fracture, occurrence of spinal cord compression, or tumor-related orthopedic surgical intervention. There were no scheduled radiographic assessments performed on study.

Important Safety Information1 • Contraindications: Xofigo is contraindicated in women who are or may • Concomitant Use With Chemotherapy: Safety and efficacy of concomitant chemotherapy with Xofigo have not been established. Outside of a become pregnant. Xofigo can cause fetal harm when administered to a clinical trial, concomitant use of Xofigo in patients on chemotherapy is pregnant woman not recommended due to the potential for additive myelosuppression. • Bone Marrow Suppression: In the randomized trial, 2% of patients in the If chemotherapy, other systemic radioisotopes, or hemibody external Xofigo arm experienced bone marrow failure or ongoing pancytopenia, radiotherapy are administered during the treatment period, Xofigo should compared to no patients treated with placebo. There were two deaths be discontinued due to bone marrow failure. For 7 of 13 patients treated with Xofigo bone marrow failure was ongoing at the time of death. Among the 13 patients • Administration and Radiation Protection: Xofigo should be received, used, and administered only by authorized persons in designated clinical settings. who experienced bone marrow failure, 54% required blood transfusions. The administration of Xofigo is associated with potential risks to other Four percent (4%) of patients in the Xofigo arm and 2% in the placebo arm persons from radiation or contamination from spills of bodily fluids such as permanently discontinued therapy due to bone marrow suppression. In the urine, feces, or vomit. Therefore, radiation protection precautions must be randomized trial, deaths related to vascular hemorrhage in association with taken in accordance with national and local regulations myelosuppression were observed in 1% of Xofigo-treated patients compared to 0.3% of patients treated with placebo. The incidence of infection-related • Adverse Reactions: The most common adverse reactions (≥10%) in the deaths (2%), serious infections (10%), and febrile neutropenia (<1%) was Xofigo arm vs the placebo arm, respectively, were nausea (36% vs 35%), similar for patients treated with Xofigo and placebo. Myelosuppression— diarrhea (25% vs 15%), vomiting (19% vs 14%), and peripheral edema notably thrombocytopenia, neutropenia, pancytopenia, and leukopenia— (13% vs 10%). Grade 3 and 4 adverse events were reported in 57% of Xofigohas been reported in patients treated with Xofigo. treated patients and 63% of placebo-treated patients. The most common hematologic laboratory abnormalities in the Xofigo arm (≥10%) vs the Monitor patients with evidence of compromised bone marrow reserve closely placebo arm, respectively, were anemia (93% vs 88%), lymphocytopenia and provide supportive care measures when clinically indicated. Discontinue (72% vs 53%), leukopenia (35% vs 10%), thrombocytopenia (31% vs 22%), Xofigo in patients who experience life-threatening complications despite and neutropenia (18% vs 5%) supportive care for bone marrow failure • Hematological Evaluation: Monitor blood counts at baseline and prior References: 1. Xofigo® (radium Ra 223 dichloride) injection [prescribing information]. Wayne, NJ: Bayer to every dose of Xofigo. Prior to first administering Xofigo, the absolute HealthCare Pharmaceuticals Inc.; May 2013. 2. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter neutrophil count (ANC) should be ≥1.5 × 109/L, the platelet count radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369(3):213-223. ≥100 × 109/L, and hemoglobin ≥10 g/dL. Prior to subsequent Please see accompanying brief summary administrations, the ANC should be ≥1 × 109/L and the platelet count ≥50 × 109/L. Discontinue Xofigo if hematologic values do not recover within of full Prescribing Information. 6 to 8 weeks after the last administration despite receiving supportive care

Xofigo (radium Ra 223 dichloride) Injection, for intravenous use Initial U.S. Approval: 2013 BRIEF SUMMARY OF PRESCRIBING INFORMATION CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE Xofigo™ is indicated for the treatment of patients with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastatic disease. 2 DOSAGE AND ADMINISTRATION 2.3 Instructions for Use/Handling General warning Xofigo (an alpha particle-emitting pharmaceutical) should be received, used and administered only by authorized persons in designated clinical settings. The receipt, storage, use, transfer and disposal Xofigo are subject to the regulations and/or appropriate licenses of the competent official organization. Xofigo should be handled by the user in a manner which satisfies both radiation safety and pharmaceutical quality requirements. Appropriate aseptic precautions should be taken. Radiation protection The administration of Xofigo is associated with potential risks to other persons (e.g., medical staff, caregivers and patient’s household members) from radiation or contamination from spills of bodily fluids such as urine, feces, or vomit. Therefore, radiation protection precautions must be taken in accordance with national and local regulations. For drug handling Follow the normal working procedures for the handling of radiopharmaceuticals and use universal precautions for handling and administration such as gloves and barrier gowns when handling blood and bodily fluids to avoid contamination. In case of contact with skin or eyes, the affected area should be flushed immediately with water. In the event of spillage of Xofigo, the local radiation safety officer should be contacted immediately to initiate the necessary measurements and required procedures to decontaminate the area. A complexing agent such as 0.01 M ethylene-diamine-tetraacetic acid (EDTA) solution is recommended to remove contamination. For patient care Whenever possible, patients should use a toilet and the toilet should be flushed several times after each use. When handling bodily fluids, simply wearing gloves and hand washing will protect caregivers. Clothing soiled with Xofigo or patient fecal matter or urine should be washed promptly and separately from other clothing. Radium-223 is primarily an alpha emitter, with a 95.3% fraction of energy emitted as alpha-particles. The fraction emitted as beta-particles is 3.6%, and the fraction emitted as gamma-radiation is 1.1%. The external radiation exposure associated with handling of patient doses is expected to be low, because the typical treatment activity will be below 8,000 kBq (216 microcurie). In keeping with the As Low As Reasonably Achievable (ALARA) principle for minimization of radiation exposure, it is recommended to minimize the time spent in radiation areas, to maximize the distance to radiation sources, and to use adequate shielding. Any unused product or materials used in connection with the preparation or administration are to be treated as radioactive waste and should be disposed of in accordance with local regulations. The gamma radiation associated with the decay of radium-223 and its daughters allows for the radioactivity measurement of Xofigo and the detection of contamination with standard instruments. 4 CONTRAINDICATIONS Xofigo is contraindicated in pregnancy. Xofigo can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Xofigo is not indicated for use in women. Xofigo is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus [see Use in Specific Populations (8.1)]. 5 WARNINGS AND PRECAUTIONS 5.1 Bone Marrow Suppression In the randomized trial, 2% of patients on the Xofigo arm experienced bone marrow failure or ongoing pancytopenia compared to no patients treated with placebo. There were two deaths due to bone marrow failure and for 7 of 13 patients treated with Xofigo, bone marrow failure was ongoing at the time of death. Among the 13 patients who experienced bone marrow failure, 54% required blood transfusions. Four percent (4%) of patients on the Xofigo arm and 2% on the placebo arm permanently discontinued therapy due to bone marrow suppression. In the randomized trial, deaths related to vascular hemorrhage in association with myelosuppression were observed in 1% of Xofigo-treated patients compared to 0.3% of patients treated with placebo. The incidence of infection-related deaths (2%), serious infections (10%), and febrile neutropenia (<1%) were similar for patients treated with Xofigo and placebo. Myelosuppression; notably thrombocytopenia, neutropenia, pancytopenia, and leukopenia; has been reported in patients treated with Xofigo. In the randomized trial, complete blood counts (CBCs) were obtained every 4 weeks prior to each dose and the nadir CBCs and times of recovery were not well characterized. In a separate single-dose phase 1 study of Xofigo, neutrophil and platelet count nadirs occurred 2 to 3 weeks after Xofigo administration at doses that were up to 1 to 5 times

the recommended dose, and most patients recovered approximately 6 to 8 weeks after administration [see Adverse Reactions (6)]. Hematologic evaluation of patients must be performed at baseline and prior to every dose of Xofigo. Before the first administration of Xofigo, the absolute neutrophil count (ANC) should be ≥ 1.5 x 109/L, the platelet count ≥ 100 x 109/L and hemoglobin ≥ 10 g/dL. Before subsequent administrations of Xofigo, the ANC should be ≥ 1 x 109/L and the platelet count ≥ 50 x 109/L. If there is no recovery to these values within 6 to 8 weeks after the last administration of Xofigo, despite receiving supportive care, further treatment with Xofigo should be discontinued. Patients with evidence of compromised bone marrow reserve should be monitored closely and provided with supportive care measures when clinically indicated. Discontinue Xofigo in patients who experience life-threatening complications despite supportive care for bone marrow failure. The safety and efficacy of concomitant chemotherapy with Xofigo have not been established. Outside of a clinical trial, concomitant use with chemotherapy is not recommended due to the potential for additive myelosuppression. If chemotherapy, other systemic radioisotopes or hemibody external radiotherapy are administered during the treatment period, Xofigo should be discontinued. 6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in another section of the label: s¬ ¬"ONE¬-ARROW¬3UPPRESSION¬[see Warnings and Precautions (5.1)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In the randomized clinical trial in patients with metastatic castration-resistant prostate cancer with bone metastases, 600 patients received intravenous injections of 50 kBq/ kg (1.35 microcurie/kg) of Xofigo and best standard of care and 301 patients received placebo and best standard of care once every 4 weeks for up to 6 injections. Prior to randomization, 58% and 57% of patients had received docetaxel in the Xofigo and placebo arms, respectively. The median duration of treatment was 20 weeks (6 cycles) for Xofigo and 18 weeks (5 cycles) for placebo. The most common adverse reactions (≥ 10%) in patients receiving Xofigo were nausea, diarrhea, vomiting, and peripheral edema (Table 3). Grade 3 and 4 adverse events were reported among 57% of Xofigo-treated patients and 63% of placebo-treated patients. The most common hematologic laboratory abnormalities in Xofigo-treated patients (≥ 10%) were anemia, lymphocytopenia, leukopenia, thrombocytopenia, and neutropenia (Table 4). Treatment discontinuations due to adverse events occurred in 17% of patients who received Xofigo and 21% of patients who received placebo. The most common hematologic laboratory abnormalities leading to discontinuation for Xofigo were anemia (2%) and thrombocytopenia (2%). Table 3 shows adverse reactions occurring in ≥ 2% of patients and for which the incidence for Xofigo exceeds the incidence for placebo. Table 3: Adverse Reactions in the Randomized Trial System/Organ Class Xofigo (n=600) Placebo (n=301) Preferred Term Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4 % % % % Blood and lymphatic system disorders Pancytopenia 2 1 0 0 Gastrointestinal disorders Nausea 36 2 35 2 Diarrhea 25 2 15 2 Vomiting 19 2 14 2 General disorders and administration site conditions Peripheral edema 13 2 10 1 Renal and urinary disorders Renal failure and impairment 3 1 1 1 Laboratory Abnormalities Table 4 shows hematologic laboratory abnormalities occurring in > 10% of patients and for which the incidence for Xofigo exceeds the incidence for placebo. Table 4: Hematologic Laboratory Abnormalities Hematologic Laboratory Abnormalities

Xoﬁgo (n=600) Placebo (n=301) Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4 % % % % Anemia 93 6 88 6 Lymphocytopenia 72 20 53 7 Leukopenia 35 3 10 <1 Thrombocytopenia 31 3 22 <1 Neutropenia 18 2 5 <1 Laboratory values were obtained at baseline and prior to each 4-week cycle.

As an adverse reaction, grade 3-4 thrombocytopenia was reported in 6% of patients on XoďŹ go and in 2% of patients on placebo. Among patients who received XoďŹ go, the laboratory abnormality grade 3-4 thrombocytopenia occurred in 1% of docetaxel naĂŻve patients and in 4% of patients who had received prior docetaxel. Grade 3-4 neutropenia occurred in 1% of docetaxel naĂŻve patients and in 3% of patients who have received prior docetaxel. Fluid Status Dehydration occurred in 3% of patients on XoďŹ go and 1% of patients on placebo. XoďŹ go increases adverse reactions such as diarrhea, nausea, and vomiting which may result in dehydration. Monitor patientsâ&#x20AC;&#x2122; oral intake and ďŹ&#x201A;uid status carefully and promptly treat patients who display signs or symptoms of dehydration or hypovolemia. Injection Site Reactions Erythema, pain, and edema at the injection site were reported in 1% of patients on XoďŹ go. Secondary Malignant Neoplasms XoďŹ go contributes to a patientâ&#x20AC;&#x2122;s overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure may be associated with an increased risk of cancer and hereditary defects. Due to its mechanism of action and neoplastic changes, including osteosarcomas, in rats following administration of radium-223 dichloride, XoďŹ go may increase the risk of osteosarcoma or other secondary malignant neoplasms [see Nonclinical Toxicology (13.1)]. However, the overall incidence of new malignancies in the randomized trial was lower on the XoďŹ go arm compared to placebo (<1% vs. 2%; respectively), but the expected latency period for the development of secondary malignancies exceeds the duration of follow up for patients on the trial. Subsequent Treatment with Cytotoxic Chemotherapy In the randomized clinical trial, 16% patients in the XoďŹ go group and 18% patients in the placebo group received cytotoxic chemotherapy after completion of study treatments. Adequate safety monitoring and laboratory testing was not performed to assess how patients treated with XoďŹ go will tolerate subsequent cytotoxic chemotherapy. 7 DRUG INTERACTIONS No formal clinical drug interaction studies have been performed. 3UBGROUPÂŹANALYSESÂŹINDICATEDÂŹTHATÂŹTHEÂŹCONCURRENTÂŹUSEÂŹOFÂŹBISPHOSPHONATESÂŹORÂŹCALCIUMÂŹ channel blockers did not affect the safety and efďŹ cacy of XoďŹ go in the randomized clinical trial. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Category X [see Contraindications (4)] XoďŹ go can cause fetal harm when administered to a pregnant woman based on its mechanism of action. While there are no human or animal data on the use of XoďŹ go in pregnancy and XoďŹ go is not indicated for use in women, maternal use of a radioactive therapeutic agent could affect development of a fetus. XoďŹ go is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with XoďŹ go. 8.3 Nursing Mothers XoďŹ go is not indicated for use in women. It is not known whether radium-223 dichloride is excreted in human milk. Because many drugs are excreted in human milk, and because of potential for serious adverse reactions in nursing infants from XoďŹ go, a decision should be made whether to discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and efďŹ cacy of XoďŹ go in pediatric patients have not been established. In single- and repeat-dose toxicity studies in rats, ďŹ ndings in the bones (depletion of osteocytes, osteoblasts, osteoclasts, ďŹ bro-osseous lesions, disruption/disorganization of the physis/growth line) and teeth (missing, irregular growth, ďŹ bro-osseous lesions in bone socket) correlated with a reduction of osteogenesis that occurred at clinically relevant doses beginning in the range of 20 â&#x20AC;&#x201C; 80 kBq (0.541 - 2.16 microcurie) per kg body weight. 8.5 Geriatric Use Of the 600 patients treated with XoďŹ go in the randomized trial, 75% were 65 years of age and over and while 33% were 75 years of age and over. No dosage adjustment is considered necessary in elderly patients. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identiďŹ ed differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Patients with Hepatic Impairment .OÂŹ DEDICATEDÂŹ HEPATICÂŹ IMPAIRMENTÂŹ TRIALÂŹ FORÂŹ 8OlGOÂŹ HASÂŹ BEENÂŹ CONDUCTED ÂŹ 3INCEÂŹ radium-223 is neither metabolized by the liver nor eliminated via the bile, hepatic impairment is unlikely to affect the pharmacokinetics of radium-223 dichloride [see Clinical Pharmacology (12.3)]. Based on subgroup analyses in the randomized clinical trial, dose adjustment is not needed in patients with mild hepatic impairment. No dose adjustments can be recommended for patients with moderate or severe hepatic impairment due to lack of clinical data.

8.7 Patients with Renal Impairment No dedicated renal impairment trial for XoďŹ go has been conducted. Based on subgroup analyses in the randomized clinical trial, dose adjustment is not needed in patients with existing mild (creatinine clearance [CrCl] 60 to 89 mL/min) or moderate (CrCl 30 to 59 mL/min) renal impairment. No dose adjustment can be recommended for patients with severe renal impairment (CrCl less than 30 mL/min) due to limited data available (n = 2) [see Clinical Pharmacology (12.3)]. 8.8 Males of Reproductive Potential Contraception Because of potential effects on spermatogenesis associated with radiation, advise men who are sexually active to use condoms and their female partners of reproductive potential to use a highly effective contraceptive method during and for 6 months after completing treatment with XoďŹ go. Infertility There are no data on the effects of XoďŹ go on human fertility. There is a potential risk that radiation by XoďŹ go could impair human fertility [see Nonclinical Toxicology (13.1)]. 10 OVERDOSAGE There have been no reports of inadvertent overdosing of XoďŹ go during clinical studies. There is no speciďŹ c antidote. In the event of an inadvertent overdose of XoďŹ go, utilize general supportive measures, including monitoring for potential hematological and gastrointestinal toxicity, and consider using medical countermeasures such as aluminum hydroxide, barium sulfate, calcium carbonate, calcium gluconate, calcium phosphate, or sodium alginate.1 3INGLEÂŹ8OlGOÂŹDOSESÂŹUPÂŹTOÂŹ ÂŹK"QÂŹ ÂŹMICROCURIE ÂŹPERÂŹKGÂŹBODYÂŹWEIGHTÂŹWEREÂŹEVALUATEDÂŹ in a phase 1 clinical trial and no dose-limiting toxicities were observed. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Animal studies have not been conducted to evaluate the carcinogenic potential of radium-223 dichloride. However, in repeat-dose toxicity studies in rats, osteosarcomas, a known effect of bone-seeking radionuclides, were observed at clinically relevant doses 7 to 12 months after the start of treatment. The presence of other neoplastic changes, including lymphoma and mammary gland carcinoma, was also reported in 12- to 15-month repeat-dose toxicity studies in rats. Genetic toxicology studies have not been conducted with radium-223 dichloride. However, the mechanism of action of radium-223 dichloride involves induction of double-strand DNA breaks, which is a known effect of radiation. Animal studies have not been conducted to evaluate the effects of radium-223 dichloride on male or female fertility or reproductive function. XoďŹ go may impair fertility and reproductive function in humans based on its mechanism of action. 17 PATIENT COUNSELING INFORMATION Advise patients: sÂŹ ÂŹ4OÂŹ BEÂŹ COMPLIANTÂŹ WITHÂŹ BLOODÂŹ CELLÂŹ COUNTÂŹ MONITORINGÂŹ APPOINTMENTSÂŹ WHILEÂŹ RECEIVINGÂŹ XoďŹ go. Explain the importance of routine blood cell counts. Instruct patients to report signs of bleeding or infections. sÂŹ ÂŹ4OÂŹ STAYÂŹ WELLÂŹ HYDRATEDÂŹ ANDÂŹ TOÂŹ MONITORÂŹ ORALÂŹ INTAKE ÂŹ mUIDÂŹ STATUS ÂŹ ANDÂŹ URINEÂŹ OUTPUTÂŹ while being treated with XoďŹ go. Instruct patients to report signs of dehydration, hypovolemia, urinary retention, or renal failure / insufďŹ ciency. sÂŹ ÂŹ4HEREÂŹAREÂŹNOÂŹRESTRICTIONSÂŹREGARDINGÂŹCONTACTÂŹWITHÂŹOTHERÂŹPEOPLEÂŹAFTERÂŹRECEIVINGÂŹ8OlGO ÂŹ Follow good hygiene practices while receiving XoďŹ go and for at least 1 week after the last injection in order to minimize radiation exposure from bodily ďŹ&#x201A;uids to household members and caregivers. Whenever possible, patients should use a toilet and the toilet should be ďŹ&#x201A;ushed several times after each use. Clothing soiled with patient fecal matter or urine should be washed promptly and separately from other clothing. Caregivers should use universal precautions for patient care such as gloves and barrier gowns when handling bodily ďŹ&#x201A;uids to avoid contamination. When handling bodily ďŹ&#x201A;uids, wearing gloves and hand washing will protect caregivers. sÂŹ ÂŹ7HOÂŹAREÂŹSEXUALLYÂŹACTIVEÂŹTOÂŹUSEÂŹCONDOMSÂŹANDÂŹTHEIRÂŹFEMALEÂŹPARTNERSÂŹOFÂŹREPRODUCTIVEÂŹ potential to use a highly effective method of birth control during treatment and for 6 months following completion of XoďŹ go treatment.

Manufactured for:

Bayer HealthCare Pharmaceuticals Inc. Wayne, NJ 07470 Manufactured in Norway XoďŹ go is a trademark of Bayer Aktiengesellschaft. ÂŠ 2013, Bayer HealthCare Pharmaceuticals Inc. All rights reserved. Revised: 05/2013 "3

Fetzima Extended-Release (Levomilnacipran) Receives FDA Approval for the Treatment of Major Depressive Disorder in Adults By Loretta Fala, Medical Writer

ajor depressive disorder (MDD), also known as clinical depression, is a chronic medical illness characterized by persistent sadness, loss of interest in normal activities, and in some cases, by physical symptoms.1 MDD is associated with serious emotional and biological manifestations that affect a person’s thoughts, feelings, behavior, mood, and physical health.1 An estimated 25 million people in the United States are affected by MDD annually; however, only 50% of patients with MDD receive treatment.2 Moreover, a national household survey revealed that 6.7% of US adults experienced a major depressive episode within a 12-month period.3 MDD has the potential to disrupt life by causing changes in sleep or appetite, poor concentration, loss of energy, low self-esteem, hopelessness, or guilt.2 Some people experience 1 episode of MDD in the course of a lifetime, whereas many people have recurrent episodes. Without treatment, an episode can last from several months to years.2 Most concerning is the fact that more than 15% of people with MDD take their own lives.4 Untreated MDD increases the risk of suicide—a leading cause of mortality in the United States that is responsible for 30,000 deaths annually.4 In addition, untreated MDD can also lead to a number of emotional, physical, and other health-related complications, including alcohol or substance abuse, anxiety, family conflicts, relationship difficulties, social isolation, and premature death from other medical conditions.1 As many as 30% of drug and alcohol users are estimated to have undetected MDD.4 Individuals who have had a stroke, or those with heart disease, diabetes, cancer, Parkinson’s disease, or HIV/ AIDS are at an increased risk for depression.4 In older adults, MDD may go undiagnosed and untreated, because symptoms such as fatigue, loss of appetite, and sleep problems are also caused by other medical conditions.1 According to one study, the average annual cost of MDD in the United States is an estimated $83.1 billion, which includes $26.1 billion in direct medical costs, $5.4 billion in suicide-related mortality costs, and $51.5 billion in workplace costs.5 These totals would be considerably higher if they captured the costs of coexisting psychiatric and medical conditions or the role of related painful conditions.5

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A study that assessed the association between treatment-resistant depression (defined as undergoing 4 different antidepressant treatment trials) and medical expenditures showed that treatment-resistant depression was associated with 29.3% higher costs (P <.001) in medical expenditures compared with patients without treatment- resistant depression.6 These higher per-patient medical expenditures were attributed to greater healthcare utilization.6 Treatments for MDD include pharmacologic therapy, psychotherapy, and electroconvulsive therapy (for some severe episodes or severe depression with psychosis).1,2 Other treatments may include transcranial magnetic stimulation, vagus nerve stimulation, aerobic exercise, and complementary and alternative medicines.1,2 The antidepressant medications used to treat patients with MDD include selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors, norepinephrine and dopamine reuptake inhibitors, atypical antidepressants, tricyclic antidepressants, monoamine oxidase inhibitors (MAOIs), or other medication strategies, including appropriate combination and augmentation approaches.1 The antidepressant drug classes are associated with class-specific side effects.1 Currently, SSRIs and serotonin–norepinephrine reuptake inhibitors are the cornerstones of managing patients with MDD.7 For the majority of adults with MDD, a combination of medication and psychotherapy is the most effective management approach.1 Finding the appropriate medication for a patient with MDD can be challenging, however, often requiring trial and error based on the individual patient’s response. Genotyping tests, including cytochrome (CY) P450 and other specific genes, can help clinicians predict how well a patient can metabolize a medication and can identify which antidepressant may be a prudent option.1 Early diagnosis and management are crucial to improving the outcomes for patients with this serious and debilitating illness.

A New Serotonin–Norepinephrine Reuptake Inhibitor for the Treatment of MDD On July 26, 2013, levomilnacipran extended release (Fetzima; Forest Laboratories), a serotonin–norepineph-

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Table 1 Levomilnacipran versus Placebo: Results for the Primary Efficacy End Point, MADRS Clinical trial

Treatment group

Study 1 (fixed-dose)

Levomilnacipran ER 40 mg dailyb Levomilnacipran ER 80 mg dailyb Levomilnacipran ER 120 mg dailyb Placebo Levomilnacipran ER 40 mg dailyb Levomilnacipran ER 80 mg dailyb Placebo Levomilnacipran ER 40-120 mg dailyb Placebo

Study 2 (fixed-dose)

Study 3 (flexible-dose)

Mean baseline score (SD)

LS mean change from baseline (SE)

Placebo-subtracted differencea (95% CI)

36 (4.1)

–14.8 (1)

–3.2 (–5.9 to –0.5)

36.1 (3.9)

–15.6 (1)

–4 (–6.7 to –1.3)

36 (3.9)

–16.5 (1)

–4.9 (–7.6 to –2.1)

35.6 (4.5)

–11.6 (1)

—

30.8 (3.4)

–14.6 (0.8)

–3.3 (–5.5 to –1.1)

31.2 (3.5)

–14.4 (0.8)

–3.1 (–5.3 to –1)

31 (3.8)

–11.3 (0.8)

—

35 (3.6)

–15.3 (0.8)

–3.1 (–5.3 to –0.9)

35.2 (3.8)

–12.2 (0.8)

—

Difference in LS mean change from baseline to end point, at week 8. Doses significantly superior to placebo. CI indicates confidence interval unadjusted for multiplicity; ER, extended release; LS, least-squares; MADRS, MontgomeryÅsberg Depression Rating Scale; SD, standard deviation; SE, standard error. Source: Fetzima (levomilnacipran) extended-release capsules prescribing information; 2013. a

rine reuptake inhibitor, was approved by the US Food and Drug Administration (FDA) for the treatment of MDD in adults.8 The approval of Fetzima was based on three 8-week, double-blind, placebo-controlled studies.9 Levomilnacipran is an active enantiomer of milnacipran, a drug that was approved by the FDA in 2009 for the treatment of fibromyalgia in adults.7,9 However, levomilnacipran is not approved for the management of fibromyalgia.9 According to Michael R. Liebowitz, MD, Professor of Clinical Psychiatry, Columbia University, New York, “As many people with MDD struggle to find a treatment that works for them, Fetzima provides patients and physicians with an additional option for treating this serious disease.”8

Mechanism of Action The exact mechanism of the antidepressant action of levomilnacipran is unknown; however, it is believed to be related to the potentiation of serotonin and norepinephrine in the central nervous system, through the inhibition of reuptake at serotonin and norepinephrine transporters. Nonclinical studies have shown that levo milnacipran is a potent and selective serotonin–norepinephrine reuptake inhibitor.9 Dosing The recommended dose for levomilnacipran is 40 mg to 120 mg once daily with or without food. The initial

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dose is 20 mg once daily for 2 days, and then an increase to 40 mg once daily. Based on the efficacy and tolerability, the dose is increased in increments of 40 mg at an interval of 2 or more days. The maximum recommended dose is 120 mg once daily. Capsules should be taken whole without being opened, chewed, or crushed.9 When discontinuing levomilnacipran, the dose should be reduced gradually whenever possible. In patients with moderate renal impairment, the dose should not exceed 80 mg once daily; in patients with severe renal impairment, the dose should not exceed 40 mg once daily.9 Levomilnacipran is available as an extended-release capsule in 20-mg, 40-mg, 80-mg, and 120-mg strengths.9 A dose adjustment is recommended when levomilnacipran is coadministered with strong inhibitors of CYP3A4 (eg, ketoconazole).9

Clinical Trials The efficacy of levomilnacipran for the treatment of MDD was evaluated in three 8-week, randomized, double-blind, placebo-controlled studies (at doses of 40120 mg once daily) in adult outpatients (aged 18-78 years) who met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria for the diagnosis of MDD. Studies 1 and 2 were fixed-dose trials, and study 3 was a flexible-dose trial.9

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Adverse Reactions Occurring in ≥5% of Patients Table 2 Receiving Levomilnacipran and at Least Twice the Rate of Patients Receiving Placebo Levomilnacipran Placebo, % 40-120 mg daily, % (N = 1040) (N = 1583)

System organ class preferred term Gastrointestinal disorders Nausea

Constipation

Vomiting

Tachycardiaa

Palpitations

Cardiac disorders 5

Reproductive system and breast disorders

Erectile dysfunctionc

Investigations Heart rate increasedd

Skin and subcutaneous tissue disorders Hyperhidrosis

Also includes sinus tachycardia and postural orthostatic tachycardia syndrome. b Percentage is relative to the number of patients in the associated demographic sex category. Fewer than 2% of female patients with major depressive disorder receiving levomilnacipran in placebo-controlled clinical studies reported adverse events related to sexual function. c Includes organic erectile dysfunction and psychogenic erectile dysfunction. d Also includes orthostatic heart rate response. Source: Fetzima (levomilnacipran) extended-release capsules prescribing information; 2013. a

ose-Related Adverse Reactions Associated with Table 3 D Levomilnacipran in Fixed-Dose Studies Daily levomilnacipran dose System organ class preferred Placebo,% 40 mg, % 80 mg, % 120 mg, % term (N = 362) (N = 366) (N = 367) (N = 180) Renal and urinary disorders Urinary hesitation

Reproductive system and breast disorders Erectile dysfunctiona

Percentage is relative to the number of male patients. Source: Fetzima (levomilnacipran) extended-release capsules prescribing information; 2013.

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The patients in study 1 received 40 mg (N = 178), 80 mg (N = 179), or 120 mg (N = 180) of levomilnacipran once daily or placebo (N = 176). The patients in study 2 received 40 mg (N = 188) or 80 mg (N = 188) of levomilnacipran once daily or placebo (N = 186). In study 3 (ie, the flexible-dose trial), the patients received placebo (N = 217) or 40 mg to 120 mg (N = 217) of levomilnacipran once daily, with 21%, 34%, and 44% of patients receiving 40 mg, 80 mg, and 120 mg, respectively, at the end of their treatment.9 Levomilnacipran was shown to be superior to placebo in all 3 studies, based on the improvement of depressive symptoms as measured by the Montgomery-Åsberg Depression Rating Scale total score (Table 1). In addition, levomilnacipran demonstrated superiority versus placebo, as measured by improvement on the Sheehan Disability Scale functional impairment total score.9 Post-hoc analyses of the relationships between treatment outcome and age, sex, and race were not suggestive of any differential responsiveness on the basis of these patient characteristics.9

Adverse Events The most common adverse reactions (≥5% incidence and at least twice the rate of placebo) associated with levomilnacipran are nausea, constipation, hyperhidrosis, heart rate increase, erectile dysfunction, tachycardia, vomiting, and palpitations. The occurrence rates of these adverse reactions compared with placebo are shown in Table 2.9 Based on pooled data from the short-term, placebo-controlled, fixed-dose studies, there were no dose- related adverse reactions (>2% overall incidence) in patients treated with levomilnacipran across the dose range of 40 mg to 120 mg once daily, with the exception of urinary hesitation and erectile dysfunction (Table 3).9 Contraindications Levomilnacipran is contraindicated in patients who are hypersensitive to levomilnacipran, milnacipran hydrochloride, or any excipient in the levomilnacipran formulation. MAOIs intended to treat psychiatric disorders should not be used with levomilnacipran or within 7 days of stopping treatment with levomilnaci pran. Levomilnacipran should not be used within 14 days of stopping an MAOI that is intended to treat psychiatric disorders. In addition, levomilnacipran should not be initiated in a patient who is being treated with linezolid or intravenous methylene blue. Levomilnacipran is contraindicated in patients with uncontrolled narrow-angle glaucoma.9

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Warnings and Precautions Boxed warning. The prescribing information for levomilnacipran includes a boxed warning about the increased risk of suicidal thinking and behavior in children, adolescents, and young adults who are taking antidepressants; patients should be monitored for worsening and emergence of suicidal thoughts and behaviors. It also states that levomilnacipran is not approved for use in pediatric patients.9 Suicidal thoughts and behaviors in adolescents and young adults. Patients should be monitored for clinical worsening and suicidal thinking or behavior.9 Serotonin syndrome. Serotonin syndrome has been reported with SSRIs and serotonin–norepinephrine reuptake inhibitors, both when taken as monotherapy, but especially when taken in combination with other sero tonergic agents (including triptans, tricyclics, fentanyl, lithium, tramadol, tryptophan, buspirone, and St John’s wort). If such symptoms occur, levomilnacipran should be discontinued and supportive treatment should be initiated. If the concomitant use of levomilnacipran with other serotonergic drugs is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.9 Elevated heart rate and blood pressure. Heart rate and blood pressure should be measured before the initiation of treatment with levomilnacipran and periodically throughout treatment. Preexisting hypertension should be controlled before initiating therapy with levomilnacipran.9 Abnormal bleeding. Treatment with levomilnacipran can increase the risk of bleeding. Patients should be cautioned about the risk of bleeding associated with the use of nonsteroidal anti-inflammatory drugs, aspirin, or other drugs that affect coagulation.9 Narrow-angle glaucoma. Mydriasis has occurred with levomilnacipran, and therefore it should be used with caution in patients with controlled narrow-angle glaucoma. Patients with or at risk for raised intraocular pressure should be monitored. Urinary hesitation or retention. Urinary hesitation or retention can occur. If symptoms of these occur, levomilnacipran should be discontinued or other appropriate medical interventions should be considered. Activation of mania/hypomania. Patients should be screened for bipolar disorder, and should be cautioned about the risk of activation of mania and hypomania. Seizures. Seizures can occur with levomilnacipran, which should be used with caution in patients with a seizure disorder. Discontinuation syndrome. When discontinuing levo

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milnacipran, the dose should be tapered when possible, and patients should be monitored for discontinuation symptoms. Hyponatremia. Hyponatremia can occur in association with the syndrome of inappropriate antidiuretic hormone secretion.9

The treatment of MDD can often be challenging. Having a novel therapeutic alternative to choose from offers a new and potentially improved option for patients whose symptoms do not improve with current therapies. Conclusion The treatment of MDD can often be challenging. Having a novel therapeutic alternative to choose from offers a new and potentially improved option for patients whose symptoms do not improve with current therapies. A new treatment option for adults with MDD became available in July 2013 with the FDA approval of levomilnacipran, an oral, extended-release serotonin–norepinephrine reuptake inhibitor. In three 8-week, randomized, double-blind, placebo-controlled clinical studies, levomilnacipran extended release (at doses of 40-120 mg daily) demonstrated significant superiority over placebo in improving depressive symptoms in adult patients with MDD. The most common adverse reactions (≥5% incidence and at least twice the rate of placebo) associated with levomilnacipran are nausea, constipation, hyperhidrosis, heart rate increase, erectile dysfunction, tachycardia, vomiting, and palpitations. n References

1. Mayo Clinic staff. Depression (major depression). February 10, 2012. www.mayo clinic.com/health/depression/DS00175/METHOD=print. Accessed August 20, 2013. 2. National Alliance on Mental Illness. Major depression. Fact sheet. Reviewed April 2013. www.nami.org/factsheets/depression_factsheet.pdf. Accessed August 20, 2013. 3. Kessler RC, Chiu WT, Demler O, et al. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62:617-627. Erratum in: Arch Gen Psychiatry. 2005;62:709. 4. National Alliance on Mental Illness. The impact and cost of mental illness: the case of depression. www.nami.org/PrinterTemplate.cfm?Section=Policymakers_Tool kit&Template=/ContentManagement/ContentDisplay.cfm&ContentID=19043. Accessed August 15, 2013. 5. Greenberg PE, Kessler RC, Birnbaum HG, et al. The economic burden of depression in the United States: how did it change between 1990 and 2000? J Clin Psychiatry. 2003;64:1465-1475. 6. Olchanski N, McInnis Myers M, Halseth M, et al. The economic burden of treatmentresistant depression. Clin Ther. 2013;35:512-522. 7. Thase ME. Levomilnacipran: a brief overview. Medscape. July 26, 2013. www. medscape.com/viewarticle/808378. Accessed August 23, 2013. 8. Cassels C. FDA approves new SNRI for major depression. Medscape. July 26, 2013. www.medscape.com/viewarticle/808481. Accessed August 14, 2013. 9. Fetzima (levomilnacipran) extended-release capsules [prescribing information]. St Louis, MO: Forest Pharmaceuticals, Inc; July 2013.

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Gilotrif (Afatinib): Second-Generation

Tyrosine Kinase Inhibitor Indicated for the First-Line Treatment of Patients with Non– Small-Cell Lung Cancer and EGFR Mutation By Lisa A. Raedler, PhD, RPh, Medical Writer

ung cancer is one of the most frequently diagnosed cancers, as well as the leading cause of cancer- related mortality in the United States.1 The American Cancer Society has estimated that more than 159,000 Americans will die from lung cancer in 2013, representing approximately 27% of all cancer deaths.1 Non–small-cell lung cancer (NSCLC), the most common form of the disease, accounts for 85% to 90% of all cases of lung cancer.2 NSCLC encompasses a number of histologies, including adenocarcinoma, nonsquamous carcinoma, large-cell carcinoma, sarcomatoid carcinoma, and adenosquamous carcinoma.2 Data from a 2005 retrospective case-control cohort study of more than 2000 patients with lung cancer show that, as can be expected, the cost burden associated with lung cancer is substantial.3 In this study, patients with lung cancer had significantly greater healthcare utilization and costs for hospitalization, emergency department visits, outpatient office visits, radiology procedures, laboratory procedures, and pharmacy-dispensed medications compared with controls (ie, people without any cancer). Approximate adjusted average costs of care across the study period—from diagnosis to death or to a maximum of 2 years—were $45,000 for patients with lung cancer and $2900 for controls.3 A more recent analysis of claims data from an oncology registry associated with a large US commercial health plan has further demonstrated the substantial cost burden associated with NSCLC.4 This study, which was published in 2013, assessed the total cost of treatment for more than 300 patients with advanced NSCLC who were continually enrolled in the plan from diagnosis until death. The average total healthcare costs ranged from approximately $19,000 to more than $167,000 for first-line treatment of NSCLC and from approximately $35,000 to more than $135,000 for second-line treatment. In this analysis, systemic therapy represented 20% to 55% of total costs of first-line treatment, and 22% to 68% of total costs for second-line treatment.4 Traditionally, patients with metastatic NSCLC have been treated with combinations of cytotoxic agents. Al-

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though the use of platinum-based “doublet” chemotherapy has improved median overall survival (OS) for patients with advanced NSCLC from 4 or 5 months (for untreated patients) to 8 to 10 months, these doublet therapies are limited by significant toxicities, including myelosuppression, nausea and vomiting, and severe fatigue.5-7 With enhanced knowledge of lung cancer tumor cell biology, targeted agents now offer the opportunity to treat patients with NSCLC using a personalized approach.8 Among North American patients with NSCLC, approximately 10% express mutations in the epidermal growth factor receptor (EGFR).7 Approximately 90% of these EGFR mutations express a deletion at exon 19 or an L858R substitution at exon 21.9,10 Patients whose tumors include either of these 2 classes of EGFR mutations have similar clinical characteristics; they are typically female Asian never-smokers with adenocarcinomas that display bronchioloalveolar features.10 Researchers continue to identify and evaluate medications that target EGFR and other relevant NSCLC mutations. In May 2013, the US Food and Drug Administration (FDA) expanded the indication of erlotinib (Tarceva) to include patients who have not previously received treatment for metastatic NSCLC and whose tumors have a deletion in exon 19 or exon 21 L858R substitution mutations in the EGFR gene as detected by the cobas EGFR Mutation Test.11 The cobas EGFR test was also approved in May 2013. Other novel kinase inhibitors that are being investigated in clinical trials for patients with EGFR mutation–positive NSCLC include dacomitinib, neratinib, pelitinib, and canertinib.8,12

Afatinib: A New Treatment Option for NSCLC In July 2013, the FDA approved afat inib (Gilotrif; Boehringer Ingelheim), a tyrosine kinase inhibitor, for the first-line treatment of patients with metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test.13 This test, known as the therascreen EGFR RGQ PCR Kit (Qiagen, Manchester, United Kingdom), is a companion diagnostic used to determine if a

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Vol 7

Special Feature

Afati

Mechanism of Action Afatinib is a pan-HER inhibitor that irreversibly blocks tyrosine kinase autophosphorylation. This results in downregulation of signaling from EGFR1, HER2, ErbB4, and other dimers in the ErbB family.16,17 Dosing and Administration For first-line patients with NSCLC and EGFR exon 19 deletion mutations or exon 21 (L858R) substitution mutations, the recommended dose of afatinib is 40 mg orally once daily until disease progression or until the drug is no longer tolerated. Afatinib should be taken at least 1 hour before or 2 hours after a meal. Missed doses of afatinib should not be taken within 12 hours of the next dose.16 LUX-Lung 3: A Phase 3 Clinical Trial In the multicenter LUX-Lung 3 trial that served as the basis for the FDA approval of afatinib, 345 patients with EGFR mutation–positive stage IIIB or IV lung adenocarcinoma were randomly assigned to treatment with afatinib or with the combination of cisplatin plus pemetrexed.14 Patients were stratified by mutation type (exon 19 deletion, L858R, or other) and race (Asian or nonAsian) before 2:1 random assignment to 40-mg oral afat inib once daily or up to 6 cycles of cisplatin plus pemet rexed at standard doses administered every 21 days. Maintenance chemotherapy was not permitted. Treatment with afatinib or with cisplatin plus pemetrexed continued until disease progression was observed by the investigators. The trial’s primary end point was PFS as determined by an independent review. Secondary end points included tumor response, OS, adverse events (AEs), and patient-reported outcomes.14

Progression-Free Survival (probability)

1.0 A Figure Progression-Free Survival by Independent Review for All Randomly Assigned Patients Events, n (%)

Progression-Free Survival Progression-free survival (probability) (probability)

patient’s tumor cells express relevant EGFR mutations.13 The approval of afatinib for the treatment of patients with NSCLC and EGFR mutation was based on the demonstration of efficacy, specifically progression-free survival (PFS), in a phase 3 multicenter clinical trial known as the LUX-Lung 3 trial.13,14 In a recent interview regarding the use of afatinib in patients with metastatic NSCLC, Corey Langer, MD, Director of Thoracic Oncology at the University of Pennsylvania’s Abramson Cancer Center, stated, “Afatinib, which is an irreversible EGFR inhibitor targeting both human epidermal growth factor receptor 1 (HER1) and HER2, may ultimately have an advantage over erlotinib….Based on my own experience with both agents, I could give one or the other equally to a newly diagnosed [metastatic NSCLC] patient with an EGFR mutation.”15

1.0 0.8

Events, N (%) Median, months

0.2

152 (66) 11.14

0.2

69 (60) 6.90

Afatinib Afatinib Cisplatin/pemetrexed Cisplatin/pemetrexed

HR, 0.58; 95% CI, 0.43 to 0.78; P < .001

0.4

180 72

151 41

120 21

230 Cisplatin/pemetrexed HR, 0.58; 95% CI, 0.43 to 0.78; P < .001 115

HR, 0.58; 95% CI, 0.43-0.78; P <.001

77 11

Factors Time (months) Time, months

No. at risk Number at risk Afatinib 230 180 151 120 77 50 31 10 3 0 Afatinib 230 180 151 120 77 50 31 10 3 00 Cisplatin/pemetrexed 115 72 41Total 21 11 7 3 2 0 Cisplatin/pemetrexed 115 72 41 21 11 7 3 2 0 0 Sex

Male

No. of

Patients CI Factors indicates confidence interval;Female HR, hazard ratio. Adapted with permission from Sequist LV, Yang JC, Yamamoto N, Age at baseline, years Total 345 et al. J Clin Oncol. 2013;31:3327-3334. < 65 Sex Male Female

≥ 65

121

224 factor stratification clinical characteristics were Race balanced between the treatNon‐Asian Age at baseline, years ment<arms. The patients’ median age was approximately 61 Asian 65 211

170 138

236 30 79

No. of Patients

No. Afat

345 Cisp 121 224 211 134

308 170 138

Smoking history The difference in PFS outcomes was even Baseline ECOG score Never smoked 0 133 more pronounced for patients whose tumors < 15 packet 211 years + stop > 1 year 1 Other current/ex‐smoker had deletion Smoking history 19 or L858R EGFR mutations. Never smoked < 15 packet years + stop > 1 year Efficacy Other current/ex‐smoker

50 7

96 249

years,≥ and the patients134 were diagnosed 65 more than 85% ofEGFR 14 mutation category The majority of patients withRace stage IV adenocarcinoma. stratification factor Del19/L858R (common) with Non‐Asian EGFR mutation–positive Del19 disease enrolled in this trial 96 249 and women were Asian East Asian (72%), never-smokers L858R (68%), EGFR mutation category (65%). EGFR mutations were predominantly exon 19 deBaseline ECOG score Del19/L858R (common) 308 letions (49%) and L858R point0 mutations (40%).14 Del19 L858R

Time (month

Afatinib No. at risk Cisplatin/pemetrexed Afatinib

0 0 3 3 6 9 12 15 18 21 24 27 6 9 12 15 18 21 24 27

Afatinib for the Treatment of EGFR M Median (months) 0.8 Afatinib Cisplatin/pemetrexed (N = 230) (N = 115) 0.6 152 (66) 69 (60) Afatinib Cisplatin/pemetrexed B 11.14 6.90 (n = 230) (n = 115) 0.4

Events, n (%) Median (months)

0.6

A (

133 211 236 30 79

1/16

The phase 3 study demonstrated that afatinib is active and safe in newly diagnosed1/1patients with EGFR 6 1/4 mutation–positive advanced NSCLC. At the time of Favors afatinib analysis. (A) Progression-free survival data cutoff for the primary Fig end2. Primary point analysis, patients of PFS, 45 patients (20%) in 14the afatinib arm and three Ha had been followed for a median of 16.4 months. Over review in patients with common mutations (del19/L85 thatFigperiod, 221 disease ECOG, progression or death events Eastern Cooperative Group. 2. Primary analysis. (A) Progression-free survival (PFS) byOncology independent review for al 14 shown inin the chemotherap were observed by(20%) an independent review. of PFS, 45 patients in the afatinib arm and threeAs patients (3%) review in patients with common (del19/L858R; n 308). (C) Forest plot of su the Figure, the median PFSmutations was significantly prolonged ECOG, Eastern Cooperative Oncology Group. for patients receiving afatinib compared with patients analysis, any events reported by investigators th receiving cisplatin and pemetrexed (11.1 vs 6.9 months, independent review were censored at the time respectively; P <.001).14 muu analysis, any eventsinreported by investigators thatmore were nonevents by been the true effect could have Patient Population The difference PFS fore, outcomes wastreatment even proindependent review were censored at the time of discrepancy; therehad shown in several preplanned sensitivity and su In the LUX-Lung 3 trial, patient demographics and nounced for patients whose tumors had deletion 19 or fore, the true treatment effect could have been underestimated, asevents. was com investigator-generated progression shown in several preplanned sensitivity analysesrate using pop Despiteand thesubgroup high response and prolo investigator-generated progression events. The with Health EGFR mutations treated with gefitinib or e www.AHDBonline.com Drug Benefits Vol 7 l Special Feature l March 2014 l American 89 clon Despite the high response and& prolonged PFS ofl patients majorrate clinical obstacles. Approximately half of with EGFR mutations treated with gefitinib or erlotinib, there are still tion tations will develop the T790M resistance mu

Table 1 E fficacy of Afatinib versus Cisplatin/Pemetrexed in the Phase 3 Study, LUX-Lung 3 Efficacy end point

Cisplatin/ pemetrexed (N = 115)

Afatinib (N = 230)

Progression-free survival14 Deaths or progressions, 152 (66.1) N (%) Median progression11.1 months free survival (95% CI, 9.6-13.6) Hazard ratio Stratified log-rank testa Overall survival14 Deaths, N (%) Median overall survival Hazard ratio Stratified log-rank testa Overall response rate (CR + PR)16 Percent per independent review Median duration of response

69 (60.0) 6.9 months (95% CI, 5.4-8.2)

0.58 (95% CI, 0.43-0.78) P <.001 116 (50.4) 59 (51.2) 28.1 months 28.2 months (95% CI, 24.6-33.0) (95% CI, 20.7-33.2) 0.91 (95% CI, 0.66-1.25) P = .55

56%

23%

11.1 months

5.5 months P = .001

Stratified by EGFR mutation status and race. CI indicates confidence interval; CR, complete response; EGFR, epidermal growth factor receptor; PR, partial response. Sources: Sequist LV, Yang JC, Yamamoto N, et al. J Clin Oncol. 2013;31:3327-3334; Gilotrif (afatinib) tablets prescribing information; 2013.

L858R EGFR mutations. In those patients, PFS was nearly doubled with afatinib compared with chemother apy (13.6 vs 6.9 months, respectively; P <.001).14 The PFS findings and other key efficacy end point analyses are summarized in Table 1.14,16

Safety In the phase 3 trial, afatinib was administered for a median of 11 months (16 cycles).14 As assessed on a per-patient basis, the mean overall compliance with afat inib was 98%. Dose reductions to less than 40 mg daily were necessary for 120 patients (52%). A total of 16 patients (7%) opted to increase the daily dose of afatinib from 40 mg to 50 mg after the first cycle.14 Altogether, 112 patients (49%) receiving afatinib and 53 patients (48%) receiving chemotherapy experienced treatment-related AEs that were grade ≥3 in severity.14 Among patients receiving afatinib, the most common treatment-related AEs were diarrhea, rash, and dryness or irritation of the skin, mucosa, and nails (Table 2). Of these, diarrhea (1.3%) and paronychia (0.9%) resulted in

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treatment discontinuation.14 Among patients receiving cisplatin plus pemetrexed, decreased appetite, fatigue, nausea, vomiting, and myelosuppression were the most common AEs. Therapy was discontinued secondary to treatment-related AEs in 8% of patients receiving afatinib and in 12% of patients receiving cisplatin plus pemetrexed.14

Warnings and Precautions Diarrhea. Diarrhea secondary to afatinib has resulted in dehydration with or without renal impairment, as well as in fatalities. In the LUX-Lung 3 trial, diarrhea occurred in 96% of the patients receiving afatinib (N = 229).16 For 15% of these patients, diarrhea was grade 3 in severity.16 Renal impairment as a consequence of diarrhea occurred in 6.1% of patients treated with afatinib, of which 3 (1.3%) were grade 3.16 For patients who develop grade 2 diarrhea that lasts more than 48 hours or diarrhea that is grade ≥3, afatinib should be withheld until diarrhea resolves to grade ≤1. Afatinib can then be resumed with appropriate dose reduction. Patients should self-administer an antidiarrheal agent, such as loperamide, at the onset of diarrhea and should continue such therapy until loose bowel movements cease for 12 hours.16 Bullous/exfoliative skin disorders. Of the 3865 patients who received afatinib across clinical trials, 6 had grade 3 cutaneous reactions characterized by bullous, blistering, and exfoliating lesions.16 In the LUX-Lung 3 study, 90% had skin reactions (rash, erythema, and acneiform rash), of which 16% were grade 3.16 Of the total patients, 7% experienced grade 1 to 3 hand-foot syndrome (palmar-plantar erythrodysesthesia syndrome).16 Patients who develop life-threatening bullous, blistering, or exfoliating lesions should discontinue using afatinib. In patients who have grade 2 skin AEs that last for more than 7 days, intolerable grade 2 skin reactions, or grade 3 skin reactions, afatinib should be withheld until the reaction resolves to grade ≤1. Afatinib can be resumed with appropriate dose reduction.16 Interstitial lung disease. Interstitial lung disease or interstitial lung disease–like adverse reactions, including lung infiltration, pneumonitis, acute respiratory distress syndrome, or allergic alveolitis, were observed in 1.5% of the 3865 patients who received afatinib across clinical trials.16 The incidence of interstitial lung disease was higher in Asian patients (2.1%) compared with non-Asian patients (1.2%). Among these cases, 0.4% were fatal. In the phase 3 trial, grade ≥3 interstitial lung disease developed in 1.3% of patients receiving afatinib, and resulted in death for 1% of patients. Afatinib should be withheld while patients with suspected interstitial lung disease undergo evaluation, and should be discontinued if a diagnosis of interstitial lung disease is confirmed.16

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Hepatic toxicity. Liver test abnormalities occurred in 10.1% of the 3865 patients who received afatinib across clinical trials.16 In 7 patients, this toxicity was fatal. In the LUX-Lung 3 trial, liver test abnormalities of any grade were observed in 17.5% of afatinib recipients.16 Periodic liver testing should be conducted during treatment with afatinib. Afatinib should be withheld in patients who develop worsening of liver function and in patients who develop severe hepatic impairment.16 Keratitis. Keratitis (ie, acute or worsening eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain, and/or red eye) occurred in 0.8% of 3865 afat inib recipients across clinical trials.16 Of the patients in the phase 3 afatinib trial, 5 developed keratitis, with 1 patient experiencing grade 3 severity.16 Afatinib should be withheld while patients with suspected keratitis are evaluated. If ulcerative keratitis is confirmed, afatinib treatment should be interrupted or discontinued. Afatinib should be used with caution in patients with a history of keratitis, ulcerative keratitis, or severe dry eye, as well as in patients who wear contact lenses.16 Embryofetal toxicity. Based on its mechanism of action, afatinib can cause fetal harm when administered during pregnancy. Patients who become pregnant while taking afatinib should be warned about the potential hazard to the fetus.16

Lung cancer remains the main cause of cancer-related death in the United States for men and women. The disease is still diagnosed mainly at advanced stages, such that prognosis is poor and long-term survival is rare. Afatinib has demonstrated improved efficacy with manageable side effects. Females of reproductive potential should use very effective contraception during treatment with afatinib, and for at least 2 weeks after the last dose of afatinib. Patients taking afatinib should contact their healthcare providers if they become pregnant or if pregnancy is suspected.16

Conclusion Lung cancer remains the main cause of cancer-related death in the United States for men and women. The disease is still diagnosed mainly at advanced stages, such that prognosis is poor and long-term survival is rare. Afatinib, the second oral kinase inhibitor approved for the initial treatment of EGFR mutation–positive metastatic NSCLC, has demonstrated improved efficacy with man-

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dverse Reactions Reported in ≥10% of Patients Table 2 A Receiving Afatinib in the LUX-Lung 3 Study Afatinib (N = 229) Adverse reaction

All grades, Grade 3,a % %

Pemetrexed/cisplatin (N = 111) All grades, %

Grade 3,a %

Gastrointestinal disorders 96 15 23 Diarrhea 71 9 15 Stomatitisb 12 0 1 Cheilitis Skin and subcutaneous tissue disorders 90 16 11 Rash/dermatitis acneiformc 21 0 1 Pruritus 31 0 2 Dry skin Infections and infestations 58 11 0 Paronychiad 13 1 5 Cystitis Metabolism and nutrition disorders 29 4 55 Decreased appetite Respiratory, thoracic, and mediastinal disorders 17 0 2 Epistaxis 11 0 6 Rhinorrhea Investigations 17 1 14 Weight decreased General disorders and administration site conditions 12 0 6 Pyrexia Eye disorders 11 0 3 Conjunctivitis

2 1 0 0 0 0 0 0 4

1 0 1 0 0

None of the adverse reactions in this table were grade 4 in severity. Includes stomatitis, aphthous stomatitis, mucosal inflammation, mouth ulceration, oral mucosa erosion, mucosal erosion, mucosal ulceration. c Includes group of rash preferred terms, acne, acne pustular, dermatitis acneiform. d Includes paronychia, nail infection, nail bed infection. Source: Gilotrif (afatinib) tablets prescribing information; 2013. a

ageable side effects relative to doublet chemotherapy. Afatinib joins erlotinib as the only FDA-approved agents for this subset of patients with NSCLC, offering them another effective alternative to cytotoxic therapy. As a pan-HER inhibitor, afatinib may confer clinical value in other cancers that overexpress EGFR and HER2. In addition to further exploration in NSCLC, investigators are evaluating afat inib monotherapy, as well as combinations with various cytotoxic and biologic agents, in breast, prostate, head and neck, and esopha gogastric cancers.18 n

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References

1. American Cancer Society. Lung cancer (non-small cell): what are the key statistics about lung cancer? Revised July 12, 2013. www.cancer.org/cancer/lungcancernon-smallcell/detailedguide/non-small-cell-lung-cancer-key-statistics. Accessed September 23, 2013. 2. American Cancer Society. Lung cancer (non-small cell): what is non-small cell lung cancer? Revised July 12, 2013. www.cancer.org/cancer/lungcancer-non-smallcell/ detailedguide/non-small-cell-lung-cancer-what-is-non-small-cell-lung-cancer. Accessed September 23, 2013. 3. Kutikova L, Bowman L, Chang S, et al. The economic burden of lung cancer and the associated costs of treatment failure in the United States. Lung Cancer. 2005;50: 143-154. 4. Henk HJ, Ray S. Treatment patterns and healthcare costs among patients with advanced non-small-cell lung cancer. Lung Cancer Manag. 2013;2:189-197. 5. Azzoli CG, Giaccone G, Temin S. American Society of Clinical Oncology Clinical Practice Guideline Update on Chemotherapy for Stage IV Nonâ&#x20AC;&#x201C;Small-Cell Lung Cancer. J Oncol Pract. 2010;6:39-43. 6. American Cancer Society. Lung cancer (non-small cell): chemotherapy for nonsmall cell lung cancer. Revised July 12, 2013. www.cancer.org/cancer/lungcancernon-smallcell/detailedguide/non-small-cell-lung-cancer-treating-chemotherapy. Accessed September 23, 2013. 7. Villaflor VM, Salgia R. Targeted agents in non-small cell lung cancer therapy: what is there on the horizon? J Carcinog. 2013;12:7. 8. Hirsh V, Melosky B, Goss G, et al. A personalized approach to treatment: use of EGFR tyrosine kinase inhibitors for the treatment of non-small-cell lung cancer in Canada. Curr Oncol. 2012;19:78-90. Erratum in: Curr Oncol. 2012;19:e228.

9. Politi K, Zakowski MF, Fan PD, et al. Lung adenocarcinomas induced in mice by mutant EGF receptors found in human lung cancers respond to a tyrosine kinase inhibitor or to down-regulation of the receptors. Genes Dev. 2006;20:1496-1510. 10. Uramoto H, Mitsudomi T. Which biomarker predicts benefit from EGFR-TKI treatment for patients with lung cancer? Br J Cancer. 2007;96:857-863. 11. US Food and Drug Administration. Drugs: erlotinib. Updated May 15, 2013. www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm352317.htm. Accessed September 24, 2013. 12. Landi L, Cappuzzo F. Irreversible EGFR-TKIs: dreaming perfection. Transl Lung Cancer Res. 2013;2:40-49. 13. US Food and Drug Administration. Drugs: afatinib. Updated July 12, 2013. www.fda.gov/drugs/informationondrugs/approveddrugs/ucm360574.htm. Accessed September 24, 2013. 14. Sequist LV, Yang JC, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013;31:3327-3334. 15. OncLive TV. Dr. Corey Langer discusses afatinib in EGFR-positive NSCLC. YouTube. August 13, 2013. www.youtube.com/watch?v=Q0Cwcfv0W58. Accessed September 23, 2013. 16. Gilotrif (afatinib) tablets [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; July 2013. 17. Solca F, Dahl G, Zoephel A, et al. Target binding properties and cellular activity of afatinib (BIBW 2992), an irreversible ErbB family blocker. J Pharmacol Exp Ther. 2012;343:342-350. 18. ClinicalTrials.gov. Afatinib. Search results. http://clinicaltrials.gov/ct2/results? term=afatinib&Search= Search. Accessed September 24, 2013.

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Ilaris (Canakinumab) Receives a New Indication for the Treatment of Systemic Juvenile Idiopathic Arthritis By Lisa A. Raedler, PhD, RPh, Medical Writer

ystemic juvenile idiopathic arthritis (SJIA) is a rare inflammatory disease, affecting approximately 10% of children diagnosed with juvenile idiopathic arthritis in the United States.1,2 The classic symptoms of SJIA include pain in the small joints of the hands, wrists, knees, and ankles; rash; and a high, spiking fever of ≥103°F that can last for weeks to months.3 By definition, SJIA can present at any point until the age of 16 years. However, a long-term outcomes study found that the median age at diagnosis of SJIA was 4 years.4 The distribution of the disease by sex is roughly equal.1,4 Studies of long-term outcomes of juvenile idiopathic arthritis have demonstrated that disease-related morbidity continues to be evident in adulthood.4-6 Among adult patients with SJIA who were evaluated more than 16 years after diagnosis, 66% described joints with limited range of motion, 52% had joint pain, and 30% reported morning stiffness.4 Adult patients with SJIA also experience impaired quality of life and poor physical functioning, as well as long-term challenges with social functioning and sexual activity.5,6 Although analyses of healthcare costs associated with SJIA are few, it is clear that children with juvenile idiopathic arthritis consume inordinate amounts of healthcare resources. A 2007 study of Canadian children showed that the total annual average direct medical cost for patients with juvenile idiopathic arthritis was almost $1700 higher (2005 Canadian dollars; range, $875$2500) than for the control patients without juvenile idiopathic arthritis.7 Higher costs for patients with juvenile idiopathic arthritis were related to specialist visits, diagnostic tests, and medication use.7 A more recent German study showed that the average total cost of juvenile idiopathic arthritis was highest among patients with seropositive polyarthritis and SJIA.8 The cost of medications, including biologics, comprised almost 50% of the total healthcare costs for these patients.8 Until very recently, the treatment options for patients with SJIA included methotrexate (Trexall); nonsteroidal anti-inflammatory drugs (NSAIDs); systemic corticosteroids; and tociliz umab (Actemra), an interleukin (IL)-6 inhibitor. Tocilizumab is indicated for patients with active SJIA aged ≥2 years and is administered once

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every 2 weeks as a 1-hour intravenous (IV) infusion.9 One additional medication was recently added as a new treatment option for this patient population.

FDA Approves Canakinumab for SJIA In May 2013, the US Food and Drug Administration (FDA) approved a new indication for canakinumab (Ilaris; Novartis) for the treatment of active SJIA in patients aged ≥2 years. Canakinumab is the first IL-1 beta inhibitor approved for the treatment of SJIA, and the only approved SJIA treatment that is given as a subcutaneous (SC) injection once monthly.10 The FDA approval of the new indication for canakin umab was based on 2 phase 3 clinical trials of patients with SJIA and demonstrated significant symptom improvement in the majority of patients receiving cana kinumab.11 This drug is already approved by the FDA for the treatment of the rare autoinflammatory diseases that form cryopyrin-associated periodic syndromes. Canakinumab Fills an Unmet Need In an interview regarding the treatment of SJIA with canakinumab, Alberto Martini, MD, Professor of Pediatrics, University of Genoa, Italy, stated, “In…a sizable proportion of patients [with SJIA], there was a big improvement in symptoms, [and] there was the possibility to reduce substantially the amount of steroids that these children were receiving….Treatment with this type of cytokine inhibitor could radically change the way we are treating [SJIA].”12 The availability of canakinumab for patients with SJIA offers an easier-to-use alternative for children and their families who wish to avoid the logistic and tolerability challenges associated with an IV therapy given every 2 weeks. “The efficacy of Ilaris, along with its monthly subcutaneous dosing, make it an exciting new option for children who are living with this debilitating disease,” said Daniel J. Lovell, MD, MPH, Associate Director, Division of Rheumatology, Cincinnati Children’s Hospital Medical Center, OH.13 Mechanism of Action Canakinumab is a selective fully human monoclonal

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Table 1 Pediatric ACR Response in Patients with SJIA at Days 15 and 29 in Study 1: Canakinumab versus Placebo Day 15 Canakinumab (N = 43), %

Placebo (N = 41), %

Day 29 Weighted difference,a %

Canakinumab (N = 43), %

Weighted difference,a %

Placebo (N = 41), %

ACR30

70 (95% CI, 56-84)

ACR50

65 (95% CI, 50-80)

76 (95% CI, 63-88)

ACR70

64 (95% CI, 49-79)

67 (95% CI, 52-81)

Weighted difference is the difference between the canakinumab and placebo response rates, adjusted for the stratification factors (ie, number of active joints, previous response to anakinra, and level of oral corticosteroid use). ACR indicates American College of Rheumatology; ACR30, ACR 30% criteria for improvement; CI, confidence interval; SJIA, systemic juvenile idiopathic arthritis. Source: Ilaris (canakinumab) injection prescribing information; 2013.

antibody that inhibits IL-1 beta, one of the proinflammatory cytokines that comprise the body’s immune system’s defenses.11 Excess production of IL-1 beta plays a prominent role in inflammatory diseases, including in patients with juvenile rheumatoid arthritis. Canakinumab inhibits inflammation by neutralizing IL-1 beta for a sustained period of time.11

Dosing and Administration The recommended dose and schedule of canakinumab in patients with SJIA is 4 mg/kg, with a maximum of 300 mg for patients with a body weight of ≥7.5 kg. Cana kinumab is administered subcutaneously every 4 weeks.11 There are no contraindications to the use of canakin umab, with the exception of patients who have confirmed hypersensitivity to the active substance of cana kinumab or to any of its excipients.11 Each monthly SC injection of canakin umab costs $16,000.14 Canakinumab’s manufacturer offers financial assistance to eligible patients who are unable to afford treatment with canakinumab.14 Phase 3 Clinical Trials Canakinumab was approved by the FDA for the treatment of SJIA on the basis of 2 randomized, multicenter, double-blind phase 3 clinical trials.15 Both trials enrolled patients who had a confirmed diagnosis of SJIA at least 2 months before enrollment in the study (mean disease duration at baseline, 3.5 years); active disease, defined as ≥2 joints with active arthritis (mean number of active joints, 15.4); documented spiking, intermittent fever (>38°C) for at least 1 day within 1 week before study drug administration; and C-reactive protein >30 mg/L.11,15 Patients were allowed to continue treatment with stable doses of methotrexate, corticosteroids, and/or NSAIDs. The tapering of corticosteroid doses was allowed according to the design of study 2.11,15

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Trial Design In study 1, patients with SJIA received a single dose of canakinumab 4 mg/kg (N = 43) or of placebo (N = 41) via SC injection. Patients were then assessed for efficacy at day 15, and had a safety analysis done up to day 29.11,15 The SJIA study 2 had a 2-part design that included an open-label, single-arm, active-treatment period (part 1), followed by a randomized, double-blind, placebo-controlled, event-driven withdrawal design (part 2). Overall, 177 patients received canakinumab 4 mg/kg (maximum, 300 mg) in part 1 of study 2, and 100 patients received canakinumab 4 mg/kg (maximum, 300 mg) or placebo every 4 weeks in part 2 of study 2.11,15 The primary objective of study 1 was to demonstrate the superiority of a single dose of canakinumab relative to placebo in the proportion of patients who achieved ≥30% improvement in an adapted pediatric American College of Rheumatology (ACR) response criterion, which included the pediatric ACR core set (ACR 30% criteria for improvement [ACR30] response) and the absence of fever (temperature of ≤38°C in the preceding 7 days) at day 15.11,15 The primary objective of study 2 was to demonstrate the prevention of flare with the use of canakinumab in patients with active SJIA. Flare was defined by a worsening of ≥30% in at least 3 of the 6 core pediatric ACR response variables, combined with an improvement of ≥30% in no more than 1 of the 6 variables, or the reappearance of fever not resulting from infection for at least 2 consecutive days.11,15 Efficacy: Study 1 The analysis of study 1 data revealed a significant improvement in patients receiving a single dose of canakinumab versus placebo at day 15.11 Table 1 pre sents the percentages of patients by pediatric ACR response rate.11

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Table 2 Adverse Reactions from 2 Pivotal Clinical Trials of Canakinumab in Patients with SJIA Study 2 Part 1

Part 2

Study 1

Canakinumab (N = 177) N (%); IRa

Canakinumab (N = 50) N (%); IRa

Placebo (N = 50) N (%); IRa

Canakinumab (N = 43) N (%); IRa

Placebo (N = 41) N (%); IRa

97 (54.8); 0.91

27 (54); 0.59

19 (38); 0.63

13 (30.2); 1.26 5 (12.2); 1.37

25 (14.1); 0.16

8 (16); 0.15

6 (12); 0.08

3 (7); 0.25

1 (2.4); 0.23

19 (10.7)

6 (12.0)

2 (4.0)

3 (7.3)

2 (1.1)

1 (2.0)

Infections Infection (eg, nasopharyngitis, [viral] upper respiratory tract infection, pneumonia, rhinitis, pharyngitis, tonsillitis, sinusitis, urinary tract infection, gastroenteritis, viral infection) Gastrointestinal disorders Upper abdominal pain Skin reactions Injection-site reaction, mildb Injection-site reaction, moderate

Incidence rate represents the exposure-adjusted incidence rate per 100 patient-days. No injection-site reaction led to study discontinuation. IR indicates incidence rate; SJIA, systemic juvenile idiopathic arthritis. Source: Ilaris (canakinumab) injection prescribing information; 2013. a

Among patients with SJIA who returned for their day 15 visit, the mean change in patient pain score (0-100 mm visual analog scale) was –50.0 mm with canakinumab (N = 43) compared with +4.5 mm with placebo (N = 25).11 The mean change in pain score among canakinumab- treated patients was consistent through day 29.11 All patients treated with canakinumab had no fever at day 3 compared with 87% of patients who received placebo.11

Efficacy: Study 2 Corticosteroid dose tapering. A total of 128 patients who entered part 1 (the open-label portion) of study 2, were taking corticosteroids. Of these, 92 patients attempted corticosteroid tapering. Of these 92 patients, 57 (62%) successfully tapered their corticosteroid doses.11 Almost half (N = 42 [46%]) of the patients discontinued treatment with corticosteroids.11,15 Time to flare. In part 2, the probability of having a flare over time was significantly lower for the canakinu mab-treated group versus the placebo group. Patients in the canakinumab group had a 64% relative reduction in the risk of flare compared with the patients receiving placebo (hazard ratio, 0.36; 95% confidence interval, 0.17-0.75).11,15 Safety Profile of Canakinumab in SJIA The most common (≥10%) adverse drug reactions in patients with SJIA who received canakinumab were in-

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fections (ie, nasopharyngitis, upper respiratory tract infections), abdominal pain, and mild-to-moderate injection-site reactions (Table 2).11,15 Serious infections. IL-1 blockade may interfere with the body’s immune response to infections. Treatment with medications that work through the inhibition of IL-1, including canakinumab, has been associated with an increased risk of serious infections. Physicians should exercise caution when administering canakin umab to patients with infections and/or a history of recurring infections or underlying conditions that may predispose them to infections.11 Canakinumab should not be administered to any patient who has an active infection that requires medical intervention.11 Canakin umab should be discontinued if a patient develops a serious infection.11 Immunizations. Live vaccines should not be given concurrently with canakinumab.11 Patients should receive all recommended vaccinations before the initiation of therapy with canakinumab.11 Hypersensitivity. Canakinumab should not be administered to any patients with a known clinical hypersensitivity to canakinumab.11 No anaphylactic reactions have been reported during clinical trials of treatment with canakinumab in patients with SJIA.11 Immunogenicity. A biosensor binding assay or a bridging immunoassay was used to detect antibodies directed against canakinumab in patients who received

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the drug. Antibodies against canakinumab were observed in 3.1% of patients who were treated with canakinumab for SJIA.11 No neutralizing antibodies were detected.11 No apparent correlation of antibody development to clinical response or adverse events was observed.11

Experts suggest that biologics, including canakinumab, are effective alternatives for children with SJIA who wish to avoid the potentially devastating toxicities of treatment with high-dose corticosteroids. Macrophage activation syndrome. Macrophage activation syndrome is a life-threatening disorder that can develop in patients with rheumatic conditions, in particular in patients with SJIA. Physicians should be attentive to any symptoms of infection or worsening of SJIA, because these are known triggers for macrophage activation syndrome. Of 201 patients with SJIA who were treated with canakinumab in clinical trials, 11 cases of macrophage activation syndrome were observed.11 In clinical trials, canakinumab did not increase the incidence of macrophage activation syndrome in patients with SJIA, but no definitive conclusion can be made at this point.11 Immunosuppression. The impact of treatment with anti–IL-1 therapy on the development of malignancies is not known. However, treatment with immunosuppressants, including canakinumab, may result in an increase in the risk of malignancies.11

Conclusion For children and adolescents with SJIA, canakinumab offers clinically and statistically significant efficacy benefits, a favorable tolerability profile, and a convenient schedule and route of administration. Experts suggest

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that biologics, including canakinumab, are effective alternatives for children with SJIA who wish to avoid the potentially devastating toxicities of treatment with highdose corticosteroids.16 Clinical studies are under way to assess the safety and efficacy of the prolonged use of various canakinumab doses, as well as to elucidate the role of canakinumab and other biologics relative to corticosteroids in patients with SJIA.16,17 n

References

1. Arthritis Foundation. Kids get arthritis too. Understanding JIA: What is juvenile arthritis? www.kidsgetarthritistoo.org/about-ja/the-basics/what-is-juvenile-arthritis-2. php. Accessed July 17, 2013. 2. Gurion R, Lehman TJA, Moorthy LN. Systemic arthritis in children: a review of clinical presentation and treatment. Int J Inflam. 2012;2012:271569. 3. Arthritis Foundation. Juvenile arthritis fact sheet. www.arthritis.org/ja-fact-sheet. php. Accessed June 11, 2013. 4. Minden K, Niewerth M, Listing J, et al. Long-term outcomes in patients with juvenile idiopathic arthritis. Arthritis Rheum. 2002;46:2392-2401. 5. Bernatsky S, Duffy C, Malleson P, et al. Economic impact of juvenile idiopathic arthritis. Arthritis Rheum. 2007;57:44-48. 6. Minden K, Niewerth M, Listing J, et al. The economic burden of juvenile idiopathic arthritis: results from the German paediatric rheumatologic database. Clin Exp Rheumatol. 2009;27:863-869. 7. Packham JC, Hall MA. Long-term follow-up of 246 adults with juvenile idiopathic arthritis: functional outcome. Rheumatology (Oxford). 2002;41:1428-1435. 8. Packham JC, Hall MA. Long-term follow-up of 246 adults with juvenile idiopathic arthritis: social function, relationships and sexual activity. Rheumatology (Oxford). 2002; 41:1440-1443. 9. Actemra (tocilizumab) injection [prescribing information]. South San Francisco, CA: Genentech, Inc; April 2013. 10. Grogan K. Second FDA thumbs-up for Novartis Ilaris. Pharma Times Online. May 10, 2013. www.pharmatimes.com/article/13-05-10/Second_FDA_thumbs-up_ for_Novartis_ Ilaris.aspx. Accessed June 19, 2013. 11. Ilaris (canakinumab) injection [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; May 2013. 12. SBARTSTV. Global medical news: ACZ885 a targeted therapy for SJIA and TRAPS. YouTube. June 6, 2013. www.youtube.com/watch?v=N5hyY7anV7M. Accessed June 19, 2013. 13. Novartis Media Relations. Novartis drug Ilaris approved by FDA to treat active systemic juvenile idiopathic arthritis, a serious form of childhood arthritis. Press release; May 10, 2013. www.novartis.com/newsroom/media-releases/en/2013/1700796. shtml. Accessed June 19, 2013. 14. Rath L. FDA approves Ilaris for systemic JIA: a biologic drug holds promise for kids with severe childhood arthritis. Arthritis Today. May 17, 2013. www.arthritistoday. org/news/ilaris-approved-for-jia-272.php. Accessed June 19, 2013. 15. Ruperto N, Brunner HI, Quartier P, et al; for the Paediatric Rheumatology International Trials Organisation and the Pediatric Rheumatology Collaborative Study Group. Two randomized trials of canakinumab in systemic juvenile idiopathic arthritis. N Engl J Med. 2012;367:2396-2406. 16. Schneider R, Laxer RM. Systemic juvenile idiopathic arthritis. Rheumatologist. May 2012. www.the-rheumatologist.org/details/article/2041587/Systemic_Juvenile_ Idiopathic_Arthritis.html. Accessed June 19, 2013. 17. ClinicalTrials.gov. Canakinumab SJIA. Search results. http://clinicaltrials.gov/ ct2/results?term=canakinumab+SJIA&Search=Search. Accessed June 19, 2013.

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Imbruvica (Ibrutinib) for Mantle-Cell Lymphoma: First Bruton’s Tyrosine Kinase Inhibitor Approved for Use in a Hematologic Malignancy

By Lisa A. Raedler, PhD, RPh, Medical Writer

antle-cell lymphoma (MCL) is a rare malignancy, comprising approximately 5% of all cases of non-Hodgkin lymphoma.1 MCL can be an aggressive cancer and most often affects men aged >60 years.1,2 The median overall survival of patients with MCL is approximately 5 to 7 years, making MCL one of the poorest prognoses among B-cell lymphomas.3 Survival outcomes of MCL are poor in part because the disease is typically diagnosed in later stages, when the gastrointestinal tract and bone marrow become involved.2 Although the data suggest a possible increase in the incidence of MCL over the past 20 years, this may be the result of improved diagnostic methods.4 Treatment decisions for MCL are based on several factors, including the patient’s age, the patient’s overall health, and the disease stage.1 In clinical practice, combinations of chemotherapy agents with anti-CD20 monoclonal antibody therapy, high-dose chemotherapy followed by autologous stem-cell transplantation, and radioimmunotherapy are relevant options for treatment-naïve patients with MCL.2 Although MCL typically responds to initial treatment, it relapses within a few years or becomes refractory to treatment, such that second-line therapy is necessary.2 As of yet, there is no consensus regarding the management of patients with relapsed and/or refractory MCL.5 There are few assessments of the cost burden associ ated with MCL. One recent cost-effectiveness study, which used US payer data, showed that the average per-patient cost of bendamustine plus rituximab, and the average per-patient cost of the R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen both exceeded $100,000.6 Until recently, bortezomib (Velcade) and lenalidomide (Revlimid) were the only treatments approved by the US Food and Drug Administration (FDA) for use in patients with MCL. Bortezomib is indicated for patients with MCL who have received at least 1 previous therapy.7 Lenalidomide is approved for use in patients with MCL whose disease relapsed or progressed after 2 previ-

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ous therapies, one of which included bortezomib.8 Novel options that are under investigation as single agents or in combination for MCL include phosphoinositide 3-kinase inhibitors (eg, idelalisib), histone deacetylase inhibitors (eg, vorinostat, panobinostat), monoclonal antibodies (eg, ofatumumab), and mammalian target of rapamycin (mTOR) inhibitors (eg, temsir olimus, everolimus).3,9

Ibrutinib for Relapsed and/or Refractory MCL On November 13, 2013, ibrutinib (Imbruvica; Pharmacyclics) was granted accelerated approval by the FDA to treat patients with MCL who have received at least 1 previous therapy.10 Ibrutinib is the first drug designed to target Bruton’s tyrosine kinase (BTK), a protein necessary for the growth and survival of B-cells.11 The approval of ibrutinib for MCL was based on the results of a phase 2 multicenter, international, single-arm trial involving 111 patients with previously treated MCL. The primary end point of this trial was the overall response rate .10,12 Michael Wang, MD, Director, Myeloma Tissue Bank, at M.D. Anderson Cancer Center, Houston, and lead investigator of the phase 2 study of ibrutinib, commented on the trial results to date, saying, “These are unprecedented response rates for monotherapy in the relapsed setting. Based on these results it is apparent that ibrutinib therapy provides a well-tolerated, effective, and convenient (orally administered) therapy for relapsed patients with MCL.13 Mechanism of Action Ibrutinib is a small molecule that inhibits BTK, a signaling molecule of the B-cell antigen receptor and cytokine receptor pathways.14 As an irreversible covalent inhibitor, ibrutinib continues to inhibit BTK even after it is metabolized.14,15 Preclinical studies have demonstrated that ibrutinib prevents the activation of downstream pathways affected by BTK, promotes cancer cell apoptosis, and inhibits cell proliferation.11,14

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Table 1 Dose Modifications for Adverse Reactions Toxicity MCL dose modification postrecovery, incidence starting dose = 560 mg First

Restart at 560 mg daily

Second

Restart at 420 mg daily

Third

Restart at 280 mg daily

Fourth

Discontinue ibrutinib

MCL indicates mantle-cell lymphoma. Source: Imbruvica (ibrutinib) capsules prescribing information; 2013.

Table 2 Best Response to Ibrutinib Therapy Investigator-assessed response Overall response rate

All patients (N = 111), % 65.8 (95% CI, 56.2, 74.5)

Complete response

17.1

Partial response

48.6

Median duration of response in months 17.5 (95% CI, 15.8, NR) CI indicates confidence interval; NR, not reached. Source: Imbruvica (ibrutinib) capsules prescribing information; 2013.

Dosing and Administration In patients with MCL who have received 1 previous therapy, the recommended dose and schedule for ibrutinib is 560 mg orally once daily. Ibrutinib should be administered at the same time each day, swallowed whole with water. Capsules should not be opened, broken, or chewed.14 Table 1 summarizes ibrutinib dose modification guidelines for patients with any grade ≥3 nonhematologic toxicity, grade ≥3 neutropenia with infection or fever, or grade 4 hematologic toxicities. Ibrutinib may be reinitiated at the starting dose after symptoms of toxicity have resolved to grade 1 or to baseline.14 Because ibrutinib is primarily metabolized by the cytochrome (CY) P3A enzyme, it should not be coadministered with strong or moderate CYP3A inhibitors. The concomitant use of strong CYP3A inhibitors that would be taken on an ongoing basis (eg, long-term ritonavir, indinavir, nelfinavir, saquinavir, boceprevir, telaprevir, nefazodone) with ibrutinib is not recommended.14 Increased drug exposure is also expected in patients with hepatic impairment. However, there are insufficient data to recommend a dose of ibrutinib in patients with baseline hepatic impairment.14 Pivotal Phase 2 Clinical Trial In the phase 2 single-arm, open-label, multicenter, international trial that led to the FDA approval of ibrutinib for MCL, Wang and colleagues enrolled 111 patients with MCL who had received multiple therapies, as

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well as patients who were bortezomib-naïve and patients who had received at least 2 cycles of bortezomib (ie, bortezomib-exposed).12 Ibrutinib was given orally at 560 mg daily in continuous 28-day cycles until disease progression. The primary end point of this phase 2 study was the overall response rate, defined as partial response and complete response.12 Duration of response, progression-free survival, overall survival, and safety served as secondary end points. Tumor response was evaluated every 2 cycles per the revised International Working Group for non-Hodgkin lymphoma criteria.12 Efficacy parameters were assessed by the investigators, as well as by an independent central review committee.12 The bortezomib-naïve and bortezomib-exposed patient subgroups were evaluated separately.12

Patient Population The median age of the patients with MCL enrolled in the phase 2 trial of ibrutinib was 68 years.12,14 Most patients (77%) were male with an Eastern Cooperative Oncology Group performance status of 0 or 1 (89%).12,14 Almost half (45%) of the enrolled patients with MCL had refractory disease, and 72% had advanced disease.12 Patients had received a median of 3 previous therapies, including (1) rituximab-containing regimens (89%); (2) hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (30%); (3) lenalidomide (24%); and (4) and stem-cell transplantation (11%).12,14 Efficacy With a median treatment duration of 8.3 months, the overall response rate was 65.8% among patients with MCL who received ibrutinib; 17.1% of patients achieved complete response and 48.6% of patients achieved partial response.14 The ibrutinib response rates did not differ between the bortezomib-naïve and bortezomib-exposed patient subgroups, or according to other baseline characteristics or risk factors associated with treatment failure.12 The overall response rate and complete response rate improved over time with continued use of ibrutinib therapy.12 Table 2 includes the efficacy parameters reported in the phase 2 clinical trial of ibrutinib.14 Safety The adverse events that were most frequently observed with continuous ibrutinib treatment were of grade 1 or 2 severity.14 The most common nonhematologic adverse events were diarrhea (51%, all grades), fatigue (41%), musculoskeletal pain (37%), peripheral edema (35%), upper respiratory tract infection (34%), nausea (31%), bruising (30%) dyspnea (27%), constipation (25%), rash (25%), abdominal pain (24%), vomiting (23%), and decreased appetite (21%).14 Grade ≥3 hema-

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tologic adverse events were neutropenia (29% ), thrombocytopenia (17%), and anemia (9%).14 Ten patients (9%) discontinued ibrutinib treatment because of adverse reactions in the MCL trial, with subdural hematoma (1.8%) representing the most frequent adverse reaction leading to discontinuation. Adverse reactions led to ibrutinib dose reductions in 14% of the patients in the MCL trial.14 During the study, a temporary increase in lymphocyte counts was reported in 33% of patients. The lymphocyte count returns to baseline by a median of 8 weeks.14

Warnings and Precautions Hemorrhage. Bleeding events, including bruising of any grade, were observed in 48% of patients with MCL who were administered ibrutinib at the recommended dose of 560 mg daily. Overall, 5% of patients with MCL had grade ≥3 bleeding events, including subdural hematoma, gastrointestinal bleeding, and hematuria. Clinicians should consider the benefits and risks of administering ibrutinib to patients who require antiplatelet or anticoagulant therapies, and the benefits and risks of withholding ibrutinib for at least 3 to 7 days pre- and postsurgery, depending on the procedure and bleeding risk.14 Infections. Fatal and nonfatal infections occurred in patients with MCL who were administered ibrutinib during the clinical trial. At least 25% of patients with MCL had grade ≥3 infections.14 Clinicians should regularly monitor patients receiving ibrutinib therapy for signs of fever and infections and evaluate promptly.14 Myelosuppression. Grade 3 or 4 cytopenias, including neutropenia (29%), thrombocytopenia (17%), and anemia (9%), were reported in 41% of patients receiving ibrutinib. Patients should undergo monthly complete blood cell counts while receiving ibrutinib therapy.14 Renal toxicity. Serious to fatal cases of renal failure have occurred with ibrutinib therapy. Increases in creatinine levels up to 1.5 times the upper limit of normal occurred in 67% of patients receiving ibrutinib and from 1.5 to 3 times the upper limit of normal in 9% of patients. Patients receiving ibrutinib should undergo periodic creatinine level monitoring and maintain hydration.14 Second primary malignancies. Other malignancies, including skin cancers (4%) and other carcinomas (1%), have been observed in patients with MCL who were treated with ibrutinib.14 Embryo-fetal toxicity. Based on animal studies, ibrutinib can cause fetal harm when administered during pregnancy. Women should be advised to avoid becoming pregnant while taking ibrutinib.14 Use in Specific Populations Pregnancy. Because animal studies have shown that

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ibrutinib can cause harm to the fetus, patients should be counseled about the potential risks to the fetus if they take ibrutinib during pregnancy or become pregnant while taking ibrutinib.14 Nursing mothers. Although it is not known whether ibrutinib is present in human milk, nursing or use of ibrutinib should be stopped, because of the potential for serious adverse reactions from ibrutinib in nursing infants.14 Pediatric use. The safety and efficacy of ibrutinib has not been established in pediatric patients.14 Geriatric use. Overall, there was no difference in the efficacy of ibrutinib between patients aged ≥65 years and younger patents. However, cardiac adverse events, infections, and gastrointestinal events occurred more frequently among older patients.14

As the first BTK inhibitor approved by the FDA, ibrutinib offers clinicians a unique treatment option for patients with MCL who have received 1 previous therapy. Orally administered ibrutinib has demonstrated uniquely high response rates, as well as a favorable toxicity profile. Renal impairment. Ibrutinib exposure is not affected in patients with creatinine clearance >25 mL/min. There are no data in patients with severe renal impairment or on dialysis.14 Hepatic impairment. Significant increases in exposure of ibrutinib are anticipated in patients with hepatic impairment. There are insufficient data to recommend a dose of ibrutinib in patients with baseline hepatic impairment.14 Females and males of reproductive potential. Women should be advised to not get pregnant while taking ibrutinib because of the potential harm to the fetus.14

Conclusion As the first BTK inhibitor approved by the FDA, ibrutinib offers clinicians a unique treatment option for patients with MCL who have received 1 previous therapy. Orally administered ibrutinib has demonstrated uniquely high response rates, as well as a favorable toxicity profile. Clinical studies are currently under way to evaluate the use of ibrutinib as part of combination regimens in MCL and other hematologic malignancies.16 n References

1. Lymphoma Research Foundation. Mantle cell lymphoma. www.lymphoma.org/ site/pp.asp?c=bkLTKaOQLmK8E&b=6300157. Accessed December 11, 2013. 2. Lymphoma Research Foundation. Getting the facts: mantle cell lymphoma. 2013. Updated January 2013. www.lymphoma.org/atf/cf/%7Baaf3b4e5-2c43-404c-afe5-fd903

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c87b254%7D/LRF_FACTSHEET_MCL_2013.PDF. Accessed December 11, 2013. 3. Leukemia and Lymphoma Society. Mantle cell lymphoma facts. Updated July 2012. www.lls.org/content/nationalcontent/resourcecenter/freeeducationmaterials/lymphoma/ pdf/mantlecelllymphoma.pdf. Accessed February 26, 2014. 4. Smedby KE, Hjalgrim H. Epidemiology and etiology of mantle cell lymphoma and other non-Hodgkin lymphoma subtypes. Semin Cancer Biol. 2011;21:293-298. 5. Kirschey S, Wagner S, Hess G. Relapsed and/or refractory mantle cell lymphoma: what role for temsirolimus? Clin Med Insights Oncol. 2012;6:153-164. 6. Su W, Quon P, Whalen J, et al. Cost-effectiveness analysis of bendamustine plus rituximab versus CHOP-R in treatment-naive patients with mantle cell (MCL) and indolent lymphomas (IL). J Clin Oncol. 2012;30(15 suppl). Abstract 6553. 7. US Food and Drug Administration. FDA approves bortezomib (Velcade) for the treatment of patients with mantle cell lymphoma who have received at least one prior therapy. May 21, 2009. www.fda.gov/AboutFDA/CentersOffices/OfficeofMedical ProductsandTobacco/CDER/ucm094929.htm. Accessed December 11, 2013. 8. US Food and Drug Administration. Drugs: lenalidomide. June 5, 2013. www.fda. gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm355438.htm. Accessed December 11, 2013. 9. Skarbnik AP, Smith MR. Therapies for mantle cell lymphoma: current challenges

and a brighter future. Discov Med. 2013;15:177-187. 10. US Food and Drug Administration. Drugs: ibrutinib. November 13, 2013. www. fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm374857.htm. Accessed December 15, 2013. 11. Akinleye A, Chen Y, Mukhi N, et al. Ibrutinib and novel BTK inhibitors in clinical development. J Hematol Oncol. 2013;6:59. 12. Wang ML, Rule S, Martin P, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2013;369:507-516. 13. Lymphoma Research Foundation. Breakthrough therapy ibrutinib effective in CLL and MCL lymphomas. August 2013. www.lymphoma.org/site/pp.asp?c=bkLTK aOQLmK8E&b=8756085. Accessed December 17, 2013. 14. Imbruvica (ibrutinib) capsules [prescribing information]. Sunnyvale, CA: Pharmacyclics, Inc; November 2013. 15. Woyach J. BTK inhibition and the mechanism of action of ibrutinib. Targeted Onc.com. August 20, 2013. www.targetedonc.com/targeted-communications/DrWoyach-on-BTK-Inhibition-and-the-Mechanism-of-Action-of-Ibrutinib. Accessed December 16, 2013. 16. ClinicalTrials.gov. Ibrutinib trials. www.clinicaltrials.gov/ct2/results?term=ibrutinib. Accessed February 26, 2013.

Call for Papers Neurology Theme Issue American Health & Drug Benefits is publishing a theme issue on neurology in September. Take part in the growing conversation regarding the aging of the population and the growing clinical and economic burdens associated with neurologic disorders. All articles will undergo the journal’s rigorous peer-review process.

ORIGINAL RESEARCH • Case studies/case series • Comparative effectiveness analyses • Cost-effective analyses • Health economics research outcomes • Drug therapy • Patient-reported outcomes • Pharmacoeconomics • Quality-of-life issues • Survey analysis

REVIEW ARTICLES • Alzheimer’s disease: diagnosis, treatment • Cost considerations in neurology • Emerging therapies • Migraine management • Multiple sclerosis • Pain medicine • Parkinson’s disease • Practice guidelines • Stroke/cerebrovascular disease

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Injectafer (Ferric Carboxymaltose Injection) Receives FDA Approval for the Treatment of Iron-Deficiency Anemia By Loretta Fala, Medical Writer

ron-deficiency anemia is the most common form of anemia.1 Iron plays a key role in producing hemoglobin (Hb) in red blood cells, which enables red blood cells to carry oxygen effectively to the body’s tissues.1,2 Anemia resulting from iron deficiency can cause tiredness, weakness, and shortness of breath.2 If left untreated, iron-deficiency anemia can become severe and can lead to heart problems, including a rapid or irregular heartbeat, which can subsequently lead to an enlarged heart or heart failure.2 Iron-deficiency anemia is most common in women with heavy menstrual cycles; women who are pregnant, breastfeeding, or those who recently gave birth; people who have undergone surgery or physical trauma; people with peptic ulcers or gastrointestinal diseases, including celiac disease, ulcerative colitis, or Crohn’s disease; and vegetarians and other individuals whose diets exclude iron-rich foods.3 Patients who are receiving blood thinners and those who have kidney failure, particularly those on dialysis, have an increased risk of iron-deficiency anemia.4 Even if the cause of iron deficiency can be identified and treated, it is generally necessary to treat the patient with medicinal iron until the deficiency is corrected and the body’s iron levels are restored.3 Therapies include oral iron therapy and intravenous (IV) iron therapy. IV iron therapy may be required to treat iron-deficiency anemia in patients who have severe iron deficiency or chronic blood loss, those who cannot tolerate oral iron, those who do not absorb iron well, patients who have kidney failure (particularly those on dialysis), or those who are receiving supplemental erythropoietin.3,4 In the United States, more than 26 million people have chronic kidney disease (CKD).5 Anemia is common in patients with CKD, and iron deficiency is the most common cause of anemia in these patients.6 In patients with CKD, anemia is associated with increased morbidity and mortality,7 diminished health-related quality of life, and considerable healthcare costs8 (Table 1). IV iron is available in a number of preparations, including iron dextran (high-molecular-weight and low-molecular-weight formulations), iron sucrose, ferric gluconate,

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ferumoxytol, and ferric carboxymaltose.9,10 IV iron therapy has been shown to raise Hb levels and replenish iron stores.11 As an adjunct to erythropoiesis-stimulating agent (ESA) therapy, IV iron therapy has become the cornerstone for optimizing Hb status and reducing ESA dosing needs.9 In fact, IV iron supplementation has been shown to reduce ESA use by 19% to 70%.12 An economic analysis of Medicare beneficiaries with stage 3 or 4 CKD and anemia showed that the patients who were not treated with IV iron or with ESAs had significantly higher rates of hospitalization, skilled nursing facility admissions, and mortality than patients who received treatment with IV iron or an ESA.8 Moreover, the total healthcare costs were higher for the patients who did not receive IV iron or ESAs.8 In the year subsequent to the index quarter, patients with CKD and anemia who did not receive IV iron or an ESA in the index quarter incurred significantly higher all-cause healthcare costs. In that study, the mean annual Medicare reimbursements totaled $42,353 (standard deviation [SD], $52,887) per patient who did not receive IV iron or an ESA compared with $34,152 (SD, $30,506) for patients who received IV iron and an ESA; $28,654 (SD, $32,068) for patients who received IV iron without an ESA; and $38,172 (SD, $35,591) for patients who received an ESA without IV iron.8 Although oral iron therapy was not measurable in the study database, the findings from this analysis suggest that therapies for anemia may be underutilized in patients with CKD and anemia.8

Injectafer a New, Nondextran IV Iron Therapy for Iron-Deficiency Anemia In July 2013, ferric carboxymaltose injection (Injectafer; American Regent) was approved by the US Food and Drug Administration (FDA) for the treatment of iron-deficiency anemia in adult patients with an unsatisfactory response to oral iron or who are intolerant of oral iron and in adult patients who have non– dialysis-dependent CKD.10,13 Injectafer is the first nondextran IV iron therapy to receive FDA approval for the treatment of iron-deficien-

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Table 1 Anemia Is a Significant Problem in US Patients with CKD CKD eGFR, mL/ Patients with CKD stage min/1.73 m2 Kidney damage and anemia, %a 1 and 2

≥60

Kidney damage with mild decrease in GFR

26.7

30-59

Moderate decrease in GFR

41.6

15-29

Severe decrease in kidney function

53.6

<15

ESRD

75.5

Anemia defined as hemoglobin <12 g/dL. CKD indicates chronic kidney disease; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; GFR, glomerular filtration rate. Source: Kidney Disease Outcomes Quality Initiative; National Kidney Foundation. Am J Kidney Dis. 2006;47(5 suppl 3):S1-S146.

cy anemia in a diverse group of patients with this condition, regardless of the underlying cause.14

Mechanism of Action Ferric carboxymaltose is a colloidal iron (III) hydroxide in complex with carboxymaltose, a carbohydrate polymer that releases iron.13 Dosing Ferric carboxymaltose is available as a 750-mg iron/15-mL single-use vial. For patients weighing 50 kg (110 lb) or more, ferric carboxymaltose is given in 2 doses, separated by at least 7 days. Each dose is given as 750 mg, for a total cumulative dose of 1500 mg of iron per course. For patients weighing less than 50 kg (110 lb), ferric carboxymaltose is given in 2 doses, separated by at least 7 days; each dose is given as 15 mg per kilogram of body weight.13

Treatment with ferric carboxymaltose may be repeated if iron-deficiency anemia recurs.13

Clinical Studies The safety and efficacy of ferric carboxymaltose injection were evaluated in 1775 patients with iron-deficiency anemia in 2 randomized, open-label, controlled clinical trials (trial 1 and trial 2). In both studies, ferric carboxymaltose was administered at a dose of 15 mg per kilogram of body weight, up to a maximum single dose of 750 mg of iron on 2 occasions, separated by at least 7 days, up to a cumulative dose of 1500 mg of iron.13 Trial 1: Iron-Deficiency Anemia in Patients Intolerant of or with an Unsatisfactory Response to Oral Iron Trial 1 was a randomized, open-label, controlled clinical study of patients with iron-deficiency anemia who had an unsatisfactory response to oral iron (cohort 1) or who were intolerant of oral iron (cohort 2) during the 14-day oral iron run-in period. The inclusion criteria before randomization included Hb <12 g/dL, ferritin ≤100 ng/mL, or ferritin ≤300 ng/mL when transferrin saturation was ≤30%. The patients in cohort 1 were randomized to receive ferric carboxymaltose or oral iron for 14 additional days. The patients in cohort 2 were randomized to receive ferric carboxymaltose or another IV iron per standard of care (90% of the patients received iron sucrose).13 In this study, the mean age of the patients was 43 years (range, 18-94 years). The primary etiologies of iron-deficiency anemia were heavy uterine bleeding (47%) and gastrointestinal disorders (17%). Table 2 lists the change in Hb from baseline to the highest value by day 35 or by time of intervention. At day 35, patients receiving ferric carboxymaltose showed

1: Mean Change in Hemoglobin from Baseline to Highest Value, Table 2 F erric Carboxymaltose Injection in Trial by Day 35 or by Time of Interventiona Cohort 1 Cohort 2 Ferric carboxymaltose Oral iron Ferric carboxymaltose IV ironb Mean hemoglobin (N = 237) (N = 244) (N = 251) (N = 245) Baseline, g/dL (SD)

10.6 (1)

9.1 (1.6)

Highest value, g/dL (SD)

12.2 (1.1)

11.4 (1.2)

12 (1.2)

Change (from baseline to highest value), g/dL (SD)

1.6 (1.2)

0.8 (0.8)

P value

9 (1.5) 11.2 (1.3)

2.9 (1.6)

.001

2.2 (1.3) .001

Modified intent-to-treat population. IV iron per standard of care. IV indicates intravenous; SD, standard deviation. Source: Injectafer (ferric carboxymaltose injection) prescribing information; 2013. a

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increases from baseline in mean ferritin (264.2 ± 224.2 ng/mL in cohort 1 and 218.2 ± 211.4 ng/mL in cohort 2) as well as transferrin saturation (13% ± 16% in cohort 1 and 20% ± 15% in cohort 2).13

Trial 2: Iron-Deficiency Anemia in Patients with Non–Dialysis-Dependent CKD Trial 2 was a randomized, open-label, controlled clinical study in patients with non–dialysis-dependent CKD. The inclusion criteria included Hb ≤11.5 g/dL, ferritin ≤100 ng/mL, or ferritin ≤300 ng/mL when transferrin saturation was ≤30%. The study patients were randomized to receive ferric carboxymaltose injection or iron sucrose injection, USP (Venofer).13 The mean age of the patients in this study was 67 years (range, 19-96 years). The baseline and the change in Hb from baseline to the highest value between baseline and day 56 or the time of intervention are shown in Table 3. At day 56, patients treated with ferric carboxymaltose showed increases from baseline in mean ferritin (734.7 ± 337.8 ng/ mL), and transferrin saturation (30% ± 17%).13 Adverse Reactions In the 2 randomized clinical trials, a total of 1775 patients were exposed to ferric carboxymaltose injection, at a dose of 15 mg/kg of body weight, and up to a maximum single dose of 750 mg of iron on 2 occasions, separated by at least 7 days, for a cumulative dose of 1500 mg of iron. The adverse reactions reported by ≥1% of patients are shown in Table 4.

Ferric Carboxymaltose Injection vs Iron Sucrose Injection Table 3 in Trial 2: Mean Change in Hemoglobin from Baseline to Highest Value, by Day 56 or by Time of Interventiona Ferric carboxymaltose Iron sucrose injection injection, USP Mean hemoglobin (N = 1249) (N = 1244) Baseline, g/dL (SD)

10.3 (0.8)

Highest value, g/dL (SD)

11.4 (1.2)

11.3 (1.1)

Change (from baseline to highest value), g/dL (SD)

1.1 (1)

0.9 (0.9)

Treatment difference, g/dL

0.21 (95% CI, 0.13-0.28)

Modified intent-to-treat population. CI indicates confidence interval; SD, standard deviation. Source: Injectafer (ferric carboxymaltose injection) prescribing information; 2013.

The most common adverse reactions (≥2%) associated with ferric carboxymaltose are nausea, hypertension, flushing, hypophosphatemia, and dizziness.13

Warning and Precautions Formal drug interaction studies have not been performed with ferric carboxymaltose.13 Contraindications. Ferric carboxymaltose is contraindicated in patients who are hypersensitive to ferric carboxymaltose or to any of its inactive components.13 Hypersensitivity reactions. Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening and fatal, have been

Table 4 F erric Carboxymaltose Injection in Clinical Trials 1 and 2: Adverse Reactions Reported in ≥1% of Patients Term

Ferric carboxymaltose, % (N = 1775)

Pooled comparators,a % (N = 1783)

Oral iron, % (N = 253)

Nausea

7.2

1.8

1.2

Hypertension

3.8

1.9

0.4

Flushing/hot flush

3.6

0.2

Hypophosphatemia

2.1

0.1

Dizziness

1.2

Vomiting

1.7

0.5

0.4

Injection-site discoloration

1.4

0.3

Headache

1.2

0.9

Alanine aminotransferase increase

1.1

0.2

Dysgeusia

1.1

2.1

Hypotension

1.9

Constipation

0.5

0.9

3.2

Includes oral iron and all formulations of intravenous iron other than ferric carboxymaltose injection. Source: Injectafer (ferric carboxymaltose injection) prescribing information; 2013.

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reported in patients receiving ferric carboxymaltose. Patients may present with shock, clinically significant hypotension, loss of consciousness, and/or collapse. Patients should be monitored for signs and symptoms of hypersensitivity during and after the administration of ferric carboxymaltose for at least 30 minutes and until clinically stable after completion of the infusion. Ferric carboxymaltose should only be administered when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions.13

The FDA approval of Injectafer, a non– dextran-containing iron therapy, provides a new IV treatment option for patients with iron-deficiency anemia who cannot use oral iron, those who have an unsatisfactory response to it, or those who have non– dialysis-dependent CKD. Hypertension. Hypertension was reported in 3.8% of patients in 2 clinical trials. Transient elevations in systolic blood pressure, sometimes occurring with facial flushing, dizziness, or nausea, were observed in 6% of patients in these 2 studies. These elevations generally occurred immediately after dosing and resolved within 30 minutes. Patients should be monitored for signs and symptoms of hypertension after each ferric carboxymaltose injection.13 Laboratory test alterations. In the 24 hours after the administration of ferric carboxymaltose, laboratory assays may overestimate serum iron and transferrin-bound iron by also measuring the iron in ferric carboxymaltose.13 Nursing mothers. Caution should be used when administering ferric carboxymaltose to a nursing woman.13 Pregnancy. Adequate and well-controlled studies in pregnant women have not been conducted. Ferric carboxymaltose should be used during pregnancy only if its potential benefit justifies the potential risk to the fetus. Pediatric use. The safety and effectiveness of ferric

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carboxymaltose have not been established in pediatric patients.13

Conclusion The FDA approval of Injectafer, a non–dextran-containing iron therapy, provides a new IV treatment option for patients with iron-deficiency anemia who cannot use oral iron, those who have an unsatisfactory response to it, or those who have non–dialysis-dependent CKD. The FDA approval of ferric carboxymaltose injection was based on 2 large, randomized controlled clinical studies of more than 3500 patients (1775 of whom were treated with ferric carboxymaltose injection). The most common adverse reactions (≥2%) associated with ferric carboxymaltose are nausea, hypertension, flushing, hypophosphatemia, and dizziness. n References

1. MedlinePlus. Iron deficiency anemia. Updated March 3, 2013. www.nlm.nih.gov/ medlineplus/ency/article/000584.htm. Accessed November 8, 2013. 2. Mayo Clinic staff. Iron deficiency anemia. March 4, 2011. www.mayoclinic.com/ health/irondeficiency-anemia/DS00323. Accessed November 7, 2013. 3. American Society of Hematology. Iron deficiency anemia. www.hematology.org/ patients/blood-disorders/anemia/5263.aspx. Accessed November 11, 2013. 4. Cleveland Clinic. Intravenous iron supplementation. Reviewed March 1, 2010. http://my.clevelandclinic.org/disorders/anemia/hic_intravenous_iron_supplementation. aspx. Accessed November 11, 2013. 5. Coresh J, Selvin E, Stevens LA, et al. Prevalence of chronic kidney disease in the United States. JAMA. 2007;298:2038-2047. 6. Gotloib L, Silverberg D, Fudin R, Shostak A. Iron deficiency is a common cause of anemia in chronic kidney disease and can often be corrected with intravenous iron. J Nephrol. 2006;19:161-167. 7. Kidney Disease Outcomes Quality Initiative (KDOQI); National Kidney Foundation. KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease. Am J Kidney Dis. 2006;47(5 suppl 3):S1-S146. 8. Knight TG, Ryan K, Schaefer CP, et al. Clinical and economic outcomes in Medicare beneficiaries with stage 3 or stage 4 chronic kidney disease and anemia: the role of intravenous iron therapy. J Manag Care Pharm. 2010;16:605-615. 9. Krikorian S, Shafai G, Shamim K. Managing iron deficiency anemia of CKD with IV iron. US Pharm. 2013;38:22-26. 10. Brooks M. FDA approves Injectafer for iron deficiency anemia. Medscape Medical News. August 1, 2013. www.medscape.com/viewarticle/808800. Accessed November 4, 2013. 11. Van Wyck DB, Roppolo M, Martinez CO, et al; for the United States Iron Sucrose (Venofer) Clinical Trials Group. A randomized, controlled trial comparing IV sucrose to oral iron in anemic patients with nondialysis-dependent CKD. Kidney Int. 2005; 68:2846-2856. 12. Shander A, Spence RK, Auerbach M. Can intravenous iron therapy meet the unmet needs created by the new restrictions on erythropoietic stimulating agents? Transfusion. 2010;50:719-732. 13. Injectafer (ferric carboxymaltose injection) [prescribing information]. Shirley, NY: American Regent, Inc; 2013. 14. Vifor Pharma. Injectafer receives US FDA approval for the treatment of iron deficiency anaemia. Press release. July 26, 2013. www.viforpharma.com/en/Media/media releases/2013/20130726_injectafer-us-approval.php. Accessed November 11, 2013.

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Invokana (Canagliflozin): First-in-Class

SGLT2 Inhibitor Approved for the Treatment of Type 2 Diabetes By Loretta Fala, Medical Writer

iabetes affects an estimated 25.8 million people in the United States—a staggering 8.3% of the population.1 In addition, 35% of US adults have prediabetes and are at high risk for developing diabetes.1 Coinciding with the aging of the US population, the prevalence of diabetes is projected to increase dramatically over the next few decades, from approximately 1 of 10 adults today to approximately 1 of 3 adults by 2050.2 Approximately 90% to 95% of all cases of diabetes are type 2 diabetes mellitus, and approximately 5% are type 1 diabetes mellitus.1 Associated with multiple comorbidities and potentially serious health implications, diabetes is the seventh leading cause of mortality in the United States.1 Diabetes accounted for total US healthcare costs of $245 billion in 2012, including $176 billion in direct medical costs and $69 billion in indirect costs (ie, increased absenteeism, reduced productivity, lost productivity resulting from early mortality, and the inability to work because of disability).3 An estimated 1 of every 5 US healthcare dollars is spent on the care of people with diabetes.3 Medical expenses for people with diabetes are more than twice as high as expenses for people without diabetes.3 Improvements in glycemic control have been shown to decrease the morbidity and mortality of patients with type 2 diabetes mellitus by decreasing chronic complications.4 Every 1% reduction in glycated hemoglobin (Hb) A1c is associated with a 35% reduction in diabetes-related microvascular complications (ie, diabetic neuropathy, nephropathy, and retinopathy).4 In a 2013 position statement, the American Diabetes Association (ADA) recommended a general target HbA1c level of <7% for adults with diabetes, with the caveat that more-stringent or less-stringent goals may be appropriate for individual patients.5 Moreover, the target goal should be individualized based on the patient’s duration of diabetes, age, comorbidities, known cardiovascular or advanced microvascular complications, and other patient factors.5 Intensive glycemic control was shown to improve the risk of some complications. In a 5-year follow-up study of 11,140 patients with type 2 diabetes mellitus, intensive blood glucose control (mean HbA1c of ≤6.5%) compared with standard glucose control (mean HbA1c of 7.3%)

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showed a significant reduction in the incidence of major microvascular events (P = .01), but did not demonstrate a significant reduction in the incidence of major macrovascular events (P = .32).6 In this study, intensive glucose control was associated with a 21% relative risk reduction of nephropathy and a 9% relative risk reduction of microalbuminuria.6 Although strides have been made in the number of people in the United States who have achieved the target HbA1c of <7%, there remains a marked need and an opportunity to improve the achievement of glycemic control targets and overall outcomes for people who have, or who are at risk for, diabetes.7

The SGLT2 Inhibitor Drug Class In recent years, the important role of the kidney in maintaining glucose homeostasis has been elucidated. Evidence suggests that in patients with type 2 diabetes mellitus, there is an increase in the amount of renal glucose that is released, thereby implicating the kidneys’ contribution to hyperglycemia.8 In hyperglycemia, excess glucose is reabsorbed by the kidney—a process that increases the renal glucose threshold and creates a cycle of chronic hyperglycemia, along with associated microvascular complications.8 The sodium-glucose cotransporter 2 (SGLT2), a cotransporter expressed in the proximal renal tubules, mediates the active transport of glucose against a concentration gradient via cotransport with sodium. SGLT2 is responsible for reabsorbing 90% of the glucose that is filtered at the glomerulus.8 The SGLT2 inhibitors represent a novel class of drugs that reduce reabsorption of filtered glucose and lower the renal threshold for glucose, thereby increasing urinary glucose excretion.8 These agents have a promising role, alongside diet and exercise, in improving glycemic control in patients with type 2 diabetes mellitus. Invokana Receives FDA Approval On March 29, 2013, the US Food and Drug Administration (FDA) approved canagliflozin (Invokana; Janssen Pharmaceuticals), the first SGLT2 inhibitor, as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.9 Canagliflozin is

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Canagliflozin Monotherapy: Results from a 26-Week Table 1 Placebo-Controlled Clinical Studya Placebo (N = 192)

Canagliflozin 100 mg (N = 195)

Canagliflozin 300 mg (N = 197)

Baseline, mean, %

7.97

8.06

8.01

Change from baseline, adjusted mean, %

0.14

–0.77

–0.03

Efficacy parameter HbA1c

Difference from placebo, adjusted mean,b % Patients achieving HbA1c <7.0%, %

–0.91c –1.16c (95% CI, –1.09 (95% CI, –1.34 to –0.73) to –0.99) 21

45b

62b

Baseline, mean, mg/dL

166

172

173

Change from baseline, adjusted mean, mg/dL

–27

–35

–36c (95% CI, –42 to –29)

–43c (95% CI, –50 to –37)

Fasting plasma glucose

Difference from placebo, adjusted mean,b mg/dL 2-hour postprandial glucose Baseline, mean, mg/dL

299

250

254

Change from baseline, adjusted mean, mg/dL

–43

–59

Difference from placebo, adjusted mean,b mg/dL

–48c –64c (95% CI, –59.1 (95% CI, –75.0 to –37.0) to –52.9)

Body weight Baseline, mean, kg

87.5

85.9

86.9

Change from baseline, adjusted mean, %

–0.6

–2.8

–3.9

–2.2c (95% CI, –2.9 to –1.6)

–3.3c (95% CI, –4.0 to –2.6)

Difference from placebo, adjusted mean,b kg

Intent-to-treat population using last observation in study before glycemic rescue therapy. b Least square mean adjusted for baseline value and stratification factors. c P <.001. CI indicates confidence interval; Hb, hemoglobin. Source: Invokana (canagliflozin) tablets prescribing information; 2013. a

not recommended for the treatment of patients with type 1 diabetes mellitus or with diabetic ketoacidosis.10 According to Mary H. Parks, MD, Director, Division of Metabolism and Endocrinology Products at the FDA’s Center for Drug Evaluation and Research, “Invokana is the first diabetes treatment approved in a new class of

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drugs known as sodium-glucose cotransporter 2 inhibitors….We continue to advance innovation with the approval of new drug classes that provide additional treatment options for chronic conditions that impact public health.”9 The safety and efficacy of canagliflozin were evaluated in 9 clinical trials involving more than 10,285 patients with type 2 diabetes.9 In these studies, canagliflozin showed an improvement in A1c levels and in fasting plasma glucose.9 The FDA’s approval of canagliflozin included a requirement for postmarketing studies, including a cardiovascular outcomes trial; an enhanced pharmacovigilance program to monitor for malignancies, severe pancreatitis, severe hypersensitivity reactions, photosensitivity reactions, liver abnormalities, and adverse pregnancy outcomes; a bone safety study; and 2 pediatric studies under the Pediatric Research Equity Act, including a safety and efficacy study and a pharmacokinetic and pharmacodynamic study.9

Dosing The oral agent canagliflozin is available in 100-mg tablets and 300-mg tablets. The recommended starting dose of canagliflozin is 100 mg once daily, taken before the first meal of the day. The dose can be increased up to 300 mg once daily in patients tolerating canagliflozin 100 mg once daily who have an estimated glomerular filtration rate (eGFR) of ≥60 mL/min/1.73 m2 and require additional glycemic control.10 Canagliflozin dosing is limited to 100 mg once daily in patients who have an eGFR of 45 mL/min/1.73 m2 to <60 mL/min/1.73 m2. Renal function should be assessed before initiating canagliflozin therapy. If the eGFR is <45 mL/min/1.73 m2, canagliflozin therapy should not be initiated. Moreover, if the eGFR falls below 45 mL/ min/1.73 m2, canagliflozin should be discontinued.10 Because the coadministration of canagliflozin and rif ampin, a nonselective inducer of several UDP glucuronosyltransferase enzymes, may decrease exposure to, and the efficacy of, canagliflozin, it is recommended that the dose of canagliflozin be increased from 100 mg to 300 mg. Patients taking canagliflozin with concomitant digoxin should have their digoxin levels monitored appropriately.10 Novel Mechanism of Action Canagliflozin is an inhibitor of SGLT2, a cotransporter that is expressed in the proximal renal tubules, that is responsible for most of the reabsorption of filtered glucose from the tubular lumen. By inhibiting SGLT2, canagliflozin reduces the reabsorption of filtered glucose and lowers the renal threshold for glucose, thereby increasing urinary glucose excretion.

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The mean absolute bioavailability of canagliflozin is approximately 65%. The coadministration of a high-fat meal and canagliflozin had no effect on the pharmaco kinetics of canagliflozin; therefore, canagliflozin may be taken with or without food. However, based on its potential to reduce postprandial plasma glucose excursions as a result of delayed intestinal glucose absorption, it is recommended that canagliflozin be taken before the first meal of the day.10 The major metabolic elimination pathway for canagliflozin is O-glucuronidation. The cytochrome P450 3A4–mediated (oxidative) metabolism of canagliflozin is minimal (approximately 7%) in humans.10

Clinical Studies Monotherapy with Canagliflozin The safety and efficacy of canagliflozin monotherapy were evaluated in a 26-week, double-blind, placebo- controlled study of 584 patients with type 2 diabetes whose disease was inadequately controlled with diet and exercise. Patients were randomized to receive canagliflozin 100 mg, canagliflozin 300 mg, or placebo, administered once daily for 26 weeks.10 At the end of the treatment period, canagliflozin 100 mg and 300 mg once daily demonstrated a significant improvement in HbA1c levels (P <.001 for both doses) compared with placebo (Table 1). Monotherapy with canagliflozin 100 mg and 300 mg helped a greater proportion of patients achieve the ADA-recommended HbA1c goal of <7% over 26 weeks versus placebo.5,10 In fact, an HbA1c goal of <7% was achieved by 45% of patients receiving canagliflozin 100 mg and by 62% of patients receiving canagliflozin 300 mg compared with 21% of patients receiving placebo.10 In addition, 100-mg and 300-mg doses of canagliflo zin showed a significant reduction in fasting plasma glucose, significant improvement in postprandial glucose, and significant reduction in percent body weight compared with placebo. Furthermore, both doses of canagliflozin showed significant (P <.001) mean changes from baseline in systolic blood pressure compared with placebo (–3.7 mm Hg for canagliflozin 100 mg and –5.4 mm Hg for canagliflozin 300 mg).10 Add-On Combination Therapy: Canagliflozin plus Metformin The safety and efficacy of canagliflozin in combination with metformin was evaluated in a 26-week, double-blind, placebo- and active-controlled trial in 1284 patients with type 2 diabetes.10 At the end of the treatment period, canagliflozin 100 mg and 300 mg once daily showed a significant improvement in HbA1c levels (P <.001 for both doses) compared Vol 7

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Canagliflozin in Combination with Metformin: Results from Table 2 a 26-Week Placebo-Controlled Triala

Efficacy parameter

Placebo + metformin (N = 183)

Canagliflozin 100 mg + metformin (N = 368)

7.96

7.94

7.95

–0.17

–0.79

–0.94

Canagliflozin 300 mg + metformin (N = 367)

HbA1c Baseline, mean, % Change from baseline, adjusted mean, % Difference from placebo, adjusted mean,b %

–0.62c –0.77c (95% CI, –0.76 (95% CI, –0.91 to –0.48) to –0.64)

Patients achieving HbA1c <7.0%, %

46c

58c

Baseline, mean, mg/dL

164

169

173

Change from baseline, adjusted mean, mg/dL

–27

–38

–30c (95% CI, –36 to –24)

–40c (95% CI, –46 to –34)

Fasting plasma glucose

Difference from placebo, adjusted mean,b mg/dL 2-hour postprandial glucose Baseline, mean, mg/dL

249

258

262

Change from baseline, adjusted mean, mg/dL

–10

–48

–57

–38c (95% CI, –49 to –27)

–47c (95% CI, –48 to –36)

Difference from placebo, adjusted mean,b mg/dL Body weight Baseline, mean, kg

86.7

88.7

85.4

Change from baseline, adjusted mean, %

–1.2

–3.7

–4.2

–2.5c (95% CI, –3.1 to –1.9)

–2.9c (95% CI, –3.5 to –2.3)

Difference from placebo, adjusted mean,b kg

with placebo when added to metformin (Table 2). Canagliflozin 100 mg plus metformin and canagliflozin 300 mg plus metformin also showed a greater proportion of patients achieving the ADA-recommended goal of HbA1c <7.0%; 46% of the canagliflozin 100-mg cohort and 58% of the canagliflozin 300-mg group compared

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Table 3 Adverse Reactions in ≥2% of Patients Receiving Canagliflozin in Four 26-Week, Placebo-Controlled Trialsa Adverse reaction

Canagliflozin Canagliflozin Placebo 100 mg 300 mg (N = 646) (N = 833) (N = 834)

Female genital mycotic infections,b %

3.2

10.4

11.4

Urinary tract infections (including urinary tract infection, cystitis, kidney infection, and urosepsis), %

4.0

5.9

4.3

Increased urination (including polyuria, pollakiuria, urine output increased, micturition urgency, and nocturia), %

0.8

5.3

4.6

Male genital mycotic infections,c %

0.6

4.2

3.7

Vulvovaginal pruritus, %

0.0

1.6

3.0

Thirst (including thirst, dry mouth, and polydipsia), %

0.2

2.8

2.3

Constipation, %

0.9

1.8

2.3

Nausea, %

1.5

2.2

2.3

These studies included 1 monotherapy trial of canagliflozin and 3 add-on combination trials with metformin, metformin and sulfonyl urea, or metformin and pioglitazone. b Female genital mycotic infections include the following adverse reactions: vulvovaginal candidiasis, vulvovaginal mycotic infection, vulvovaginitis, vaginal infection, vulvitis, and genital fungal infection. c Male genital mycotic infections include the following adverse reactions: balanitis or balanoposthitis, Candida balanitis, and genital fungal infection. Source: Invokana (canagliflozin) tablets prescribing information; 2013. a

with 30% of the group receiving placebo plus metformin achieved an HbA1c level of <7%.10

Additional Clinical Trials Canagliflozin was evaluated for safety and efficacy in 7 other clinical trials, and was shown to improve Hb1c levels and fasting plasma glucose in these studies. Adverse Events The most common adverse reactions reported in ≥2% of patients with canagliflozin include female genital mycotic infections, urinary tract infection, and increased urination (Table 3). Contraindications Canagliflozin is contraindicated in patients with a serious hypersensitivity reaction to canagliflozin, as

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well as in patients with severe renal impairment, patients with end-stage renal disease, or patients on dialysis. There are no boxed warnings associated with the use of canagliflozin.

Warnings and Precautions Hypotension Canagliflozin causes intravascular volume contraction. Symptomatic hypotension can occur after initiating canagliflozin, particularly in patients with impaired renal function (eGFR of <60 mL/min/1.73 m2), elderly patients, patients receiving either diuretics or medications that interfere with the renin-angiotensin-aldosterone system (RAAS; eg, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers), or patients with low systolic blood pressure.10 Before initiating canagliflozin in patients with 1 or more of these characteristics, volume status should be assessed and corrected. The signs and symptoms of hypotension should be monitored after therapy is initiated.10 Impairment in Renal Function Canagliflozin increases serum creatinine and decreases eGFR. Patients with hypovolemia may be more susceptible to these changes. Renal function abnormalities can occur after initiating canagliflozin. More frequent renal function monitoring is recommended in patients with an eGFR of <60 mL/min/1.73 m2.10 Hyperkalemia Canagliflozin can lead to hyperkalemia. Patients with moderate renal impairment who are taking medications that interfere with potassium excretion, such as potassium-sparing diuretics, or medications that interfere with the RAAS are more likely to develop hyperkalemia. Serum potassium levels should be monitored after initiating canagliflozin in patients with impaired renal function and in patients who are predisposed to hyperkalemia as a result of medications or other medical conditions.10 Hypoglycemia Associated with Concomitant Use of Insulin and Insulin Secretagogues Insulin and insulin secretagogues are known to cause hypoglycemia. Canagliflozin can increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue. Therefore, a lower dose of insulin or of insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with canagliflozin.10 Genital Mycotic Infections Canagliflozin increases the risk for genital mycotic

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infections. Patients with a history of genital mycotic infections and uncircumcised males are more likely to develop genital mycotic infections. Patients should be monitored and treated appropriately.10

Hypersensitivity Reactions Hypersensitivity reactions (eg, generalized urticaria), some serious, were reported with treatment with canagliflozin; these reactions generally occurred within hours to days after initiating canagliflozin. If hypersensitivity reactions occur, canagliflozin should be discontinued, and patients should be treated according to the standard of care and monitored until the signs and symptoms resolve.10 Increases in Low-Density Lipoprotein Cholesterol Dose-related increases in low-density lipoprotein cholesterol occur with canagliflozin. Low-density lipoprotein cholesterol should be monitored and patients should be treated per standard of care after initiating canagliflozin.10 Macrovascular Outcomes No clinical studies have established conclusive evidence of macrovascular risk reduction with canagliflozin or with any other antidiabetic drug.10 Conclusion In March 2013, canagliflozin, an oral SGLT2 inhibitor, became the first member in this drug class to receive FDA approval for the management of patients with type 2 diabetes. Canagliflozin is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. This medication has a novel mode of action: by inhibiting the SGLT2 in the proximal renal tubules, canagliflozin reduces glucose

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reabsorption in the kidney and increases the amount of glucose excreted in the urine.

In March 2013, canagliflozin, an oral SGLT2 inhibitor, became the first member in this drug class to receive FDA approval for the management of patients with type 2 diabetes. Canagliflozin was evaluated for safety and efficacy in 9 clinical trials involving more than 10,285 patients with type 2 diabetes. In these studies, canagliflozin was shown to improve HbA1c levels and fasting plasma glucose. The most common (incidence, ≥5%) adverse reactions associated with canagliflozin were female genital mycotic infections, urinary tract infections, and increased urination. n

References

1. Centers for Disease Control and Prevention. National diabetes fact sheet: national estimates and general information on diabetes and prediabetes in the United States, 2011. 2011. www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf. Accessed May 15, 2013. 2. Boyle JP, Thompson TJ, Gregg EW, et al. Projection of the year 2050 burden of diabetes in the US population: dynamic modeling of incidence, mortality, and prediabetes prevalence. Popul Health Metr. 2010;8:29. 3. American Diabetes Association. Economic costs of diabetes in the U.S. in 2012. Diabetes Care. 2013;36:1033-1046. 4. American Diabetes Association. Implications of the United Kingdom Prospective Diabetes Study. Diabetes Care. 2002;25(suppl 1):S28-S32. 5. American Diabetes Association. Standards of medical care in diabetes—2013. Diabetes Care. 2013;36(suppl 1):S11-S66. 6. ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560-2572. 7. Cheung BM, Ong KL, Cherny SS, et al. Diabetes prevalence and therapeutic target achievement in the United States, 1999 to 2006. Am J Med. 2009;122:443-453. 8. Triplitt CL. Understanding the kidneys’ role in blood glucose regulation. Am J Manag Care. 2012;18(1 suppl):S11-S16. 9. US Food and Drug Administration. FDA approves Invokana to treat type 2 diabetes: first in a new class of diabetes drugs. Press release; March 29, 2013. www.fda.gov/News Events/Newsroom/PressAnnouncements/ucm345848.htm. Accessed May 3, 2013. 10. Invokana (canagliflozin) tablets [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc; 2013.

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Kadcyla (Ado-Trastuzumab Emtansine): First Antibody-Drug Conjugate Approved for the Treatment of HER2-Positive Metastatic Breast Cancer By Lisa A. Raedler, PhD, RPh, Medical Writer

pproximately 25% of women who are diagnosed with breast cancer have HER2-positive tumors. The HER2 gene, which resides on chromosome 17, directs tumor cells to manufacture HER2 protein. This protein is a cell-surface receptor that compels the tumor cell to grow and to divide more frequently than normal, making HER2-positive breast cancer an aggressive phenotype. Before the advent of HER2-directed therapies, patients diagnosed with HER2-positive disease had significantly shorter disease-free survival compared with patients with other breast cancer subtypes.1

Unmet Need in Trastuzumab-Resistant Breast Cancer The American Cancer Society estimates that approximately 232,340 women will be diagnosed with invasive breast cancer, and approximately 39,620 deaths will occur from the disease in 2013.2 Since 1989, death rates from breast cancer have declined, with relatively larger decreases in women aged <50 years, in part as a result of earlier detection and increasingly improved treatments.2 Much of the increased survival for patients with HER2-positive breast cancer is attributed to the development of HER2-targeted therapies, including trastuzumab (Herceptin), pertuzumab (Perjeta), and lapatinib (Tykerb).3 The first phase 3 clinical trial that compared trastuzumab plus chemotherapy versus chemotherapy alone in patients with HER2-positive metastatic breast cancer demonstrated robust improvements in response rate (50% vs 32%, respectively), median time to progression (7.4 months vs 4.6 months, respectively), and median overall survival ([OS] 25.1 months vs 20.3 months, respectively) with the addition of trastuzumab.4 In addition, 2 meta-analyses have confirmed the OS benefit of adding HER2-targeted therapy to standard treatment in patients with early-stage or metastatic HER2-positive breast cancer.5,6 However, primary and secondary resistance to trastuzumab occurs in the advanced breast cancer setting: none of these patients is cured. In 2013, approximately

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13,000 patients with HER2-positive metastatic breast cancer will have disease recurrence after trastuzumab treatment.7 Concerted efforts are under way to identify the mechanisms of trastuzumab resistance, as well as novel “druggable” targets for this patient population.8 Currently, treatment strategies for patients with trastuzumab-resistant HER2-positive breast cancer are selected on the basis of patient-specific factors (ie, age, comorbidities), disease-related factors, and cost.9 Therapy alternatives include the combination of pertuzumab, trastuzumab, and a taxane; lapatinib plus trastuzumab; lapatinib plus capecitabine; and the continued use of trastuzumab plus chemotherapy.10

FDA Approval of Ado-Trastuzumab Emtansine Fills an Unmet Need In February 2013, the US Food and Drug Administration (FDA) granted accelerated approval for ado-trastuz umab emtansine (Kadcyla; Genentech), also known as T-DM1, for the treatment of patients with HER2-positive metastatic breast cancer who were previously treated with trastuzumab and with taxanes.11 The approval was based on the result of a single, open-label trial of patients with HER2-positive metastatic breast cancer: T-DM1 demonstrated a significant 5.8-month improvement in median OS and a 3.2-month improvement in median progression-free survival (PFS) compared with the combination of lapatinib plus capecitabine.12 In an interview regarding T-DM1, Hope S. Rugo, MD, Director, Breast Oncology Clinical Trials Program, University of California, San Francisco, stated, “Use of the immunoconjugate—trastuzumab linked to a microtubule inhibitor [DM1]—was shown in trials to be better in every way: response, progression-free survival, overall survival, and tolerability.”9 According to the drug manufacturer, 1 cycle (once in 21 days) of T-DM1 costs $9800. Dosing and Administration T-DM1 is administered intravenously at 3.6 mg/kg on day 1 of a 21-day cycle. No loading dose or premedica-

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tions are required. Treatment with T-DM1 should be continued until disease progression or until unacceptable toxicity occurs. For the first infusion, T-DM1 should be administered over 90 minutes. Patients should be observed during the infusion and for at least 90 minutes after the initial dose for fever, chills, or other infusion-related reactions. For subsequent infusions, T-DM1 can be administered over 30 minutes if previous infusions were well tolerated. Patients should be observed during the infusion and for at least 30 minutes after. T-DM1 should not be administered at doses greater than 3.6 mg/kg. T-DM1 should not be substituted for or coadministered with trastuzumab.12

Dose Modifications Based on Toxicity

The dose of T-DM1 may be modified if hematologic or nonhematologic toxicities occur, including grade 3 or 4 cytopenias; cardiac, hepatic, or renal toxicities; pulmonary complications; neurotoxicity; or other toxicities. In general, T-DM1 is withheld until resolution, followed by restarting therapy at the same dose or at a reduced dose, depending on the type of toxicity and whether it was attributable to T-DM1.12

Mechanism of Action T-DM1 is a HER2-targeted antibody drug conjugate. The antibody is the humanized anti-HER2 immuno globulin G1, ado-trastuzumab. The small-molecule drug DM1 is a microtubule inhibitor. On binding to subdomain IV of the HER2 receptor, T-DM1 undergoes receptor-mediated internalization and lysosomal degradation, resulting in intracellular release of DM1-containing cytotoxic catabolites. Binding of DM1 to tubulin disrupts microtubule networks in the cell, resulting in cell-cycle arrest and cell death. In vitro studies have shown that similar to trastuzumab, T-DM1 inhibits HER2 receptor signaling, mediates antibody-dependent cell-mediated cytotoxicity, and inhibits shedding of the HER2 extracellular domain in human breast cancer cells that overexpress the HER2 gene.12 The availability of an antibody drug conjugate for selected patients with breast cancer offers an exciting and novel approach, particularly for women who wish to avoid the side effects of chemotherapy. According to Julie R. Gralow, MD, Director, Breast Medical Oncology, Seattle Cancer Care Alliance, WA, T-DM1 “is a true magic bullet. For the 20% to 25% of breast cancer patients that have HER2-positive breast cancer (HER2-expressing breast cancer), this is an antibody that can take chemotherapy directly to the tumor cell and deliver it inside the cell. Then the bulk of the body does not get exposed to the chemotherapy.”13

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EMILIA: A Phase 3 Clinical Trial T-DM1 was approved by the FDA based on the results of the EMILIA trial, a randomized, multicenter, open-label trial of 991 patients with HER2-positive, unresectable, locally advanced or metastatic breast cancer.14 Previous taxane- and trastuzumab-based therapies were required before trial enrollment. Patients who had only received previous adjuvant therapy were required to have disease recurrence during or within 6 months of completing adjuvant therapy. Tumor samples were required to show evidence of HER2 overexpression, defined as 3+ immunohistochemistry by Dako’s HercepTest, or evidence of HER2 overexpression defined as a fluo rescence in situ hybridization (FISH) amplification ratio of ≥2.0 by Dako’s HER2 FISH pharmDx test kit.12,14 Trial Design and Patient Population. Patients in the EMILIA trial were randomized to T-DM1 or to lapatinib domization was stratified by plus capecitabine.12 Ran world region (ie, United States, Western Europe, or other), the number of previous chemotherapy regimens used for unresectable locally advanced or metastatic disease, and by visceral versus nonvisceral disease as determined by the investigators. T-DM1 was given intravenously at 3.6 mg/kg on day 1 of a 21-day cycle. Lapatinib was administered orally at 1250 mg once daily in a 21-day cycle. Capecitabine was administered orally at 1000 mg/m2 twice daily on days 1 through 14 of a 21-day cycle. Patients were treated with T-DM1 or with lapatinib plus capecitabine until disease progression, consent withdrawal, or until reaching an unacceptable toxicity level.12 The patient demographics and baseline tumor characteristics were balanced between treatment arms in the EMILIA trial.12 All patients had metastatic disease at study entry. The median age was approximately 53 years (range, 24-84 years); 74% of patients were white, 18% were Asian, and 5% were black. All but 5 patients were women. Tumor prognostic characteristics, including hormone receptor status (positive, 55%; negative, 43%), presence of visceral disease (68%) and nonvisceral disease only (33%), and the number of metastatic sites (<3, 61%; ≥3, 37%), were similar in the study arms.12 Efficacy. Of the 991 patients who were enrolled in the EMILIA trial, 978 received treatment.15 The median dose intensity was 99.9% for patients receiving T-DM1, 77.2% for patients receiving capecitabine, and 93.4% for patients treated with lapatinib. The key study findings are summarized in Table 1. Dose reduction was necessary for 16.3% of patients in the T-DM1 arm; capecitabine doses and lapatinib doses were reduced for 53.4% and 27.3% of the patients, respectively.15 At the time of the primary efficacy analysis, median

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EMILIA: Efficacy End Points of Ado-Trastuzumab Table 1 Emtansine versus Lapatinib plus Capecitabine Outcome parameter PFS (independent review) Patients, N (%) Median PFS, mo Hazard ratio, stratifieda (95% CI) P value (log-rank test, stratifieda) Overall survivalb Patients, N (%) Median survival, mo Hazard ratio, stratifieda (95% CI) P value (log-rank testa) OR rate (independent review) Patients with measurable disease, N Patients with OR, N (%) Difference (95% CI) Duration of OR Patients with OR, N Median duration, mo (95% CI)

Ado-trastuzumab emtansine (N = 495)

Lapatinib plus capecitabine (N = 496)

265 (53.5) 9.6

304 (61.3) 6.4

0.650 (0.549-0.771) <.001

149 (30.1) 30.9

182 (36.7) 25.1

0.682 (0.548-0.849) .006 397

389

173 (43.6)

120 (30.8)

12.7 (6.0-19.4) 173 12.6 (8.4-20.8)

120 6.5 (5.5-7.2)

Stratified by world region (ie, United States, Western Europe, or other), number of previous chemotherapeutic regimens for locally advanced or metastatic disease (0-1 vs >1), and visceral versus nonvisceral disease. b The second interim analysis for OS was conducted when 331 events were observed. The results are presented in this table. CI indicates confidence interval; OR, objective response; OS, overall survival; PFS, progression-free survival. Source: Kadcyla (ado-trastuzumab emtansine) for injection prescribing information; 2013. a

time with therapy was 5.7 months for T-DM1, 4.9 months for lapatinib, and 4.8 months for capecitabine.12 The coprimary efficacy end points were PFS based on tumor response assessments by an independent review committee and on OS. PFS was defined as the time from the date of randomization to the date of disease progression or death from any cause (whichever occurred earlier). OS was defined as the time from the date of randomization to the date of death from any cause. Secondary end points included PFS based on investigator tumor response assessments, objective response rate, duration of response, and time to symptom progression.12 Subgroup analyses using baseline patient characteristics indicated that the use of single-agent T-DM1 was

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superior to lapatinib plus capecitabine for all patient subsets except those aged ≥65 years.14 A subsequent biomarker analysis demonstrated that patients in EMILIA whose tumors expressed high HER2 messenger RNA levels derived more benefit from T-DM1 than patients with lower levels of expression. In high HER2 expressors, the median PFS was 34.1 months with T-DM1 versus 24.8 months with lapatinib plus capecitabine.16

Safety Profile Single-agent T-DM1 has been evaluated in 884 patients with HER2-positive metastatic breast cancer.12 These patients received a median of 7.6 months of T-DM1 treatment. The most common (frequency, ≥25%) drug-related adverse events (AEs) seen in patients receiving T-DM1 were fatigue, nausea, musculoskeletal pain, thrombocytopenia, headache, increased transaminases, and constipation. Grades 3 and 4 AEs were reported in 43.1% of patients receiving T-DM1 and in 59.2% of patients receiving lapatinib plus capecitabine. Overall, 32 (6.5%) patients discontinued T-DM1 as a result of an AE. The most common AEs leading to T-DM1 withdrawal were thrombocytopenia and increased transaminases. Eighty (16.3%) patients receiving T-DM1 experienced AEs leading to dose reductions. These AEs included thrombocytopenia, increased transaminases, and peripheral neuropathy. AEs that led to dose delays occurred in 23.7% of patients receiving T-DM1 and included neutropenia, thrombocytopenia, leukopenia, fatigue, increased transaminases, and pyrexia.12 Hepatotoxicity. Serious hepatotoxicity has been reported, including liver failure and death, in patients receiving T-DM1. Serum transaminases and bilirubin should be monitored before the initiation of T-DM1 treatment and before each T-DM1 dose. The dose of T-DM1 should be reduced or discontinued as appropriate in cases of increased serum transaminases or increased total bilirubin.12 Cardiac Toxicity. T-DM1 administration may lead to reductions in left-ventricular ejection fraction. Left-ventricular function should be evaluated in all patients before and during treatment with T-DM1. Treatment should be withheld if a clinically significant decrease in left-ventricular function is detected.12 Warnings and Precautions A number of adverse reactions associated with T-DM1 are discussed in the “Warnings and Precautions” section of the prescribing information and are summarized in Table 2.12

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Table 2 Ado-Trastuzumab Emtansine: Warnings and Precautions Warnings and precautions

Description

Infusion reactions

• Occurred in 1.4% of patients receiving the drug; 1 case of a serious, allergic/anaphylactic-like reaction was reported • Characterized by flushing, chills, pyrexia, dyspnea, hypotension, wheezing, bronchospasm, tachycardia • Monitor patients closely for infusion reactions, particularly during first infusion

Extravasation

• Occurs within 24 hours of infusion • Characterized by mild erythema, tenderness, skin irritation, pain, swelling at the infusion site • Monitor the infusion site closely for possible subcutaneous infiltration during administration

Thrombocytopenia

• Occurred in 31.2% of patients; 14.5% were grade 3/4 • Higher incidence and severity of thrombocytopenia were noted in Asian patients • Monitor platelet counts frequently

Peripheral neuropathy

• Occurred in 21.2% of patients; 2.2% were grade 3/4 • Monitor frequently for signs and symptoms of neurotoxicity

Hepatic toxicity and hepatic failure

• Mainly asymptomatic transient increases in serum transaminase concentrations • Because T-DM1 can cause elevated serum transaminases and bilirubin, liver enzymes should be monitored frequently • Serious hepatobiliary disorders, including ≥2 deaths resulting from severe drug-induced liver injury and associated hepatic encephalopathy, were reported • Of 884 patients in T-DM1 clinical trials, 3 had NRH of the liver identified from liver biopsies; consider NRH in patients with clinical symptoms of portal hypertension, normal transaminases, and no manifestations of cirrhosis

Left-ventricular dysfunction

• A decrease of LVEF to <40% has been observed in patients treated with T-DM1 • Left-ventricular dysfunction occurred in 1.8% of patients receiving T-DM1 and in 3.3% of patients treated with lapatinib plus capecitabine in the randomized trial • Assess LVEF before initiation of T-DM1 and at regular intervals (eg, every 3 months) during treatment to ensure LVEF is within the institution’s normal limits

Pulmonary toxicity

• Cases of interstitial lung disease (eg, pneumonitis), including some leading to acute respiratory distress syndrome or death, have been reported • Pneumonitis incidence was 0.8% in clinical trials, including 1 case of grade 3

Embryo-fetal toxicity

• Exposure to T-DM1 can result in embryo-fetal death or birth defects • Patients should be advised of this risk and the need for effective contraception

LVEF indicates left-ventricular ejection fraction; NRH, nodular regenerative hyperplasia; T-DM1, ado-trastuzumab emtansine. Source: Kadcyla (ado-trastuzumab emtansine) for injection prescribing information; 2013.

The FDA has issued a warning to prescribers advising that they should add “ado-” to the nonproprietary name “trastuzumab” when discussing T-DM1 to avoid confusion between Herceptin and Kadcyla, which was reported in clinical trials.17

Conclusion T-DM1, which several experts have called a “magic bullet,” combines trastuzumab and DM1 without causing traditional chemotherapy side effects, such as alopecia, neutropenia, or vomiting. For first-, second-, and third-line patients with HER2-positive metastatic breast cancer who are resistant to trastuzumab and to taxanes, single-agent T-DM1 offers clinically and statistically significant OS and PFS benefits, with a favor-

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able tolerability profile on a convenient, once-every-3week dosing schedule. n

References

1. Slamon DJ, Clark GM, Wong SG, et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235: 177-182. 2. American Cancer Society. Breast cancer: what are the key statistics about breast cancer? February 26, 2013. www.cancer.org/cancer/breastcancer/detailedguide/breastcancer-key-statistics. Accessed May 13, 2013. 3. Swain SM, Kim S-B, Cortes J, et al. Confirmatory overall survival (OS) analysis of CLEOPATRA: a randomized, double-blind, placebo-controlled phase 3 study with pertuzumab (P), trastuzumab (T), and docetaxel (D) in patients (pts) with HER2-positive first-line (1L) metastatic breast cancer (MBC). Cancer Res. 2012;72(24 suppl 3):Abstract P5-18-26. 4. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344:783-792. 5. Viani GA, Afonso SL, Stefano EJ, et al. Adjuvant trastuzumab in the treatment of HER2-positive early breast cancer: a meta-analysis of published randomized trials. BMC Cancer. 2007;7:153.

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6. Harris CA, Ward RL, Dobbins TA, et al. The efficacy of HER2-targeted agents in metastatic breast cancer: a meta-analysis. Ann Oncol. 2011;22:1308-1317. 7. Genentech. Kadcyla (ado-trastuzumab emtansine) is the first FDA-approved antibody-drug conjugate (ADC) for HER2-positive metastatic breast cancer. Kadcyla fact sheet. February 2013. www.genentech-forum.com/files/documents/kadcyla-fact-sheet. pdf. Accessed May 21, 2013. 8. Tsang RY, Finn RS. Beyond trastuzumab: novel therapeutic strategies in HER2-positive metastatic breast cancer. Br J Cancer. 2012;106:6-13. 9. Patient Power. ASCO update: the latest news in advanced breast cancer. YouTube. June 15, 2012. www.youtube.com/watch?v=ET8upnD1ujw. Accessed May 21, 2013. 10. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines)®: Breast Cancer. Version 3.2013. May 3, 2013. www. nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed May 21, 2013. 11. US Center for Drug Evaluation and Research. Kadcyla approval letter. February 22, 2013. www.accessdata.fda.gov/drugsatfda_docs/nda/2013/125427Orig1s000Approv.pdf. Accessed May 21, 2013. 12. Kadcyla (ado-trastuzumab emtansine) for injection [prescribing information].

South San Francisco, CA: Genentech, Inc; February 2013. 13. Patient Power. What does new HER-2 positive drug approval mean for advanced breast cancer? YouTube. March 13, 2013. www.youtube.com/watch?v=WkNLKKf WHB8. Accessed May 21, 2013. 14. Verma S, Miles D, Gianni L, et al, for the EMILIA Study Group. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012;367:1783-1791. 15. EMILIA: T-DM1 demonstrates greater safety, efficacy for advanced HER2-positive breast cancer. ASCO Daily News. June 2012. http://chicago2012.asco.org/ASCO DailyNews/LBA1.aspx. Accessed May 21, 2013. 16. Baselga J, Verma S, Ro J, et al. Relationship between tumor biomarkers (BM) and efficacy in EMILIA, a phase III study of trastuzumab emtansine (T-DM1) in HER2-positive metastatic breast cancer (MBC). Abstract presented at the 2013 AACR Annual Meeting; April 6-10, 2013; Washington, DC. Abstract LB-63. 17. US Food and Drug Administration. FDA warns about potential medication errors resulting from confusion regarding nonproprietary name for breast cancer drug Kadcyla (ado-trastuzumab emtansine). Podcast; updated May 7, 2013. www.fda.gov/Drugs/ DrugSafety/DrugSafetyPodcasts/ucm351075.htm. Accessed May 23, 2013.

Sanjiv S. Agarwala, MD

THIRD ANNUAL CONFERENCE

WORLD CUTANEOUS MALIGNANCIES CONGRESS

™

OCT. 29 - OCT. 31, 2014

www.regonline.com/WCMC2014

WORLD THIRD ANNUAL CONFERENCE CUTANEOUS GLOBAL BIOMARKERS MALIGNANCIES CONSORTIUM Clinical Approaches to Targeted Technologies CONGRESS

Professor of Medicine Temple University School of Medicine Chief, Medical Oncology & Hematology St. Luke’s Cancer Center Bethlehem, PA

GBC CONFERENCE CHAIRS Jorge E. Cortes, MD

Chair, CML and AML Sections D.B. Lane Cancer Research Distinguished Professor for Leukemia Research Department of Leukemia Division of Cancer Medicine The University of Texas MD Anderson Cancer Center Houston, TX

™

OCT. 31 - NOV. 1, 2014

www.regonline.com/GBC2014

Roy S. Herbst, MD, PhD

Ensign Professor of Medicine Professor of Pharmacology Chief of Medical Oncology Director, Thoracic Oncology Research Program Associate Director for Translational Research Yale Cancer Center New Haven, CT

Marriott Marquis San Francisco • San Francisco, California WCMC GBC2014RegisterToday_21214

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NEW

NOW AVAILABLE FOR THE TREATMENT OF MAJOR DEPRESSIVE DISORDER (MDD) The efficacy and safety of BRINTELLIX in the treatment of MDD was established in1: 6 short-term (6- to 8-week) randomized, double-blind, placebo-controlled, fixed-dose studies (including a dedicated study in the elderly) based on mean change from baseline to endpoint in MADRS or HAM-D24 total scores  1 long-term (24- to 64-week) maintenance study in adults based on time to recurrence of depressive episodes*  In clinical studies the most common adverse reactions (incidence ≥5% and at least twice the rate of placebo in 6- to 8-week studies) were nausea, constipation, and vomiting  In pooled 6- to 8-week placebo-controlled studies, the incidence of patients who received BRINTELLIX and discontinued because of adverse reactions ranged from 5% to 8% over the 5 to 20 mg/day doses compared to 4% for placebo; nausea was the most common adverse reaction reported as a reason for discontinuation 

*Recurrence of a depressive episode is defined as MADRS total score ≥22 or lack of efficacy as judged by the investigators. Please visit BRINTELLIXHCP.com to learn more.

INDICATION

BRINTELLIX is indicated for the treatment of major depressive disorder in adults.

IMPORTANT SAFETY INFORMATION WARNING: SUICIDAL THOUGHTS AND BEHAVIORS Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was a trend toward reduced risk with antidepressant use in patients aged 65 and older. In patients of all ages who are started on antidepressant therapy, monitor closely for worsening, and for emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber. BRINTELLIX has not been evaluated for use in pediatric patients.

Serotonin Syndrome: The development of a potentially life-threatening serotonin syndrome has been reported with serotonergic antidepressants (SNRIs, SSRIs, and others), including BRINTELLIX, when used alone but more often when used concomitantly with other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John’s Wort), and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Serotonin syndrome symptoms may include mental status changes (eg, agitation, hallucinations, delirium, and coma), autonomic instability (eg, tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (eg, tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (eg, nausea, vomiting, diarrhea). If such symptoms occur, discontinue BRINTELLIX and any concomitant serotonergic agents, and initiate supportive symptomatic treatment. If concomitant use of BRINTELLIX is clinically warranted, patients should be made aware of and monitored for potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.

CONTRAINDICATIONS Hypersensitivity: Hypersensitivity to vortioxetine or any components of the BRINTELLIX formulation. Angioedema has been reported in patients treated with BRINTELLIX.

Abnormal Bleeding: Treatment with serotonergic antidepressants (SSRIs, SNRIs, and others) may increase the risk of abnormal bleeding. Patients should be cautioned about the increased risk of bleeding when BRINTELLIX is coadministered with NSAIDs, aspirin, or other drugs that affect coagulation.

Monoamine Oxidase Inhibitors (MAOIs): Due to an increased risk of serotonin syndrome, do not use MAOIs intended to treat psychiatric disorders with BRINTELLIX or within 21 days of stopping treatment with BRINTELLIX. Do not use BRINTELLIX within 14 days of stopping an MAOI intended to treat psychiatric disorders. Do not start BRINTELLIX in a patient who is being treated with linezolid or intravenous methylene blue.

Activation of Mania/Hypomania: Activation of mania/hypomania can occur with antidepressant treatment. Prior to initiating treatment with an antidepressant, screen patients for bipolar disorder. As with all antidepressants, use BRINTELLIX cautiously in patients with a history or family history of bipolar disorder, mania, or hypomania.

WARNINGS AND PRECAUTIONS Clinical Worsening and Suicide Risk: All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. Consideration should be given to changing the therapeutic regimen,including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality (anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, and mania), especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Families and caregivers of patients being treated with antidepressants for MDD or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients daily.

Hyponatremia: Hyponatremia has occurred as a result of serotonergic drugs and in many cases, appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Elderly patients and patients taking diuretics or who are otherwise volume-depleted can be at greater risk. More severe or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. Discontinue BRINTELLIX in patients with symptomatic hyponatremia and initiate appropriate medical intervention. Adverse Reactions: The most commonly observed adverse reactions for BRINTELLIX in 6- to 8-week placebo-controlled studies (incidence ≥5% and at least twice the rate of placebo) were by dose (5 mg, 10 mg, 15 mg, 20 mg) vs placebo: nausea (21%, 26%, 32%, 32% vs 9%), constipation (3%, 5%, 6%, 6% vs 3%), and vomiting (3%, 5%, 6%, 6% vs 1%). Drug Interactions: Concomitant administration of BRINTELLIX and strong CYP2D6 inhibitors or strong CYP inducers may require a dose adjustment of BRINTELLIX. Reference: 1. Brintellix (vortioxetine) prescribing information. Takeda Pharmaceuticals.

Please see adjacent pages for Brief Summary of Prescribing Information and visit BRINTELLIXHCP.com for full Prescribing Information and Medication Guide.

BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION BRINTELLIX (vortioxetine) tablets, for oral use WARNING: SUICIDAL THOUGHTS AND BEHAVIORS Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was a trend toward reduced risk with antidepressant use in patients aged 65 and older [see Warnings and Precautions]. In patients of all ages who are started on antidepressant therapy, monitor closely for worsening, and for emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber [see Warnings and Precautions]. BRINTELLIX has not been evaluated for use in pediatric patients [see Use in Specific Populations]. INDICATIONS AND USAGE Major Depressive Disorder BRINTELLIX is indicated for the treatment of major depressive disorder (MDD). The efficacy of BRINTELLIX was established in six 6 to 8 week studies (including one study in the elderly) and one maintenance study in adults. CONTRAINDICATIONS • Hypersensitivity to vortioxetine or any components of the formulation. Angioedema has been reported in patients treated with BRINTELLIX. • The use of MAOIs intended to treat psychiatric disorders with BRINTELLIX or within 21 days of stopping treatment with BRINTELLIX is contraindicated because of an increased risk of serotonin syndrome. The use of BRINTELLIX within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated [see Warnings and Precautions]. Starting BRINTELLIX in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome [see Warnings and Precautions]. WARNINGS AND PRECAUTIONS Clinical Worsening and Suicide Risk Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled studies of antidepressant drugs (selective serotonin reuptake inhibitors [SSRIs] and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with MDD and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a trend toward reduction with antidepressants compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled studies in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term studies of nine antidepressant drugs in over 4,400 patients. The pooled analyses of placebo-controlled studies in adults with MDD or other psychiatric disorders included a total of 295 short-term studies (median duration of two months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1. The risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1 of the BRINTELLIX Full Prescribing Information, which states: 14 additional cases in patients under the age of 18, 5 additional cases in patients between 18 and 24 years of age. There was 1 fewer case in patients between 25 and 64 years of age and 6 fewer cases in patients 65 years of age and over. No suicides occurred in any of the pediatric studies. There were suicides in the adult studies, but the number was not sufficient to reach any conclusion about drug effect on suicide. It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebocontrolled maintenance studies in adults with depression that the use of antidepressants can delay the recurrence of depression.

All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania have been reported in adult and pediatric patients being treated with antidepressants for MDD as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Families and caregivers of patients being treated with antidepressants for MDD or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Screening Patients for Bipolar Disorder A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled studies) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that BRINTELLIX is not approved for use in treating bipolar depression. Serotonin Syndrome The development of a potentially life-threatening serotonin syndrome has been reported with serotonergic antidepressants including BRINTELLIX, when used alone but more often when used concomitantly with other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John’s Wort), and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome. The concomitant use of BRINTELLIX with MAOIs intended to treat psychiatric disorders is contraindicated. BRINTELLIX should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with a MAOI such as linezolid or intravenous methylene blue in a patient taking BRINTELLIX. BRINTELLIX should be discontinued before initiating treatment with the MAOI [see Contraindications]. If concomitant use of BRINTELLIX with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John’s Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases. Treatment with BRINTELLIX and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated. Abnormal Bleeding The use of drugs that interfere with serotonin reuptake inhibition, including BRINTELLIX, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, and other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to drugs that inhibit serotonin reuptake have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages.

Patients should be cautioned about the increased risk of bleeding when BRINTELLIX is coadministered with NSAIDs, aspirin, or other drugs that affect coagulation or bleeding [see Drug Interactions]. Activation of Mania/Hypomania Symptoms of mania/hypomania were reported in <0.1% of patients treated with BRINTELLIX in pre-marketing clinical studies. Activation of mania/ hypomania has been reported in a small proportion of patients with major affective disorder who were treated with other antidepressants. As with all antidepressants, use BRINTELLIX cautiously in patients with a history or family history of bipolar disorder, mania, or hypomania. Hyponatremia Hyponatremia has occurred as a result of treatment with serotonergic drugs. In many cases, hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). One case with serum sodium lower than 110 mmol/L was reported in a subject treated with BRINTELLIX in a pre-marketing clinical study. Elderly patients may be at greater risk of developing hyponatremia with a serotonergic antidepressant. Also, patients taking diuretics or who are otherwise volume depleted can be at greater risk. Discontinuation of BRINTELLIX in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which can lead to falls. More severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label. • Hypersensitivity [see Contraindications] • Clinical Worsening and Suicide Risk [see Warnings and Precautions] • Serotonin Syndrome [see Warnings and Precautions] • Abnormal Bleeding [see Warnings and Precautions] • Activation of Mania/Hypomania [see Warnings and Precautions] • Hyponatremia [see Warnings and Precautions] Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice. Patient Exposure BRINTELLIX was evaluated for safety in 4746 patients (18 years to 88 years of age) diagnosed with MDD who participated in pre-marketing clinical studies; 2616 of those patients were exposed to BRINTELLIX in 6 to 8 week, placebocontrolled studies at doses ranging from 5 mg to 20 mg once daily and 204 patients were exposed to BRINTELLIX in a 24 week to 64 week placebocontrolled maintenance study at doses of 5 mg to 10 mg once daily. Patients from the 6 to 8 week studies continued into 12-month open-label studies. A total of 2586 patients were exposed to at least one dose of BRINTELLIX in open-label studies, 1727 were exposed to BRINTELLIX for six months and 885 were exposed for at least one year. Adverse Reactions Reported as Reasons for Discontinuation of Treatment In pooled 6 to 8 week placebo-controlled studies the incidence of patients who received BRINTELLIX 5 mg/day, 10 mg/day, 15 mg/day and 20 mg/day and discontinued treatment because of an adverse reaction was 5%, 6%, 8% and 8%, respectively, compared to 4% of placebo-treated patients. Nausea was the most common adverse reaction reported as a reason for discontinuation. Common Adverse Reactions in Placebo-Controlled MDD Studies The most commonly observed adverse reactions in MDD patients treated with BRINTELLIX in 6 to 8 week placebo-controlled studies (incidence ≥5% and at least twice the rate of placebo) were nausea, constipation and vomiting. Table 2 shows the incidence of common adverse reactions that occurred in ≥2% of MDD patients treated with any BRINTELLIX dose and at least 2% more frequently than in placebo-treated patients in the 6 to 8 week placebocontrolled studies. Table 2 of the BRINTELLIX Full Prescribing Information shows the incidence of common adverse reactions that occurred in ≥2% of MDD patients treated with any BRINTELLIX dose and at least 2% more frequently than in placebotreated patients in the 6- to 8-week placebo-controlled studies. The following values from Table 2 show the percentage of patients exhibiting the adverse reaction while receiving BRINTELLIX 5 mg (N=1013), 10 mg (N=699), 15 mg (N=449), 20 mg (N=455), and placebo (N=1621) respectively. Gastrointestinal Disorders: Nausea (21%, 26%, 32%, 32%, vs. 9%); Diarrhea (7%, 7%, 10%, 7%, vs. 6%); Dry Mouth (7%, 7%, 6%, 8%, vs. 6%); Constipation (3%, 5%, 6%, 6%, vs. 3%); Vomiting (3%, 5%, 6%, 6%, vs. 1%); Flatulence (1%, 3%, 2%, 1%, vs. 1%); Nervous System Disorders: Dizziness (6%, 6%, 8%, 9%, vs. 6%); Psychiatric Disorders: Abnormal Dreams (<1%, <1%, 2%, 3%, vs. 1%); Skin and Subcutaneous Tissue Disorders: Pruritus (including pruritus generalized) (1%, 2%, 3%, 3%, vs. 1%). Nausea Nausea was the most common adverse reaction and its frequency was doserelated (Table 2). It was usually considered mild or moderate in intensity and the median duration was 2 weeks. Nausea was more common in females than

males. Nausea most commonly occurred in the first week of BRINTELLIX treatment with 15 to 20% of patients experiencing nausea after 1 to 2 days of treatment. Approximately 10% of patients taking BRINTELLIX 10 mg/day to 20 mg/day had nausea at the end of the 6 to 8 week placebo-controlled studies. Sexual Dysfunction Difficulties in sexual desire, sexual performance and sexual satisfaction often occur as manifestations of psychiatric disorders, but they may also be consequences of pharmacologic treatment. In the MDD 6 to 8 week controlled trials of BRINTELLIX, voluntarily reported adverse reactions related to sexual dysfunction were captured as individual event terms. These event terms have been aggregated and the overall incidence was as follows. In male patients the overall incidence was 3%, 4%, 4%, 5% in BRINTELLIX 5 mg/day, 10 mg/day, 15 mg/day, 20 mg/day, respectively, compared to 2% in placebo. In female patients, the overall incidence was <1%, 1%, <1%, 2% in BRINTELLIX 5 mg/day, 10 mg/day, 15 mg/day, 20 mg/day, respectively, compared to <1% in placebo. Because voluntarily reported adverse sexual reactions are known to be underreported, in part because patients and physicians may be reluctant to discuss them, the Arizona Sexual Experiences Scale (ASEX), a validated measure designed to identify sexual side effects, was used prospectively in seven placebo-controlled trials. The ASEX scale includes five questions that pertain to the following aspects of sexual function: 1) sex drive, 2) ease of arousal, 3) ability to achieve erection (men) or lubrication (women), 4) ease of reaching orgasm, and 5) orgasm satisfaction. The presence or absence of sexual dysfunction among patients entering clinical studies was based on their ASEX scores. For patients without sexual dysfunction at baseline (approximately 1/3 of the population across all treatment groups in each study), Table 3 shows the incidence of patients that developed treatment-emergent sexual dysfunction when treated with BRINTELLIX or placebo in any fixed dose group. Physicians should routinely inquire about possible sexual side effects. The presence or absence of sexual dysfunction among patients entering clinical studies was based on their ASEX scores. For patients without sexual dysfunction at baseline (approximately 1/3 of the population across all treatment groups in each study), the following values from Table 3 of the BRINTELLIX Full Prescribing Information show the ASEX incidence of patients who developed treatment-emergent sexual dysfunction when treated with BRINTELLIX or placebo in any fixed-dose group. The incidence in female patients treated with BRINTELLIX 5 mg (N=65), 10 mg (N=94), 15 mg (N=57), 20 mg (N=67) or placebo (N=135), respectively was 22%, 23%, 33%, 34% vs. 20%. For male patients, the incidence of treatment-emergent sexual dysfunction when treated with BRINTELLIX 5 mg (N=67), 10 mg (N=86), 15 mg (N=67), 20 mg (N=59) or placebo (N=162), respectively was 16%, 20%, 19%, 29% vs. 14%. Incidence was based on the number of subjects with sexual dysfunction during the study / number of subjects without sexual dysfunction at baseline. Sexual dysfunction was defined as a subject scoring any of the following on the ASEX scale at two consecutive visits during the study: 1) total score ≥19; 2) any single item ≥5; 3) three or more items each with a score ≥4. The sample size for each dose group was the number of patients without sexual dysfunction at baseline. Physicians should routinely inquire about possible sexual side effects. Adverse Reactions Following Abrupt Discontinuation of BRINTELLIX Treatment Discontinuation symptoms have been prospectively evaluated in patients taking BRINTELLIX 10 mg/day, 15 mg/day, and 20 mg/day using the Discontinuation-Emergent Signs and Symptoms (DESS) scale in clinical trials. Some patients experienced discontinuation symptoms such as headache, muscle tension, mood swings, sudden outbursts of anger, dizziness, and runny nose in the first week of abrupt discontinuation of BRINTELLIX 15 mg/day and 20 mg/day. Laboratory Tests BRINTELLIX has not been associated with any clinically important changes in laboratory test parameters in serum chemistry (except sodium), hematology and urinalysis as measured in the 6 to 8 week placebo-controlled studies. Hyponatremia has been reported with the treatment of BRINTELLIX [see Warnings and Precautions]. In the 6-month, double-blind, placebocontrolled phase of a long-term study in patients who had responded to BRINTELLIX during the initial 12-week, open-label phase, there were no clinically important changes in lab test parameters between BRINTELLIX and placebo-treated patients. Weight BRINTELLIX had no significant effect on body weight as measured by the mean change from baseline in the 6 to 8 week placebo-controlled studies. In the 6-month, double-blind, placebo-controlled phase of a long-term study in patients who had responded to BRINTELLIX during the initial 12-week, open-label phase, there was no significant effect on body weight between BRINTELLIX and placebo-treated patients. Vital Signs BRINTELLIX has not been associated with any clinically significant effects on vital signs, including systolic and diastolic blood pressure and heart rate, as measured in placebo-controlled studies.

Other Adverse Reactions Observed in Clinical Studies The following listing does not include reactions: 1) already listed in previous tables or elsewhere in labeling, 2) for which a drug cause was remote, 3) which were so general as to be uninformative, 4) which were not considered to have significant clinical implications, or 5) which occurred at a rate equal to or less than placebo. Ear and labyrinth disorders — vertigo Gastrointestinal disorders — dyspepsia Nervous system disorders — dysgeusia Vascular disorders — flushing DRUG INTERACTIONS CNS Active Agents Monoamine Oxidase Inhibitors Adverse reactions, some of which are serious or fatal, can develop in patients who use MAOIs or who have recently been discontinued from an MAOI and started on a serotonergic antidepressant(s) or who have recently had SSRI or SNRI therapy discontinued prior to initiation of an MAOI [see Contraindications and Warnings and Precautions]. Serotonergic Drugs Based on the mechanism of action of BRINTELLIX and the potential for serotonin toxicity, serotonin syndrome may occur when BRINTELLIX is coadministered with other drugs that may affect the serotonergic neurotransmitter systems (e.g., SSRIs, SNRIs, triptans, buspirone, tramadol, and tryptophan products etc.). Closely monitor symptoms of serotonin syndrome if BRINTELLIX is co-administered with other serotonergic drugs. Treatment with BRINTELLIX and any concomitant serotonergic agents should be discontinued immediately if serotonin syndrome occurs [see Warnings and Precautions]. Other CNS Active Agents No clinically relevant effect was observed on steady state lithium exposure following coadministration with multiple daily doses of BRINTELLIX. Multiple doses of BRINTELLIX did not affect the pharmacokinetics or pharmacodynamics (composite cognitive score) of diazepam. A clinical study has shown that BRINTELLIX (single dose of 20 or 40 mg) did not increase the impairment of mental and motor skills caused by alcohol (single dose of 0.6 g/kg). Details on the potential pharmacokinetic interactions between BRINTELLIX and bupropion can be found in Section 7.3, Potential for Other Drugs to Affect BRINTELLIX. Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin) Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of case-control and cohort design have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. These studies have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and SNRIs are coadministered with warfarin. Following coadministration of stable doses of warfarin (1 to 10 mg/day) with multiple daily doses of BRINTELLIX, no significant effects were observed in INR, prothrombin values or total warfarin (protein bound plus free drug) pharmacokinetics for both R- and S-warfarin [see Drug Interactions]. Coadministration of aspirin 150 mg/day with multiple daily doses of BRINTELLIX had no significant inhibitory effect on platelet aggregation or pharmacokinetics of aspirin and salicylic acid [see Drug Interactions]. Patients receiving other drugs that interfere with hemostasis should be carefully monitored when BRINTELLIX is initiated or discontinued [see Warnings and Precautions]. Potential for Other Drugs to Affect BRINTELLIX Reduce BRINTELLIX dose by half when a strong CYP2D6 inhibitor (e.g., bupropion, fluoxetine, paroxetine, quinidine) is coadministered. Consider increasing the BRINTELLIX dose when a strong CYP inducer (e.g., rifampicin, carbamazepine, phenytoin) is coadministered. The maximum dose is not recommended to exceed three times the original dose (Figure 1). Figure 1. Impact of Other Drugs on Vortioxetine PK

Potential for BRINTELLIX to Affect Other Drugs No dose adjustment for the comedications is needed when BRINTELLIX is coadministered with a substrate of CYP1A2 (e.g., duloxetine), CYP2A6, CYP2B6 (e.g., bupropion), CYP2C8 (e.g., repaglinid), CYP2C9 (e.g., S-warfarin), CYP2C19 (e.g., diazepam), CYP2D6 (e.g., venlafaxine), CYP3A4/5 (e.g., budesonide), and P-gp (e.g., digoxin). In addition, no dose adjustment for lithium, aspirin, and warfarin is necessary. Vortioxetine and its metabolites are unlikely to inhibit the following CYP enzymes and transporter based on in vitro data: CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, and P-gp. As such, no clinically relevant interactions with drugs metabolized by these CYP enzymes would be expected. In addition, vortioxetine did not induce CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP3A4/5 in an in vitro study in cultured human hepatocytes. Chronic administration of BRINTELLIX is unlikely to induce the metabolism of drugs metabolized by these CYP isoforms. Furthermore, in a series of clinical drug interaction studies, coadministration of BRINTELLIX with substrates for CYP2B6 (e.g., bupropion), CYP2C9 (e.g., warfarin), and CYP2C19 (e.g., diazepam), had no clinical meaningful effect on the pharmacokinetics of these substrates (Figure 2). Because vortioxetine is highly bound to plasma protein, coadministration of BRINTELLIX with another drug that is highly protein bound may increase free concentrations of the other drug. However, in a clinical study with coadministration of BRINTELLIX (10 mg/day) and warfarin (1 mg/day to 10 mg/day), a highly protein-bound drug, no significant change in INR was observed [see Drug Interactions]. Figure 2. Impact of Vortioxetine on PK of Other Drugs

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C Risk Summary There are no adequate and well-controlled studies of BRINTELLIX in pregnant women. Vortioxetine caused developmental delays when administered during pregnancy to rats and rabbits at doses 15 and 10 times the maximum recommended human dose (MRHD) of 20 mg, respectively. Developmental delays were also seen after birth in rats at doses 20 times the MRHD of vortioxetine given during pregnancy and through lactation. There were no teratogenic effects in rats or rabbits at doses up to 77 and 58 times, the MRHD of vortioxetine, respectively, given during organogenesis. The incidence of malformations in human pregnancies has not been established for BRINTELLIX. All human pregnancies, regardless of drug exposure, have a background rate of 2 to 4% for major malformations, and 15 to 20% for pregnancy loss. BRINTELLIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Clinical Considerations Neonates exposed to SSRIs or SNRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability and constant crying. These features are consistent with either a direct toxic effect of these classes of drugs or possibly, a drug discontinuation syndrome. It should be noted that in some cases, the clinical picture is consistent with serotonin syndrome [see Warnings and Precautions]. When treating a pregnant woman with

BRINTELLIX during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. Neonates exposed to SSRIs in pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in one to two per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. Several recent epidemiologic studies suggest a positive statistical association between SSRI use in pregnancy and PPHN. Other studies do not show a significant statistical association. A prospective longitudinal study was conducted of 201 pregnant women with a history of major depression, who were either on antidepressants or had received antidepressants less than 12 weeks prior to their last menstrual period, and were in remission. Women who discontinued antidepressant medication during pregnancy showed a significant increase in relapse of their major depression compared to those women who remained on antidepressant medication throughout pregnancy. When treating a pregnant woman with BRINTELLIX, the physician should carefully consider both the potential risks of taking a serotonergic antidepressant, along with the established benefits of treating depression with an antidepressant. Animal Data In pregnant rats and rabbits, no teratogenic effects were seen when vortioxetine was given during the period of organogenesis at oral doses up to 160 and 60 mg/kg/day, respectively. These doses are 77 and 58 times, in rats and rabbits, respectively, the maximum recommended human dose (MRHD) of 20 mg on a mg/m2 basis. Developmental delay, seen as decreased fetal body weight and delayed ossification, occurred in rats and rabbits at doses equal to and greater than 30 and 10 mg/kg (15 and 10 times the MRHD, respectively) in the presence of maternal toxicity (decreased food consumption and decreased body weight gain). When vortioxetine was administered to pregnant rats at oral doses up to 120 mg/kg (58 times the MRHD) throughout pregnancy and lactation, the number of live-born pups was decreased and early postnatal pup mortality was increased at 40 and 120 mg/kg. Additionally, pup weights were decreased at birth to weaning at 120 mg/kg and development (specifically eye opening) was slightly delayed at 40 and 120 mg/kg. These effects were not seen at 10 mg/kg (5 times the MRHD). Nursing Mothers It is not known whether vortioxetine is present in human milk. Vortioxetine is present in the milk of lactating rats. Because many drugs are present in human milk and because of the potential for serious adverse reactions in nursing infants from BRINTELLIX, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Clinical studies on the use of BRINTELLIX in pediatric patients have not been conducted; therefore, the safety and effectiveness of BRINTELLIX in the pediatric population have not been established. Geriatric Use No dose adjustment is recommended on the basis of age (Figure 3). Results from a single-dose pharmacokinetic study in elderly (>65 years old) vs. young (24 to 45 years old) subjects demonstrated that the pharmacokinetics were generally similar between the two age groups. Of the 2616 subjects in clinical studies of BRINTELLIX, 11% (286) were 65 and over, which included subjects from a placebo-controlled study specifically in elderly patients. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients. Serotonergic antidepressants have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event [see Warnings and Precautions]. Use in Other Patient Populations No dose adjustment of BRINTELLIX on the basis of race, gender, ethnicity, or renal function (from mild renal impairment to end-stage renal disease) is necessary. In addition, the same dose can be administered in patients with mild to moderate hepatic impairment (Figure 3). BRINTELLIX has not been studied in patients with severe hepatic impairment. Therefore, BRINTELLIX is not recommended in patients with severe hepatic impairment.

Figure 3. Impact of Intrinsic Factors on Vortioxetine PK

DRUG ABUSE AND DEPENDENCE BRINTELLIX is not a controlled substance. OVERDOSAGE Human Experience There is limited clinical trial experience regarding human overdosage with BRINTELLIX. In pre-marketing clinical studies, cases of overdose were limited to patients who accidentally or intentionally consumed up to a maximum dose of 40 mg of BRINTELLIX. The maximum single dose tested was 75 mg in men. Ingestion of BRINTELLIX in the dose range of 40 to 75 mg was associated with increased rates of nausea, dizziness, diarrhea, abdominal discomfort, generalized pruritus, somnolence, and flushing. Management of Overdose No specific antidotes for BRINTELLIX are known. In managing over dosage, consider the possibility of multiple drug involvement. In case of overdose, call Poison Control Center at 1-800-222-1222 for latest recommendations. Distributed and marketed by: Takeda Pharmaceuticals America, Inc. Deerfield, IL 60015 Marketed by: Lundbeck Deerfield, IL 60015 BRINTELLIX is a trademark of H. Lundbeck A/S and is used under license by Takeda Pharmaceuticals America, Inc. ÂŠ2013 Takeda Pharmaceuticals America, Inc. LUN205P R1_Brf. September 2013 90243 L-LUN-0913-2

Mirvaso (Brimonidine): First Topical Gel Approved by the FDA for the Treatment of Facial Erythema of Rosacea

By Loretta Fala, Medical Writer

osacea, a chronic and potentially life-disrupting skin condition, affects an estimated 16 million people in the United States.1,2 Although rosacea generally affects the facial area, it can also occur on the neck, ears, scalp, or chest.2 The manifestations of rosacea include facial erythema; visible blood vessels; swollen, red acne-like bumps; dry eyes; and swollen, reddened eyelids.2,3 Rosacea is classified into 4 major subtypes2: • Subtype 1, erythematotelangiectatic rosacea • Subtype 2, papulopustular rosacea • Subtype 3, phymatous rosacea • Subtype 4, ocular rosacea. Occurring most frequently in middle-aged women with fair skin, rosacea also affects all population segments.3 Individuals between the ages of 30 and 60 years, people who have a family history of rosacea, and those who tend to blush or flush easily are at increased risk for rosacea.2,3 A severe and rare complication of rosacea is rhinophyma, an enlargement of the sebaceous glands in the nose resulting in a buildup of tissue on and around the nose, which generally occurs more frequently in men and develops slowly over several years.3 Factors that can trigger rosacea include spicy foods, alcohol, temperature extremes, sunlight, strenuous activity, hot baths or saunas, and emotional stress.3 Corticosteroids (eg, prednisone) and vasodilators, including some blood pressure medications, can also trigger rosacea.3 Although the pathophysiology of rosacea is not fully understood, it is thought to be an inflammatory disorder characterized by neurovascular dysregulation and inflammation that produce physiochemical and structural changes in the skin, as described by Del Rosso and colleagues.4 Vasculature, dermal matrix degeneration, pilosebaceous unit abnormalities, and interactions with microbial organisms are among the multiple factors that may play a role in rosacea.5 Contributors to inflammation may include antimicrobial peptides, processing enzymes, and toll-like receptors (a class of proteins).6 The facial manifestations of rosacea have a substantial psychosocial impact on patients. Based on a survey of 502 women with rosacea, 54% of these women waited ≥7 months after symptom onset before seeking medical assistance, and the mean time from symptom onset to

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diagnosis was 12.9 months (median, 6 months).7 Overall, the survey revealed that rosacea was associated with a negative self-perception and a negative first impression by others, regardless of the observer’s own appearance.7 In another survey of 801 patients with rosacea conducted in 2012 by the National Rosacea Society, 61% of patients with erythematotelangiectatic rosacea (characterized by facial redness) revealed that rosacea had inhibited their social lives; this percentage increased to 72% among patients with moderate or severe facial erythema.8 Moreover, 77% of patients with papulopustular rosacea and 85% of patients with phymatous rosacea reported that the condition had a negative impact on their social lives.8 Although there is no known cure for rosacea, medical treatment can help control the disorder and alleviate symptoms. However, only a small portion of patients affected by rosacea are receiving treatment.1 Without treatment, rosacea can worsen over time—sign and symptoms may flare up for weeks to months, then recede, followed by a repeat flare-up.3 The clinical diagnosis of rosacea requires differentiating between rosacea and acne, because both conditions may have a similar appearance, particularly in the presence of papules or pustules.7 The therapeutic goals for rosacea include managing the clinical signs and physical symptoms while addressing the patient’s emotional health and quality of life.6 Treatment approaches for rosacea include lifestyle changes, skin care regimens, patient education, topical treatment, and systemic pharmacologic therapy, or a combination of oral and topical therapies.7

Mirvaso, a New Topical Treatment for Facial Erythema of Rosacea In August 2013, brimonidine topical gel, 0.33% (Mirvaso; Galderma) was approved by the US Food and Drug Administration (FDA) for the topical treatment of the facial erythema of rosacea in adults aged ≥18 years. Mirvaso is the first topical agent to receive FDA approval for the treatment of facial erythema of rosacea.9 According to J. Mark Jackson, MD, Clinical Professor of Medicine, University of Louisville, KY, and a principal investigator of the phase 3 clinical trials, “The FDA

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approval of Mirvaso marks a turning point in rosacea treatment: we are now able to provide patients who deal with the daily frustrations caused by the redness [ie, erythema] of rosacea with an effective therapy.” Dr Jackson emphasized that facial erythema “is the most common symptom of rosacea, but until now, physicians have been without prescription treatment options to specifically address this patient need.”9

Mechanism of Action Brimonidine is a relatively selective alpha-2 adrenergic agonist. The topical application of brimonidine gel may reduce erythema through direct vasoconstriction.10 Brimonidine is extensively metabolized by the liver. Urinary excretion is the major route of elimination of brimonidine and its metabolites.10 Dosing A pea-sized amount of brimonidine gel is applied once daily to each of the 5 areas of the face—central forehead, chin, nose, and each cheek. Brimonidine topical gel should be applied smoothly and evenly as a thin layer across the entire face, avoiding the eyes and lips. Immediately after applying brimonidine topical gel, hand washing is recommended. Brimonidine topical gel is not for oral, ophthalmic, or intravaginal use.10 Brimonidine topical gel, 0.33% is available as an aqueous gel containing 5 mg of brimonidine tartrate, equivalent to 3.3 mg of brimonidine-free base.10 Clinical Trials The efficacy of brimonidine topical gel was evaluated for the treatment of moderate-to-severe, persistent (nontransient) facial erythema of rosacea in 2 randomized, double-blind clinical trials of 553 adults who were treated once daily for 4 weeks with brimonidine topical gel or vehicle gel. The baseline disease severity was graded using a 5-point clinical erythema assessment scale and a 5-point patient self-assessment scale, on which patients scored moderate or severe on both scales.10 In both pivotal trials, the primary efficacy end point was 2-grade composite success, defined as the proportion of patients with a 2-grade improvement on the clinical erythema assessment and patient self-assessment measured at hours 3, 6, 9, and 12 on day 29. In addition to day 29, efficacy was also evaluated on day 1 and day 15.10 The 2-grade composite success summary from study 1 is shown in Table 1. The success summary for study 2 is shown in Table 2. In both studies, the efficacy of topical brimonidine gel 0.5% was shown to be significantly superior to the vehicle gel throughout 12 hours on days 1, 15, and 29, with significant differences observed as early as 30 minutes after the initial application on day 1 (all P <.001).11

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rimonidine Topical Gel: 2-Grade Composite Efficacy Table 1 B on Day 29 in Study 1 2-grade composite success in clinical erythema assessment and patient self-assessment measures

Patients who achieved success Brimonidine topical gel, % (N = 129)

Vehicle gel, % (N = 131)

Hour 3

Hour 6

Hour 9

Hour 12

Source: Mirvaso (brimonidine) topical gel prescribing information; 2013.

rimonidine Topical Gel: 2-Grade Composite Efficacy Table 2 B on Day 29 in Study 2 2-grade composite success in clinical erythema assessment and patient self-assessment measures

Patients who achieved success Brimonidine topical gel, % (N = 148)

Vehicle gel, % (N = 145)

Hour 3

Hour 6

Hour 9

Hour 12

Source: Mirvaso (brimonidine) topical gel prescribing information; 2013.

Safety In controlled clinical trials with brimonidine topical gel, the most common adverse reactions (incidence, ≥1%) included erythema, flushing, skin burning sensation, and contact dermatitis.10 In an open-label, long-term study in 276 patients with persistent (nontransient) facial erythema who applied brimonidine topical gel for at least 1 year, the most common adverse events (≥4% of patients) were flushing (10%), erythema (8%), rosacea (5%), nasopharyngitis (5%), skin burning sensation (4%), increased intraocular pressure (4%), and headache (4%).10 Allergic contact dermatitis was reported in approximately 1% of patients in clinical studies. Of the 2 patients who underwent patch testing with individual product ingredients, 1 patient was found to be sensitive to brimonidine tartrate, and the other patient was sensitive to phenoxyethanol, a preservative.10 Warnings and Precautions Potentiation of vascular insufficiency. Brimonidine topical gel should be used with caution in patients with

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depression, cerebral or coronary insufficiency, Raynaud’s phenomenon, orthostatic hypotension, thromboangiitis obliterans, scleroderma, or Sjögren’s syndrome.10 Severe cardiovascular disease. Alpha-2 adrenergic agonists can lower blood pressure. Brimonidine topical gel should be used with caution in patients with severe or unstable or uncontrolled cardiovascular disease. Serious adverse reactions following ingestion of brimonidine topical gel. After the accidental ingestion of brimonidine topical gel by 2 young children, 1 or both children experienced serious adverse reactions, including lethargy, respiratory distress with apneic episodes (requiring intubation), sinus bradycardia, confusion, psychomotor hyperactivity, and diaphoresis. Both children were hospitalized overnight and were discharged the next day without sequelae. Brimonidine topical gel should be kept out of the reach of children.

For the first time ever, patients with rosacea now have an efficient topical treatment option for the persistent facial erythema that is associated with rosacea, as a result of the FDA approval of brimonidine topical gel, 0.33%. Erythema and flushing. In clinical trials, some individuals discontinued the use of brimonidine because of erythema or flushing. The effect of brimonidine topical gel may begin to diminish hours after application. For some individuals in the clinical trials, erythema was reported to return worse compared with the severity at baseline. Intermittent flushing occurred in some patients treated with brimonidine topical gel. The onset of flushing relative to the application of brimonidine topical gel varies, ranging from approximately 30 minutes to several hours. Erythema and flushing resolve after the discontinuation of brimonidine topical gel.10

Drug Interactions Caution should be exercised when using beta-blockers, antihypertensive agents, and/or cardiac glycosides, because alpha-2 agonists may reduce blood pressure.10 Although specific drug–drug interaction studies have

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not been conducted with brimonidine topical gel, the possibility of an additive or potentiating effect with central nervous system depressants (ie, alcohol, barbiturates, opiates, sedatives, or anesthetics) should be considered. Monoamine oxidase inhibitors (MAOIs) may interfere with the metabolism of brimonidine and may potentially result in an increased systemic side effect, such as hypotension. Caution is advised for patients taking MAOIs, which can affect the metabolism and uptake of circulating amines.10

Conclusion For the first time ever, patients with rosacea now have an efficient topical treatment option for the persistent facial erythema that is associated with rosacea, as a result of the FDA approval of brimonidine topical gel, 0.33% in August 2013. In 2 pivotal clinical studies of 4-week duration, brimonidine topical gel demonstrated a significantly greater improvement in the erythema of rosacea compared with the vehicle gel. The most common adverse reactions (incidence, ≥1%) in controlled clinical trials included erythema, flushing, skin burning sensation, and contact dermatitis. n References

1. National Rosacea Society. If you have rosacea, you’re not alone. www.rosacea.org/ patients/index.php. Accessed September 18, 2013. 2. National Rosacea Society. All about rosacea. www.rosacea.org/patients/allabout rosacea.php. Accessed September 27, 2013. 3. Mayo Clinic staff. Rosacea. August 17, 2013. www.mayoclinic.com/health/rosacea/ DS00308/METHOD=print&DSECTION=all. Accessed September 30, 2013. 4. Del Rosso JQ, Gallo RL, Kircik L, et al. Why is rosacea considered to be an inflammatory disorder? The primary role, clinical relevance, and therapeutic correlations of abnormal innate immune response in rosacea-prone skin. J Drugs Dermatol. 2012;11: 694-700. 5. Aroni K, Tsagroni E, Kavantzas N, et al. A study of the pathogenesis of rosacea: how angiogenesis and mast cells may participate in a complex multifactorial process. Arch Dermatol Res. 2008;300:125-131. 6. Cribier B. Pathophysiology of rosacea: redness, telangiectasia, and rosacea. Ann Dermatol Venereol. 2011;138(suppl 3):S184-S191. 7. Luftman DB. Best practices in: psychosocial impact of rosacea. Skin Allergy News. 2011; 42:10-11. www.skinandallergynews.com/uploads/media/BP_PsychImpactRosacea_ 01. pdf. Accessed October 7, 2013. 8. National Rosacea Society. Rosacea patients feel effects of their condition in social settings. Rosacea Rev. Fall 2012. www.rosacea.org/rr/2012/fall/article_3.php. Accessed October 8, 2013. 9. FDA approves Mirvaso: Galderma receives FDA approval of Mirvaso for the topical treatment of facial erythema of rosacea. August 26, 2013. www.drugs.com/new drugs/galderma-receives-fda-approval-mirvaso-topical-facial-erythema-rosacea3881.html. Accessed October 5, 2013. 10. Mirvaso (brimonidine) topical gel [prescribing information]. Fort Worth, TX: Galderma Laboratories, LP; August 2013. 11. Fowler J Jr, Jackson M, Moore A, et al. Efficacy and safety of once-daily topical brimonidine tartrate gel 0.5% for the treatment of moderate to severe facial erythema of rosacea: results of two randomized, double-blind, and vehicle-controlled pivotal studies. J Drugs Dermatol. 2013;12:650-656.

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Latuda (Lurasidone HCl) Receives 2 New Indications for Use in Bipolar Depression as Monotherapy and as Adjunctive Therapy with Lithium or Valproate By Loretta Fala, Medical Writer

ipolar disorder is a disruptive, long-term illness associated with mood swings ranging from the lows of depression to the highs of mania, and in some cases, symptoms of depression and mania at the same time (ie, mixed episodes).1 The symptoms of bipolar disorder may vary from person to person. Mood swings associated with bipolar disorder have the potential to cause substantial difficulties in relationships, work, or school. Moreover, manic episodes can be severe and, in some cases, even harmful.1 According to the National Institute of Mental Health, an estimated 2.6% of the US adult population—approximately 5.7 million people—are affected by bipolar disorder.2 The median age of onset for bipolar disorder is 25 years.2 According to the Centers for Disease Control and Prevention, in 2011, patients with bipolar disorder had a 39.1% inpatient hospitalization rate compared with a 4.5% rate for patients with other behavioral healthcare diagnoses.3 Overall, bipolar disorder is the most expensive behavioral health diagnosis, attributed mostly to indirect costs, including lost productivity, absenteeism, and presenteeism (ie, attending work while sick).3 The comorbid conditions associated with bipolar disorder include anxiety, substance abuse, panic disorder, and eating disorders, among others. The risk of suicide is increased in patients with bipolar disorder, particularly in those who also have anxiety and substance abuse.4 The total economic burden of bipolar disorder, including direct and indirect costs, in the United States was estimated to be $45 billion in 1991.5,6 A 2009 analysis estimated that the total costs of bipolar disorder were dramatically higher, totaling $151 billion in direct and indirect costs.7 Of this total, bipolar I disorder accounted for $30.7 billion, and bipolar II disorder accounted for $120.3 billion.7 Bipolar disorder requires lifelong treatment, which may include medication, psychological counseling or therapy, and education and support groups.1 The aim of initial treatment is to balance moods immediately, and once symptoms are stabilized, maintenance therapy is

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used to manage bipolar disorder on a long-term basis. Failure to adhere to maintenance treatment increases the risk for relapse and the escalation of minor mood changes into full-blown episodes of mania or depression.1 Early diagnosis and management may help to improve outcomes for patients and to reduce associated healthcare costs. Medications used to treat bipolar disorder include lithium, anticonvulsants, antipsychotics, antidepressants, benzodiazepines, and a combination of olanzapine and fluoxetine. These agents have class-specific adverse effects. Finding an appropriate treatment for an individual patient generally involves a trial-and-error approach and an adjustment to a new medication. In addition, some medications can take weeks or even months to manifest the full therapeutic effect.1 “Patients with bipolar disorder spend the majority of their symptomatic time in the depressed phase of the illness. This phase most commonly results in impaired function, a remarkable decrease in quality of life and may lead to increased risk for attempted suicide,” said Joseph Calabrese, MD, Professor of Psychiatry and Director of the Mood Disorders Program, University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, OH. “Unfortunately, there are very few treatments specifically approved to treat the symptoms of bipolar depression, which represents a very large unmet medical need for patients and their families.”

A New Atypical Antipsychotic Agent for the Treatment of Bipolar Depression In June 2013, lurasidone hydrochloride (HCl; Latuda; Sunovion Pharmaceuticals), an oral atypical antipsychotic, was approved by the US Food and Drug Administration (FDA) for 2 new indications—as monotherapy, and as adjunctive therapy with lithium or with valproate for the treatment of adult patients with major depressive episodes associated with bipolar I disorder (bipolar depression). Latuda was previously approved by the FDA in 2010 for the treatment of patients with schizophrenia.8

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L urasidone HCl Monotherapy: Primary Efficacy Results Table 1 for Studies in Depressive Episodes Associated with Bipolar I Disorder (MADRS Scores) Primary efficacy measure: MADRS PlaceboLS mean subtracted Treatment Mean baseline change from differencea group score (SD) baseline (SE) (95% CI) Lurasidone HCl (20-60 mg daily)b

30.3 (5)

–15.4 (0.8)

–4.6 (–6.9 to –2.3)

Lurasidone HCl (80-120 mg daily)

30.6 (4.9)

–15.4 (0.8)

–4.6 (–6.9 to –2.3)

30.5 (5)

–10.7 (0.8)

—

Placebo

Difference (drug minus placebo) in LS mean change from baseline. Treatment group significantly superior to placebo. NOTE: Bipolar I disorder is also referred to as bipolar depression. CI indicates confidence interval, unadjusted for multiple comparisons; HCl, hydrochloride; LS, least-squares; MADRS, Montgomery-Åsberg Depression Rating Scale; SD, standard deviation; SE, standard error. Source: Latuda (lurasidone hydrochloride) tablets prescribing information; 2013. a

The approval of lurasidone HCl was supported by 2 clinical trials, one that evaluated its efficacy as monotherapy, and another that evaluated its efficacy as adjunctive therapy in adults with depressive episodes associated with bipolar depression.8,9

Mechanism of Action The mechanism of action of lurasidone HCl for the treatment of bipolar depression and schizophrenia is unknown. Its efficacy may be mediated through a combination of central dopamine D2 and serotonin type 2 (5-HT2A) receptor antagonism. Lurasidone HCl is an antagonist with high affinity binding at the D2 receptors and the 5-HT serotonin receptors 5-HT2A and 5-HT7 receptors.8 In short-term, placebo-controlled trials of patients with bipolar depression and schizophrenia, no postbaseline QT prolongations exceeding 500 msec were reported in patients treated with lurasidone HCl or placebo.8 Dosing For the treatment of bipolar depression, the recommended starting oral dose of lurasidone HCl as monotherapy or as adjunctive therapy with either lithium or valproate is 20 mg daily, with no dose titration required; the recommended dose for lurasidone HCl is 20 mg daily to 120 mg daily.8 The maximum recommended dose of lu rasidone HCl, as monotherapy or as adjunctive therapy with lithium or valproate, is 120 mg daily. Lurasidone HCl should be taken with food (at least 350 calories): adminis-

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tration with food substantially increases the absorption of lurasidone HCl. Lurasidone HCl is available as tablets in 20-mg, 40-mg, 60-mg, 80-mg, and 120-mg strengths.8 In patients with moderate and severe renal impairment, the recommended starting dose of lurasidone HCl is 20 mg daily, and the maximum recommended dose is 80 mg daily. In patients with moderate and severe hepatic impairment, the recommended starting dose is 20 mg daily. The maximum recommended dose is 80 mg daily for patients with moderate hepatic impairment and 40 mg daily for patients with severe hepatic impairment.8 With the concomitant use of a moderate cytochrome (CY) P3A4 inhibitor (eg, diltiazem), the dose of lurasidone HCl should be reduced to half of the original dose level. The recommended starting dose is 20 mg daily, and the maximum recommended dose is 80 mg daily. With the concomitant use of a moderate CYP3A4 inducer, it may be necessary to increase the dose of lurasidone HCl. Lurasidone HCl should not be used concomitantly with a strong CYP3A4 inducer (eg, rifampin, avasimibe, St John’s wort, phenytoin, carbamazepine). Grapefruit and grapefruit juice should be avoided by patients taking lurasidone HCl, because the juice may inhibit the CYP3A4 enzyme and alter the concentrations of lurasidone HCl.8

Clinical Studies Lurasidone HCl as Monotherapy The efficacy of lurasidone HCl as monotherapy was demonstrated in a 6-week, randomized, double-blind, placebo-controlled trial of 485 adult patients who met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria for major depressive episodes associated with bipolar I disorder, with or without rapid cycling, and without psychotic features.8 These patients ranged in age from 18 to 74 years, with a mean age of 41.5 years. The patients were randomized to receive 1 of 2 flexible-dose ranges of lurasidone HCl (2060 mg daily or 80-120 mg daily) or to placebo.8 The Montgomery-Åsberg Depression Rating Scale (MADRS), a 10-item clinician-rated scale with total scores ranging from 1 (no depressive features) to 60 (maximum score), was used as the primary rating instrument to measure depressive symptoms in this study. The primary end point was the change from baseline in MADRS score at week 6. The Clinical Global Impression-Bipolar-Severity of Illness scale (CGI-BP-S), a clinician-rated scale that measures the patient’s current illness state on a 7-point scale, with a higher score associated with greater illness severity, served as the secondary rating instrument.8 Based on this clinical trial, lurasidone HCl was found to be superior to placebo for the low-dose range

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(20-60 mg daily) and the high-dose range (80-120 mg daily) in reducing the MADRS and CGI-BP-S scores at week 6 (Table 1). The high-dose range did not show additional efficacy, on average, compared with the lowdose range.8

Lurasidone HCl as Adjunctive Therapy with Lithium or Valproate The efficacy of lurasidone HCl as an adjunctive therapy with lithium or valproate was demonstrated in a 6-week, randomized, double-blind, placebo-controlled trial of 340 adult patients who met the DSM-IV-TR criteria for major depressive episodes associated with bipolar I disorder, with or without rapid cycling, and without psychotic features. These patients ranged in age from 18 to 72 years, with a mean age of 41.7 years. Patients who remained symptomatic after treatment with lithium or valproate were randomized to receive lurasidone HCl at flexible doses of 20 mg to 120 mg daily, or to placebo.8 To assess depressive symptoms in this study, the MADRS was used as the primary rating instrument. The primary end point was the change from baseline in MADRS score at week 6. The key secondary instrument was the CGI-BP-S scale. In this study, lurasidone HCl as an adjunctive therapy with lithium or valproate was superior to placebo at reducing MADRS and CGI-BP-S scores at week 6 (Table 2).8 Safety The most frequently observed adverse reactions (incidence ≥5% and at least twice the rate for placebo) associated with the use of lurasidone HCl as monotherapy for bipolar depression (daily doses ranging from 20-120 mg) reported in clinical trials were akathisia, extrapyramidal symptoms (ie, bradykinesia, cogwheel rigidity, drooling, dystonia, extrapyramidal disorder, glabellar reflex abnormal, hypokinesia, muscle rigidity, oculogyric crisis, oromandibular dystonia, Parkinsonism, psychomotor retardation, tongue spasm, torticollis, tremor, and trismus), somnolence, nausea, vomiting, diarrhea, and anxiety. At daily doses ranging from 20 mg to 120 mg as adjunctive therapy with lithium or valproate for bipolar depression, the most frequent adverse reactions (incidence ≥5% and at least twice the rate of placebo) were akathisia and somnolence.8 Contraindications Lurasidone HCl is contraindicated in patients with a known hypersensitivity to lurasidone HCl or any components in the formulation. Other contraindications for lurasidone HCl include concomitant use with a strong CYP3A4 inhibitor (eg, ketoconazole) or a strong CYP3A4 inducer (eg, rifampin).8

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Lurasidone HCl Adjunctive Therapy with Lithium or Valproate: Table 2 Primary Efficacy Results for Studies in Depressive Episodes Associated with Bipolar I Disorder (MADRS Scores) Primary efficacy measure: MADRS PlaceboLS mean subtracted Mean baseline change from differencea score (SD) baseline (SE) (95% CI)

Treatment group Lurasidone HCl (20-120 mg daily)b + lithium or valproate

30.6 (5.3)

–17.1 (0.9)

–3.6 (–6 to –1.1)

Placebo + lithium or valproate

30.8 (4.8)

–13.5 (0.9)

—

Difference (drug minus placebo) in LS mean change from baseline. Treatment group statistically significantly superior to placebo. NOTE: Bipolar I disorder is also referred to as bipolar depression. CI indicates confidence interval, unadjusted for multiple comparisons; HCl, hydrochloride; LS, least-squares; MADRS, Montgomery-Åsberg Depression Rating Scale; SD, standard deviation; SE, standard error. Source: Latuda (lurasidone hydrochloride) tablets prescribing information; 2013. a

Warnings and Precautions Boxed warning. The prescribing information for lu rasidone HCl includes a boxed warning stating that elderly patients with dementia-related psychosis who are treated with antipsychotic drugs have an increased risk of death. Lurasidone HCl is not approved for the treatment of patients with dementia-related psychosis. The boxed warning also states that there is an increased risk of suicidal thinking and suicidal behavior in children, adolescents, and young adults taking antidepressants, and patients should be monitored for worsening and emergence of suicidal thoughts and behaviors when taking lurasidone HCl.8 Neuroleptic malignant syndrome (NMS). NMS is a potentially fatal symptom complex that has been reported with the use of antipsychotic drugs, including lurasidone HCl. The management of NMS should include immediate discontinuation of lurasidone HCl or other antipsychotic drugs not essential to concurrent therapy. Patients should be monitored carefully.8 Tardive dyskinesia. If signs and symptoms of tardive dyskinesia appear in a patient taking lurasidone HCl, drug discontinuation should be considered if clinically appropriate. However, some patients may require treatment with lurasidone HCl despite the presence of tardive dyskinesia. Metabolic changes. Atypical antipsychotic drugs have been associated with metabolic changes, including hyperglycemia, dyslipidemia, and weight gain, that may increase cardiovascular and cerebrovascular risk. Pa-

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tients should be monitored for symptoms of hypergly cemia, including polydipsia, polyuria, polyphagia, and weakness. Glucose should be monitored regularly in patients with diabetes or who are at risk for diabetes. Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics. Weight gain has been observed with the use of atypical antipsychotics. The clinical monitoring of weight is recommended. Hyperprolactinemia. Prolactin elevations may occur with use of lurasidone HCl and other dopamine D2 receptor antagonists. Leukopenia, neutropenia, and agranulocytosis. Complete blood counts should be performed in patients with a preexisting low white blood cell count or a history of leukopenia or neutropenia. If a clinically significant decline in white blood cells occurs in the absence of other causative factors, the discontinuation of lurasidone HCl should be considered.

The approval of lurasidone HCl for bipolar depression adds a new treatment option for patients suffering from this serious illness. Orthostatic hypotension and syncope. Dizziness, tachycardia or bradycardia, and syncope may occur with the use of lurasidone HCl, especially early in treatment. In patients with known cardiovascular or cerebrovascular disease, and in antipsychotic-naïve patients, a lower starting dose and slower titration should be considered.8

Use in Specific Populations Pregnancy. Lurasidone HCl should only be used during pregnancy if the potential benefit justifies the potential risk.8 Nursing mothers. Lurasidone HCl should be discontinued by nursing mothers or nursing should be discontinued while taking lurasidone HCl. The risk of drug discontinuation to the mother should be considered.8

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Conclusion Bipolar depression is a lifelong illness associated with serious morbidity and a heavy economic toll. In June 2013, the FDA approved 2 new indications for the oral atypical antipsychotic lurasidone HCl for the treatment of depressive episodes associated with bipolar depression; the drug was approved as monotherapy, and as adjunctive therapy with lithium or valproate. Previously, this drug was approved by the FDA for the treatment of schizophrenia in 2010. The approval of lurasidone HCl for bipolar depression adds a new treatment option for patients suffering from this serious illness. In 2 trials, lurasidone HCl demonstrated significant improvements in depressive symptoms after 6 weeks compared with placebo, as monotherapy, and as adjunctive therapy with lithium or valproate, in patients with depressive episodes associated with bipolar depression. In clinical trials of patients with bipolar depression, the most common adverse reactions in patients receiving lurasidone HCl as monotherapy were akathisia, extrapyramidal symptoms, somnolence, nausea, vomiting, diarrhea, and anxiety. In patients receiving lurasidone HCl as adjunctive therapy with lithium or valproate, the most common adverse reactions were akathisia and somnolence. n References

1. Mayo Clinic staff. Diseases and conditions: bipolar disorder. January 18, 2012. www.mayoclinic.com/health/bipolar-disorder/DS00356. Accessed August 26, 2013. 2. National Institute of Mental Health. The numbers count: mental disorders in America. www.nimh.nih.gov/health/publications/the-numbers-count-mental-disordersin-america/index.shtml#Bipolar. Accessed August 27, 2013. 3. Centers for Disease Control and Prevention. Burden of mental illness. Updated July 1, 2011. www.cdc.gov/mentalhealth/basics/burden.htm. Accessed August 28, 2013. 4. Sagman D, Tohen M. Comorbidity in bipolar disorder. March 23, 2009. Psychiatr Times. www.psychiatrictimes.com/bipolar-disorder/comorbidity-bipolar-disorder/page/ 0/1?_EXT_4_pageNumber=3&_EXT_4_comsort=of. Accessed August 28, 2013. 5. Hirschfeld RM, Vornik LA. Bipolar disorder—costs and comorbidity. Am J Manag Care. 2005;11(3 suppl):S85-S90. 6. Wyatt RJ, Henter I. An economic evaluation of manic-depressive illness—1991. Soc Psychiatry Psychiatr Epidemiol. 1995;30:213-219. 7. Dilsaver SC. An estimate of the minimum economic burden of bipolar I and II disorders in the United States: 2009. J Affect Disord. 2011;129:79-83. 8. Latuda (lurasidone hydrochloride) tablets [prescribing information]. Marlborough, MA: Sunovion Pharmaceuticals Inc; July 2013. 9. Lowes R. Lurasidone approved for bipolar depression. Medscape. July 1, 2013. www. medscape.com/viewarticle/807204. Accessed August 26, 2013.

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Nesina, Kazano, and Oseni: Three

Alogliptin-Based Agents Approved for the Treatment of Type 2 Diabetes

By Loretta Fala, Medical Writer

iabetes affects an estimated 25.8 million people in the United States—a staggering 8.3% of the population.1 Type 2 diabetes accounts for 90% to 95% of all adult cases of diabetes.1 In addition, an estimated 35% of US adults aged ≥20 years have prediabetes, and the prevalence of prediabetes jumps to 50% in adults aged ≥65 years.1 The number of people with diabetes is projected to rise dramatically over the next few decades, from approximately 1 in 10 adults today to as many as 1 in 3 by 2050.2 This increased prevalence is attributed to the aging population, the increasing number of high-risk groups, and a longer life expectancy for patients with diabetes.2 In addition to being the seventh leading cause of mortality in the United States, diabetes is associated with serious morbidities, including cardiovascular disease, stroke, and nervous system damage.1 It is also the leading cause of kidney failure, nontraumatic lower-limb amputations, and new cases of blindness in adults.1

Economic Burden In 2012, diabetes accounted for an estimated $245 billion in total costs in the United States, including $176 billion in direct medical costs and $69 billion in indirect costs (ie, disability and lost or reduced productivity).3 Hospital inpatient care accounted for the largest portion (43%) of the total medical expenses. Patients with diagnosed diabetes incurred an average of $13,700 annually in medical expenditures, of which $7900 was attributed directly to diabetes.3 Overall, medical expenditures for patients with diabetes are 2.3 times higher than expenditures for persons without diabetes, with more than 1 in 5 healthcare dollars in the United States attributed to diabetes.3 Healthcare costs are expected to increase as the prevalence of diabetes rises in subsequent years. By the year 2034, the annual costs attributed to diabetes are projected to reach $336 billion (in 2007 US dollars).4 Glycemic Control Improvements in glycemic control have been shown to benefit patients with diabetes.5 In fact, every 1% reduction in hemoglobin (Hb) A1c is correlated with a Vol 7

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35% decrease in microvascular complications associated with diabetes.5 A 1% reduction in HbA1c is also linked to a 15% relative risk reduction in nonfatal myocardial infarction, although this benefit does not extend to stroke or to all-cause mortality.6 In a 2012 position statement, the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) reinforced the importance of a patient-centered approach to managing hyperglycemia in type 2 diabetes.6 The ADA and EASD also emphasize the role of diet, exercise, and education as the hallmarks of type 2 diabetes treatment. Other recommendations include tailoring glycemic targets and glucose therapies to the individual patient and engaging patients in healthcare decisions—an approach that may improve adherence to treatment.6 For initial treatment of patients with type 2 diabetes, the ADA and EASD recommend lifestyle changes (ie, healthy eating, weight control, increased physical activity) and metformin monotherapy.6 If the target A1c goal is not achieved within 3 months, a 2-drug combination therapy with metformin plus one of the following agents is recommended: a sulfonylurea, a thiazolidinedione, a dipeptidyl peptidase (DPP)-4 inhibitor, a glucagon-like peptide (GLP)-1 receptor agonist, or insulin (usually basal).6 If an individualized A1c target is not achieved after 3 months, a 3-drug combination is recommended; and if the target A1c is not achieved after 3 to 6 months, a more complex insulin strategy is warranted, usually in combination with 1 or 2 noninsulin agents.6

Three New Agents for Type 2 Diabetes On January 25, 2013, the US Food and Drug Administration (FDA) approved 3 new oral agents for use with diet and exercise to improve glycemic control in adults with type 2 diabetes—alogliptin (Nesina; Takeda Pharmaceuticals), alogliptin/metformin hydrochloride (Kazano; Takeda Pharmaceuticals), and alogliptin/pioglitazone (Oseni; Takeda Pharmaceuticals).7 (Metformin and pioglitazone have been previously approved by the FDA for the management of type 2 diabetes.) All 3 agents contain the new DPP-4 inhibitor alogliptin, and none of

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logliptin versus Placebo: Glycemic Parameters at Table 1 A Week 26 Alogliptin 25-mg cohort

Placebo cohort

(N = 128)

(N = 63)

7.9

8.0

–0.6

Difference from placebo (adjusted meana with 95% confidence interval)

–0.6b (–0.8 to –0.3)

—

% of patients who achieved A1c ≤7%

(N = 129)

(N = 64)

Mean baseline

172

173

Change from baseline (adjusted meana)

–16

–28b (–40 to –15)

—

Glycemic parameters A1c, % Mean baseline A1c Change from baseline (adjusted meana)

Fasting plasma glucose, mg/dL

Difference from placebo (adjusted meana with 95% confidence interval)

Least squares means adjusted for treatment, baseline value, geographic region, and disease duration. b P <.01 versus placebo. Source: Nesina (alogliptin) tablets prescribing information; 2013. a

dverse Reactions in ≥4% of Patients Receiving Alogliptin Table 2 A 25 mg and More Often than in Patients Receiving Placebo Alogliptin 25 mg, N (%) (N = 5902)

Placebo, N (%) (N = 2926)

Active comparator, N (%) (N = 2257)

Nasopharyngitis

257 (4.4)

89 (3.0)

113 (5.0)

Headache

247 (4.2)

72 (2.5)

121 (5.4)

Upper respiratory tract infection

247 (4.2)

61 (2.1)

113 (5.0)

Adverse reactions

Source: Nesina (alogliptin) tablets prescribing information; 2013.

them is indicated for the treatment of patients with type 1 diabetes or with diabetic ketoacidosis.8-11 Nesina is the single alogliptin agent; Kazano is a fixeddose combination of alogliptin and metformin, a biguanide; and Oseni is a fixed-dose combination of alogliptin and pioglitazone, a thiazolidinedione.7 According to Mary Parks, MD, Director of the Division of Metabolism and Endocrinology Products in the FDA’s Center for Drug Evaluation and Research, “Controlling blood sugar levels is very important in the overall treatment and care of diabetes. Alogliptin helps stimulate the release of insulin after a meal, which leads to better blood sugar control.”7

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Nesina (alogliptin) Dosing Alogliptin (Nesina) is an oral tablet available in 3 strengths—25 mg, 12.5 mg, and 6.25 mg. The recommended dose for patients with normal renal function or with mild renal impairment is 25 mg once daily. Alogliptin can be taken with or without food. If the patient has moderate or severe renal impairment, the dose should be adjusted.9 Mechanism of Action Alogliptin is a DPP-4 inhibitor that slows the inactivation of the incretin hormones GLP-1 and glucose-dependent insulinotropic polypeptide, thereby increasing their bloodstream concentrations in a glucose-dependent manner in patients with type 2 diabetes. Alogliptin selectively binds to and inhibits DPP-4 (but not DPP-8 or DPP-9) activity in vitro at concentrations approximating therapeutic exposures.9 Clinical Studies The FDA approval of alogliptin as monotherapy (Nesina) was based on safety and efficacy data from 14 clinical studies with approximately 8500 patients with type 2 diabetes.7 With its approval, the FDA required 5 postmarketing studies for alogliptin—1 a cardiovascular outcomes trial; 2 enhanced pharmacovigilance programs to monitor liver abnormalities, serious cases of pancreatitis, and severe hypersensitivity reactions; and 2 pediatric safety and efficacy studies under the Pediatric Research Equity Act.7 The safety and efficacy of alogliptin as monotherapy were evaluated in a 26-week, double-blind, placebo-controlled study in patients with type 2 diabetes inadequately controlled with diet and exercise. Treatment with alogliptin 25 mg demonstrated statistically significant improvements from baseline in A1c and fasting plasma glucose compared with placebo at week 26 (Table 1).9 Adverse Events The most common adverse reactions reported in ≥4% of patients receiving alogliptin 25 mg that were also more frequent than in the placebo arm were nasopharyngitis, headache, and upper respiratory tract infection (Table 2).9 In clinical trials that compared alogliptin and placebo, adverse events included acute pancreatitis (0.2% vs <0.1%, respectively), hypersensitivity (0.6% vs 0.8%, respectively), and hypoglycemia (1.5% vs 1.6%, respectively). Table 3 outlines the warnings and precautions associated with the use of alogliptin based on clinical trials, as well as postmarketing studies. Contraindications Alogliptin is contraindicated in patients with a histo-

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Table 3 Warnings and Precautions: Alogliptin Alone, Alogliptin/Metformin, and Alogliptin/Pioglitazone Warnings and precautions Acute pancreatitis

Alogliptin

Alogliptin/ Alogliptin/ metformin pioglitazone

Acute pancreatitis cases have been reported postmarketing If pancreatitis is suspected, promptly discontinue treatment Hypersensitivity

√

Serious hypersensitivity reactions have been reported postmarketing, including anaphylaxis, angioedema, and severe cutaneous adverse reactions: in such cases, promptly discontinue treatment with agents noted, assess for other potential causes, institute appropriate monitoring and treatment, and initiate alternative antidiabetes therapies

√

Hepatic failure cases, sometimes fatal, have been reported postmarketing; causality cannot be excluded If liver injury is detected, promptly interrupt treatment with these agents and assess patient for probable cause, then treat the cause, if possible, to resolution or to stabilization Do not restart agents noted if liver injury is confirmed and no alternative etiology can be found Hypoglycemia

√

When used with an insulin secretagogue (eg, sulfonylurea) or with insulin, a lower dose of the insulin secretagogue or insulin may be required to mimimize the risk of hypoglycemia when used in combination with any of these 3 agents Macrovascular outcomes

√

No clinical studies have established conclusive evidence of macrovascular risk reduction with any of these 3 agents or with any other antidiabetic drug

√

Hepatic effects

Additional warnings and precautions for alogliptin/metformin Lactic acidosis Patients should be warned against excessive alcohol intake Alogliptin/metformin is not recommended in patients with hepatic impairment Alogliptin/metformin is contraindicated in renal impairment Vitamin B12 deficiency

√

Metformin may lower vitamin B12 levels Monitor hematologic parameters annually Radiologic studies

√

Alogliptin/metformin should be temporarily discontinued in patients undergoing radiologic studies with intravascular administration of iodinated contrast materials or any surgical procedures necessitating restricted intake of food and fluids

√

Additional warnings for alogliptin/pioglitazone Congestive heart failure Fluid retention may occur and can exacerbate or lead to congestive heart failure Combination use with insulin and use in patients with NYHA stage I or II congestive heart failure may increase risk Monitor patients for signs and symptoms of congestive heart failure Edema

√

Dose-related edema may occur Fractures Increased incidence of fractures in female patients has been reported Current standards of care for assessing and maintaining bone health should be applied

√

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Table 3 Warnings and Precautions: Alogliptin Alone, Alogliptin/Metformin, and Alogliptin/Pioglitazone (Continued) Warnings and precautions Bladder cancer

Alogliptin/ Alogliptin/ metformin pioglitazone

Alogliptin

Preclinical and clinical trial data, and results from an observational study suggest an increased risk of bladder cancer in pioglitazone users The observational data further suggest an increased risk with duration of use Alogliptin/pioglitazone should not be used in patients with active bladder cancer, and used with caution in patients with a history of bladder cancer Macular edema

√

Macular edema has been reported in some patients taking pioglitazone Regular eye exams are recommended, with prompt evaluation for acute visual changes Ovulation

√

Therapy with pioglitazone, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women

√

NYHA indicates New York Heart Association. Sources: Nesina (alogliptin) tablets prescribing information; 2013. Kazano (alogliptin and metformin) tablets prescribing information; 2013. Oseni (alogliptin and pioglitazone) tablets prescribing information; 2013.

ry of a serious hypersensitivity reaction to alogliptin- containing products, including anaphylaxis, angioedema, or severe cutaneous adverse reactions. Alogliptin is not associated with a boxed warning.

Kazano (alogliptin/metformin) Dosing Alogliptin/metformin (Kazano) is an oral tablet available in 2 strengths—alogliptin 12.5 mg/metformin 500 mg, and alogliptin 12.5 mg/metformin 1000 mg. The starting dose of alogliptin/metformin is individualized based on the patient’s current regimen. Alogliptin/ metformin is taken twice daily with food. Dosing may be adjusted based on effectiveness and tolerability, without exceeding the maximum recommended daily dose of alogliptin 25 mg/metformin 2000 mg.8 Mechanism of Action The combination of alogliptin and metformin hydrochloride—2 antihyperglycemic agents with complementary and distinct mechanisms of action—improves glycemic control in patients with type 2 diabetes.8 The alogliptin mechanism of action was discussed earlier in this article. Metformin is a biguanide that improves glucose tolerance in patients with type 2 diabetes, lowering basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Metformin does not produce hypoglycemia in patients with type 2 diabetes or in healthy persons, except in special circumstances, and does not cause hyperinsulinemia. With

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metformin therapy, insulin secretion remains unchanged and fasting insulin levels and day-long plasma insulin response may actually decrease.8

Clinical Studies The FDA approval of alogliptin/metformin was based on 4 clinical studies in more than 2500 patients with type 2 diabetes.7 The FDA required that 2 postmarketing studies be conducted with alogliptin/metformin to monitor for liver abnormalities, serious cases of pancreatitis, and severe hypersensitivity reactions through an enhanced pharmacovigilance program. A pediatric safety and efficacy study under the Pediatric Research Equity Act was also required by the FDA.7 A 26-week, double-blind, placebo-controlled study assessed the safety and efficacy of alogliptin/metformin coadministration in patients whose type 2 diabetes was inadequately controlled with diet and exercise alone. A total of 784 patients (mean baseline A1c, 8.4%) were randomized to 1 of 7 treatment groups. Significant improvements in A1c levels were demonstrated in the 2 combination treatment arms—alogliptin 12.5 mg/metformin 500 mg, and alogliptin 12.5 mg/ metformin 1000 mg compared with the respective individual component regimens of alogliptin alone and metformin alone (Table 4). Significant improvements in fasting plasma glucose were also demonstrated in the 2 treatment arms of alogliptin/ metformin versus the respective individual component regimens of each drug alone (Table 4).8 In a 26-week, double-blind, placebo-controlled study, 527 patients already receiving metformin (mean baseline A1c, 8%) were randomized to receive alogliptin 12.5 mg,

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Table 4 Glycemic Parameters: Alogliptin, Metformin, and Alogliptin/Metformin Combination, at Week 26 Alogliptin/metformin

Glycemic parameters

Placebo

A1c, %

Alogliptin 12.5 mg twice daily

(N = 102) (N = 104)

Metformin 500 mg 1000 mg twice daily twice daily

Alogliptin 12.5 mg/ Alogliptin 12.5 mg/ metformin 500 mg metformin 1000 mg twice daily twice daily

(N = 103)

(N = 108)

(N = 102)

(N = 111)

Mean baseline A1c

8.5

8.4

8.5

8.4

8.5

8.4

Change from baseline (adjusted meanb)

0.1

–0.6

–0.7

–1.1

–1.2

–1.6

Difference from metformin (adjusted meanb with 95% CI)

—

–0.6c (–0.9 to –0.3)

–0.4c (–0.7 to –0.2)

Difference from alogliptin (adjusted meanb with 95% CI)

—

–0.7c (–1.0 to –0.4)

–1.0c (–1.3 to –0.7)

% of patients who achieved A1c ≤7%d

47c

59c

Fasting plasma glucose, g/dLa

(N = 106)

(N = 110)

(N = 106)

(N = 112)

187

177

180

181

176

185

Change from baseline (adjusted meanb)

–10

–12

–32

–46

Difference from metformin (adjusted meanb with 95% CI)

—

–20c (–33 to –8)

–14c (–26 to –2)

Difference from alogliptin (adjusted meanb with 95% CI)

—

–22c (–35 to –10)

–36c (–49 to –24)

Mean baseline

(N = 105) (N = 106)

a Intent-to-treat population using the last observation on study before discontinuation of double-blind study medication or sulfonylurea rescue therapy for patients needing rescue. b Least squares means adjusted for treatment, geographic region, and baseline value. c P <.05 compared with metformin and alogliptin alone. d Compared using logistic regression. CI indicates confidence interval. Source: Kazano (alogliptin and metformin) tablets prescribing information; 2013.

alogliptin 25 mg, or placebo once daily. During the treatment period, patients continued to use a stable dose of metformin (median daily dose, 1700 mg). Alogliptin 25 mg in combination with metformin showed statistically significant improvements from baseline in A1c and fasting plasma glucose levels at week 26 compared with placebo (Table 5).8 A 52-week study with 803 patients showed that alogliptin 25 mg, in combination with pioglitazone and metformin, was statistically superior in lowering A1c and fasting plasma glucose levels compared with the titration of pioglitazone from 30 mg to 45 mg at week 26 and at week 52 in patients whose disease was inadequately controlled with pioglitazone 30 mg and metformin.8

Adverse Events The most common adverse reactions reported in clinical trials in ≥4% of patients using alogliptin/metformin were upper respiratory tract infection, nasopharyngitis, diarrhea, hypertension, back pain, and urinary tract infection.8 Table 3 lists the warnings and precautions

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associated with alogliptin/metformin, based on clinical studies, as well as in postmarketing studies.

Boxed Warning Alogliptin/metformin was approved with a boxed warning about lactic acidosis, a rare but serious complication that can occur from metformin accumulation. The risk increases with conditions such as sepsis, dehydration, excess alcohol intake, hepatic impairment, renal impairment, and acute congestive heart failure. If acidosis is suspected, alogliptin/metformin should be discontinued and the patient should be hospitalized immediately. Contraindications Alogliptin/metformin is contraindicated in patients with renal impairment; normal renal function should be verified before initiating treatment with this medication, and at least annually thereafter. The use of alogliptin/metformin is also contraindicated in patients with metabolic acidosis, including diabetic ketoacidosis.

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lycemic Parameters at Week 26: Alogliptin as Table 5 G Add-on to Metformin Glycemic parameters A1c, % Mean baseline A1c Change from baseline (adjusted meana)

Alogliptin 25 mg + metformin

Placebo + metformin

(N = 203)

(N = 103)

7.9

8.0

–0.6

–0.1

Difference from metformin (adjusted meana with 95% confidence interval)

–0.5b (–0.7 to –0.3)

—

Difference from placebo (adjusted meana with 95% confidence interval)

—

% of patients who achieved A1c ≤7%

44b

(N = 204)

(N = 104)

Mean baseline

172

180

Change from baseline (adjusted meana)

–17

–17b (–26 to –9)

—

Fasting plasma glucose, mg/dL

Difference from placebo (adjusted meana with 95% confidence interval)

Least squares means adjusted for treatment, baseline value, geographic region, and baseline metformin dose. b P <.001 compared with placebo. Source: Kazano (alogliptin and metformin) tablets prescribing information; 2013. a

In addition, alogliptin/metformin is contraindicated in patients with a history of a serious hypersensitivity reaction to alogliptin or to metformin (the components of alogliptin/ metformin), such as anaphylaxis, angioedema, or severe cutaneous adverse reactions.

Oseni (alogliptin/pioglitazone) Dosing Alogliptin/pioglitazone (Oseni) is an oral tablet available in several strengths: alogliptin 25 mg/pioglitazone 15 mg, alogliptin 25 mg/pioglitazone 30 mg, alogliptin 25 mg/pioglitazone 45 mg, alogliptin 12.5 mg/pioglitazone 15 mg, alogliptin 12.5 mg/pioglitazone 30 mg, and alogliptin 12.5 mg/pioglitazone 45 mg. The starting dose of alogliptin/pioglitazone should be individualized based on the patient’s current regimen and concurrent medical condition but should not exceed a daily dose of alogliptin 25 mg and pioglitazone 45 mg. Alogliptin/pioglitazone can be taken with or without food. In patients with New York Heart Association (NYHA) class I or II heart failure, the initial dose of pio glitazone should be limited to 15 mg once daily. In patients with moderate renal impairment, the dose

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of alogliptin/pioglitazone should be adjusted. Alogliptin/ pioglitazone is not recommended for patients with severe renal impairment or with end-stage renal disease that requires dialysis. In patients taking strong cytochrome (CY)P2C8 inhibitors (eg, gemfibrozil), the maximum recommended dose of pioglitazone is 15 mg once daily.10

Mechanism of Action The combination of 2 antihyperglycemic agents— alogliptin and pioglitazone—with 2 complementary and distinct mechanisms of action improves glycemic control in patients with type 2 diabetes.10 The alogliptin mechanism of action was discussed earlier. Pioglitazone, a thiazolidinedione, is an agonist for peroxisome proliferator-activated receptor gamma; activation of these nuclear receptors modulates the transcription of a number of insulin-responsive genes involved in the control of glucose and lipid metabolism.10 Clinical Studies The FDA approval of alogliptin/pioglitazone (Oseni) was based on 4 clinical studies in more than 1500 patients with type 2 diabetes.7 The FDA required an enhanced pharmacovigilance program for alogliptin/pioglitazone to monitor for liver abnormalities, serious cases of pancreatitis, and severe hypersensitivity reactions.7 Based on a 26-week, double-blind, active-controlled study of 655 patients whose disease was inadequately controlled with diet and exercise alone, the coadministration of alogliptin 25 mg with pioglitazone 30 mg showed a significant improvement from baseline in A1c and fasting plasma glucose compared with alogliptin 25 mg alone or with pioglitazone 30 mg alone (Table 6).10 In a 26-week, double-blind, placebo-controlled study, 1554 patients already receiving metformin (mean baseline A1c, 8.5%) were randomized to 1 of 12 groups—placebo; alogliptin alone (12.5 mg or 25 mg); pioglitazone alone (15 mg, 30 mg, or 45 mg); or alogliptin (12.5 mg or 25 mg) in combination with 15 mg, 30 mg, or 45 mg of pioglitazone. During the treatment period, patients continued to take a stable dose of metformin (median daily dose, 1700 mg). When added to metformin, the coadministration of alogliptin and pioglitazone showed significant improvements from baseline in A1c and fasting plasma glucose levels at week 26 compared with placebo, with alogliptin alone, or with pioglitazone alone.10 In a 52-week study of 803 patients, adding alogliptin 25 mg to pioglitazone used in combination with metformin was statistically superior in lowering A1c and fasting plasma glucose levels compared with the titration of pioglitazone from 30 mg to 45 mg at weeks 26 and 52 in patients whose disease was inadequately controlled with pioglitazone 30 mg plus metformin.10

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Adverse Events The most common adverse reactions reported in ≥4% of patients receiving coadministration of alogliptin 25 mg and pioglitazone 15 mg, 30 mg, or 45 mg in clinical trials were nasopharyngitis, back pain, and upper respiratory tract infection.10 Table 3 provides additional safety information, including the warnings and precautions associated with the use of alogliptin/pioglitazone, based on clinical trials, and in postmarketing studies. Boxed Warning Alogliptin/pioglitazone was approved with a boxed warning, stating that thiazolidinediones, including pio glitazone, cause or exacerbate congestive heart failure in some patients. In addition, alogliptin/pioglitazone should be used with caution in patients with liver disease. Contraindications Alogliptin/pioglitazone is contraindicated in patients with a serious hypersensitivity reaction to alogliptin or pioglitazone, such as anaphylaxis, angioedema, or severe cutaneous adverse reactions. Alogliptin/pioglitazone is also contraindicated in patients with established NYHA class III or IV heart failure. Conclusion Three new oral treatment options for type 2 diabetes became available in 2013 with the FDA approval of alogliptin alone, alogliptin in combination with metformin, and alogliptin in combination with pioglitazone. These 3 independent agents are indicated as adjuncts to diet and exercise to improve glycemic control in patients with type 2 diabetes. They are not indicated for use in patients with type 1 diabetes or with diabetic ketoacidosis. Each of these 3 medications has unique benefits and potential adverse events and contraindications, based on the individual components of the specific medication. All 3 agents contain alogliptin, a novel DPP-4 inhibitor, with a positive safety profile. Of these new agents, the novel fixed-dose combination of alogliptin plus pioglit azone is the first treatment option in the United States to include a DPP-4 inhibitor and a thiazolidinedione in a single tablet,11 providing patients with type 2 diabetes a new approach to glycemic control. In clinical studies that evaluated the efficacy of alogliptin alone, alogliptin/metformin combination, and alogliptin/ pioglitazone combination plus other type 2 diabetes treatments, all 3 agents demonstrated clinically meaningful and significant improvements in patients’ HbA1c levels versus comparators in patients with type 2 diabetes. n References

1. Centers for Disease Control and Prevention. National diabetes fact sheet: national estimates and general information on diabetes and prediabetes in the United States,

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lycemic Parameters at Week 26: Alogliptin and Table 6 G Pioglitazone Coadministration

Glycemic parameters

Alogliptin 25 mg + Alogliptin Pioglitazone pioglitazone 25 mg 30 mg 30 mg

A1c, %

(N = 160)

(N = 153)

(N = 158)

Mean baseline A1c

8.8

Change from baseline (adjusted meana)

–1

–1.2

–1.7

Difference from alogliptin 25 mg (adjusted meana with 95% CI)

–0.8b (–1 to –0.5)

Difference from pioglitazone 30 mg (adjusted meana with 95% CI)

–0.6b (–0.8 to –0.3)

% of patients who achieved A1c ≤7%

63b

Fasting plasma glucose, mg/dL

(N = 162)

(N = 157)

(N = 162)

Mean baseline

189

185

Change from baseline (adjusted meana)

–26

–37

–50

Difference from alogliptin 25 mg (adjusted meana with 95% CI)

–25b (–34 to –15)

Difference from pioglitazone 30 mg (adjusted meana with 95% CI)

–13b (–22 to –4)

Least squares means adjusted for treatment, geographic region, and baseline value. b P <.01 compared with alogliptin 25 mg or pioglitazone 30 mg. CI indicates confidence interval. Source: Oseni (alogliptin and pioglitazone) tablets prescribing information; 2013. a

2011. 2011. www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf. Accessed April 15, 2013. 2. Boyle JP, Thompson TJ, Gregg EW, et al. Projection of the year 2050 burden of diabetes in the US population: dynamic modeling of incidence, mortality, and prediabetes prevalence. Popul Health Metr. 2010;8:29. 3. American Diabetes Association. Economic costs of diabetes in the US in 2012. Diabetes Care. 2013;36:1033-1046. 4. Huang ES, Basu A, O’Grady M, Capretta JC. Projecting the future diabetes population size and related costs for the US. Diabetes Care. 2009;32:2225-2229. 5. American Diabetes Association. Implications of the United Kingdom Prospective Diabetes Study. Diabetes Care. 1998;21:2180-2184. 6. Inzucchi SE, Bergenstal RM, Buse JB, et al; American Diabetes Association (ADA), European Association for the Study of Diabetes (EASD). Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2012;35:1364-1379. Erratum in Diabetes Care. 2013;36:490. 7. US Food and Drug Administration. FDA approves three new drug treatments for type 2 diabetes. News release; January 25, 2013. Updated January 28, 2013. www.fda.gov/News Events/Newsroom/PressAnnouncements/ucm336942.htm. Accessed April 16, 2013. 8. Kazano (alogliptin and metformin HCl) tablets [prescribing information]. Deerfield, IL: Takeda Pharmaceuticals America, Inc; 2013. 9. Nesina (alogliptin) tablets [prescribing information]. Deerfield, IL: Takeda Pharmaceuticals America, Inc; 2013. 10. Oseni (alogliptin and pioglitazone) tablets [prescribing information]. Deerfield, IL: Takeda Pharmaceuticals America, Inc; 2013. 11. Nordqvist J. Three type 2 diabetes pills from Takeda approved by FDA. Medical News Today. January 27, 2013. www.medicalnewstoday.com/articles/255487.php. Accessed April 15, 2013.

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Otrexup (Methotrexate) Injection: Novel

Methotrexate Delivery System for Patients with Rheumatoid Arthritis By Lisa A. Raedler, PhD, RPh, Medical Writer

heumatoid arthritis (RA) is a chronic, systemic autoimmune disease that affects at least 1.3 million adults in the United States.1 Symptoms include pain, stiffness, swelling, and limited motion and function of many joints, particularly the small joints in the hands and feet.1 A diagnosis of RA is made on the basis of symptoms, physical examination results, and blood tests that are positive for anemia, rheumatoid factor, antibodies, and elevated erythrocyte sedimentation rate.1 Continued inflammation of the synovium can lead to cartilage and bone damage.1,2 Although the etiology of RA is unknown, there is an association with genetic factors and environmental exposures.2 Risk factors include smoking, reproductive hormone exposures, dietary factors, and microbial exposure, as well as having human leukocyte antigen class II genotypes (eg, DR4 and DRB1 molecules).2 In addition to affecting the functioning and quality of life of patients, RA exacts a heavy economic toll on patients, employers, and payers. A recent study highlights the significant cost borne by American workers who live with RA and their employers.3 The research was conducted using a database of US employees’ administrative healthcare and payroll data for individuals enrolled in an employer-sponsored insurance plan for at least 1 year.3 Compared with employees who do not have RA, an employee with RA incurs approximately $5200 more in annual healthcare costs.3 Workers with RA also pay an average of $1500 more per person for prescription medications annually, and are absent from work approximately 3.5 more days annually.3 On the whole, patients with RA cost their employers across the United States approximately $5.8 billion annually.3 Today’s treatment of RA is symptom-based and often requires a combination of agents.1 Typically, therapy begins with disease-modifying antirheumatic drugs (DMARDs), such as methotrexate, leflunomide, hydroxychloroquine, or sulfasalazine.1 DMARDs are administered along with nonsteroidal anti-inflammatory drugs (NSAIDs) and/or low-dose corticosteroids to reduce swelling, pain, and fever.1 The treatment course for more serious cases of RA

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includes biologic agents, which are also considered DMARDs, that target specific aspects of the immune system.1 These drugs include abatacept (Orencia), ada limumab (Humira), anakinra (Kineret), certolizumab (Cimzia), etanercept (Enbrel), golimumab (Simponi), infliximab (Remicade), rituximab (Rituxan), and toci lizumab (Actemra). The most recently approved agent for RA in adults, tofacitinib (Xeljanz), is an oral inhibitor of Janus kinase–mediated cell signaling.4 As unique biomarkers, genetic defects, and drug targets are identified, the development of novel RA agents continues. A recent genome-wide association study identified 42 new genes that confer the risk for RA at a genome-wide level of significance, bringing the total of known RA risk genes to 101.5 Although many current RA therapies target these genes, these findings suggest that drugs that are currently approved for other indications may be repurposed for use in patients with RA.5 Other novel targeting agents, including inhibitors of granulocyte-macrophage colony-stimulating factor receptors, have been shown to suppress cytokine responses in patients with RA.6

Otrexup: Novel Delivery of Methotrexate In October 2013, the US Food and Drug Administration (FDA) approved the first methotrexate injection (MTXI) for subcutaneous (SC) use (Otrexup; Antares Pharma).7 This once-weekly self-administered injection is indicated for adults with severe active RA who have had inadequate response to or are intolerant of first-line therapy.7 MTXI was also approved for use in children with active polyarticular juvenile idiopathic arthritis.7 The approval of MTXI was based on the demonstration of bioavailability in a 12-week, open-label, crossover study comparing the relative bioavailability of MTXI with oral methotrexate.8 Data from this study were presented at the 2013 annual meeting of the American College of Rheumatology. Originally developed as an oncology drug, methotrexate has become a cornerstone in the treatment of RA.9 In a recent interview regarding his experience in the study of MTXI, Michael Schiff, MD, Clinical Professor

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of Medicine in the Division of Rheumatology at the University of Colorado, stated, “This new delivery system for methotrexate provides a welcome option for physicians and their patients to continue effective use of methotrexate….The availability of an easy and safe way to administer subcutaneous methotrexate may…enable more patients to realize the possibility of continued disease control.”7 The use of parenteral methotrexate for the treatment of RA is less popular as a result of the challenges related to self-administration. Patients with RA may have compromised manual dexterity, needle phobia, and/or a lack of confidence in safely self-injecting with a vial, a needle, or a syringe, which can be barriers to use.7 Kevin Deane, MD, of the Division of Rheumatology at the University of Colorado stated, “Injectable [methotrexate] to date has come in a large vial, and [the] patient draws up medication and injects it.... Drawing up and administering this medication may be somewhat difficult for some patients to do, especially with arthritic conditions.”10

Mechanism of Action Methotrexate, an inhibitor of dihydrofolic acid reductase, interferes with DNA synthesis, repair, and cellular replication.11 Cells that are actively proliferating are particularly susceptible to these effects. The mechanism of action of methotrexate in RA is unknown. It may work by altering immune function.11 Dosing and Administration MTXI is a single-dose, easy-to-use autoinjector for once-weekly SC use.11 It is available in doses ranging from 10 mg to 25 mg in 5-mg increments and is administered in the abdomen or thigh.11 The MTXI dose can be adjusted gradually for optimal outcomes. Therapeutic response to methotrexate is usually seen within 3 to 6 weeks and continues for 12 weeks or more.11 The optimal duration of MTXI therapy is unknown.11 Healthcare professionals should ensure that patients understand that MTXI is administered once weekly. The daily use of methotrexate has resulted in fatal toxicity.11 Clinical Trials Bioavailability Study The bioavailability of MTXI was assessed in an open-label, crossover study in which 49 adults with RA who had been receiving methotrexate for 3 months or more were given 10 mg, 15 mg, 20 mg, or 25 mg of methotrexate.8 They were randomized to receive either oral methotrexate, MTXI injected in the abdomen, or MTXI injected in the thigh.8 Blood samples were collected for analysis before the drug’s administration and at 13 time

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elative Bioavailability of Subcutaneous Methotrexate Table 1 R versus Oral Methotrexate MTXI dose, mg Relative bioavailability, % 10

121

114

131

141

MTXI indicates methotrexate injection. Source: Schiff MH, et al. Arthritis Rheum. 2013;65(10 suppl):S337S338.

points of 15 minutes to 12 hours after drug administration.8 The average age of patients with RA who enrolled in the bioavailability study was 61 years and they had been diagnosed with RA for an average of 13 years.8 Their mean body mass index was 30.7 kg/m2.8 Pharmacokinetic parameters of interest included the area under the plasma concentration time curve (AUC), the maximum drug concentration, and the time of occurrence for maximum drug concentration. Safety was determined using the incidence of treatment-emergent adverse events (AEs), including injection-site reactions, as well as by monitoring laboratory parameters and vital signs.8 The analysis of pharmacokinetic parameters demonstrated that 4 hours after administration, the bioavailability of MTXI (administered in the thigh) was consistently greater than oral methotrexate at all dose levels (10-25 mg).8 At doses of 10 mg, 15 mg, 20 mg, and 25 mg, the relative bioavailability calculations (AUC of MTXI vs oral methotrexate) were 121%, 114%, 131%, and 141%, respectively, as summarized in Table 1.8 No bioavailability plateau was seen for MTXI, whereas the bioavailability of oral methotrexate plateaued at a dose of 15 mg.8

“The availability of an easy and safe way to administer subcutaneous methotrexate may…enable more patients to realize the possibility of continued disease control.” Phase 2 Clinical Trial A phase 2, multicenter, open-label, single-dose, single-arm, in-clinic study enrolled 101 adults with RA to evaluate the ease of use of MTXI.12 The autoinjected product was tested with the intention of addressing the concerns of patients with RA regarding self-administering methotrexate using a conventional vial and syringe.12 The patients in the trial received MTXI at a dose of 10 mg, 15 mg, 20 mg, or 25 mg weekly.12 Dosing was

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determined by investigators based on each patient’s previous methotrexate regimen and disease status (ie, controlled or uncontrolled) at the time of study enrollment. Of the 101 patients enrolled, 99 patients were evaluable.12 Most patients (79%) were female, with an average age of 61 years.12 These patients had been diagnosed with RA for an average of 13 years.12 All patients had received methotrexate for at least 3 months before enrolling in the study.12 Overall, 20% of patients had received SC methotrexate, and their functional status ranged from mild to severe; 89% were in American College of Rheumatology Functional Class II or III.12

Of the 99 evaluable patients, 94% reported VAS scores of ≤10 on day 1, and 87% had scores of ≤5 on day 1. All 99 patients handled the autoinjector successfully. The primary outcome measure in this phase 2 trial of MTXI was pain associated with SC administration as measured using a 100-mm visual analog scale (VAS).12 The administration sites were evaluated before administration and at 15 minutes, 1 hour, 6 hours, and 24 hours after self-administration.12 The mean administration-site pain ratings for all enrolled patients (N = 101) were 3.6 on day 1 and 1.4 on day 2 (standard deviations, ±9.1 and ±3.2, respectively).12 Of the 99 evaluable patients, 94% reported VAS scores of ≤10 on day 1, and 87% had scores of ≤5 on day 1.12 All 99 patients handled the autoinjector successfully.12 Of 404 skin sites that were evaluated after MTXI administration, 92% reported no erythema, with the balance showing “very slight, barely perceptible” erythema.12 Three patients experienced AEs while taking MTXI, including sick sinus syndrome, exostosis, and headache.12 None of these was considered to be related to the study drug.12

Safety Methotrexate and MTXI were safe and well tolerated in the bioavailability study.8 The few AEs that were observed with MTXI were deemed transient and manageable. None required medical treatment.8 Two serious AEs were deemed unrelated to treatment, including 1 death from myocardial infarction in a 79-year-old man with a history of heart disease.8 Contraindications MTXI is contraindicated in pregnant women, nursing mothers, patients with alcoholism or liver disease, patients with immunodeficiency syndromes, patients with

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preexisting blood dyscrasias, and patients with hypersensitivity to methotrexate.11

Warnings and Precautions Boxed warning. Like the oral formulation of methotrexate, MTXI labeling includes a boxed warning for multiple safety risks, including embryo-fetal toxicity and death.11 These warnings include11: • Serious toxic reactions and death; patients taking methotrexate should be closely monitored for bone marrow, liver, lung, skin, and kidney toxicities • Fetal death and congenital anomalies; methotrexate is contraindicated in pregnancy • Unexpectedly severe and sometimes fatal bone marrow suppression, aplastic anemia, and gastrointestinal toxicity; these events were reported when methotrexate and some NSAIDs were administered concurrently • Hepatotoxicity, fibrosis, and cirrhosis after prolonged use • Interstitial pneumonitis • Diarrhea, ulcerative stomatitis, hemorrhagic enteritis, and death from intestinal perforation • Severe and occasionally fatal skin reactions • Potentially fatal opportunistic infections. Laboratory tests needed. Patients who are candidates for MTXI should undergo a complete blood count with differential and platelet counts, hepatic enzymes, renal function tests, and a chest x-ray before initiating therapy. During MTXI therapy, clinicians should monitor hematology parameters at least monthly, and monitor renal and liver function parameters every 1 to 2 months. Embryo-fetal toxicity. Fetal death and congenital anomalies have been reported with methotrexate use. MTXI is not recommended for women of childbearing age unless its benefits outweigh risks. Steps to avoid conception should be taken if either partner is receiving MTXI therapy. Malignant lymphomas. Non-Hodgkin lymphoma and other tumors have been observed in patients taking lowdose oral methotrexate. In some cases, however, malignancies that arose during treatment regressed completely after methotrexate withdrawal. Before initiating antilymphoma treatment, MTXI should be discontinued. Additional warnings. Additional warnings and precautions related to MTXI include organ-system toxicity, infection, skin reactions, dizziness and fatigue, malignant lymphomas, as well as gastrointestinal, hematologic, hepatic, neurologic, pulmonary, and renal complications. Additional information regarding these warnings and precautions is listed in Table 2. Conclusion The FDA approval of a new delivery system for the administration of methotrexate adds a new and conve-

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Table 2 System-Specific Warnings and Precautions for Subcutaneous Methotrexate Risk category

Description of potential risk

Guidance

Organ-system toxicity

• MTXI has the potential for serious toxicity; patients using MTXI should be closely monitored for bone marrow, liver, lung, and kidney toxicities. Toxic effects may be related to dose or frequency at any dose

• If adverse reactions occur, MTXI should be discontinued or the dose reduced; correction with leucovorin calcium and/ or acute intermittent hemodialysis with a high-flux dialyzer may be warranted. If MTXI therapy is reinstituted, it should be done cautiously • Because methotrexate has not been well studied in older individuals, relatively low doses should be considered in elderly patients and they should be closely monitored

Gastrointestinal

• MTXI should be used with extreme caution in patients with peptic ulcer disease or ulcerative colitis • Unexpectedly severe and at times fatal gastrointestinal toxicity have been documented in patients taking methotrexate (usually high dose) in combination with some NSAIDs

• Interruption of MTXI therapy is necessary if diarrhea and ulcerative stomatitis occur • Dehydration resulting from vomiting, diarrhea, or stomatitis warrants discontinuation of MTXI until recovery

Hematologic

• Because MTXI can suppress hematopoiesis, anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, and/or thrombocytopenia can occur. In controlled clinical trials conducted with a different formulation of methotrexate in 128 patients with RA, 2 patients had leukopenia, 6 had thrombocytopenia, and 2 had pancytopenia • When administered with some NSAIDs, high doses of MTXI may cause severe and sometimes fatal bone marrow suppression and aplastic anemia • Patients with severe granulocytopenia and fever should be evaluated as soon as possible. Such patients usually require parenteral broad-spectrum antibiotic therapy

• MTXI should be used with extreme caution in patients with preexisting hematopoietic impairment. The drug should be stopped immediately if a significant drop in blood counts is observed

Hepatic

• MTXI can cause hepatotoxicity in patients with RA, ranging from • Special caution should be taken in elevated transaminases to fibrosis and cirrhosis patients with preexisting liver damage • In RA, methotrexate hepatotoxicity may be associated with age at and impaired hepatic function first use and duration of therapy. Other risk factors, such as total cumulative dose, diabetes, and advanced age, as well as lifestyle factors including alcoholism and obesity may be associated, but have not been confirmed • Liver function tests should be performed at baseline and at 4- to 8-week intervals in patients receiving MTXI for RA • Patients with a history of excessive alcohol use, abnormal baseline liver function test values, or chronic hepatitis B or C infection should undergo liver biopsy before MTXI treatment • During treatment, liver biopsy should be performed if liver function test abnormalities are persistent or if serum albumin levels fall below the normal range • MTXI should be discontinued in patients who show persistent abnormal liver function tests, those who do not consent to liver biopsy, and in any patient whose liver biopsy exhibits moderateto-severe changes

Infection

• Patients with an active infection should use MTXI with extreme caution • Opportunistic infections, especially Pneumocystis pneumonia, may occur with MTXI

Neurologic

• Leukoencephalopathy after intravenous methotrexate administration has been reported in patients who have had craniospinal irradiation. Discontinuation of methotrexate does not always resolve neurotoxicity

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• Live virus vaccines are not recommended and may be ineffective when given during MTXI therapy

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Table 2 System-Specific Warnings and Precautions for Subcutaneous Methotrexate (Continued) Risk category

Description of potential risk

Guidance

Neurologic (Continued)

• Transient acute neurologic syndrome has been reported in patients treated with high-dose methotrexate. This stroke-like encephalopathy can manifest as confusion, hemiparesis, transient blindness, seizures, and coma. Its exact cause is unknown

Pulmonary

• Use of methotrexate may result in lung disease, including acute or chronic interstitial pneumonitis. This may occur at any time during therapy and has occurred at low doses of methotrexate. Lung disease may not be fully reversible and can be fatal • Symptoms of pulmonary distress, especially a dry nonproductive cough, and nonspecific pneumonitis occurring during MTXI therapy may indicate a dangerous lesion • Other symptoms can include fever, cough, dyspnea, hypoxemia, and an infiltrate on chest x-ray. Infection (pneumonia) must be excluded

• If pulmonary symptoms are observed, MTXI treatment should be interrupted and the patient should be closely monitored

Renal

• High doses of methotrexate used in the treatment of osteosarcoma can cause renal damage that may lead to acute renal failure

• Renal function, adequate hydration, urine alkalinization, and levels of serum methotrexate and creatinine should be monitored

Skin

• Dermatologic reactions, including severe reactions and fatalities, have been reported in children and adults within days of taking oral, intramuscular, intravenous, or intrathecal methotrexate administration at any dose

Dizziness and fatigue

• MTXI use may lead to dizziness and fatigue

• Patients should be cautious when driving or using machinery

MTXI indicates methotrexate injection; NSAIDs, nonsteroidal anti-inflammatory drugs; RA, rheumatoid arthritis. Source: Otrexup (methotrexate) injection prescribing information; 2013.

nient treatment option for patients with RA. Although the literature documents the clinical utility of SC methotrexate in patients with active RA, this dosing alternative is often overlooked by clinicians. Methotrexate administered subcutaneously using an autoinjector is a well-tolerated, effective, and nearly pain-free alternative for patients with severe RA who have had inadequate response to or who are intolerant of first-line therapy. In addition to higher drug exposure levels with MTXI, easy self-administration of the medication with this first-in-class autoinjector may help to improve patient adherence and overall clinical outcomes. n

References

1. Ruderman E, Tambar S. Rheumatoid arthritis. Updated August 2012. www. rheumatology.org/practice/clinical/patients/diseases_and_conditions/ra.asp. Accessed January 4, 2014. 2. Centers for Disease Control and Prevention. Rheumatoid arthritis. Updated November 19, 2012. www.cdc.gov/arthritis/basics/rheumatoid.htm. Accessed January 4, 2014. 3. Kleinman NL, Cifaldi MA, Smeeding JE, et al. Annual incremental health benefit costs and absenteeism among employees with and without rheumatoid arthritis. J Occup Environ Med. 2013;55:240-244.

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4. Xeljanz (tofacitinib) tablets [prescribing information]. New York, NY: Pfizer Inc; November 2013. 5. Okada Y, Wu D, Trynka G, et al. Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature. 2013 Dec 25 [Epub ahead of print]. 6. Burmester GR, Feist E, Sleeman MA, et al. Mavrilimumab, a human monoclonal antibody targeting GM-CSF receptor-α, in subjects with rheumatoid arthritis: a randomised, double-blind, placebo-controlled, phase I, first-in-human study. Ann Rheum Dis. 2011;70:1542-1549. 7. Antares Pharma, Inc. Otrexup (methotrexate) injection approved by FDA: a new treatment for adults with rheumatoid arthritis, children with polyarticular idiopathic arthritis, and adults with psoriasis. Press release. October 14, 2013. www.antarespharma. com/files/8613/8175/5363/OTREXUP_FDA_Approval.pdf. Accessed January 4, 2014. 8. Schiff MH, Simon LS, Freundlich B, et al. Drug exposure limitations of oral methotrexate (MTX) at doses >15 mgs may be overcome by using a subcutaneous MTX auto-injector in patients with rheumatoid arthritis (RA). Arthritis Rheum. 2013;65 (10 suppl):S337-S338. 9. Gower T. Understanding methotrexate, a cornerstone in RA treatment: how did a cancer drug become a staple in rheumatoid arthritis treatment? www.arthritistoday. org/about-arthritis/types-of-arthritis/rheumatoid-arthritis/treatment-plan/treatmentchoices/understanding-methotrexate.php. Accessed January 5, 2014. 10. Brooks M. FDA OKs Methotrexate Autoinjector (Otrexup). Medscape. October 18, 2013. www.medscape.com/viewarticle/812821. Accessed January 28, 2014. 11. Otrexup (methotrexate) injection [prescribing information]. Ewing, NJ: Antares Pharma, Inc; October 2013. 12. Kivitz AJ, McLain D, Hill J, et al. Nearly pain free self-administration of methotrexate using an investigational auto-injector: results of a phase-2 clinical trial in rheumatoid arthritis patients with mild-to-severe functional limitations. Arthritis Rheum. 2013;65(10 suppl):S565.

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Pomalyst (Pomalidomide): A New Third-

Generation Immunomodulatory Drug for Relapsed and/or Refractory Multiple Myeloma

By Lynne Lederman, PhD, Medical Writer

ultiple myeloma (MM) is characterized by the clonal expansion of malignant plasma cells that proliferate in the bone marrow, which typically produce large amounts of an abnormal immunoglobulin-like protein.1,2 The etiology of MM is unknown, but is associated with exposure to particular chemicals or to radiation and with being overweight or obese.3,4 MM is often preceded by monoclonal gammopathy of undetermined significance, an asymptomatic plasma-cell disorder, which may progress through asymptomatic smoldering MM before becoming symptomatic MM.2,5

The Burden of Myeloma Approximately 10% to 15% of all hematologic malignancies and 20% of deaths from hematologic cancers result from MM.2,5 The American Cancer Society estimates that in 2013, 22,350 Americans will be newly diagnosed with MM and 10,710 Americans will die from the disease.4 This represents an increase in the number of cases but not of deaths compared with in 2012.4,6 The frequent signs and symptoms of MM include fatigue, bone pain, osteolytic bone lesions, and/or compression fractures.7 Myeloma-related or gan or tissue damage (eg, hyper calcemia, anemia, renal dysfunction, or bone lesions) is required to establish a diagnosis of symptomatic MM.1 The median survival for patients with MM has increased from <1 year before the introduction of alkylating agents in the 1960s, to almost 2 years after the development of high-dose chemotherapy and autologous stem-cell transplant in the 1980s.2,8 Since approximately 2000, the development of novel, targeted thera pies, including the immunomodulatory drugs (IMiDs) thalidomide (Thal omid) and lenalidomide (Revlimid) and the proteasome inhibitor bortezomib (Velcade), have increased survival to a median of 5.4 years.8,9 However, a recent analysis shows that it is primarily patients aged >65 years who have benefited the most from novel agents, and there remains a need for additional new therapies for younger patients and to effect a cure.9 The Challenge of Relapsed, Refractory Myeloma Although MM may be initially sensitive to treatment,

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it remains incurable.2,8 MM almost always eventually relapses, the duration of remission shortens with each successive therapy,10 and it becomes more resistant to chemotherapy over time,2 indicating a need for additional salvage therapies. The 2012 US Food and Drug Administration (FDA) accelerated approval of carfilzomib (Kyprolis), which is indicated for the treatment of relapsed and/or refractory MM, provides another treatment option,11 as does the continuing development of other antimyeloma agents.12

Pomalidomide: A Third-Generation Immunomodulatory Drug On February 8, 2013, the FDA approved pomalidomide (Pomalyst; Celgene), the most recent IMiD, for the treatment of patients with MM who have received at least 2 previous therapies, including lenalidomide and bortezomib, and have demonstrated disease progression within 60 days of the completion of the last therapy.12 The FDA accelerated the approval of pomalidomide based on a phase 2 clinical trial. Value-Based Cancer Care discussed the FDA approval of pomalidomide with Paul G. Richardson, MD, Clinical Director, Jerome Lipper Center for Multiple Myeloma, and Professor of Medicine, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, who conducts clinical trials of pomalidomide, among other antimyeloma therapies.13-16 “I want to applaud the FDA. They moved very quickly with it, and they have been very proactive in meeting unmet medical needs,” said Dr Richardson. “Pomalidomide absolutely fills an unmet need for patients,” he emphasized. Of note, the approval is based on response rate, and any clinical benefit, such as increased survival or improvement of symptoms, has not been confirmed.17 Pomalidomide is an analog of thalidomide and is the third agent in the immunomodulatory class that includes thalidomide and lenalidomide.12 Although thalidomide, particularly when combined with dexamethasone, is very active against MM, it is associated with dose-limiting adverse effects, including somnolence, constipation, neuropathy, and thromboembolic events. Derivatives of thalidomide, including lenalidomide and pomalidomide,

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egistration Trial Results: Pomalidomide Alone and in Table 1 R Combination with Low-Dose Dexamethasone Pomalidomidea (N = 108)

Pomalidomide plus low-dose dexamethasone (N = 113)

ORR,b N (%)

8 (7.4)

33 (29.2)

95% CI for ORR, %

3.3-14.1

21.0-38.5

Complete response, N (%)

0 (0.0)

1 (0.9)

Partial response, N (%)

8 (7.4)

32 (28.3)

Median, months

7.4

95% CI for DOR, months

5.1-9.2

Response

Duration of response

Results are before the addition of dexamethasone. ORR = partial response plus complete response per European Group for Blood and Marrow Transplantation criteria. CI indicates confidence interval; DOR, duration of response; NE, not established (the median has not yet been reached); ORR, overall response rate. Source: Pomalyst (pomalidomide) capsules prescribing information; 2013. a

have been developed that have their own safety and efficacy profiles. Like lenalidomide, pomalidomide is thought to act directly on myeloma cell adhesion and by decreasing factors that are required for myeloma cell survival, leading to cell death, and indirectly by modulating cells in the bone marrow microenvironment.18 According to Dr Richardson, for patients with MM whose disease is resistant to lenalidomide and to bortezomib, the orally available and generally well-tolerated pomalidomide provides a major step forward.

Phase 2 Registration Trial Results The FDA accelerated the approval of pomalidomide based on the results of an open-label, randomized phase 2 clinical trial that included 221 patients with relapsed MM refractory to the last therapy and who had received at least lenalidomide and bortezomib. Response rate was the primary objective.12,19 The patients were randomly assigned to receive pomalidomide plus low-dose dexamethasone (pomalidomide 4 mg once daily for 21 of 28 days plus low-dose dexamethasone 40 mg daily for patients aged ≤75 years or 20 mg daily for patients aged ≥75 years on days 1, 8, 15, and 22 of each 28-day cycle; N = 113) or pomalidomide alone (N = 108) until disease progression. Patients in the pomalidomide alone arm were allowed to add low-dose dexamethasone on disease progression.

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For the efficacy analysis, 221 patients were evaluable for response; 219 patients were evaluable for safety, including 112 patients who received pomalidomide plus low-dose dexamethasone and 107 patients who received pomalidomide alone. Of those 107 patients, 61 had lowdose dexamethasone added during the treatment period. The overall response rate was 7.4% in the pomalidomide arm and 29.2% in the arm receiving pomalidomide plus low-dose dexamethasone (Table 1). The duration of response was 7.4 months in the arm receiving pomalidomide plus low-dose dexamethasone, and it was not reached in the pomalidomide-alone arm.17

Dosing Pomalidomide is administered orally at a starting dose of 4 mg once daily on days 1 to 21 of each 28-day cycle. The cycles are repeated until disease progression. Pomalidomide capsules should be swallowed whole, with water, at least 2 hours before or 2 hours after a meal, and should not be taken with food. Dexamethasone may be used in combination with pomalidomide, for example, at the doses administered in the registration phase 2 trial. Important Safety Information for Pomalidomide The prescribing information for pomalidomide contains a Boxed Warning about serious adverse events that may occur with this drug, including17: • Pomalidomide is contraindicated in pregnancy, because it is an analog of the teratogen thalidomide, which can cause life-threatening birth defects. For women of childbearing age, pregnancy must be excluded before treatment, and pregnancy must be prevented during treatment by the use of 2 reliable contraceptive methods • Deep-vein thrombosis (DVT) and pulmonary embolism (PE) can occur in patients with MM who are treated with pomalidomide • Pomalidomide is available only through a restricted Risk Evaluation and Mitigation Strategy (REMS) program. Although patients in the pomalidomide registration trial received mandated prophylaxis or antithrombotic agents (either aspirin [81%], heparin [21%], warfarin [16%], or clopidogrel [3%]), 3% of patients developed venous thromboembolism.17 Therefore, the risk for DVT and PE should be evaluated for each patient to decide on the use of prophylaxis against thrombolic events.17,20 Patients treated with pomalidomide should be monitored for hematologic toxicities, particularly neutropenia, which was the most frequent grade 3 or 4 adverse event reported (43% of patients). The pomalidomide dose may be modified depending on the degree of neu-

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tropenia or thrombocytopenia.17 Other clinically significant adverse reactions and drug interactions are listed in Table 2.

Restricted Distribution Program Because of the potential for embryonic and fetal toxicities, pomalidomide will only be available in the United States through a restricted distribution program called the Pomalyst REMS program.17,20 The Pomalyst REMS program requires that all patients be enrolled and agree to comply with its requirements before they can receive pomalidomide, both as an initial prescription and at each subsequent prescription refill. In addition, only certified prescribers can prescribe pomalidomide, and only certified pharmacies can dispense pomalidomide.20 Conclusions The FDA approval of pomalidomide adds a new treatment option for patients with myeloma whose disease has relapsed after treatment with other drugs or has developed resistance to the other options. In his discussion with Value-Based Cancer Care, Dr Richardson said that “pomalidomide is the most potent immunomodulatory drug we have tested so far. Its efficacy is reflected by the fact that it is able to overcome resistance to both lenalidomide and bortezomib. Because it is able to achieve a response in about a third of patients who are both resistant to lenalidomide and bortezomib, it has provided a major step forward and an excellent choice after lenalidomide and bortezomib fail.” Pomalidomide works very well with dexamethasone, as currently indicated, and it also “partners well” with other agents, including bortezomib or carfilzomib. Combination trials with pomalidomide are ongoing, and the results for efficacy and safety are promising. n References

1. International Myeloma Working Group. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol. 2003;121:749-757. 2. Laubach J, Richardson P, Anderson K. Multiple myeloma. Annu Rev Med. 2011;62:249-264. 3. American Cancer Society. Multiple myeloma overview. 2013. www.cancer.org/ acs/groups/cid/documents/webcontent/003065-pdf.pdf. Accessed February 28, 2013. 4. American Cancer Society. Cancer Facts & Figures 2013. Atlanta, GA: American Cancer Society; 2013. 5. Kyle RA, Rajkumar SV. Multiple myeloma. Blood. 2008;111:2962-2972. 6. American Cancer Society. Cancer Facts & Figures 2012. Atlanta, GA: American Cancer Society; 2012. 7. Rajkumar SV. Multiple myeloma. Curr Probl Cancer. 2009;33:7-64. 8. Kumar SK, Rajkumar SV, Dispenzieri A, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2008;111:2516-2520. 9. Kumar S, Dispenzieri A, Gertz MA, et al. Continued improvement in survival in multiple myeloma and the impact of novel agents. Blood (ASH Annual Meeting Abstracts). 2012;120:Abstract 3972. 10. Rajkumar SV. Multiple myeloma: 2012 update on diagnosis, risk-stratification,

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linically Important Adverse Reactions and Drug Table 2 C Interactions Associated with Pomalidomide Adverse reaction/ drug interaction

Comments

Dizziness

18% of patients (1% grade 3 or 4)

Confusional state

12% of patients (3% grade 3 or 4)

Neuropathy

18% neuropathy; 9% peripheral neuropathy

Drugs that may increase pomalidomide plasma concentrations

CYP3A, CYP1A2, or P-gp inhibitors: coadministration of pomalidomide with drugs that are strong inhibitors of CYP1A2, CYP3A (eg, ketoconazole), or P-gp could increase exposure and should be avoided

Drugs that may decrease pomalidomide plasma concentrations

CYP3A, CYP1A2, or P-gp inducers: coadministration of pomalidomide with drugs that are strong inducers of CYP1A2, CYP3A (eg, rifampin), or P-gp could decrease exposure and should be avoided

Cigarette smoking

May reduce pomalidomide exposure as a result of CYP1A2 induction and reduce the efficacy of pomalidomide

CY indicates cytochrome; P-gp, permeability glycoprotein. Source: Pomalyst (pomalidomide) capsules prescribing information; 2013. and management. Am J Hematol. 2012;87:78-88. 11. Food and Drug Administration Drug Approvals and Databases. Carfilzomib. www. fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm312945.htm. Accessed July 21, 2012. 12. FDA News Release. FDA approves Pomalyst for advanced multiple myeloma. Press release. February 8, 2013. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ ucm338895.htm. Accessed February 12, 2013. 13. Richardson PG, Siegel D, Baz R, et al. Phase I study of pomalidomide MTD, safety and efficacy in patients with refractory multiple myeloma who have received lenalidomide and bortezomib. Blood. 2012 Dec 14 [Epub ahead of print]. 14. Richardson PG, Jakubowiak A, Bahlis NJ, et al. Treatment outcomes with pomalidomide (POM) in combination with low-dose dexamethasone (LoDex) in patients with relapsed and refractory multiple myeloma (RRMM) and Del(17p13) and/or t(4;14)(p16;q32) cytogenetic abnormalities who have received prior therapy with lenalidomide (LEN) and bortezomib (BORT). Blood (ASH Annual Meeting Abstracts). 2012;120:Abstract 4053. 15. Vij R, Richardson PG, Jagannath S, et al. Pomalidomide with or without lowdose dexamethasone in patients with relapsed/refractory multiple myeloma: outcomes in patients refractory to lenalidomide and bortezomib. J Clin Oncol. 2012;30(suppl):Abstract 8016. 16. Vij R, Hofmeister CC, Richardson PG, et al. Pomalidomide (POM) with lowdose dexamethasone (LoDEX) in patients with relapsed and refractory multiple myeloma (RRMM): outcomes based on prior treatment exposure. Blood (ASH Annual Meeting Abstracts). 2012;120:Abstract 4070. 17. Pomalyst (pomalidomide) capsules, for oral use. Prescribing information. Summit, NJ: Celgene Corporation; February 2013. 18. Latif T, Chauhan N, Khan R, et al. Thalidomide and its analogues in the treatment of multiple myeloma. Exp Hematol Oncol. 2012;1:27-34. 19. Celgene Corporation. U.S. Food and Drug Administration approves Pomalyst (pomalidomide) for the treatment of patients with relapsed and refractory multiple myeloma. Press release. February 8, 2013. www.businesswire.com/news/home/201302 08005889/en/U.S.-Food-Drug-Administration-Approves-POMALYST%C2%AEpomalidomide. Accessed March 1, 2013. 20. Celgene Corporation. Prescriber guide to Pomalyst REMS. 2013. www.pomalystrems. com/pdf/POM_Prescriber_Guide_2_6_13.pdf. Accessed February 28, 2013.

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Revlimid (Lenalidomide) Receives a New Indication for the Treatment of Patients with Relapsed or Progressing Mantle-Cell Lymphoma By Lisa A. Raedler, PhD, RPh, Medical Writer

antle-cell lymphoma (MCL), which accounts for approximately 6% of new non–Hodgkin lymphoma diagnoses, is a rare and often aggressive cancer.1,2 MCL is most often diagnosed in older white adults (typically patients are in their mid-60s) and is usually in advanced stages.1,2 Splenomegaly and lymph node enlargement are typically present, in addition to bone marrow, liver, and gastrointestinal tract involvement.2 Although genetic abnormalities (ie, translocations of chromosomes 11 and 14) and the overexpression of cyclin D1 are characteristic of MCL, their clinical and prognostic implications remain unclear.1,3 A recent analysis of 62 cases of MCL demonstrated that other disease features, particularly blastoid (vs classical) morphology and the presence of TP53 gene mutations, are significantly correlated with poor clinical outcomes.3 MCL is an uncommon diagnosis in the United States. A study using Surveillance, Epidemiology and End Results (SEER) registry data collected between 1992 and 2001 documented an incidence rate of 0.51 per 100,000 person-years.4 In this analysis, patients diagnosed with MCL were more likely to be white and male.4 An 8% annual increase in the incidence of MCL was noted during the 10-year time frame over which data were collected, but researchers hypothesized that changes in diagnostic practices explained this trend.4 The clinical course of MCL can be indolent or moderately aggressive at diagnosis. Over time, however, the disease invariably becomes clinically aggressive and refractory to cytotoxic chemotherapy.5 Data reported in 1995 suggest that patients with MCL have the worst long-term survival among patients with all B-cell lymphoma subtypes, with a median survival of approximately 3 years.6 In a more recent series of patients with MCL, this estimate has increased to approximately 5 years, possibly as a result of the use of anthracycline-containing treatment regimens, stem-cell transplantation, advances in supportive care, and the general improvement of life span.7 Although assessments of the cost burden associated with MCL are few, the results of a recent cost-effective-

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ness analysis that was conducted using US payer data showed that total per-patient costs for patients with MCL exceeded $100,000.8 This study, which compared the combination of bendamustine and rituximab (BR) with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) in treatment-naïve patients with MCL, calculated average per-patient costs of $115,191 and $100,261 for BR and R-CHOP, respectively.8 Until recently, bortezomib (Velcade) was the only drug approved by the US Food and Drug Administration (FDA) for the treatment of patients with MCL, specifically those who have received at least 1 previous therapy.9 In clinical practice, combinations of chemotherapy with anti-CD20 monoclonal antibody therapy, highdose chemotherapy followed by stem-cell transplant, and radioimmunotherapy are viable options for the treatment of patients with MCL.5 Novel options that are being investigated in MCL clinical trials include cytotoxic agents (bendamustine, cladribine); monoclonal antibodies (rituximab); mTOR inhibitors (temsirolimus, which is approved in Europe for MCL); cyclin-dependent kinase inhibitors (flavopiridol); histone deacetylase inhibitors; B-cell leukemia/ lymphoma-2 inhibitors; Bruton’s tyrosine kinase inhibitors; and immunotoxins.10

Revlimid a New Treatment Option for Patients with MCL In June 2013, the FDA approved the immunomodulatory agent lenalidomide (Revlimid; Celgene Corporation) for the treatment of patients with MCL whose disease has relapsed or progressed after 2 previous therapies, one of which included bortezomib.11 The approval of lenalidomide for MCL was based on the demonstration of efficacy (overall response rate [ORR] and duration of response) in a phase 2 multicenter clinical trial of 134 heavily pretreated patients with MCL.11 Data from this trial, known as the MCL001 EMERGE study, were presented at the annual meeting of the American Society of Hematology in December 2012 and were published in September 2013.12,13

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In a recent interview regarding his experience in this phase 2 trial of lenalidomide in patients with MCL, Andre Goy, MD, MS, Chairman and Director, and Chief of Lymphoma, John Theurer Cancer Center, Hackensack, NJ, stated, “What was very important was the duration of response….Here, the median duration of response was more than 16 months…regardless of the number of prior therapies; bulky, high tumor load; [and] prior high-dose chemotherapy refractory to the last therapy or refractory to bortezomib.”14 Lenalidomide is also approved for use in combination with dexamethasone in patients with multiple myeloma (MM) who have received at least 1 previous therapy, and in patients with transfusion-dependent anemia resulting from low- or intermediate-1–risk myelodysplastic syndromes (MDS) associated with a deletion 5q abnormality with or without additional cytogenetic abnormalities.15

Mechanism of Action As an analog of thalidomide, lenalidomide has immunomodulatory, antiangiogenic, and antineoplastic properties. In vitro, the drug inhibits cell proliferation and induces programmed cell death of specific hematopoietic tumor cells, including MM, MCL, and MDS associated with a deletion 5q abnormality. Lenalidomide also has immunomodulatory properties: it activates T-cells and natural killer cells, increases the number of natural killer T-cells, and inhibits proinflammatory cytokines, such as tumor necrosis factor-alpha and interleukin-6, by monocytes.15 Phase 2 Clinical Trial: MCL-001 EMERGE In the phase 2 multicenter MCL-001 EMERGE trial, Goy and colleagues enrolled 134 patients with MCL who had been treated with multiple therapies, including rituximab, cyclophosphamide, and anthracycline.13 All patients had MCL that had relapsed or had progressed within 12 months of therapy with bortezomib or whose disease was refractory to bortezomib. Lenalidomide was given as a single agent at a dose of 25 mg daily administered on days 1 to 21 of a 28-day cycle until disease progression, unacceptable toxicity, or voluntary withdrawal.13 The lenalidomide dose was 10 mg once daily for 21 days every 28 days for patients with a creatinine clearance between 30 mL/min and 59 mL/min.15 The primary end points of the MCL-001 EMERGE study were ORR and duration of response.13 Duration of response was defined as the time from initial response to documented disease progression.15 Secondary end points included complete response (CR), progression-free survival, time to progression, overall survival, and safety.13

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Phase 2 Study Efficacy Results: Lenalidomide in Table 1 Patients with Relapsed/Refractory or Progressing MCL Efficacy end point

Independent central review (N = 134)

Investigator assessed (N = 134)

Overall response rate, % Complete response, % Median duration of response, mo Median time to response, mo

28 7.5 16.6 (95% CI, 7.7-26.7) 2.2

32 16 18.5 (95% CI, 12.8-26.7) 2.0

Median progression-free survival, mo Median overall survival, mo

4 (95% CI, 3.6-5.6) 19.0 (95% CI, 12.5-23.9)

3.8 (95% CI, 3.5-6.8) 19 (95% CI, 12.5-23.9)

CI indicates confidence interval; MCL, mantle-cell lymphoma. Source: Revlimid (lenalidomide) capsules prescribing information; 2013.

The efficacy parameters were assessed by investigators, as well as by an independent central review committee.13

Patient Population The median age of patients enrolled in the phase 2 study of lenalidomide was 67 years.13 The majority of patients in this trial were male (81%) and white (96%), with advanced (stage III/IV) MCL (93%).13,15 Of these patients, 78% had received 3 or more previous treatments (median, 4; range, 2-10).13 Efficacy The phase 2 study demonstrated that lenalidomide monotherapy is active and safe in patients with MCL whose disease has relapsed or progressed after bortezomib therapy or whose disease was refractory to bortezomib. According to independent central review, the ORR was 28% (7.5% CR) and the median duration of response was 16.6 months. According to investigators, the ORR was 32% (16% CR) and the median duration of response was 18.5 months. Table 1 includes these data, as well as secondary end point data, from the phase 2 study of lenalidomide.13 Adverse Events More than half of the patients (58%) received 3 or more cycles of lenalidomide in this trial.13 The median duration of therapy was 95 days (range, 1-1002 days) and the average dose of lenalidomide was 20 mg daily.13 Of the patients with MCL, 38% required a dose reduction of lenalidomide.13 The most common grade 3 or 4 adverse events reported in the study were neutropenia (43%), thrombocytopenia (27%), anemia (11%), pneumonia (8%), and fatigue (7%).13 Other adverse events of any grade included

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Dose Adjustments for Hematologic Table 2 Lenalidomide Toxicities during Treatment of MCL Toxicity Thrombocytopenia When platelets fall to <50,000/mcL

Neutropenia

Other grade 3 or 4 toxicities

Lenalidomide dose recommendation Interrupt lenalidomide treatment and perform CBC tests weekly

When platelets return to ≥50,000/mcL

Resume lenalidomide at 5 mg less than the previous dose Lenalidomide should not be dosed below 5 mg daily

When neutrophils fall to <1000/mcL for at least 7 days or to <1000/mcL with an associated temperature ≥38.5°C or to <500/mcL

Interrupt lenalidomide treatment and perform CBC tests weekly

When neutrophils return to ≥1000/mcL

Resume lenalidomide at 5 mg less than the previous dose Lenalidomide should not be dosed below 5 mg daily

Treatment should be held for other grade 3 or 4 toxicities that are judged to be related to lenalidomide When toxicity has resolved to grade 2 or lower, lenalidomide can be restarted at next lower dose level, at the physician’s discretion

CBC indicates complete blood count; MCL, mantle-cell lymphoma. Source: Revlimid (lenalidomide) capsules prescribing information; 2013.

tarting Dose Adjustments for Patients with MCL and Table 3 S Renal Impairment Creatinine clearance Lenalidomide Renal impairment level (Cockcroft-Gault) adjusted dose Moderate impairment

30-60 mL/min

10 mg every 24 hrs

Severe impairment

<30 mL/min not requiring dialysis

15 mg every 48 hrs

End-stage renal disease

<30 mL/min requiring dialysis

5 mg once daily On dialysis days, lenalidomide should be administered after dialysis

MCL indicates mantle-cell lymphoma. Source: Revlimid (lenalidomide) capsules prescribing information; 2013.

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tumor flare reaction (10%), deep-vein thrombosis (4%), pulmonary embolism (2%), and invasive second primary malignancies (2%).13,15 A total of 19% of the patients in this study discontinued lenalidomide therapy because of adverse events.13

Dosing and Administration For patients with MCL whose disease relapsed or progressed after bortezomib therapy or was refractory to bortezomib, the recommended dose and schedule for lenalidomide is 25 mg orally once daily on days 1 to 21 of repeated 28-day cycles.15 Lenalidomide should be taken at approximately the same time each day, either with or without food.15 The FDA approval of lenalidomide for the treatment of patients with MCL also included an approval of a new 20-mg capsule strength of this agent.15 Table 2 summarizes lenalidomide dose modification guidelines for patients with grade 3 or 4 neutropenia or thrombocytopenia, or with other grade 3 or 4 toxicities that are believed to be drug-related.15 Because lenalidomide is primarily excreted unchanged by the kidneys, patients with moderate or severe renal impairment, including patients on dialysis, should receive lower initial starting doses.15 Specific dose recommendations for lenalidomide in patients with MCL and renal insufficiency are provided in Table 3.15 Warnings and Precautions Embryo-Fetal Toxicity Lenalidomide, a thalidomide analog, should not be used during pregnancy. Thalidomide causes human birth defects and embryo-fetal death. Pregnancy must be excluded before the start of lenalidomide treatment and must be prevented during treatment by the use of 2 reliable contraception methods. Because the blood may be given to a pregnant female patient whose fetus must not be exposed to lenalidomide, patients taking lenalidomide must not donate blood during treatment and for 1 month after discontinuation of the drug. Given this embryo-fetal risk, access to lenalidomide is restricted under a Risk Evaluation and Mitigation Strategy (REMS) program, known as the Revlimid REMS program.15 Hematologic Toxicity In the phase 2 trial of lenalidomide in MCL, grade 3 or 4 neutropenia and grade 3 or 4 thrombocytopenia were reported in 43% and 28% of patients, respectively.13 Patients with MCL who take lenalidomide should have their complete blood count (CBC) monitored.15 CBC tests are recommended weekly for the first cycle (28 days), every 2 weeks during cycles 2 to 4, and then monthly while receiving lenalidomide therapy.15

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Venous Thromboembolism Some patients with MCL who received lenalidomide experienced venous thromboembolic events, typically deep venous thrombosis and pulmonary embolism.15 It is not known whether prophylactic anticoagulation or antiplatelet therapy prescribed in conjunction with lenalidomide can minimize the risk of venous thromboembolism.15 Allergic Reactions Lenalidomide has been associated with angioedema and serious dermatologic reactions, including Stevens- Johnson syndrome and toxic epidermal necrolysis. Such reactions can be fatal. Physicians should consider interruption or discontinuation of lenalidomide for grade 2 to 3 skin reactions. Lenalidomide must be permanently discontinued if angioedema, grade 4 rash, exfoliative or bullous rash occur, or if Stevens-Johnson syndrome occurs or toxic epidermal necrolysis is suspected. Lenalidomide should not be given to any patient who experienced a grade 4 rash while receiving thalidomide.15 Tumor Lysis Syndrome Fatalities secondary to tumor lysis syndrome have been documented in patients taking lenalidomide. Because patients with high tumor burden before treatment are at risk for tumor lysis syndrome, healthcare professionals should monitor these patients closely and take appropriate precautions.15 Tumor Flare Reaction Patients with MCL taking lenalidomide should be monitored for tumor flare reaction, which is characterized by lymph node swelling, low-grade fever, pain, and rash.15 Of patients in the MCL trial, 10% experienced grade 1 or grade 2 tumor flare reaction in the first cycle of lenalidomide treatment.13 One of these patients developed tumor flare reaction again in cycle 11.13 If grades 1 and 2 tumor flare reaction occur, lenalidomide can be continued without interruption or modification, at the physician’s discretion.15 Corticosteroids, nonsteroidal anti-inflammatory drugs, and/or narcotic analgesics can be used for symptom management.15 Patients who experience more severe tumor flare reaction (grade 3 or 4) should not receive lenalidomide treatment until the tumor flare reaction resolves to grade 1 or less.15 Second Primary Malignancies Patients taking lenalidomide should be monitored for the development of second malignancies.15 In the MCL

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trial, 3 patients (2%) developed invasive second primary malignancies.13

Conclusion Lenalidomide, the first oral drug approved for the treatment of patients with MCL, has demonstrated efficacy with manageable toxicities in heavily pretreated patients whose disease has relapsed or progressed after bortezomib or is refractory to bortezomib. Lenalidomide joins bortezomib as the only 2 FDA-approved agents currently available for this rare and often aggressive form of B-cell lymphoma. Because it is not cytotoxic, lenalidomide may offer clinical value when combined with other treatments for MCL. Current clinical trials are evaluating the use of lenalidomide in combination with rituximab, bendamustine, and/or bortezomib in patients with MCL for use as first- or second-line treatment.16 n References

1. Leukemia and Lymphoma Society. Mantle cell lymphoma facts. Revised July 2012. www.lls.org/content/nationalcontent/resourcecenter/freeeducationmaterials/lymphoma/ pdf/mantlecelllymphoma.pdf. Accessed July 30, 2013. 2. National Cancer Institute. Mantle cell lymphoma: disease information. 2010 Hematopoietic and Lymphoid Database. Updated February 5, 2013. http://seer.cancer. gov/seertools/hemelymph/ 2010/. Accessed July 30, 2013. 3. Slotta-Huspenina J, Koch I, de Leval L, et al. The impact of cyclin D1 mRNA isoforms, morphology and p53 in mantle cell lymphoma: p53 alterations and blastoid morphology are strong predictors of a high proliferation index. Haematologica. 2012; 97:1422-1430. 4. Morton LM, Wang SS, Devesa SS, et al. Lymphoma incidence patterns by WHO subtype in the United States, 1992-2001. Blood. 2006;107:265-276. 5. Ghielmini M, Zucca E. How I treat mantle cell lymphoma. Blood. 2009;114:1469-1476. 6. Zucca E, Roggero E, Pinotti G, et al. Patterns of survival in mantle cell lymphoma. Ann Oncol. 1995;6:257-262. 7. Herrmann A, Hoster E, Zwingers T, et al. Improvement of overall survival in advanced stage mantle cell lymphoma. J Clin Oncol. 2009;27:511-518. 8. Su W, Quon P, Whalen J, et al. Cost-effectiveness analysis of bendamustine plus rituximab versus CHOP-R in treatment-naive patients with mantle cell (MCL) and indolent lymphomas (IL). J Clin Oncol. 2012;30(suppl). Abstract 6553. 9. US Food and Drug Administration. FDA approves bortezomib (Velcade) for the treatment of patients with mantle cell lymphoma who have received at least one prior therapy. Updated May 21, 2009. www.fda.gov/AboutFDA/CentersOffices/Officeof MedicalProductsandTobacco/CDER/ucm09 4929.htm. Accessed September 17, 2013. 10. Goy A, Kahl B. Mantle cell lymphoma: the promise of new treatment options. Crit Rev Oncol Hematol. 2011;80:69-86. 11. US Food and Drug Administration. Drugs: lenalidomide. Updated June 5, 2013. www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm355438.htm. Accessed September 18, 2013. 12. Goy A, Sinha R, Williams ME, et al. Phase II multicenter study of single-agent lenalidomide in subjects with mantle cell lymphoma who relapsed or progressed after or were refractory to bortezomib: the MCL-001 “EMERGE” study. Presented at the American Society of Hematology annual meeting; December 8-11, 2012; Atlanta, GA. 13. Goy A, Sinha R, Williams ME, et al. Single-agent lenalidomide in patients with mantle-cell lymphoma who relapsed or progressed after or were refractory to bortezomib: phase II MCL-001 (EMERGE) study. J Clin Oncol. 2013 Sep 3. Epub ahead of print. 14. OncLiveTV. Dr. Goy on lenalidomide for mantle cell lymphoma. YouTube. June 10, 2013. www.youtube.com/watch?v=l-oV-Y6OvBE. Accessed July 30, 2013. 15. Revlimid (lenalidomide) capsules [prescribing information]. Summit, NJ: Celgene Corporation; June 2013. 16. ClinicalTrials.gov. Lenalidomide mantle cell lymphoma. Search results. http:// clinicaltrials.gov/ct2/results?term=lenalidomide+mantle+cell+lymphoma&Search= Search. Accessed September 18, 2013.

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For your members with COPD (chronic obstructive pulmonary disease)

The only once-daily ICS/LABA (inhaled corticosteroid/long-acting beta2-agonist) for the maintenance treatment of COPD. Contact your GlaxoSmithKline Account Manager to schedule a presentation. Indications • BREO ELLIPTA is a combination inhaled corticosteroid/long-acting beta2 -adrenergic agonist (ICS/LABA) indicated for the longterm, once-daily, maintenance treatment of airﬂow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema. BREO ELLIPTA is also indicated to reduce exacerbations of COPD in patients with a history of exacerbations. • BREO ELLIPTA is NOT indicated for the relief of acute bronchospasm or for the treatment of asthma.

Important Safety Information for BREO ELLIPTA WARNING: ASTHMA-RELATED DEATH • Long-acting beta2-adrenergic agonists (LABAs), such as vilanterol, one of the active ingredients in BREO ELLIPTA, increase the risk of asthma-related death. A placebo-controlled trial with another LABA (salmeterol) showed an increase in asthma-related deaths in subjects receiving salmeterol. This finding with salmeterol is considered a class effect of all LABAs, including vilanterol. • The safety and efficacy of BREO ELLIPTA in patients with asthma have not been established. BREO ELLIPTA is not indicated for the treatment of asthma. CONTRAINDICATIONS • BREO ELLIPTA is contraindicated in patients with severe hypersensitivity to milk proteins or who have demonstrated hypersensitivity to either fluticasone furoate, vilanterol, or any of the excipients. WARNINGS AND PRECAUTIONS • BREO ELLIPTA should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of COPD. • BREO ELLIPTA should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. Acute symptoms should be treated with an inhaled, short-acting beta2 -agonist. • BREO ELLIPTA should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medications containing LABAs, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Patients using BREO ELLIPTA should not use another medicine containing a LABA (e.g., salmeterol, formoterol fumarate, arformoterol tartrate, indacaterol) for any reason. • Oropharyngeal candidiasis has occurred in patients treated with BREO ELLIPTA. Advise patients to rinse the mouth without swallowing following inhalation to help reduce the risk of oropharyngeal candidiasis. • An increase in the incidence of pneumonia has been observed in subjects with COPD receiving BREO ELLIPTA. There was also an increased incidence of pneumonias resulting in hospitalization. In some incidences these pneumonia events were fatal. – In replicate 12-month studies of 3255 subjects with COPD who had experienced a COPD exacerbation in the previous year, there was a higher incidence of pneumonia reported in subjects receiving BREO ELLIPTA 100/25 mcg (6% [51 of 806 subjects]), fluticasone furoate (FF)/vilanterol (VI) 50/25 mcg (6% [48 of 820 subjects]), and FF/VI 200/25 mcg (7% [55 of 811 subjects]) than in subjects receiving VI 25 mcg (3% [27 of 818 subjects]). There was no fatal pneumonia in subjects receiving VI or FF/VI 50/25 mcg. There was fatal pneumonia in 1 subject receiving BREO ELLIPTA at the approved strength (100/25 mcg) and in 7 subjects receiving FF/VI 200/25 mcg (<1% for each treatment group). • Physicians should remain vigilant for the possible development of pneumonia in patients with COPD, as the clinical features of such infections overlap with the symptoms of COPD exacerbations. • Patients who use corticosteroids are at risk for potential worsening of existing tuberculosis; fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex. A more serious or even fatal course of chickenpox or measles may occur in susceptible patients. Use caution in patients with the above because of the potential for worsening of these infections. • Particular care is needed for patients who have been transferred from systemically active corticosteroids to inhaled corticosteroids because deaths due to adrenal insufficiency have occurred in patients with asthma during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. Taper patients slowly from systemic corticosteroids if transferring to BREO ELLIPTA. • Hypercorticism and adrenal suppression may occur with very high dosages or at the regular dosage of inhaled corticosteroids in susceptible individuals. If such changes occur, discontinue BREO ELLIPTA slowly.

Important Safety Information for BREO ELLIPTA (cont’d) WARNINGS AND PRECAUTIONS (cont’d) • Caution should be exercised when considering the coadministration of BREO ELLIPTA with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, clarithromycin, conivaptan, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, troleandomycin, voriconazole) because increased systemic corticosteroid and cardiovascular adverse effects may occur. • If paradoxical bronchospasm occurs, discontinue BREO ELLIPTA and institute alternative therapy. • Vilanterol can produce clinically significant cardiovascular effects in some patients as measured by increases in pulse rate, systolic or diastolic blood pressure, and also cardiac arrhythmias, such as supraventricular tachycardia and extrasystoles. If such effects occur, BREO ELLIPTA may need to be discontinued. BREO ELLIPTA should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension. • Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing inhaled corticosteroids. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, postmenopausal status, tobacco use, advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants, oral corticosteroids) should be monitored and treated with established standards of care. Since patients with COPD often have multiple risk factors for reduced BMD, assessment of BMD is recommended prior to initiating BREO ELLIPTA and periodically thereafter. • Glaucoma, increased intraocular pressure, and cataracts have been reported in patients with COPD following the long-term administration of inhaled corticosteroids. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts. • Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, ketoacidosis, and in patients who are unusually responsive to sympathomimetic amines. • Be alert to hypokalemia and hyperglycemia. ADVERSE REACTIONS • The most common adverse reactions (≥3% and more common than placebo) reported in two 6-month clinical trials with BREO ELLIPTA (and placebo) were nasopharyngitis, 9% (8%); upper respiratory tract infection, 7% (3%); headache, 7% (5%); and oral candidiasis, 5% (2%). • In addition to the events reported in the 6-month studies, adverse reactions occurring in ≥3% of the subjects treated with BREO ELLIPTA in two 1-year studies included COPD, back pain, pneumonia, bronchitis, sinusitis, cough, oropharyngeal pain, arthralgia, hypertension, influenza, pharyngitis, diarrhea, peripheral edema, and pyrexia. DRUG INTERACTIONS • Caution should be exercised when considering the coadministration of BREO ELLIPTA with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, clarithromycin, conivaptan, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, troleandomycin, voriconazole) because increased systemic corticosteroid and cardiovascular adverse effects may occur. • BREO ELLIPTA should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors, tricyclic antidepressants, or drugs known to prolong the QTc interval, or within 2 weeks of discontinuation of such agents, because the effect of adrenergic agonists, such as vilanterol, on the cardiovascular system may be potentiated by these agents. • Use beta-blockers with caution as they not only block the pulmonary effect of beta-agonists, such as vilanterol, but may produce severe bronchospasm in patients with reversible obstructive airways disease. • Use with caution in patients taking non–potassium-sparing diuretics, as electrocardiographic changes and/or hypokalemia associated with non–potassium-sparing diuretics may worsen with concomitant beta-agonists. USE IN SPECIFIC POPULATIONS • Use BREO ELLIPTA with caution in patients with moderate or severe hepatic impairment. Fluticasone furoate exposure may increase in these patients. Monitor for systemic corticosteroid effects. Please see Brief Summary of Prescribing Information, including Boxed Warning, for BREO ELLIPTA on the following pages. BREO ELLIPTA was developed in collaboration with

BRIEF SUMMARY BREOTM ELLIPTATM (fluticasone furoate and vilanterol inhalation powder) FOR ORAL INHALATION USE The following is a brief summary only; see full prescribing information for complete product information WARNING: ASTHMA-RELATED DEATH Long-acting beta2-adrenergic agonists (LABA) increase the risk of asthma-related death. Data from a large placebo-controlled US trial that compared the safety of another LABA (salmeterol) with placebo added to usual asthma therapy showed an increase in asthma-related deaths in subjects receiving salmeterol. This finding with salmeterol is considered a class effect of LABA, including vilanterol, an active ingredient in BREO ELLIPTA [see Warnings and Precautions (5.1)]. The safety and efficacy of BREO ELLIPTA in patients with asthma have not been established. BREO ELLIPTA is not indicated for the treatment of asthma. 1 INDICATIONS AND USAGE BREO ELLIPTA is a combination inhaled corticosteroid/long-acting beta2-adrenergic agonist (ICS/LABA) indicated for the long-term, once-daily, maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema. BREO ELLIPTA is also indicated to reduce exacerbations of COPD in patients with a history of exacerbations. Important Limitations of Use: BREO ELLIPTA is NOT indicated for the relief of acute bronchospasm or for the treatment of asthma. 4 CONTRAINDICATIONS The use of BREO ELLIPTA is contraindicated in patients with severe hypersensitivity to milk proteins or who have demonstrated hypersensitivity to either fluticasone furoate, vilanterol, or any of the excipients [see Warnings and Precautions (5.11), Description (11) of full prescribing information]. 5 WARNINGS AND PRECAUTIONS 5.1 Asthma-Related Death Data from a large placebo-controlled trial in subjects with asthma showed that LABA may increase the risk of asthma-related death. Data are not available to determine whether the rate of death in patients with COPD is increased by LABA. A 28-week, placebo-controlled, US trial comparing the safety of another LABA (salmeterol) with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in subjects receiving salmeterol (13/13,176 in subjects treated with salmeterol vs 3/13,179 in subjects treated with placebo; relative risk: 4.37 [95% CI: 1.25, 15.34]). The increased risk of asthmarelated death is considered a class effect of LABA, including vilanterol, one of the active ingredients in BREO ELLIPTA. No study adequate to determine whether the rate of asthma-related death is increased in subjects treated with BREO ELLIPTA has been conducted. The safety and efficacy of BREO ELLIPTA in patients with asthma have not been established. BREO ELLIPTA is not indicated for the treatment of asthma. 5.2 Deterioration of Disease and Acute Episodes BREO ELLIPTA should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of COPD. BREO ELLIPTA has not been studied in patients with acutely deteriorating COPD. The initiation of BREO ELLIPTA in this setting is not appropriate. BREO ELLIPTA should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. BREO ELLIPTA has not been studied in the relief of acute symptoms and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled, short-acting beta2-agonist. When beginning treatment with BREO ELLIPTA, patients who have been taking oral or inhaled, short-acting beta2-agonists on a regular basis (e.g., 4 times a day) should be instructed to discontinue the regular use of these drugs and to use them only for symptomatic relief of acute respiratory symptoms. When prescribing BREO ELLIPTA, the healthcare provider should also prescribe an inhaled, short-acting beta2-agonist and instruct the patient on how it should be used. Increasing inhaled, short-acting beta2-agonist use is a signal of deteriorating disease for which prompt medical attention is indicated. COPD may deteriorate acutely over a period of hours or chronically over several days or longer. If BREO ELLIPTA no longer controls symptoms of bronchoconstriction; the patientâ&#x20AC;&#x2122;s inhaled, shortacting, beta2-agonist becomes less effective; or the patient needs more short-acting beta2-agonist than usual, these may be markers of deterioration of disease. In this setting a re-evaluation of the patient and the COPD treatment regimen should be undertaken at once. Increasing the daily dose of BREO ELLIPTA beyond the recommended dose is not appropriate in this situation. 5.3 Excessive Use of BREO ELLIPTA and Use With Other Long-Acting Beta2Agonists BREO ELLIPTA should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medicines containing LABA, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Patients using BREO ELLIPTA should not use another medicine containing a LABA (e.g., salmeterol, formoterol fumarate, arformoterol tartrate, indacaterol) for any reason. 5.4 Local Effects of Inhaled Corticosteroids In clinical trials, the development of localized infections of the mouth and pharynx with Candida albicans has occurred in subjects treated with BREO ELLIPTA. When such an infection develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while treatment with BREO ELLIPTA continues, but at times therapy with BREO ELLIPTA may need to be interrupted. Advise the patient to rinse his/her mouth without swallowing following inhalation to help reduce the risk of oropharyngeal candidiasis. 5.5 Pneumonia An increase in the incidence of pneumonia has been observed in subjects with COPD receiving the fluticasone furoate/vilanterol combination, including BREO ELLIPTA 100 mcg/25 mcg, in clinical trials. There was also an increased incidence of pneumonias resulting in hospitalization. In some incidences

these pneumonia events were fatal. Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as the clinical features of such infections overlap with the symptoms of COPD exacerbations. In replicate 12-month trials in 3,255 subjects with COPD who had experienced a COPD exacerbation in the previous year, there was a higher incidence of pneumonia reported in subjects receiving the fluticasone furoate/vilanterol combination (50 mcg/25 mcg: 6% [48 of 820 subjects]; 100 mcg/25 mcg: 6% [51 of 806 subjects]; or 200 mcg/25 mcg: 7% [55 of 811 subjects]) than in subjects receiving vilanterol 25 mcg (3% [27 of 818 subjects]). There was no fatal pneumonia in subjects receiving vilanterol or fluticasone furoate/vilanterol 50 mcg/25 mcg. There was fatal pneumonia in 1 subject receiving fluticasone furoate/vilanterol 100 mcg/25 mcg and in 7 subjects receiving fluticasone furoate/vilanterol 200 mcg/25 mcg (less than 1% for each treatment group). 5.6 Immunosuppression Persons who are using drugs that suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in susceptible children or adults using corticosteroids. In such children or adults who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If a patient is exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If a patient is exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chickenpox develops, treatment with antiviral agents may be considered. Inhaled corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infections of the respiratory tract; systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex. 5.7 Transferring Patients From Systemic Corticosteroid Therapy Particular care is needed for patients who have been transferred from systemically active corticosteroids to inhaled corticosteroids because deaths due to adrenal insufficiency have occurred in patients with asthma during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary-adrenal (HPA) function. Patients who have been previously maintained on 20 mg or more of prednisone (or its equivalent) may be most susceptible, particularly when their systemic corticosteroids have been almost completely withdrawn. During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery, or infection (particularly gastroenteritis) or other conditions associated with severe electrolyte loss. Although BREO ELLIPTA may control COPD symptoms during these episodes, in recommended doses it supplies less than normal physiological amount of glucocorticoid systemically and does NOT provide the mineralocorticoid activity that is necessary for coping with these emergencies. During periods of stress or a severe COPD exacerbation, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their physicians for further instruction. These patients should also be instructed to carry a warning card indicating that they may need supplementary systemic corticosteroids during periods of stress or severe COPD exacerbation. Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to BREO ELLIPTA. Prednisone reduction can be accomplished by reducing the daily prednisone dose by 2.5 mg on a weekly basis during therapy with BREO ELLIPTA. Lung function (mean forced expiratory volume in 1 second [FEV1]), beta-agonist use, and COPD symptoms should be carefully monitored during withdrawal of oral corticosteroids. In addition, patients should be observed for signs and symptoms of adrenal insufficiency, such as fatigue, lassitude, weakness, nausea and vomiting, and hypotension. Transfer of patients from systemic corticosteroid therapy to BREO ELLIPTA may unmask allergic conditions previously suppressed by the systemic corticosteroid therapy (e.g., rhinitis, conjunctivitis, eczema, arthritis, eosinophilic conditions). During withdrawal from oral corticosteroids, some patients may experience symptoms of systemically active corticosteroid withdrawal (e.g., joint and/or muscular pain, lassitude, and depression) despite maintenance or even improvement of respiratory function. 5.8 Hypercorticism and Adrenal Suppression Inhaled fluticasone furoate is absorbed into the circulation and can be systemically active. Effects of fluticasone furoate on the HPA axis are not observed with the therapeutic dose of BREO ELLIPTA. However, exceeding the recommended dosage or coadministration with a strong cytochrome P450 3A4 (CYP3A4) inhibitor may result in HPA dysfunction [see Warnings and Precautions (5.9), Drug Interactions (7.1)]. Because of the possibility of significant systemic absorption of inhaled corticosteroids in sensitive patients, patients treated with BREO ELLIPTA should be observed carefully for any evidence of systemic corticosteroid effects. Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response. It is possible that systemic corticosteroid effects such as hypercorticism and adrenal suppression (including adrenal crisis) may appear in a small number of patients who are sensitive to these effects. If such effects occur, BREO ELLIPTA should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids, and other treatments for management of COPD symptoms should be considered. 5.9 Drug Interactions With Strong Cytochrome P450 3A4 Inhibitors Caution should be exercised when considering the coadministration of BREO ELLIPTA with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, clarithromycin, conivaptan, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, troleandomycin, voriconazole) because increased systemic corticosteroid and increased cardiovascular adverse effects may occur [see Drug Interactions (7.1), Clinical Pharmacology (12.3) of full prescribing information]. 5.10 Paradoxical Bronchospasm As with other inhaled medicines, BREO ELLIPTA

can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with BREO ELLIPTA, it should be treated immediately with an inhaled, short-acting bronchodilator; BREO ELLIPTA should be discontinued immediately; and alternative therapy should be instituted. 5.11 Hypersensitivity Reactions Hypersensitivity reactions may occur after administration of BREO ELLIPTA. There have been reports of anaphylactic reactions in patients with severe milk protein allergy after inhalation of other powder products containing lactose; therefore, patients with severe milk protein allergy should not take BREO ELLIPTA [see Contraindications (4)]. 5.12 Cardiovascular Effects Vilanterol, like other beta2-agonists, can produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, systolic or diastolic blood pressure, and also cardiac arrhythmias, such as supraventricular tachycardia and extrasystoles. If such effects occur, BREO ELLIPTA may need to be discontinued. In addition, beta-agonists have been reported to produce electrocardiographic changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression, although the clinical significance of these findings is unknown. In healthy subjects, large doses of inhaled fluticasone furoate/vilanterol (4 times the recommended dose of vilanterol, representing a 12-fold higher systemic exposure than seen in patients with COPD) have been associated with clinically significant prolongation of the QTc interval, which has the potential for producing ventricular arrhythmias. Therefore, BREO ELLIPTA, like other sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension. 5.13 Reduction in Bone Mineral Density Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing inhaled corticosteroids. The clinical significance of small changes in BMD with regard to long-term consequences such as fracture is unknown. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, postmenopausal status, tobacco use, advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants, oral corticosteroids) should be monitored and treated with established standards of care. Since patients with COPD often have multiple risk factors for reduced BMD, assessment of BMD is recommended prior to initiating BREO ELLIPTA and periodically thereafter. If significant reductions in BMD are seen and BREO ELLIPTA is still considered medically important for that patient’s COPD therapy, use of medicine to treat or prevent osteoporosis should be strongly considered. In replicate 12-month trials in 3,255 subjects with COPD, bone fractures were reported by 2% of subjects receiving the fluticasone furoate/vilanterol combination (50 mcg/25 mcg: 2% [14 of 820 subjects]; 100 mcg/25 mcg: 2% [19 of 806 subjects]; or 200 mcg/25 mcg: 2% [14 of 811 subjects]) than in subjects receiving vilanterol 25 mcg alone (less than 1% [8 of 818 subjects]). 5.14 Glaucoma and Cataracts Glaucoma, increased intraocular pressure, and cataracts have been reported in patients with COPD following the long-term administration of inhaled corticosteroids. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts. In replicate 12-month trials in 3,255 subjects with COPD, similar incidences of ocular effects (including glaucoma and cataracts) were reported in subjects receiving the fluticasone furoate/vilanterol combination (50 mcg/25 mcg: less than 1% [7 of 820 subjects]; 100 mcg/25 mcg: 1% [12 of 806 subjects]; 200 mcg/25 mcg: less than 1% [7 of 811 subjects]) as those receiving vilanterol 25 mcg alone (1% [9 of 818 subjects]). 5.15 Coexisting Conditions BREO ELLIPTA, like all medicines containing sympathomimetic amines, should be used with caution in patients with convulsive disorders or thyrotoxicosis and in those who are unusually responsive to sympathomimetic amines. Doses of the related beta2-adrenoceptor agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis. 5.16 Hypokalemia and Hyperglycemia Beta-adrenergic agonist medicines may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects. The decrease in serum potassium is usually transient, not requiring supplementation. Beta-agonist medications may produce transient hyperglycemia in some patients. In 4 clinical trials of 6- and 12-month duration evaluating BREO ELLIPTA in subjects with COPD, there was no evidence of a treatment effect on serum glucose or potassium. 6 ADVERSE REACTIONS LABA, such as vilanterol, one of the active ingredients in BREO ELLIPTA, increase the risk of asthma-related death. BREO ELLIPTA is not indicated for the treatment of asthma. [See Boxed Warnings and Warnings and Precautions (5.1).] Systemic and local corticosteroid use may result in the following: Increased risk of pneumonia in COPD [see Warnings and Precautions (5.5)]; Increased risk for decrease in bone mineral density [see Warnings and Precautions (5.13)]. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. The clinical program for BREO ELLIPTA included 7,700 subjects with COPD in two 6-month lung function trials, two 12-month exacerbation trials, and 6 other trials of shorter duration. A total of 2,034 subjects have received at least 1 dose of BREO ELLIPTA 100 mcg/25 mcg, and 1,087 subjects have received higher doses of fluticasone furoate/vilanterol. The safety data described below are based on the confirmatory 6-month and 12-month trials. Adverse reactions observed in the other trials were similar to those observed in the confirmatory trials. 6-Month Trials: The incidence of adverse reactions associated with BREO ELLIPTA in Table 1 is based on 2 placebo-controlled, 6-month clinical trials (Trials 1 and 2; n = 1,224 and n = 1,030, respectively). Of the 2,254 subjects, 70% were male and 84% were Caucasian. They had a mean age of 62 years and an average smoking

history of 44 pack years, with 54% identified as current smokers. At screening, the mean postbronchodilator percent predicted FEV1 was 48% (range: 14% to 87%), the mean postbronchodilator FEV1/forced vital capacity (FVC) ratio was 47% (range: 17% to 88%), and the mean percent reversibility was 14% (range: -41% to 152%). Subjects received 1 inhalation once daily of the following: BREO ELLIPTA 100 mcg/25 mcg, fluticasone furoate/vilanterol 50 mcg/25 mcg, fluticasone furoate/ vilanterol 200 mcg/25 mcg, fluticasone furoate 100 mcg, fluticasone furoate 200 mcg, vilanterol 25 mcg, or placebo. Table 1. Adverse Reactions With ≥3% Incidence and More Common Than Placebo With BREO ELLIPTA in Subjects With Chronic Obstructive Pulmonary Disease

Adverse Event

BREO ELLIPTA 100 mcg/25 mcg (n = 410) %

Vilanterol 25 mcg (n = 408) %

Fluticasone Furoate 100 mcg (n = 410) %

Placebo (n = 412) %

Infections and infestations Nasopharyngitis Upper respiratory tract infection Oropharyngeal candidiasisa

Nervous system disorders Headache

Includes terms oral candidiasis, oropharyngeal candidiasis, candidiasis, and oropharyngitis fungal.

12-Month Trials: Long-term safety data is based on two 12-month trials (Trials 3 and 4; n = 1,633 and n = 1,622, respectively). Trials 3 and 4 included 3,255 subjects, of which 57% were male and 85% were Caucasian. They had a mean age of 64 years and an average smoking history of 46 pack years, with 44% identified as current smokers. At screening, the mean postbronchodilator percent predicted FEV1 was 45% (range: 12% to 91%), and the mean postbronchodilator FEV1/FVC ratio was 46% (range: 17% to 81%), indicating that the subject population had moderate to very severely impaired airflow obstruction. Subjects received 1 inhalation once daily of the following: BREO ELLIPTA 100 mcg/25 mcg, fluticasone furoate/vilanterol 50 mcg/25 mcg, fluticasone furoate/vilanterol 200 mcg/25 mcg, or vilanterol 25 mcg. In addition to the events shown in Table 1, adverse reactions occurring in greater than or equal to 3% of the subjects treated with BREO ELLIPTA (N = 806) for 12 months included COPD, back pain, pneumonia [see Warnings and Precautions (5.5)], bronchitis, sinusitis, cough, oropharyngeal pain, arthralgia, hypertension, influenza, pharyngitis, diarrhea, peripheral edema, and pyrexia. 7 DRUG INTERACTIONS 7.1 Inhibitors of Cytochrome P450 3A4 Fluticasone furoate and vilanterol, the individual components of BREO ELLIPTA, are both substrates of CYP3A4. Concomitant administration of the potent CYP3A4 inhibitor ketoconazole increases the systemic exposure to fluticasone furoate and vilanterol. Caution should be exercised when considering the coadministration of BREO ELLIPTA with longterm ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, clarithromycin, conivaptan, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, troleandomycin, voriconazole) [see Warnings and Precautions (5.9) and Clinical Pharmacology (12.3) of full prescribing information]. 7.2 Monoamine Oxidase Inhibitors and Tricyclic Antidepressants Vilanterol, like other beta2-agonists, should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors, tricyclic antidepressants, or drugs known to prolong the QTc interval or within 2 weeks of discontinuation of such agents, because the effect of adrenergic agonists on the cardiovascular system may be potentiated by these agents. Drugs that are known to prolong the QTc interval have an increased risk of ventricular arrhythmias. 7.3 Beta Adrenergic Receptor Blocking Agents Beta-blockers not only block the pulmonary effect of beta-agonists, such as vilanterol, a component of BREO ELLIPTA, but may produce severe bronchospasm in patients with reversible obstructive airways disease. Therefore, patients with COPD should not normally be treated with beta-blockers. However, under certain circumstances, there may be no acceptable alternatives to the use of beta-adrenergic blocking agents for these patients; cardioselective beta-blockers could be considered, although they should be administered with caution. 7.4 Non–Potassium-Sparing Diuretics The electrocardiographic changes and/ or hypokalemia that may result from the administration of non-potassium-sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by betaagonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the coadministration of beta-agonists with non–potassium-sparing diuretics. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic Effects: Pregnancy Category C. There are no adequate and well-controlled trials with BREO ELLIPTA in pregnant women. Corticosteroids and beta2-agonists have been shown to be teratogenic in laboratory animals when administered systemically at relatively low dosage levels. Because animal studies are not always predictive of human response, BREO ELLIPTA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Women should be advised to contact their physicians if they become pregnant while

taking BREO ELLIPTA. Fluticasone Furoate and Vilanterol: There was no evidence of teratogenic interactions between fluticasone furoate and vilanterol in rats at approximately 9 and 40 times, respectively, the maximum recommended human daily inhalation dose (MRHDID) in adults (on a mcg/m2 basis at maternal inhaled doses of fluticasone furoate and vilanterol, alone or in combination, up to approximately 95 mcg/kg/day). Fluticasone Furoate: There were no teratogenic effects in rats and rabbits at approximately 9 and 2 times, respectively, the MRHDID in adults (on a mcg/ m2 basis at maternal inhaled doses up to 91 and 8 mcg/kg/day in rats and rabbits, respectively). There were no effects on perinatal and postnatal development in rats at approximately 3 times the MRHDID in adults (on a mcg/m2 basis at maternal doses up to 27 mcg/kg/day). Vilanterol: There were no teratogenic effects in rats and rabbits at approximately 13,000 and 160 times, respectively, the MRHDID in adults (on a mcg/m2 basis at maternal inhaled doses up to 33,700 mcg/kg/day in rats and on an AUC basis at maternal inhaled doses up to 591 mcg/kg/day in rabbits). However, fetal skeletal variations were observed in rabbits at approximately 1,000 times the MRHDID in adults (on an AUC basis at maternal inhaled or subcutaneous doses of 5,740 or 300 mcg/kg/ day, respectively). The skeletal variations included decreased or absent ossification in cervical vertebral centrum and metacarpals. There were no effects on perinatal and postnatal development in rats at approximately 3,900 times the MRHDID in adults (on a mcg/m2 basis at maternal oral doses up to 10,000 mcg/kg/day). Nonteratogenic Effects: Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Such infants should be carefully monitored. 8.2 Labor and Delivery There are no adequate and well-controlled human trials that have investigated the effects of BREO ELLIPTA during labor and delivery. Because beta-agonists may potentially interfere with uterine contractility, BREO ELLIPTA should be used during labor only if the potential benefit justifies the potential risk. 8.3 Nursing Mothers It is not known whether fluticasone furoate or vilanterol are excreted in human breast milk. However, other corticosteroids and beta2-agonists have been detected in human milk. Since there are no data from controlled trials on the use of BREO ELLIPTA by nursing mothers, caution should be exercised when it is administered to a nursing woman. 8.5 Geriatric Use Based on available data, no adjustment of the dosage of BREO ELLIPTA in geriatric patients is necessary, but greater sensitivity in some older individuals cannot be ruled out. Clinical trials of BREO ELLIPTA for COPD included 2,508 subjects aged 65 and older and 564 subjects aged 75 and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger subjects. 8.6 Hepatic Impairment Fluticasone furoate systemic exposure increased by up to 3-fold in subjects with hepatic impairment compared with healthy subjects. Hepatic impairment had no effect on vilanterol systemic exposure. Use BREO ELLIPTA with caution in patients with moderate or severe hepatic impairment. Monitor patients for corticosteroid-related side effects [see Clinical Pharmacology (12.3) of full prescribing information]. 8.7 Renal Impairment There were no significant increases in either fluticasone furoate or vilanterol exposure in subjects with severe renal impairment (CrCl<30 mL/min) compared with healthy subjects. No dosage adjustment is required in patients with renal impairment [see Clinical Pharmacology (12.3) of full prescribing information]. 10 OVERDOSAGE No human overdosage data has been reported for BREO ELLIPTA. BREO ELLIPTA contains both fluticasone furoate and vilanterol; therefore, the risks associated with overdosage for the individual components described below apply to BREO ELLIPTA. 10.1 Fluticasone Furoate Because of low systemic bioavailability (15.2%) and an absence of acute drug-related systemic findings in clinical trials, overdosage of fluticasone furoate is unlikely to require any treatment other than observation. If used at excessive doses for prolonged periods, systemic effects such as hypercorticism may occur [see Warnings and Precautions (5.8)]. Single- and repeat-dose trials of fluticasone furoate at doses of 50 to 4,000 mcg have been studied in human subjects. Decreases in mean serum cortisol were observed at dosages of 500 mcg or higher given once daily for 14 days. 10.2 Vilanterol The expected signs and symptoms with overdosage of vilanterol are those of excessive beta-adrenergic stimulation and/or occurrence or exaggeration of any of the signs and symptoms of beta-adrenergic stimulation (e.g., angina, hypertension or hypotension, tachycardia with rates up to 200 beats/ min, arrhythmias, nervousness, headache, tremor, seizures, muscle cramps, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, insomnia, hyperglycemia, hypokalemia, metabolic acidosis). As with all inhaled sympathomimetic medicines, cardiac arrest and even death may be associated with an overdose of vilanterol. Treatment of overdosage consists of discontinuation of BREO ELLIPTA together with institution of appropriate symptomatic and/or supportive therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medicine can produce bronchospasm. Cardiac monitoring is recommended in cases of overdosage. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility BREO ELLIPTA: No studies of carcinogenicity, mutagenicity, or impairment of fertility were conducted with BREO ELLIPTA; however, studies are available for the individual components, fluticasone furoate and vilanterol, as described below. Fluticasone Furoate: Fluticasone furoate produced no treatment-related increases in the incidence of tumors in 2-year inhalation studies in rats and mice at inhaled doses up to 9 and 19 mcg/kg/day, respectively (approximately equal to the MRHDID in adults on a mcg/m2 basis). Fluticasone furoate did not induce gene mutation in bacteria or chromosomal damage in a mammalian cell mutation test in mouse lymphoma L5178Y cells in vitro. There was also no evidence of genotoxicity in the in vivo micronucleus test in rats. No evidence of impairment of fertility was observed

in male and female rats at inhaled fluticasone furoate doses up to 29 and 91 mcg/kg/ day, respectively (approximately 3 and 9 times, respectively, the MRHDID in adults on a mcg/m2 basis). Vilanterol: In a 2-year carcinogenicity study in mice, vilanterol caused a statistically significant increase in ovarian tubulostromal adenomas in females at an inhalation dose of 29,500 mcg/kg/day (approximately 8,750 times the MRHDID in adults on an AUC basis). No increase in tumors was seen at an inhalation dose of 615 mcg/kg/ day (approximately 530 times the MRHDID in adults on an AUC basis). In a 2-year carcinogenicity study in rats, vilanterol caused statistically significant increases in mesovarian leiomyomas in females and shortening of the latency of pituitary tumors at inhalation doses greater than or equal to 84.4 mcg/kg/day (greater than or equal to approximately 45 times the MRHDID in adults on an AUC basis). No tumors were seen at an inhalation dose of 10.5 mcg/kg/day (approximately 2 times the MRHDID in adults on an AUC basis). These tumor findings in rodents are similar to those reported previously for other beta-adrenergic agonist drugs. The relevance of these findings to human use is unknown. Vilanterol tested negative in the following genotoxicity assays: the in vitro Ames assay, in vivo rat bone marrow micronucleus assay, in vivo rat unscheduled DNA synthesis (UDS) assay, and in vitro Syrian hamster embryo (SHE) cell assay. Vilanterol tested equivocal in the in vitro mouse lymphoma assay. No evidence of impairment of fertility was observed in reproductive studies conducted in male and female rats at inhaled vilanterol doses up to 31,500 and 37,100 mcg/kg/day, respectively (approximately 12,000 and 14,000 times, respectively, the MRHDID in adults on a mcg/m2 basis). 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide and Instructions for Use) 17.1 Asthma-Related Death Patients should be informed that LABA, such as vilanterol, one of the active ingredients in BREO ELLIPTA, increase the risk of asthmarelated death. BREO ELLIPTA is not indicated for the treatment of asthma. 17.2 Not for Acute Symptoms BREO ELLIPTA is not meant to relieve acute symptoms of COPD and extra doses should not be used for that purpose. Acute symptoms should be treated with a rescue inhaler such as albuterol. The physician should provide the patient with such medicine and instruct the patient in how it should be used. Patients should be instructed to notify their physicians immediately if they experience any of the following: Symptoms get worse; Need for more inhalations than usual of their rescue inhaler; Significant decrease in lung function as outlined by the physician. Patients should not stop therapy with BREO ELLIPTA without physician/provider guidance since symptoms may recur after discontinuation. 17.3 Do Not Use Additional Long-Acting Beta2-Agonists When patients are prescribed BREO ELLIPTA, other medicines containing a LABA should not be used. 17.4 Risks Associated With Corticosteroid Therapy Local Effects: Patients should be advised that localized infections with Candida albicans occurred in the mouth and pharynx in some patients. If oropharyngeal candidiasis develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while still continuing therapy with BREO ELLIPTA, but at times therapy with BREO ELLIPTA may need to be temporarily interrupted under close medical supervision. Rinsing the mouth without swallowing after inhalation is advised to help reduce the risk of thrush. Pneumonia: Patients with COPD who have received BREO ELLIPTA have a higher risk of pneumonia and should be instructed to contact their healthcare providers if they develop symptoms of pneumonia (e.g., fever, chills, change in sputum color, increase in breathing problems). Immunosuppression: Patients who are on immunosuppressant doses of corticosteroids should be warned to avoid exposure to chickenpox or measles and, if exposed, to consult their physicians without delay. Patients should be informed of potential worsening of existing tuberculosis, fungal, bacterial, viral, or parasitic infections, or ocular herpes simplex. Hypercorticism and Adrenal Suppression: Patients should be advised that BREO ELLIPTA may cause systemic corticosteroid effects of hypercorticism and adrenal suppression. Additionally, patients should be instructed that deaths due to adrenal insufficiency have occurred during and after transfer from systemic corticosteroids. Reduction in Bone Mineral Density: Patients who are at an increased risk for decreased BMD should be advised that the use of corticosteroids may pose an additional risk. Ocular Effects: Long-term use of inhaled corticosteroids may increase the risk of some eye problems (cataracts or glaucoma); regular eye examinations should be considered. 17.5 Risks Associated With Beta-Agonist Therapy Patients should be informed of adverse effects associated with beta2-agonists, such as palpitations, chest pain, rapid heart rate, tremor, or nervousness. BREO and ELLIPTA are trademarks of GlaxoSmithKline. BREO ELLIPTA was developed in collaboration with

BRE:1BRS

Simbrinza (Brinzolamide/Brimonidine Tartrate) Receives FDA Approval for the Treatment of Open-Angle Glaucoma or Ocular Hypertension By Loretta Fala, Medical Writer

laucoma affects an estimated 2.2 million people in the United States, and is estimated to affect as many as 3 million people by 2020.1 Its prevalence is projected to rise with the aging of the US population.2 Glaucoma has the potential to destroy retinal ganglion cells in the optic nerve, which can lead to severe vision loss and blindness.1 In fact, glaucoma is a leading cause of blindness in the United States, accounting for 9% to 12% of all cases of blindness.3 The 2 main types of glaucoma are open-angle glaucoma and angle-closure glaucoma.4 Open-angle glaucoma, also referred to as primary or chronic glaucoma, is the most common type, accounting for ≥90% of all cases of glaucoma.4 People aged ≥60 years are at an increased risk for glaucoma, particularly in the Hispanic population.5 The risk for open-angle glaucoma increases at age ≥40 years.5 African Americans are 15 times more likely to have glaucoma-related visual impairment than Caucasians.3 Patients with glaucoma often have increased intraocular pressure (IOP)—a condition that may prevent retinal ganglion cells from receiving a brain-derived neurotrophic factor (a protein required for retinal ganglion cell survival) from nearby cells in the optic nerve.1 An estimated 70% of patients with glaucoma have a history of elevated IOP.1 An elevated baseline IOP is one of the only modifiable risk factors associated with open-angle glaucoma.6 Other potentially modifiable factors, including IOP fluctuation and nutrition, are also being studied.6 Ocular hypertension is characterized by an IOP of >21 mm Hg, the upper limit of normal IOP in the general population.7 According to several population studies, an estimated 4% to 10% of people aged ≥40 years will have an IOP of ≥21 mm Hg without detectable signs of damage from glaucoma.7 Glaucoma imposes a substantial burden on a person’s quality of life, affecting driving, walking, and reading, and it may also lead to social withdrawal and depression.2 Vision loss has a dramatic societal and economic impact, because it may result in disability, suffering, and loss of productivity.8 Glaucoma accounts for an estimated $2.9

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billion in direct costs annually in the United States.2 These costs may actually be higher than currently estimated, given that many people with glaucoma are unaware that they have the condition.2 Furthermore, the financial burden of glaucoma increases with the severity of the disease.2 Glaucoma is an underdiagnosed condition that has a profound need for earlier diagnosis, which can help to slow its progression and improve patient outcomes.2 Glaucoma is often undiagnosed because it is relatively asymptomatic, particularly in the early stages, and a person may not seek medical attention until loss of vision occurs.2 In addition, many patients with diagnosed glaucoma are either not receiving treatment or their treatment is delayed.2 Proactive, early management can reduce the overall disease burden of glaucoma, and potentially its economic burden as well.2

Management of Open-Angle Glaucoma and Ocular Hypertension: Challenges and Opportunities The Early Manifest Glaucoma Trial, a 6-year collaborative study, confirmed the accumulating medical evidence showing that reducing eye pressure in the early stages of glaucoma slowed the progression of the disease.9 Another major study, the Ocular Hypertension Treatment Study (N = 1636), showed that topical ocular hypotensive therapy delayed or prevented the onset of primary open-angle glaucoma in patients with an elevated IOP, thereby reducing the development of glaucoma by more than 50%.10 A follow-up study of the Ocular Hypertension Treatment Study (N = 203) demonstrated that the use of daily topical ocular hypotensive therapy reduced the development of primary open-angle glaucoma in African-American patients by nearly 50%.11 The key therapeutic goal for glaucoma is to manage or to reduce IOP to mitigate the likelihood of optic nerve damage.12 Overall in the United States, pharmacologic treatment (with an ophthalmic solution) is the primary treatment choice, or a combination of medication and laser treatment.12 Pharmacologic treatments include sev-

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eral drug classes, such as prostaglandin analogs, beta- blockers, alpha agonists, carbonic anhydrase inhibitors, miotics, and combination medications.12 Medications for the treatment of glaucoma are associated with class-specific adverse events; however, the incidence of these side effects may vary from one agent to another. Moreover, some patients may be allergic or be sensitive to preservatives used in ophthalmic agents.12 When monitoring or treating patients, it may be challenging for clinicians to find an IOP range that helps to stabilize the patient’s visual fields and optic nerve and/or retinal nerve fiber status.13 Inadequate medication adherence is often another barrier to the optimal management of glaucoma, particularly when patients forget to administer their prescribed eye drops.12,13 A patient’s failure to follow the prescribed therapeutic regimen can result in serious consequences, including continued optic neuropathy and vision loss.13 Comorbid conditions (eg, diabetes, hypertension, hyperlipidemia) and associated polypharmacy may also have an impact on medication adherence.13

Simbrinza: Fixed-Dose Combination Indicated for Reduction of Intraocular Pressure On April 19, 2013, the US Food and Drug Administration (FDA) approved brinzolamide 1%/brimonidine tartrate 0.2% ophthalmic suspension (Simbrinza; Alcon Laboratories) for the reduction of elevated IOP in patients with primary open-angle glaucoma or ocular hypertension.14 Brinzolamide 1% plus brimonidine tartrate 0.2% is a fixed-dose combination of a carbonic anhydrase inhibitor and an alpha-2 adrenergic receptor agonist that is indicated for the reduction of elevated IOP.14 Brinzolamide/brimonidine is currently the only fixeddose combination therapy for glaucoma without a beta- blocker that is available in the United States.14 Commenting on the FDA approval of the new combination therapy, Gregory J. Katz, MD, Glaucoma Service, St Joseph Mercy Medical Center, Ann Arbor, MI, stated, “Glaucoma must be treated over the course of one’s life, and elevated eye pressure must be managed every day. It’s exciting to now have a product available that combines 2 effective compounds into one multidose combination, offering sustained control.”14 Dosing Simbrinza contains the fixed dose combination of 10 mg/mL of brinzolamide plus 2 mg/mL of brimonidine tartrate.15 The recommended dosage of brinzolamide/ brimonidine fixed-dose combination is 1 drop in the affected eye(s) 3 times daily. If more than 1 topical ophthalmic drug is being used, the drugs should be administered at least 5 minutes apart.15

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Mechanism of Action Simbrinza is a combination of 2 agents that decrease elevated IOP—brinzolamide, a carbonic anhydrase inhibitor, and brimonidine tartrate, an alpha-2 adrenergic receptor agonist. Brinzolamide inhibits carbonic anhydrase in the ciliary processes of the eye to decrease aqueous humor secretion, presumably by slowing the formation of bicarbonate ions and with subsequent reduction in sodium and fluid transport.15 Brinzolamide has a peak ocular hypotensive effect occurring between 2 and 3 hours after dosing.15 Brimonidine tartrate has a peak ocular hypotensive effect that occurs 2 hours after dosing. The result is a reduction in IOP.15 Clinical Studies The FDA approval of brinzolamide/brimonidine combination was based on 2 pivotal phase 3 clinical trials that involved approximately 1300 patients with open- angle glaucoma or with ocular hypertension.14 These studies, both 3 months in duration, assessed the IOP- lowering effect of brinzolamide 1%/brimonidine 0.2% ophthalmic suspension dosed 3 times daily compared with individually administered 1% brinzolamide 3 times daily and 0.2% brimonidine 3 times daily.16,17 The IOP-lowering effect of brinzolamide/brimonidine ophthalmic suspension was 1 mm Hg to 3 mm Hg greater than the effect of monotherapy with either 1% brinzolamide or with 0.2% brimonidine throughout the duration of the clinical trials.15 Table 1 shows the least square means for IOP (mm Hg) and the results of study 1 at week 2, week 6, and month 3.15 Table 2 shows the results for study 2.15 In both studies, the baseline mean IOP values were similar among treatment groups at all the 4 time points that were measured.16,17 Furthermore, the primary end points were achieved in both studies, and the brinzolamide/brimonidine combination was shown to be statistically superior at lowering IOP at month 3 for all time points compared with each of the individual components of the combination.16,17 In both studies, the brinzolamide/brimonidine combination therapy also achieved between a 5-mm Hg to 9-mm Hg reduction from baseline to month 3.14,16,17 In addition, the safety profile of the brinzolamide/brimonidine combination was similar to the safety profile of each of the individual components of the combination alone.16,17 Safety Profile Adverse Events The most common adverse reactions, occurring in approximately 3% to 5% of patients, included blurred vision, eye irritation, dysgeusia, dry mouth, and eye allergy.15

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Table 1 Study 1: Brinzolamide/Brimonidine Combination Therapy versus Brinzolamide or Brimonidine Alonea Brinzolamide/ brimonidine combination therapy (N = 209)

Brinzolamide (N = 224)

Brimonidine (N = 216)

Mean intraocular pressure, mm Hg

Difference (95% CI)b

Mean intraocular pressure, mm Hg

Difference (95% CI)b

8:00 am

20.4

22.0

–1.6 (–2.3 to –0.9)

22.4

–2.0 (–2.7 to –1.3)

10:00 am

17.1

20.5

–3.4 (–4.1 to –2.7)

19.4

–2.3 (–3.0 to –1.6)

3:00 pm

18.4

20.4

–1.9 (–2.6 to –1.3)

20.6

–2.2 (–2.9 to –1.5)

5:00 pm

16.6

19.7

–3.2 (–3.9 to –2.5)

18.4

–1.9 (–2.6 to –1.2)

8:00 am

20.4

21.9

–1.5 (–2.2 to –0.8)

22.6

–2.3 (–3.0 to –1.6)

10:00 am

17.5

20.2

–2.7 (–3.4 to –2.0)

19.5

–2.0 (–2.7 to –1.3)

3:00 pm

18.9

20.2

–1.2 (–1.9 to –0.5)

21.1

–2.1 (–2.8 to –1.4)

5:00 pm

17.0

19.7

–2.6 (–3.3 to –1.9)

18.6

–1.5 (–2.2 to –0.8)

8:00 am

20.5

21.6

–1.1 (–1.8 to –0.4)

23.3

–2.8 (–3.5 to –2.1)

10:00 am

17.2

20.4

–3.2 (–3.9 to –2.5)

19.7

–2.5 (–3.2 to –1.8)

3:00 pm

18.7

20.4

–1.8 (–2.5 to –1.1)

21.3

–2.6 (–3.3 to –1.9)

5:00 pm

17.0

20.0

–3.0 (–3.7 to –2.3)

18.8

–1.8 (–2.5 to –1.1)

Study 1 time points Week 2

Week 6

Month 3

Based on the intent-to-treat population, defined as all patients who received the study drug and completed >1 on-therapy study visit. b These estimates are based on least square means derived from a linear mixed model that accounts for correlated intraocular pressure measurements within patient; the difference reflects the results with brinzolamide/brimonidine combination therapy minus the individual component. CI indicates confidence interval. Source: Simbrinza (brinzolamide/brimonidine tartrate) ophthalmic suspension prescribing information; 2013. a

Brinzolamide is a sulfonamide, and although it is administered topically, it is absorbed systemically. Adverse reactions attributed to sulfonamide may occur. Fatalities have occurred as a result of severe reactions to sulfonamides.15 Sensitization may recur when a sulfonamide is readministered, regardless of the route of administration. If signs of serious reactions or hypersensitivity occur, brinzolamide plus brimonidine should be discontinued.15

Precautions The management of patients with acute angle-closure glaucoma requires therapeutic interventions in addition to ocular hypotensive agents. The combination of brinzolamide plus brimonidine has not been studied in patients with acute angle-closure glaucoma. Brinzolamide/brimonidine is associated with an in-

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creased potential for developing corneal edema in patients with low endothelial cell counts.15 The preservative in brinzolamide/brimonidine—benzalkonium chloride—may be absorbed by soft contact lenses. Therefore, contact lenses should be removed during the administration of brinzolamide/brimonidine and may be reinserted 15 minutes after administration.15 Brimonidine tartrate, a component of the brinzolamide/brimonidine combination, had a <5% mean decrease in blood pressure 2 hours after dosing in clinical studies; caution should be exercised in treating patients with severe cardiovascular disease.15 In addition, brimonidine tartrate may potentiate syndromes associated with vascular insufficiency. It should be used with caution in patients with depression, cerebral or coronary insufficiency, Raynaud’s phenomenon, orthostatic hypotension, or thromboangiitis obliterans.15

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Table 2 Study 2: Brinzolamide/Brimonidine Combination Therapy versus Brinzolamide or Brimonidine Alonea Brinzolamide/ brimonidine combination therapy (N = 218)

Brinzolamide (N = 229)

Brimonidine (N = 232)

Mean intraocular pressure, mm Hg

Difference (95% CI)b

Mean intraocular pressure, mm Hg

Difference (95% CI)b

8:00 am

20.5

22.2

–1.7 (–2.4 to –1.0)

22.8

–2.4 (–3.1 to –1.7)

10:00 am

17.4

20.7

–3.3 (–4.0 to –2.6)

19.2

–1.8 (–2.5 to –1.2)

3:00 pm

18.7

20.5

–1.7 (–2.4 to –1.1)

21.1

–2.3 (–3.0 to –1.6)

5:00 pm

16.5

20.1

–3.6 (–4.3 to –2.9)

18.3

–1.8 (–2.4 to –1.1)

8:00 am

20.7

21.9

–1.2 (–1.9 to –0.5)

23.2

–2.5 (–3.2 to –1.8)

10:00 am

17.4

20.5

–3.1 (–3.8 to –2.4)

19.7

–2.3 (–3.0 to –1.6)

3:00 pm

19.3

20.2

–0.8 (–1.5 to –0.2)

21.2

–1.9 (–2.6 to –1.2)

5:00 pm

16.9

19.9

–3.0 (–3.7 to –2.3)

18.5

–1.7 (–2.4 to –1.0)

8:00 am

21.1

22.0

–1.0 (–1.7 to –0.3)

23.2

–2.2 (–2.9 to –1.5)

10:00 am

18.0

20.8

–2.8 (–3.5 to –2.1)

19.9

–1.9 (–2.6 to –1.2)

3:00 pm

19.5

20.7

–1.2 (–1.9 to –0.5)

21.5

–2.0 (–2.7 to –1.3)

5:00 pm

17.2

20.4

–3.2 (–3.9 to –2.5)

18.9

–1.7 (–2.4 to –1.0)

Study 2 time points Week 2

Week 6

Month 3

Based on the intent-to-treat population, defined as all patients who received the study drug. These estimates are based on least square means derived from a linear mixed model that accounts for correlated intraocular pressure measurements within patient; the difference reflects the results with brinzolamide/brimonidine combination therapy minus the individual component. CI indicates confidence interval. Source: Simbrinza (brinzolamide/brimonidine tartrate) ophthalmic suspension prescribing information; 2013. a

There have been reports of bacterial keratitis associated with the use of multiple-dose containers of topical ophthalmic products. These containers have been inadvertently contaminated by patients who, in most cases, had a concurrent corneal disease or a disruption of the ocular epithelial surface.15 Brinzolamide/brimonidine ophthalmic suspension has not been specifically studied in patients with severe hepatic or renal impairment, and it is not recommended in these patients.15

Contraindications Brinzolamide plus brimonidine is contraindicated in patients who are hypersensitive to any component of this med ication, and in neonates and in infants (aged <2 years).15 Drug Interactions The concomitant administration of brinzolamide/bri-

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monidine ophthalmic suspension with oral carbonic anhydrase inhibitors is not recommended because of the potential additive effect of these medications. The use of brinzolamide/brimonidine with high-dose salicylate may result in acid-base and electrolyte alterations. Moreover, its use with central nervous system depressants may result in an additive or potentiating effect.15 The concomitant use of brinzolamide/brimonidine ophthalmic suspension with antihypertensives or with cardiac glycosides may result in an additive or potentiating effect on blood pressure lowering.15 The use of the brinzolamide/brimonidine combination with tricyclic antidepressants may blunt the hypotensive effect of systemic clonidine, and it is unknown whether its use with this class of drugs interferes with the effect of IOP lowering. The use of the ophthalmic suspension combination with monoamine oxidase inhibitors may result in increased hypotension.15

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Conclusion A new treatment option for patients with open-angle glaucoma or with ocular hypertension became available in April 2013 when the FDA approved Simbrinza, the fixed-dose combination of 1% brinzolamide, a carbonic anhydrase inhibitor, and 0.2% brimonidine tartrate, an alpha-2 adrenergic receptor agonist. Brinzolamide/bri-

Brinzolamide/brimonidine ophthalmic suspension is the first combination therapy approved for glaucoma in the United States that does not contain a beta-blocker. monidine ophthalmic suspension is the first combination therapy approved for glaucoma in the United States that does not contain a beta-blocker. The approval of this new combination therapy was based on 2 pivotal clinical trials of approximately 1300 patients with open-angle glaucoma or with ocular hypertension. In both studies, the combination therapy was significantly superior to the individual components of the combination at lowering IOP in patients with open-angle glaucoma. n

References

1. National Institutes of Health. Glaucoma fact sheet. Updated March 29, 2013. http:// report.nih.gov/nihfactsheets/ViewFactSheet.aspx?csid=92. Accessed May 25, 2013.

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2. Varma R, Lee PP, Goldberg I, Kotak S. An assessment of the health and economic burdens of glaucoma. Am J Ophthalmol. 2011;152:515-522. 3. Glaucoma Research Foundation. Glaucoma facts and stats. Reviewed April 22, 2013. www.glaucoma.org/glaucoma/glaucoma-facts-and-stats.php. Accessed May 26, 2013. 4. Glaucoma Research Foundation. Types of glaucoma. Reviewed May 24, 2012. www.glaucoma.org/glaucoma/types-of-glaucoma.php. Accessed May 26, 2013. 5. Mayo Clinic. Glaucoma: risk factors. October 2, 2012. www.mayoclinic.com/ health/glaucoma/DS00283/DSECTION=risk-factors. Accessed May 27, 2012. 6. Coleman AL, Miglior S. Risk factors for glaucoma onset and progression. Surv Ophthalmol. 2008;53(suppl 1):S3-S10. 7. Chang-Godinich A, Roy H, Bell JA, et al. Ocular hypertension. Medscape. Updated April 29, 2013. http://emedicine.medscape.com/article/1207470-overview. Accessed June 4, 2013. 8. Centers for Disease Control and Prevention. Vision Health Initiative (VHI): fast facts. Updated November 5, 2009. www.cdc.gov/visionhealth/basic_information/fast_ facts.htm. Accessed June 3, 2013. 9. Heijl A, Leske MC, Bengtsson B, et al; for the Early Manifest Glaucoma Trial Group. Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial. Arch Ophthalmol. 2002;120:1268-1279. 10. Kass MA, Heuer DK, Higginbotham EJ, et al; for the Ocular Hypertension Treatment Study Group. The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol. 2002;120:701-713. 11. Higginbotham EJ, Gordon MO, Beiser JA, et al; for the Ocular Hypertension Treatment Study Group. The Ocular Hypertension Treatment Study: topical medication delays or prevents primary open-angle glaucoma in African American individuals. Arch Ophthalmol. 2004;122:813-820. 12. Radhakrishnan S, Iwach A. Glaucoma medications and their side effects. Glaucoma Research Foundation. Updated August 21, 2012. www.glaucoma.org/treatment/ glaucoma-medications-and-their-side-effects.php. Accessed June 5, 2013. 13. Oâ&#x20AC;&#x2122;Brien KK, Chock AW, Opere CA. An overview of glaucoma management for pharmacists. US Pharm. April 2010. www.uspharmacist.com/continuing_education/ ceviewtest/lessonid/106698/. Accessed June 5, 2013. 14. Alcon News Center. Alcon announces FDA approval of Simbrinza suspension, a new beta blocker-free, fixed-combination therapy for glaucoma patients. Press release. April 19, 2013. www.alcon.com/news-center/news-item.aspx?id=281. Accessed May 23, 2013. 15. Simbrinza (brinzolamide/brimonidine tartrate) ophthalmic suspension [prescribing information]. Fort Worth, TX: Alcon Laboratories, Inc; 2013. 16. Katz G, Dubiner H, Samples J, et al. Three-month randomized trial of fixed-combination brinzolamide, 1%, and brimonidine, 0.2%. JAMA Ophthalmol. 2013 April 11 [Epub ahead of print]. 17. Nguyen QH, McMenemy MG, Realini T, et al. Phase 3 randomized 3-month trial with an ongoing 3-month safety extension of fixed-combination brinzolamide 1%/brimonidine 0.2%. J Ocul Pharmacol Ther. 2013;29:290-297.

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Simponi (Golimumab) Receives New FDA Indication as the First Subcutaneous Anti-TNF Therapy for Ulcerative Colitis By Loretta Fala, Medical Writer

lcerative colitis (UC), an inflammatory bowel disease that often causes chronic inflammation of the digestive tract, can be debilitating and may lead to life-threatening complications.1 UC affects more than 620,000 people in the United States.2 More common than Crohn’s disease, the incidence of UC is 1.2 cases to 20.3 cases per 100,000 people annually, whereas Crohn’s disease has an incidence of 0.03 cases to 15.6 cases per 100,000 people anually.3 Although UC can occur at any age, it is diagnosed most frequently in young adults between the ages of 15 years and 25 years.4 Men and women are affected equally by UC; however, men in their 50s and 60s are more likely to be diagnosed with UC than women of those age-groups.4 The onset of UC is thought to be triggered by a combination of factors, including environment, genetics, and immune-system overactivity.4 UC is associated with potentially serious complications, including intestinal bleeding, severe abdominal distention, and, in rare cases, toxic megacolon.4 UC is also associated with substantial costs, which were underestimated in the past.5 Based on a 2010 analysis, the total economic burden of UC in the United States is estimated to be $8.1 billion to $14.9 billion annually and accounts for annual per-patient direct medical costs ranging from $6217 to $11,477 (in 2008 dollars).5 In that analysis, hospitalizations accounted for 41% to 55% of the direct medical costs, and indirect costs accounted for an estimated 33% of the total costs. Moreover, direct costs, hospitalizations, and surgeries increased as the severity of UC worsened.5 Early diagnosis and management of UC are crucial to improving outcomes, given that effective treatment may control UC and help achieve remission of the disease.6 The therapeutic goals for UC are to reduce the inflammation that triggers the signs and symptoms, which in turn may lead to symptom relief and to longterm remission.1 Treatment helps to decrease the abnormal inflammation in the lining of the colon, permitting the colon to heal.7 Moreover, treatment often helps to alleviate diarrhea, rectal bleeding, abdominal pain, and other symptoms.1,7

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Medications used to treat UC include the aminosalicylates, corticosteroids, immunomodulators, and the biologic therapies known as anti–tumor necrosis factor (TNF) agents.8 Antibiotics may also be used to combat infections, such as abscesses, that may occur in association with UC.8 In recent years, the availability and use of anti-TNF therapies have helped to change the landscape of UC management, because these agents have shown efficacy in achieving steroid-free remission and mucosal healing.6

A New Subcutaneous Option for the Treatment of UC On May 15, 2013, golimumab (Simponi; Janssen Biotech) injection was approved by the US Food and Drug Administration (FDA) for the treatment of UC that is resistant to previous treatment or requires continuous steroid therapy.9 Golimumab is the first and only subcutaneously administered anti–TNF-alpha therapy approved by the FDA to induce and maintain clinical response in patients with UC and to improve the endoscopic appearance of the mucosa during induction.10 It is also indicated to induce clinical remission in patients with UC and to achieve and sustain clinical remission in induction responders.10,11 The FDA approval of golimumab, a self-injectable biologic therapy, for the treatment of UC was based on 2 major clinical studies in patients with moderate-tosevere UC. Golimumab was previously approved by the FDA for the treatment of psoriatic arthritis, alone or in combination with methotrexate, and for active ankylosing spondylitis. On July 19, 2013, golimumab (Simponi Aria) was approved by the FDA for patients with rheumatoid arthritis in combination with methotrexate. According to Andrew E. Mulberg, MD, CPI, Deputy Director, Division of Gastroenterology and Inborn Errors Products, FDA’s Center for Drug Evaluation and Research, “Simponi is an important new treatment option for patients with moderate-to-severe ulcerative colitis. It is critical that patients suffering from the serious and painful symptoms of ulcerative colitis have additional treatment options since patients experience the effects of the disease and respond to treatments differently.”9

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Lead investigator, William J. Sandborn, MD, Professor of Medicine and Chief, Division of Gastroenterology, and Director, University of California, San Diego (UCSD) Inflammatory Bowel Disease Center, UCSD School of Medicine, commented, “The FDA approval of Simponi brings an important, new subcutaneous therapeutic option to adults living with moderate-to-severe ulcerative colitis, a disease where treatment options have been limited. Simponi has demonstrated significant benefits in the treatment of ulcerative colitis, a chronic inflammatory bowel disease, and represents a meaningful addition to the treatment armamentaria for gastroenterologists.”12

Mechanism of Action Golimumab is a human monoclonal antibody that binds to the soluble and transmembrane bioactive forms of human TNF-alpha to its receptors, thereby inhibiting the biologic activity of TNF-alpha (a cytokine protein). Elevated TNF-alpha levels in the blood, synovium, and joints have been implicated in the pathophysiology of several chronic inflammatory diseases, such as rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. TNF-alpha is an important mediator of the articular inflammation that is characteristic of these diseases. The exact mechanism by which golimumab is beneficial in patients with UC is unknown.11 Dosing The recommended initial dose of golimumab for UC is 200 mg by subcutaneous injection at week 0, followed by 100 mg at week 2 and then 100 mg every 4 weeks. Golimumab is available in 50-mg/0.5-mL and 100-mg/ 1-mL single-dose, prefilled SmartJect autoinjectors, and 50-mg/0.5-mL and 100-mg/1-mL single-dose, prefilled syringes.11 Clinical Studies The safety and efficacy of golimumab were evaluated in 2 randomized, double-blind, placebo-controlled studies of patients aged ≥18 years. In Trial UC-1, an induction trial conducted in patients with moderate-to-severe active UC, a greater proportion of patients achieved clinical response and clinical remission, and showed improvement of the endoscopic appearance of the mucosa at week 6 in the golimumab 200/100-mg group compared with the placebo group (Table 1).11 Trial UC-2, a randomized withdrawal maintenance trial, evaluated patients who achieved clinical response with golimumab induction and tolerated treatment with golimumab (Table 2). In this study, a greater proportion of patients maintained clinical response through week 54

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UC-1 Trial: Efficacy Results of 6-Week Induction of Table 1 Golimumab versus Placebo in Patients with Ulcerative Colitis Golimumab Placebo, 200/100 mg, Treatment Efficacy % % difference, P parameter (N = 256) (N = 257) % value Clinical responsea at week 6

22 (95% CI, 14-30)

<.001

Clinical remissiona at week 6

12 (95% CI, 7-18)

<.001

Improvement of endoscopic appearance of the mucosa at week 6a

15 (95% CI, 6-23)

.005

Patients who had a prohibited change in concomitant UC medication, an ostomy, or a colectomy; discontinued trial agent because of a lack of therapeutic effect; or had a dose adjustment in Trial UC-2 were considered not to be in clinical response, clinical remission, or not to have an endoscopic improvement. CI indicates confidence interval; UC, ulcerative colitis. Source: Simponi (golimumab) injection prescribing information; 2013.

C-2 Trial: Efficacy Results of 54-Week Maintenance Table 2 U with Golimumab versus Placeboa Golimumab Placebo, 200/100 mg, Treatment Efficacy % % difference, P parameter (N = 156) (N = 154) % value Clinical responseb through week 54

19 (95% CI, 8-30)

<.001

Clinical remissionb at week 30 and week 54c

13 (95% CI, 4-22)

.003

These results are based on patients who were in clinical response to golimumab at trial entry. b Patients who had a prohibited change in concomitant UC medication, an ostomy, or a colectomy; discontinued golimumab because of a lack of therapeutic effect; or had a dose adjustment in Trial UC-2 were considered not to be in clinical response, clinical remission, or not to have an endoscopic improvement. c A patient had to be in remission at weeks 30 and 54 (without a loss of response at any point) to achieve sustained remission. CI indicates confidence interval; UC, ulcerative colitis. Source: Simponi (golimumab) injection prescribing information; 2013. a

in the group receiving golimumab 100 mg compared with the placebo group. Trial UC-2 also reassessed patients receiving golimumab in clinical response (which included the subset of patients in clinical remission) in Trial UC-1 for clinical remission at week 30 and week 54. A greater proportion of patients had clinical remission at week 30 and week 54 without demonstrating a

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dverse Drug Reactions Reported by ≥1% of Patients Receiving Golimumab and with a Higher Incidence than with Table 3 A Placebo in Phase 3 Trials of Rheumatoid Arthritis, Psoriatic Arthritis, and Ankylosing Spondylitis through Week 16a Golimumab ± DMARDs, % Placebo ± DMARDs, % Adverse reaction (N = 1659) (N = 639) Infections/infestations Upper respiratory tract infection (ie, nasopharyngitis, pharyngitis, laryngitis, rhinitis) Viral infections (eg, influenza, herpes) Bronchitis Superficial fungal infections Sinusitis General disorders and administration-site conditions Injection-site reaction (eg, injection-site erythema, urticaria, induration, pain, bruising, pruritus, irritation, paresthesia) Investigations Alanine aminotransferase increased Aspartate aminotransferase increased Vascular disorders Hypertension Central nervous system disorders Dizziness Paresthesia Gastrointestinal disorders Constipation

Patients may have taken concomitant methotrexate, sulfasalazine, hydroxychloroquine, low-dose corticosteroids (≤10 mg of prednisone daily or equivalent), and/or nonsteroidal anti-inflammatory drugs during the trials. DMARDs indicates disease-modifying antirheumatic drugs. Source: Simponi (golimumab) injection prescribing information; 2013. a

loss of response at any time point through week 54 in the group receiving golimumab 100 mg compared with the placebo group.11

Adverse Events The most common adverse reactions (incidence >5%) are upper respiratory tract infection, nasopharyngitis, and injection-site reactions. Additional adverse events include vascular disorders, central nervous system disorders, and gastrointestinal disorders (Table 3).11 Serious infections leading to hospitalization or death, including tuberculosis (TB), bacterial sepsis, invasive fungal (ie, histoplasmosis), and other opportunistic infections, have occurred in patients receiving golimumab. Lymphoma and other malignancies, some fatal, have been reported in children and in adolescent patients treated with TNF blockers, of which golimumab is a member.11 Other Warnings and Precautions Boxed warning. Golimumab was approved with a boxed warning about serious infections and malignancy.

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Therapy with golimumab should not be started during an active infection. If an infection develops, the patient should be monitored carefully and golimumab treatment should be stopped if the infection becomes serious. Patients should be tested for latent TB before the initiation of golimumab therapy. If the TB test is positive, treatment should be started for TB before initiating therapy with golimumab. Patients should be monitored for active TB during treatment, even if the initial latent TB test is negative.11 Invasive fungal infections. For patients who develop a systemic illness while taking golimumab, empiric antifungal therapy should be considered for those who live in or travel to regions where mycoses are endemic. Hepatitis B reactivation. Hepatitis B virus carriers should be monitored during and several months after therapy with golimumab. If reactivation occurs, treatment with golimumab should be discontinued and antiviral therapy should be initiated. Malignancies. The incidence of lymphoma was greater than in the general US population. Cases of

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other malignancies have been observed among patients receiving TNF blockers. Heart failure. The worsening or new onset of heart failure may occur with golimumab. If worsening symptoms occur, the use of golimumab should be stopped. Demyelinating diseases. The exacerbation or new onset of demyelinating diseases may occur with golimumab. Hypersensitivity reactions. Serious systemic hypersensitivity reactions, including anaphylaxis, may occur with golimumab. Live vaccines. Live vaccines should not be given concurrently with golimumab.11

Use in Specific Populations Pregnancy. There are no adequate and well-controlled trials of golimumab in pregnant women. Golimumab should be used during pregnancy only if clearly needed. Nursing mothers. It is not known whether golimu mab is excreted in human milk or absorbed systemically after ingestion. Because many drugs are excreted in human milk, and there is a potential for adverse reactions from golimumab in nursing infants, consideration should be given as to whether to discontinue nursing or to discontinue golimumab, taking into account the importance of the drug to the mother. Pediatric use. The safety and effectiveness of golimumab in pediatric patients aged <18 years have not been established. Geriatric use. With respect to UC, there were insufficient numbers of patients aged ≥65 years to determine whether they respond different from patients aged 18 years to 65 years. Because there is generally a higher incidence of infections in the geriatric population, caution should be used in treating geriatric patients with golimumab.11 Conclusion The FDA approved Simponi (golimumab) injection in May 2013 for a new indication—the treatment of UC that is resistant to previous treatment or that requires continuous steroid therapy. Golimumab was previously approved by the FDA for the treatment of rheumatoid arthritis in combination with methotrexate, for the treatment of psoriatic arthritis either alone or in com bination with methotrexate, and for the treatment of ankylosing spondylitis. Golimumab, a biologic agent, is the first and only subcutaneous anti–TNF-alpha therapy approved by the FDA to induce and maintain clinical response and to improve the endoscopic appearance of the mucosa during induction. Golimumab is also indicated to induce

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clinical remission and to achieve and sustain clinical remission in induction responders.

Golimumab, a biologic agent, is the first and only subcutaneous anti–TNF-alpha therapy approved by the FDA to induce and maintain clinical response and to improve the endoscopic appearance of the mucosa during induction. The FDA approval of golimumab for the treatment of patients with UC was based on 2 clinical studies in patients with moderate-to-severe UC. In the first study, a greater proportion of golimumab-treated patients achieved clinical response, clinical remission, and improved the endoscopic appearance of the mucosa at 6 weeks compared with the placebo group. In the second study, patients who responded to golimumab were randomly assigned to receive golimumab or placebo. Based on this study, a greater proportion of golimumab-treated patients maintained a clinical response through week 54 and demonstrated clinical remission at week 30 and week 54 compared with the placebo group. The most common adverse reactions (incidence >5%) seen with golimumab are upper respiratory tract infection, nasopharyngitis, and injection-site reactions. n

References

1. Mayo Clinic. Ulcerative colitis. October 10, 2012. www.mayoclinic.com/health/ ulcerative-colitis/DS00598. Accessed June 10, 2013. 2. National Digestive Diseases Information Clearinghouse. Digestive diseases statistics for the United States. Updated May 10, 2012. http://digestive.niddk.nih.gov/ statistics/statistics.aspx. Accessed June 10, 2013. 3. Danese S, Fiocchi C. Ulcerative colitis. N Engl J Med. 2011;365:1713-1725. 4. Crohn’s and Colitis Foundation of America. Living with ulcerative colitis. April 30, 2010. www.ccfa.org/resources/living-ulcerative-colitis.html. Accessed June 10, 2013. 5. Cohen RD, Yu AP, Wu EQ, et al. Systemic review: the costs of ulcerative colitis in Western countries. Aliment Pharmacol Ther. 2010;31:693-707. 6. Danese S, Colombel JF, Peyrin-Biroulet L, et al. Review article: the role of anti-TNF in the management of ulcerative colitis—past, present and future. Aliment Pharmacol Ther. 2013;37:855-866. 7. Crohn’s and Colitis Foundation of America. Colitis treatment options. www.ccfa. org/what-are-crohns-and-colitis/what-is-ulcerative-colitis/colitis-treatment-options. html. Accessed June 17, 2013. 8. Crohn’s and Colitis Foundation of America. Colitis medication options. www. ccfa.org/what-are-crohns-and-colitis/what-is-ulcerative-colitis/colitis-medication. html. Accessed February 25, 2014. 9. US Food and Drug Administration. FDA approves Simponi to treat ulcerative colitis. Press release. May 15, 2013. Updated May 17, 2013. www.fda.gov/NewsEvents/ Newsroom/PressAnnouncements/ucm352383.htm. Accessed June 10, 2013. 10. Janssen Biotech’s Simponi receives FDA approval for ulcerative colitis. May 20, 2013. CenterWatch News Online. www.centerwatch.com/news-online/article/4737/. Accessed June 11, 2013. 11. Simponi (golimumab) injection [prescribing information]. Horsham, PA: Janssen Biotech, Inc; May 2013. 12. Crohn’s and Colitis Foundation of America. Simponi (golimumab) receives FDA approval for ulcerative colitis. Press release. May 16, 2013. www.ccfa.org/news/ simponi.html. Accessed June 12, 2013.

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Simponi Aria (Golimumab): A New

Intravenous TNF Inhibitor for the Treatment of Patients with Moderate-to-Severe Rheumatoid Arthritis

By Loretta Fala, Medical Writer

heumatoid arthritis (RA), a chronic inflammatory autoimmune disorder that affects the lining, or synovium, of the joints, affects 1.3 million people in the United States.1,2 In addition to causing painful swelling that may eventually lead to bone erosion and joint deformity, RA can also affect other organs of the body, including the skin, eyes, lungs, and blood vessels.1,2 Although RA can occur in people in their 20s and 30s, it usually begins after age 40, affecting more than twice as many women as men.1,2 The average age of patients with RA is 66.8 years.2 In its early stage, RA may first affect smaller joints (ie, those that attach the fingers and toes), and as the disease progresses, it spreads to the knees, ankles, elbows, hips, and shoulders.1 An estimated 22% of all deaths from arthritis and other rheumatic conditions are attributed to RA.3 Aside from being associated with a high risk of disability and mortality, people with RA are twice as likely to die as persons of the same age without RA.3 Approximately 40% of all deaths associated with RA are attributed to cardiovascular causes, including ischemic heart disease and stroke.3 RA also has a substantial impact on a patient’s functional status and quality of life. One study showed that people with RA were 40% more likely to report fair or poor general health and twice as likely to have a health-related physical activity limitation.3,4 RA is also associated with substantial costs. According to one study, RA accounted for $19.3 billion (2005 dollars) in societal costs excluding intangible costs, and $39.2 billion including intangible costs (ie, consequences of RA).5 The management of patients with RA is aimed at reducing joint pain and swelling, alleviating stiffness, and preventing joint damage.2 According to the 2012 American College of Rheumatology (ACR) recommendations for the use of disease-modifying antirheumatic drugs (DMARDs) and biologic agents, including tumor necrosis factor (TNF) blockers, in the treatment of RA, “The goal for each RA patient should be low disease activity or remission. In ideal circumstances, RA remission should be the target of therapy, but in others, low disease

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activity may be an acceptable target,” the authors of the updated guidelines state.6 The ACR recommendations also state that decisions about treating to target are left to the clinician who is caring for the individual patient, based on the patient’s preferences, comorbid conditions, and other relevant factors. Moreover, treatment plans involve patient-tailored risk-benefit analysis based on the clinician’s assessment and collaboration with the patient.6 The nonpharmacologic treatment of RA generally includes a combination of joint protection, the use of heat or cold to reduce pain, and physical or occupational therapy.2 Other self-management approaches include maintaining a healthy body weight and performing physical activity as appropriate, depending on the patient’s level of physical mobility.2 Because joint damage caused by RA occurs early, generally within the first 2 years of disease onset, it is vital that RA be diagnosed and treated early.1,2 The ACR panel recommended more aggressive treatment in early RA in the 2012 update than in the previous 2008 recommendations, most likely based on the potential for better outcomes, prevention of irreversible joint damage, preservation of physical function and health-related quality of life, and reduced work-related disability.6

Simponi Aria: A New Intravenous Option for RA In July 2013, the US Food and Drug Administration (FDA) approved golimumab for infusion (Simponi Aria; Janssen Biotech), a TNF inhibitor, for the treatment of moderate-to-severe RA in combination with methotrexate.7 Golimumab (Simponi) injection for subcutaneous use was previously approved by the FDA in 2009 for moderately to severely active RA in combination with methotrexate.7,8 In May 2013, golimumab for subcutaneous use received a new indication from the FDA for the treatment of ulcerative colitis that is resistant to previous treatment or requires continuous steroid therapy.9 According to John Hardin, MD, Director of Osteoarthritis at the Arthritis Foundation in Atlanta, and Pro-

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fessor of Medicine at Albert Einstein College of Medicine in the Bronx, NY, the availability of golimumab IV allows for its administration at an infusion center, which ensures that the patient is receiving the appropriate dose, because patient self-injection techniques may vary.7 Dr Hardin commented, “Logistically, it’s easier in some cases with IV infusions.”7

Proportion of Patients with an ACR Response: Table 1 Golimumab IV plus Methotrexate versus Placebo plus Methotrexate in the GO-FURTHER Trial

Mechanism of Action Golimumab, a TNF blocker, is a human monoclonal antibody that binds to the soluble and the transmembrane bioactive forms of human TNF-alpha to its receptors. This interaction prevents the binding of TNF-alpha to its receptors, thereby inhibiting the biological activity of TNF-alpha (a cytokine protein).10 Elevated TNF-alpha levels in the blood, synovia, and joints have been implicated in the pathophysiology of RA. TNF-alpha is an important mediator of the articular inflammation that is characteristic of RA.10

ACR20

Active RA, despite methotrexate treatment Placebo + methotrexate, % (N = 197)a

Golimumab IV + methotrexate, % (N = 395)a

95% confidence intervalb

Week 14

25.9-41.4

Week 24

23.3-39.4

Week 14 9

15.3-27.2

Week 24

15.1-28.4

Week 14 3

5.3-13.4

Week 24 4

8.8-18.1

ACR50

ACR70

N reflects randomized patients. For difference in proportions. ACR indicates American College of Rheumatology; ACR20, ACR 20% improvement response criteria; ACR50, ACR 50% improvement response criteria; ACR70, ACR 70% improvement response criteria; IV, intravenous; RA, rheumatoid arthritis. Source: Simponi Aria (golimumab) injection prescribing information; 2013. a

Dosing The recommended dose of golimumab IV for patients with moderate-to-severe RA is 2 mg/kg as an IV infusion over 30 minutes at weeks 0 and 4, and then every 8 weeks. The dilution of supplied golimumab IV solution with 0.9% weight/volume sodium chloride is required before administration. Golimumab IV should be given in combination with methotrexate. Other nonbiologic DMARDs, corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), and/or analgesics may be continued during treatment with golimumab IV.10 Phase 3 Clinical Trial: GO-FURTHER The FDA approval of the new indication for golimu mab IV was based on the randomized, double-blind, phase 3, placebo-controlled trial known as GO-FURTHER, which included 592 patients (aged ≥18 years) with moderately to severely active RA despite concurrent treatment with methotrexate who had not previously received a biologic TNF blocker. Patients were randomized to either golimumab IV 2 mg/kg (N = 395) or to placebo (N = 197) over a 30-minute IV infusion at weeks 0, 4, and every 8 weeks thereafter in addition to their weekly maintenance dose of methotrexate (15-25 mg/kg).10,11 All patients who were initially receiving placebo plus methotrexate in the trial received golimumab IV plus methotrexate after week 24; however, the trial remained blinded until all patients had completed 52 weeks of treatment. Efficacy data were collected and analyzed through week 52. Patients were allowed to continue receiving stable doses of concomitant low-dose corticosteroids (equal to ≤10 mg of prednisone daily) and/or NSAIDs, and patients might have received oral methotrexate during the

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trial. The use of other DMARDs, including cytotoxic agents or other biologics, was prohibited.10 The primary end point in this trial was the percentage of patients who achieved an American College of Rheumatology (ACR)20 response at week 14.9 ACR20 is defined by the ACR as a 20% improvement in tender and swollen joint counts and a 20% improvement in at least 3 of the 5 remaining ACR core set measures—patient global assessment, physician global assessment, pain, disability, and an acute-phase reactant.12 ACR50 represents a 50% improvement in these measures, and ACR70 represents a 70% improvement.12 A total of 58.5% of the patients in the golimumab IV plus methotrexate group achieved a 20% improvement in their ACR20 score at week 14 compared with 24.9% (49:197) of the patients in the placebo plus methotrexate group (P <.001).7,11 Moreover, a larger proportion of patients treated with golimumab IV plus methotrexate had a disease activity score (DAS) of a good or moderate (European League Against Rheumatism) response (81% vs 40%, respectively), and a greater median improvement in health assessment questionnaire scores (0.5 vs 0.125, respectively) versus placebo plus methotrexate (P <.001). Table 1 shows that a greater percentage of patients in the active arm achieved ACR20 at week 14 and ACR50 at week 24 than patients in the placebo arm.10 In all components of the ACR response criteria, im-

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Components of ACR Response at Week 14: Golimumab Table 2 IV plus Methotrexate versus Placebo plus Methotrexate in the GO-FURTHER Trial Active RA, despite methotrexate treatment Placebo + methotrexate (N = 197)a

Golimumab IV + methotrexate (N = 395)a

Baseline

Week 14

Baseline

Week 14

Baseline

6.5

Week 14

5.6

3.9

Swollen joints, N (0-66)

Tender joints, N (0-68)

Patient’s assessment of pain (0-10)

Patient’s global assessment of disease activity (0-10) Baseline

6.5

Week 14

5.5

4.0

Physician’s global assessment of disease activity (0-10) Baseline

6.3

6.2

Week 14

4.9

3.1

Baseline

1.6

Week 14

1.4

1.1

Baseline

2.2

2.8

Week 14

1.8

0.9

HAQ score (0-3)

CRP, mg/dL (0-1)

N reflects randomized patients; actual number of patients evaluable for each end point may vary. NOTE: All values are means. ACR indicates American College of Rheumatology; CRP, C-reactive protein; HAQ, health assessment questionnaire; IV, intravenous; RA, rheumatoid arthritis. Source: Simponi Aria (golimumab) injection prescribing information; 2013.

provement was either equal among the 2 groups or was greater in the golimumab IV plus methotrexate group than in the placebo plus methotrexate group (Table 2). In addition, at week 14, a greater proportion of patients who received golimumab IV plus methotrexate (15%) achieved a low level of disease activity, as measured by a DAS28 using C-reactive protein (DAS28-CRP) score of <2.6 compared with patients treated with placebo plus methotrexate (5%; 95% confidence interval, 6.3%15.5% for the difference).10 The DAS28-CRP is an index of disease activity for the 28 joints that are fre-

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quently affected by RA based on CRP levels.13

Adverse Events The most common adverse reactions (incidence >3%) are upper respiratory tract infection, viral infection, bronchitis, hypertension, and rash.10 Golimumab contains a boxed warning about serious infections and malignancy. Serious infections that can lead to hospitalization or to death, including tuberculosis, bacterial sepsis, and invasive fungal (ie, histoplasmosis) and other opportunistic infections have occurred in patients receiving golimumab. Therapy with golimumab should not be started during an active infection. If an infection develops, the patient should be monitored carefully and golimumab treatment should be stopped if the infection becomes serious. Patients should be tested for latent tuberculosis before the initiation of golimumab therapy. If the tuberculosis test is positive, treatment should be started for tuberculosis before initiating golimumab. Patients should be monitored for active tuberculosis during treatment, even if the initial latent tuberculosis test is negative. Lymphoma and other malignancies, some fatal, have been reported in children and in adolescent patients who were treated with TNF blockers, of which golimumab is a member.10 Warnings and Precautions Invasive fungal infections. For patients who develop a systemic illness while taking golimumab IV, empiric antifungal therapy should be considered for those who live in or travel to regions where mycoses are endemic.10 Hepatitis B reactivation. Hepatitis B virus carriers should be monitored during and several months after therapy. If reactivation occurs, golimu mab should be discontinued and antiviral therapy should be initiated.10 Malignancies. More cases of lymphoma have been observed among patients receiving TNF blockers compared with patients in the control groups. Cases of other malignancies have been observed among patients receiving TNF blockers.10 Heart failure. The worsening or new onset of heart failure may occur with golimumab. If worsening symptoms occur, the use of golimumab should be stopped.10 Demyelinating diseases. The exacerbation or new onset of demyelinating diseases may occur with golimumab.10 Hypersensitivity reactions. Serious systemic hypersensitivity reactions, including anaphylaxis, may occur with golimumab.10 Switching between DMARDs. Care should be taken when switching from one biologic agent to another biologic agent, because overlapping biologic activity may further increase the risk of infection.10

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Hematologic cytopenias. In postmarketing reports, pancytopenia, leukopenia, neutropenia, aplastic anemia, and thrombocytopenia have occurred in patients receiving TNF blockers. In clinical studies, cases of pancyto penia, leukopenia, neutropenia, and thrombocytopenia have occurred in patients treated with golimumab IV. Caution should be exercised when using TNF blockers, including golimumab IV, in patients who have or have had significant cytopenias.10

Drug Interactions Abatacept. In controlled trials, the concurrent administration of another TNF blocker and abatacept, a selective T-cell costimulation modulator, was associated with a greater proportion of serious infections than the use of a TNF blocker alone. The combination therapy, compared with the use of a TNF blocker alone, has not demonstrated improved clinical benefit in the treatment of RA. The combination of TNF blockers, including golimumab IV, and abatacept is therefore not recommended.10 Anakinra. The concurrent administration of anakinra, an interleukin-1 antagonist, and another TNF blocker, was associated with a greater portion of serious infections and neutropenia but with no additional benefit compared with the TNF blocker alone. The combination of anakinra with TNF blockers, including golimu mab IV, is therefore not recommended.10 Live vaccines. Live vaccines should not be given concurrently with golimumab.10 Use in Specific Populations Pregnancy. There are no adequate and well-controlled trials of golimu mab in pregnant women. Golimumab should be used during pregnancy only if clearly needed.10 Nursing mothers. It is unknown whether golimumab is excreted in human milk or is absorbed systemically after ingestion. Because many drugs are excreted in human milk and there is a potential for adverse reactions in nursing infants from golimumab, consideration should be given as to whether to discontinue nursing or to discontinue golimumab, taking into account the importance of the drug to the mother.10 Pediatric use. The safety and effectiveness of golimumab in pediatric patients aged <18 years have not been established.10 Geriatric use. With respect to RA, there were no overall differences in serious adverse events, serious infections, and adverse events in golimumab-treated patients aged ≥65 years (N = 155) compared with younger golimumab-treated patients. Because there is usually a higher incidence of infections in the geriatric population in general, caution should be used in treating geriatric patients with golimumab.10

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Conclusion The approval of golimumab IV by the FDA in July 2013 for the treatment of moderate-to-severe RA in combination with methotrexate adds a new TNF inhibitor to the treatment options of patients with this chronic and debilitating disease. An earlier, subcutaneous version of golimumab subcutaneous injection had been approved by the FDA in 2009 for moderately to severely active RA in combination with methotrexate. The IV route means in-office administration of the medication, which can be an advantage in cases where patient adherence is problematic, which can greatly affect outcomes. The safety and efficacy of golimumab IV were assessed in the GO-FURTHER randomized, double-blind, placebo-controlled trial in adults with moderate-to-severe RA with moderately to severely active RA despite concurrent methotrexate therapy. The improvements associated with golimumab IV plus methotrexate, compared with placebo plus methotrexate, were observed by week 2. The most common adverse reactions occurring in >3% of patients using golimumab IV are upper respiratory tract infection, viral infection, bronchitis, hypertension, and rash. n References

1. Mayo Clinic. Rheumatoid arthritis. July 27, 2013. www.mayoclinic.com/health/ rheumatoid-arthritis/DS00020. Accessed July 31, 2013. 2. Arthritis Foundation. Rheumatoid arthritis fact sheet. 2008. www.arthritis.org/ files/images/newsroom/media-kits/Rheumatoid_Arthritis_Fact_Sheet.pdf. Accessed July 31, 2013. 3. Centers for Disease Control and Prevention. Rheumatoid arthritis. Updated November 19, 2012. www.cdc.gov/arthritis/basics/rheumatoid.htm. Accessed July 31, 2013. 4. Dominick KL, Ahern FM, Gold CH, Heller DA. Health-related quality of life among older adults with arthritis. Health Qual Life Outcomes. 2004;2:5. 5. Birnbaum H, Pike C, Kaufman R, et al. Societal cost of rheumatoid arthritis patients in the US. Curr Med Res Opin. 2010;26:77-90. 6. Singh JA, Furst DE, Bharat A, et al. 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken). 2012;64:625-639. 7. Brown T; Medscape News. FDA approves intravenous golimumab (Simponi Aria) for rheumatoid arthritis. Press release. July 18, 2013. www.medscape.com/viewarticle/ 807965. Accessed July 31, 2013. 8. Simponi (golimumab) injection [package insert]. Horsham, PA: Janssen Biotech, Inc; 2013. 9. US Food and Drug Administration. FDA approves Simponi to treat ulcerative colitis. Press release. May 15, 2013. Updated May 17, 2013. www.fda.gov/NewsEvents/ Newsroom/PressAnnouncements/ucm352383.htm. Accessed August 6, 2013. 10. Simponi Aria (golimumab) injection [prescribing information]. Horsham, PA: Janssen Biotech, Inc; 2013. 11. Weinblatt ME, Bingham CO 3rd, Mendelsohn AM, et al. Intravenous golimu mab is effective in patients with active rheumatoid arthritis despite methotrexate therapy with responses as early as week 2: results of the phase 3, randomised, multicentre, double-blind, placebo-controlled GO-FURTHER trial. Ann Rheum Dis. 2013; 72:381-389. 12. Felson DT, Anderson JJ, Boers M, et al. American College of Rheumatology preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum. 1995; 38:727-735. 13. Wells G, Becker JC, Teng J, et al. Validation of the 28-joint Disease Activity Score (DAS28) and European League Against Rheumatism response criteria based on C-reactive protein against disease progression in patients with rheumatoid arthritis, and comparison with the DAS28 based on erythrocyte sedimentation rate. Ann Rheum Dis. 2009;68:954-960.

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Stelara (Ustekinumab) Receives New FDA Indication for the Treatment of Patients with Active Psoriatic Arthritis By Loretta Fala, Medical Writer

soriatic arthritis (PsA), a chronic, inflammatory disease that causes pain, stiffness, and swelling in and around the joints, generally develops between the ages of 30 and 50 years, but it can affect people of all ages, including children.1 In the United States, the overall prevalence of PsA is estimated to range from 101 to 250 cases per 100,000 people; however, the prevalence of PsA has historically been challenging to determine, because of its misdiagnosis and the lack of widely accepted diagnostic criteria.2 PsA is sometimes misdiagnosed as rheumatoid arthritis, gout, or osteoarthritis.3 Both PsA and psoriasis are chronic autoimmune diseas3 es. Of the estimated 7.5 million patients (approximately 2.2% of the US population) who have psoriasis, 10% to 30% will also develop PsA.3,4 Although the exact cause of PsA is unknown, research suggests that it develops from a combination of genetic (ie, heredity) and environmental factors.1 In addition, immune system conditions, infection, and physical trauma may play a role in the development of PsA.5 PsA may also be triggered by a streptococcal throat infection.3 PsA also has a substantial impact on the patient’s psychological and psychosocial functioning and daily living activities.2 The visible nature of skin involvement may also lead to embarrassment, self-consciousness, and, in some cases, depression. Moreover, PsA may be associated with an increased risk for osteoporosis and cardiovascular disease, as well as an increased risk for other inflammatory conditions, including uveitis and iritis.2 Patients with PsA have a slightly increased risk for high blood pressure, high cholesterol, obesity, or diabetes.3 Anemia and fatigue are also common in patients with PsA.3 Based on a 2010 review of 49 studies, PsA accounts for nearly $1.9 billion in direct annual healthcare costs.2 Hospitalizations are the key driver of the direct costs, accounting for approximately 60% of the total direct costs. Indirect costs, including disability and lost productivity, account for 52% to 72% of the total costs.2 Furthermore, worsening physical function and disease activity are associated with increases in both direct and indirect costs.2 The early diagnosis and treatment of PsA are essential to relieving pain and inflammation and to helping prevent progressive joint involvement and damage.5 The

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therapeutic goals for patients with PsA are to alleviate symptoms, including pain and skin symptoms; to protect the joints; and to maintain mobility.3,5 Treatment decisions are based on disease severity, the number of joints involved, and associated skin symptoms.5 Treatments for PsA may include a combination of nonpharmacologic and pharmacologic options. Nonpharmacologic approaches include exercise, heat and cold therapy, water therapy, the use of splints, joint protection and energy conservation, and surgery (when severely damaged joints need replacement).3,5 Pharmacologic treatments include nonsteroidal anti-inflammatory drugs (NSAIDs) and disease-modifying antirheumatic drugs (DMARDs).5 Corticosteroid injections may be useful in patients with PsA and swollen joints.3 DMARDs are generally used in patients with erosive disease or in patients who fail to respond to NSAIDs.5 DMARDs that are effective in treating PsA include methotrexate, sulfasalazine (Azulfidine), cyclosporine, and leflunomide (Arava).3 In addition to reducing the signs and symptoms of PsA, the biologic DMARDs also slow the progression of joint damage. The biologic DMARDs include the following tumor necrosis factor (TNF)-α inhibitors: adalimumab (Humira), etanercept (Enbrel), golimumab (Simponi), and infliximab (Remicade).3 Recently, ustekin umab—a new biologic DMARD that targets the interleukin (IL)-12 and IL-23 cytokines—became available for the treatment of patients with PsA.6

Stelara Injection: A New Biologic Option for Patients with PsA In September 2013, the US Food and Drug Administration (FDA) approved a new indication for ustekinumab (Stelara; Janssen Biotech), alone or in combination with methotrexate, for the treatment of adult patients (aged ≥18 years) with active PsA.6 Ustekinumab, a human immunoglobulin (Ig)G1κ monoclonal antibody that targets the shared p40 protein subunit of the IL-12 and IL-23 cytokines,7 is the first and only anti–IL-12/23 therapy approved by the FDA for adults with PsA.8 According to study investigator Alice B. Gottlieb, MD, Chief and Dermatologist-in-Chief in the Department of Dermatology at Tufts Medical Center, “It is

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critical for dermatologists and rheumatologists to be able to offer new and novel treatment options to our adult patients living with psoriatic arthritis, a disease where additional biologic options are very much needed.”8 She further commented, “Therapy that targets the cytokines interleukin-12 (IL-12) and interleukin-23 (IL-23), two naturally occurring proteins believed to play a role in the development of this debilitating immune-mediated inflammatory disease, could improve patient care.”8

Mechanism of Action Ustekinumab is a human IgG1κ monoclonal antibody that binds with specificity to the shared p40 protein subunit used by the IL-12 and IL-23 cytokines. These naturally occurring cytokines are involved in inflammatory and immune responses, such as natural killer cell activation and CD4+ T-cell differentiation and activation.7 Levels of IL-12, IL-23, and p40 are elevated in the skin and blood of patients with psoriasis, and in the blood of patients with PsA, implicating IL-12 and IL-23 in the pathophysiology of psoriatic inflammatory diseases. In in vitro models, ustekinumab was shown to disrupt IL-12– and IL-23–mediated signaling and cytokine cascades by upsetting the interaction of these cytokines with a shared cell-surface receptor chain, IL-12Rβ1.7 Dosing Ustekinumab is administered by subcutaneous injection. For the treatment of PsA, the initial recommended dose is 45 mg followed 4 weeks later by 45 mg every 12 weeks. For patients with coexistent moderate-to-severe plaque psoriasis weighing >100 kg (220 lb), the recommended dose is 90 mg initially and, 4 weeks later, followed by 90 mg every 12 weeks.7 Ustekinumab injection is available in several dosage forms and strengths: 45 mg/0.5 mL in a single-use prefilled syringe, 45 mg/0.5 mL in a single-use vial, and 90 mg/mL in a single-use prefilled syringe. Ustekinumab is intended for use under the guidance and supervision of a physician. It should only be administered to patients who will be closely monitored and who will have regular follow-up visits with a physician. After proper training in subcutaneous injection technique, a patient may self-inject with ustekinumab if a physician determines that it is appropriate.7 Clinical Studies The safety and efficacy of ustekinumab were evaluated in 927 patients in 2 randomized, double-blind, placebo- controlled studies of patients aged ≥18 years with active PsA (≥5 swollen joints and ≥5 tender joints), despite therapy with NSAIDs or DMARDs. The patients enrolled in these studies had a diagnosis of PsA for a mini-

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mum of 6 months. The patients had the following subtypes of PsA: polyarticular arthritis with the absence of rheumatoid nodules (39%), spondylitis with peripheral arthritis (28%), asymmetric peripheral arthritis (21%), distal interphalangeal involvement (12%), and arthritis mutilans (0.5%). More than 70% of the patients had enthesitis (ie, inflammation of the sites where tendons, ligaments, and joint capsules of the fascia attach to the bone) at baseline, and more than 40% had dactylitis (ie, inflammation of a finger or toe) at baseline.7 The patients in study 1 (N = 615) and study 2 (N = 312) were randomized to receive treatment with ustekin umab 45 mg or 90 mg or with placebo subcutaneously at weeks 0 and 4, followed by dosing every 12 weeks. Approximately 50% of the patients continued to receive stable doses of methotrexate (≤25 mg weekly).7 In study 1, 80% of the patients had previously received DMARDs; previous treatment with an anti–TNF-α agent was not allowed. In study 2, 86% of the patients had previously received DMARDs, and 58% had previously received an anti–TNF-α agent, of whom more than 70% had discontinued their anti–TNF-α treatment for lack of efficacy or intolerance at any time.7 The primary end point in study 1 and study 2 was the percentage of patients achieving an ACR20 response at week 24.7 ACR20 is defined by the American College of Rheumatology (ACR) as a 20% improvement in tender and swollen joint counts and a 20% improvement in at least 3 of the 5 following ACR core set measures: patient and physician global assessments, patient-assessed pain, patient self-assessed disability, and an acute-phase reactant.9 Other responses measured included the presence of lesions over the body surface area (0%-3% = mild; 3%10% = moderate; and >10% = severe)10; and the Psoriasis Area and Severity Index (PASI), which measures 3 features of psoriatic plaque—redness, scaling, and thickness—where each is assigned a rating of 0 to 4, with 4 being the worst.11 The extent of involvement of each region of the body is given a rating of 0 to 6; the subsequent total score can range from 0 to 72.11 The clinical response results for studies 1 and 2 are shown in Table 1. In both studies, at week 24 a greater proportion of patients achieved ACR20, ACR50, and PASI 75 response in the ustekinumab 45-mg and 90-mg groups compared with those receiving placebo. ACR70 responses were also higher in the ustekinumab 45-mg and 90-mg cohorts, although the difference was not statistically significant in study 2. The responses were similar in patients regardless of previous TNF-α exposure.7 The results of the components of the ACR response criteria from study 1 are shown in Table 2. In the 2 groups receiving ustekinumab (45 mg and 90 mg), improvements in enthesitis and dactylitis scores were ob-

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Table 1 U stekinumab in 2 PsA Clinical Studies: ACR20, ACR50, ACR70, and PASI 75 Responses at Week 24 PsA study 1

PsA study 2

Ustekinumab

Placebo (N = 206)

45 mg (N = 205)

90 mg (N = 204)

Placebo (N = 104)

45 mg (N = 103)

90 mg (N = 105)

ACR20 response, N (%)

47 (23)

87 (42)

101 (50)

21 (20)

45 (44)

46 (44)

ACR50 response, N (%)

18 (9)

51 (25)

57 (28)

7 (7)

18 (17)

24 (23)

ACR70 response, N (%)

5 (2)

25 (12)

29 (14)

3 (3)

7 (7)

9 (9)

Patients with ≥3% body surface area,a N

146

145

149

16 (11)

83 (57)

93 (62)

4 (5)

41 (51)

45 (56)

Measurement

PASI 75 response, N (%)

Number of patients with ≥3% body surface area psoriasis skin involvement at baseline. ACR indicates American College of Rheumatology; ACR20, 20% improvement in tender and swollen joint counts and 20% improvement in at least 3 of 5 ACR core set measures (ACR50 and ACR70 indicate 50% or 70% improvement); PASI 75, 75% reduction in Psoriasis Area and Severity Index (PASI) score; PsA, psoriatic arthritis. Source: Stelara (ustekinumab) injection prescribing information; 2013.

served at week 24 compared with placebo. The patients receiving ustekinumab also showed improvement in physical function compared with patients receiving placebo, as assessed by the Health Assessment Questionnaire–Disability Index at week 24.7

Safety The safety of ustekinumab was assessed in 927 patients in 2 randomized, double-blind, placebo-controlled studies in adult patients with active PsA. The overall safety profile of ustekinumab in patients with PsA was consistent with the safety profile seen in clinical trials of patients with psoriasis. In the placebo-controlled groups of the PsA clinical trials, a higher incidence in several adverse events was seen in patients receiving ustekinumab compared with patients receiving placebo, including arthralgia (3% vs 1%, respectively), nausea (3% vs 1%, respectively), and dental infections (1% vs 0.6%, respectively).7 The most common adverse events (incidence ≥3% and more than with placebo) were nasopharyngitis, upper respiratory tract infection, headache, and fatigue.7 Drug Interactions Drug interaction studies have not been conducted with ustekinumab.7 Live vaccines should not be given concurrently with ustekinumab. CYP450 substrates. The formation of cytochrome (CY) P450 enzymes can be altered by increased levels of certain cytokines during chronic inflammation. Thus, ustekinumab, an antagonist of IL-12 and IL-23, could normalize the formation of CYP450 enzymes. On initiation of ustekinumab in patients who are receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index, monitoring for therapeutic

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effect or drug concentration should be considered. Allergen immunotherapy. Ustekinumab has not been evaluated in patients who have undergone allergy immunotherapy. Ustekinumab may decrease the protective effect of allergen immunotherapy, which may increase the risk for an allergic reaction.

Contraindications Ustekinumab is contraindicated in patients with clinically significant hypersensitivity to ustekinumab or to any of the excipients.7 Warnings and Precautions Infections. Ustekinumab may increase the risk for infections and the reactivation of latent infections. Serious bacterial, fungal, and viral infections were observed in patients receiving ustekinumab. In the PsA clinical studies, serious infections included cholecystitis. Ustekinu mab should not be started during any clinically important active infection. If a serious infection develops, ustekinumab should be stopped until the infection resolves. Serious infections from mycobacteria, Salmonella, and Bacillus Calmette–Guérin vaccinations have been reported in patients who are genetically deficient in IL-12 or IL-23. Diagnostic tests for these infections should be considered as dictated by the clinical circumstances. Tuberculosis. Patients should be evaluated for tuberculosis infection before initiating treatment with ustekinu mab, which should not be administered to patients with active tuberculosis. Patients receiving ustekinumab should be monitored closely for signs and symptoms of active tuberculosis. Treatment of latent tuberculosis should be initiated before administering ustekinumab.

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Malignancies. Ustekinumab is an immunosuppressant, and it may increase the risk for malignancy. Hypersensitivity reactions. Anaphylaxis and angioedema have been reported postmarketing. If an anaphylactic or other clinically significant hypersensitivity reaction occurs, the appropriate therapy should be given and ustekinumab should be discontinued. Reversible posterior leukoencephalopathy syndrome (RPLS). One case of RPLS was observed during the psoriasis clinical development program; no additional cases of RPLS were observed in the PsA clinical development program.7 Pregnancy. There are no adequate and well-controlled studies of ustekinumab in pregnant women. Ustekinumab should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.7 Nursing mothers. Caution should be used when ustekinumab is administered to a nursing woman.7 Pediatric/geriatric use. The safety of ustekinumab in pediatric patients has not been established. And although no differences in safety or efficacy were observed between older and younger subjects in clinical trials, the number of adults aged ≥65 years was not sufficient to compare their response to younger patients.7

stekinumab in PsA Study 1: Mean Change from Table 2 U Baseline in ACR Response Criteria, at Week 24

Conclusion A novel biologic option became available for patients with PsA with the approval of a new indication for ustekinumab, the first and only anti–IL-12/23 therapy approved by the FDA for this complex and potentially debilitating condition. Previously approved by the FDA for the treatment of adults with moderate-tosevere plaque psoriasis, ustekinumab is now also indicated for the treatment of patients with active PsA. Evidence from phase 3 randomized, double-blind, placebo-controlled studies shows the benefits of ustekinumab for adults with PsA. Patients who received ustekinumab showed improvement in physical function compared with patients who received placebo at week 24. n

HAQ-DI

References

1. National Psoriasis Foundation. Facts about psoriatic arthritis. www.psoriasis.org/ document.doc?id=1493. Accessed November 21, 2013. 2. Lee S, Mendelsohn A, Sarnes E. The burden of psoriatic arthritis: a literature review from a global health systems perspective. P T. 2010;35:680-689. 3. Emery P, Ash Z; for the American College of Rheumatology. Psoriatic arthritis. Fact sheet. Updated September 2012. www.rheumatology.org/Practice/Clinical/Patients/ Diseases_And_Conditions/Psoriatic_Arthritis/. Accessed November 26, 2013. 4. National Psoriasis Foundation. Statistics. www.psoriasis.org/learn_statistics. Accessed November 20, 2013. 5. The Cleveland Clinic Foundation. Psoriatic arthritis. http://my.clevelandclinic. org/orthopaedics-rheumatology/diseases-conditions/hic-psoriatic-arthritis.aspx. Accessed November 22, 2013. 6. Walsh N. FDA OKs Stelara for psoriatic arthritis. MedPage Today. September 24, 2013. www.medpage today.com/Rheumatology/Arthritis/41808. Accessed November 19, 2013. 7. Stelara (ustekinumab) injection [prescribing information]. Horsham, PA: Jans-

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Ustekinumab Placebo 45 mg 90 mg (N = 206) (N = 205) (N = 204)

Measurement

Number of swollen joints (0-66 counted) Baseline, N

Mean change at week 24, N

–3

–5

–6

–4

–8

–9

6.1

6.2

6.6

–0.5

–2.0

–2.6

6.1

6.3

6.4

–0.5

–2.0

–2.5

5.8

5.7

6.1

–1.4

–2.6

–3.1

1.2

–0.1

–0.3

–0.4

Number of tender joints (0-68 counted) Baseline, N Mean change at week 24, N Patient’s assessment of pain

Baseline, N Mean change at week 24, N Patient global assessment

Baseline, N Mean change at week 24, N Physician global assessmenta Baseline, N Mean change at week 24, N b

Baseline, N Mean change at week 24, N CRP

Baseline, mg/dL

1.6

1.7

1.8

Mean change at week 24, mg/dL

0.01

–0.5

–0.8

VAS score: 0 = best, 10 = worst. HAQ-DI: 0 = best, 3 = worst; measures the patient’s ability to perform daily activities. c CRP normal range, 0-1 mg/dL. ACR indicates American College of Rheumatology; CRP, C-reactive protein; HAQ-DI, Health Assessment Questionnaire–Disability Index; PsA, psoriatic arthritis; VAS, visual analog scale. Source: Stelara (ustekinumab) injection prescribing information; 2013. a

sen Biotech, Inc; September 2013. 8. Johnson & Johnson. Stelara (ustekinumab) receives FDA approval to treat active psoriatic arthritis: first and only anti-IL-12/23 treatment approved for adult patients living with psoriatic arthritis. Press release. September 23, 2013. www.investor.jnj. com/releasedetail.cfm?ReleaseID=792461. Accessed November 20, 2013. 9. Felson DT, Anderson JJ, Boers M, et al; for the American College of Rheumatology. American College of Rheumatology. Preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum. 1995;38:727-735. 10. Van Voorhees A, Feldman SR, Koo JY, et al; for the National Psoriasis Foundation. The psoriasis and psoriatic arthritis pocket guide: treatment algorithms and management options. 2009. www.psoriasis.org/document.doc?id=354. Accessed November 25, 2013. 11. Goodless D. What is a PASI score? Updated May 21, 2008. http://psoriasis.about. com/od/psoriasisfaqs/ f/pasi.htm. Accessed November 21, 2013.

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REVLIMID is indicated for the treatment of patients withwith REVLIMID is indicated for the treatment of patients mantle cellcell lymphoma (MCL) whose disease hashas relapsed or or mantle lymphoma (MCL) whose disease relapsed progressed afterafter twotwo priorprior therapies, oneone of which included bortezomib. progressed therapies, of which included bortezomib. REVLIMID is not indicated andand not not recommended for the treatment of of REVLIMID is not indicated recommended for the treatment patients withwith chronic lymphocytic leukemia (CLL) outside of controlled patients chronic lymphocytic leukemia (CLL) outside of controlled clinical trials. clinical trials.

For patients with For patients with

RELAPSED RELAPSEDOR ORREFRACTORY REFRACTORY MANTLE MANTLECELL CELLLYMPHOMA LYMPHOMA WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS THROMBOEMBOLISM WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS THROMBOEMBOLISM See full information for complete boxedboxed warning. Seeprescribing full prescribing information for complete warning. EMBRYO-FETAL TOXICITY EMBRYO-FETAL TOXICITY • Lenalidomide, a thalidomide analogue, caused limb limb abnormalities in a developmental monkey studystudy similar • Lenalidomide, a thalidomide analogue, caused abnormalities in a developmental monkey similar to birth defects caused by thalidomide in humans. If lenalidomide is used during pregnancy, it may cause to birth defects caused by thalidomide in humans. If lenalidomide is used during pregnancy, it may cause birthbirth defects or embryo-fetal death. defects or embryo-fetal death. • Pregnancy mustmust be excluded before startstart of treatment. Prevent pregnancy during treatment by the • Pregnancy be excluded before of treatment. Prevent pregnancy during treatment byuse the of use of two reliable methods of contraception. two reliable methods of contraception. REVLIMID is available only only through a restricted distribution program called the REVLIMID REMS™ program REVLIMID is available through a restricted distribution program called the REVLIMID REMS™ program ® ® (formerly known as the program”). (formerly known as“RevAssist the “RevAssist program”). HEMATOLOGIC TOXICITY. REVLIMID can cause signifi cant cant neutropenia and thrombocytopenia. HEMATOLOGIC TOXICITY. REVLIMID can cause signifi neutropenia and thrombocytopenia. • For with with del 5q syndromes, monitor complete bloodblood counts weekly for the rst first • patients For patients delmyelodysplastic 5q myelodysplastic syndromes, monitor complete counts weekly forfithe 8 weeks and monthly thereafter. 8 weeks and monthly thereafter. VENOUS THROMBOEMBOLISM VENOUS THROMBOEMBOLISM • Signifi cantly increased risk of deep vein vein thrombosis (DVT)(DVT) and pulmonary embolism (PE) (PE) in patients with with • Signifi cantly increased risk of deep thrombosis and pulmonary embolism in patients multiple myeloma receiving REVLIMID with with dexamethasone. multiple myeloma receiving REVLIMID dexamethasone. For more information, pleaseplease visit www.REVLIMID.com or callor1-888-423-5436. For more information, visit www.REVLIMID.com call 1-888-423-5436. REVLIMID is only through a restricted distribution program, REVLIMID REMS™. REVLIMID is available only available through a restricted distribution program, REVLIMID REMS™. Please see Brief Summary of full Information, including Boxed WARNINGS, CONTRAINDICATIONS, Please see Brief Summary ofPrescribing full Prescribing Information, including Boxed WARNINGS, CONTRAINDICATIONS, WARNINGS AND AND PRECAUTIONS, and ADVERSE REACTIONS, and Important Safety Information on the pages. WARNINGS PRECAUTIONS, and ADVERSE REACTIONS, and Important Safety Information onfollowing the following pages.

EffiEffi cacy andand safety of REVLIMID were evaluated in pretreated patients with cacy safety of REVLIMID were evaluated in pretreated patients with 1 1 advanced disease advanced disease • In •a multicenter, single-arm, single-agent, open-label studystudy (N=134)* In a multicenter, single-arm, single-agent, open-label (N=134)* % % % % • 92 (124/134) of patients had had stagestage III-IVIII-IV disease; 78 78 (105/134) of patients had had received ≥3 prior systemic • 92 (124/134) of patients disease; (105/134) of patients received ≥3 prior systemic % (81/134) % (74/134) therapies; 60%60 (81/134) of patients werewere refractory to prior bortezomib; 55%55 (74/134) of patients werewere refractory therapies; of patients refractory to prior bortezomib; of patients refractory to last therapy to prior last prior therapy • Refractory disease was was defined as without any response of PR during treatment with with bortezomib or a or a • Refractory disease defined as without any response ofor PRbetter or better during treatment bortezomib bortezomib-containing regimen; relapsed disease was was defined as progression within one one yearyear afterafter treatment with with bortezomib-containing regimen; relapsed disease defined as progression within treatment † † bortezomib or a or bortezomib-containing regimen bortezomib a bortezomib-containing regimen • Patients received REVLIMID 25 mg onceonce dailydaily for 21 everyevery 28 days. Treatment was was continued until until • Patients received REVLIMID 25 orally, mg orally, fordays 21 days 28 days. Treatment continued disease progression, unacceptable toxicity, or withdrawal of consent disease progression, unacceptable toxicity, or withdrawal of consent *134 patients evaluated for safety; 133 patients evaluated for effifor cacy. *134 patients evaluated for safety; 133 patients evaluated effi1 cacy.1 †

1 † 1 Had received prior treatment with anthracycline or mitoxantrone, cyclophosphamide, rituximab, and bortezomib, alone or in combination. Had received prior treatment with anthracycline or mitoxantrone, cyclophosphamide, rituximab, and bortezomib, alone or in combination.

1‡ 1‡ REVLIMID may help continue thethe fight against relapsed or refractory MCL REVLIMID may help continue fight against relapsed or refractory MCL § § %% %%

26 26 ORR ORR

(34/133) (34/133)

Overall response rate rate (CR (CR + CRu + PR) Overall response + CRu + PR) (95%(95% CI: 18.4, 33.9)33.9) CI: 18.4,

77 CR CR

(9/133) (9/133)

Complete response rate rate (CR (CR + CRu) Complete response + CRu) (95%(95% CI: 3.1, 12.5)12.5) CI: 3.1,

median median

DOR DOR 16.6 16.6months months (n=34) (n=34)

Median duration of response (95%(95% CI: 7.7, 26.7)26.7) Median duration of response CI: 7.7, • Median timetime to response was was 2.22.2 months (range: 1.8 to • Median to response months (range: 1.813tomonths) 13 months) CI=confi dence dence interval; CR=complete response; CRu=complete response unconfiunconfi rmed; rmed; DOR=duration of response; ORR=overall response rate; PR=partial response. CI=confi interval; CR=complete response; CRu=complete response DOR=duration of response; ORR=overall response rate; PR=partial response. ‡ §

1 1 Based‡Based on all evaluable patients who received ≥1 dose REVLIMID. on all evaluable patients who received ≥1ofdose of REVLIMID. § Response was determined based based on review of radiographic scans scans by an independent reviewreview committee, according to a modifi ed version of the of International Workshop Response was determined on review of radiographic by an independent committee, according to a modifi ed version the International Workshop Lymphoma Response CriteriaCriteria (Cheson, 1999);1999); ORR was neddefi as:ned CRas: + CRu PR.1,2 Lymphoma Response (Cheson, ORRdefi was CR ++CRu + PR.1,2

CONTRAINDICATIONS CONTRAINDICATIONS

Pregnancy: Pregnancy: • REVLIMID can cause fetal harm whenwhen administered to a pregnant female. Lenalidomide is contraindicated in females who are • REVLIMID can cause fetal harm administered to a pregnant female. Lenalidomide is contraindicated in females whopregnant. are pregnant. If thisIfdrug is used duringduring pregnancy or if the becomes pregnant whilewhile takingtaking this drug, the patient should be apprised of theof the this drug is used pregnancy or ifpatient the patient becomes pregnant this drug, the patient should be apprised potential hazard to thetofetus potential hazard the fetus Allergic Reactions: Allergic Reactions: • REVLIMID is contraindicated in patients who have demonstrated hypersensitivity (e.g.,(e.g., angioedema, Stevens-Johnson syndrome, toxic toxic • REVLIMID is contraindicated in patients who have demonstrated hypersensitivity angioedema, Stevens-Johnson syndrome, epidermal necrolysis) to lenalidomide epidermal necrolysis) to lenalidomide

ADVERSE REACTIONS ADVERSE REACTIONS

Mantle Cell Lymphoma Mantle Cell Lymphoma • Grade 3 and34and adverse eventsevents reported in ≥5% of patients treated with REVLIMID in theinMCL trial (N=134) included neutropenia (43%), • Grade 4 adverse reported in ≥5% of patients treated with REVLIMID the MCL trial (N=134) included neutropenia (43%), thrombocytopenia (28%),(28%), anemia (11%),(11%), pneumonia (9%), (9%), leukopenia (7%), (7%), fatiguefatigue (7%), (7%), diarrhea (6%), (6%), dyspnea (6%), (6%), and febrile neutropenia (6%) (6%) thrombocytopenia anemia pneumonia leukopenia diarrhea dyspnea and febrile neutropenia • Serious adverse eventsevents reported in ≥2inpatients treated with REVLIMID monotherapy for MCL included chronic obstructive pulmonary • Serious adverse reported ≥2 patients treated with REVLIMID monotherapy for MCL included chronic obstructive pulmonary disease, clostridium difficile sepsis, basalbasal cell carcinoma, and supraventricular tachycardia disease, clostridium difficolitis, cile colitis, sepsis, cell carcinoma, and supraventricular tachycardia • Adverse eventsevents reported in ≥15% of patients treated with REVLIMID in theinMCL trial included neutropenia (49%), thrombocytopenia (36%), • Adverse reported in ≥15% of patients treated with REVLIMID the MCL trial included neutropenia (49%), thrombocytopenia (36%), fatigue (34%), anemia (31%), diarrhea (31%), nausea (30%), coughcough (28%), pyrexia (23%), rash (22%), dyspnea (18%), pruritus (17%), fatigue (34%), anemia (31%), diarrhea (31%), nausea (30%), (28%), pyrexia (23%), rash (22%), dyspnea (18%), pruritus (17%), peripheral edema (16%), constipation (16%), and leukopenia (15%)(15%) peripheral edema (16%), constipation (16%), and leukopenia • Adverse eventsevents occurring in patients treated with REVLIMID in theinMCL trial resulted in at least one dose interruption in 76in(57%) patients, • Adverse occurring in patients treated with REVLIMID the MCL trial resulted in at least one dose interruption 76 (57%) patients, at least one dose reduction in 51in(38%) patients, and discontinuation of treatment in 26in(19%) patients at least one dose reduction 51 (38%) patients, and discontinuation of treatment 26 (19%) patients References: 1. Revlimid [package insert].insert]. Summit, NJ: Celgene Corp; 2013. 2. Cheson BD, Horning SJ, SJ, References: 1. Revlimid [package Summit, NJ: Celgene Corp; 2013. 2. Cheson BD, Horning CoiffierCoiffi B, eteral.B,Report of an international workshop to standardize response criteriacriteria for non-Hodgkin’s et al. Report of an international workshop to standardize response for non-Hodgkin’s lymphomas. NCI Sponsored International Working Group.Group. J Clin Oncol. 1999;17(4):1244-1253. lymphomas. NCI Sponsored International Working J Clin Oncol. 1999;17(4):1244-1253. ® REVLIMID is a ®registered trademark of Celgene Corporation. REVLIMID is a registered trademark of Celgene Corporation. REVLIMID REMS™ is a trademark of Celgene Corporation. REVLIMID REMS™ is a trademark of Celgene Corporation. © 2013 Celgene Corporation © 2013 Celgene Corporation 12/1312/13 US-REV130050g US-REV130050g

Important Safety Information WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS THROMBOEMBOLISM Embryo-Fetal Toxicity Do not use REVLIMID during pregnancy. Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study. Thalidomide is a known human teratogen that causes severe life-threatening human birth defects. If lenalidomide is used during pregnancy, it may cause birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting REVLIMID treatment. Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after REVLIMID treatment. To avoid embryo-fetal exposure to lenalidomide, REVLIMID is only available through a restricted distribution program, the REVLIMID REMS™ program (formerly known as the “RevAssist®” program). Information about the REVLIMID REMS™ Program is available at www.celgeneriskmanagement.com or by calling the manufacturer’s toll-free number 1-888-423-5436. Hematologic Toxicity (Neutropenia and Thrombocytopenia) REVLIMID can cause significant neutropenia and thrombocytopenia. Eighty percent of patients with del 5q myelodysplastic syndrome (MDS) had to have a dose delay/reduction during the major study. Thirty-four percent of patients had to have a second dose delay/reduction. Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the study. Patients on therapy for del 5q MDS should have their complete blood counts monitored weekly for the first 8 weeks of therapy and at least monthly thereafter. Patients may require dose interruption and/or reduction. Patients may require use of blood product support and/or growth factors. Venous Thromboembolism REVLIMID has demonstrated a significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients with multiple myeloma (MM) who were treated with REVLIMID and dexamethasone therapy. Patients and physicians are advised to be observant for the signs and symptoms of thromboembolism. Patients should be instructed to seek medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. It is not known whether prophylactic anticoagulation or antiplatelet therapy prescribed in conjunction with REVLIMID may lessen the potential for venous thromboembolism. The decision to take prophylactic measures should be done carefully after an assessment of an individual patient’s underlying risk factors.

CONTRAINDICATIONS

Pregnancy: • REVLIMID can cause fetal harm when administered to a pregnant female. Lenalidomide is contraindicated in females who are pregnant. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus Allergic Reactions: • REVLIMID is contraindicated in patients who have demonstrated hypersensitivity (e.g., angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide

WARNINGS AND PRECAUTIONS

Embryo-Fetal Toxicity: • REVLIMID is an analogue of thalidomide, a known human teratogen that causes life-threatening human birth defects or embryo-fetal death. An embryo-fetal development study in monkeys indicated that lenalidomide produced malformations in the offspring of female monkeys who received the drug during pregnancy, similar to birth defects observed in humans following exposure to thalidomide during pregnancy • Females of Reproductive Potential: Must avoid pregnancy for at least 4 weeks before beginning REVLIMID therapy, during therapy, during dose interruptions and for at least 4 weeks after completing therapy. Must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control beginning 4 weeks prior to initiating treatment with REVLIMID, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of REVLIMID therapy. Must obtain 2 negative pregnancy tests prior to initiating therapy • Males: Lenalidomide is present in the semen of patients receiving the drug. Males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID and for up to 28 days after discontinuing REVLIMID, even if they have undergone a successful vasectomy. Male patients taking REVLIMID must not donate sperm • Blood Donation: Patients must not donate blood during treatment with REVLIMID and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to REVLIMID

REVLIMID REMS Program

Because of embryo-fetal risk, REVLIMID is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) the REVLIMID REMS Program (formerly known as the “RevAssist®” Program). Prescribers and pharmacies must be certified with the program and patients must sign an agreement form and comply with the requirements. Further information about the REVLIMID REMS program is available at www.celgeneriskmanagement.com or by telephone at 1-888-423-5436. Hematologic Toxicity: REVLIMID can cause significant neutropenia and thrombocytopenia. Patients may require dose interruption and/or dose reduction. MCL: Patients taking REVLIMID for MCL should have their complete blood counts monitored weekly for the first cycle (28 days), every 2 weeks during cycles 2-4, and then monthly thereafter. In the MCL trial, Grade 3 or 4 neutropenia was reported in 43% of the patients. Grade 3 or 4 thrombocytopenia was reported in 28% of the patients. Venous Thromboembolism: Venous thromboembolic events (predominantly deep venous thrombosis and pulmonary embolism) have occurred in patients with MCL treated with lenalidomide monotherapy. It is not known whether prophylactic anticoagulation or antiplatelet therapy prescribed in conjunction with REVLIMID may lessen the potential for venous thromboembolism.

Increased Mortality in Patients With CLL: In a clinical trial in the first line treatment of patients with CLL, single agent REVLIMID therapy increased the risk of death as compared to single agent chlorambucil. In an interim analysis, there were 34 deaths among 210 patients on the REVLIMID treatment arm compared to 18 deaths among 211 patients in the chlorambucil treatment arm, and hazard ratio for overall survival was 1.92 [95% CI: 1.08-3.41], consistent with a 92% increase in risk of death. Serious adverse cardiovascular reactions, including atrial fibrillation, myocardial infarction, and cardiac failure occurred more frequently in the REVLIMID treatment arm. REVLIMID is not indicated and not recommended for use in CLL outside of controlled clinical trials. Second Primary Malignancies: Patients with MM treated with lenalidomide in studies including melphalan and stem cell transplantation had a higher incidence of second primary malignancies, particularly acute myelogenous leukemia (AML) and Hodgkin lymphoma, compared to patients in the control arms who received similar therapy but did not receive lenalidomide. Monitor patients for the development of second malignancies. Take into account both the potential benefit of lenalidomide and the risk of second primary malignancies when considering treatment with lenalidomide. Hepatotoxicity: Hepatic failure, including fatal cases, has occurred in patients treated with lenalidomide in combination with dexamethasone. The mechanism of drug-induced hepatotoxicity is unknown. Pre-existing viral liver disease, elevated baseline liver enzymes, and concomitant medications may be risk factors. Monitor liver enzymes periodically. Stop REVLIMID upon elevation of liver enzymes. After return to baseline values, treatment at a lower dose may be considered. Allergic Reactions: Angioedema and serious dermatologic reactions including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported. These events can be fatal. Patients with a prior history of Grade 4 rash associated with thalidomide treatment should not receive REVLIMID. REVLIMID interruption or discontinuation should be considered for Grade 2-3 skin rash. REVLIMID must be discontinued for angioedema, Grade 4 rash, exfoliative or bullous rash, or if SJS or TEN is suspected and should not be resumed following discontinuation for these reactions. REVLIMID capsules contain lactose. Risk-benefit of REVLIMID treatment should be evaluated in patients with lactose intolerance. Tumor Lysis Syndrome: Fatal instances of tumor lysis syndrome (TLS) have been reported during treatment with lenalidomide. The patients at risk of TLS are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken. Tumor Flare Reaction: Tumor flare reaction (TFR) occurred during investigational use of lenalidomide for CLL and lymphoma, and is characterized by tender lymph node swelling, low grade fever, pain and rash. REVLIMID is not indicated and not recommended for use in CLL outside of controlled clinical trials. Monitoring and evaluation for TFR is recommended in patients with MCL. Tumor flare may mimic the progression of disease (PD). In patients with Grade 3 or 4 TFR, it is recommended to withhold treatment with lenalidomide until TFR resolves to ≤ Grade 1. In the MCL trial, approximately 10% of subjects experienced TFR; all reports were Grade 1 or 2 in severity. All of the events occurred in cycle 1 and one patient developed TFR again in cycle 11. Lenalidomide may be continued in patients with Grade 1 and 2 TFR without interruption or modification, at the physician’s discretion. Patients with Grade 1 or 2 TFR may also be treated with corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs) and/or narcotic analgesics for management of TFR symptoms. Patients with Grade 3 or 4 TFR may be treated for management of symptoms per the guidance for treatment of Grade 1 and 2 TFR.

ADVERSE REACTIONS

Mantle Cell Lymphoma • Grade 3 and 4 adverse events reported in ≥5% of patients treated with REVLIMID in the MCL trial (N=134) included neutropenia (43%), thrombocytopenia (28%), anemia (11%), pneumonia (9%), leukopenia (7%), fatigue (7%), diarrhea (6%), dyspnea (6%), and febrile neutropenia (6%) • Serious adverse events reported in ≥2 patients treated with REVLIMID monotherapy for MCL included chronic obstructive pulmonary disease, clostridium difficile colitis, sepsis, basal cell carcinoma, and supraventricular tachycardia • Adverse events reported in ≥15% of patients treated with REVLIMID in the MCL trial included neutropenia (49%), thrombocytopenia (36%), fatigue (34%), anemia (31%), diarrhea (31%), nausea (30%), cough (28%), pyrexia (23%), rash (22%), dyspnea (18%), pruritus (17%), peripheral edema (16%), constipation (16%), and leukopenia (15%) • Adverse events occurring in patients treated with REVLIMID in the MCL trial resulted in at least one dose interruption in 76 (57%) patients, at least one dose reduction in 51 (38%) patients, and discontinuation of treatment in 26 (19%) patients

DRUG INTERACTIONS

Periodic monitoring of digoxin plasma levels, in accordance with clinical judgment and based on standard clinical practice in patients receiving this medication, is recommended during administration of REVLIMID.

USE IN SPECIFIC POPULATIONS

Pregnancy: If pregnancy does occur during treatment, immediately discontinue the drug. Under these conditions, refer patient to an obstetrician/ gynecologist experienced in reproductive toxicity for further evaluation and counseling. Any suspected fetal exposure to REVLIMID must be reported to the FDA via the MedWatch program at 1-800-332-1088 and also to Celgene Corporation at 1-888-423-5436. Nursing Mothers: It is not known whether REVLIMID is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the mother. Pediatric Use: Safety and effectiveness in pediatric patients below the age of 18 have not been established. Geriatric Use: Since elderly patients are more likely to have decreased renal function, care should be taken in dose selection. Monitor renal function. Renal Impairment: Since REVLIMID is primarily excreted unchanged by the kidney, adjustments to the starting dose of REVLIMID are recommended to provide appropriate drug exposure in patients with moderate (CLcr 30-60 mL/min) or severe renal impairment (CLcr <30 mL/min) and in patients on dialysis. REVLIMID is only available through a restricted distribution program, REVLIMID REMS™. Please see Brief Summary of full Prescribing Information, including Boxed WARNINGS, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS, on the following pages.

REVLIMID [lenalidomide] capsules, for oral use The following is a brief summary for mantle cell lymphoma; refer to full prescribing information for complete product information WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS THROMBOEMBOLISM Embryo-Fetal Toxicity Do not use REVLIMID during pregnancy. Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study. Thalidomide is a known human teratogen that causes severe lifethreatening human birth defects. If lenalidomide is used during pregnancy, it may cause birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting REVLIMID® treatment. Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after REVLIMID treatment [see Warnings and Precautions (5.1), and Medication Guide (17)]. To avoid embryo-fetal exposure to lenalidomide, REVLIMID is only available through a restricted distribution program, the REVLIMID REMS™ program (formerly known as the “RevAssist®” program) (5.2). Information about the REVLIMID REMS™ program is available at www.celgeneriskmanagement.com or by calling the manufacturer’s tollfree number 1-888-423-5436. Hematologic Toxicity (Neutropenia and Thrombocytopenia) REVLIMID can cause significant neutropenia and thrombocytopenia. Eighty percent of patients with del 5q myelodysplastic syndromes had to have a dose delay/reduction during the major study. Thirty-four percent of patients had to have a second dose delay/reduction. Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the study. Patients on therapy for del 5q myelodysplastic syndromes should have their complete blood counts monitored weekly for the first 8 weeks of therapy and at least monthly thereafter. Patients may require dose interruption and/or reduction. Patients may require use of blood product support and/or growth factors [see Dosage and Administration (2.2)]. Venous Thromboembolism REVLIMID has demonstrated a significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients with multiple myeloma who were treated with REVLIMID and dexamethasone therapy. Patients and physicians are advised to be observant for the signs and symptoms of thromboembolism. Patients should be instructed to seek medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. It is not known whether prophylactic anticoagulation or antiplatelet therapy prescribed in conjunction with REVLIMID may lessen the potential for venous thromboembolism. The decision to take prophylactic measures should be done carefully after an assessment of an individual patient’s underlying risk factors [see Warnings and Precautions (5.4)]. 1 INDICATIONS AND USAGE 1.3 Mantle Cell Lymphoma REVLIMID is indicated for the treatment of patients with mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib. 1.4 Limitations of Use: REVLIMID is not indicated and is not recommended for the treatment of patients with CLL outside of controlled clinical trials [see Warnings and Precautions (5.5)]. 2 DOSAGE AND ADMINISTRATION REVLIMID should be taken orally at about the same time each day, either with or without food. REVLIMID capsules should be swallowed whole with water. The capsules should not be opened, broken, or chewed. 2.3 Mantle Cell Lymphoma The recommended starting dose of REVLIMID is 25 mg/day orally on Days 1-21 of repeated 28-day cycles for relapsed or refractory mantle cell lymphoma. Treatment should be continued until disease progression or unacceptable toxicity. Treatment is continued, modified or discontinued based upon clinical and laboratory findings. Dose Adjustments for Hematologic Toxicities During MCL Treatment Dose modification guidelines as summarized below are recommended to manage Grade 3 or 4 neutropenia or thrombocytopenia or other Grade 3 or 4 toxicities considered to be related to REVLIMID.

Platelet counts Thrombocytopenia during treatment in MCL When Platelets Recommended Course Fall to <50,000/mcL Interrupt REVLIMID treatment and follow CBC weekly Return to ≥50,000/mcL Resume REVLIMID at 5 mg less than the previous dose. Do not dose below 5 mg daily Absolute Neutrophil counts (ANC) Neutropenia during treatment in MCL When Neutrophils Recommended Course Fall to <1000/mcL for at least 7 days Interrupt REVLIMID treatment and follow OR CBC weekly Falls to < 1,000/mcL with an associated temperature ≥ 38.5°C OR Falls to < 500 /mcL Return to ≥1,000/mcL Resume REVLIMID at 5 mg less than the previous dose. Do not dose below 5 mg daily Other Grade 3 / 4 Toxicities in MCL For other Grade 3/4 toxicities judged to be related to REVLIMID, hold treatment and restart at the physician’s discretion at next lower dose level when toxicity has resolved to ≤ Grade 2. Starting Dose Adjustment for Renal Impairment in MCL: 2.4 Starting Dose for Renal Impairment in MCL Since REVLIMID is primarily excreted unchanged by the kidney, adjustments to the starting dose of REVLIMID are recommended to provide appropriate drug exposure in patients with moderate or severe renal impairment and in patients on dialysis. Based on a pharmacokinetic study in patients with renal impairment due to non-malignant conditions, REVLIMID starting dose adjustment is recommended for patients with CLcr < 60 mL/min. Non-dialysis patients with creatinine clearances less than 11 mL/min and dialysis patients with creatinine clearances less than 7 mL/min have not been studied. The recommendations for initial starting doses for patients with MCL are as follows: Table 1: Starting Dose Adjustments for Patients with Renal Impairment in MCL Category Renal Function Dose in MCL (Cockcroft-Gault) Moderate Renal CLcr 30-60 mL/min 10 mg Impairment Every 24 hours Severe Renal CLcr < 30 mL/min 15 mg Impairment (not requiring dialysis) Every 48 hours End Stage CLcr < 30 mL/min 5 mg Renal Disease (requiring dialysis) Once daily. On dialysis days, administer the dose following dialysis. After initiation of REVLIMID therapy, subsequent REVLIMID dose modification is based on individual patient treatment tolerance, as described elsewhere (see section 2). 4 CONTRAINDICATIONS 4.1 Pregnancy REVLIMID can cause fetal harm when administered to a pregnant female. Limb abnormalities were seen in the offspring of monkeys that were dosed with lenalidomide during organogenesis. This effect was seen at all doses tested. Due to the results of this developmental monkey study, and lenalidomide’s structural similarities to thalidomide, a known human teratogen, lenalidomide is contraindicated in females who are pregnant [see Boxed Warning]. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Warnings and Precautions (5.1, 5.2), Use in Special Populations (8.1), (8.6)]. 4.2 Allergic Reactions REVLIMID is contraindicated in patients who have demonstrated hypersensitivity (e.g., angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide [see Warnings and Precautions (5.8)]. 5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Toxicity REVLIMID is a thalidomide analogue and is contraindicated for use during pregnancy. Thalidomide is a known human teratogen that causes lifethreatening human birth defects or embryo-fetal death [see Use in Specific Populations (8.1)]. An embryo-fetal development study in monkeys indicates that lenalidomide produced malformations in the offspring of Cosmos Communications

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female monkeys who received the drug during pregnancy, similar to birth defects observed in humans following exposure to thalidomide during pregnancy. REVLIMID is only available through the REVLIMID REMS™ program (formerly known as the “RevAssist® program”) [see Warnings and Precautions (5.2)]. Females of Reproductive Potential Females of reproductive potential must avoid pregnancy for at least 4 weeks before beginning REVLIMID therapy, during therapy, during dose interruptions and for at least 4 weeks after completing therapy. Females must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control, beginning 4 weeks prior to initiating treatment with REVLIMID, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of REVLIMID therapy. Two negative pregnancy tests must be obtained prior to initiating therapy. The first test should be performed within 10-14 days and the second test within 24 hours prior to prescribing REVLIMID therapy and then weekly during the first month, then monthly thereafter in women with regular menstrual cycles or every 2 weeks in women with irregular menstrual cycles [see Use in Specific Populations (8.6)]. Males Lenalidomide is present in the semen of patients receiving the drug. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID and for up to 28 days after discontinuing REVLIMID, even if they have undergone a successful vasectomy. Male patients taking REVLIMID must not donate sperm [see Use in Specific Populations (8.6)]. Blood Donation Patients must not donate blood during treatment with REVLIMID and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to REVLIMID. 5.2 REVLIMID REMS™ program Because of the embryo-fetal risk [see Warnings and Precautions (5.1)], REVLIMID is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS), the REVLIMID REMS™ program (formerly known as the “RevAssist®” program). Required components of the REVLIMID REMS™ program include the following: • Prescribers must be certified with the REVLIMID REMS™ program by enrolling and complying with the REMS requirements. • Patients must sign a Patient-Prescriber agreement form and comply with the REMS requirements. In particular, female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements [see Use in Specific Populations (8.6)] and males must comply with contraception requirements [see Use in Specific Populations (8.6)]. • Pharmacies must be certified with the REVLIMID REMS™ program, must only dispense to patients who are authorized to receive REVLIMID and comply with REMS requirements. Further information about the REVLIMID REMS™ program is available at www.celgeneriskmanagement.com or by telephone at 1-888-423-5436. 5.3 Hematologic Toxicity REVLIMID can cause significant neutropenia and thrombocytopenia. Patients taking REVLIMID for MDS should have their complete blood counts monitored weekly for the first 8 weeks and at least monthly thereafter. Patients taking REVLIMID for MM should have their complete blood counts monitored every 2 weeks for the first 12 weeks and then monthly thereafter. Patients taking REVLIMID for MCL should have their complete blood counts monitored weekly for the first cycle (28 days), every 2 weeks during cycles 2-4, and then monthly thereafter. Patients may require dose interruption and/or dose reduction [see Dosage and Administration (2.1, 2.2, 2.3)]. Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the MDS study. In the 48% of patients who developed Grade 3 or 4 neutropenia, the median time to onset was 42 days (range, 14-411 days), and the median time to documented recovery was 17 days (range, 2-170 days). In the 54% of patients who developed Grade 3 or 4 thrombocytopenia, the median time to onset was 28 days (range, 8-290 days), and the median time to documented recovery was 22 days (range, 5-224 days [see Boxed Warning and Dosage and Administration (2.2)]. In the pooled MM trials Grade 3 and 4 hematologic toxicities were more frequent in patients treated with the combination of REVLIMID and dexamethasone than in patients treated with dexamethasone alone [see Adverse Reactions (6.1)].

In the MCL trial, Grade 3 or 4 neutropenia was reported in 43% of the patients. Grade 3 or 4 thrombocytopenia was reported in 28% of the patients. 5.4 Venous Thromboembolism Venous thromboembolic events (predominantly deep venous thrombosis and pulmonary embolism) have occurred in patients with multiple myeloma treated with lenalidomide combination therapy [see Boxed Warning] and patients with MDS or MCL treated with lenalidomide monotherapy. A significantly increased risk of DVT and PE was observed in patients with multiple myeloma who were treated with REVLIMID and dexamethasone therapy in a clinical trial [see Boxed Warning]. It is not known whether prophylactic anticoagulation or antiplatelet therapy prescribed in conjunction with REVLIMID may lessen the potential for venous thromboembolism. The decision to take prophylactic measures should be done carefully after an assessment of an individual patient’s underlying risk factors. 5.5 Increased Mortality in Patients with CLL In a prospective randomized (1:1) clinical trial in the first line treatment of patients with chronic lymphocytic leukemia, single agent REVLIMID therapy increased the risk of death as compared to single agent chlorambucil. In an interim analysis, there were 34 deaths among 210 patients on the REVLIMID treatment arm compared to 18 deaths among 211 patients in the chlorambucil treatment arm, and hazard ratio for overall survival was 1.92 [95% CI: 1.08 – 3.41], consistent with a 92% increase in the risk of death. The trial was halted for safety in July 2013. Serious adverse cardiovascular reactions, including atrial fibrillation, myocardial infarction, and cardiac failure occurred more frequently in the REVLIMID treatment arm. REVLIMID is not indicated and not recommended for use in CLL outside of controlled clinical trials. 5.6 Second Primary Malignancies Patients with multiple myeloma treated with lenalidomide in studies including melphalan and stem cell transplantation had a higher incidence of second primary malignancies, particularly acute myelogenous leukemia (AML) and Hodgkin lymphoma, compared to patients in the control arms who received similar therapy but did not receive lenalidomide. Monitor patients for the development of second malignancies. Take into account both the potential benefit of lenalidomide and the risk of second primary malignancies when considering treatment with lenalidomide. 5.7 Hepatotoxicity Hepatic failure, including fatal cases, has occurred in patients treated with lenalidomide in combination with dexamethasone. In clinical trials, 15% of patients experienced hepatotoxicity (with hepatocellular, cholestatic and mixed characteristics); 2% of patients with multiple myeloma and 1% of patients with myelodysplasia had serious hepatotoxicity events. The mechanism of drug-induced hepatotoxicity is unknown. Pre-existing viral liver disease, elevated baseline liver enzymes, and concomitant medications may be risk factors. Monitor liver enzymes periodically. Stop REVLIMID upon elevation of liver enzymes. After return to baseline values, treatment at a lower dose may be considered. 5.8 Allergic Reactions Angioedema and serious dermatologic reactions including StevensJohnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported. These events can be fatal. Patients with a prior history of Grade 4 rash associated with thalidomide treatment should not receive REVLIMID. REVLIMID interruption or discontinuation should be considered for Grade 2-3 skin rash. REVLIMID must be discontinued for angioedema, Grade 4 rash, exfoliative or bullous rash, or if SJS or TEN is suspected and should not be resumed following discontinuation for these reactions. REVLIMID capsules contain lactose. Risk-benefit of REVLIMID treatment should be evaluated in patients with lactose intolerance. 5.9 Tumor Lysis Syndrome Fatal instances of tumor lysis syndrome have been reported during treatment with lenalidomide. The patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken. 5.10 Tumor Flare Reaction Tumor flare reaction has occurred during investigational use of lenalidomide for CLL and lymphoma, and is characterized by tender lymph node swelling, low grade fever, pain and rash. REVLIMID is not indicated and not recommended for use in CLL outside of controlled clinical trials. Monitoring and evaluation for tumor flare reaction (TFR) is recommended in patients with MCL. Tumor flare reaction may mimic progression of disease (PD). In the MCL trial, 13/134 (10%) of subjects experienced TFR; all reports were Grade 1 or 2 in severity. All of the events occurred in cycle 1 and one patient developed TFR again in cycle 11. Lenalidomide may be continued in patients with Grade 1 and 2 TFR without interruption or modification, at the physician’s discretion. Patients with Grade 1 and 2 TFR may also be treated with corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs) and/or narcotic analgesics for management of TFR symptoms. In patients with Grade 3 or 4 TFR, it is recommended to Cosmos Communications

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withhold treatment with lenalidomide until TFR resolves to ≤ Grade 1. Patients with Grade 3 or 4 TFR may be treated for management of symptoms per the guidance for treatment of Grade 1 and 2 TFR. 6 ADVERSE REACTIONS The following adverse reactions are described in detail in other labeling sections: • Neutropenia and thrombocytopenia [see Boxed Warnings, Warnings and Precautions (5.3)] • Deep vein thrombosis and pulmonary embolism [see Boxed Warnings, Warnings and Precautions (5.4)] • Increased Mortality in Patients with CLL [see Warnings and Precautions (5.5)] • Second Primary Malignancies [see Warnings and Precautions (5.6)] • Hepatotoxicity [see Warnings and Precautions (5.7)] • Allergic Reactions [see Warnings and Precautions (5.8)] • Tumor lysis syndrome [see Warnings and Precautions (5.9)] • Tumor flare reactions [see Warnings and Precautions (5.10)] Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. 6.3 Clinical Trials Experience in Mantle Cell Lymphoma In the MCL trial, a total of 134 patients received at least 1 dose of REVLIMID. Their median age was 67 (range 43-83) years, 128/134 (96%) were Caucasian, 108/134 (81%) were males and 82/134 (61%) had duration of MCL for at least 3 years. Table 7 summarizes the most frequently observed adverse reactions regardless of relationship to treatment with REVLIMID. Across the 134 patients treated in this study, median duration of treatment was 95 days (1-1002 days). Seventy-eight patients (58%) received 3 or more cycles of therapy, 53 patients (40%) received 6 or more cycles, and 26 patients (19%) received 12 or more cycles. Seventy-six patients (57%) underwent at least one dose interruption due to adverse events, and 51 patients (38%) underwent at least one dose reduction due to adverse events. Twenty-six patients (19%) discontinued treatment due to adverse events. Table 7: Incidence of Adverse Reactions (≥10%) or Grade 3 / 4 AE (in at least 2 patients) in Mantle Cell Lymphoma All AEs1 Grade 3/4 AEs2 System Organ Class/Preferred Term (N=134) (N=134) n (%) n (%) General disorders and administration site conditions Fatigue 45 (34) 9 (7) Pyrexia$ 31 (23) 3 (2) Edema peripheral 21 (16) 0 Asthenia$ 19 (14) 4 (3) General physical health deterioration 3 (2) 2 (1) Gastrointestinal disorders Diarrhea$ 42 (31) 8 (6) Nausea$ 40 (30) 1 (<1) Constipation 21 (16) 1 (<1) Vomiting$ 16 (12) 1 (<1) Abdominal pain$ 13 (10) 5 (4) Musculoskeletal and connective tissue disorders Back pain 18 (13) 2 (1) Muscle spasms 17 (13) 1 (<1) Arthralgia 11 (8) 2 (1) Muscular weakness$ 8 (6) 2 (1) Respiratory, thoracic and mediastinal disorders Cough 38 (28) 1 (<1) Dyspnea$ 24 (18) 8 (6) Pleural Effusion 10 (7) 2 (1) Hypoxia 3 (2) 2 (1) Pulmonary embolism 3 (2) 2 (1) Respiratory distress$ 2 (1) 2 (1) Oropharyngeal pain 13 (10) 0 Infections and infestations Pneumonia@ $ 19 (14) 12 (9) Upper respiratory tract infection 17 (13) 0 Cellulitis$ 3 (2) 2 (1) Bacteremia$ 2 (1) 2 (1) Staphylococcal sepsis$ 2 (1) 2 (1) Urinary tract infection$ 5 (4) 2 (1) (continued)

Table 7: Incidence of Adverse Reactions (≥10%) or Grade 3 / 4 AE (in at least 2 patients) in Mantle Cell Lymphoma All AEs1 Grade 3/4 AEs2 System Organ Class/Preferred Term (N=134) (N=134) n (%) n (%) Skin and subcutaneous tissue disorders Rash + 30 (22) 2 (1) Pruritus 23 (17) 1 (<1) Blood and lymphatic system disorders Neutropenia 65 (49) 58 (43) Thrombocytopenia% $ 48 (36) 37 (28) Anemia$ 41 (31) 15 (11) Leukopenia$ 20 (15) 9 (7) Lymphopenia 10 (7) 5 (4) Febrile neutropenia$ 8 (6) 8 (6) Metabolism and nutrition disorders Decreased appetite 19 (14) 1 (<1) Hypokalemia 17 (13) 3 (2) Dehydration$ 10 (7) 4 (3) Hypocalcemia 4 (3) 2 (1) Hyponatremia 3 (2) 3 (2) Renal and urinary disorders Renal failure$ 5 (4) 2 (1) Vascular disorders Hypotension@ $ 9 (7) 4 (3) Deep vein thrombosis$ 5 (4) 5 (4) Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tumor flare 13 (10) 0 Squamous cell carcinoma of skin$ 4 (3) 4 (3) Investigations Weight decreased 17 (13) 0 1-MCL trial AEs – All treatment emergent AEs with ≥10% of subjects 2-MCL trial Grade 3/4 AEs – All treatment-emergent Grade 3/4 AEs in 2 or more subjects $-MCL trial Serious AEs – All treatment-emergent SAEs in 2 or more subjects @ - AEs where at least one resulted in a fatal outcome % - AEs where at least one was considered to be Life Threatening (if the outcome of the event was death, it is included with death cases) # - All PTs under SOC of Infections except for rare infections of Public Health interest will be considered listed + - All PTs under HLT of Rash will be considered listed The following adverse events which have occurred in other indications and not described above have been reported (5-10%) in patients treated with REVLIMID monotherapy for mantle cell lymphoma. General disorders and administration site conditions: Chills Musculoskeletal and connective tissue disorders: Pain in extremity Nervous system disorders: Dysguesia, headache, neuropathy peripheral Infections and infestations: Respiratory tract infection, sinusitis, nasopharyngitis Skin and subcutaneous tissue disorders: Dry skin, night sweats The following serious adverse events not described above and reported in 2 or more patients treated with REVLIMID monotherapy for mantle cell lymphoma. Respiratory, Thoracic and Mediastinal Disorders: Chronic obstructive pulmonary disease Infections and Infestations: Clostridium difficile colitis, sepsis Neoplasms benign, malignant and unspecified (incl cysts and polyps): Basal cell carcinoma Cardiac Disorder: Supraventricular tachycardia 6.4 Postmarketing Experience The following adverse drug reactions have been identified from the worldwide post-marketing experience with REVLIMID: Allergic conditions (angioedema, SJS, TEN), tumor lysis syndrome (TLS) and tumor flare reaction (TFR), pneumonitis, hepatic failure, including fatality, toxic hepatitis, cytolytic hepatitis, cholestatic hepatitis, and mixed cytolytic/cholestatic hepatitis and transient abnormal liver laboratory tests. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure [see Warnings and Precautions Section (5.5 to 5.8)]. Cases of hypothyroidism and hyperthyroidism have also been reported. Optimal control of thyroid function is recommended before start of Cosmos Communications

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treatment. Baseline and ongoing monitoring of thyroid function is recommended. 7 DRUG INTERACTIONS Results from human in vitro studies show that REVLIMID is neither metabolized by nor inhibits or induces the cytochrome P450 pathway suggesting that lenalidomide is not likely to cause or be subject to P450-based metabolic drug interactions. In vitro studies demonstrated that REVLIMID is not a substrate of human breast cancer resistance protein (BCRP), multidrug resistance protein (MRP) transporters MRP1, MRP2, or MRP3, organic anion transporters (OAT) OAT1 and OAT3, organic anion transporting polypeptide 1B1 (OATP1B1 or OATP2), organic cation transporters (OCT) OCT1 and OCT2, multidrug and toxin extrusion protein (MATE) MATE1, and organic cation transporters novel (OCTN) OCTN1 and OCTN2. In vitro, lenalidomide is a substrate, but is not an inhibitor of P-glycoprotein (P-gp). 7.1 Digoxin When digoxin was co-administered with multiple doses of REVLIMID (10 mg/day) the digoxin Cmax and AUC0-∞ were increased by 14%. Periodic monitoring of digoxin plasma levels, in accordance with clinical judgment and based on standard clinical practice in patients receiving this medication, is recommended during administration of REVLIMID. 7.2 Warfarin Co-administration of multiple dose REVLIMID (10 mg) with single dose warfarin (25 mg) had no effect on the pharmacokinetics of total lenalidomide or R- and S-warfarin. Expected changes in laboratory assessments of PT and INR were observed after warfarin administration, but these changes were not affected by concomitant REVLIMID administration. It is not known whether there is an interaction between dexamethasone and warfarin. Close monitoring of PT and INR is recommended in multiple myeloma patients taking concomitant warfarin. 7.3 Concomitant Therapies That May Increase the Risk of Thrombosis Erythropoietic agents, or other agents that may increase the risk of thrombosis, such as estrogen containing therapies, should be used with caution in multiple myeloma patients receiving lenalidomide with dexamethasone [see Warnings and Precautions (5.4)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category X [see Boxed Warnings and Contraindications (4.1)] Risk Summary REVLIMID can cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy. REVLIMID is a thalidomide analogue. Thalidomide is a human teratogen, inducing a high frequency of severe and life-threatening birth defects such as amelia (absence of limbs), phocomelia (short limbs), hypoplasticity of the bones, absence of bones, external ear abnormalities (including anotia, micropinna, small or absent external auditory canals), facial palsy, eye abnormalities (anophthalmos, microphthalmos), and congenital heart defects. Alimentary tract, urinary tract, and genital malformations have also been documented and mortality at or shortly after birth has been reported in about 40% of infants. Lenalidomide caused thalidomide-type limb defects in monkey offspring. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. If pregnancy does occur during treatment, immediately discontinue the drug. Under these conditions, refer patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. Any suspected fetal exposure to REVLIMID must be reported to the FDA via the MedWatch program at 1-800-332-1088 and also to Celgene Corporation at 1-888-423-5436. Animal data In an embryo-fetal developmental toxicity study in monkeys, teratogenicity, including thalidomide-like limb defects, occurred in offspring when pregnant monkeys received oral lenalidomide during organogenesis. Exposure (AUC) in monkeys at the lowest dose was 0.17 times the human exposure at the maximum recommended human dose (MRHD) of 25 mg. Similar studies in pregnant rabbits and rats at 20 times and 200 times the MRHD respectively, produced embryo lethality in rabbits and no adverse reproductive effects in rats. In a pre- and post-natal development study in rats, animals received lenalidomide from organogenesis through lactation. The study revealed a few adverse effects on the offspring of female rats treated with lenalidomide at doses up to 500 mg/kg (approximately 200 times the human dose of 25 mg based on body surface area). The male offspring exhibited slightly delayed sexual maturation and the female offspring had slightly lower body weight gains during gestation when bred to male offspring. As with thalidomide, the

rat model may not adequately address the full spectrum of potential human embryo-fetal developmental effects for lenalidomide. 8.3 Nursing mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from lenalidomide, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric use Safety and effectiveness in pediatric patients below the age of 18 have not been established. 8.5 Geriatric use REVLIMID has been used in multiple myeloma (MM) clinical trials in patients up to 86 years of age. Of the 703 MM patients who received study treatment in Studies 1 and 2, 45% were age 65 or over while 12% of patients were age 75 and over. The percentage of patients age 65 or over was not significantly different between the REVLIMID/dexamethasone and placebo/dexamethasone groups. Of the 353 patients who received REVLIMID/dexamethasone, 46% were age 65 and over. In both studies, patients > 65 years of age were more likely than patients ≤ 65 years of age to experience DVT, pulmonary embolism, atrial fibrillation, and renal failure following use of REVLIMID. No differences in efficacy were observed between patients over 65 years of age and younger patients. REVLIMID has been used in del 5q MDS clinical trials in patients up to 95 years of age. Of the 148 patients with del 5q MDS enrolled in the major study, 38% were age 65 and over, while 33% were age 75 and over. Although the overall frequency of adverse events (100%) was the same in patients over 65 years of age as in younger patients, the frequency of serious adverse events was higher in patients over 65 years of age than in younger patients (54% vs. 33%). A greater proportion of patients over 65 years of age discontinued from the clinical studies because of adverse events than the proportion of younger patients (27% vs.16%). No differences in efficacy were observed between patients over 65 years of age and younger patients. REVLIMID has been used in a mantle cell lymphoma (MCL) clinical trial in patients up to 83 years of age. Of the 134 patients with MCL enrolled in the MCL trial, 63% were age 65 and over, while 22% of patients were age 75 and over. The overall frequency of adverse events was similar in patients over 65 years of age and in younger patients (98% vs. 100%). The overall incidence of grade 3 and 4 adverse events was also similar in these 2 patient groups (79% vs. 78%, respectively). The frequency of serious adverse events was higher in patients over 65 years of age than in younger patients (55% vs. 41%). No differences in efficacy were observed between patients over 65 years of age and younger patients. Since elderly patients are more likely to have decreased renal function, care should be taken in dose selection. Monitor renal function. 8.6 Females of Reproductive Potential and Males REVLIMID can cause fetal harm when administered during pregnancy [see Use in Specific Populations (8.1)]. Females of reproductive potential must avoid pregnancy 4 weeks before therapy, while taking REVLIMID, during dose interruptions and for at least 4 weeks after completing therapy. Females Females of reproductive potential must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control simultaneously (one highly effective form of contraception – tubal ligation, IUD, hormonal (birth control pills, injections, hormonal patches, vaginal rings or implants) or partner’s vasectomy and one additional effective contraceptive method – male latex or synthetic condom, diaphragm or cervical cap. Contraception must begin 4 weeks prior to initiating treatment with REVLIMID, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of REVLIMID therapy. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy. Females of reproductive potential should be referred to a qualified provider of contraceptive methods, if needed. Females of reproductive potential must have 2 negative pregnancy tests before initiating REVLIMID. The first test should be performed within 10-14 days, and the second test within 24 hours prior to prescribing REVLIMID. Once treatment has started and during dose interruptions, pregnancy testing for females of reproductive potential should occur weekly during the first 4 weeks of use, then pregnancy testing should be repeated every 4 weeks in females with regular menstrual cycles. If menstrual cycles are irregular, the pregnancy testing should occur every 2 weeks. Pregnancy testing and counseling should be performed if a patient misses her period or if there is any abnormality in her menstrual bleeding. REVLIMID treatment must be discontinued during this evaluation. Cosmos Communications

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Males Lenalidomide is present in the semen of males who take REVLIMID. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID, during dose interruptions and for up to 28 days after discontinuing REVLIMID, even if they have undergone a successful vasectomy. Male patients taking REVLIMID must not donate sperm 8.7 Renal Impairment Since lenalidomide is primarily excreted unchanged by the kidney, adjustments to the starting dose of REVLIMID are recommended to provide appropriate drug exposure in patients with moderate (CLcr 30-60 mL/min) or severe renal impairment (CLcr < 30 mL/min) and in patients on dialysis [see Dosage and Administration (2.4)]. 8.8 Hepatic Impairment No dedicated study has been conducted in patients with hepatic impairment. The elimination of unchanged lenalidomide is predominantly by the renal route. 10 OVERDOSAGE There is no specific experience in the management of lenalidomide overdose in patients; although in dose-ranging studies, some patients were exposed to up to 150 mg and in single-dose studies, some patients were exposed to up to 400 mg. In studies, the dose-limiting toxicity was essentially hematological. In the event of overdose, supportive care is advised. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, mutagenesis, impairment of fertility Carcinogenicity studies with lenalidomide have not been conducted. Lenalidomide was not mutagenic in the bacterial reverse mutation assay (Ames test) and did not induce chromosome aberrations in cultured human peripheral blood lymphocytes, or mutations at the thymidine kinase (tk) locus of mouse lymphoma L5178Y cells. Lenalidomide did not increase morphological transformation in Syrian Hamster Embryo assay or induce micronuclei in the polychromatic erythrocytes of the bone marrow of male rats. A fertility and early embryonic development study in rats, with administration of lenalidomide up to 500 mg/kg (approximately 200 times the human dose of 25 mg, based on body surface area) produced no parental toxicity and no adverse effects on fertility. 17 PATIENT COUNSELING INFORMATION See FDA-approved Patient labeling (Medication Guide) Embryo-Fetal Toxicity Advise patients that REVLIMID is contraindicated in pregnancy [see Contraindicatons (4.1)]. REVLIMID is a thalidomide analog and can cause serious birth defects or death to a developing baby. [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)]. • Advise females of reproductive potential that they must avoid pregnancy while taking REVLIMID and for at least 4 weeks after completing therapy. • Initiate REVLIMID treatment in females of reproductive potential only following a negative pregnancy test. • Advise females of reproductive potential of the importance of monthly pregnancy tests and the need to use two different forms of contraception including at least one highly effective form simultaneously during REVLIMID therapy, during dose interruption and for 4 weeks after she has completely finished taking REVLIMID. Highly effective forms of contraception other than tubal ligation include IUD and hormonal (birth control pills, injections, patch or implants) and a partner’s vasectomy. Additional effective contraceptive methods include latex or synthetic condom, diaphragm and cervical cap. • Instruct patient to immediately stop taking REVLIMID and contact her doctor if she becomes pregnant while taking this drug, if she misses her menstrual period, or experiences unusual menstrual bleeding, if she stops taking birth control, or if she thinks FOR ANY REASON that she may be pregnant. • Advise patient that if her doctor is not available, she can call 1-888-668-2528 for information on emergency contraception [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. • Advise males to always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID and for up to 28 days after discontinuing REVLIMID, even if they have undergone a successful vasectomy. • Advise male patients taking REVLIMID that they must not donate sperm [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. • All patients must be instructed to not donate blood while taking REVLIMID, during dose interruptions and for 1 month following discontinuation of REVLIMID [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)].

REVLIMID REMS™ program Because of the risk of embryo-fetal toxicity, REVLIMID is only available through a restricted program called the REVLIMID REMS™ program (formerly known as the “RevAssist®” program) [see Warnings and Precautions (5.2)]. • Patients must sign a Patient-Prescriber agreement form and comply with the requirements to receive REVLIMID. In particular, females of reproductive potential must comply with the pregnancy testing, contraception requirements and participate in monthly telephone surveys. Males must comply with the contraception requirements [see Use in Specific Populations (8.6)]. • REVLIMID is available only from pharmacies that are certified in REVLIMID REMS™ program. Provide patients with the telephone number and website for information on how to obtain the product. Hematologic Toxicity Inform patients that REVLIMID is associated with significant neutropenia and thrombocytopenia [see Boxed Warnings and Warnings and Precautions (5.3)]. Venous Thromboembolism Inform patients that REVLIMID/dexamethasone has demonstrated significant increased risk of DVT and PE in patients with multiple myeloma [see Boxed Warnings and Warning and Precautions (5.4)]. Increased Mortality in Patients with CLL Inform patients that REVLIMID had increased mortality in patients with CLL and serious adverse cardiovascular reactions, including atrial fibrillation, myocardial infarction, and cardiac failure [see Warning and Precautions (5.5)]. Second Primary Malignancies Inform patients of the potential risk of developing second primary malignancies during treatment with REVLIMID. Hepatotoxicity Inform patients of the risk of hepatotoxicity, including hepatic failure and death, and to report any signs and symptoms associated with this event to their healthcare provider for evaluation. Allergic Reactions Inform patients of the potential for allergic reactions including hypersensitivity, angioedema, Stevens Johnsons Syndrome, or toxic epidermal necrolysis if they had such a reaction to THALOMID and report symptoms associated with these events to their healthcare provider for evaluation. Tumor Lysis Syndrome Inform patients of the potential risk of tumor lysis syndrome and to report any signs and symptoms associated with this event to their healthcare provider for evaluation. Tumor Flare Reaction Inform patients of the potential risk of tumor flare reaction and to report any signs and symptoms associated with this event to their healthcare provider for evaluation. Dosing Instructions Inform patients to take REVLIMID once daily at about the same time each day, either with or without food. The capsules should not be opened, broken, or chewed. REVLIMID should be swallowed whole with water. Instruct patients that if they miss a dose of REVLIMID, they may still take it up to 12 hours after the time they would normally take it. If more than 12 hours have elapsed, they should be instructed to skip the dose for that day. The next day, they should take REVLIMID at the usual time. Warn patients to not take 2 doses to make up for the one that they missed. Manufactured for: Celgene Corporation Summit, NJ 07901 REVLIMID®, RevAssist®, and THALOMID® are registered trademarks of Celgene Corporation. REVLIMID REMS™ is a trademark of Celgene Corporation. U.S. Pat. Nos. 5,635,517; 6,045,501; 6,281,230; 6,315,720; 6,555,554; 6,561,976; 6,561,977; 6,755,784; 6,908,432; 7,119,106; 7,189,740; 7,468,363; 7,465,800; 7,855,217; 7,968,569 ©2005-2013 Celgene Corporation, All Rights Reserved. REV_MCL_HCP_BSv18 11_2013

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Tafinlar (Dabrafenib) and Mekinist (Trametinib): Two Oral Targeted Kinase

Inhibitors for the Treatment of Patients with Metastatic Melanoma and BRAF Mutations

By Lisa A. Raedler, PhD, RPh, Medical Writer

utaneous melanoma, although not the most common skin cancer, is the most deadly.1 Based on data collected between 2003 and 2009, the 5-year survival rate for Americans with metastatic melanoma remains very low—only 16%—for all disease stages and for both sexes.2 The National Cancer Institute has estimated that approximately 1 in 49 people will be diagnosed with melanoma in the United States, and more than 9450 people will die of this disease in 2013.2 The incidence of melanoma is increasing in the United States, particularly among children and adolescents.2 An analysis of first-time melanoma diagnosis in patients aged 18 to 39 years that occurred between 1970 and 2009 showed that the incidence of melanoma increased 8-fold among young women and 4-fold among young men.3 A study using data from 1973 to 2009 documented an average 2% annual increase in melanoma for children under age 19 years, particularly for girls and adolescents between 15 and 19 years.4 These trends in melanoma diagnosis rates are concerning because of the severity of the disease and the potential impact on healthcare resource utilization. An analysis of Medicare claims data from 1991 to 2005 demonstrated that patients with melanoma, particularly those with metastatic disease, utilize substantial healthcare resources.5 In this study, patients with metastatic melanoma had a monthly average of more than $11,000 in total healthcare costs, the majority of which was related to inpatient hospital services.5 Of note, this cost analysis was conducted before the availability of novel therapies recently approved for metastatic melanoma, including ipilimumab (Yervoy) and vemurafenib (Zelboraf).

FDA Approves 2 New Options for Melanoma In May 2013, the US Food and Drug Administration (FDA) approved 2 BRAF mutation targeted agents— dabrafenib (Tafinlar; GlaxoSmithKline), a BRAF mutation inhibitor, and trametinib (Mekinist; GlaxoSmithKline), a MEK inhibitor—for the treatment of patients with metastatic melanoma.6,7

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Dabrafenib is indicated for the treatment of patients with unresectable or metastatic melanoma and the BRAF V600E mutation as detected by a test that was approved by the FDA together with this agent. Dabraf enib is not indicated for the treatment of patients with the wild-type BRAF melanoma because of the potential risk of tumor promotion in those patients.8 Dabrafenib’s approval was based on a progression-free survival (PFS) benefit, as demonstrated in a multicenter, international, open-label, randomized, active-controlled trial.8 Trametinib is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or BRAF V600K mutation as detected by the FDA-approved test. Trametinib is not indicated for the treatment of patients who have received previous therapy with a BRAF inhibitor.9 The approval of trametinib was based on the demonstration of improved PFS in a multicenter, international, open-label, randomized, active-controlled trial.9 Approximately 50% of patients with cutaneous melanoma have a BRAF gene mutation.10,11 Concurrent with the approvals of dabrafenib and trametinib, the FDA approved the THxID BRAF assay (bioMérieux, Inc; Hazlewood, MO) for the detection of BRAF V600E and BRAF V600K mutations.6,7 In an interview regarding the recent advances in treatments for patients with metastatic melanoma, Lynn M. Schuchter, MD, Chief of Hematology/Oncology at the University of Pennsylvania, stated, “Now we have this wealth of options to consider.…It is amazing that, in 2013, chemotherapy is not the first or second choice for patients with melanoma. It is now targeted therapies, if appropriate, or immunotherapy.”12

Dosing and Administration The recommended dabrafenib dose is 150 mg taken orally twice daily, approximately 12 hours apart, until disease progression or until unacceptable toxicity occurs.8 Patients should take dabrafenib at least 1 hour before a meal or at least 2 hours after a meal. A missed dose

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Dabrafenib versus Dacarbazine: Progression-Free Table 1 Survival and Confirmed Objective Response Results in the Pivotal Phase 3 Trial Dabrafenib (N = 187)

Results Progression-free survival Events, N (%) Progressive disease Death Median, mo Hazard ratioa P valueb

Dacarbazine (N = 63)

78 (42) 41 (65) 76 (41) 41 (65) 2 (1) 0 5.1 (95% CI, 4.9-6.9) 2.7 (95% CI, 1.5-3.2) 0.33 (95% CI, 0.20-0.54) <.001

Confirmed tumor responses 52% (95% CI, 44-59) 17% (95% CI, 9-29) Objective response rate 6 (3) 0 Complete response, N (%) 91 (48) 11 (17) Partial response, N (%) Median duration of response, mo

5.6 (95% CI, 5.4-NR)

NR (95% CI, 5.0-NR)

Pike estimator, stratified by disease state. Stratified log-rank test. CI indicates confidence interval; NR, not reached. Source: Tafinlar (dabrafenib) capsules prescribing information; 2013. a

of dabrafenib can be taken up to 6 hours before the next dose. Dabrafenib capsules should not be opened, crushed, or broken.8 No dose adjustment is recommended for patients with new primary cutaneous malignancies.8 The recommended trametinib dose is 2 mg taken orally once daily until disease progression or until unacceptable toxicity.9 Patients should take trametinib at least 1 hour before a meal or 2 hours after a meal. A missed trametinib dose should not be taken within 12 hours of the next dose.9

Mechanism of Action In cancer cells, mutated BRAF genes lead to over active BRAF signaling and uncontrolled downstream signaling via the MEK/ERK pathway. Ultimately, overactive BRAF signaling results in cell proliferation and resistance to programmed cell death or apoptosis.13,14 Both dabrafenib and trametinib inhibit kinases that are involved with these signaling pathways to arrest cancer-cell growth.8,9 Specifically, dabrafenib inhibits some mutations of BRAF kinases,8 and trametinib reversibly inhibits MEK1 and MEK2 activation and MEK1 and MEK2 kinase activity.9 Phase 3 Clinical Trial: Dabrafenib In a pivotal phase 3 clinical trial of dabrafenib, 250 patients with unresectable stage III or stage IV melanoma and a documented BRAF V600E mutation were ran-

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domly assigned to oral dabrafenib twice daily (N = 187) or to intravenous dacarbazine 1000 mg/m2 every 3 weeks (N = 63), respectively, in a 3:1 ratio.8,15 Patients who had received previous treatment with a BRAF inhibitor or a zation was MEK inhibitor were excluded.15 Randomi stratified by disease stage at baseline.15 The primary end point of this study was PFS, as determined by investigators.8,15 An independent radiology review committee assessed the additional efficacy outcome measures of PFS, confirmed objective response rate (ORR), and duration of response in prespecified supportive analyses.8,15 The patients in the study were allowed to cross over to the alternative treatment when their disease progressed. The median age of the patients was 52 years. Most patients were male (60%), white (99%), with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 (67%), and had M1c disease (66%) and normal lactate dehydrogenase (62%). All patients had BRAF V600E mutations as determined by a clinical trial assay at a centralized testing site.8,15

Efficacy In this study, the median PFS was significantly greater with dabrafenib compared with dacarbazine—5.1 months versus 2.7 months, respectively (hazard ratio [HR], 0.33; 95% confidence interval [CI], 0.20-0.54).8 The median PFS findings were similar in an independent review (6.7 months vs 2.9 months, respectively; HR, 0.35; 95% CI, 0.20-0.61).16 Table 1 summarizes the PFS, the confirmed ORR, and the duration of response in the phase 3 study of da brafenib in patients with BRAF mutation–positive advanced melanoma.8 Updated overall survival (OS) data from the phase 3 study of dabrafenib versus dacarbazine were presented during the June 2013 American Society of Clinical Oncology annual meeting.17 With median follow-up times of 15 months and 13 months for the dabrafenib and dacarbazine cohorts, respectively, OS was 18.2 months in patients who received dabrafenib compared with 15.6 months for those receiving dacarbazine (HR, 0.76; 95% CI, 0.48-1.21), but this difference was not statistically significant.17 Because 57% of the patients who had originally received dacarbazine crossed over to dabrafenib, the OS benefit from the initial dabrafenib therapy was likely obscured.17 Safety In the phase 3 trial, 53% of patients who received dabrafenib and 44% of patients who received dacarbazine had treatment-related adverse events (grade ≥2).15 The most common adverse events with dabrafenib were

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skin-related effects, fever, fatigue, arthralgia, and headache.15 Table 2 summarizes the adverse reactions that occurred in ≥10% (all grades) or in ≥2% (grade 3 or 4) of patients who received dabrafenib.8 Grade 3 or 4 adverse events were uncommon in both groups.15 The incidence of adverse events resulting in the permanent discontinuation of the study medication in this trial was 3% with dabrafenib and with dacarbazine.8,15

Warnings and Precautions New Cutaneous Malignancies Dabrafenib is associated with an increased incidence of cutaneous squamous-cell carcinoma, keratoacanthoma, and melanoma.8 In the phase 3 clinical trial, cutaneous squamous-cell carcinomas (cuSCC) and keratoacanthomas occurred in 7% (14:187) of patients who received dabrafenib and in none of the patients receiving dacarbazine.8,15 The incidence of cuSCC was 11% across the clinical trials of dabrafenib that included 586 patients, with a median time to first cuSCC of 9 weeks (range, 1-53 weeks).8 Of the patients receiving dabrafenib, 3 (2%) developed new primary malignant melanomas. None of the patients receiving dacarbazine were diagnosed with new primary malignant melanoma in the phase 3 trial.8,15 Dermatologic evaluations are recommended before the initiation of dabrafenib, every 2 months while receiving dabrafenib, and for up to 6 months after the discontinuation of dabrafenib.8 Serious Febrile Drug Reactions In the phase 3 study, 3.7% (7:187) of patients receiving dabrafenib and none of the patients treated with dacarbazine had serious febrile drug reactions (ie, serious fever or fever of any severity accompanied by hypotension, rigors or chills, dehydration, or renal failure in the absence of another identifiable cause such as infection).8,15 Fever (serious and nonserious) occurred in 28% of patients who received dabrafenib and in 10% of patients receiving dacarbazine.8,15

Other Adverse Events, Precautions Dabrafenib has also been associated with hyperglycemia, uveitis and iritis, and glucose-6-phosphate dehydrogenase deficiency.8 Patients receiving dabrafenib should be routinely monitored for visual symptoms, as well as for hemolytic anemia.8 Serum glucose levels should be monitored in patients who have preexisting diabetes or hyperglycemia.8 Because dabrafenib can cause fetal harm, women of reproductive potential should be warned of the potential risk to a fetus. Dabrafenib may also render hormonal contraceptives less effective, such that an alternative method of contraception should be used.8

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elected Common Adverse Reactions in ≥10% (All Grades) Table 2 S or in ≥2% (Grade 3 or 4) of Patients Receiving Dabrafenib Dabrafenib (N = 187)

Dacarbazine (N = 59)

All grades, Grade 3 All grades, Grade 3 % or 4, % % or 4,b %

System organ class/ adverse reactionsa

Skin and subcutaneous tissue disorders Hyperkeratosis

Alopecia

Palmar-plantar erythrodysesthesia syndrome

Rash

Arthralgia

Back pain

Myalgia

Papillomac

Cutaneous squamous-cell carcinomas and keratoacanthomasd

Nervous system disorder Headache General disorder/ administration site condition Pyrexia Musculoskeletal and connective tissue disorders

Benign, malignant, and unspecified neoplasms

Gastrointestinal disorder Constipation Respiratory/thoracic/ mediastinal disorder Cough Infections/infestation Nasopharyngitis

Adverse drug reactions reported using MedDRA and graded using CTCAE version 4.0 for assessment of toxicity. b Grade 4 adverse reactions limited to hyperkeratosis (N = 1) and constipation (N = 1). c Includes skin papilloma and papilloma. d Cases of cutaneous squamous-cell carcinoma were required to be reported as grade 3 per protocol. CTCAE indicates Common Terminology Criteria for Adverse Events; MedDRA, Medical Dictionary for Regulatory Activities; NA, not applicable. Source: Tafinlar (dabrafenib) capsules prescribing information; 2013. a

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Table 3 Recommended Dose Modifications for Dabrafenib Adverse reaction

Dose modification

Fever of 101.3ºF-104°F

Withhold dabrafenib until fever resolves; resume dabrafenib at same dose or at a reduced dose level according to product labeling

Fever >104°F or fever complicated by rigors, hypotension, dehydration, or renal failure

Discontinue permanently or withhold dabrafenib until reaction resolves; resume dabrafenib at a reduced dose level according to the drug labeling

Intolerable grade 2 adverse reactions or any grade 3 adverse reactions

Withhold dabrafenib until reaction resolves to grade ≤1; resume dabrafenib at a reduced dose level according to the drug labeling

First occurrence of any grade 4 adverse reaction

Discontinue permanently or withhold dabrafenib until adverse reaction resolves to grade ≤1; resume dabrafenib at a reduced dose level according to the drug labeling

Recurrent grade 4 adverse Discontinue dabrafenib permanently reaction, intolerable grade 2 or any grade 3 or 4 adverse reaction with dabrafenib 50 mg twice daily Common Terminology Criteria for Adverse Events version 4.0. Source: Tafinlar (dabrafenib) capsules prescribing information; 2013.

Trametinib versus Chemotherapy: Progression-Free Table 4 Survival and Confirmed Objective Response Results in a Phase 3 Trial Trametinib (N = 214)

Results

Chemotherapy (N = 108)

Progression-free survival 117 (55) 77 (71) Events, N (%) 107 (50) 70 (65) Progressive disease 10 (5) 7 (6) Death 4.8 (95% CI, 4.3-4.9) 1.5 (95% CI, 1.4-2.7) Median, mo Hazard ratioa P value (log-rank test)

0.47 (95% CI, 0.34-0.65) <.001

Confirmed tumor responses Objective response rate 22% (95% CI, 17-28) 4 (2) Complete response, N (%) 43 (20) Partial response, N (%) Median duration of response, mo

8% (95% CI, 4-15) 0 9 (8)

5.5 (95% CI, 4.1-5.9) NR (95% CI, 3.5-NR)

Pike estimator, stratified by disease state. CI indicates confidence interval; NR, not reached. Source: Mekinist (trametinib) tablets prescribing information; 2013.

Table 3 summarizes the recommended dose modifications related to adverse reactions potentially associated with dabrafenib.

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Phase 3 Clinical Trial: Trametinib The FDA approval of trametinib was based on the demonstration of improved PFS in a phase 3, international, open-label, randomized, active-controlled trial that enrolled 322 patients with histologically confirmed stage IIIc or stage IV melanoma.9,18 Patients were determined to be BRAF V600E or V600K mutation–positive based on centralized testing.9 No more than 1 previous chemotherapy regimen was permitted, and patients with previous exposure to BRAF inhibitors or to MEK inhibitors were ineligible for the trial.9,18 Patients with abnormal left-ventricular ejection fraction (LVEF), a history of acute coronary syndrome within the past 6 months, or with current evidence of New York Heart Association Class II or greater congestive heart failure were excluded from the trial.9 The patients in the trial were randomized to oral trametinib once daily or to intravenous chemotherapy with either dacarbazine or paclitaxel every 3 weeks.9 On disease progression, patients who were randomized to chemotherapy were allowed to cross over to trametinib.9,18 The patients’ median age was 54 years, and they were mostly male (54%) and white (99%).9 All patients had a baseline ECOG performance status of 0 or 1. Most patients (94%) had metastatic disease, had stage M1c (64%), had no history of brain metastasis (97%), and had not previously received chemotherapy for advanced or metastatic disease (66%).9 BRAF V600 mutations included BRAF V600E (87%), BRAF V600K (12%), or both (<1%).9 Almost half (47%) of the patients crossed over to the trametinib arm at the time of disease progression with chemotherapy.9,18 Efficacy PFS, the study’s primary end point, and OS, a secondary end point, were significantly improved with trametinib. The investigators reported a statistically significant increase in PFS in the patients who were treated with trametinib compared with the patients who received chemotherapy (HR, 0.45; 95% CI, 0.330.63; P <.001).9,18 The median PFS was 4.8 months for patients taking trametinib (95% CI, 4.3-4.9) compared with 1.5 months for patients receiving chemotherapy (95% CI, 1.4-2.7).9,18 The significant improvement in PFS was observed in all patient subgroups, with the exception of the subgroups with the V600K mutation and in patients aged ≥65 years.18 The 6-month OS rate was 81% in the trametinib group compared with 67% in the chemotherapy group, a significant difference despite crossover (HR, 0.54; 95% CI, 0.32-0.92; P = .01).18 Table 4 summarizes the PFS, confirmed ORR, and the duration of response findings in the phase 3 study of

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trametinib in patients with BRAF mutation–positive advanced melanoma.9

Safety Rash, diarrhea, and peripheral edema were the most common adverse effects in patients who received trametinib in the phase 3 clinical trial.18 No secondary skin neoplasms were observed.18 Of patients receiving trametinib, 9% had adverse reactions that resulted in permanent drug discontinuation, including decreased LVEF, pneumonitis, renal failure, diarrhea, and rash.9 Table 5 summarizes the adverse reactions that occurred in ≥10% of patients who were treated with trametinib and at a higher incidence than in the control arm.9 Warnings and Precautions Several serious adverse events have been seen with trametinib in clinical trials. Serious events include cardiomyopathy, skin toxicity, and retinal pigment epithelial detachment (RPED). Cardiomyopathy In the phase 3 trial, cardiomyopathy (including car diac failure, left-ventricular dysfunction, or decreased LVEF) occurred in 7% (14:211) of patients who received trametinib and in none of those receiving chemotherapy.9,17 Cardiomyopathy resolved in 10 of these 14 patients.9 Trametinib therapy should be discontinued if the absolute LVEF value decreases by 10% from pretreatment values and is less than the lower limit of normal.9 If symptomatic cardiomyopathy or persistent, asymptomatic LVEF dysfunction does not resolve within 4 weeks, trametinib should be permanently discontinued.9 Skin Toxicity The overall incidence of skin toxicity—including rash, dermatitis, acneiform rash, palmar-plantar erythrodys esthesia syndrome, erythema—was 87% in patients who received trametinib compared with 13% in chemotherapy-receiving patients in the phase 3 study.9 Severe skin toxicity occurred in 12% of the patients in the trametinib arm.9 Overall, 6% of patients who received trametinib were hospitalized, most often for secondary skin infections requiring intravenous antibiotics or severe skin adverse events without secondary infection.9 Patients receiving trametinib should be carefully monitored for skin-related adverse events and for secondary infections.9 Retinal Detachment Ophthalmologic examinations, including retinal evaluations, were performed before treatment and at

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elected Adverse Reactions in ≥10% of Patients Receiving Table 5 S Trametinib and at a Higher Incidence than in the Control Arma Trametinib (N = 211)

Chemotherapy (N = 99)

All grades,b Grade 3 All grades,b Grade 3 % or 4,c % % or 4,c %

Adverse reactions Skin and subcutaneous tissue disorders Rash

Dermatitis acneiform

Dry skin

Pruritus

Paronychia

Lymphedemaf

Hypertension

Hemorrhageg

Gastrointestinal disorders Diarrhea Stomatitis

Abdominal pain

Vascular disorders

Events included are higher in the trametinib arm compared with in the chemotherapy arm by ≥5% in overall incidence or by ≥2% grade 3 or 4 adverse reactions higher in the trametinib arm compared with the chemotherapy arm. b National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. c Grade 4 adverse reactions were limited to rash (N = 1) in the trametinib arm and diarrhea (N = 1) in the chemotherapy arm. d Includes stomatitis, aphthous stomatitis, mouth ulceration, and mucosal inflammation. e Includes abdominal pain, abdominal pain lower, abdominal pain upper, and abdominal tenderness. f Includes lymphedema, edema, and peripheral edema. g Includes epistaxis, gingival bleeding, hematochezia, rectal hemorrhage, melena, vaginal hemorrhage, hemorrhoidal hemorrhage, hematuria, and conjunctival hemorrhage. Source: Mekinist (trametinib) tablets prescribing information; 2013. a

regular intervals during the phase 3 study. One patient receiving trametinib developed RPED, and no cases of RPED were identified in patients receiving chemotherapy.9 The reduction in visual acuity secondary to RPED resolved after a median of 11.5 days (range, 3-71 days) after interruption of trametinib dosing.9 Ophthalmologic evaluations should be performed any time a patient reports visual disturbances while using trametinib. If available, these results should be compared with baseline.9 Withhold trametinib therapy for up to 3 weeks if RPED is diagnosed.9

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Table 6 Warnings and Precautions for Trametinib Clinical trial findings

Recommendations regarding the monitoring and use of trametinib

Cardiomyopathy, cardiac failure, left-ventricular dysfunction, or decreased LVEF

• Median time to onset of cardiomyopathy with trametinib is 63 days (range, 16-156 days) • At the recommended dose, approximately 11% of patients receiving trametinib had evidence of cardiomyopathy (decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF of ≥10% compared with baseline); 5% had a decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF of ≥20% below baseline

• Perform LVEF assessments using echocardiogram or multigated acquisition scan before trametinib initiation, 1 month after initiation, and then at 2- to 3-month intervals • Withhold trametinib if absolute LVEF value decreases by 10% from pretreatment and is less than the lower limit of normal • Permanently discontinue trametinib for symptomatic cardiomyopathy or persistent, asymptomatic LVEF dysfunction

Retinal pigment epithelial detachment

• In the phase 3 study, 1 patient developed RPED • RPED was seen in 14 of the 1749 patients across all clinical trials of trametinib • A reduction in visual acuity secondary to RPED resolved after a median of 11.5 days (range, 3-71 days) after interruption of trametinib; abnormal ities in ocular coherence tomography persisted beyond 1 month in at least several cases

• Perform ophthalmologic evaluations when a patient reports visual disturbances • Withhold trametinib for up to 3 weeks when RPED is diagnosed • If resolution of RPED is documented on repeat ophthalmologic evaluation within 3 weeks, resume trametinib at a reduced dose

Retinal vein occlusion

RVO can lead to macular edema, decreased visual function, neovascularization, and glaucoma; RVO was seen in 4 (0.2%) patients in all clinical trials of trametinib

• Any patient-reported vision loss or other visual disturbances should undergo urgent (within 24 hrs) ophthalmologic evaluation • Permanently discontinue trametinib in patients with documented RVO

Interstitial lung disease

• In the phase 3 study, 5 of the 211 patients who were treated with trametinib were hospitalized for ILD or pneumonitis • The first presentation of ILD or pneumonitis occurred at a median of 160 days (range, 60172 days) • ILD or pneumonitis occurred in 6 of 329 patients who received trametinib at the recommended dose in clinical trials

• Withhold trametinib in patients with new or progressive pulmonary symptoms (ie, cough, dyspnea, hypoxia, pleural effusion, infiltrates) pending clinical investigations • Patients diagnosed with treatment-related ILD or pneumonitis should discontinue trametinib permanently

Skin toxicity

• Skin toxicity (ie, rash, dermatitis, acneiform rash, palmar-plantar erythrodysesthesia syndrome, erythema) was 87% in patients treated with trametinib • Severe skin toxicity occurred in 12% of patients treated with trametinib • Skin toxicity was observed in patients treated with trametinib after 15 days (median), with a range of 1 to 221 days; the median time to skin toxicity resolution was 48 days (range, 1-282 days) • Of patients with skin toxicity, 12% required trametinib dose reductions and 1% permanently discontinued trametinib

• Patients receiving trametinib should be monitored for skin toxicities and for secondary infections

Embryofetal toxicity

Trametinib can cause fetal harm when administered to a pregnant woman

• Female patients of reproductive potential should use highly effective contraception during therapy with trametinib and for 4 mo after treatment • Patients who are taking trametinib should contact their provider if pregnancy is suspected • If trametinib is used during pregnancy, or if the patient becomes pregnant while taking trametinib, she should be apprised of the potential hazard to a fetus

ILD indicates interstitial lung disease; LVEF, left-ventricular ejection fraction; RPED, retinal pigment epithelial detachment; RVO, retinal vein occlusion. Sources: Mekinist (trametinib) tablets prescribing information; 2013; Flaherty KT, Robert C, Hersey P, et al. N Engl J Med. 2012;367:107-114.

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Additional Adverse Events Trametinib has also been associated with retinal vein occlusion, interstitial lung disease, and embryofetal toxicity.9 Patients diagnosed with treatment-related retinal vein occlusion, interstitial lung disease, or pneumonitis should discontinue trametinib therapy permanently.9 Female patients of reproductive potential should use highly effective contraception during trametinib therapy and for 4 months after treatment.9 Table 6 summarizes these warnings and precautions associated with the use of trametinib, as well as recommendations for monitoring and appropriate drug use.

The addition of these 2 oral agents to the armamentarium of immunotherapies, targeted agents, and chemotherapy for the treatment of advanced melanoma offers hope for improved patient outcomes. Conclusion For adults with BRAF-mutated metastatic melanoma, the new kinase inhibitors dabrafenib and trametinib have demonstrated clinically and statistically significant efficacy and manageable toxicity profiles. Although dabrafenib and trametinib were initially approved as single agents, clinicians have expressed interest in their potential value when used in combination for the treatment of advanced melanoma.19 Based on data from a phase 1/2 study comparing da足 brafenib monotherapy with the combination, in January 2014 the FDA approved the use of dabrafenib in combination with trametinib for the treatment of adults with unresectable or metastatic melanoma and a BRAF V600E or BRAF V600K mutation.20 The addition of these 2 oral agents to the armamentarium of immunotherapies, targeted agents, and chemo-

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therapy for the treatment of patients with advanced melanoma offers hope for improved patient outcomes. n

References

1. Skin Cancer Foundation. What is melanoma? www.skincancer.org/skin-cancer-足 information/melanoma. Accessed July 24, 2013. 2. National Cancer Institute. SEER cancer statistics review 1975-2010. Updated June 14, 2013. http://seer.cancer.gov/csr/1975_2010/. Accessed July 7, 2013. 3. Reed KB, Brewer JD, Lohse CM, et al. Increasing incidence of melanoma among young adults: an epidemiological study in Olmsted County, Minnesota. Mayo Clin Proc. 2012;87:328-334. 4. Wong JR, Harris JK, Rodriguez-Galindo C, Johnson KJ. Incidence of childhood and adolescent melanoma in the United States: 1973-2009. Pediatrics. 2013;131:846-854. 5. Davis KL, Mitra D, Kotapati S, et al. Direct economic burden of high-risk and metastatic melanoma in the elderly: evidence from the SEER-Medicare linked database. Appl Health Econ Health Policy. 2009;7:31-41. 6. US Food and Drug Administration. Drugs: dabrafenib. Updated May 30, 2013. www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm354477.htm. Accessed July 7, 2013. 7. US Food and Drug Administration. Drugs: trametinib. Updated May 30, 2013. www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm354478.htm. Accessed July 7, 2013. 8. Tafinlar (dabrafenib) capsules [prescribing information]. Research Triangle Park, NC: GlaxoSmithKline; May 2013. 9. Mekinist (trametinib) tablets [prescribing information]. Research Triangle Park, NC: GlaxoSmithKline; May 2013. 10. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949-954. 11. Jakob JA, Bassett RL Jr, Ng CS, et al. NRAS mutation status is an independent prognostic factor in metastatic melanoma. Cancer. 2012;118:4014-4023. 12. IMNG Medical Media. Melanoma advances make chemo third-tier therapy. YouTube. Posted by ElsGlobalMedicalNews. June 1, 2013. www.youtube.com/watch?v= Vw2GmsgT620. Accessed July 24, 2013. 13. Wong KK. Recent developments in anti-cancer agents targeting the Ras/Raf/ MEK/ERK pathway. Recent Pat Anticancer Drug Discov. 2009;4:28-35. 14. McCubrey JA, Steelman LS, Abrams SL, et al. Roles of the RAF/MEK/ERK and PI3K/PTEN/AKT pathways in malignant transformation and drug resistance. Adv Enzyme Regul. 2006;46:249-279. 15. Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012;380:358-365. 16. American Society of Clinical Oncology. Dabrafenib extends progression-free survival in metastatic melanoma, has high clinical activity in brain metastases. ASCO Annual Meeting. ASCO News Daily: LBA8500. http://chicago2012.asco.org/ ASCODailyNews/LBA8500.aspx. Accessed July 31, 2013. 17. Hauschild A, Grob JJ, Demidov LV, et al. An update on BREAK-3, a phase III, randomized trial: dabrafenib (DAB) versus dacarbazine (DTIC) in patients with BRAF V600E-positive mutation metastatic melanoma (MM). J Clin Oncol. 2013;31 (15 suppl):Abstract 9013. 18. Flaherty KT, Robert C, Hersey P, et al; for the METRIC Study Group. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012;367:107-114. 19. CurrentMedicine.TV. Phase 2 studies of BRAF plus MEK inhibitors to treat melanoma. YouTube. October 4, 2012. www.youtube.com/watch?v=UG2pX98X2z4. Accessed July 24, 2013. 20. US Food and Drug Administration. FDA approves Mekinist in combination with Tafinlar for advanced melanoma. Press release. January 10, 2014. Updated January 15, 2014. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm381159.htm. Accessed March 5, 2014.

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Tecfidera (Dimethyl Fumarate), a New Oral Therapy Approved by the FDA for the Treatment of Relapsing Forms of Multiple Sclerosis By Loretta Fala, Medical Writer

ultiple sclerosis (MS) is a chronic, inflammatory, potentially debilitating disease of the central nervous system (CNS) that disrupts the communication between the brain, spinal cord, and other areas of the body.1 MS may also result in nerve deterioration, which is an irreversible condition. The symptoms of MS can vary widely, depending on which nerves are affected and on the extent of the nerve damage.1 The most common symptoms associated with MS include fatigue, numbness, spasticity, vision problems, and bowel and bladder problems.2 Women are twice as likely as men to be affected by MS.1 It most frequently affects individuals between the ages of 20 and 40 years and those who have a family history of the disease. Certain infections (eg, Epstein-Barr virus) and autoimmune diseases (eg, thyroid disease, type 1 diabetes, or inflammatory bowel disease) may predispose a person to MS. Caucasians whose families originated in northern Europe have the highest risk for developing MS. Moreover, MS is more common in Europe, southern Canada, northern United States, New Zealand, and southeastern Australia.1 There are 4 types of MS, including relapsing-remitting MS (RRMS), secondary progressive, primary progressive, and progressive relapsing.2 RRMS is the most common type, accounting for 85% of initial diagnoses of MS.2 RRMS is characterized by temporary periods of relapses or exacerbations of neurologic functioning, followed by periods of remission in which partial or complete recovery occurs.3 MS, particularly if untreated or in the advanced phase, is associated with multiple symptoms that can impose a substantial burden on the patientâ&#x20AC;&#x2122;s mobility, daily activities, cognitive function, physical well-being, and overall quality of life.4 Patients with MS are at risk for depression, osteoporosis, pressure sores, and other complications. MS also has a marked impact on caregivers and on society and the healthcare system.4 According to a systematic review of MS-related healthcare cost studies published between 2007 and 2012, total

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all-cause (direct and indirect) costs for MS ranged from $8528 to $54,244 per patient annually.5 Direct costs accounted for an average of 77% (range, 64%-91%) of the total costs, with prescription medications accounting for the majority of the direct costs. Indirect costs accounted for approximately 23% (9%-36%) of the total costs. In fact, the direct all-care healthcare costs for MS ranked second only to congestive heart failure compared with other chronic conditions in a recent analysis.5 This systematic review did not take into account some of the newer and more costly treatments or the costs associated with the impaired disability, early retirement, and diminished quality of life associated with MS.5 The early diagnosis and early treatment of MS are crucial, because permanent CNS damage may occur even before a person experiences symptoms.6 Although no cure is available for MS, effective treatment strategies can help to slow the progression of the disease, manage symptoms, and improve function.7 One of the most dramatic treatment advances in recent decades is the development of disease-modifying therapies for MS. The disease-modifying therapies have been shown to be effective at reducing disease activity and disease progression in many patients with relapsing forms of MS.7 Consequently, adherence to prescribed therapy is important to achieve optimal outcomes. Until recently, the disease-modifying therapies for MS included beta interferons (interferon beta-1a and interferon beta-1b), glatiramer acetate, natalizumab, mitoxantrone, and 2 oral therapiesâ&#x20AC;&#x201D;fingolimod and teriflunomide.1 Corticosteroids may also be used to reduce inflammation during a relapse.1 Other strategies that may improve the symptoms of MS include physical therapy, muscle relaxants, medications to reduce fatigue and to improve walking, and medications that may be prescribed for depression, pain, and bladder or bowel control problems.1 Lifestyle and behavioral approaches, including rest, exercise, nutrition, and stress management, may also help to alleviate some of the symptoms of MS.1

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Dimethyl Fumarate: A New First-Line Oral Option In March 2013, the US Food and Drug Administration (FDA) approved dimethyl fumarate (Tecfidera; Biogen Idec), a nuclear factor (erythroid-derived 2)–like 2 (Nrf2) activator, for the first-line treatment of adults with relapsing forms of MS.8 Dimethyl fumarate is a methyl ester of fumaric acid available as a delayed-release oral therapy.8-10 According to Russell Katz, MD, Director, Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research, “No drug provides a cure for multiple sclerosis so it is important to have a variety of treatment options available for patients.” He added, “Multiple sclerosis can impair movement, sensation, and thinking and have a profound impact on a person’s quality of life.”8 Mechanism of Action The mechanism by which dimethyl fumarate exerts its therapeutic effect in MS is unknown. Dimethyl fumarate and the metabolite monomethyl fumarate have been shown to activate the Nrf2 pathway in vitro and in vivo in animals and in humans. The Nrf2 pathway is involved in the cellular response to oxidative stress. Monomethyl fumarate has been identified as a nicotinic acid receptor agonist in vitro.10 Dosing The starting dose for dimethyl fumarate is 120 mg twice daily orally for 7 days.10 After 7 days, the dose should be increased to the maintenance dose of 240 mg twice daily orally. Dimethyl fumarate should be swallowed whole and intact, and should not be crushed or chewed. The capsule contents of dimethyl fumarate should not be sprinkled on food. Dimethyl fumarate can be taken with or without food; administration with food may reduce the incidence of flushing. It is recommended that a complete blood cell count be performed before the initiation of therapy with dimethyl fumarate to identify patients with preexisting low lymphocyte counts. Dimethyl fumarate is available as a delayed-release capsule in 120-mg and 240-mg strengths.10 Clinical Studies The safety and efficacy of dimethyl fumarate were demonstrated in 2 studies, Determination of the Efficacy and Safety of Oral Fumarate in Relapsing-Remitting MS (DEFINE) and Comparator and an Oral Fumarate in Relapsing-Remitting Multiple Sclerosis (CONFIRM), which evaluated dimethyl fumarate taken 2 or 3 times daily in patients with RRMS.10-12 The starting dose for dimethyl fumarate was 120 mg 2 or 3 times daily for the first 7 days, followed by an increase to 240 mg twice or 3 times daily. Both studies included patients who had at

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least 1 relapse over the year preceding the trial or who had a brain magnetic resonance imaging (MRI) scan demonstrating at least 1 gadolinium-enhancing (Gd+) lesion within 6 weeks of randomization.10 The Expanded Disability Status Scale (EDSS) score was also assessed; to be included in the trials, patients could have scores ranging from 0 to 5. Neurologic evaluations were performed at baseline, then every 3 months, and at the time of suspected relapse. MRI evaluations were conducted at baseline, at month 6, and at years 1 and 2 in a subset of patients (44% in the DEFINE trial and 48% in the CONFIRM trial).10

Study 1: The DEFINE Study Study 1, the DEFINE study, was a 2-year randomized, double-blind, placebo-controlled trial of 1234 patients with RRMS.10,11 The primary end point was the proportion of relapsed patients at 2 years. Other end points at 2 years included the number of new or newly enlarging T2 hyperintense lesions, the number of new T1 hypointense lesions, the number of Gd+ lesions, annualized relapse rate, and the time to confirmed disability progression. The confirmed disability progression was defined as at least a 1-point increase from the baseline EDSS score (a 1.5-point increase for patients with a baseline EDSS score of 0) sustained for 12 weeks. Patients in study 1 were randomized to receive dimethyl fumarate 240 mg twice daily (N = 410), dimethyl fumarate 240 mg 3 times daily (N = 416), or placebo (N = 408) for up to 2 years.10 The median age of the patients was 39 years, the median time since diagnosis was 4 years, and the median EDSS score at baseline was 2. The median time of using the study drug for all treatment arms was 96 weeks. The percentages of patients who completed 96 weeks while taking the study drug per treatment group were 69% for those assigned to dimethyl fumarate 240 mg twice daily, 69% for those assigned to dimethyl fumarate 240 mg 3 times daily, and 65% for patients assigned to placebo.10 The clinical and MRI findings for study 1 are shown in Table 1. Dimethyl fumarate was shown to have a significant effect on all of the end points described above; the 240-mg 3-times-daily dose showed no additional benefit versus the 240-mg twice-daily dose.10 Study 2: The CONFIRM Study Study 2, the CONFIRM study, was a 2-year randomized, double-blind, placebo-controlled trial in patients with RRMS that also included an open-label comparator arm. The primary end point was the annualized relapse rate at 2 years. Other end points at 2 years included the number of new or newly enlarging T2 hyperintense lesions, the number of T1 hypointense lesions, the

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Table 1 The DEFINE Study: Clinical and MRI Results with Dimethyl Fumarate in Patients with RRMS Dimethyl fumarate Clinical/imaging findings 240 mg twice daily Placebo Clinical results

P value

(N = 410)

(N = 408)

27 49

46 —

<.001

0.172 53

0.364 —

<.001

16 38

27 —

.005

(N = 152)

(N = 165)

Mean new or newly enlarging T2 lesions over 2 years, N

2.6

Patients with no new or newly enlarging lesions, %

0.1 (0)

1.8 (0)

Patients with lesions, % 0 lesions 1 lesion 2 lesions 3-4 lesions ≥5 lesions

93 5 <1 0 <1

62 10 8 9 11

Relative odds reduction, %

—

<.001

Mean new T1 hypointense lesions during 2 years, N

1.5

5.6

<.001

Patients relapsing (primary end point), % Relative risk reduction, % Annualized relapse rate Relative reduction, % Proportion with disability progression, % Relative risk reduction, % MRI results

Mean Gd+ lesions at 2 years, N (median)

<.001

Gd+ indicates gadolinium-enhancing; MRI, magnetic resonance imaging; RRMS, relapsing-remitting multiple sclerosis. Source: Tecfidera (dimethyl fumarate) delayed-release capsules prescribing information; 2013.

number of Gd+ lesions, the proportion of patients with relapsed disease, and the time to confirmed disability progression as defined in study 1. Patients in study 2 were randomized to receive dimethyl fumarate 240 mg twice daily (N = 359), dimethyl fumarate 240 mg 3 times daily (N = 345), an open-label comparator (N = 350), or placebo (N = 363) for up to 2 years.10 The median age of the patients was 37 years, the median time since diagnosis was 3 years, and the median EDSS score at baseline was 2.5. The median time using the study drug for all treatment arms was 96 weeks. The percentages of patients who completed 96 weeks with the study drug per treatment group were 72% for patients assigned to dimethyl fumarate 240 mg twice daily, 70% for patients assigned to dimethyl fumarate 240 mg 3 times daily, and 64% for patients assigned to placebo. The clinical and MRI results for study 2 are shown in Table 2. Dimethyl fumarate demonstrated a significant effect on the relapse and MRI end points described above. No significant effect was seen on disability progression. The dimethyl fumarate 240-mg 3-times-daily dose resulted in no additional benefit versus the dimethyl fumarate 240-mg twice-daily dose.10

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Safety In placebo-controlled and uncontrolled clinical trials, a total of 2513 patients received dimethyl fumarate and were followed for up to 4 years, with an overall exposure of 4603 person-years.10 Approximately 1162 patients received more than 2 years of treatment with dimethyl fumarate. The adverse reaction profile of dimethyl fumarate in the uncontrolled clinical studies was consistent with the experience in the placebo-controlled studies. The most common adverse reactions (incidence ≥10% and ≥2% more than placebo) for dimethyl fumarate were flushing, abdominal pain, diarrhea, and nausea.10 The prescribing information for dimethyl fumarate does not include any boxed warnings. In addition, there are no contraindications for dimethyl fumarate in the FDA-approved labeling. Warnings and Precautions Lymphopenia. Dimethyl fumarate may decrease lymphocyte counts. Low lymphocyte counts can increase the risk of infection; however, in clinical trials, no significant increase in infections was seen in patients taking dimethyl fumarate.8 Before initiating treatment with di-

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Table 2 The CONFIRM Study: Clinical and MRI Results with Dimethyl Fumarate in Patients with RRMS Dimethyl fumarate Clinical/imaging findings 240 mg twice daily Placebo Clinical end points

P value

(N = 359)

(N = 363)

0.224 44

0.401 —

<.001

Proportion relapsing (primary end point), % Relative risk reduction, %

29 34

41 —

.002

Proportion with disability progression, % Relative risk reduction, %

13 21

17 —

.25

(N = 147)

(N = 144)

Mean new or newly enlarging T2 lesions over 2 years, N

5.1

17.4

Patients with no new or newly enlarging lesions, %

0.5 (0)

2 (0)

Patients with lesions, % 0 lesions 1 lesion 2 lesions 3-4 lesions ≥5 lesions

80 11 3 3 3

61 17 6 2 14

Relative odds reduction, %

—

<.001

Mean new T1 hypointense lesions during 2 years, N

<.001

Annualized relapse rate Relative reduction, %

MRI end points

Mean Gd+ lesions at 2 years, % (median)

<.001

methyl fumarate, a recent complete blood count (ie, within 6 months) should be available.10 A complete blood count is recommended annually and as clinically indicated. Withholding treatment in patients with serious infections should be considered.10 Flushing. Dimethyl fumarate may cause flushing (eg, warmth, redness, itching, and/or a burning sensation). In clinical trials, 40% of patients receiving dimethyl fumarate experienced flushing. Symptoms of flushing generally began soon after initiating treatment and usually improved or resolved over time.10

fumarate is excreted in human milk. Caution should be exercised when dimethyl fumarate is administered to a nursing woman.10

With the FDA approval of dimethyl fumarate in 2013, a new, disease-modifying first-line oral treatment option became available for patients with relapsing forms of MS.

Drug Interactions No potential drug interactions with dimethyl fumarate or with monomethyl fumarate were identified in the in vitro cytochrome P inhibition and induction studies, or in P-glycoprotein studies.10

Pediatric use. The safety and effectiveness of dimethyl fumarate in pediatric patients have not been established.10 Geriatric use. Clinical studies of dimethyl fumarate did not include sufficient numbers of patients aged ≥65 years to determine whether they respond different from younger patients.10

Use in Specific Populations Pregnancy. There are no adequate and well-controlled studies in pregnant women. Dimethyl fumarate should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus.10 Nursing mothers. It is not known whether dimethyl

Conclusion With the FDA approval of dimethyl fumarate in 2013, a new, disease-modifying first-line oral treatment option became available for patients with relapsing forms of MS. Based on findings from 2 key clinical trials in this patient population, patients treated with dimethyl fuma-

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rate had significantly fewer MS relapses compared with patients who received placebo. In one of these trials, treatment with dimethyl fumarate was also associated with a significant reduction in the rate of disability progression associated with MS compared with placebo. The most frequently reported adverse reactions associated with dimethyl fumarate were flushing, abdominal pain, diarrhea, and nausea. n

References

1. Mayo Clinic staff. Diseases and conditions: multiple sclerosis. December 15, 2012. www.mayoclinic.org/diseases-conditions/multiple-sclerosis/basics/definition/CON20026689. Accessed January 23, 2014. 2. National Multiple Sclerosis Society. How relapsing-remitting MS (RRMS) differs from progressive courses of MS. www.nationalmssociety.org/about-multiple-sclerosis/ relapsing-ms/relapsing-remitting-ms-rrms/how-rrms-differs-from-progressive-coursesof-ms/index.aspx. Accessed January 23, 2014. 3. National Multiple Sclerosis Society. What we know about relapsing-remitting MS (RRMS). www.nationalmssociety.org/about-multiple-sclerosis/relapsing-ms/relapsingremitting-ms-rrms/index.aspx. Accessed January 23, 2014.

4. National Multiple Sclerosis Society. Living with advanced MS. www.nationalms society.org/about-multiple-sclerosis/living-with-advanced-ms/index.aspx. Accessed January 27, 2014. 5. Adelman G, Rane SG, Villa KF. The cost burden of multiple sclerosis in the United States: a systematic review of the literature. J Med Econ. 2013;16:639-647. 6. National Multiple Sclerosis Society. Adherence: starting a disease-modifying therapy and sticking with it. www.nationalmssociety.org/about-multiple-sclerosis/what-we-knowabout-ms/treatments/adherence/index.aspx. Accessed January 27, 2014. 7. National Multiple Sclerosis Society. Treatments. www.nationalmssociety.org/aboutmultiple-sclerosis/what-we-know-about-ms/treatments/index.aspx. Accessed January 27, 2014. 8. US Food and Drug Administration. FDA approves new multiple sclerosis treatment: Tecfidera. Press release. March 27, 2013. Updated March 28, 2013. www.fda. gov/NewsEvents/Newsroom/PressAnnouncements/ucm345528.htm. Accessed January 22, 2014. 9. MedlinePlus. Dimethyl fumarate. Revised July 15, 2013. www.nlm.nih.gov/medline plus/druginfo/meds/a613028.html. Accessed January 22, 2014. 10. Tecfidera (dimethyl fumarate) delayed-release capsules [prescribing information]. Cambridge, MA: Biogen Idec Inc; March 2013. 11. Gold R, Kappos L, Arnold DL, et al; for the DEFINE Study Investigators. Placebo- controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med. 2012;367:1098-1107. Erratum in: N Engl J Med. 2012;367:2362. 12. Fox RJ, Miller DH, Phillips JT, et al; for the CONFIRM Study Investigators. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med. 2012;367:1087-1097. Erratum in: N Engl J Med. 2012;367:1673.

Call for Papers American Health & Drug Benefits offers an open forum for all healthcare participants to exchange ideas and present their data, innovations, and initiatives to facilitate patient-centered healthcare and benefit design models that meet the needs of all stakeholders—Distributors, Employers, Manufacturers, Patients, Payers, Providers, Purchasers, Regulators, and Researchers. Readers are invited to submit articles that aim at improving the quality of patient care and patient well-being while reducing or controlling costs, enhancing the health of communities and patient populations, as well as other topics relevant to benefit design with specific implications to policymakers, payers, and employers.

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• Adherence Concerns • Benefit Design • Case Studies • Comorbidities and Cost Issues • Cost-Effectiveness Comparisons • Decision-Making Tools • Ethics in Medicine • Health Economics Research

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NEW

For the treatment of elevated IOP

UNLOCK NEW TREATMENT POSSIBILITIES

SIMBRINZA™ Suspension provided additional 1-3 mm Hg IOP lowering compared to the individual components1 ■ IOP measured at 8 AM, 10 AM, 3 PM, and 5 PM was reduced by 21-35% at Month 32-4 ■ Efficacy proven in two pivotal Phase 3 randomized, multicenter, double-masked, parallel-group, 3-month, 3-arm, contribution-of-elements studies2,3 ■ The most frequently reported adverse reactions (3-5%) were blurred vision, eye irritation, dysgeusia (bad taste), dry mouth, and eye allergy1 ■ Only available beta-blocker-free fixed combination2,3 INDICATIONS AND USAGE SIMBRINZA™ (brinzolamide/brimonidine tartrate ophthalmic suspension) 1%/0.2% is a fixed combination indicated in the reduction of elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension. Dosage and Administration The recommended dose is one drop of SIMBRINZA™ Suspension in the affected eye(s) three times daily. Shake well before use. SIMBRINZA™ Suspension may be used concomitantly with other topical ophthalmic drug products to lower intraocular pressure. If more than one topical ophthalmic drug is being used, the drugs should be administered at least five (5) minutes apart. IMPORTANT SAFETY INFORMATION Contraindications SIMBRINZA™ Suspension is contraindicated in patients who are hypersensitive to any component of this product and neonates and infants under the age of 2 years. Warnings and Precautions Sulfonamide Hypersensitivity Reactions—Brinzolamide is a sulfonamide, and although administered topically, is absorbed systemically. Sulfonamide attributable adverse reactions may occur. Fatalities have occurred due to severe reactions to sulfonamides. Sensitization may recur when a sulfonamide is readministered irrespective of the route of administration. If signs of serious reactions or hypersensitivity occur, discontinue the use of this preparation. Corneal Endothelium—There is an increased potential for developing corneal edema in patients with low endothelial cell counts. References: 1. SIMBRINZA™ Suspension Package Insert. 2. Katz G, DuBiner H, Samples J, et al. Three-month randomized trial of fixed-combination brinzolamide, 1%, and brimonidine, 0.2% [published online ahead of print April 11, 2013]. JAMA Ophthalmol. doi:10.1001/jamaophthalmol.2013.188. 3. Nguyen QH, McMenemy MG, Realini T, et al. Phase 3 randomized 3-month trial with an ongoing 3-month safety extension of fixedcombination brinzolamide 1%/brimonidine 0.2%. J Ocul Pharmacol Ther. 2013;29(3): 290-297. 4. Data on file, 2013.

MG13003JAD

Severe Hepatic or Renal Impairment (CrCl <30 mL/min)—SIMBRINZA™ Suspension has not been specifically studied in these patients and is not recommended. Adverse Reactions In two clinical trials of 3 months’ duration with SIMBRINZA™ Suspension, the most frequent reactions associated with its use occurring in approximately 3-5% of patients in descending order of incidence included: blurred vision, eye irritation, dysgeusia (bad taste), dry mouth, and eye allergy. Adverse reaction rates with SIMBRINZA™ Suspension were comparable to those of the individual components. Treatment discontinuation, mainly due to adverse reactions, was reported in 11% of SIMBRINZA™ Suspension patients. Drug Interactions—Consider the following when prescribing SIMBRINZA™ Suspension: Concomitant administration with oral carbonic anhydrase inhibitors is not recommended due to the potential additive effect. Use with high-dose salicylate may result in acid-base and electrolyte alterations. Use with CNS depressants may result in an additive or potentiating effect. Use with antihypertensives/cardiac glycosides may result in additive or potentiating effect on lowering blood pressure. Use with tricyclic antidepressants may blunt the hypotensive effect of systemic clonidine and it is unknown if use with this class of drugs interferes with IOP lowering. Use with monoamine oxidase inhibitors may result in increased hypotension. For additional information about SIMBRINZA™ Suspension, please see Brief Summary of full Prescribing Information on adjacent page.

BRIEF SUMMARY OF PRESCRIBING INFORMATION INDICATIONS AND USAGE SIMBRINZA™ (brinzolamide/brimonidine tartrate ophthalmic suspension) 1%/0.2% is a fixed combination of a carbonic anhydrase inhibitor and an alpha 2 adrenergic receptor agonist indicated for the reduction of elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension. DOSAGE AND ADMINISTRATION The recommended dose is one drop of SIMBRINZA™ Suspension in the affected eye(s) three times daily. Shake well before use. SIMBRINZA™ Suspension may be used concomitantly with other topical ophthalmic drug products to lower intraocular pressure. If more than one topical ophthalmic drug is being used, the drugs should be administered at least five (5) minutes apart. DOSAGE FORMS AND STRENGTHS Suspension containing 10 mg/mL brinzolamide and 2 mg/mL brimonidine tartrate. CONTRAINDICATIONS Hypersensitivity - SIMBRINZA™ Suspension is contraindicated in patients who are hypersensitive to any component of this product. Neonates and Infants (under the age of 2 years) - SIMBRINZA™ Suspension is contraindicated in neonates and infants (under the age of 2 years) see Use in Specific Populations WARNINGS AND PRECAUTIONS Sulfonamide Hypersensitivity Reactions - SIMBRINZA™ Suspension contains brinzolamide, a sulfonamide, and although administered topically is absorbed systemically. Therefore, the same types of adverse reactions that are attributable to sulfonamides may occur with topical administration of SIMBRINZA™ Suspension. Fatalities have occurred due to severe reactions to sulfonamides including Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias. Sensitization may recur when a sulfonamide is re-administered irrespective of the route of administration. If signs of serious reactions or hypersensitivity occur, discontinue the use of this preparation [see Patient Counseling Information] Corneal Endothelium - Carbonic anhydrase activity has been observed in both the cytoplasm and around the plasma membranes of the corneal endothelium. There is an increased potential for developing corneal edema in patients with low endothelial cell counts. Caution should be used when prescribing SIMBRINZA™ Suspension to this group of patients. Severe Renal Impairment - SIMBRINZA™ Suspension has not been specifically studied in patients with severe renal impairment (CrCl < 30 mL/min). Since brinzolamide and its metabolite are excreted predominantly by the kidney, SIMBRINZA™ Suspension is not recommended in such patients. Acute Angle-Closure Glaucoma - The management of patients with acute angle-closure glaucoma requires therapeutic interventions in addition to ocular hypotensive agents. SIMBRINZA™ Suspension has not been studied in patients with acute angle-closure glaucoma. Contact Lens Wear - The preservative in SIMBRINZA™, benzalkonium chloride, may be absorbed by soft contact lenses. Contact lenses should be removed during instillation of SIMBRINZA™ Suspension but may be reinserted 15 minutes after instillation [see Patient Counseling Information]. Severe Cardiovascular Disease - Brimonidine tartrate, a component of SIMBRINZATM Suspension, has a less than 5% mean decrease in blood pressure 2 hours after dosing in clinical studies; caution should be exercised in treating patients with severe cardiovascular disease. Severe Hepatic Impairment - Because brimonidine tartrate, a component of SIMBRINZA™ Suspension, has not been studied in patients with hepatic impairment, caution should be exercised in such patients. Potentiation of Vascular Insufficiency - Brimonidine tartrate, a component of SIMBRINZATM Suspension, may potentiate syndromes associated with vascular insufficiency. SIMBRINZA™ Suspension should be used with caution in patients with depression, cerebral or coronary insufficiency, Raynaud’s phenomenon, orthostatic hypotension, or thromboangitis obliterans. Contamination of Topical Ophthalmic Products After Use - There have been reports of bacterial keratitis associated with the use of multiple-dose containers of topical ophthalmic products. These containers have been inadvertently contaminated by patients who, in most cases, had a concurrent corneal disease or a disruption of the ocular epithelial surface [see Patient Counseling Information]. ADVERSE REACTIONS Clinical Studies Experience - Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to the rates in the clinical studies of another drug and may not reflect the rates observed in practice. SIMBRINZA™ Suspension - In two clinical trials of 3 months duration 435 patients were treated with SIMBRINZA™ Suspension, and 915 were treated with the two individual components. The most frequently reported adverse reactions in patients treated with SIMBRINZA™ Suspension occurring in approximately 3 to 5% of patients in descending order of incidence were blurred vision, eye irritation, dysgeusia (bad taste), dry mouth, and eye allergy. Rates of adverse reactions reported with the individual components were comparable. Treatment discontinuation, mainly due to adverse reactions, was reported in 11% of SIMBRINZA™ Suspension patients. Other adverse reactions that have been reported with the individual components during clinical trials are listed below.

Brinzolamide 1% - In clinical studies of brinzolamide ophthalmic suspension 1%, the most frequently reported adverse reactions reported in 5 to 10% of patients were blurred vision and bitter, sour or unusual taste. Adverse reactions occurring in 1 to 5% of patients were blepharitis, dermatitis, dry eye, foreign body sensation, headache, hyperemia, ocular discharge, ocular discomfort, ocular keratitis, ocular pain, ocular pruritus and rhinitis. The following adverse reactions were reported at an incidence below 1%: allergic reactions, alopecia, chest pain, conjunctivitis, diarrhea, diplopia, dizziness, dry mouth, dyspnea, dyspepsia, eye fatigue, hypertonia, keratoconjunctivitis, keratopathy, kidney pain, lid margin crusting or sticky sensation, nausea, pharyngitis, tearing and urticaria. Brimonidine Tartrate 0.2% - In clinical studies of brimonidine tartrate 0.2%, adverse reactions occurring in approximately 10 to 30% of the subjects, in descending order of incidence, included oral dryness, ocular hyperemia, burning and stinging, headache, blurring, foreign body sensation, fatigue/drowsiness, conjunctival follicles, ocular allergic reactions, and ocular pruritus. Reactions occurring in approximately 3 to 9% of the subjects, in descending order included corneal staining/erosion, photophobia, eyelid erythema, ocular ache/pain, ocular dryness, tearing, upper respiratory symptoms, eyelid edema, conjunctival edema, dizziness, blepharitis, ocular irritation, gastrointestinal symptoms, asthenia, conjunctival blanching, abnormal vision and muscular pain. The following adverse reactions were reported in less than 3% of the patients: lid crusting, conjunctival hemorrhage, abnormal taste, insomnia, conjunctival discharge, depression, hypertension, anxiety, palpitations/arrhythmias, nasal dryness and syncope. Postmarketing Experience - The following reactions have been identified during postmarketing use of brimonidine tartrate ophthalmic solutions in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. The reactions, which have been chosen for inclusion due to either their seriousness, frequency of reporting, possible causal connection to brimonidine tartrate ophthalmic solutions, or a combination of these factors, include: bradycardia, hypersensitivity, iritis, keratoconjunctivitis sicca, miosis, nausea, skin reactions (including erythema, eyelid pruritus, rash, and vasodilation), and tachycardia. Apnea, bradycardia, coma, hypotension, hypothermia, hypotonia, lethargy, pallor, respiratory depression, and somnolence have been reported in infants receiving brimonidine tartrate ophthalmic solutions [see Contraindications]. DRUG INTERACTIONS Oral Carbonic Anhydrase Inhibitors - There is a potential for an additive effect on the known systemic effects of carbonic anhydrase inhibition in patients receiving an oral carbonic anhydrase inhibitor and brinzolamide ophthalmic suspension 1%, a component of SIMBRINZA™ Suspension. The concomitant administration of SIMBRINZA™ Suspension and oral carbonic anhydrase inhibitors is not recommended. High-Dose Salicylate Therapy - Carbonic anhydrase inhibitors may produce acid-base and electrolyte alterations. These alterations were not reported in the clinical trials with brinzolamide ophthalmic suspension 1%. However, in patients treated with oral carbonic anhydrase inhibitors, rare instances of acid-base alterations have occurred with high-dose salicylate therapy. Therefore, the potential for such drug interactions should be considered in patients receiving SIMBRINZA™ Suspension. CNS Depressants - Although specific drug interaction studies have not been conducted with SIMBRINZA™, the possibility of an additive or potentiating effect with CNS depressants (alcohol, opiates, barbiturates, sedatives, or anesthetics) should be considered. Antihypertensives/Cardiac Glycosides - Because brimonidine tartrate, a component of SIMBRINZA™ Suspension, may reduce blood pressure, caution in using drugs such as antihypertensives and/or cardiac glycosides with SIMBRINZA™ Suspension is advised. Tricyclic Antidepressants - Tricyclic antidepressants have been reported to blunt the hypotensive effect of systemic clonidine. It is not known whether the concurrent use of these agents with SIMBRINZA™ Suspension in humans can lead to resulting interference with the IOP lowering effect. Caution is advised in patients taking tricyclic antidepressants which can affect the metabolism and uptake of circulating amines. Monoamine Oxidase Inhibitors - Monoamine oxidase (MAO) inhibitors may theoretically interfere with the metabolism of brimonidine tartrate and potentially result in an increased systemic side-effect such as hypotension. Caution is advised in patients taking MAO inhibitors which can affect the metabolism and uptake of circulating amines. USE IN SPECIFIC POPULATIONS Pregnancy - Pregnancy Category C: Developmental toxicity studies with brinzolamide in rabbits at oral doses of 1, 3, and 6 mg/ kg/day (20, 60, and 120 times the recommended human ophthalmic dose) produced maternal toxicity at 6 mg/kg/day and a significant increase in the number of fetal variations, such as accessory skull bones, which was only slightly higher than the historic value at 1 and 6 mg/kg. In rats, statistically decreased body weights of fetuses from dams receiving oral doses of 18 mg/kg/day (180 times the recommended human ophthalmic dose) during gestation were proportional to the reduced maternal weight gain, with no statistically significant effects on organ or tissue development. Increases in unossified sternebrae, reduced ossification of the skull, and unossified hyoid that occurred at 6 and 18 mg/kg were not statistically significant. No treatment-related malformations were seen. Following oral adminis-

tration of 14C-brinzolamide to pregnant rats, radioactivity was found to cross the placenta and was present in the fetal tissues and blood. Developmental toxicity studies performed in rats with oral doses of 0.66 mg brimonidine base/kg revealed no evidence of harm to the fetus. Dosing at this level resulted in a plasma drug concentration approximately 100 times higher than that seen in humans at the recommended human ophthalmic dose. In animal studies, brimonidine crossed the placenta and entered into the fetal circulation to a limited extent. There are no adequate and well-controlled studies in pregnant women. SIMBRINZA™ Suspension should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers - In a study of brinzolamide in lactating rats, decreases in body weight gain in offspring at an oral dose of 15 mg/ kg/day (150 times the recommended human ophthalmic dose) were observed during lactation. No other effects were observed. However, following oral administration of 14C-brinzolamide to lactating rats, radioactivity was found in milk at concentrations below those in the blood and plasma. In animal studies, brimonidine was excreted in breast milk. It is not known whether brinzolamide and brimonidine tartrate are excreted in human milk following topical ocular administration. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from SIMBRINZA™ (brinzolamide/brimonidine tartrate ophthalmic suspension) 1%/0.2%, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use - The individual component, brinzolamide, has been studied in pediatric glaucoma patients 4 weeks to 5 years of age. The individual component, brimonidine tartrate, has been studied in pediatric patients 2 to 7 years old. Somnolence (50-83%) and decreased alertness was seen in patients 2 to 6 years old. SIMBRINZA™ Suspension is contraindicated in children under the age of 2 years [see Contraindications]. Geriatric Use - No overall differences in safety or effectiveness have been observed between elderly and adult patients. OVERDOSAGE Although no human data are available, electrolyte imbalance, development of an acidotic state, and possible nervous system effects may occur following an oral overdose of brinzolamide. Serum electrolyte levels (particularly potassium) and blood pH levels should be monitored. Very limited information exists on accidental ingestion of brimonidine in adults; the only adverse event reported to date has been hypotension. Symptoms of brimonidine overdose have been reported in neonates, infants, and children receiving brimonidine as part of medical treatment of congenital glaucoma or by accidental oral ingestion. Treatment of an oral overdose includes supportive and symptomatic therapy; a patent airway should be maintained. PATIENT COUNSELING INFORMATION Sulfonamide Reactions - Advise patients that if serious or unusual ocular or systemic reactions or signs of hypersensitivity occur, they should discontinue the use of the product and consult their physician. Temporary Blurred Vision - Vision may be temporarily blurred following dosing with SIMBRINZA™ Suspension. Care should be exercised in operating machinery or driving a motor vehicle. Effect on Ability to Drive and Use Machinery - As with other drugs in this class, SIMBRINZA™ Suspension may cause fatigue and/or drowsiness in some patients. Caution patients who engage in hazardous activities of the potential for a decrease in mental alertness. Avoiding Contamination of the Product - Instruct patients that ocular solutions, if handled improperly or if the tip of the dispensing container contacts the eye or surrounding structures, can become contaminated by common bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions [see Warnings and Precautions ]. Always replace the cap after using. If solution changes color or becomes cloudy, do not use. Do not use the product after the expiration date marked on the bottle. Intercurrent Ocular Conditions - Advise patients that if they have ocular surgery or develop an intercurrent ocular condition (e.g., trauma or infection), they should immediately seek their physician’s advice concerning the continued use of the present multidose container. Concomitant Topical Ocular Therapy - If more than one topical ophthalmic drug is being used, the drugs should be administered at least five minutes apart. Contact Lens Wear - The preservative in SIMBRINZA™, benzalkonium chloride, may be absorbed by soft contact lenses. Contact lenses should be removed during instillation of SIMBRINZA™ Suspension, but may be reinserted 15 minutes after instillation. ©2013 Novartis U.S. Patent No: 6,316,441 ALCON LABORATORIES, INC. Fort Worth, Texas 76134 USA 1-800-757-9195 alcon.medinfo@alcon.com

MG13003JAD

Xiaflex (Collagenase Clostridium Histolyticum), First Drug Approved by the FDA for Peyronie’s Disease By Loretta Fala, Medical Writer

eyronie’s disease, also known as curvature of the penis or chronic inflammation of the tunica albuginea, is the development of fibrous scar tissue inside the penis that causes curved, painful erections.1 This condition may prevent a man from having sex or may cause erectile dysfunction.2 The curvature associated with Peyronie’s disease may worsen over time.2 Although the exact cause of Peyronie’s disease is not completely understood, it is thought to result from the rupturing of small blood vessels inside the penis, which may have been damaged during sex, during athletic activity, or as the result of an accident.2 The estimated prevalence of Peyronie’s disease ranges from 1% to 23%.3 Although Peyronie’s disease can occur in men of all ages, its prevalence increases with age.2 Heredity may also play a role. Men who have a connective tissue disorder, including Dupuytren’s contracture, a cord-like thickening that causes the fingers to pull inward, may have an increased risk for Peyronie’s disease.2 A number of other factors that may be linked to Peyronie’s disease include hypertension, diabetes, obesity, hyperlipidemia, smoking, and pelvic surgery.4 In addition to interfering with sexual intercourse, Peyronie’s disease may cause anxiety or stress, place strain on the relationship with a sexual partner, or even make fathering a child challenging because intercourse is difficult or impossible.2 The pain, disfigurement, and erectile dysfunction associated with Peyronie’s disease can impose substantial duress on affected men, including a loss of psychosexual well-being.4 For patients whose symptoms are mild, a watchful waiting approach is sometimes recommended.1 For patients whose symptoms are more serious, medication or surgery may be recommended by a physician.1 Surgical procedures, including penile implant, are generally not recommended until the curvature of the penis stops increasing and the patient’s erections have been pain-free for at least 6 months.2

First Drug Approved for Peyronie’s Disease In December 2013, collagenase clostridium histolyticum for injection (Xiaflex; Auxilium Pharmaceuticals) became the first pharmacologic treatment to receive US Food and Drug Administration (FDA) approval for the treatment of Peyronie’s disease in men with a palpable

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plaque and curvature deformity of at least 30 degrees at the start of therapy. Xiaflex, a biologic agent, is made from the protein product of collagenase clostridium histolyticum, a living organism.5 According to Audrey Gassman, MD, Deputy Director, Division of Bone, Reproductive and Urologic Products in the FDA’s Center for Drug Evaluation and Research, the approval of Xiaflex “expands the available treatment options for men experiencing Peyronie’s disease, and enables them, in consultation with their doctor, to choose the most appropriate treatment option.”5 Collagenase clostridium histolyticum was approved by the FDA in 2010 for the treatment of adult patients with Dupuytren’s contracture with a palpable cord.

Mechanism of Action Collagenases are proteinases that hydrolyze collagen in its native triple helical conformation under physiologic conditions, resulting in the lysis of collagen deposits.6 The signs and symptoms of Peyronie’s disease are caused by a collagen plaque. The injection of collagen clostridium histolyticum into a Peyronie’s plaque, which is comprised mostly of collagen, may result in the enzymatic disruption of the plaque. After this disruption of the plaque, penile curvature deformity and the patient bother caused by Peyronie’s disease are reduced.6 Dosing and Administration Collagenase clostridium histolyticum should be administered by a healthcare provider who is experienced in the treatment of male urologic diseases. Collagenase clostridium histolyticum lyophilized powder should be reconstituted with only the supplied diluent before use. A treatment cycle consists of 2 collagenase clostridium histolyticum injection procedures and a penile modeling procedure. A penile injection must be induced; a single intracavernosal injection of 10 mcg or 20 mcg of alprostadil may be used for this purpose.6 With the penis in the erect state, the target area in the Peyronie’s plaque to be injected must be identified and marked. The penis should be in a flaccid state before collagenase clostridium histolyticum is injected. On each of 2 days, 1 to 3 days apart, 0.58 mg of collagenase clostridium histolyticum is injected into the

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Collagenase Clostridium Histolyticum: Median Percent Table 1 Change in Penile Curvature Deformity from Baseline to Week 52 Study 1 Study 2 Collagenase Collagenase clostridium clostridium histolyticum Placebo histolyticum Placebo Penile (N = 199) (N = 104) (N = 202) (N = 107) curvature Baseline mean, degrees

48.8

51.3

49.6

Mean change,a %

–35

–17.8

–33.2

–21.8

Treatment difference, % (95% CI)

–17.2b (–26.7 to –7.6)

–11.4b (–19.5 to –3.3)

Mean percent change, treatment difference, 95% CI, and P value were based on an analysis of variance model with factors for treatment, stratum of baseline penile curvature, and their interaction using last observation carried forward in the modified intent-to-treat population. b P <.01. CI indicates confidence interval. Source: Xiaflex (collagenase clostridium histolyticum) for injection prescribing information; 2013. a

target plaque, according to the injection procedure. A penile modeling procedure is performed 1 to 3 days after the second injection of each treatment cycle. For each plaque causing the curvature deformity, up to 4 treatment cycles may be administered. Each treatment cycle may be repeated at approximately 6-week intervals. If the curvature deformity is less than 15 degrees after the first, second, or third treatment cycle, or if further treatment is not clinically indicated, then subsequent treatment cycles should not be administered.6 This treatment is available as a single-use glass vial containing 0.9 mg of collagenase clostridium histolyticum as a sterile, lyophilized powder for reconstitution. It is also available as a sterile diluent in a single-use glass vial.6

Clinical Studies The efficacy of collagenase clostridium histolyticum was evaluated in 2 randomized, double-blind, placebo- controlled trials of 832 adult men with Peyronie’s disease (Study 1 and Study 2). To be included in the study, patients had to have penile curvature deformity of at least 30 degrees in the stable phase of Peyronie’s disease. Patients were excluded if they had a ventral curvature deformity, an isolated hourglass deformity, or a calcified plaque that could have interfered with the injection technique. At baseline, penile pain was either not present or was mild in most (98%) patients.6 Patients received up to 4 treatment cycles of collagenase clostridium histolyticum or of placebo (weeks 0, 6, 12, 18), and were followed in a nontreatment follow-up

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period (weeks 24-52). In each treatment cycle, 2 injections of collagenase clostridium histolyticum or 2 injections of placebo were administered 1 to 3 days apart. A penile modeling procedure was performed on patients at the study site 1 to 3 days after the second injection of the cycle. The treatment cycle was repeated at approximately 6-week intervals for up to 3 additional times, for a maximum of 8 total injection procedures and 4 total modeling procedures. Patients were also instructed to perform penile modeling at home for 6 weeks after each treatment cycle.6 The coprimary end points in Study 1 and Study 2 were the percent change from baseline to week 52 in penile curvature deformity and the change in the bother domain score of the Peyronie’s Disease Questionnaire from baseline to week 52. The bother domain score is a composite of patient-reported items, including concern about erection pain, erection appearance, and the impact of Peyronie’s disease on intercourse and on the frequency of intercourse.6 Patients with Peyronie’s disease receiving collagenase clostridium histolyticum had significantly improved penile curvature deformity compared with patients receiving placebo (Table 1). Moreover, the improvement in curvature deformity was numerically similar among patients with baseline curvature deformity from 30 degrees to 60 degrees and those with curvature deformity from 61 degrees to 90 degrees.6 Patients receiving collagenase clostridium histolyticum also had a significant reduction in patient-reported bother associated with Peyronie’s disease compared with patients receiving placebo (Table 2). The reduction in the bother domain score was numerically similar between patient groups stratified by degree of baseline curvature deformity (30-60 degrees and 61-90 degrees).6

Safety The safety data for collagenase clostridium histolyticum were obtained from controlled and uncontrolled clinical studies in 1044 patients with Peyronie’s disease who received a total of 7466 injections of collagenase clostridium histolyticum.6 The most common (≥25%) adverse reactions reported in patients treated with collagenase clostridium histolyticum and at an incidence greater than in patients receiving placebo were penile hematoma, penile swelling, and penile pain.6 Warnings and Precautions Boxed warning. The prescribing information for collagenase clostridium histolyticum contains a boxed warning stating that corporal rupture (penile fracture) was reported as an adverse reaction in 5 of 1044 (0.5%) patients treated with this drug in clinical studies. In 9 (0.9%) of the patients, a diagnosis of corporal rupture cannot be excluded. Severe penile hematoma was also

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reported as an adverse reaction in 39 (3.7%) patients treated with collagenase clostridium histolyticum. The boxed warning also states that collagenase clostridium histolyticum is available for the treatment of Peyronie’s disease only through a restricted Risk Evaluation and Mitigation Strategy program.6 Contraindications. Collagenase clostridium histoly ticum is contraindicated in patients with Peyronie’s plaques that involve the penile urethra and in patients with a history of severe allergic reaction to this drug or to collagenase used in other applications.6 Tendon rupture or serious injury. Collagenase clostridium histolyticum should not be injected into tendons, nerves, blood vessels, or other collagen-containing structures of the hand. Injection into these structures may result in possible permanent injury, such as tendon rupture or ligament damage.6 Serious injury to the penis. Collagenase clostridium histolyticum should not be injected into the urethra, nerves, blood vessels, corpora cavernosa, or other collagen-containing structures of the penis. Injection into these structures may result in possible permanent injury, such as corporal rupture (penile fracture).6 Allergic reactions. Healthcare providers should be prepared to address severe allergic reactions after collagenase clostridium histolyticum injections.6 Patients with abnormal coagulation. Collagenase clostridium histolyticum should be used with caution in patients with abnormal coagulation, including patients who have received anticoagulant medications, other than low-dose aspirin, within 7 days of the injection.6 Drug interactions. Collagenase clostridium histolyticum should be used with caution in patients receiving anticoagulant therapies, except for low-dose aspirin.

Use in Specific Populations Pregnancy. There are no adequate and well-controlled studies of collagenase clostridium histolyticum in pregnant women. Collagenase clostridium histolyticum should only be used during pregnancy if clearly needed.6 Nursing mothers. It is not known whether collagenase clostridium histolyticum is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when collagenase clostridium histolyticum is administered to a nursing woman.6 Pediatric use. The safety and effectiveness of collagenase clostridium histolyticum in pediatric patients aged <18 years have not been established.6 Geriatric use. Of the 551 patients receiving colla genase clostridium histolyticum in the clinical trials of Peyronie’s disease, 100 (18%) were aged ≥65 years and 5 (0.9%) were aged ≥75 years. No overall differences in safety were observed in these patients.6

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Collagenase Clostridium Histolyticum: Mean Change in Table 2 Peyronie’s Disease Bother Domain Score from Baseline to Week 52 Study 1 Study 2 Collagenase Collagenase Bother clostridium clostridium domain histolyticum Placebo histolyticum Placebo score (N = 199) (N = 104) (N = 202) (N = 107) Baseline mean, degrees Mean change,a %

7.5

7.4

8.2

–2.8

–1.6

–2.6

–1.5

Treatment difference, % (95% CI)

–1.2b (–2.4 to –0.03)

–1.1b (–2.1 to –0.002)

Mean change, treatment difference, 95% CI, and P value were based on an analysis of variance model with factors for treatment, stratum of baseline penile curvature, and their interaction using last observation carried forward in the modified intent-to-treat population. b P <.05. CI indicates confidence interval. Source: Xiaflex (collagenase clostridium histolyticum) for injection prescribing information; 2013. a

Conclusion The recent FDA approval of a new indication for collagenase clostridium histolyticum marks the availability of the first pharmacologic treatment option for men with Peyronie’s disease, which is the only alternative to surgery. This approval offers patients with Peyronie’s disease who are not candidates for a surgical procedure a new, and the only, noninvasive approach to therapy. Treatment with collagenase clostridium histolyticum showed a significant improvement in penile curvature deformity in patients with Peyronie’s disease and a significant reduction in patient-reported bother associated with Peyronie’s disease. The most frequent adverse reactions reported in ≥25% of patients treated with collagenase clostridium histolyticum and at an incidence greater than in patients receiving placebo were penile hematoma, penile swelling, and penile pain. n References

1. Nordqvist C. What is Peyronie’s disease? What causes Peyronie’s disease? Medical News Today. March 8, 2012. www.medicalnewstoday.com/articles/242682.php. Accessed January 2, 2014. 2. Mayo Clinic staff. Diseases and conditions: Peyronie’s disease. August 18, 2011. www.mayoclinic.com/health/peyronies-disease/DS00427/METHOD=print. Accessed December 30, 2013. 3. National Kidney and Urologic Diseases Information Clearinghouse. Peyronie’s disease. Updated March 23, 2012. http://kidney.niddk.nih.gov/KUDiseases/pubs/peyronie/ index.aspx#1. Accessed January 3, 2014. 4. Levine LA. The clinical and psychosocial impact of Peyronie’s disease. Am J Manag Care. 2013;19(4 suppl):S55-S61. 5. US Food and Drug Administration. FDA approves first drug treatment for Peyronie’s disease. Press release. December 6, 2013. www.fda.gov/newsevents/newsroom/press announcements/ucm377849.htm. Accessed January 2, 2014. 6. Xiaflex (collagenase clostridium histolyticum) for injection [prescribing information]. Chesterbrook, PA: Auxilium Pharmaceuticals, Inc; December 2013.

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4TH ANNUAL CONFERENCE

MAY 6-9, 2014 LOEWS HOLLYWOOD HOTEL â&#x20AC;˘ LOS ANGELES, CA Government and Employers Co-Chairs Jayson Slotnik, JD, MPH

F. Randy Vogenberg, PhD, RPh

Vice President of Reimbursement Strategy & Innovation United BioSource Corporation

Principal Institute for Integrated Healthcare

Personalized Medicine and Payers Co-Chairs Michael A. Kolodziej, MD National Medical Director Oncology Solutions Aetna

Grant Lawless, RPh, MD, FACP Program Director Associate Professor University of Southern California

Oncology Practice Management, Advocacy, and Navigation Co-Chairs Linda Bosserman, MD, FACP

President Wilshire Oncology Medical Group

Vicki Kennedy, LCSW

Vice President, Program Development and Delivery Cancer Support Community

AVBCC Leadership Burt Zweigenhaft, BS President and CEO OncoMed

Gary M. Owens, MD

President Gary Owens Associates

www.AVBCConline.org

Craig K. Deligdish, MD Hematologist/ Oncologist Oncology Resource Networks

HELD IN PARTNERSHIP WITH

AVBCC2014chairs Asize_13114

NEW FOR 2014! Principles in Value and Market Access Educational sessions for Product Managers, Reimbursement Specialists, Account Managers, and Marketers focusing on access, reimbursement, proving product value, and international markets.

Xofigo (Radium Ra 223 Dichloride): The

First Alpha Particle–Emitting Radioactive Agent for the Treatment of Castration-Resistant Prostate Cancer with Symptomatic Bone Metastases By Lisa A. Raedler, PhD, RPh, Medical Writer

rostate cancer is the second leading cause of cancer-related death in the United States among men and the most frequently diagnosed cancer in American males. Among patients with metastatic prostate cancer, up to approximately 90% have bone metastases.1 The median survival after the diagnosis of bone metastasis associated with prostate cancer is approximately 3 years.2 Bone metastases have serious and debilitating clinical consequences, including pain that requires opioids and/or radiotherapy, hypercalcemia, pathologic fracture, spinal cord compression, and nerve root compression.3 Prostate cancer places a significant burden on the US healthcare system. Using Surveillance, Epidemiology and End Results (SEER) data, Stokes and colleagues estimated the survival of men aged ≥65 years who were diagnosed with prostate cancer between the calendar years of 1991 and 2002.4 The medical cost data were obtained from the SEER-Medicare database and were estimated during specific phases of cancer care. These cost estimates were then combined with survival data to determine the total lifetime costs and the prostate cancer–related lifetime costs. The model estimated total lifetime medical costs of approximately $110,500 per patient (in 2004 US dollars).4 The prostate cancer–related costs made up approximately 31% of the total costs, or more than $34,000 per patient.4 Patients with prostate cancer and bone metastases utilize an inordinate amount of healthcare resources. A retrospective, observational study using health insurance claims data for episodes of care from September 2002 to June 2011 demonstrated that, among patients with prostate cancer, the cost of a skeletal-related event ranged from approximately $11,700 for an outpatient episode to more than $54,000 for an inpatient episode.5

Unmet Need in Patients with Prostate Cancer and Bone Metastases According to the National Cancer Institute, in 2013, more than 238,500 men will be diagnosed with prostate cancer and more than 29,700 will die from the disease.

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More than 2.5 million American men are currently living with prostate cancer.6 Currently, 4 bone-targeted therapies are available for men with prostate cancer, including zoledronic acid (Zometa), denosumab (Prolia), samarium-153 ethylene diamine tetramethylene phosphonate (EDTMP; Quadramet), and strontium-89 (Metastron). None of these 4 agents has been proved to prolong overall survival (OS) in large phase 3 randomized trials. The 2 radiopharmaceuticals, strontium-89 and samarium-153 EDTMP, are beta-particle emitters. Both were approved by the US Food and Drug Administration (FDA) on the basis of randomized phase 3 clinical trials that demonstrated an improvement in pain in patients with metastatic prostate cancer.7,8 By contrast, sipuleucel-T (Provenge), abiraterone (Zytiga), and enzalutamide (Xtandi) have demonstrated advantages in OS in patients with metastatic prostate cancer, but these agents do not target disease that has spread to bone and are not indicated specifically for patients with prostate cancer plus bone metastases.9-11

FDA Approves Radium-223 for Metastatic CRPC with Bone Metastases In May 2013, the FDA approved radium Ra 223 dichloride (Xofigo injection, formerly known as Alpharadin; Bayer HealthCare Pharmaceuticals) for the treatment of patients with castration-resistant prostate cancer (CRPC) plus symptomatic bone metastases and no known visceral metastatic disease.12 In a prespecified interim analysis, radium Ra 223 dichloride (radium-223) combined with best standard of care demonstrated a significant 3.2-month (hazard ratio, 0.70; 95% confidence interval, 0.55-0.88; P = .00185) improvement in median OS compared with placebo plus best standard of care.13 The improvement in OS was supported by a delay in time to the first symptomatic skeletal-related event favoring the radium-223 arm.13 In an interview regarding this new radiopharmaceutical, Daniel P. Petrylak, MD, Director of the Genitouri-

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Probability of survival

Figure Kaplan-Meier Overall Survival Curves from the Phase 3 Clinical Trial of Radium-223 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0

Xofigo Placebo

0 3 6 9 12 15 18 21 24 27 30 33 36 39

Time, months Number of patients at risk Xofigo 614 578 504 369 277 178 105 80 41 18 7 1 0 0 Placebo 307 288 228 157 104 67 39 24 14 7 4 2 1 0

Source: Xofigo (radium Ra 223 dichloride) injection prescribing information; 2013.

nary Oncology Program at the Yale Cancer Center, New Haven, CT, noted that radium-223 “is the first isotope to show a survival benefit [in advanced prostate cancer]…. Now we need to do the studies to know how to best sequence these drugs.”14 The availability of radium-223 offers a novel therapeutic alternative for patients with CRPC and bone metastasis, particularly for those who wish to avoid the side effects of chemotherapy. According to Nicholas J. Vogelzang, MD, a genitourinary oncologist at Comprehensive Cancer Centers of Nevada, Las Vegas, “In general, about half of [patients with advanced prostate cancer] say they will not take chemotherapy. For them, [radium-223] is a wonderful option because it suppresses the cancer, controls the pain, and extends their life.”15 According to the drug manufacturer, 6 cycles of treatment with radium-223 cost $69,000.16

Mechanism of Action and Pharmacodynamics The active component in Xofigo is the alpha particle– emitting isotope radium-223, which mimics calcium and forms complexes with the bone mineral hydroxyapatite at areas of increased bone turnover, such as bone metastases. The high energy transfer of alpha emitters increases the breaking frequency of double-strand DNA in adjacent cells, leading to an antitumor effect on bone metastases. The alpha particle range from radium-223 dichloride localizes the impact of the drug and limits damage to the surrounding normal tissue.17 In a phase 2 randomized trial that compared radi-

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um-223 and placebo, a significant difference was seen in favor of radium-223 in all 5 biomarkers for bone turnover.17

Dosing and Administration The recommended dose and schedule for radium-223 is 50 kBq/kg body weight, which is administered by slow intravenous injection over 1 minute every 4 weeks for a total of 6 injections. The safety and efficacy of radium-223 beyond 6 injections have not been studied.17 No dosage adjustment is necessary in elderly patients. No dose adjustments can be recommended for patients with moderate or severe hepatic impairment because of a lack of clinical data. No dose adjustment can be recommended for patients with severe renal impairment (creatinine clearance <30 mL/min) because of the limited available data.17 ALSYMPCA: A Pivotal Phase 3 Clinical Trial Radium-223 was approved by the FDA based on the results of a single, phase 3 clinical trial—the Alpharadin in Patients with Symptomatic Hormone Refractory Prostate Cancer with Skeletal Metastases (ALSYMPCA) trial—a randomized, multicenter, double-blind study of more than 800 patients with CRPC and symptomatic bone metastases. Patients were stratified by baseline alkaline phosphatase, bisphosphonate use, and previous docetaxel exposure.17 Trial Design In the ALSYMPCA trial, patients were randomly assigned in a 2:1 ratio to receive radium-223 50 kBq/kg intravenously every 4 weeks for 6 cycles plus best standard of care (N = 541) or to matching placebo plus best standard of care (N = 268). Best standard of care included local external beam radiation therapy [EBRT], corticosteroids, antiandrogens, estrogens, estramustine, or ketoconazole.17 Therapy was continued until unacceptable toxicity or until initiation of cytotoxic chemotherapy, other systemic radioisotope, hemibody EBRT, or other investigational drugs. The primary efficacy end point was OS. A key secondary efficacy end point was time to first symptomatic skeletal event, which was defined as EBRT to relieve skeletal symptoms, new symptomatic pathologic bone fracture, occurrence of spinal cord compression, or tumor-related orthopedic surgical intervention. There were no scheduled radiographic assessments performed during the study. All patients were to continue androgen-deprivation therapy.17 Patient Population Patient demographics and baseline disease character-

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istics were balanced between the 2 arms. The patients’ median age was 71 years (range, 44-94 years), with a racial distribution of 94% white, 4% Asian, 2% black, and <1% other. The Eastern Cooperative Oncology Group performance status was 0 to 1 in 86% of patients.17 Overall, 85% of the patients had ≥6 bone scan lesions; of those, 40% had >20 lesions or a superscan. For cancer-related pain, 54% of the patients received opiate pain medications, 44% received nonopiate pain medications, and 2% received no pain medication. Overall, bisphosphonates were used by 41% of patients. More than half (58%) of the patients had previously received docetaxel.17 During the study period, 83% of the patients in the radium-223 arm and 82% of the patients in the placebo arm were also using gonadotropin-releasing hormone agonists; 21% and 34% of patients, respectively, were using concomitant antiandrogens. The use of systemic corticosteroids (41%) and bisphosphonates (40%) was equal between the 2 arms.17

Overall Survival of Radium-223 versus Placebo: Interim Table 1 and Updated Analyses from the Phase 3 Trial Radium-223 plus Placebo plus best best standard of care standard of care

Efficacy The prespecified interim analysis of ALSYMPCA revealed a significant improvement in OS in patients receiving radium-223 plus best standard of care compared with patients receiving placebo plus best standard of care (Figure), with a median OS of 14.0 months with radium-223 versus 11.2 months with placebo, for a difference of 3.2 months (Table 1).13,17 The median duration of treatment was 20 weeks (6 cycles) with radium-223 and 18 weeks (5 cycles) with placebo.17 An updated OS analysis performed before the patient crossover with an additional 214 events yielded findings that confirmed the OS advantage of radium-223 versus placebo, resulting in a median OS of 14.9 months with radium-223 versus 11.3 months with placebo, for a 3.6month difference (Table 1).17 The survival results were supported by a delay in the time to first symptomatic skeletal event favoring the radium-223 arm. The majority of events consisted of treatment with EBRT to bone metastases.17

Median survival, mo

Safety Profile The most common (≥10%) adverse reactions in patients receiving radium-223 were nausea, diarrhea, vomiting, and peripheral edema (Table 2).18 Grade 3 or 4 adverse events were reported in 57% of patients receiving radium-223 and in 63% of patients receiving placebo.17 The most common (≥10%) hematologic laboratory abnormalities in patients receiving radium-223 were anemia, lymphocytopenia, leukopenia, thrombocytopenia, and neutropenia. Grade 3 or 4 lymphocytopenia was reported in 20% of patients receiving radium-223 and in 7% of patients receiving placebo (Table 3).17

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Interim analysis Randomized patients, N Deaths, N (%) Censored, N (%) Median survival, mo

(95% CI)

541

268

191 (35.3)

123 (45.9)

350 (64.7)

145 (54.1)

14.0

11.2

(12.1-15.8)

P value

(9.0-13.2) .00185

Hazard ratio (95% CI)c

0.695 (0.552-0.875)

Updated analysis Randomized patients, N Deaths, N (%) Censored, N (%) a

(95% CI) Hazard ratio (95% CI)

614

307

333 (54.2)

195 (63.5)

281 (45.8)

112 (36.5)

14.9

11.3

(13.9-16.1)

(10.4-12.8)

0.695 (0.581-0.832)

Survival time is calculated as months from date of randomization to date of death from any cause. Patients who are not deceased at time of analysis are censored on the last date a patient was known to be alive or was lost to follow-up. b P value is stratified by total alkaline phosphatase, current use of bisphosphonates, and previous use of docetaxel. c Hazard ratio adjusted for total alkaline phosphatase, current use of bisphosphonates, and previous use of docetaxel; hazard ratio <1 favors radium-223 dichloride. CI indicates confidence interval. Source: Xofigo (radium Ra 223 dichloride) injection prescribing information; 2013. a

Dehydration occurred in 3% of patients receiving radium-223 and in 1% of patients receiving placebo. Treatment discontinuations resulting from adverse events occurred in 17% of patients who received radium-223 and in 21% of patients who received placebo.17

Warnings and Precautions Fluid status. Radium-223 can result in adverse reactions such as diarrhea, nausea, and vomiting, which may result in dehydration. Patients’ oral intake and fluid status should be carefully monitored, and patients who display signs or symptoms of dehydration or hypovolemia should be promptly treated.17 Secondary malignant neoplasms. Radium-223 contributes to a patient’s overall long-term cumulative radiation exposure, which may be associated with increased risk of cancer and hereditary defects. Because of its

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dverse Reactions ≥2% Higher with Xofigo than with Table 2 A Placebo in the Phase 3 Trial Xofigo (N = 600) Placebo (N = 301) System/organ class preGrades 1-4, Grades 3-4, Grades 1-4, Grades 3-4, ferred term % % % % Blood and lymphatic system disorders Pancytopenia

Gastrointestinal disorders Nausea

Diarrhea

Vomiting

General disorders and administration site conditions Peripheral edema

Renal and urinary disorders Renal failure and impairment

Source: Xofigo (radium Ra 223 dichloride) injection prescribing information; 2013.

ematologic Reactions ≥10% Higher with Xofigo than Table 3 H with Placebo in the Phase 3 Trial Xofigo (N = 600) Placebo (N = 301) Hematologic laboratory Grades Grades Grades Grades abnormalities 1-4, % 3-4, % 1-4, % 3-4, % Anemia

Lymphocytopenia

Leukopenia

Thrombocytopenia

Neutropenia

Source: Xofigo (radium Ra 223 dichloride) injection prescribing information; 2013.

mechanism of action and neoplastic changes, including osteosarcomas in rats after receiving radium-223, radium-223 may increase the risk of osteosarcoma or other secondary malignant neoplasms. However, the overall incidence of new malignancies in the randomized ALSYMPCA trial was lower in the radium-223 arm compared with in the placebo arm (<1% vs 2%, respectively). The expected latency period for the development of secondary malignancies exceeds the duration of follow-up for patients in the trial.17 Subsequent treatment with cytotoxic chemotherapy. In the ALSYMPCA trial, 16% of patients included in the radium-223 cohort and 18% of patients in the place-

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bo cohort received cytotoxic chemotherapy after completion of the study treatments. Adequate safety monitoring and laboratory testing were not performed to assess how patients who were treated with radium-223 will tolerate subsequent cytotoxic chemotherapy.17 Contraception. Because of the potential effects on spermatogenesis that is associated with radiation treatment, men who are sexually active and their female partners of reproductive potential should be advised to use highly effective contraceptives during and for 6 months after completing treatment with radium-223.17 This new therapy is not to be used in women. Bone marrow failure. In the ALSYMPCA trial, 2% of patients in the radium-223 arm had bone marrow failure or ongoing pancytopenia compared with none of the patients receiving placebo. In addition, 2 deaths resulted from bone marrow failure. For 7 of the 13 patients who were treated with radium-223, bone marrow failure was ongoing at the time of death. Among the 13 patients who had bone marrow failure, 54% required blood transfusions. In that study, 4% of patients in the radium-223 arm and 2% of patients in the placebo arm discontinued therapy as a result of bone marrow suppression.17 Myelosuppression. Deaths related to vascular hemorrhage in association with myelosuppression were observed in 1% of patients receiving radium-223 compared with in 0.3% of patients receiving placebo. The incidence (2%) of infection-related deaths, serious infections (10%), and febrile neutropenia (<1%) was similar for patients receiving radium-223 and for patients receiving placebo.17 Myelosuppression (ie, thrombocytopenia, neutropenia, pancytopenia, and leukopenia) has been reported in patients treated with radium-223. Complete blood counts were obtained every 4 weeks before each dose. Nadir complete blood counts and bone marrow recovery times were not well characterized in ALSYMPCA.17 In a single-dose phase 1 study of radium-223, neutrophil and platelet count nadirs occurred 2 to 3 weeks after the administration of radium-223 at doses of 1 to 5 times that of the recommended dose. Most patients recovered 6 to 8 weeks after administration.17 Monitoring. Hematologic evaluation of patients must be performed at baseline and before every dose of radium-223. Absolute neutrophil counts, platelet counts, and hemoglobin levels must meet minimum requirements as specified in the product’s labeling information. If these values do not recover within 6 to 8 weeks after the last administration of radium-223, despite supportive care, treatment should be discontinued.17 Patients with evidence of compromised bone marrow reserve should be monitored closely and should be provided with supportive-care measures when clinically indicated. Radium-223 should be discontinued in patients

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who experience life-threatening complications despite supportive care for bone marrow failure.17 The safety and efficacy of concomitant chemotherapy with radium-223 have not been established. Outside of a clinical trial, the concomitant use of radium-223 with chemotherapy is not recommended because of the potential for additive myelosuppression. If chemotherapy, other systemic radioisotopes, or hemibody external radiotherapy are administered during the treatment period, radium-223 should be discontinued.17

For patients with advanced prostate cancer and bone metastases, single- agent radium-223 offers clinically and statistically significant efficacy benefits, with a favorable tolerability profile and a convenient dosing schedule. Conclusion For patients with advanced prostate cancer and bone metastases, single-agent radium-223 offers clinically and statistically significant efficacy benefits, with a favorable tolerability profile and a convenient dosing schedule. Experts suggest that this bone-targeting radiopharmaceutical is a viable treatment option for men with CRPC who have received, or who are ineligible for, or who prefer to delay or to avoid cytotoxic chemotherapy. Combination studies with radium-223 and hormonal agents, immunomodulatory agents, and doce taxel are pending or are under way to further elucidate the role of radium-223 as a part of the armamentarium for patients with prostate cancer.18 n

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References

1. Scher HI, Morris MJ, Kelly WK, et al. Prostate cancer clinical trial end points: “RECIST”ing a step backwards. Clin Cancer Res. 2005;11:5223-5232. 2. Coleman RE. Skeletal complications of malignancy. Cancer. 1997;80(8 suppl): 1558-1594. 3. Coleman RE. Clinical features of metastatic bone disease and risk of skeletal morbidity. Clin Cancer Res. 2006;12(20 pt 2):6243S-6249S. 4. Stokes ME, Ishak J, Proskorovsky I, et al. Lifetime economic burden of prostate cancer. BMC Health Serv Res. 2011;11:349. 5. Hagiwara M, Delea TE, Saville MW, Chung K. Healthcare utilization and costs associated with skeletal-related events in prostate cancer patients with bone metastases. Prostate Cancer Prostatic Dis. 2013;16:23-27. 6. National Cancer Institute. Prostate Cancer. www.cancer.gov/cancertopics/types/ prostate. Accessed June 13, 2013. 7. Porter AT, McEwan AJ. Strontium-89 as an adjuvant to external beam radiation improves pain relief and delays disease progression in advanced prostate cancer: results of a randomized controlled trial. Semin Oncol. 1993;20(3 suppl 2):38-43. 8. Medical Services Advisory Committee. Samarium-153-lexidronam for bone pain due to skeletal metastases. Final assessment report. MSAC application 1016. August 1999. www.msac.gov.au/internet/msac/publishing.nsf/Content/FA4579BED311BC 15CA2575AD0082FD8A/$File/1016%20-%20Samarium153lexidronam%20for%20 bone%20pain%20due%20to%20skeletal%20metastases%20Report.pdf. Accessed June 13, 2013. 9. Kantoff PW, Higano CS, Shore ND, et al; for the IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411-422. 10. de Bono JS, Oudard S, Ozguroglu M, et al; for the TROPIC Investigators. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010;376:1147-1154. 11. Xtandi (enzalutamide) capsules [prescribing information]. Northbrook, IL: Astellas Pharma US, Inc; 2012. 12. US Food and Drug Administration. Radium Ra 223 dichloride. Updated May 15, 2013. www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm352393.htm? source=govdelivery. Accessed June 13, 2013. 13. Parker C, Heinrich D, O’Sullivan JM, et al. Overall survival benefit of radium-223 chloride (Alpharadin) in the treatment of patients with symptomatic bone metastases in castration-resistant prostate cancer (CRPC): a phase 3 randomized trial (ALSYMPCA). Eur J Cancer. 2011;47(suppl 2):3. 14. OncLive TV. Dr Petrylak discusses the isotope radium-223. YouTube. February 28, 2012. www.youtube.com/watch?feature=player_detailpage&v=A-jLlybtyeQ. Accessed June 13, 2013. 15. Targeted Communications. Dr Vogelzang reviews radium-223 in metastatic prostate cancer. YouTube. April 22, 2013. www.youtube.com/watch?feature=player _detailpage&v=1KLLrQuJk_g. Accessed June 13, 2013. 16. Dooren JC. Bayer gets FDA approval for advanced prostate cancer drug. Wall Street Journal. May 15, 2013. http://online.wsj.com/article/SB1000142412788732476 7004578485552000140508.html. Accessed June 13, 2013. 17. Xofigo (radium Ra 223 dichloride) injection [prescribing information]. Wayne, NJ: Bayer HealthCare Pharmaceuticals, Inc; May 2013. 18. Sartor O. Radium-223 (Alpharadin): a novel targeted alpha-emitter for bone- metastatic castrate-resistant prostate cancer. PCRI Insights. May 2012:9-14.

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FETZIMA™ (levomilnacipran) extended-release capsules, for oral use Brief Summary of full Prescribing Information Initial U.S. Approval: 2009 (milnacipran) WARNING: SUICIDAL THOUGHTS AND BEHAVIORS Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was a reduction in risk with antidepressant use in patients aged 65 and older. In patients of all ages who are started on antidepressant therapy, monitor closely for worsening, and for emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber [see Warnings and Precautions]. FETZIMA is not approved for use in pediatric patients [see Use in Specific Populations]. INDICATIONS AND USAGE: FETZIMA, a serotonin and norepinephrine reuptake inhibitor (SNRI) is indicated for the treatment of major depressive disorder (MDD). The efficacy of FETZIMA was established in three 8-week, randomized, double-blind, placebo-controlled studies in adult patients with a diagnosis of MDD [see Clinical Studies in the full Prescribing Information]. Limitation of Use: FETZIMA is not approved for the management of fibromyalgia. The efficacy and safety of FETZIMA for the management of fibromyalgia have not been established. CONTRAINDICATIONS: Hypersensitivity to levomilnacipran, milnacipran HCl or to any excipient in the formulation. The use of MAOIs intended to treat psychiatric disorders with FETZIMA or within 7 days of stopping treatment with FETZIMA is contraindicated because of an increased risk of serotonin syndrome. The use of FETZIMA within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated. Starting FETZIMA in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome [see Dosage and Administration in the full Prescribing Information and Warnings and Precautions]. Uncontrolled Narrow-Angle Glaucoma: Do not use FETZIMA in patients with uncontrolled narrow-angle glaucoma. In clinical studies, FETZIMA was associated with an increased risk of mydriasis. Mydriasis has been reported with other SNRIs and FETZIMA [see Warnings and Precautions]. WARNINGS AND PRECAUTIONS: Suicidal Thoughts and Behaviors in Adolescents and Young Adults Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a longstanding concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phase of treatment. Pooled analyses of short-term placebo-controlled studies of antidepressant drugs (selective serotonin reuptake inhibitors [SSRIs] and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with MDD and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled studies in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term studies of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo controlled studies in adults with MDD or other psychiatric disorders included a total of 295 short-term studies (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1 of the full Prescribing Information. There were 14 additional cases reported in patients under the age of 18, while 5 additional cases were reported in patients between 18 and 24 years of age. Patients between 25 and 64 years of age reported 1 fewer case of suicidality, while patients 65 years of age and over reported 6 fewer cases. No suicides occurred in any of the pediatric studies. There were suicides in the adult studies, but the number was not sufficient to reach any conclusion about drug effect on suicide. It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebocontrolled maintenance studies in adults with depression that the use of antidepressants can delay the recurrence of depression. All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms: anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms [see Dosage and Administration in the full Prescribing Information and Warnings and Precautions for a description of the risks of discontinuation of FETZIMA]. Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for FETZIMA should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose. Screening patients for bipolar disorder - A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled studies) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that FETZIMA is not approved for use in treating bipolar depression. Serotonin Syndrome - The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John’s Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome. The concomitant use of FETZIMA with MAOIs intended to treat psychiatric disorders is contraindicated. FETZIMA should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to

initiate treatment with a MAOI such as linezolid or intravenous methylene blue in a patient taking FETZIMA. FETZIMA should be discontinued before initiating treatment with the MAOI [see Dosage and Administration in the full Prescribing Information and Contraindications]. If concomitant use of FETZIMA with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John’s Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases. Treatment with FETZIMA and any concomitant serotonergic agents, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated. Elevated Blood Pressure - SNRIs, including FETZIMA, have been associated with increases in blood pressure. Blood pressure should be measured prior to initiating treatment and periodically throughout FETZIMA treatment. Pre-existing hypertension should be controlled before initiating treatment with FETZIMA. Caution should be exercised in treating patients with pre-existing hypertension, cardiovascular, or cerebrovascular conditions that might be compromised by increases in blood pressure. For patients who experience a sustained increase in blood pressure while receiving FETZIMA, discontinuation or other appropriate medical intervention should be considered. Table 2 in the full Prescribing Information shows the mean changes in blood pressure, sustained hypertension, and upward shifts in hypertensive status that were observed in FETZIMA-treated patients in the short-term placebocontrolled studies. Values shown in parentheses are shown as FETZIMA 40-120 mg/day, followed by Placebo. The Mean changes from baseline to end of treatment, in mm Hg were: Systolic blood pressure (SBP): (3.0, -0.4); Diastolic blood pressure (DBP): (3.2, -0.0). The % of patients with Sustained Hypertension were as follows: Broad Criteria (SBP * 140 mm Hg and an increase * 15 mm Hg OR DBP * 90 mm Hg and an increase * 10 mm Hg for at least 3 consecutive visits: (1.8, 1.2); Strict Criteria (SBP * 140 mm Hg and an increase * 15 mm Hg AND DBP * 90 mm Hg and an increase * 10 mm Hg for at least 3 consecutive visits: (0.3, 0.1). The % of patients with Upward Shifts in Hypertensive Statusa (Normal/ Pre-hypertensive Stage I/ Stage II) were: (10.4, 7.1). a: Normal Blood Pressure: SBP < 120 mm Hg and DBP < 80 mm Hg; Prehypertension: SBP * 120 mm Hg and ) 139 mm Hg or DBP * 80 mm Hg and ) 89 mm Hg; Stage I hypertension: SBP * 140 mm Hg and ) 159 mm Hg or DBP * 90 mm Hg and ) 99 mm Hg; Stage II hypertension: SBP * 160 mm Hg or DBP * 100 mm Hg. In the short-term, placebo-controlled MDD studies, the mean increase from initiation of treatment in systolic BP was 3 mm Hg and diastolic BP was 3.2 mm Hg, as compared to no change in the placebo group. There were no dose-related changes in systolic and diastolic blood pressure observed. In patients exposed to one-year, open-label treatment of FETZIMA (doses range from 40120 mg once daily), the mean change from initiation of treatment in systolic BP was 3.9 mm Hg and diastolic BP was 3.1 mm Hg. In the short-term, placebo-controlled studies, 11.6% of patients met orthostatic hypotension criteria (SBP or DBP) in the FETZIMA group compared to 9.7% in the placebo group. Orthostatic reductions of blood pressure * 10 mm Hg in DBP occurred in 5.8%, 6.1% and 9.8% of FETZIMA-treated patients with doses of 40, 80 and 120 mg/day respectively, compared to 6.2% of placebo-treated patients. Concomitant use of FETZIMA with drugs that increase blood pressure and heart rate has not been evaluated and such combinations should be used with caution. Effects of FETZIMA on blood pressure in patients with significant hypertension or cardiac disease have not been systematically evaluated. FETZIMA should be used with caution in these patients. Elevated Heart Rate - SNRIs including FETZIMA have been associated with increased heart rate. Heart rate should be measured prior to initiating treatment and periodically throughout FETZIMA treatment. Pre-existing tachyarrhythmias and other cardiac disease should be treated before starting therapy with FETZIMA. For patients who experience a sustained increase in heart rate while receiving FETZIMA, discontinuation or other appropriate medical intervention should be considered. In short-term clinical studies, FETZIMA treatment was associated with a mean increase in heart rate of 7.4 beats per minute (bpm) compared to a mean decrease of 0.3 bpm in placebo-treated patients. Heart rate increase in FETZIMA-treated patients receiving doses of 40 mg, 80 mg and 120 mg was 7.2, 7.2, and 9.1 bpm. FETZIMA has not been systematically evaluated in patients with a cardiac rhythm disorder. Abnormal Bleeding - SSRIs and SNRIs, including FETZIMA, may increase the risk of bleeding events. Concomitant use of aspirin, non-steroidal anti-inflammatory drugs (NSAIDS), warfarin, and other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages. Patients should be cautioned about the risk of bleeding associated with the concomitant use of FETZIMA and NSAIDs, aspirin, or other drugs that affect coagulation or bleeding. Controlled Narrow-Angle Glaucoma - Mydriasis has been reported in association with SNRIs, including FETZIMA; therefore, FETZIMA should be used cautiously in patients with controlled narrow-angle glaucoma. Patients with raised intraocular pressure or those at risk of acute narrow-angle glaucoma (angle-closure glaucoma) should be monitored. Do not use FETZIMA in patients with uncontrolled narrow-angle glaucoma [see Contraindications]. Urinary Hesitation or Retention - The noradrenergic effect of SNRIs including FETZIMA, can affect urethral resistance. In the controlled short-term studies, urinary hesitation occurred in 4%, 5% and 6% of FETZIMA-treated patients receiving doses of 40, 80 and 120 mg, respectively, compared to no patients in the placebo group. Caution is advised in the use of FETZIMA in patients prone to obstructive urinary disorders. If symptoms of urinary hesitation, urinary retention, or dysuria develop during treatment with FETZIMA, consideration should be given to the possibility that they might be drug-related, and discontinuation or other appropriate medical intervention should be considered. Activation of Mania/Hypomania - Symptoms of mania/hypomania were reported in 0.2% of FETZIMA-treated patients and 0.2% of placebo-treated patients in clinical studies. Activation of mania/hypomania has also been reported in a small proportion of patients with mood disorders who were treated with other antidepressants. As with all antidepressants, use FETZIMA cautiously in patients with a history or family history of bipolar disorder, mania, or hypomania. Seizures - FETZIMA has not been systematically evaluated in patients with a seizure disorder. Patients with a history of seizures were excluded from clinical studies. FETZIMA should be prescribed with caution in patients with a seizure disorder. One case of seizure has been reported in pre-marketing clinical studies with FETZIMA. Discontinuation Syndrome - There have been reports of adverse events occurring upon discontinuation of serotonergic antidepressants, particularly when discontinuation is abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms. Monitor patients for these symptoms when discontinuing FETZIMA. Reduce the dose gradually whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, consider resuming the previously prescribed dose. Subsequently, the dose may be decreased, but at a more gradual rate [see Dosage and Administration in the full Prescribing Information]. Hyponatremia - Although no adverse events of hyponatremia were reported for FETZIMA-treated patients in the clinical studies, hyponatremia has occurred as a result of treatment with SSRIs and SNRIs. In many cases, hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted can be at greater risk. FETZIMA should be discontinued in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which can lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. ADVERSE REACTIONS: The following adverse reactions are discussed in greater detail in other sections of the label: Hypersensitivity [see Contraindications]; Suicidal Thoughts and Behaviors in Adolescents and Young Adults; Serotonin Syndrome; Elevated Blood Pressure; Elevated Heart Rate; Abnormal Bleeding [see Warnings and Precautions]; Narrow-Angle Glaucoma [see Contraindications and Warnings and Precautions]; Urinary Hesitation or Retention; Activation of Mania/Hypomania; Seizure; Discontinuation Syndrome; Hyponatremia [see Warnings and Precautions]. Clinical Studies Experience - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice. Patient exposure - The safety of FETZIMA was evaluated in 2,673 patients (18-78 years of age) diagnosed with MDD who participated in clinical studies, representing 942 patient-years of exposure. Among the 2,673 FETZIMA-treated patients, 1,583 were exposed to FETZIMA in short-term, placebo-controlled studies. There were 825 patients who continued from shortterm studies into a one-year, open-label extension study. Of the 2,673 patients exposed to at least one dose

of FETZIMA, 737 patients were exposed to FETZIMA for at least 6 months and 367 were exposed for one year. In these studies FETZIMA was given at doses ranging from 40-120 mg once daily and was given without regard to food. Adverse reactions reported as reasons for discontinuation of treatment - In the short-term placebo-controlled pre-marketing studies for MDD, 9% of the 1,583 patients who received FETZIMA (40120 mg) discontinued treatment due to an adverse event, compared with 3% of the 1,040 placebo-treated patients in those studies. The most common adverse reaction leading to discontinuation in at least 1% of the FETZIMA-treated patients in the short-term placebo-controlled studies was nausea (1.5%). Common adverse reactions in placebo-controlled MDD studies - The most commonly observed adverse events in FETZIMA-treated MDD patients in placebo-controlled studies (incidence * 5% and at least twice the rate of placebo) were: nausea, constipation, hyperhidrosis, heart rate increased, erectile dysfunction, tachycardia, vomiting, and palpitations. Table 3 in the full Prescribing Information shows the incidence of adverse reactions that occurred in * 2% of FETZIMA-treated MDD patients and at least twice the rate of placebo in the placebo-controlled studies. Values shown in parentheses are shown as FETZIMA 40-120 mg/day (N=1583) %, followed by Placebo (N=1040) %. Gastrointestinal disorders: Nausea (17, 6); Constipation (9, 3); Vomiting (5, 1); Cardiac disorders: Tachycardiaa (6, 2); Palpitations (5, 1); Reproductive system and breast disordersb: Erectile dysfunctionc (6, 1); Testicular paind (4, < 1); Ejaculation disordere (5, < 1); Investigations: Heart rate increasedf (6, 1); Blood pressure increasedg (3, 1); Renal and urinary disorders: Urinary hesitation (4, 0); Skin and subcutaneous tissue disorders: Hyperhidrosis (9, 2); Rashh (2, 0); Vascular disorders: Hot flush (3, 1); Hypotensioni (3, 1); Hypertensionj (3, 1); Metabolism and nutrition disorders: Decreased appetite (3, 1). a: Tachycardia also includes: sinus tachycardia and postural orthostatic tachycardia syndrome; b: Percentage is relative to the number of patients in the associated demographic sex category. Fewer than 2% of FETZIMA-treated MDD female patients in placebo-controlled clinical studies reported adverse events related to sexual function; c: erectile dysfunction includes: erectile dysfunction, organic erectile dysfunction and psychogenic erectile dysfunction; d: testicular pain includes: testicular pain, epididymitis, and seminal vesiculitis; e: ejaculation disorder includes: ejaculation disorder, ejaculation delayed, ejaculation failure, and premature ejaculation; f: Heart rate increased also includes: orthostatic heart rate response increased; g: Blood pressure increased also includes: blood pressure systolic increased, blood pressure diastolic increased and blood pressure orthostatic increased; h: Rash also includes: rash generalized, rash maculopapular, rash erythematous and rash macular; i: Hypotension also includes: orthostatic hypotension and dizziness postural; j: Hypertension also includes: labile hypertension; N = number of patients in the Safety Population. Dose-related adverse reactions - In pooled data from the short-term placebo-controlled fixed-dose studies, there were no dose-related adverse reactions (greater than 2% overall incidence) in patients treated with FETZIMA across the dose range 40-120 mg once daily, with the exception of erectile dysfunction and urinary hesitation. See Table 4 in the full Prescribing Information which provides the incidence of dose-related adverse reactions reported in at least 2% of the FETZIMA treatment group and at an incidence that was greater than in the placebo group. The first 3 values show adverse reactions in the % of patients in the FETZIMA group that had taken a dose of 40 mg/d [N=366], 80 mg/d [N=367] and 120 mg/d [N=180] respectively. The fourth value shows adverse reactions in the % of patients in the placebo group [N=362]. Urinary hesitation (4, 5, 6; 0); Erectile dysfunction a (6, 8, 10; 2). a: Percentage is relative to the number of male patients; N = number of patients in the Safety Population. Other adverse reactions observed in clinical studies - Other infrequent adverse reactions, not described elsewhere in the label, occurring at an incidence of < 2% in MDD patients treated with FETZIMA were: Cardiac disorders: Angina pectoris; Supraventricular and Ventricular extrasystoles; Eye disorders: Dry eye; Vision blurred; Conjunctival hemorrhage; General disorders: Chest pain; Thirst; Gastrointestinal disorders: Abdominal pain; Flatulence; Investigations disorders: Blood cholesterol increased; Liver function test abnormal; Nervous System disorders: Migraine; Paraesthesia; Syncope; Extrapyramidal disorder; Psychiatric disorders: Agitation; Anger; Bruxism; Panic attack; Tension; Aggression; Renal and Urinary disorders: Pollakiuria; Hematuria; Proteinuria; Respiratory, thoracic and mediastinal disorders: Yawning; Skin and subcutaneous tissue disorders: Dry skin; Pruritus; Urticaria. DRUG INTERACTIONS: Other than CYP3A4 drug interactions, FETZIMA is predicted, based on in vitro studies, to have a low potential to be involved in clinically significant pharmacokinetic drug interactions. Monoamine Oxidase Inhibitors (MAOIs) - [see Dosage and Administration in the full Prescribing Information, Contraindications, and Warnings and Precautions]. Serotonergic Drugs - [see Dosage and Administration in the full Prescribing Information, Contraindications, and Warnings and Precautions]. Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin) - Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of case-control and cohort design have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. These studies have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and SNRIs are co-administered with warfarin. Patients receiving warfarin therapy should be carefully monitored when FETZIMA is initiated or discontinued [see Warnings and Precautions]. Potential for Other Drugs to Affect FETZIMA - Dose adjustment is recommended when FETZIMA is co-administered with strong inhibitors of CYP3A4 (e.g. ketoconazole) [see Dosage and Administration in the full Prescribing Information]. An in vivo study showed a clinically meaningful increase in levomilnacipran exposure when FETZIMA was co-administered with the CYP3A4 inhibitor ketoconazole (see Figure 1). No dose adjustment of FETZIMA is needed when co-administered with a CYP3A4 inducer or substrate. In vivo studies showed no clinically meaningful change in levomilnacipran exposure when co-administered with the CYP3A4 inducer carbamazepine or the CYP3A4 substrate alprazolam (see Figure 1). No dose adjustment of FETZIMA is needed when co-administered with inhibitors of CYP2C8, CYP2C19, CYP2D6, CYP2J2, P-glycoprotein, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, or OCT2. In vitro studies suggested that CYP2C8, CYP2C19, CYP2D6, and CYP2J2 had minimal contributions to metabolism of levomilnacipran. In addition, levomilnacipran is not a substrate of BCRP, OATP1B1, OATP1B3, OAT1, OAT3, or OCT2 and is a weak substrate of P-gp. Figure 1 PK Interactions between Levomilnacipran (LVM) and Other Drugs Drug Interaction OTHER DRUG ON LVM CYP3A4 Inhibitor By Ketoconazole

CYP3A4 Inducer By Carbamazepine CYP3A4 Substrate By Alprazolam LVM ON OTHER DRUG CYP3A4 Substrate On Carbamazepine CYP3A4 Substrate On Alprazolam

Fold Change and 90% CI

Recommendation

USE IN SPECIFIC POPULATIONS: Pregnancy - Pregnancy Category C: Risk Summary - There are no adequate and well-controlled studies of FETZIMA in pregnant women. Neonates exposed to dual reuptake inhibitors of serotonin and norepinephrine (such as FETZIMA), or selective serotonin reuptake inhibitors late in the third trimester have developed complications that can arise immediately upon delivery. Levomilnacipran was not teratogenic in rats or rabbits when given during the period of organogenesis at doses up to 8 or 16 times the maximum recommended human dose (MRHD) of 120 mg on a mg/m2 basis, respectively. However, an increase in early post natal rat pup mortality was seen at a dose equivalent to 5 times the MRHD given during pregnancy and lactation. FETZIMA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Clinical Considerations - Neonates exposed to SSRIs or SNRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of these classes of drugs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome [see Warnings and Precautions]. A prospective longitudinal study of 201 women with history of major depression who were euthymic at the beginning of pregnancy, showed women who discontinued antidepressant medication during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressant medication. Animal Data - No teratogenic effects were observed when levomilnacipran was administered to pregnant rats or rabbits during the period of organogenesis at oral doses up to 100 mg/kg/day. This dose is 8 and 16 times (in rats and rabbits, respectively) the maximum recommended human dose (MRHD) of 120 mg on a mg/m2 basis. Fetal body weights were reduced in rats, and skeletal ossification was delayed in both rats and rabbits at this dose; these effects were not observed in either species at doses up to 30 mg/kg/day, 2.4 times the MRHD in rats or 5 times the MRHD in rabbits. When levomilnacipran was administered to pregnant rats at an oral dose of 60 mg/kg/day, 5 times the MRHD, during organogenesis and throughout pregnancy and lactation, there was an increase in early postnatal pup mortality; no pup mortality was seen at 20 mg/kg/day, 1.6 times the MRHD. Among the surviving pups, pre- and post-weaning pup weight gain was reduced up to at least 8 weeks of age; however, physical and functional development, including reproductive performance of the progeny, was not affected. The effects on body weight gain were not seen at 7 mg/kg/day, 0.6 times the MRHD. Nursing Mothers - It is not known if FETZIMA is present in human milk. Studies have shown that levomilnacipran is present in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from FETZIMA, a decision should be made whether to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use - Clinical studies on the use of FETZIMA in pediatric patients have not been conducted; therefore, the safety and effectiveness of FETZIMA in the pediatric population have not been established. FETZIMA is not approved for use in pediatric patients [see Boxed Warning and Warnings and Precautions]. Geriatric Use - No dose adjustment is recommended on the basis of age (see Figure 2). In a multiple-dose clinical pharmacokinetic study, elderly subjects (> 65 years) had a slightly higher exposure (Cmax by 24% and AUC by 26%) of levomilnacipran than younger subjects (18-45 years). Of the total number of subjects in clinical studies of FETZIMA, 2.8% of patients were age 65 or older. Because levomilnacipran is predominately excreted by the kidney, renal clearance of levomilnacipran should be considered when determining the dose [see Dosage and Administration in the full Prescribing Information]. SSRIs and SNRIs, including FETZIMA, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event [see Warnings and Precautions]. Hepatic Impairment - Hepatic elimination of levomilnacipran is low. Dose adjustment is not recommended in subjects with mild (Child-Pugh score of 1-6), moderate (Child-Pugh score of 7-9), or severe (Child-Pugh score of 10-13) hepatic impairment (see Figure 2). Renal Impairment - Renal excretion plays a predominant role in the elimination of levomilnacipran. Dose adjustment is not recommended for patients with mild (creatinine clearance of 60-89 ml/min) renal impairment. Dosing adjustment is recommended for patients with moderate (creatinine clearance of 30 - 59 ml/min) or severe (creatinine clearance of 15-29 ml/min) renal impairment (see Figure 2). FETZIMA is not recommended for patients with end stage renal disease [see Dosage and Administration in the full Prescribing Information]. Gender - Dose adjustment based on gender is not recommended (see Figure 2). Figure 2 Effect of Intrinsic Factors on Levomilnacipran PK Population Description

Fold Change and 90% CI

Recommendation

AGE >65 years

Cmax

No dose adjustment

AUC GENDER Females

Cmax

No dose adjustment

AUC RENAL IMPAIRMENT Mild

Cmax

Moderate

Cmax

No dose adjustment

AUC Maximum 80 mg/d

AUC Severe

Cmax

Maximum 40 mg/d

AUC HEPATIC IMPAIRMENT Mild

Cmax

Moderate

Cmax

Severe

Cmax

No dose adjustment

AUC No dose adjustment

AUC

0 Cmax AUC

Maximum 80 mg/d

Cmax AUC

No dose adjustment

Cmax AUC

No dose adjustment

Cmax AUC

No dose adjustment

Cmax AUC

0.50 0.75 1.00 1.25 1.50 1.75 2.00 Change relative to reference

Potential for FETZIMA to Affect Other Drugs - No dose adjustment of the concomitant medication is recommended when FETZIMA is administered with a substrate of CYP3A4, CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, P-gp, OATP1B1, OATP1B3, OAT1, OAT3, or OCT2. In vitro studies have shown that levomilnacipran is not an inhibitor of CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, P-gp, OATP1B1, OATP1B3, OAT1, OAT3, or OCT2. Concomitant use of FETZIMA with alprazolam or carbamazepine, substrates of CYP3A4, had no signiﬁcant effect on alprazolam or carbamazepine plasma concentrations (see Figure 1). Central Nervous System (CNS)-Active Agents - The risk of using FETZIMA in combination with other CNS-active drugs has not been systematically evaluated. Consequently, caution is advised when FETZIMA is prescribed in combination with other CNS-active drugs, including those with a similar mechanism of action. Alcohol - In an in vitro study, alcohol interacted with the extended-release properties of FETZIMA. If FETZIMA is taken with alcohol, a pronounced accelerated drug release may occur. It is recommended that FETZIMA extended-release capsules not be taken with alcohol.

Change relative to reference

The data shown for elderly subjects (>65 years) are relative to younger subjects (18-45 years). The data shown for female subjects are relative to male subjects. The data shown for renal and hepatic impairment are relative to subjects with normal renal and hepatic function, respectively.

DRUG ABUSE AND DEPENDENCE: Controlled Substance - FETZIMA is not a controlled substance. Abuse FETZIMA has not been systematically studied in animals or humans for its potential for abuse. There was no evidence suggestive of drug-seeking behavior in the clinical studies. It is not possible to predict on the basis of clinical experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for a history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of FETZIMA (e.g., development of tolerance or drug-seeking behavior). Dependence - FETZIMA has not been systematically studied in animals or humans for its potential for dependence. OVERDOSAGE: Human Experience - There is limited clinical experience with FETZIMA overdose in humans. In clinical studies, cases of ingestions up to 360 mg daily were reported with none being fatal. Management of Overdose - No speciﬁc antidotes for FETZIMA are known. In managing overdose, provide supportive care, including close medical supervision and monitoring, and consider the possibility of multiple drug involvement. In case of an overdose, consult a Certiﬁed Poison Control Center (1-800-222-1222) for up-to-date guidance and advice. The high volume of distribution of levomilnacipran suggests that dialysis will not be effective in reducing levomilnacipran plasma concentrations. Distributed by: Licensed from Pierre Fabre Medicament Forest Pharmaceuticals, Inc. Subsidiary of Forest Laboratories, Inc. St. Louis, MO 63045 USA © 2013 Forest Laboratories, Inc. Revised: July 2013 039-14000099 – A – RMC19200 – 08/13 Please also see full Prescribing Information at www.fetzima.com

Important mportant Safety ty In Information Info (continued) Warni s and Precautions Warnings SNRIs, includin includingg FETZIMA, hav have been associated with increases in blood pressure. ssure. Blood pressure pressure should sh be measured prior to initiating treatment and periodically cally throughout throughou FETZIMA treatment. Pre-existing hypertension should be controlled led bef before initiating treatment with FETZIMA. Use with caution in patients with pre-existing hypertension, cardiovascular, or cerebrovascular conditions that might be compromised by increases in blood pressure. Concomitant use of FETZIMA with drugs that increase blood pressure and heart rate has not been evaluated and such combinations should be used with caution. For patients who experience a sustained increase in blood pressure, discontinuation or other appropriate medical intervention should be considered. SNRIs, including FETZIMA, have been associated with an increase in heart rate. Heart rate should be measured prior to initiating treatment and periodically throughout FETZIMA treatment. Pre-existing tachyarrhythmias and other cardiac disease should be treated before starting therapy with FETZIMA. For patients who experience a sustained increase in heart rate, discontinuation or other appropriate medical intervention should be considered.

Licensed from Pierre Fabre Medicament FETZIMA is a trademark of Forest Laboratories, Inc. ÂŠ 2014 Forest Laboratories, Inc. FTZ14166-BC 01/14

SSRIs and SNRIs, including FETZIMA, may increase the risk of bleeding events, some serious. Concomitant use of aspirin, NSAIDs, warfarin, and other anticoagulants may add to this risk. Mydriasis has been reported in association with SNRIs including FETZIMA; therefore, FETZIMA should be used with caution in patients with controlled narrow-angle glaucoma. Patients with raised intraocular pressure or those at risk of acute narrow-angle (angle-closure) glaucoma should be monitored. DO NOT use FETZIMA in patients with uncontrolled narrow-angle glaucoma. FETZIMA can affect urethral resistance. In clinical studies, urinary hesitation occurred in 4%, 5% and 6% of FETZIMA-treated patients receiving doses of 40, 80, and 120 mg, respectively, compared to no patients in the placebo group. Caution is advised when using FETZIMA in patients prone to obstructive urinary disorders. Symptoms of mania/hypomania were reported in 0.2% of FETZIMA-treated patients and 0.2% of placebo-treated patients in clinical studies. As with all antidepressants, FETZIMA should be used cautiously in patients with a history or family history of bipolar disorder, mania or hypomania. Prior to initiating

INTRODUCING FETZIMA™

SNRI S NRI therapy thera that significantly improves depressive symptoms and functional impairment depressive Siign SSignificant gnif ific ican antt im impr improvement prov ovem em in depressive symptoms demonstrated across 3 dosage strengths 120 mg)1-4 ((40 (4 0 mg, mg, 80 mg, mg, aand nd 1 Primary efficacy endpoin endpoint*: At week 8, least squares (LS) mean difference from placebo in change from baseline in MADRS total score was -3.2 at 40 mg/ mg/day (P<0.05), -4.0 at 80 mg/day (P<0.01), and -4.9 at 120 mg/day (P<0.001) in Asnis et al; -3.3 at 40 mg/day (P<0.01) and --3.1 at 80 mg/day (P<0.01) in Bakish et al; and -3.1 at 40 mg-120 mg/day (P<0.01) in Sambunaris et al1-4

Significant SSi ign gnif ific ican antt im impr improvement prov ovem em in functional impairment1-4 Secondary efficacy endp endpoint*: At week 8, LS mean difference from placebo in change from baseline in SDS total score was -1.4 at 40 mg/day (P=NS†), -2.5 at 80 mg/day (P<0.05), and -2.6 at 120 mg/day (P<0.05) in Asnis et al; -1.8 at 40 mg/day (P<0.05) and -2.7 at 80 m mg/day (P<0.01) in Bakish et al; and -2.6 at 40 mg-120 mg/day (P<0.01) in Sambunaris et al2-5 **IIIn *In n 3 88-wee 8-week, week, k, ran random randomized, domize ized, d, dou double-blind, placebo-controlled studies (2 fixed dose and 1 flexible dose) in adults with MDD, MADRS mean baseline total scores across acr oss al alll trea ttreatment reatme tment nt gro groups ups we w were 36, 31, and 35 in each study, respectively. SDS mean baseline total scores were 21, 17, and 20 in each study, respectively.

Most M Mo stt ccommon ommo om mon n ad adve adverse verr events In placebo-controlled studies, st the most commonly observed adverse events (AEs) in patients (incidence ≥5% and at least twice the rate of placebo placebo) were: nausea (17% vs 6%), constipation (9% vs 3%), hyperhidrosis (9% vs 2%), heart rate increased dysfunction (6% vs 1%), tachycardia (6% vs 2%), vomiting (5% vs 1%), and palpitations (5% vs 1%)1 (6% vs 1%), erectile dysfu

TThee on Th only lyy d dose-related ossee-re rela late la t AEs (>2%) were urinary hesitation and erectile dysfunction1 te Data pooled from the sh short-term, placebo-controlled, fixed-dose studies. Urinary hesitation was observed in 4% of patients on 40 mg/day, 5% on 80 mg/day, 6% on 120 mg/day, and 0% on placebo. Erectile dysfunction was reported by 6% of patients on 40 mg/day, 8% on 80 mg/day, 10% on 120 mg/day, and 2% on placebo1 NS=Not significant. MADRS, Montgomery-Asberg Depression Rating Scale. SDS, Sheehan Disability Scale.

†

Important Safety Information (continued) Warnings and Precautions Adverse Reactions treatment with FETZIMA, patients should be adequately screened to determine The most commonly observed adverse reactions in MDD patients treated with if they are at risk for bipolar disorder. FETZIMA is not approved for use in treating FETZIMA in placebo-controlled studies (incidence ≥5% and at least twice the bipolar depression. rate of placebo) were: nausea, constipation, hyperhidrosis, heart rate increased, erectile dysfunction, tachycardia, vomiting, and palpitations. FETZIMA should be prescribed with caution in patients with a seizure disorder. Discontinuation symptoms, some serious, have been reported with discontinuation References: 1. Fetzima (levomilnacipran extended-release capsules) [package insert]. St. Louis, MO: Forest Pharmaceuticals, Inc.; 2013. 2. Asnis GM, Bose A, Gommoll CP, Chen C, Greenberg WM. Efficacy and safety of levomilnacipran sustained release of serotonergic antidepressants such as FETZIMA. Gradual dose reduction is 40 mg, 80 mg, or 120 mg in major depressive disorder: a phase 3, randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2013;74(3):242-248. 3. Bakish D, Bose A, Gommoll C, et al. Levomilnacipran ER 40 mg and 80 mg in patients recommended, instead of abrupt discontinuation, whenever possible. Monitor with major depressive disorder: a phase III, randomized, double-blind, fixed-dose, placebo-controlled study. J Psychiatry Neurosci. patients when discontinuing FETZIMA. If intolerable symptoms occur following 2013;DOI:10.1503/jpn.130040. 4. Sambunaris A, Bose A, Gommoll CP, Chen C, Greenberg WM, Sheehan DV. A phase III, doublea dose decrease or upon discontinuation of treatment, consider resuming the blind, placebo-controlled, flexible-dose study of levomilnacipran extended release in patients with major depressive disorder. J Clin Psychopharmacol. 2013;DOI:10.1097/JCP.0000000000000060. 5. Data on file. Forest Laboratories, Inc. previously prescribed dose and decreasing the dose at a more gradual rate. Advise patients that if they are treated with diuretics or are otherwise volume depleted, or are elderly, they may be at greater risk of developing hyponatremia while taking FETZIMA. Although no cases of hyponatremia resulting from FETZIMA treatment were reported in the clinical studies, hyponatremia has occurred as a result of treatment with SSRIs and SNRIs. FETZIMA should be discontinued in patients with symptomatic hyponatremia and appropriate New medical intervention should be instituted. Please see additional Important Safety Information, including Boxed Warning, on the back cover and brief summary of Prescribing Information on the preceding pages.

Depression can be overwhelming

New For the Treatment of Major Depressive Disorder (MDD) in Adults FETZIMA is not approved for the management of fibromyalgia, and its efficacy and safety have not been established for that use

Important Safety Information WARNING: SUICIDAL THOUGHTS AND BEHAVIORS Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in shortterm studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was a reduction in risk with antidepressant use in patients aged 65 and older. In patients of all ages who are started on antidepressant therapy, monitor closely for worsening, and for emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber. FETZIMA is not approved for use in pediatric patients.

Contraindications FETZIMA is contraindicated in patients with a hypersensitivity to levomilnacipran, milnacipran HCl, or to any excipient in the formulation. The use of MAOIs intended to treat psychiatric disorders with FETZIMA or within 7 days of stopping treatment with FETZIMA is contraindicated due to an increased risk of serotonin syndrome. The use of FETZIMA within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated. Starting FETZIMA in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated due to an increased risk of serotonin syndrome. Do not use FETZIMA in patients with uncontrolled narrow-angle glaucoma. In clinical studies, FETZIMA was associated with an increased risk of mydriasis. Warnings and Precautions All patients being treated with antidepressants should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the first few months of treatment and when increasing or decreasing the dose. Consider changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse or includes symptoms of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, mania, or suicidality that are

severe, abrupt in onset, or were not part of the patientâ&#x20AC;&#x2122;s presenting symptoms. Families and caregivers of patients being treated with antidepressants should be alerted about the need to monitor patients daily. Prescriptions for FETZIMA should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose. Serotonin Syndrome: The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs both when taken alone, but especially when co-administered with other serotonergic agents (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. Johnâ&#x20AC;&#x2122;s Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Symptoms of serotonin syndrome may include mental status changes (eg, agitation, hallucinations, delirium, and coma), autonomic instability (eg, tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (eg, tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms. If symptoms of serotonin syndrome occur, discontinue FETZIMA immediately and initiate supportive treatment. If concomitant use of FETZIMA with other serotonergic drugs is clinically warranted, patients should be aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.

Please see Boxed Warning above, and additional Important Safety Information and brief summary of Prescribing Information on the preceding pages.