AHDB March/April 2015 Vol 8 Payor's Guide by Dalia Buffery

MARCH 2015

VOLUME 8 I SPECIAL FEATURE

THE PEER-REVIEWED FORUM FOR REAL-WORLD EVIDENCE IN BENEFIT DESIGN™

FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

™

Sixth Annual Payers’ Guide to New FDA Approvals FOREWORD The Sixth Annual Payers’ Guide to FDA Approvals INTRODUCTION New FDA Drug Approvals Hit an 18-Year High in 2014 Gary M. Owens, MD NOVEL PHARMACEUTICALS 2014 FDA Approvals of Brand-Name Prescription Drugs in 2014 Product Profiles of Select Drugs Approved in 2014 A 2015 PIPELINE PREVIEW Once-Fatal Conditions Have Become Chronic: Early Trends in the FDA’s 2015 Approvals Gary Branning, MBA

8 8

Product Profiles of Select Drugs Approved in Early 2015

SARY

NOW APPROVED

LENVIMATM (lenvatinib) is indicated for the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC).

Visit LENVIMAinfo.com Important Safety Information Warnings and Precautions Hypertension was reported in 73% of LENVIMA-treated patients (of which 44% were ≥ Grade 3) and 16% of patients in the placebo group. Control blood pressure prior to treatment and monitor blood pressure after 1 week, then every 2 weeks for the first 2 months, and then at least monthly during treatment. Withhold LENVIMA for Grade 3 hypertension; resume at a reduced dose when hypertension is controlled at ≤ Grade 2. Discontinue LENVIMA for life-threatening hypertension. Cardiac dysfunction was reported in 7% of LENVIMA-treated patients (2% Grade 3 or greater). Monitor patients for clinical symptoms or signs of cardiac decompensation. Withhold LENVIMA for development of Grade 3 cardiac dysfunction until improved to Grade 0 or 1 or baseline. Resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of cardiac dysfunction. Discontinue LENVIMA for Grade 4 cardiac dysfunction. Arterial thromboembolic events were reported in 5% of LENVIMA-treated patients; events of Grade 3 or greater were 3%. Discontinue LENVIMA following an arterial thrombotic event. LENVIMA has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months. 4% of LENVIMA-treated patients experienced an increase in ALT and 5% experienced an increase in AST that was Grade 3 or greater. Monitor liver function before initiation and during treatment with LENVIMA. Withhold LENVIMA for the development of ≥ Grade 3 liver impairment until resolved to Grade 0 to 1 or baseline. Resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of hepatotoxicity. Discontinue LENVIMA for hepatic failure. Proteinuria was reported in 34% of LENVIMA-treated patients (of which 11% were Grade 3). Monitor for proteinuria before initiation of, and periodically during treatment. Obtain a 24 hour urine protein if urine dipstick proteinuria ≥2+ is detected. Withhold LENVIMA for ≥ 2 grams of proteinuria/24 hours and resume at a reduced dose when proteinuria is <2 gm/24 hours. Discontinue LENVIMA for nephrotic syndrome.

Events of renal impairment were reported in 14% of LENVIMAtreated patients. Renal failure or impairment ≥ Grade 3 was 3% in LENVIMA-treated patients. Withhold LENVIMA for development of Grade 3 or 4 renal failure / impairment until resolved to Grade 0 to 1 or baseline. Resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of renal impairment. Events of gastrointestinal perforation or fistula were reported in 2% of LENVIMAtreated patients. Discontinue LENVIMA in patients who develop gastrointestinal perforation or life-threatening fistula. QT/QTc interval prolongation was reported in 9% of LENVIMA-treated patients (2% Grade 3 or greater). Monitor ECG in patients with congenital long QT syndrome, CHF, bradyarrhythmias, or patients taking drugs known to prolong the QT interval. Monitor and correct electrolyte abnormalities in all patients. Withhold LENVIMA for the development of ≥ Grade 3 QT interval prolongation. Resume LENVIMA at a reduced dose when QT prolongation resolves to Grade 0 or 1 or baseline. Hypocalcemia ≥ Grade 3 was reported in 9% of LENVIMA-treated patients. Monitor blood calcium levels at least monthly and replace calcium as necessary during LENVIMA treatment. Interrupt and adjust LENVIMA dosing as necessary depending on severity, presence of ECG changes, and persistence of hypocalcemia. Reversible posterior leukoencephalopathy syndrome (RPLS) was reported in 3 patients across clinical studies in which 1108 patients received LENVIMA. Confirm the diagnosis of RPLS with MRI. Withhold LENVIMA for RPLS until fully resolved. Resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of neurologic symptoms. Hemorrhagic events occurred in 35% of LENVIMA-treated patients and in 18% of the placebo group. The incidence of Grade 3-5 hemorrhage was similar between arms at 2% and 3%, respectively. The most frequently reported hemorrhagic event was epistaxis (11% Grade 1 and 1% Grade 2). Discontinuation due to hemorrhagic events occurred in 1% of LENVIMA-treated patients. There was one case of fatal intracranial hemorrhage among 16 patients who received LENVIMA and had CNS metastases at baseline. Withhold LENVIMA for the development of Grade 3 hemorrhage until resolved to Grade 0 to 1. Resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of hemorrhage. Discontinue LENVIMA in patients who experience Grade 4 hemorrhage. LENVIMA impairs exogenous thyroid suppression. Elevation of TSH level above 0.5 mU/L was observed post baseline in 57% of LENVIMA-treated patients. Monitor TSH levels monthly and adjust thyroid replacement medication as needed. LENVIMA can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with LENVIMA and for at least 2 weeks following completion of therapy. Advise women not to breastfeed during treatment with LENVIMA. Adverse Reactions The most common adverse reactions observed in LENVIMA-treated patients vs. placebo treated patients respectively were hypertension (73% vs 16%), fatigue (67% vs 35%), diarrhea (67% vs 17%), arthralgia/myalgia (62% vs 28%), decreased appetite (54% vs 18%), weight decreased (51% vs 15%), nausea (47% vs 25%), stomatitis (41% vs 8%), headache (38% vs 11%), vomiting (36% vs 15%), proteinuria (34% vs 3%), palmar-plantar erythrodysesthesia syndrome (32% vs 1%), abdominal pain (31% vs 11%), and dysphonia (31% vs 5%).

Please see Brief Summary of Prescribing Information on the following pages. LENVIMATM is a trademark used by Eisai Inc. under license from Eisai R&D Management Co., Ltd. © 2015 Eisai Inc. All rights reserved. Printed in USA/February 2015 LENV0014

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LENVIMA™ (lenvatinib) BRIEF SUMMARY – See package insert for full prescribing information. 1 INDICATIONS AND USAGE LENVIMA is indicated for the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC). 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dose The recommended daily dose of LENVIMA is 24 mg (two 10 mg capsules and one 4 mg capsule) orally taken once daily with or without food. Continue LENVIMA until disease progression or until unacceptable toxicity occurs. Take LENVIMA at the same time each day. If a dose is missed and cannot be taken within 12 hours, skip that dose and take the next dose at the usual time of administration. Severe Renal or Hepatic Impairment The recommended dose of LENVIMA is 14 mg taken orally once daily in patients with severe renal impairment (creatinine clearance [CLcr] less than 30 mL/min calculated by the Cockroft-Gault equation) or severe hepatic impairment (Child-Pugh C). 2.2 Dose Modifications Hypertension • Assess blood pressure prior to and periodically during treatment. Initiate or adjust medical management to control blood pressure prior to and during treatment. • Withhold LENVIMA for Grade 3 hypertension that persists despite optimal antihypertensive therapy; resume at a reduced dose (see Table 1) when hypertension is controlled at less than or equal to Grade 2. • Discontinue LENVIMA for life-threatening hypertension. Cardiac dysfunction or hemorrhage • Discontinue for a Grade 4 event. • Withhold LENVIMA for development of Grade 3 event until improved to Grade 0 or 1 or baseline. • Either resume at a reduced dose (see Table 1) or discontinue LENVIMA depending on the severity and persistence of the adverse event. Arterial thrombotic event • Discontinue LENVIMA following an arterial thrombotic event. Renal failure and impairment or hepatotoxicity • Withhold LENVIMA for development of Grade 3 or 4 renal failure/impairment or hepatotoxicity until resolved to Grade 0 to 1 or baseline. • Either resume at a reduced dose (see Table 1) or discontinue LENVIMA depending on the severity and persistence of renal impairment or hepatotoxicity. • Discontinue LENVIMA for hepatic failure. Proteinuria • Withhold LENVIMA for ≥2 grams of proteinuria/24 hours. • Resume at a reduced dose (see Table 1) when proteinuria is <2 gm/24 hours. • Discontinue LENVIMA for nephrotic syndrome. Gastrointestinal perforation or fistula formation • Discontinue LENVIMA in patients who develop gastrointestinal perforation or life-threatening fistula. QT prolongation • Withhold LENVIMA for the development of Grade 3 or greater QT interval prolongation. • Resume LENVIMA at a reduced dose (see Table 1) when QT prolongation resolves to Grade 0 or 1 or baseline. Reversible posterior leukoencephalopathy syndrome (RPLS) • Withhold for RPLS until fully resolved. • Upon resolution, resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of neurologic symptoms. Manage other adverse reactions according to the instructions in Table 1. Based on the absence of clinical experience, there are no recommendations on resumption of dosing in patients with Grade 4 clinical adverse reactions that resolve. Table 1

Recommended Dose Modifications for Persistent and Intolerable Grade 2 or Grade 3 Adverse Reactions or Grade 4 Laboratory Abnormalitiesa Adverse Reaction

Modification

Adjusted Doseb

First occurrence

Interrupt until resolved to Grade 0-1 or baseline

20 mg (two 10 mg capsules) orally once daily

Second occurrencec

Interrupt until resolved to Grade 0-1 or baseline

14 mg (one 10 mg capsule plus one 4 mg capsule) orally once daily

Third occurrencec

Interrupt until resolved to Grade 0-1 or baseline

10 mg (one 10 mg capsule) orally once daily

Initiate medical management for nausea, vomiting, or diarrhea prior to interruption or dose reduction of LENVIMA Reduce dose in succession based on the previous dose level (24 mg, 20 mg, or 14 mg per day) c Refers to the same or a different adverse reaction that requires dose modification 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Hypertension In Study 1 hypertension was reported in 73% of LENVIMA-treated patients and 16% of patients in the placebo group. The median time to onset of new or worsening hypertension was 16 days for LENVIMA-treated patients. The incidence of Grade 3 hypertension was 44% as compared to 4% for placebo, and the incidence of Grade 4 hypertension was less than 1% in LENVIMA-treated patients and none in the placebo group. Control blood pressure prior to treatment with LENVIMA. Monitor blood pressure after 1 week, then every 2 weeks for the first 2 months, and then at least monthly thereafter during treatment with LENVIMA. Withhold LENVIMA for Grade 3 hypertension despite optimal antihypertensive therapy; resume at a reduced dose when hypertension is controlled at less than or equal to Grade 2. Discontinue LENVIMA for life-threatening hypertension. 5.2 Cardiac Dysfunction In Study 1, cardiac dysfunction, defined as decreased left or right ventricular function, cardiac failure, or pulmonary edema, was reported in 7% of LENVIMA-treated patients (2% Grade 3 or greater) and 2% (no Grade 3 or greater) of patients in the placebo group. The majority of these cases in LENVIMA-treated patients (14 of 17 cases) were based on findings of decreased ejection fraction as assessed by echocardiography. Six of 261 (2%) LENVIMAtreated patients in Study 1 had greater than 20% reduction in ejection fraction as measured by echocardiography compared to no patients who received placebo. Monitor patients for clinical symptoms or signs of cardiac decompensation. Withhold LENVIMA for development of Grade 3 cardiac dysfunction until improved to Grade 0 or 1 or baseline. Either resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of cardiac dysfunction. Discontinue LENVIMA for Grade 4 cardiac dysfunction. 5.3 Arterial Thromboembolic Events In Study 1, arterial thromboembolic events were reported in 5% of LENVIMA-treated patients and 2% of patients in the placebo group. The incidence of arterial thromboembolic events of Grade 3 or greater was 3% in LENVIMAtreated patients and 1% in the placebo group. Discontinue LENVIMA following an arterial thrombotic event. The safety of resuming LENVIMA after an arterial thromboembolic event has not been established and LENVIMA has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months. 5.4 Hepatotoxicity In Study 1, 4% of LENVIMA-treated patients experienced an increase in alanine aminotransferase (ALT) and 5% experienced an increase in aspartate aminotransferase (AST) that was Grade 3 or greater. No patients in the placebo group experienced Grade 3 or greater increases in ALT or AST. Across clinical studies in which 1108 patients received LENVIMA, hepatic failure (including fatal events) was reported in 3 patients and acute hepatitis was reported in 1 patient. Monitor liver function before initiation of LENVIMA, then every 2 weeks for the first 2 months, and at least monthly thereafter during treatment. Withhold LENVIMA for the development of Grade 3 or greater liver impairment until resolved to Grade 0 to 1 or baseline. Either resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of hepatotoxicity. Discontinue LENVIMA for hepatic failure. a b

5.5 Proteinuria In Study 1, proteinuria was reported in 34% of LENVIMA-treated patients and 3% of patients in the placebo group. The incidence of Grade 3 proteinuria in LENVIMA-treated patients was 11% compared to none in the placebo group. Monitor for proteinuria before initiation of, and periodically throughout treatment. If urine dipstick proteinuria greater than or equal to 2+ is detected, obtain a 24 hour urine protein. Withhold LENVIMA for ≥2 grams of proteinuria/24 hours and resume at a reduced dose when proteinuria is <2 gm/24 hours. Discontinue LENVIMA for nephrotic syndrome. 5.6 Renal Failure and Impairment In Study 1, events of renal impairment were reported in 14% of LENVIMA-treated patients compared to 2% of patients in the placebo group. The incidence of Grade 3 or greater renal failure or impairment was 3% in LENVIMA-treated patients and 1% in the placebo group. The primary risk factor for severe renal impairment in LENVIMA-treated patients was dehydration/hypovolemia due to diarrhea and vomiting. Withhold LENVIMA for development of Grade 3 or 4 renal failure/impairment until resolved to Grade 0 to 1 or baseline. Either resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of renal impairment. 5.7 Gastrointestinal Perforation and Fistula Formation In Study 1, events of gastrointestinal perforation or fistula were reported in 2% of LENVIMA-treated patients and 0.8% of patients in the placebo group. Discontinue LENVIMA in patients who develop gastrointestinal perforation or life-threatening fistula. 5.8 QT Interval Prolongation In Study 1, QT/QTc interval prolongation was reported in 9% of LENVIMA-treated patients and 2% of patients in the placebo group. The incidence of QT interval prolongation of Grade 3 or greater was 2% in LENVIMA-treated patients compared to no reports in the placebo group. Monitor electrocardiograms in patients with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, or those who are taking drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics. Monitor and correct electrolyte abnormalities in all patients. Withhold LENVIMA for the development of Grade 3 or greater QT interval prolongation. Resume LENVIMA at a reduced dose when QT prolongation resolves to Grade 0 or 1 or baseline. 5.9 Hypocalcemia In Study 1, 9% of LENVIMA-treated patients experienced Grade 3 or greater hypocalcemia compared to 2% in the placebo group. In most cases hypocalcemia responded to replacement and dose interruption/dose reduction. Monitor blood calcium levels at least monthly and replace calcium as necessary during LENVIMA treatment. Interrupt and adjust LENVIMA dosing as necessary depending on severity, presence of ECG changes, and persistence of hypocalcemia. 5.10 Reversible Posterior Leukoencephalopathy Syndrome Across clinical studies in which 1108 patients received LENVIMA, there were 3 reported events of reversible posterior leukoencephalopathy syndrome (RPLS). Confirm the diagnosis of RPLS with MRI. Withhold for RPLS until fully resolved. Upon resolution, resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of neurologic symptoms. 5.11 Hemorrhagic Events In Study 1, hemorrhagic events occurred in 35% of LENVIMA-treated patients and in 18% of the placebo group. However, the incidence of Grade 3-5 hemorrhage was similar between arms at 2% and 3%, respectively. The most frequently reported hemorrhagic event was epistaxis (11% Grade 1 and 1% Grade 2). Discontinuation due to hemorrhagic events occurred in 1% of LENVIMA-treated patients. Across clinical studies in which 1108 patients received LENVIMA, Grade 3 or greater hemorrhage was reported in 2% of patients. In Study 1, there was 1 case of fatal intracranial hemorrhage among 16 patients who received lenvatinib and had CNS metastases at baseline. Withhold LENVIMA for the development of Grade 3 hemorrhage until resolved to Grade 0 to 1. Either resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of hemorrhage. Discontinue LENVIMA in patients who experience Grade 4 hemorrhage. 5.12 Impairment of Thyroid Stimulating Hormone Suppression LENVIMA impairs exogenous thyroid suppression. In Study 1, 88% of all patients had a baseline thyroid stimulating hormone (TSH) level less than or equal to 0.5 mU/L. In those patients with a normal TSH at baseline, elevation of TSH level above 0.5 mU/L was observed post baseline in 57% of LENVIMA-treated patients as compared with 14% of patients receiving placebo. Monitor TSH levels monthly and adjust thyroid replacement medication as needed in patients with DTC. 5.13 Embryofetal Toxicity Based on its mechanism of action and data from animal reproduction studies, LENVIMA can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of lenvatinib during organogenesis at doses below the recommended human dose resulted in embryotoxicity, fetotoxicity, and teratogenicity in rats and rabbits. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with LENVIMA and for at least 2 weeks following completion of therapy. 6 ADVERSE REACTIONS The following adverse reactions are discussed elsewhere in the label. Please see the Warnings and Precautions sections in the full prescribing information. • Hypertension • Cardiac Dysfunction • Arterial Thromboembolic Events • Hepatotoxicity • Proteinuria • Renal Failure and Impairment • Gastrointestinal Perforation and Fistula Formation • QT Interval Prolongation • Hypocalcemia • Reversible Posterior Leukoencephalopathy Syndrome • Hemorrhagic Events • Impairment of Thyroid Stimulating Hormone Suppression 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. Safety data obtained in 1108 patients with advanced solid tumors who received LENVIMA as a single agent across multiple clinical studies was used to further characterize risks of serious adverse drug reactions. The median age was 60 years (range 21-89 years). The dose range was 0.2 mg to 32 mg. The median duration of exposure in the entire population was 5.5 months. The safety data described below are derived from Study 1 which randomized (2:1) patients with radioactive iodinerefractory differentiated thyroid cancer (RAI-refractory DTC) to LENVIMA (n=261) or placebo (n=131). The median treatment duration was 16.1 months for LENVIMA and 3.9 months for placebo. Among 261 patients who received LENVIMA in Study 1, median age was 64 years, 52% were women, 80% were White, 18% were Asian, and 2% were Black; 4% identified themselves as having Hispanic or Latino ethnicity. In Study 1, the most common adverse reactions observed in LENVIMA-treated patients (greater than or equal to 30%) were, in order of decreasing frequency, hypertension, fatigue, diarrhea, arthralgia/myalgia, decreased appetite, weight decreased, nausea, stomatitis, headache, vomiting, proteinuria, palmar-plantar erythrodysesthesia (PPE) syndrome, abdominal pain, and dysphonia. The most common serious adverse reactions (at least 2%) were pneumonia (4%), hypertension (3%), and dehydration (3%). Adverse reactions led to dose reductions in 68% of patients receiving LENVIMA and 5% of patients receiving placebo; 18% of patients discontinued LENVIMA and 5% discontinued placebo for adverse reactions. The most common adverse reactions (at least 10%) resulting in dose reductions of LENVIMA were hypertension (13%), proteinuria (11%), decreased appetite (10%), and diarrhea (10%); the most common adverse reactions (at least 1%) resulting in discontinuation of LENVIMA were hypertension (1%) and asthenia (1%). Table 2 presents the percentage of patients in Study 1 experiencing adverse reactions at a higher rate in LENVIMAtreated patients than patients receiving placebo in the double-blind phase of the DTC study.

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Table 2

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TableAdverse 2 Reactions AdverseOccurring Reactionsin Occurring Patients with in Patients a Between-Group with a Between-Group Difference of Difference Greater of Greater The background of major risk birthofdefects and miscarriage the indicated population unknown; however, Therisk background major birth defects and for miscarriage for the indicatedispopulation is unknown; however, than or Equal than to 5% or Equal All Grades to 5% or AllGreater Gradesthan or Greater or Equal than to 2% or Equal Grades to 2% 3 and Grades 4 3 and 4 the background in the U.S. population major birthofdefects is 2-4% and of miscarriage 15-20% ofis 15-20% of therisk background riskgeneral in the U.S. generalofpopulation major birth defects is 2-4% and of ismiscarriage clinically recognized clinicallypregnancies. recognized pregnancies. 24 mg LENVIMA 24LENVIMA mg Placebo Placebo Data Data N=261 N=131 N=261 N=131 Animal Data Animal Data 3-4 All Grades 3-4 Grades In 3-4an embryofetal All Grades All Grades 3-4 Grades All Grades study, daily oral administration of lenvatinib of mesylate at doses greater than greater or In an development embryofetal development study, daily oral administration lenvatinib mesylate at doses than or Adverse Reaction (%) (%) (%) (%) (%) (%) (%) equal to 0.3 mg/kg Adverse Reaction (%) [approximately 0.14 times the recommended human dose human based on body surface area surface (BSA)] toarea (BSA)] to equal to 0.3 mg/kg [approximately 0.14 times the recommended dose based on body Vascular Disorders Vascular Disorders pregnant ratspregnant during organogenesis resulted in dose-related decreases indecreases mean fetalinbody weight, delayed fetaldelayed fetal rats during organogenesis resulted in dose-related mean fetal body weight, a a and dose-related increases in fetal external (parietal edema and tail abnormalities), visceral, andvisceral, and and dose-related increases in fetal external (parietal edema and tail abnormalities), 73 73 44 44 16 16 4 4 ossifications,ossifications, HypertensionHypertension thanGreater 80% postimplantation loss was observed at 1.0 mg/kg/day 0.5 skeletalGreater anomalies. than 80% postimplantation loss was observed at 1.0(approximately mg/kg/day (approximately 0.5 Hypotension Hypotension 9 9 2 2 2 2 0 0 skeletal anomalies. times the recommended human dose human based on BSA). times the recommended dose based on BSA). Gastrointestinal Gastrointestinal Disorders Disorders of lenvatinib of mesylate to pregnant duringrabbits organogenesis resulted in fetal external Daily oral administration lenvatinib mesylaterabbits to pregnant during organogenesis resulted in fetal external Diarrhea Diarrhea 67 67 9 9 17 17 0 0 Daily oral administration (short tail), visceral (retroesophageal subclavian artery), and skeletal anomalies doses greater than greater or equalthan to or equal to (short tail), visceral (retroesophageal subclavian artery), and skeletalatanomalies at doses Nausea Nausea 47 47 2 2 25 25 1 1 0.03 mg/kg (approximately 0.03 times the human of 24 mg based onmg body surface area).surface At the area). 0.03 mg/kg 0.03 mg/kg (approximately 0.03 timesdose the human dose of 24 based on body At the 0.03 mg/kg b b 41 41 5 5 8 8 0 0 dose, increased Stomatitis Stomatitis post-implantation loss, including 1 fetal death,1was observed. abortifacient in dose, increased post-implantation loss, including fetalalso death, was alsoLenvatinib observed.was Lenvatinib was abortifacient in in late abortions in approximately one-third of the rabbitsoftreated at a dose level 0.5 mg/kg/day rabbits, resulting in late abortions in approximately one-third the rabbits treated at of a dose level of 0.5 mg/kg/day Vomiting Vomiting 36 36 2 2 15 15 0 0 rabbits, resulting c 0.5 times the0.5 recommended clinical dose clinical of 24 mg based onmg BSA). (approximately times the recommended dose of 24 based on BSA). Abdominal pain Abdominal painc 31 31 2 2 11 11 1 1 (approximately 8.2 Lactation ConstipationConstipation 29 29 0.4 0.4 15 15 1 1 8.2 Lactation Risk Summary 25 25 1 1 2 2 0 0 Risk Summary Oral paind Oral paind It is not known LENVIMA is LENVIMA present in is human milk. However, lenvatinib and its metabolites excreted are excreted It iswhether not known whether present in human milk. However, lenvatinib and its are metabolites Dry mouth Dry mouth 17 17 0.4 0.4 8 8 0 0 in rat milk at in concentrations higher than inhigher maternal Because of the potential for potential serious adverse reactions rat milk at concentrations thanplasma. in maternal plasma. Because of the for serious adverse reactions Dyspepsia Dyspepsia 13 13 0.4 0.4 4 4 0 0 in nursing infants from infants LENVIMA, women to discontinue during treatment with LENVIMA. in nursing fromadvise LENVIMA, advise women tobreastfeeding discontinue breastfeeding during treatment with LENVIMA. General Disorders Generaland Disorders Administration and Administration Site Conditions Site Conditions Data Data Fatiguee Fatiguee 67 67 11 11 35 35 4 4 Animal Data Animal Data of radiolabeled lenvatinib to lenvatinib lactating Sprague Dawley rats,Dawley lenvatinib-related Following administration of radiolabeled to lactating Sprague rats, lenvatinib-related Edema peripheral Edema peripheral 21 21 0.4 0.4 8 8 0 0 Following administration radioactivity radioactivity was approximately 2 times higher (basedhigher on AUC) in milk compared to compared maternal plasma. was approximately 2 times (based on AUC) in milk to maternal plasma. Musculoskeletal Musculoskeletal and Connective and Connective Tissue Disorders Tissue Disorders 8.3 Females and Males of Reproductive Potential 8.3 Females and Males of Reproductive Potential f f Arthralgia/Myalgia Arthralgia/Myalgia 62 62 5 5 28 28 3 3 ContraceptionContraception MetabolismMetabolism and Nutrition and Disorders Nutrition Disorders Based on itsBased mechanism action, LENVIMA cause fetal to a pregnanttowoman. on its of mechanism of action,can LENVIMA canharm causewhen fetal administered harm when administered a pregnant woman. Weight decreased Weight decreased 51 51 13 13 15 15 1 1 Advise females of reproductive potential to use effective contraception during treatment LENVIMA Advise females of reproductive potential to use effective contraception duringwith treatment withand LENVIMA and Decreased appetite Decreased appetite 54 54 7 7 18 18 1 1 for at least 2for weeks following completion therapy. of therapy. at least 2 weeks followingofcompletion Dehydration Dehydration 9 9 2 2 2 2 1 1 Infertility Infertility Nervous System Nervous Disorders System Disorders Females Females result inmay reduced in females potential. potential. LENVIMA resultfertility in reduced fertilityofinreproductive females of reproductive Headache Headache 38 38 3 3 11 11 1 1 LENVIMA may Males Dysgeusia Dysgeusia 18 18 0 0 3 3 0 0 Males LENVIMA may result inmay damage reproductive tissues leading to reduced of unknown LENVIMA resulttoinmale damage to male reproductive tissues leadingfertility to reduced fertility duration. of unknown duration. Dizziness Dizziness 15 15 0.4 0.4 9 9 0 0 8.4 Pediatric 8.4Use Pediatric Use Renal and Urinary Renal and Disorders Urinary Disorders The safety and of LENVIMA of in LENVIMA pediatric patients havepatients not been established. Theeffectiveness safety and effectiveness in pediatric have not been established. Proteinuria Proteinuria 34 34 11 11 3 3 0 0 Juvenile Animal Data Animal Data Juvenile Skin and Subcutaneous Skin and Subcutaneous Tissue Disorders Tissue Disorders Daily oral administration of lenvatinib of mesylate to juvenile for 8 weeks on postnatal daypostnatal 21 Daily oral administration lenvatinib mesylaterats to juvenile rats starting for 8 weeks starting on day 21 Palmar-plantar Palmar-plantar erythrodysesthesia erythrodysesthesia 32 32 3 3 1 1 0 0 (approximately equal to a human agepediatric of 2 years) in growth retardation weight body weight (approximately equalpediatric to a human ageresulted of 2 years) resulted in growth(decreased retardationbody (decreased consumption, and decreases the width and/or lengthand/or of thelength femur of andthetibia) andand secondary gain,food decreased food consumption, andindecreases in the width femur tibia) and secondary 21 21 0.4 0.4 3 3 0 0 gain, decreased Rashg Rashg and reproductive organ immaturity doses greater than greater or equalthan to 2or mg/kg delaysdevelopment in physical development and reproductive organatimmaturity at doses equal to 2 mg/kg Alopecia Alopecia 12 12 0 0 5 5 0 0 delays in physical 1.2 to 5 times1.2 thetoclinical by AUC at thebyrecommended human dose).human Decreased (approximately 5 timesexposure the clinical exposure AUC at the recommended dose).length Decreased length Hyperkeratosis Hyperkeratosis 7 7 0 0 2 2 0 0 (approximately of the femur of andthetibia persisted following 4 weeks of recovery. of lenvatinib was femur and tibia persisted following 4 weeksInofgeneral, recovery.the In toxicologic general, theprofile toxicologic profile of lenvatinib was Respiratory,Respiratory, Thoracic and Thoracic Mediastinal and Mediastinal Disorders Disorders similar between juvenile and juvenile adult rats, though including broken teethbroken at all dose at mortality at similar between and adult toxicities rats, though toxicities including teethlevels at alland dosemortality levels and Dysphonia Dysphonia 31 31 1 1 5 5 0 0 the 10 mg/kg/day level (attributed primary duodenal lesions) occurred at earlier treatment time-points the 10dose mg/kg/day dose levelto(attributed to primary duodenal lesions) occurred at earlier treatmentintime-points in Cough Cough 24 24 0 0 18 18 0 0 juvenile rats.juvenile rats. 8.5Use Geriatric Use Epistaxis Epistaxis 12 12 0 0 1 1 0 0 8.5 Geriatric Of 261 patients whopatients receivedwho LENVIMA in LENVIMA Study 1, 118 (45.2%) greaterwere than greater or equalthan to 65oryears and of age and Of 261 received in Study 1, were 118 (45.2%) equaloftoage 65 years PsychiatricPsychiatric Disorders Disorders 29 (11.1%) were greaterwere than greater or equalthan to 75oryears No overall safety or effectiveness were 29 (11.1%) equaloftoage. 75 years of age.differences No overallindifferences in safety or effectiveness were Insomnia Insomnia 12 12 0 0 3 3 0 0 observed between these subjects andsubjects younger and subjects. observed between these younger subjects. Infections and Infections Infestations and Infestations 8.6 Renal Impairment h 10 10 1 1 1 1 0 0 8.6 Renal Impairment Dental and oral Dental infections and oral infectionsh recommended in patients with mild or moderate renal impairment. patients with severe with severe No doseisadjustment is recommended in patients with mild or moderate renal In impairment. In patients Urinary tract Urinary infectiontract infection 11 11 1 1 5 5 0 0 No dose adjustment renal impairment, recommended dose is 14 mgdose taken once withPatients end stage renal weredisease were renal the impairment, the recommended is 14 mgdaily. takenPatients once daily. with enddisease stage renal Cardiac Disorders Cardiac Disorders not studied. not studied. Electrocardiogram Electrocardiogram QT prolongedQT prolonged 9 9 2 2 2 2 0 0 8.7 Hepatic8.7 Impairment Hepatic Impairment No dose adjustment recommended in patients with mild or with moderate hepatic impairment. In patients with No dose isadjustment is recommended in patients mild or moderate hepatic impairment. In patients with a a Includes hypertension, Includes hypertension, hypertensive hypertensive crisis, increased crisis,blood increased pressure blood diastolic, pressureand diastolic, increased and increased severe hepatic impairment, the recommended dose is 14 mg taken once severe hepatic impairment, the recommended dose is 14 mgdaily. taken once daily. blood pressure blood pressure b b 10 OVERDOSAGE 10 OVERDOSAGE Includes aphthous Includes stomatitis, aphthousstomatitis, stomatitis,glossitis, stomatitis, mouth glossitis, ulceration, mouthand ulceration, mucosaland inflammation mucosal inflammation c c Includes abdominal Includes discomfort, abdominal discomfort, abdominal pain, abdominal abdominal pain, pain abdominal lower, pain abdominal lower, pain abdominal upper, pain upper, There is no specific for overdose with LENVIMA. to the high protein binding, lenvatinib is not There isantidote no specific antidote for overdose withDue LENVIMA. Dueplasma to the high plasma protein binding, lenvatinib is not abdominal tenderness, abdominal tenderness, epigastric discomfort, epigastric discomfort, and gastrointestinal and gastrointestinal pain pain expected to be dialyzable. reactions in patients single doses single of LENVIMA asLENVIMA high as 40asmghigh were expected to beAdverse dialyzable. Adverse reactionsreceiving in patients receiving doses of as 40 mg were d d Includes oral Includes pain, glossodynia, oral pain, glossodynia, and oropharyngeal and oropharyngeal pain pain similar to thesimilar adverse reported in the clinicalinstudies at thestudies recommended dose. to events the adverse events reported the clinical at the recommended dose. e e Includes asthenia, Includesfatigue, asthenia, andfatigue, malaiseand malaise 17 PATIENT INFORMATION 17COUNSELING PATIENT COUNSELING INFORMATION f f Includes musculoskeletal Includes musculoskeletal pain, back pain, pain,pain backinpain, extremity, pain inarthralgia, extremity, and arthralgia, myalgiaand myalgia Advise the patient read the FDA-approved patient labeling (Patient Information). Advisetothe patient to read the FDA-approved patient labeling (Patient Information). g g Includes rash Includes macular, rash rash macular, maculo-papular, rash maculo-papular, rash generalized, rash generalized, and rash and rash h h Hypertension:Hypertension: Includes gingivitis, Includesoral gingivitis, infection, oralparotitis, infection,pericoronitis, parotitis, pericoronitis, periodontitis, periodontitis, sialoadenitis, sialoadenitis, tooth abscess, tooth abscess, Advise patients to undergo bloodregular pressure monitoring to contact their health care if blood Advise patientsregular to undergo blood pressureand monitoring and to contact theirprovider health care provider if blood and tooth infection and tooth infection pressure is elevated. A clinically important A clinically adverse important reaction adverse occurring reaction more occurring frequently moreinfrequently LENVIMA-treated in LENVIMA-treated patients thanpatients patientsthan patients pressure is elevated. Cardiac Dysfunction: receiving placebo, receiving but placebo, with an incidence but with an of incidence less than 5% of less wasthan pulmonary 5% wasembolism pulmonary (3%, embolism including (3%, fatal including reports fatal vs reportsCardiac vs Dysfunction: Advise patients thatpatients LENVIMA canLENVIMA cause cardiac dysfunction to immediately contact theircontact healthcare Advise that can cause cardiacand dysfunction and to immediately theirprovider healthcare provider 2%, respectively). 2%, respectively). if they experience clinical symptoms cardiac dysfunction as shortness of shortness breath or swelling if theyany experience any clinicalofsymptoms of cardiacsuch dysfunction such as of breathoforankles. swelling of ankles. Table 3 Table Laboratory 3 Laboratory Abnormalities Abnormalities with a Difference with a Difference of at Least of ≥2% at in Least Grade ≥2%3 -in4Grade Events3 - 4 Events Arterial Thrombotic Events Arterial Thrombotic Events and at a Higher and atIncidence a Higher in Incidence LENVIMA-Treated in LENVIMA-Treated Patientsa Patientsa Advise patients to seek immediate attention for attention new onsetforchest acutepain neurologic Advise patients to seekmedical immediate medical newpain onsetorchest or acutesymptoms neurologic symptoms consistent withinfarction myocardial infarction or stroke. myocardial or stroke. Laboratory Laboratory AbnormalityAbnormality LENVIMA 24LENVIMA mg 24 mg Placebo Placebo consistent with Hepatotoxicity: Hepatotoxicity: b b b b N=258 N=258 N=131 N=131 Advise they will needlab to tests undergo lab testsfortoliver monitor for liver report any new Advise patients thatpatients they willthat need to undergo to monitor function and function to reportand anytonew Grades 3-4 Grades 3-4 Grades 3-4 Grades 3-4 symptoms indicating symptoms indicating hepatic toxicity or failure. hepatic toxicity or failure. (%) (%) (%) (%) Proteinuria and Renal Failure/Impairment: Proteinuria and Renal Failure/Impairment: Chemistry Chemistry Advise they will needregular to undergo regular lab testsfortokidney monitor for kidney Advise patients thatpatients they willthat need to undergo lab tests to monitor function and function protein inand protein in the urine. the urine. Creatinine increased Creatinine increased 3 3 0 0 Gastrointestinal or fistula formation: Gastrointestinal perforation orperforation fistula formation: Alanine aminotransferase Alanine aminotransferase (ALT) increased (ALT) increased 4 4 0 0 Advise that the risk of gastrointestinal and to seek immediate Advise patients thatpatients LENVIMA canLENVIMA increasecan the increase risk of gastrointestinal perforation orperforation fistula andortofistula seek immediate Aspartate aminotransferase Aspartate aminotransferase (AST) increased (AST) increased 5 5 0 0 medical for severepain. abdominal pain. medical attention for attention severe abdominal Hypocalcemia Hypocalcemia 9 9 2 2 Events: HemorrhagicHemorrhagic Events: HypokalemiaHypokalemia 6 6 1 1 Advise that the risk and for bleeding and to contact theirprovider health care Advise patients thatpatients LENVIMA canLENVIMA increasecan the increase risk for bleeding to contact their health care for provider for bleeding orofsymptoms of severe bleeding. bleeding or symptoms severe bleeding. Lipase increased Lipase increased 4 4 1 1 Embryofetal Toxicity: Embryofetal Toxicity: HematologyHematology Advise females of reproductive potential of the fetus and to healthcare inform theirprovider healthcare Advise females of reproductive potential of the potential riskpotential to a fetusrisk andtotoa inform their of provider of Platelet countPlatelet decreased count decreased 2 2 0 0 a known orpregnancy. suspectedAdvise pregnancy. Advise females of reproductive potential to use effective contraception during a known or suspected females of reproductive potential to use effective contraception during a a treatment with LENVIMA and2for at least 2 weeks followingofcompletion treatment with LENVIMA and for at least weeks following completion therapy. of therapy. With at least With 1 grade at least increase 1 grade from increase baseline from baseline b b Lactation: Lactation: Subject with Subject at leastwith 1 post at least baseline 1 post laboratory baseline value laboratory value Advise nursing women tobreastfeeding discontinue breastfeeding during treatment with LENVIMA. Advise nursing women to discontinue during treatment with LENVIMA. In addition the In following addition the laboratory followingabnormalities laboratory abnormalities (all Grades) occurred (all Grades) in greater occurred than in greater 5% of LENVIMA-treated than 5% of LENVIMA-treated patients and patients at a rateand thatatwas a rate two-fold that was or higher two-fold thanorinhigher patients thanwho in patients receivedwho placebo: received hypoalbuminemia, placebo: hypoalbuminemia, increased alkaline increased phosphatase, alkaline phosphatase, hypomagnesemia, hypomagnesemia, hypoglycemia, hypoglycemia, hyperbilirubinemia, hyperbilirubinemia, hypercalcemia, hypercalcemia, hypercholesterolemia, hypercholesterolemia, increased serum increased amylase, serum andamylase, hyperkalemia. and hyperkalemia. 7 DRUG INTERACTIONS 7 DRUG INTERACTIONS 7.1 Effect of7.1Other Effect Drugs of Other on Lenvatinib Drugs on Lenvatinib No dose adjustment No doseofadjustment LENVIMA of is LENVIMA recommended is recommended when co-administered when co-administered with CYP3A, with P-glycoprotein CYP3A, P-glycoprotein (P-gp), and (P-gp), and breast cancerbreast resistance cancerprotein resistance (BCRP) protein inhibitors (BCRP) andinhibitors CYP3A and andP-gp CYP3A inducers. and P-gp inducers. 8 USE IN8SPECIFIC USE INPOPULATIONS SPECIFIC POPULATIONS 8.1 Pregnancy 8.1 Pregnancy Risk Summary Risk Summary Based on its Based mechanism on itsof mechanism action andofdata action fromand animal data reproduction from animal reproduction studies, LENVIMA studies, canLENVIMA cause fetal canharm cause fetal harm when administered when administered to a pregnanttowoman. a pregnant In animal woman. reproduction In animal reproduction studies, oral studies, administration oral administration of lenvatinib of lenvatinib is aoftrademark Eisai R&D Management Ltd. andtois Eisai licensed LENVIMA™ LENVIMA™ is a trademark Eisai R&DofManagement Co., Ltd. andCo., is licensed Inc. to Eisai Inc. during organogenesis during organogenesis at doses below at doses the recommended below the recommended human dose human resulteddose in embryotoxicity, resulted in embryotoxicity, fetotoxicity, and fetotoxicity, and 2015 All rights reserved. Printed in USA/February 2015 LENV0176 © 2015 Eisai©Inc. AllEisai rightsInc. reserved. Printed in USA/February 2015 LENV0176 teratogenicityteratogenicity in rats and rabbits. in rats There and rabbits. are noThere available are no human available data informing human data theinforming drug-associated the drug-associated risk. Advise risk. Advise pregnant women pregnant of thewomen potential of the riskpotential to a fetus. risk to a fetus.

EDITORIAL BOARD EDITOR-IN-CHIEF

David B. Nash, MD, MBA Founding Dean, The Dr Raymond C. and Doris N. Grandon Professor, Jefferson School of Population Health Thomas Jefferson University, Philadelphia, PA DEPUTY EDITORS

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

Gregory Shaeffer, MBA, RPh, FASHP Vice President, Consulting Pharmacy Healthcare Solutions AmerisourceBurgen, Harrisburg, PA 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 GOVERNMENT

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

Kelly Huang, PhD Operating Partner, Spindletop Capital Austin, TX 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 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, BCACP Staff Vice President HealthCore, Inc., Wilmington, DE David W. Wright, MPH President, Institute for Interactive Patient Care Bethesda, MD 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 Byron C. Scott, MD, MBA Medical Director National Clinical Medical Leader Truven Health Analytics, Chicago, IL Albert Tzeel, MD, MHSA, FACPE Regional Medical Director Medicare Operations, North Florida Humana, Jacksonville MANAGED MARKETS

Jeffrey A. Bourret, PharmD, MS, BCPS, 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 PATIENT ADVOCACY

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

Jeff Jianfei Guo, BPharm, MS, PhD Professor of Pharmacoeconomics & Pharmacoepidemiology, College of Pharmacy Univ. of Cincinnati Medical Center, OH PHARMACY BENEFIT DESIGN

Joel V. Brill, MD, AGAF, CHCQM Chief Medical Officer, Predictive Health, Phoenix, AZ Teresa DeLuca, MD, MBA Assistant Clinical Professor, Psychiatry, Mount Sinai School of Medicine, New York, NY 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, FAMCP 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 Presbyterian College, Clinton, SC 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

PAYER-PROVIDER FINANCES

Bruce Pyenson, FSA, MAAA Principal & Consulting Actuary Milliman, Inc, New York, NY

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

PERSONALIZED MEDICINE

SPECIALTY PHARMACY

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

Josh Feldstein President & CEO, CAVA, The Center for Applied Value Analysis, Inc, Norwalk, CT

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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 2015

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Introducing…

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AccessSIVEXTRO assists healthcare professionals in the determination of whether treatment could be covered by the applicable third-party payer based on coverage guidelines provided by the payer, and patient information provided by the healthcare provider under appropriate authorization following the provider’s exclusive determination of medical necessity. Many factors affect third-party reimbursement. Cubist and AccessSIVEXTRO make no representations or guarantees that insurance reimbursement or any other payment will be available. This service is for informational purposes only. Cubist and AccessSIVEXTRO make no representations or warranties, expressed or implied, as to the accuracy of the information. Responsibility for the use of this service is agreed upon and accepted by all providers and other users of this information. Cubist does not guarantee, and assumes no responsibility for the quality, scope, or availability of the AccessSIVEXTRO support services including but not limited to reimbursement support services, patient education, and other support services. AccessSIVEXTRO support services are included within the cost of the product and have no independent value to providers apart from the product. Cubist reserves the right to rescind, revoke, or amend this offer at any time without notice. Void where prohibited by law.

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TABLE OF CONTENTS 12

Foreword The Sixth Annual Payers’ Guide to FDA Approvals

I ntroduction New FDA Drug Approvals Hit an 18-Year High in 2014 Gary M. Owens, MD

Novel Pharmaceuticals 2014 FDA Approvals of Brand-Name Prescription Drugs in 2014

40 Afrezza (Insulin Human) Inhalation Powder Approved for the Treatment of Patients with Type 1 or Type 2 Diabetes 44 49

A kynzeo (Netupitant and Palonosetron), a Dual-Acting Oral Agent, Approved by the FDA for the Prevention of Chemotherapy-Induced Nausea and Vomiting yramza (Ramucirumab) Approved for the Treatment of Advanced Gastric Cancer and C Metastatic Non–Small-Cell Lung Cancer

54 Once-a-Day Harvoni (Ledipasvir plus Sofosbuvir), a New Oral Combination for the Treatment of Patients with Genotype 1 Chronic Hepatitis C Infection 66 Imbruvica (Ibrutinib), First-in-Class Bruton’s Tyrosine Kinase Inhibitor, Receives Expanded Indications for Patients with Relapsed Chronic Lymphocytic Leukemia 70

I nvokamet (Canagliflozin plus Metformin HCl): First Fixed-Dose Combination with an SGLT2 Inhibitor Approved for the Treatment of Patients with Type 2 Diabetes

J akafi (Ruxolitinib): First FDA-Approved Medication for the Treatment of Patients with Polycythemia Vera

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. Contact Information: For subscription information and editorial queries, please contact: editorial@engagehc.com; phone: 732-992-1892; fax: 732-992-1881.

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TABLE OF CONTENTS

(Continued) 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 © 2015 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.

92 Jardiance (Empagliflozin), an SGLT2 Inhibitor, Receives FDA Approval for the Treatment of Patients with Type 2 Diabetes 96

Keytruda (Pembrolizumab): First PD-1 Inhibitor Approved for Previously Treated Unresectable or Metastatic Melanoma

101 Ofev (Nintedanib): First Tyrosine Kinase Inhibitor Approved for the Treatment of Patients with Idiopathic Pulmonary Fibrosis 105 Otezla (Apremilast), an Oral PDE-4 Inhibitor, Receives FDA Approval for the Treatment of Patients with Active Psoriatic Arthritis and Plaque Psoriasis 111 Sivextro (Tedizolid Phosphate) Approved for the Treatment of Adults with Acute Bacterial Skin and Skin-Structure Infections 122 Soolantra (Ivermectin) 1% Cream: A Novel, Antibiotic-Free Agent Approved for the Treatment of Patients with Rosacea Continued on page 10

Address all editorial correspondence to: editorial@engagehc.com Phone: 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.

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TABLE OF CONTENTS

(Continued)

126 Tanzeum (Albiglutide): A Once-Weekly GLP-1 Receptor Agonist Subcutaneous Injection Approved for the Treatment of Patients with Type 2 Diabetes 131 Trulicity (Dulaglutide): A New GLP-1 Receptor Agonist Once-Weekly Subcutaneous Injection Approved for the Treatment of Patients with Type 2 Diabetes 135 Velcade (Bortezomib) Receives 2 New FDA Indications: For Retreatment of Patients with Multiple Myeloma and for First-Line Treatment of Patients with Mantle-Cell Lymphoma 142 Viekira Pak (Ombitasvir, Paritaprevir, and Ritonavir Tablets; Dasabuvir Tablets): All-Oral Fixed Combination Approved for Genotype 1 Chronic Hepatitis C Infection 148 Zontivity (Vorapaxar), First-in-Class PAR-1 Antagonist, Receives FDA Approval for Risk Reduction of Heart Attack, Stroke, and Cardiovascular Death 157 Zydelig (Idelalisib): First-in-Class PI3 Kinase Inhibitor Approved for the Treatment of 3 Hematologic Malignancies 163 Zykadia (Ceritinib) Approved for Patients with Crizotinib-Resistant ALK-Positive Non–Small-Cell Lung Cancer 167 A 2015 Pipeline Preview Once-Fatal Conditions Have Become Chronic: Early Trends in the FDA’s 2015 Approvals Gary Branning, MBA 171 Glyxambi (Empagliflozin/Linagliptin): A Dual-Acting Oral Medication Approved for the Treatment of Patients with Type 2 Diabetes 176 Lenvima (Lenvatinib), a Multireceptor Tyrosine Kinase Inhibitor, Approved by the FDA for the Treatment of Patients with Differentiated Thyroid Cancer 180 Opdivo (Nivolumab): Second PD-1 Inhibitor Receives FDA Approval for Unresectable or Metastatic Melanoma

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March 2015

Vol 8

Special Feature

NOW AVAILABLE

www.glyxambi.com

FOREWORD

The Sixth 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 a preview of some of the key trends in the 2015 drug pipeline. This 2015 edition represents the sixth 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, new combinations of previously approved drugs—an important feature that is increasing in importance in drug research and development—as well as important new or expanded indications, some for drugs approved only a couple of months earlier for the first time. The goal of this special feature is to provide a practical, detailed, and evidence-based resource for medical and pharmacy directors to guide their benefit design decision-making process. In 2014, the FDA reached an 18-year high in drug approvals totaling 41 NMEs or new biologic pharmaceuticals, the highest number since 1996. This new edition of the Guide includes in-depth updates on 23 new drugs, including 20 drugs approved in 2014 and 3 approvals in early 2015. In his introduction to this edition, “New FDA Drug Approvals Hit an 18-Year High in 2014” (page 15), Dr Owens reflects on some of the key regulatory trends that were seen this

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past year in the FDA approval process, such as expanding the accelerated approval of new and promising drugs and the increasing number of orphan drugs coming to market; some of these trends are being carried into 2015. This is followed by the “FDA Approvals of Brand-Name Prescription Drugs in 2014” (page 22), listing all NMEs and biologic license applications approved by the FDA in 2014, as well as the long list of all new indications, combinations, formulations, dosage forms, and new vaccines added to the pharmaceutical options in 2014. In lieu of the thorough review of key drugs in the 2015 pipeline, this edition of the Guide provides for the first time a review of early trends in the FDA approvals in 2015. Mr Branning’s ar ticle, “Once-Fatal Conditions Have Become Chronic: Early Trends in the FDA’s 2015 Approvals” (page 167), opens a window into the new drugs coming into market in 2015. In addition, 3 in-depth updates are provided for new drugs or indications approved by the FDA in the first quarter of 2015. A more in-depth article on the oncology/hematology pipeline will be provided in a future issue of the journal. American Health & Drug Benefits will continue to provide this Guide in the coming years to offer healthcare stakeholders a tool for applying up-todate information on new pharmaceuticals into their benefit design decisions and patient care. 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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March 2015

Vol 8

Special Feature

What is the value of one year on velCaDe (bortezomib)? ®

for patients with previously untreated multiple myeloma, 1 year of treatment with velCaDe in combination with MP* delivered a >1-year sustained median overall survival (os) advantage.1† At 60.1-month median follow-up: VELCADE (bortezomib)+MP provided a median OS of 56.4 months vs 43.1 months with MP alone (HR=0.695 [95% CI, 0.57-0.85]; p<0.05) At 3-year median follow-up: VELCADE+MP provided an OS advantage over MP that was not regained with subsequent therapies Of the 69% of MP patients who received subsequent therapies, 50% received VELCADE or a VELCADE-containing regimen1 Results were achieved using VELCADE twice weekly followed by a weekly dosing for a median of 50 weeks (54 weeks planned)1

the additional value of choice of administration. Subcutaneous VELCADE demonstrated efficacy consistent with IV for the primary endpoints2‡: At 12 weeks, subcutaneous VELCADE: 43% achieved overall response rate (ORR) and 7% complete response (CR) vs IV: 42% ORR and 8% CR § II

The median age of patients in the VISTA† trial was 71 years (range: 48-91).

At 24 weeks, subcutaneous VELCADE ± dexamethasone: 53% achieved ORR and 11% CR vs IV: 51% ORR and 12% CR§ II More than 80% of previously untreated patients starting on VELCADE receive subcutaneous administration 3¶

Indication and Important Safety Information for VELCADE® (bortezomib) INDICATION VELCADE (bortezomib) is indicated for the treatment of patients with multiple myeloma. CONTRAINDICATIONS VELCADE is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. VELCADE is contraindicated for intrathecal administration. Fatal events have occurred with intrathecal administration of VELCADE. WARNINGS, PRECAUTIONS, AND DRUG INTERACTIONS ▼ Peripheral neuropathy: Manage with dose modification or discontinuation. Patients with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment. ▼ hypotension: Use caution when treating patients taking antihypertensives, with a history of syncope, or with dehydration. ▼ Cardiac toxicity: Worsening of and development of cardiac failure have occurred. Closely monitor patients with existing heart disease or risk factors for heart disease. ▼ Pulmonary toxicity: Acute respiratory syndromes have occurred. Monitor closely for new or worsening symptoms.

▼ Posterior reversible encephalopathy syndrome: Consider MRI imaging for onset of visual or neurological symptoms; discontinue VELCADE if suspected. ▼ Gastrointestinal toxicity: Nausea, diarrhea, constipation, and vomiting may require use of antiemetic and antidiarrheal medications or fluid replacement. ▼ thrombocytopenia or neutropenia: Monitor complete blood counts regularly throughout treatment. ▼ tumor lysis syndrome: Closely monitor patients with high tumor burden. ▼ hepatic toxicity: Monitor hepatic enzymes during treatment. ▼ embryo-fetal risk: Women should avoid becoming pregnant while being treated with VELCADE. Advise pregnant women of potential embryo-fetal harm. ▼ Closely monitor patients receiving VELCADE in combination with strong CyP3a4 inhibitors. Avoid concomitant use of strong CyP3a4 inducers. ADVERSE REACTIONS Most commonly reported adverse reactions (incidence ≥20%) in clinical studies include nausea, diarrhea, thrombocytopenia, neutropenia, peripheral neuropathy, fatigue, neuralgia, anemia, leukopenia, constipation, vomiting, lymphopenia, rash, pyrexia, and anorexia. Please see Brief Summary for VELCADE adjacent to this advertisement. For Reimbursement Assistance, call 1-866-VELCADE (835-2233), Option 2, or visit VELCADE-HCP.com.

*Melphalan+prednisone. † VISTA TRIAL: a randomized, open-label, international phase 3 trial (N=682) evaluating the efficacy and safety of VELCADE administered intravenously in combination with MP vs MP in previously untreated multiple myeloma. The primary endpoint was TTP. Secondary endpoints were CR, ORR, PFS, and overall survival. At a prespecified interim analysis (median follow-up 16.3 months), VELCADE+MP resulted in significantly superior results for TTP (median 20.7 months with VELCADE+MP vs 15.0 months with MP [p=0.000002]), PFS, overall survival, and ORR. Further enrollment was halted and patients receiving MP were offered VELCADE in addition. Updated analysis was performed. ‡ SuBCuTAnEouS VS IV was a randomized (2:1), open-label, non-inferiority phase 3 trial (N=222) in patients with relapsed multiple myeloma designed to establish whether subcutaneous VELCADE (bortezomib) was non-inferior to intravenous administration.2 Non-inferiority was defined as retaining 60% of the intravenous treatment effect, measured by ORR, at the end of 4 cycles.2 The primary endpoint was ORR at 4 cycles. The secondary endpoints were response rate at 8 cycles, median TTP and PFS (months), 1-year OS, and safety. § Responses were based on criteria established by the European Group for Blood and Marrow Transplantation.2 II 82 patients (55%) in the subcutaneous VELCADE group and 39 patients (53%) in the IV group received dexamethasone. ¶ Out of 275 estimated unique patients receiving VELCADE as of May 2013.3 References: 1. Mateos MV, Richardson PG, Schlag R, et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial. J Clin Oncol. 2010;28(13):2259-2266. 2. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 2011;12(5):431-440. 3. Data on file 59, Millennium Pharmaceuticals, Inc.

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VELC3X0043_A_Velcade_BS_7x10_r3.indd 1

Embryo-fetal: Pregnancy Category D. Women of reproductive potential should avoid becoming pregnant while being treated with VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses. ADVERSE EVENT DATA: Safety data from phase 2 and 3 studies of single-agent VELCADE 1.3 mg/m2/dose administered intravenously twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously-treated multiple myeloma (N=1008) and previously-treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma. In the integrated analysis, the most commonly reported (≥10%) adverse reactions were nausea (49%), diarrhea NOS (46%), fatigue (41%), peripheral neuropathies NEC (38%), thrombocytopenia (32%), vomiting NOS (28%), constipation (25%), pyrexia (21%), anorexia (20%), anemia NOS (18%), headache NOS (15%), neutropenia (15%), rash NOS (13%), paresthesia (13%), dizziness (excl vertigo 11%), and weakness (11%). Eleven percent (11%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (4%) and neutropenia (2%). A total of 26% of patients experienced a serious adverse reaction during the studies. The most commonly reported serious adverse reactions included diarrhea, vomiting, and pyrexia (3% each), nausea, dehydration, and thrombocytopenia (2% each), and pneumonia, dyspnea, peripheral neuropathies NEC, and herpes zoster (1% each). In the phase 3 VELCADE+melphalan and prednisone study in previously untreated multiple myeloma, the safety profile of VELCADE administered intravenously in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone. The most commonly reported adverse reactions in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (48% vs 42%), neutropenia (47% vs 42%), peripheral neuropathy (46% vs 1%), nausea (39% vs 21%), diarrhea (35% vs 6%), neuralgia (34% vs <1%), anemia (32% vs 46%), leukopenia (32% vs 28%), vomiting (26% vs 12%), fatigue (25% vs 14%), lymphopenia (23% vs 15%), constipation (23% vs 4%), anorexia (19% vs 6%), asthenia (16% vs 7%), pyrexia (16% vs 6%), paresthesia (12% vs 1%), herpes zoster (11% vs 3%), rash (11% vs 2%), abdominal pain upper (10% vs 6%), and insomnia (10% vs 6%). In the phase 3 VELCADE subcutaneous vs intravenous study in relapsed multiple myeloma, safety data were similar between the two treatment groups. The most commonly reported adverse reactions in this study were peripheral neuropathy NEC (37% vs 50%), thrombocytopenia (30% vs 34%), neutropenia (23% vs 27%), neuralgia (23% vs 23%), anemia (19% vs 23%), diarrhea (19% vs 28%), leukopenia (18% vs 20%), nausea (16% vs 14%), pyrexia (12% vs 8%), vomiting (9% vs 11%), asthenia (7% vs 16%), and fatigue (7% vs 15%). The incidence of serious adverse reactions was similar for the subcutaneous treatment group (20%) and the intravenous treatment group (19%). The most commonly reported SARs were pneumonia and pyrexia (2% each) in the subcutaneous treatment group and pneumonia, diarrhea, and peripheral sensory neuropathy (3% each) in the intravenous treatment group. DRUG INTERACTIONS: Bortezomib is a substrate of cytochrome P450 enzyme 3A4, 2C19 and 1A2. Co-administration of ketoconazole, a strong CYP3A4 inhibitor, increased the exposure of bortezomib by 35% in 12 patients. Monitor patients for signs of bortezomib toxicity and consider a bortezomib dose reduction if bortezomib must be given in combination with strong CYP3A4 inhibitors (eg, ketoconazole, ritonavir). Co-administration of omeprazole, a strong inhibitor of CYP2C19, had no effect on the exposure of bortezomib in 17 patients. Co-administration of rifampin, a strong CYP3A4 inducer, is expected to decrease the exposure of bortezomib by at least 45%. Because the drug interaction study (n=6) was not designed to exert the maximum effect of rifampin on bortezomib PK, decreases greater than 45% may occur. Efficacy may be reduced when VELCADE is used in combination with strong CYP3A4 inducers; therefore, concomitant use of strong CYP3A4 inducers is not recommended in patients receiving VELCADE. St. John’s wort (Hypericum perforatum) may decrease bortezomib exposure unpredictably and should be avoided. Co-administration of dexamethasone, a weak CYP3A4 inducer, had no effect on the exposure of bortezomib in 7 patients. Co-administration of melphalan-prednisone increased the exposure of bortezomib by 17% in 21 patients. However, this increase is unlikely to be clinically relevant. USE IN SPECIFIC POPULATIONS: Nursing Mothers: It is not known whether bortezomib 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 VELCADE, 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 VELCADE in children has not been established. Geriatric Use: No overall differences in safety or effectiveness were observed between patients ≥age 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out. Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, VELCADE should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer’s prescribing information. Patients with Hepatic Impairment: The exposure of bortezomib is increased in patients with moderate and severe hepatic impairment. Starting dose should be reduced in those patients. Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication. Please see full Prescribing Information for VELCADE at VELCADEHCP.com.

VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners. Millennium Pharmaceuticals, Inc., Cambridge, MA 02139 Copyright © 2013, Millennium Pharmaceuticals, Inc. V-12-0306a All rights reserved. Printed in USA V-14-0258

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INDICATIONS: VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma. VELCADE for Injection is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy. CONTRAINDICATIONS: VELCADE is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. VELCADE is contraindicated for intrathecal administration. Fatal events have occurred with intrathecal administration of VELCADE. WARNINGS AND PRECAUTIONS: Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory; however, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain, or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. In the Phase 3 relapsed multiple myeloma trial comparing VELCADE subcutaneous vs intravenous, the incidence of Grade ≥2 peripheral neuropathy events was 24% for subcutaneous and 39% for intravenous. Grade ≥3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 15% in the intravenous treatment group. Starting VELCADE subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy. Patients experiencing new or worsening peripheral neuropathy during VELCADE therapy may require a decrease in the dose and/or a less dose-intense schedule. In the VELCADE vs dexamethasone phase 3 relapsed multiple myeloma study, improvement in or resolution of peripheral neuropathy was reported in 48% of patients with ≥Grade 2 peripheral neuropathy following dose adjustment or interruption. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma. Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 8%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics. Cardiac Toxicity: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have occurred during VELCADE therapy, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing, heart disease should be closely monitored. In the relapsed multiple myeloma study of VELCADE vs dexamethasone, the incidence of any treatment-related cardiac disorder was 8% and 5% in the VELCADE and dexamethasone groups, respectively. The incidence of adverse reactions suggestive of heart failure (acute pulmonary edema, pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock) was ≤1% for each individual reaction in the VELCADE group. In the dexamethasone group, the incidence was ≤1% for cardiac failure and congestive cardiac failure; there were no reported reactions of acute pulmonary edema, pulmonary edema, or cardiogenic shock. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established. Pulmonary Toxicity: Acute Respiratory Distress Syndrome (ARDS) and acute diffuse infiltrative pulmonary disease of unknown etiology, such as pneumonitis, interstitial pneumonia, and lung infiltration have occurred in patients receiving VELCADE. Some of these events have been fatal. In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, consider interrupting VELCADE until a prompt, comprehensive, diagnostic evaluation is conducted. Posterior Reversible Encephalopathy Syndrome (PRES): Posterior Reversible Encephalopathy Syndrome (PRES; formerly termed Reversible Posterior Leukoencephalopathy Syndrome (RPLS)) has occurred in patients receiving VELCADE. PRES is a rare, reversible, neurological disorder, which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing PRES, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing PRES is not known. Gastrointestinal Toxicity: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting, sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration. Interrupt VELCADE for severe symptoms. Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern, with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice-weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study of VELCADE vs dexamethasone, the incidence of bleeding (≥Grade 3) was 2% on the VELCADE arm and <1% on the dexamethasone arm. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. Gastrointestinal and intracerebral hemorrhage has been reported in association with VELCADE. Transfusions may be considered. Tumor Lysis Syndrome: Tumor lysis syndrome has been reported with VELCADE therapy. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. Monitor patients closely and take appropriate precautions. Hepatic Toxicity: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic reactions include hepatitis, increases in liver enzymes, and hyperbilirubinemia. Interrupt VELCADE therapy to assess reversibility. There is limited re-challenge information in these patients.

INTRODUCTION

New FDA Drug Approvals Hit an 18-Year High in 2014 By Gary M. Owens, MD President, Gary Owens Associates, Ocean View, DE

here were 41 new drug approvals by the US Food and Drug Administration (FDA) in 2014, the highest number since 1996, when a record 53 new drugs were approved.1,2 This number is significantly higher than the 27 drugs approved in 2013. As has been the case for the past 3 years, specialty and orphan drugs dominated the approval list. By comparison, 1996, the record year for new drug approvals, had only 2 biologic drugs approved: interferon beta-1a (Avonex) for the treatment of multiple sclerosis and insulin lispro (Huma log) for the treatment of diabetes. Notably, the largest selling drug of all time, atorvastatin (Lipitor), was part of the 1996 approvals. In just less than 2 decades, the drug approval landscape has undergone a seismic shift, with 28 of the 41 new drugs approved in 2014 considered biologic or specialty agents. Even more astounding is that 41% of the newly approved agents in 2014 are for the treatment of rare diseases.2

Rare Diseases Rare diseases continue to attract a large proportion of the drug development focus. The first ever biologic treatments for idiopathic pulmonary fibrosis—pirfenidone (Esbriet) and nintedanib (Ofev)—were approved in October 2014. New treatments for orphan diseases, such as Morquio syndrome and multicentric Castleman’s disease, also emerged in 2014. As noted, 41% (17) of the new drugs approved in 2014 were classified as orphan drugs (Table), because they target rare diseases.2 Also in 2014, eliglustat (Cerdelga) was approved as the only first-line oral therapy for certain adults with Gaucher disease type 1. This trend of increasing drug approvals for orphan diseases is expected to continue into 2015, with the first drug ever to be approved by the FDA for Waldenström’s macroglobulinemia, ibrutinib (Imbruvica), already approved in early 2015. Infectious Disease Treatments in the Spotlight The FDA approvals in 2014 encompassed 10 therapeutic categories, an increase from the 8 clinical areas in 2013. Infectious diseases as a whole had the highest number (N = 11) of approvals, a definite turnaround

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from the recent past, where FDA approvals of infectious disease treatments were relatively few. While grabbing the lion’s share of headlines, agents for the treatment of hepatitis C virus (HCV) infection accounted for only 2 approvals. The remaining approved treatments were broadly distributed across bacterial, fungal, viral, and parasitic infections. Certainly, the most visible approvals in 2014 were for the new direct-acting antiviral drugs for the treatment of HCV. The new combination of ledipasvir and sofosbuvir (Harvoni) and the new triplet of ombitasvir, paritaprevir, and ritonavir tablets, copacked with dasabuvir tablets (Viekira Pak), which are the first direct-acting antiviral drug combinations for the treatment of HCV, were definitely the most publicized launches in 2014. In the first 8 weeks after the launch of ledipasvir plus sofosbuvir in October, sales were growing even faster than for sofosbuvir (Sovaldi), the previous record-setting treatment for HCV infection approved in 2013. Although the final figures are not yet in, experts estimate that sofosbuvir will have racked up more than $2 billion in sales in less than 3 months in 2014.3 Also included in the infectious diseases approvals are 3 antibiotics for the treatment of skin and soft-tissue infections—oritavancin (Orbactiv), dalbavancin (Dalvance), and tedizolid phosphate (Sivextro).4 In addition, a fourth antibacterial, the combination of ceftolozane and tazobactam (Zerbaxa), was approved in 2014 for the treatment of adults with complicated intra-abdominal or urinary tract infections. All 4 antibacterial drugs were granted the Qualified Infectious Disease Product (QIDP) designation. These are the first 4 drugs to receive the QIDP designation by the FDA, a designation granted by the FDA to drugs deemed to have particular promise.4 Commenting on these 4 approvals, Edward Cox, MD, MPH, Director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research, said, “The approval of several new antibacterial drugs this year demonstrates that we are making progress in increasing the availability of treatment options for patients and physicians. We must continue to help foster the development of new antibacterial drugs and encourage prudent use of existing treatments to conserve their utility.” 4

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INTRODUCTION

Cancer Drugs Remain Among the Top Approvals in 2014 In 2014, treatments for cancer continued to be among the top approvals, with 9 new medications, as in 2013. Notable among the new approvals were several agents for metastatic melanoma, including 2 programmed cell death (PD)-1 immunotherapies5: 1. The first combination therapy of trametinib (Mekinist) tablets and dabrafenib (Tafinlar) capsules approved for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or a BRAF V600K mutation 2. The first 2 PD-1–blocking agents, nivolumab (Op divo) and pembrolizumab (Keytruda), approved for the treatment of patients with unresectable or metastatic melanoma and disease progression after receiving ipilimumab (Yervoy) if they are BRAF V600 mutation–positive. Hematologic malignancies also saw a number of ad-

vances in 2014, with the approval of agents such as5: 1. Ofatumumab (Arzerra Injection) in combination with chlorambucil, for the treatment of previously untreated patients with chronic lymphocytic leukemia for whom fludarabine-based therapy is considered inappropriate 2. Idelalisib (Zydelig) tablets for the treatment of patients with relapsed chronic lymphocytic leukemia, in combination with rituximab (Rituxan), for whom rituximab alone would be considered appropriate therapy as a result of other comorbidities 3. Blinatumomab (Blincyto) for the treatment of Philadelphia chromosome–negative relapsed or refractory B-cell precursor acute lymphoblastic leukemia. For the treatment of solid organ tumors, 2014 witnessed the launch of several novel agents. Ramucirumab (Cyramza), a recombinant monoclonal antibody of the immunoglobulin G1 class that binds to vascular endothelial growth factor receptor-2 and blocks the activa-

Table Orphan Drugs Approved in 2014 Brand (generic) name

Manufacturer

Indication(s)

Beleodaq (belinostat)

Spectrum Pharmaceuticals

Relapsed or refractory peripheral T-cell lymphoma

Blincyto (blinatumomab)

Amgen

Philadelphia chromosome–negative relapsed or refractory B-cell precursor ALL

Cerdelga (eliglustat)

Genzyme

Gaucher disease

Cyramza (ramucirumab)

Eli Lilly

As a single agent/in combination with paclitaxel: advanced gastric or gastroesophageal junction adenocarcinoma In combination with docetaxel: metastatic NSCLC

Esbriet (pirfenidone)

InterMune

Idiopathic pulmonary fibrosis

Hetlioz (tasimelteon)

Vanda Pharmaceuticals

Non–24-hour sleep-wake disorder

Impavido (miltefosine)

Paladin Therapeutics

Forms of leishmaniasis

Keytruda (pembrolizumab)

Merck

Unresectable or metastatic melanoma

Lynparza (olaparib)

AstraZeneca

Deleterious or suspected deleterious germline BRCA-mutated advanced ovarian cancer

Myalept (metreleptin)

Amylin Pharmaceuticals

Complications of lipodystrophy associated with leptin deficiency

Northera (droxidopa)

Chelsea Therapeutics

Orthostatic dizziness, lightheadedness, or the “feeling that you are about to black out” with symptomatic neurogenic orthostatic hypotension

Ofev (nintedanib)

Boehringer Ingelheim

Idiopathic pulmonary fibrosis

Opdivo (nivolumab)

Bristol-Myers Squibb

Unresectable or metastatic melanoma

Sylvant (siltuximab)

Janssen Biotech

Multicentric Castleman’s disease

Vimizim (elosulfase alfa)

BioMarin Pharmaceutical

Mucopolysaccharidosis type IVA

Zydelig (idelalisib)

Gilead Sciences

Relapsed CLL in combination with rituximab, relapsed follicular B-cell non-Hodgkin lymphoma, and relapsed small lymphocytic lymphoma

Zykadia (ceritinib)

Novartis

ALK-positive metastatic NSCLC

ALK indicates anaplastic lymphoma kinase; ALL, acute lymphoblastic leukemia; CLL, chronic lymphocytic leukemia; NSCLC, non–small-cell lung cancer.

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INTRODUCTION

tion of the receptor, was approved for the treatment of patients with advanced or metastatic gastric or gastroesophageal junction adenocarcinoma. Ceritinib (Zykadia) is a therapeutic alternative for patients with metastatic, ALK (anaplastic lymphoma kinase)-positive non–small-cell lung cancer that has progressed or has become intolerant to crizotinib (Xalkori).5

2014 FDA Approval Statistics According to the FDA’s report on its annual drug approvals, 2014 was a year of many firsts.2 Notable was the number of first-in-class agents approved. Of the 41 drugs approved, 17 (41%) were considered by the FDA to be first in class. These agents provide novel mechanisms of action for treating medical conditions not currently provided by existing therapies.5 As noted, this matches the 41% of orphan drugs approved for rare diseases. Similarly, 17 (41%) of the novel drugs were designated by the Center for Drug Evaluation and Research as fast track approvals, which are drugs with the potential to address unmet medical needs.2 Among the 2014 new drugs, 9 (22%) were designated as breakthrough therapies, based on preliminary clinical evidence demonstrating that the drug may result in substantial improvement on at least 1 clinically significant end point over other available therapies. Breakthrough therapy status is designed to help shorten the development time of potentially clinically promising new therapies. Drugs that were approved as breakthrough therapies in 2014 include the combination of ledipasvir and sofosbuvir; the triplet of ombitasvir, paritaprevir, and ritonavir, plus dasabuvir; blinatumomab; and idelalisib.2 Furthermore, 61% of all 2014 approvals were done under the FDA’s priority review program, and 8 drugs were approved through the accelerated approval process. Finally, 78% of the new drugs in 2014 were approved on the first cycle of review, and 63% were approved in the United States before being approved in other countries.2 Conclusion The year 2014 was very active in terms of FDA drug approvals, only surpassed by the 1996 record high of 53. The trends seen in previous years continue, with the ma-

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jority of new approvals being in the specialty drug category, and the cancer and orphan or rare diseases are among the top priorities in drug research and development.

The year 2014 was very active in terms of FDA drug approvals, only surpassed by the 1996 record high of 53. The trends seen in previous years continue, with the majority of new approvals being in the specialty drug category, and the cancer and orphan or rare diseases are among the top priorities in drug research and development. Unlike 2013, the year 2014 saw the emergence of a substantial number of new agents for the treatment of infectious diseases, including the first 2 all-oral therapies for HCV infection. Overall, 2014 was an exciting year for new drug approvals, thereby providing some substantial challenges for Pharmacy & Therapeutics committees and for benefit design programs. n Author Disclosure Statement Dr Owens is a consultant to Alexion Pharmaceuticals, Bayer, Biogen Idec, Celgene, Eli Lilly, Janssen, Millennium Pharmaceuticals, Novartis, and Vertex Pharmaceuticals.

References

1. US Food and Drug Administration. New molecular entity and new therapeutic biological product approvals for 2014. Updated January 14, 2015. www.fda.gov/ Drugs/DevelopmentApprovalProcess/DrugInnovation/ucm429247.htm. Accessed February 5, 2015. 2. US Food and Drug Administration. Center for Drug Evaluation and Research. Novel new drugs 2014 summary. January 2015. www.fda.gov/downloads/Drugs/ DevelopmentApprovalProcess/DrugInnovation/UCM430299.pdf. Accessed February 4, 2015. 3. Millman J. This drug costs $1,125 per pill and is about to shatter sales records. Wonkblog. Washington Post. December 19, 2014. www.washingtonpost.com/blogs/ wonkblog/wp/2014/12/19/this-drug-costs-1125-per-pill-and-is-about-to-shatter-salesrecords/. Accessed January 22, 2015. 4. US Food and Drug Administration. FDA approves Orbactiv to treat skin infections. Press release. August 6, 2014. www.fda.gov/NewsEvents/Newsroom/Press Announcements/ucm408475.htm. Accessed February 8, 2015. 5. US Food and Drug Administration. Hematology/oncology (cancer) approvals & safety notifications. Updated February 4, 2015. www.fda.gov/Drugs/InformationOn Drugs/ApprovedDrugs/ucm279174.htm. Accessed February 8, 2015.

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NOW APPROVED For the treatment of idiopathic pulmonary fibrosis (IPF) To learn more about patient support services available through the BI OPEN DOORSTM patient support program, please call 1-866-OPENDOOR (673-6366) to speak with an OPEN DOORSTM customer service representative.

To help your members with IPF, and learn more about OFEV capsules, please visit www.OFEV.com. You may also contact your Boehringer Ingelheim Representative to schedule a presentation about OFEV.

INDICATION AND USAGE OFEV is indicated for the treatment of idiopathic pulmonary fibrosis (IPF).

IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS Elevated Liver Enzymes The safety and efficacy of OFEV has not been studied in patients with moderate (Child Pugh B) or severe (Child Pugh C) hepatic impairment. Treatment with OFEV is not recommended in patients with moderate or severe hepatic impairment. In clinical trials, administration of OFEV was associated with elevations of liver enzymes (ALT, AST, ALKP, GGT) and bilirubin. Liver enzyme increases were reversible with dose modification or interruption and not associated with clinical signs or symptoms of liver injury. Conduct liver function tests (ALT, AST, and bilirubin) prior to treatment with OFEV, monthly for 3 months, and every 3 months thereafter, and as clinically indicated. Dosage modifications, interruption, or discontinuation may be necessary for liver enzyme elevations. Gastrointestinal Disorders Diarrhea Diarrhea was the most frequent gastrointestinal event reported in 62% versus 18% of patients treated with OFEV and placebo, respectively. In most patients, the event was of mild to moderate intensity and occurred within the first 3 months of treatment. Diarrhea led to permanent dose reduction in 11% of patients treated with OFEV compared to 0 placebo-treated patients. Diarrhea led to discontinuation of OFEV in 5% of the patients compared to <1% of placebotreated patients.

Dosage modifications or treatment interruptions may be necessary in patients with adverse reactions of diarrhea. Treat diarrhea at first signs with adequate hydration and antidiarrheal medication (e.g., loperamide), and consider treatment interruption if diarrhea continues. OFEV treatment may be resumed at the full dosage (150 mg twice daily), or at the reduced dosage (100 mg twice daily), which subsequently may be increased to the full dosage. If severe diarrhea persists despite symptomatic treatment, discontinue treatment with OFEV. Nausea and Vomiting Nausea was reported in 24% versus 7% and vomiting was reported in 12% versus 3% of patients treated with OFEV and placebo, respectively. In most patients, these events were of mild to moderate intensity. Nausea led to discontinuation of OFEV in 2% of patients. Vomiting led to discontinuation of OFEV in 1% of the patients. For nausea or vomiting that persists despite appropriate supportive care including anti-emetic therapy, dose reduction or treatment interruption may be required. OFEV treatment may be resumed at the full dosage (150 mg twice daily), or at the reduced dosage (100 mg twice daily), which subsequently may be increased to the full dosage. If severe nausea or vomiting does not resolve, discontinue treatment with OFEV. Embryofetal Toxicity OFEV is Pregnancy category D. It can cause fetal harm when administered to a pregnant woman. If OFEV is used during pregnancy, or if the patient becomes pregnant while taking OFEV, the patient should be advised of the potential hazard to a fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with OFEV and to use adequate contraception during treatment and at least 3 months after the last dose of OFEV.

IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS (cont’d)

DRUG INTERACTIONS

Arterial Thromboembolic Events Arterial thromboembolic events have been reported in patients taking OFEV. In clinical trials, arterial thromboembolic events were reported in 2.5% of patients treated with OFEV and 0.8% of placebo-treated patients. Myocardial infarction was the most common adverse reaction under arterial thromboembolic events, occurring in 1.5% of OFEV-treated patients compared to 0.4% of placebo-treated patients. Use caution when treating patients at higher cardiovascular risk including known coronary artery disease. Consider treatment interruption in patients who develop signs or symptoms of acute myocardial ischemia. Risk of Bleeding Based on the mechanism of action (VEGFR inhibition), OFEV may increase the risk of bleeding. In clinical trials, bleeding events were reported in 10% of patients treated with OFEV and in 7% of patients treated with placebo. Use OFEV in patients with known risk of bleeding only if the anticipated benefit outweighs the potential risk. Gastrointestinal Perforation Based on the mechanism of action, OFEV may increase the risk of gastrointestinal perforation. In clinical trials, gastrointestinal perforation was reported in 0.3% of patients treated with OFEV, compared to 0 cases in the placebo-treated patients. Use caution when treating patients who have had recent abdominal surgery. Discontinue therapy with OFEV in patients who develop gastrointestinal perforation. Only use OFEV in patients with known risk of gastrointestinal perforation if the anticipated benefit outweighs the potential risk.

P-glycoprotein (P-gp) and CYP3A4 Inhibitors and Inducers Coadministration with oral doses of a P-gp and CYP3A4 inhibitor, ketoconazole, increased exposure to nintedanib by 60%. Concomitant use of potent P-gp and CYP3A4 inhibitors (e.g., erythromycin) with OFEV may increase exposure to nintedanib. In such cases, patients should be monitored closely for tolerability of OFEV. Management of adverse reactions may require interruption, dose reduction, or discontinuation of therapy with OFEV. Coadministration with oral doses of a P-gp and CYP3A4 inducer, rifampicin, decreased exposure to nintedanib by 50%. Concomitant use of P-gp and CYP3A4 inducers (e.g., carbamazepine, phenytoin, and St. John’s wort) with OFEV should be avoided as these drugs may decrease exposure to nintedanib. Anticoagulants Nintedanib is a VEGFR inhibitor, and may increase the risk of bleeding. Monitor patients on full anticoagulation therapy closely for bleeding and adjust anticoagulation treatment as necessary.

ADVERSE REACTIONS • Adverse reactions reported in ≥5% of patients treated with OFEV and more commonly than in patients treated with placebo included diarrhea (62% vs. 18%), nausea (24% vs. 7%), abdominal pain (15% vs 6%), liver enzyme elevation (14% vs 3%), vomiting (12% vs 3%), decreased appetite (11% vs 5%), weight decreased (10% vs 3%), headache (8% vs 5%), and hypertension (5% vs 4%). • The most frequent serious adverse reactions reported in patients treated with OFEV, more than placebo, were bronchitis (1.2% vs. 0.8%) and myocardial infarction (1.5% vs. 0.4%). The most common adverse events leading to death in patients treated with OFEV, more than placebo, were pneumonia (0.7% vs. 0.6%), lung neoplasm malignant (0.3% vs. 0%), and myocardial infarction (0.3% vs. 0.2%). In the predefined category of major adverse cardiovascular events (MACE) including MI, fatal events were reported in 0.6% of OFEV-treated patients and 1.8% of placebo-treated patients.

USE IN SPECIFIC POPULATIONS Nursing Mothers • Excretion of nintedanib and/or its metabolites into human milk is probable. Because of the potential for serious adverse reactions in nursing infants from OFEV, 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. Hepatic Impairment • Monitor for adverse reactions and consider dose modification or discontinuation of OFEV as needed for patients with mild hepatic impairment (Child Pugh A). Treatment of patients with moderate (Child Pugh B) and severe (Child Pugh C) hepatic impairment with OFEV is not recommended. Smokers • Smoking was associated with decreased exposure to OFEV, which may alter the efficacy profile of OFEV. Encourage patients to stop smoking prior to treatment with OFEV and to avoid smoking when using OFEV. OFHCPISIOCT15

Please see accompanying Brief Summary for OFEV on next page.

OFEV is a registered trademark of and used under license from Boehringer Ingelheim International GmbH. Copyright © 2014 Boehringer Ingelheim International GmbH. ALL RIGHTS RESERVED. (10/14) NIN633306MHC

OFEV® (nintedanib) capsules, for oral use BRIEF SUMMARY OF PRESCRIBING INFORMATION Please see package insert for full Prescribing Information, including Patient Information INDICATIONS AND USAGE: OFEV is indicated for the treatment of idiopathic pulmonary fibrosis (IPF). DOSAGE AND ADMINISTRATION: Testing Prior to OFEV Administration: Conduct liver function tests prior to initiating treatment with OFEV [see Warnings and Precautions]. Recommended Dosage: The recommended dosage of OFEV is 150 mg twice daily administered approximately 12 hours apart. OFEV capsules should be taken with food and swallowed whole with liquid. OFEV capsules should not be chewed or crushed because of a bitter taste. The effect of chewing or crushing of the capsule on the pharmacokinetics of nintedanib is not known. If a dose of OFEV is missed, the next dose should be taken at the next scheduled time. Advise the patient to not make up for a missed dose. Do not exceed the recommended maximum daily dosage of 300 mg. Dosage Modification due to Adverse Reactions: In addition to symptomatic treatment, if applicable, the management of adverse reactions of OFEV may require dose reduction or temporary interruption until the specific adverse reaction resolves to levels that allow continuation of therapy. OFEV treatment may be resumed at the full dosage (150 mg twice daily), or at the reduced dosage (100 mg twice daily), which subsequently may be increased to the full dosage. If a patient does not tolerate 100 mg twice daily, discontinue treatment with OFEV [see Warnings and Precautions and Adverse Reactions]. Dose modifications or interruptions may be necessary for liver enzyme elevations. For aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3 times to <5 times the upper limit of normal (ULN) without signs of severe liver damage, interrupt treatment or reduce OFEV to 100 mg twice daily. Once liver enzymes have returned to baseline values, treatment with OFEV may be reintroduced at a reduced dosage (100 mg twice daily), which subsequently may be increased to the full dosage (150 mg twice daily) [see Warnings and Precautions and Adverse Reactions]. Discontinue OFEV for AST or ALT elevations >5 times ULN or >3 times ULN with signs or symptoms of severe liver damage. CONTRAINDICATIONS: None WARNINGS AND PRECAUTIONS: Elevated Liver Enzymes: The safety and efficacy of OFEV has not been studied in patients with moderate (Child Pugh B) or severe (Child Pugh C) hepatic impairment. Treatment with OFEV is not recommended in patients with moderate or severe hepatic impairment [see Use in Specific Populations]. In clinical trials, administration of OFEV was associated with elevations of liver enzymes (ALT, AST, ALKP, GGT). Liver enzyme increases were reversible with dose modification or interruption and not associated with clinical signs or symptoms of liver injury. The majority (94%) of patients with ALT and/or AST elevations had elevations <5 times ULN. Administration of OFEV was also associated with elevations of bilirubin. The majority (95%) of patients with bilirubin elevations had elevations <2 times ULN [see Use in Specific Populations]. Conduct liver function tests (ALT, AST, and bilirubin) prior to treatment with OFEV, monthly for 3 months, and every 3 months thereafter, and as clinically indicated. Dosage modifications or interruption may be necessary for liver enzyme elevations. Gastrointestinal Disorders: Diarrhea: Diarrhea was the most frequent gastrointestinal event reported in 62% versus 18% of patients treated with OFEV and placebo, respectively [see Adverse Reactions)]. In most patients, the event was of mild to moderate intensity and occurred within the first 3 months of treatment. Diarrhea led to permanent dose reduction in 11% of patients treated with OFEV compared to 0 placebo-treated patients. Diarrhea led to discontinuation of OFEV in 5% of the patients compared to <1% of placebo-treated patients. Dosage modifications or treatment interruptions may be necessary in patients with adverse reactions of diarrhea. Treat diarrhea at first signs with adequate hydration and antidiarrheal medication (e.g., loperamide), and consider treatment interruption if diarrhea continues. OFEV treatment may be resumed at the full dosage (150 mg twice daily), or at the

reduced dosage (100 mg twice daily), which subsequently may be increased to the full dosage. If severe diarrhea persists despite symptomatic treatment, discontinue treatment with OFEV (nintedanib). Nausea and Vomiting: Nausea was reported in 24% versus 7% and vomiting was reported in 12% versus 3% of patients treated with OFEV and placebo, respectively [see Adverse Reactions]. In most patients, these events were of mild to moderate intensity. Nausea led to discontinuation of OFEV in 2% of patients. Vomiting led to discontinuation of OFEV in 1% of the patients. For nausea or vomiting that persists despite appropriate supportive care including anti-emetic therapy, dose reduction or treatment interruption may be required. OFEV treatment may be resumed at the full dosage (150 mg twice daily), or at the reduced dosage (100 mg twice daily), which subsequently may be increased to the full dosage. If severe nausea or vomiting does not resolve, discontinue treatment with OFEV. Embryofetal Toxicity: OFEV can cause fetal harm when administered to a pregnant woman. Nintedanib was teratogenic and embryofetocidal in rats and rabbits at less than and approximately 5 times the maximum recommended human dose (MRHD) in adults (on an AUC basis at oral doses of 2.5 and 15 mg/ kg/day in rats and rabbits, respectively). If OFEV is used during pregnancy, or if the patient becomes pregnant while taking OFEV, the patient should be advised of the potential hazard to a fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with OFEV and to use adequate contraception during treatment and at least 3 months after the last dose of OFEV [see Use in Specific Populations]. Arterial Thromboembolic Events: Arterial thromboembolic events have been reported in patients taking OFEV. In clinical trials, arterial thromboembolic events were reported in 2.5% of patients treated with OFEV and 0.8% of placebo-treated patients. Myocardial infarction was the most common adverse reaction under arterial thromboembolic events, occurring in 1.5% of OFEVtreated patients compared to 0.4% of placebo-treated patients. Use caution when treating patients at higher cardiovascular risk including known coronary artery disease. Consider treatment interruption in patients who develop signs or symptoms of acute myocardial ischemia. Risk of Bleeding: Based on the mechanism of action (VEGFR inhibition), OFEV may increase the risk of bleeding. In clinical trials, bleeding events were reported in 10% of patients treated with OFEV and in 7% of patients treated with placebo. Use OFEV in patients with known risk of bleeding only if the anticipated benefit outweighs the potential risk. Gastrointestinal Perforation: Based on the mechanism of action, OFEV may increase the risk of gastrointestinal perforation. In clinical trials, gastrointestinal perforation was reported in 0.3% of patients treated with OFEV, compared to 0 cases in the placebo-treated patients. Use caution when treating patients who have had recent abdominal surgery. Discontinue therapy with OFEV in patients who develop gastrointestinal perforation. Only use OFEV in patients with known risk of gastrointestinal perforation if the anticipated benefit outweighs the potential risk. ADVERSE REACTIONS: The following adverse reactions are discussed in greater detail in other sections of the labeling: Liver Enzyme and Bilirubin Elevations [see Warnings and Precautions]; Gastrointestinal Disorders [see Warnings and Precautions]; Embryofetal Toxicity [see Warnings and Precautions]; Arterial Thromboembolic Events [see Warnings and Precautions]; Risk of Bleeding [see Warnings and Precautions]; Gastrointestinal Perforation [see Warnings and Precautions]. 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 of OFEV was evaluated in over 1000 IPF patients with over 200 patients exposed to OFEV for more than 2 years in clinical trials. OFEV was studied in three randomized, double-blind, placebo-controlled, 52-week trials. In the phase 2 (Study 1) and phase 3 (Studies 2 and 3) trials, 723 patients with IPF received OFEV 150 mg twice daily and 508 patients received placebo. The median duration of exposure was 10 months for patients treated with OFEV and 11 months for patients treated with placebo. Subjects ranged in age from 42 to

89 years (median age of 67 years). Most patients were male (79%) and Caucasian (60%). The most frequent serious adverse reactions reported in patients treated with OFEV (nintedanib), more than placebo, were bronchitis (1.2% vs. 0.8%) and myocardial infarction (1.5% vs. 0.4%). The most common adverse events leading to death in patients treated with OFEV, more than placebo, were pneumonia (0.7% vs. 0.6%), lung neoplasm malignant (0.3% vs. 0%), and myocardial infarction (0.3% vs. 0.2%). In the predefined category of major adverse cardiovascular events (MACE) including MI, fatal events were reported in 0.6% of OFEV-treated patients and 1.8% of placebo-treated patients. Adverse reactions leading to permanent dose reductions were reported in 16% of OFEV-treated patients and 1% of placebo-treated patients. The most frequent adverse reaction that led to permanent dose reduction in the patients treated with OFEV was diarrhea (11%). Adverse reactions leading to discontinuation were reported in 21% of OFEV-treated patients and 15% of placebo-treated patients. The most frequent adverse reactions that led to discontinuation in OFEV-treated patients were diarrhea (5%), nausea (2%), and decreased appetite (2%). The most common adverse reactions with an incidence of ≥5% and more frequent in the OFEV than placebo treatment group are listed in Table 1. Table 1 Adverse Reactions Occurring in ≥5% of OFEV-treated Patients and More Commonly Than Placebo in Studies 1, 2, and 3 Adverse Reaction Gastrointestinal disorders Diarrhea Nausea Abdominal paina Vomiting Hepatobiliary disorders Liver enzyme elevationb Metabolism and nutrition disorders Decreased appetite Nervous systemic disorders Headache Investigations Weight decreased Vascular disorders Hypertensionc

OFEV, 150 mg n=723

Placebo n=508

62% 24% 15% 12%

18% 7% 6% 3%

14%

11%

10%

Includes abdominal pain, abdominal pain upper, abdominal pain lower, gastrointestinal pain and abdominal tenderness. b Includes gamma-glutamyltransferase increased, hepatic enzyme increased, alanine aminotransferase increased, aspartate aminotransferase increased, hepatic function abnormal, liver function test abnormal, transaminase increased, blood alkaline phosphatase-increased, alanine aminotransferase abnormal, aspartate aminotransferase abnormal, and gamma-glutamyltransferase abnormal. c Includes hypertension, blood pressure increased, hypertensive crisis, and hypertensive cardiomyopathy. a

In addition, hypothyroidism was reported in patients treated with OFEV, more than placebo (1.1% vs. 0.6%). DRUG INTERACTIONS: P-glycoprotein (P-gp) and CYP3A4 Inhibitors and Inducers: Nintedanib is a substrate of P-gp and, to a minor extent, CYP3A4. Coadministration with oral doses of a P-gp and CYP3A4 inhibitor, ketoconazole, increased exposure to nintedanib by 60%. Concomitant use of P-gp and CYP3A4 inhibitors (e.g., erythromycin) with OFEV may increase exposure to nintedanib. In such cases, patients should be monitored closely for tolerability of OFEV. Management of adverse reactions may require interruption, dose reduction, or discontinuation of therapy with OFEV. Coadministration with oral doses of a P-gp and CYP3A4 inducer, rifampicin, decreased exp sure to nintedanib by 50%. Concomitant use of P-gp and CYP3A4 inducers (e.g., carbamazepine, phenytoin, and St. John’s wort) with OFEV should be avoided as these drugs may decrease exposure to nintedanib. Anticoagulants: Nintedanib is a VEGFR inhibitor, and may increase the risk of bleeding. Monitor patients on full anticoagulation therapy closely for bleeding and adjust

anticoagulation treatment as necessary [see Warnings and Precautions]. USE IN SPECIFIC POPULATIONS: Pregnancy: Pregnancy Category D. [See Warnings and Precautions]: OFEV (nintedanib) can cause fetal harm when administered to a pregnant woman. If OFEV is used during pregnancy, or if the patient becomes pregnant while taking OFEV, the patient should be apprised of the potential hazard to a fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with OFEV. In animal reproduction toxicity studies, nintedanib caused embryofetal deaths and teratogenic effects in rats and rabbits at less than and approximately 5 times the maximum recommended human dose (MRHD) in adults (on a plasma AUC basis at maternal oral doses of 2.5 and 15 mg/kg/day in rats and rabbits, respectively). Malformations included abnormalities in the vasculature, urogenital, and skeletal systems. Vasculature anomalies included missing or additional major blood vessels. Skeletal anomalies included abnormalities in the thoracic, lumbar, and caudal vertebrae (e.g., hemivertebra, missing, or asymmetrically ossified), ribs (bifid or fused), and sternebrae (fused, split, or unilaterally ossified). In some fetuses, organs in the urogenital system were missing. In rabbits, a significant change in sex ratio was observed in fetuses (female:male ratio of approximately 71%:29%) at approximately 15 times the MRHD in adults (on an AUC basis at a maternal oral dose of 60 mg/kg/day). Nintedanib decreased post-natal viability of rat pups during the first 4 post-natal days when dams were exposed to less than the MRHD (on an AUC basis at a maternal oral dose of 10 mg/kg/day). Nursing Mothers: Nintedanib and/or its metabolites are excreted into the milk of lactating rats. Milk and plasma of lactating rats have similar concentrations of nintedanib and its metabolites. Excretion of nintedanib and/or its metabolites into human milk is probable. There are no human studies that have investigated the effects of OFEV on breast-fed infants. Because of the potential for serious adverse reactions in nursing infants from OFEV, 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 in pediatric patients have not been established. Geriatric Use: Of the total number of subjects in phase 2 and 3 clinical studies of OFEV, 60.8% were 65 and over, while 16.3% were 75 and over. In phase 3 studies, no overall differences in effectiveness were observed between subjects who were 65 and over and younger subjects; no overall differences in safety were observed

between subjects who were 65 and over or 75 and over and younger subjects, but greater sensitivity of some older individuals cannot be ruled out. Hepatic Impairment: Nintedanib is predominantly eliminated via biliary/fecal excretion (>90%). No dedicated pharmacokinetic (PK) study was performed in patients with hepatic impairment. Monitor for adverse reactions and consider dose modification or discontinuation of OFEV (nintedanib) as needed for patients with mild hepatic impairment (Child Pugh A). The safety and efficacy of nintedanib has not been investigated in patients with hepatic impairment classified as Child Pugh B or C. Therefore, treatment of patients with moderate (Child Pugh B) and severe (Child Pugh C) hepatic impairment with OFEV is not recommended [see Warnings and Precautions]. Renal Impairment: Based on a single-dose study, less than 1% of the total dose of nintedanib is excreted via the kidney. Adjustment of the starting dose in patients with mild to moderate renal impairment is not required. The safety, efficacy, and pharmacokinetics of nintedanib have not been studied in patients with severe renal impairment (<30 mL/min CrCl) and end-stage renal disease. Smokers: Smoking was associated with decreased exposure to OFEV, which may alter the efficacy profile of OFEV. Encourage patients to stop smoking prior to treatment with OFEV and to avoid smoking when using OFEV. OVERDOSAGE: In the trials, one patient was inadvertently exposed to a dose of 600 mg daily for a total of 21 days. A non-serious adverse event (nasopharyngitis) occurred and resolved during the period of incorrect dosing, with no onset of other reported events. Overdose was also reported in two patients in oncology studies who were exposed to a maximum of 600 mg twice daily for up to 8 days. Adverse events reported were consistent with the existing safety profile of OFEV. Both patients recovered. In case of overdose, interrupt treatment and initiate general supportive measures as appropriate. PATIENT COUNSELING INFORMATION: Advise the patient to read the FDA-approved patient labeling (Patient Information). Liver Enzyme and Bilirubin Elevations: Advise patients that they will need to undergo liver function testing periodically. Advise patients to immediately report any symptoms of a liver problem (e.g., skin or the whites of eyes turn yellow, urine turns dark or brown (tea colored), pain on the right side of stomach, bleed or bruise more easily than normal, lethargy) [see Warnings and Precautions]. Gastrointestinal Disorders: Inform patients that gastrointestinal disorders such as diarrhea, nausea,

and vomiting were the most commonly reported gastrointestinal events occurring in patients who received OFEV (nintedanib). Advise patients that their healthcare provider may recommend hydration, antidiarrheal medications (e.g., loperamide), or anti-emetic medications to treat these side effects. Temporary dosage reductions or discontinuations may be required. Instruct patients to contact their healthcare provider at the first signs of diarrhea or for any severe or persistent diarrhea, nausea, or vomiting [see Warnings and Precautions and Adverse Reactions]. Pregnancy: Counsel patients on pregnancy planning and prevention. Advise females of childbearing potential of the potential hazard to a fetus and to avoid becoming pregnant while receiving treatment with OFEV. Advise females of childbearing potential to use adequate contraception during treatment, and for at least 3 months after taking the last dose of OFEV. Advise female patients to notify their doctor if they become pregnant during therapy with OFEV [see Warnings and Precautions and Use in Specific Populations]. Arterial Thromboembolic Events: Advise patients about the signs and symptoms of acute myocardial ischemia and other arterial thromboembolic events and the urgency to seek immediate medical care for these conditions [see Warnings and Precautions]. Risk of Bleeding: Bleeding events have been reported. Advise patients to report unusual bleeding [see Warnings and Precautions]. Gastrointestinal Perforation: Serious gastrointestinal perforation events have been reported. Advise patients to report signs and symptoms of gastrointestinal perforation [see Warnings and Precautions]. Nursing Mothers: Advise patients to discontinue nursing while taking OFEV or discontinue OFEV while nursing [see Use in Specific Populations]. Smokers: Encourage patients to stop smoking prior to treatment with OFEV and to avoid smoking when using with OFEV. Administration: Instruct patients to swallow OFEV capsules whole with liquid and not to chew or crush the capsules due to the bitter taste. Advise patients to not make up for a missed dose [see Dosage and Administration]. Copyright ÂŠ 2014 Boehringer Ingelheim International GmbH ALL RIGHTS RESERVED OF-BS-10-14

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FDA Approvals of Brand-Name Prescription Drugs in 2014 I. New Pharmaceuticals: New Molecular Entities and New Biologic License Applications Approved in 2014 Akynzeo (NME; new combination) (Netupitant [NME] and palonosetron; Eisai) Class/route: Antiemetic; oral Indication: For the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of chemotherapy Beleodaq (NME) (Belinostat; Spectrum Pharmaceuticals) Class/route: Histone deacetylase inhibitor; intravenous Indication: For the treatment of patients with relapsed or refractory peripheral T-cell lymphoma, a type of NHL Approval considerations: Accelerated approval, priority review, orphan drug Belsomra (NME) (Suvorexant; Merck, Sharpe & Dohme Corporation) Class/route: Orexin receptor antagonist; oral Indication: For the treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance Blincyto (BLA) (Blinatumomab; Amgen) Class/route: CD19-directed CD3 T-cell engager; intravenous Indication: Treatment of Philadelphia chromosome– negative relapsed or refractory B-cell precursor acute lymphoblastic leukemia Approval considerations: Breakthrough therapy, priority review, orphan drug, REMS

Class/route: Human vascular endothelial growth factor receptor-2 antagonist; intravenous Indications: As a single agent or in combination with paclitaxel, for the treatment of advanced gastric or gastroesophageal junction adenocarcinoma, in patients with disease progression during or after previous fluoropyrimidine- or platinum-containing chemotherapy; in combination with docetaxel, for the treatment of metastatic non–small-cell lung cancer in patients with disease progression during or after platinum- based chemotherapy Approval considerations: Priority review, orphan drug Dalvance (NME) (Dalbavancin; Durata Therapeutics) Class/route: Glycopeptide antibiotic; intravenous Indication: Treatment of adults with acute bacterial skin and skin structure infections caused by susceptible isolates of the gram-positive microorganisms Staphylococcus aureus, Streptococcus pyogenes, Streptococcus agalactiae, and Streptococcus anginosus Approval consideration: Priority review, QIDP

Cerdelga (NME) (Eliglustat; Genzyme) Class/route: Glucosylceramide synthase inhibitor; oral Indication: For long-term treatment of adults with Gaucher disease type 1 who are CYP2D6 extensive metabolizers, intermediate metabolizers, or poor metabolizers as detected by an FDA-cleared test Approval considerations: Priority review, orphan drug

Entyvio (BLA) (Vedolizumab; Takeda Pharmaceuticals) Class/route: Integrin receptor antagonist; intravenous Indications: Treatment of adults with moderately to severely active ulcerative colitis who have had an inadequate response with, lost response to, or were intolerant to a TNF blocker or an immunomodulator; or had an inadequate response with, were intolerant to, or demonstrated dependence on corticosteroids; treatment of adults with moderately to severely active Crohn’s disease who have had an inadequate response with, lost response to, or were intolerant to a TNF blocker or immunomodulator; or had an inadequate response with, were intolerant to, or demonstrated dependence on corticosteroids Approval consideration: Priority review

Cyramza (BLA) (Ramucirumab; Eli Lilly)

Esbriet (NME) (Pirfenidone; InterMune)

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Class/route: Pyridone; oral Indication: Treatment of idiopathic pulmonary fibrosis Approval considerations: Breakthrough therapy, fast track, priority review, orphan drug Farxiga (NME) (Dapaglifozin; Bristol-Myers Squibb/AstraZeneca) Class/route: SGLT2 inhibitor; oral Indications: As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus Harvoni (NME; new combination) (Ledipasvir [NME] and sofosbuvir; Gilead Sciences) Classes/route: Fixed-dose combination of an HCV NS5A inhibitor and an HCV nucleotide analog NS5B polymerase inhibitor; oral Indication: Treatment of genotype 1 chronic hepatitis C infection in adults; first fixed-dose combination without interferon or ribavirin Approval considerations: Priority review, breakthrough therapy [2015 new dosages approved: 5 mg; 10 mg] Hetlioz (NME) (Tasimelteon; Vanda Pharmaceuticals) Class/route: Melatonin receptor agonist; oral Indication: Treatment of non–24-hour sleep-wake disorder Approval considerations: Priority review, orphan drug Impavido (NME) (Miltefosine; Paladin Therapeutics) Class/route: Anthelmintic antineoplastic; oral Indications: For the treatment of individuals aged ≥12 years weighing ≥66 lb (30 kg) with visceral leishmaniasis resulting from Leishmania donovani; cutaneous leishmaniasis resulting from Leishmania braziliensis, Leishmania guyanensis, and Leishmania panamensis; and mucosal leishmaniasis resulting from L braziliensis Approval considerations: Fast track, priority review, orphan drug Jardiance (NME) (Empagliflozin; Boehringer Ingelheim) Class/route: SGLT2 inhibitor; oral Indication: As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus Jublia (NME) (Efinaconazole; Valeant Pharmaceuticals International) Class/route: Triazole antifungal agent; topical Indication: For the treatment of onychomycosis of the toenails resulting from Trichophyton rubrum and Trichophyton mentagrophytes

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Kerydin (NME) (Tavaborole; Anacor Pharmaceuticals) Class/route: Oxaborole antifungal; topical Indication: For the treatment of onychomycosis of the toenails resulting from Trichophyton rubrum or Trichophyton mentagrophytes Keytruda (BLA) (Pembrolizumab; Merck) Class/route: PD-1–blocking antibody; intravenous Indication: Treatment of patients with unresectable or metastatic melanoma and disease progression after ipilimumab therapy and, if BRAF V600 mutation– positive, a BRAF inhibitor Approval considerations: Breakthrough therapy, accelerated approval, priority review, orphan drug Lumason (NME) (Sulfur hexafluoride lipid microsphere; Bracco Diagnostics) Class/route: Ultrasound contrast agent; intravenous Indication: For use in patients with suboptimal echocardiograms to opacify the left-ventricular chamber and to improve the delineation of the left-ventricular endocardial border Lynparza (NME) (Olaparib; AstraZeneca) Class/route: Poly (ADP-ribose) polymerase inhibitor; oral Indications: For advanced ovarian cancer in patients with deleterious or suspected deleterious germline BRCA mutation (as detected by an FDA-approved test) who have been treated with 3 or more previous lines of chemotherapy Approval considerations: Accelerated approval, priority review, orphan drug Movantik (NME) (Naloxegol; AstraZeneca) Class/route: Peripherally acting opioid receptor antagonists; oral Indication: For opioid-induced constipation in adults with chronic noncancer pain Approval consideration: Priority review Myalept (BLA) (Metreleptin; Amylin Pharmaceuticals) Class/route: Leptin analog; subcutaneous Indication: For the treatment of complications of leptin deficiency, as replacement therapy, in addition to diet, in patients with congenital generalized or acquired generalized lipodystrophy Approval considerations: Priority review, orphan drug, REMS

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Neuraceq (NME) (Florbetaben F18 injection; Piramal Imaging) Class/route: Radioactive diagnostic agent; intravenous Indication: For positron emission tomography imaging of the brain to estimate beta-amyloid neuritic plaque density in adults with cognitive impairment who are being evaluated for Alzheimer’s disease and other causes of cognitive decline Northera (NME) (Droxidopa; Chelsea Therapeutics) Class/route: Vasopressor; oral Indication: Treatment of orthostatic dizziness, lightheadedness, or the “feeling that you are about to black out” in adults with symptomatic neurogenic orthostatic hypotension caused by primary autonomic failure (Parkinson’s disease, multiple system atrophy, and pure autonomic failure), dopamine beta-hydroxylase deficiency, and nondiabetic autonomic neuropathy Approval considerations: Accelerated approval, priority review, orphan drug Ofev (NME) (Nintedanib; Boehringer Ingelheim) Class/route: Tyrosine kinase inhibitor; oral Indication: Treatment of idiopathic pulmonary fibrosis Approval considerations: Breakthrough therapy, fast track, priority review, orphan drug Opdivo (BLA) (Nivolumab; Bristol-Myers Squibb) Class/route: PD-1–blocking antibody; intravenous Indication: Treatment of unresectable or metastatic melanoma and disease progression after ipilimumab and, if BRAF V600 mutation–positive, a BRAF inhibitor Approval considerations: Breakthrough therapy, accelerated approval, priority review, orphan drug [2015 new indication: lung cancer] Orbactiv (NME) (Oritavancin; The Medicines Company) Class/route: Lipoglycopeptide antibacterial drug; intravenous Indication: Treatment of adults with acute bacterial skin and skin structure infections caused or suspected to be caused by susceptible bacteria, including S aureus (including methicillin-susceptible and methicillin- resistant strains), various Streptococcus species, and Enterococcus faecalis Approval considerations: Priority review, QIDP Otezla (NME) (Apremilast; Celgene)

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Class/route: Phosphodiesterase 4 inhibitor; oral Indications: Treatment of adults with active psoriatic arthritis, and patients with moderate-to-severe plaque psoriasis who are candidates for phototherapy or systemic therapy Plegridy (BLA) (Peginterferon beta-1a; Biogen Idec) Class/route: Interferon beta; subcutaneous Indication: Treatment of relapsing forms of multiple sclerosis Rapivab (NME) (Peramivir; BioCryst Pharmaceuticals) Class/route: Neuraminidase inhibitor; intravenous Indication: Treatment of acute uncomplicated influenza in patients aged ≥18 years who have been symptomatic for no more than 2 days Sivextro (NME) (Tedizolid phosphate; Cubist Pharmaceuticals) Class/route: Oxazolidinone-class antibacterial; intravenous and oral Indication: Treatment of adults with acute bacterial skin and skin structure infections caused by designated susceptible bacteria, including S aureus (including methicillin-resistant strains and methicillin-susceptible strains), various Streptococcus species, and E faecalis Approval considerations: Priority review, QIDP Striverdi Respimat (NME) (Olodaterol; Boehringer Ingelheim) Class/route: Long-acting beta2-adrenergic agonist; oral inhalation Indication: For long-term, once-daily maintenance bronchodilator treatment of airflow obstruction in patients with COPD, including chronic bronchitis and/or emphysema Sylvant (BLA) (Siltuximab; Janssen Biotech) Class/route: Interleukin-6 antagonist; intravenous Indication: Treatment of patients with multicentric Castleman’s disease who are HIV-negative and human herpesvirus-8–negative Approval considerations: Priority review, orphan drug Tanzeum (BLA) (Albiglutide; GlaxoSmithKline) Class/route: GLP-1 receptor agonist; subcutaneous Indication: As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus Approval consideration: REMS

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Trulicity (BLA) (Dulaglutide; Lilly) Class/route: GLP-1 receptor agonist; subcutaneous Indication: As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus Approval consideration: REMS Viekira Pak (NME; new combination) (Ombitasvir [NME], paritaprevir [NME], and ritonavir, copackaged with dasabuvir [NME]; AbbVie) Classes/route: HCV NS5A inhibitor, HCV NS3/4A protease inhibitor, and HCV nonnucleoside NS5B palm polymerase inhibitor; oral Indication: For the treatment, with or without ribavirin, of patients with genotype 1 chronic HCV infection, including those with compensated cirrhosis; fixed-dose combination Approval considerations: Breakthrough therapy, priority review Vimizim (BLA) (Elosulfase alfa; BioMarin Pharmaceutical) Class/route: Hydrolytic lysosomal glycosaminoglycan– specific enzyme; intravenous Indication: Treatment of mucopolysaccharidosis type IVA (Morquio A syndrome) Approval considerations: Priority review, orphan drug Xtoro (NME) (Finafloxacin; Alcon Laboratories) Class/route: Fluoroquinolone antimicrobial; topical otic suspension Indication: Treatment of acute otitis externa caused by susceptible strains of Pseudomonas aeruginosa and S aureus Approval consideration: Priority review

Zerbaxa (NME; new combination) (Ceftolozane [NME] and tazobactam; Cubist Pharmaceuticals) Class/route: A cephalosporin antibacterial drug and a beta-lactamase inhibitor; intravenous Indications: For the treatment of complicated intra-abdominal infections, in combination with metronidazole, and for the treatment of complicated urinary tract infections, including pyelonephritis Approval considerations: Priority review, QIDP Zontivity (NME) (Vorapaxar; Merck) Class/route: Protease-activated receptor-1 antagonist; oral Indication: For the reduction of thrombotic cardiovascular events in patients with a history of myocardial infarction or with peripheral arterial disease Zydelig (NME) (Idelalisib; Gilead Sciences) Class/route: Phosphoinositide-3 kinase-delta inhibitor; oral Indications: Treatment of relapsed chronic lymphocytic leukemia, in combination with rituximab, in patients for whom rituximab alone would be considered appropriate therapy because of other comorbidities; relapsed follicular B-cell NHL in patients who have received at least 2 previous systemic therapies; and relapsed small lymphocytic lymphoma in patients who have received at least 2 previous systemic therapies Approval considerations: Accelerated approval, priority review, orphan drug, REMS Zykadia (NME) (Ceritinib; Novartis) Class/route: ALK tyrosine kinase inhibitor; oral Indication: Treatment of ALK-positive metastatic non– small-cell lung cancer in patients who have progressed on or are intolerant to crizotinib Approval considerations: Breakthrough therapy, accelerated approval, priority review, orphan drug

ALK indicates anaplastic lymphoma kinase; BLA, biologic license application; COPD, chronic obstructive pulmonary disease; FDA, US Food and Drug Administration; GLP-1, glucagon-like peptide-1; HCV, hepatitis C virus; NHL, non-Hodgkin lymphoma; NME, new molecular entity; QIDP, Qualified Infectious Disease Product; PD-1, programmed-cell death 1; REMS, Risk Evaluation and Mitigation Strategy; SGLT2, sodium-glucose cotransporter 2; TNF, tumor necrosis factor.

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II. New Combinations and New Indications Approved in 2014 Afrezza (new indication) (Insulin human; MannKind Corporation) Class/route: Insulin human; inhaled powder New indication: Rapid-acting insulin to be used at the beginning of each meal to improve glycemic control in adults with type 1 or type 2 diabetes mellitus New formulation: Rapid-acting inhaled insulin Approval consideration: REMS Akynzeo (new combination) See NMEs/BLAs listing Arzerra (new indication) (Ofatumumab; GlaxoSmithKline) Class/route: CD20 monoclonal antibody; intravenous New indication: For first-line treatment, in combination with chlorambucil, of treatment-naïve patients with CLL for whom fludarabine-based therapy is inappropriate Existing indication: For the treatment of patients with CLL that is refractory to fludarabine or to alemtuzumab Avastin (new indications) (Bevacizumab; Genentech) Class/route: VEGF-specific angiogenesis inhibitor; intravenous New indications: For the treatment of persistent, recurrent, or metastatic cervical cancer in combination with paclitaxel and cisplatin or paclitaxel and topotecan; and for the treatment of platinum-resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan Existing indications: First-line or second-line treatment of metastatic colorectal cancer with intravenous 5-fluorouracil–based chemotherapy; for second-line treatment of metastatic colorectal cancer in patients who have pro gressed on a first-line bevacizumab-containing regimen with fluoropyrimidine- irinotecan- or, fluoropyrimidine- oxaliplatin–based chemotherapy; with carboplatin and paclitaxel for first-line treatment of unresectable, locally advanced, recurrent or metastatic nonsquamous non– small-cell lung cancer; and as a single agent for adults with progressive glioblastoma after previous therapy; metastatic renal-cell carcinoma with interferon alfa Approval consideration: Priority review Contrave (new combination) (Naltrexone and bupropion; Takeda Pharmaceuticals) Classes/route: Opioid antagonist and aminoketone antidepressant; oral Indication: As an adjunct to a reduced-calorie diet and

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increased physical activity for chronic weight management in adults with an initial body mass index of ≥30 kg/m2 or ≥27 kg/m2 in the presence of at least ≥1 weight-related comorbidities Eliquis (new indications) (Apixaban; Bristol-Myers Squibb) Class/route: Factor Xa inhibitor anticoagulant; oral New indications: For prophylactic therapy of DVT that may lead to PE in patients who have undergone hip/ knee replacement surgery; for the treatment of DVT and PE, and for risk reduction of recurrent DVT and PE after initial therapy Existing indication: For risk reduction of stroke and systemic embolism in patients with nonvalvular atrial fibrillation Approval consideration: REMS Eylea (new indications) (Aflibercept; Regeneron Pharmaceuticals) Class/route: VEGF inhibitor; intravitreal New indications: For the treatment of diabetic macular edema; first VEGF inhibitor approved for dosing on a less than monthly basis for the treatment of diabetic macular edema Existing indications: For the treatment of neovascular (wet) age-related macular degeneration, and for the treatment of macular edema after retinal vein occlusion Approval considerations: Breakthrough therapy, priority review [2015 new indication: Diabetic retinopathy in patients with diabetic macular edema] Harvoni (new combination) See NMEs/BLAs listing Humira (new patient population) (Adalimumab; AbbVie) Class/route: Tumor necrosis factor blocker; subcutaneous New patient population: Pediatric Crohn’s disease patients aged ≥6 years Indications: For reducing the signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in adults with moderately to severely active rheumatoid arthritis; reducing the signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis in patients aged ≥2 years; reducing the signs and symptoms, inhibiting the progression of structural damage, and improving physical function in adults with active psoriatic arthritis;

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reducing the signs and symptoms of active ankylosing spondylitis in adults; reducing the signs and symptoms and inducing and maintaining clinical remission in adults with moderately to severely active Crohn’s disease who have had an inadequate response to conventional therapy; reducing the signs and symptoms and inducing and maintaining clinical remission in patients aged ≥6 years with moderately to severely active Crohn’s disease who have had an inadequate response to corticosteroids or immunomodulators, such as azathioprine, 6-mercaptopurine, or methotrexate; inducing and sustaining clinical remission in adults with moderately to severely active ulcerative colitis who have had an inadequate response to immunosuppressants, such as corticosteroids, azathioprine, or 6-mercaptopurine; treatment of adults with moderate-to-severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy, and when other systemic therapies are medically less appropriate Imbruvica (new indication) (Ibrutinib; Pharmacyclics) Class/route: Bruton’s tyrosine kinase inhibitor; oral New indications: Treatment of patients with relapsed CLL who have received at least 1 previous therapy and treatment of patients with CLL with 17p deletion Existing indication: Treatment of patients with mantle- cell lymphoma who have received at least 1 previous therapy Approval considerations: Breakthrough therapy, priority review, orphan drug [2015 new indication: Waldenström’s macroglobulinemia] Invega Sustenna (new indication) (Paliperidone palmitate; Janssen Pharmaceuticals) Class/route: Atypical antipsychotic; oral New indication: For the once-monthly treatment of schizoaffective disorder, as monotherapy and as an adjunct to mood stabilizers and/or antidepressants (first FDA approval for this indication) Indication: Treatment of schizophrenia Invokamet (new combination) (Canagliflozin and metformin hydrochloride; Janssen Pharmaceuticals) Classes/route: SGLT2 inhibitor and biguanide; oral Indication: As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus who are not adequately controlled with a regimen containing metformin or canagliflozin or in patients already receiving canagliflozin and metformin

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Jakafi (new indication) (Ruxolitinib; Incyte Corporation) Class/route: Janus-associated kinase inhibitor; oral New indication: For the treatment of patients with polycythemia vera who have had an inadequate response to or are intolerant of hydroxyurea Existing indication: For the treatment of intermediate- risk or high-risk myelofibrosis Approval considerations: Priority review, orphan drug Lemtrada (new indication) (Alemtuzumab; Genzyme Corporation) Class/route: CD52-directed cytolytic monoclonal antibody; intravenous New indication: For the treatment of patients with relapsing forms of multiple sclerosis Existing indication: For the treatment of B-cell CLL Mekinist plus Tafinlar (new combination) (Trametinib and dabrafenib; GlaxoSmithKline) Classes/route: BRAF kinase inhibitor and MEK kinase inhibitor; oral Indication: For the treatment of advanced melanoma that is unresectable or metastatic in patients with the BRAF V600E or BRAF V600K mutation Approval considerations: Accelerated approval, priority review Minivelle (new indication) (Estradiol; Noven Pharmaceuticals) Class/route: Estrogen; transdermal New indication: For the prevention of postmenopausal osteoporosis Existing indication: Treatment of moderate-to-severe vasomotor symptoms resulting from menopause Namzaric (new combination) (Memantine hydrochloride extended release and donepezil hydrochloride; Forest Laboratories) Classes/route: NMDA receptor antagonist and acetylcholinesterase inhibitor; oral Indication: For the treatment of moderate-to-severe dementia of the Alzheimer’s type in patients stabilized on memantine hydrochloride and donepezil hydrochloride Obredon (new combination) (Hydrocodone bitartrate and guaifenesin; Novotec Pharma) Classes/route: Opioid antitussive and expectorant; oral Indications: For the symptomatic relief of cough and to loosen mucus associated with the common cold

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Olysio (new combination) (Simeprevir; Janssen; for use with sofosbuvir [Sovaldi; Gilead]) Class/route: HCV NS3/4A protease inhibitor; oral New combination: For use in combination with sofosbuvir as an all-oral, interferon-free, ribavirin-free treatment for adults with genotype 1 chronic HCV infection Existing combination: For the treatment of genotype 1 chronic HCV infection in combination with pegylated interferon and ribavirin regimen Omidria (new combination) (Phenylephrine and ketorolac; Omeros Corporation) Classes/route: Alpha 1-adrenergic receptor agonist and nonselective cyclooxygenase inhibitor; intraocular Indications: For the maintenance of pupil size by preventing intraoperative miosis and for reducing postoperative pain Onexton (new combination) (Clindamycin/benzoyl peroxide; Valeant Pharma ceuticals International) Class/route: Lincosamide antibacterial; topical gel Indication: For the topical treatment of acne vulgaris in patients aged ≥12 years Ozurdex (new indication) (Dexamethasone; Allergan) Class/route: Corticosteroid; intravitreal injection New indication: For the treatment of diabetic macular edema Existing indications: Treatment of macular edema after branch retinal vein occlusion or central retinal vein occlusion, and for the treatment of noninfectious uveitis affecting the posterior segment of the eye Priftin (new indication) (Rifapentine; sanofi-aventis) Class/route: Rifamycin antimycobacterial; oral New indication: In combination with isoniazid, for the treatment of latent tuberculosis infection in patients aged ≥2 years who are at high risk for progression to tuberculosis disease Existing indication: For the treatment of active pulmonary tuberculosis in adults and children aged ≥12 years caused by Mycobacterium tuberculosis Promacta (new indication) (Eltrombopag; GlaxoSmithKline) Class/route: Thrombopoietin receptor agonist; oral New indication: For the treatment of patients with severe aplastic anemia who have had an insufficient response to immunosuppressive therapy

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Existing indications: For the treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenia who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy; thrombocytopenia in patients with chronic hepatitis C to allow the initiation and maintenance of interferon-based therapy Approval considerations: Breakthrough therapy, priority review Saxenda (new version of Victoza; new indication) (Liraglutide [rDNA origin] injection; Novo Nordisk) Class/route: GLP-1 receptor agonist; subcutaneous New indication: For chronic weight management as an adjunct to a reduced-calorie diet and increased physical activity in adults with an initial body mass index ≥30 kg/m2 or ≥27 kg/m2 and at least 1 weight-related comorbid condition; this is a new version of Victoza (liraglutide [rDNA origin]), which is indicated for adults with type 2 diabetes Approval consideration: REMS Somatuline Depot (new indication) (Lanreotide; Ipsen Pharmaceuticals) Class/route: Somatostatin analog; injection New indication: For the treatment of patients with unresectable, moderately or well-differentiated, locally advanced or metastatic gastroenteropancreatic neuroendocrine tumors to improve progression-free survival Existing indication: For the long-term treatment of acromegalic patients who have had an inadequate response to or cannot be treated with surgery and/or radiotherapy Soolantra (new indication; new formulation) (Ivermectin 1%; Galderma) Class/route: Antibiotic-free anti-inflammatory cream; topical New indication: For once-daily treatment of patients with inflammatory lesions, bumps, and pimples, of rosacea; this is the first time ever ivermectin cream is approved for use in humans; it was previously only available for use (in different form) in livestock New formulation: 1% cream for humans Trezix (new combination) (Acetaminophen, caffeine, and dihydrocodeine bitartrate; WraSer Pharmaceuticals) Classes/route: Nonopiate, nonsalicylate analgesic and antipyretic; central nervous system and cardiovascular stimulant; and semisynthetic narcotic analgesic; oral Indication: Relief of moderate-to-moderately severe pain

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Triumeq (new combination) (Abacavir, dolutegravir, and lamivudine; ViiV Healthcare) Classes/route: Integrase strand transfer inhibitor (dolu tegravir) and nucleoside analogue reverse transcriptase inhibitors (abacavir and lamivudine); oral Indication: For the treatment of patients with HIV-1 infection Velcade (new indications) (Bortezomib; Millennium Pharmaceuticals) Class/routes: Proteasome inhibitor; intravenous, subcutaneous New indications: Retreatment of adults with multiple myeloma that had previously responded to bortezomib and relapsed at least 6 months after completion of previous treatment with bortezomib; first-line treatment of newly diagnosed patients with mantle-cell lymphoma Existing indications: For the treatment of patients with multiple myeloma or with mantle-cell lymphoma Viekira Pak (new combination) See NMEs/BLAs listing Vitekta (new combination) (Elvitegravir; Gilead Sciences) Class/route: HIV-1 integrase strand transfer inhibitor; oral Indication: Used in combination with an HIV protease inhibitor coadministered with ritonavir and with other antiretroviral drug(s) for the treatment of HIV-1 infection in antiretroviral treatment–experienced adults Xgeva (new indication) (Denosumab; Amgen) Class/route: RANK ligand inhibitor; subcutaneous New indication: Treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy Existing indications: Prevention of skeletal-related events

in patients with bone metastases from solid tumors, and for the treatment of adults and skeletally mature adolescents with giant-cell tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity Approval consideration: Orphan drug Xigduo XR (new combination) (Dapagliflozin and metformin hydrochloride extended release; AstraZeneca) Classes/route: SGLT2 inhibitor and biguanide; oral Indication: To improve glycemic control in adults with type 2 diabetes when treatment with dapagliflozin and with metformin is appropriate Xolair (new indication) (Omalizumab; Genentech) Class/route: Anti-immunoglobulin E antibody; subcutaneous New indication: First biologic and first medicine approved by the FDA for the treatment of chronic idiopathic urticaria in adults and adolescents aged ≥12 years who remain symptomatic despite H1 antihistamine treatment Existing indication: Treatment of moderate-to-severe persistent asthma in patients aged ≥12 years with a positive skin test or in vitro reactivity to a perennial aeroallergen and symptoms that are inadequately controlled with inhaled corticosteroids Zerbaxa (new combination) See NMEs/BLAs listing Zorvolex (new indication) (Diclofenac; Iroko Pharmaceuticals) Class/route: NSAID; oral New indication: For the management of osteoarthritis pain Existing indication: For the management of mild-to- moderate acute pain

BLA indicates biologic license application; CLL, chronic lymphocytic leukemia; DVT, deep-vein thrombosis; GLP1, glucagon-like peptide-1; HCV, hepatitis C virus; NMDA, N-methyl-D-aspartate; NME, new molecular entity; NSAID, nonsteroidal anti-inflammatory drug; PE, pulmonary embolism; REMS, Risk Evaluation and Mitigation Strategy; SGLT2, sodium-glucose cotransporter 2; VEGF, vascular endothelial growth factor.

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III. New Formulations/Dosage Forms/Dosages/Patient Population Approved in 2014 Abilify Maintena (new dosage form) (Aripiprazole; Otsuka Pharmaceutical) Class/route: Atypical antipsychotic; intramuscular New dosage form: Extended-release injectable suspension in a prefilled dual-chamber syringe Indication: For the treatment of schizophrenia

Bunavail (new formulation) (Buprenorphine and naloxone; BioDelivery Sciences) Class/route: Partial opioid agonist; oral New formulation: Buccal film Indication: For the maintenance treatment of opioid dependence

Acticlate (new dosages) (Doxycycline hyclate USP; Aqua Pharmaceuticals) Class/route: Tetracycline-class antimicrobial; oral New dosages: 75-mg and 150-mg tablets Indications: For the treatment of Rickettsial infections, sexually transmitted infections, respiratory tract infections, specific bacterial infections, ophthalmic infections, and anthrax, including inhalational anthrax (postexposure); alternative treatment for selected infections when penicillin is contraindicated; adjunctive therapy in acute intestinal amebiasis and severe acne; prophylaxis of malaria

Bydureon (new dosage form) (Exenatide; AstraZeneca) Class/route: GLP-1 receptor agonist; subcutaneous New dosage form: Extended-release formula in a 2-mg pen; already available as a single-dose tray containing a 2-mg vial Indication: As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus

Arnuity Ellipta (new formulation) (Fluticasone furoate; GlaxoSmithKline) Class/route: Corticosteroid; oral inhalation New formulation: Once-daily oral inhalation of 100 mcg or 200 mcg using Ellipta inhaler Indication: For the once-daily maintenance treatment of asthma as prophylactic therapy in patients aged â&#x2030;Ľ12 years Auryxia (new formulation) (Ferric citrate: Keryx Biopharmaceuticals) Class/route: Phosphate binder; oral New formulation: The first and only absorbable ironbased phosphate binder proven to manage hyperphosphatemia Indication: For the control of serum phosphorus levels in patients with chronic kidney disease on dialysis Aveed (new formulation) (Testosterone undecanoate; Endo Pharmaceuticals) Class/route: Androgen; intramuscular injection New formulation: Intramuscular; already available in oral, subcutaneous, buccal, and transdermal formulations Indication: For testosterone replacement therapy in adult men for conditions associated with a deficiency or absence of endogenous testosterone, such as congenital or acquired primary hypogonadism, or congenital or acquired hypogonadotropic hypogonadism Approval consideration: REMS

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Copaxone (new dosage) (Glatiramer acetate; Teva Pharmaceutical Industries) Class/route: Immunomodulator; subcutaneous injection New dosage: Three-times weekly of 40 mg/mL, a less frequent dose than the 20 mg/mL daily that is still available for use Indication: For the treatment of patients with relapsing form of multiple sclerosis Dyloject (new dosage form) (Diclofenac; Hospira) Class/route: NSAID; intravenous New dosage form: Intravenous bolus injection over 15 seconds Indications: For use in adults for the management of mild-to-moderate pain and for the management of moderate-to-severe pain alone or in combination with opioid analgesics Embeda (new formulation) (Morphine sulfate and naltrexone hydrochloride; Pfizer) Classes/route: Opioid agonist and opioid antagonist; oral New formulation: Has properties that are expected to Âreduce oral abuse when the drug is crushed; capsules should be swallowed whole to avoid exposure to a potentially fatal dose of morphine 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

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Epanova (new formulation) (Omega-3-carboxylic acids; AstraZeneca) Class/route: Omega-3 fatty acid; oral New formulation: Omega-3 in free fatty acid form Indications: As an adjunct to diet to reduce triglyceride levels in adults with severe (≥500 mg/dL) hypertriglyceridemia Erwinaze (new dosage form) (Asparaginase Erwinia chrysanthemi; Jazz Pharmaceuticals) Class/routes: Antineoplastic; intramuscular, intravenous New dosage form: Intravenous Indication: As a component of a multiagent chemotherapeutic regimen for the treatment of patients with acute lymphoblastic leukemia who have developed hypersensitivity to Escherichia coli–derived asparaginase Evzio (new formulation) (Naloxone hydrochloride; Kaleo) Class/routes: Opioid antagonist; intramuscular, subcutaneous New formulation: Handheld autoinjector Indication: For the treatment of proliferating infantile hemangioma requiring systemic therapy Approval consideration: Priority review

Hemangeol (new formulation) (Propranolol hydrochloride; Pierre Fabre Dermatologie) Class/route: Beta-adrenergic blocker; oral New formulation: Oral solution for pediatric use Indication: For the treatment of proliferating infantile hemangioma requiring systemic therapy Approval consideration: Orphan drug Hysingla ER (new formulation) (Hydrocodone bitartrate; Purdue Pharma) Class/route: Opioid agonist; oral New formulation: Extended-release opioid tablet with abuse-deterrent properties that make it difficult to crush, break, or dissolve, which is intended to reduce, but not entirely prevent, abuse of the drug when taken

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Iluvien (new dosage form) (Fluocinolone acetonide intravitreal implant; Alimera Sciences) Class/route: Corticosteroid; intravitreal injection New dosage form: Single injection of the microinsert provides sustained treatment for 36 months Indication: Treatment of diabetic macular edema in patients who have been previously treated with a course of corticosteroids and did not have a clinically significant rise in intraocular pressure Incruse Ellipta (new formulation) (Umeclidinium; GlaxoSmithKline) Class/route: Anticholinergic; oral inhalation New formulation: Once-daily bronchodilator Indication: For long-term, once-daily maintenance treatment of airflow obstruction in patients with COPD

Granix (new dosage form) (Tbo-filgrastim; Teva Pharmaceutical Industries) Class/route: Leukocyte growth factor; subcutaneous New dosage form: Injection for self-administration by patients and caregivers; previously only for administration by a healthcare professional Indication: For reduction in the duration of severe neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia

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orally/chewed 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 Approval considerations: Priority review, REMS

Izba (new dosage) (Travoprost; Alcon Laboratories) Class/route: Prostaglandin analog; ophthalmic solution New dosage: 0.003% ophthalmic solution; already available as a 0.004% solution Indication: For reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension Kalbitor (new patient population) (Ecallantide; Dyax Corporation) Class/route: Plasma kallikrein inhibitor; subcutaneous New patient population: For the treatment of patients aged ≥12 years; previously indicated only for adults Indication: Treatment of acute attacks of hereditary angioedema in patients aged ≥12 years Kalydeco (new patient population) (Ivacaftor; Vertex Pharmaceuticals Incorporated) Class/route: CFTR; oral New patient population: Treatment of cystic fibrosis in patients aged ≥6 years who have the R117H mutation in the CFTR gene Indication: For the treatment of cystic fibrosis in patients aged ≥6 years who have 1 of the following mutations in the CFTR gene: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R [2015 new patient population: All indications were expanded to include patients aged 2-5 years]

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Kerydin (new dosage form) (Tavaborole; Anacor Pharmaceuticals) Class/route: Oxaborole antifungal; topical New dosage form: First oxaborole antifungal available as a topical solution Indication: Topical treatment of onychomycosis of the toenails from Trichophyton rubrum or Trichophyton mentagrophytes Lumizyme (new patient population) (Alglucosidase alfa; Genzyme Corporation) Class/route: Hydrolytic lysosomal glycogen-specific enzyme; intravenous New patient population: Treatment of patients with infantile-onset Pompe disease, including patients aged <8 years Existing indication: For patients aged ≥8 years with Pompe disease Minivelle (new dosage) See New Combinations/ Indications listing Monovisc (new dosage form) (Sodium hyaluronate; Anika Therapeutics) Class/route: High-molecular-weight hyaluronic acid; intra-articular New dosage form: First FDA-approved single injection with hyaluronic acid from a nonanimal source Indication: For the treatment of pain in osteoarthritis of the knee in patients who have failed to respond adequately to conservative nonpharmacologic therapy or simple analgesics (eg, acetaminophen) Natesto (new formulation) (Testosterone; Endo Pharmaceuticals) Class/route: Androgen; intranasal New formulation: Nasal gel; already available as a topical gel, subcutaneous pellet, transdermal patch, oral tablet, intramuscular injection, buccal patch Indication: For replacement therapy in males for conditions associated with a deficiency or absence of endogenous testosterone Noxafil (new formulation) (Posaconazole; Merck Sharp & Dohme Corporation) Class/routes: Azole antifungal; intravenous, oral New formulation: Intravenous injection; already available as delayed-release tablets and oral suspension Indications: As an intravenous injection, delayed-release tablets, and oral suspension, for prophylaxis of invasive Aspergillus and Candida infections in patients at high risk of developing these infections as a result of being severely immunocompromised, such as recipients of hematopoietic stem-cell transplant with graft versus host

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disease or those with hematologic malignancies with prolonged neutropenia from chemotherapy; as an oral suspension, for the treatment of oropharyngeal candidiasis, including oropharyngeal candidiasis refractory to itraconazole and/or fluconazole Approval consideration: Priority review Pennsaid 2% (new dosage) (Diclofenac sodium; Horizon Pharma) Class/route: NSAID; topical Indication: For the treatment of osteoarthritis pain of the knee New dosage: First twice-daily topical NSAID available in the United States for the treatment of pain of osteoarthritis of the knee Priftin (new patient population) See New Combinations/ Indications listing Purixan (new formulation) (Mercaptopurine; Nova Laboratories) Class/route: Nucleoside metabolic inhibitor; oral New formulation: Oral suspension Indication: For the treatment of patients with acute lymphoblastic leukemia as a component of a combination maintenance therapy regimen Approval consideration: Orphan drug QNASL (new formulation, new patient population) (Beclomethasone dipropionate; Teva Pharmaceutical Industries) Class/route: Corticosteroid; intranasal New formulation: 40-mcg nasal aerosol for children aged 4-11 years; already available in 80-mcg nasal aerosol for patients aged ≥12 years Indication: For the treatment of nasal symptoms associated with allergic rhinitis Qudexy XR (new formulation) (Topiramate; Upsher-Smith Laboratories) Class/route: Antiepileptic; oral New formulation: Extended-release capsules Indications: As initial monotherapy in patients aged ≥10 years with partial-onset or primary generalized tonic-clonic seizures; as an adjunctive therapy in patients ≥2 years with partial-onset or primary generalized tonic-clonic seizures; and as an adjunctive therapy in patients ≥2 years with seizures associated with Lennox- Gastaut syndrome

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NOVEL PHARMACEUTICALS 2014

Rapivab (new formulation) (Peramivir; BioCryst Pharmaceuticals) Class/route: Neuraminidase inhibitor; intravenous New formulation: Single intravenous dose Indication: Treatment of acute uncomplicated influenza in patients aged ≥18 years who have been symptomatic for no more than 2 days Rasuvo (new formulation) (Methotrexate; Medac Pharma) Class/route: Folate analog metabolic inhibitor; subcutaneous New formulation: Subcutaneous; already available in oral, intramuscular, intravenous, intra-arterial, and intrathecal formulations Indications: For the management of patients with severe, active rheumatoid arthritis or with 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 Retin-A Micro (new dosage form) (Tretinoin gel; Valeant Pharmaceuticals) Class/route: Retinoid; topical New dosage form: Tretinoin gel microsphere, 0.08% Indication: Treatment of acne vulgaris Reyataz (new formulation) (Atazanavir; Bristol-Myers Squibb) Class/route: Protease inhibitor; oral New formulation: Oral powder; already available as a capsule Indication: For use in combination with other antiretroviral agents for the treatment of HIV-1 infection for patients aged ≥3 months weighing ≥10 kg Approval consideration: Priority review Ryanodex (new dosage) (Dantrolene sodium; Eagle Pharmaceuticals) Class/route: Skeletal muscle relaxant; intravenous New dosage: 250-mg single-vial dose Indications: Treatment of malignant hyperthermia in conjunction with appropriate supportive measures, and for the prevention of malignant hyperthermia in patients at high risk Approval considerations: Priority review, orphan drug Signafor Lar (new formulation) (Pasireotide; Novartis) Class/route: Somatostatin analog; intramuscular New formulation: Injectable suspension Indication: For the treatment of patients with acromegaly who have had an inadequate response to surgery and/

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or for whom surgery is not an option Approval consideration: Orphan drug Soolantra (new formulation) See New Combinations/ Indications listing Sotylize (new formulation) (Sotalol hydrochloride; Arbor Pharmaceuticals) Class/route: Antiarrhythmic; oral New formulation: Oral solution; already available as an oral tablet Indications: For the treatment of life-threatening ventricular arrhythmias, and for the maintenance of normal sinus rhythm in patients with highly symptomatic atrial fibrillation/flutter Spiriva Respimat (new dosage form) (Tiotropium bromide; Boehringer Ingelheim) Class/route: Anticholinergic; oral inhalation New dosage form: Slow-moving mist in an inhaled spray Indications: For the long-term, once-daily maintenance treatment of bronchospasm associated with COPD and for reducing COPD exacerbations Targiniq ER (new formulation) (Oxycodone hydrochloride extended-release and naloxone hydrochloride extended-release tablets; Purdue Pharma) Classes/route: Opioid agonist and opioid antagonist; oral New formulation: Extended-release/long-acting oral tablets with abuse-deterrent properties that are expected to deter, but not entirely prevent, opioid abuse via snorting or injection 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 Approval consideration: REMS Tivorbex (new dosages) (Indomethacin; Iroko Pharmaceuticals) Class/route: NSAID; oral New dosages: 20 mg orally 3 times daily or 40 mg orally 2 or 3 times daily; already available as 25-mg and 50-mg doses Indication: For the treatment of mild-to-moderate acute pain in adults Tybost (new formulation) (Cobicistat; Gilead Sciences) Class/route: CYP3A inhibitor; oral New formulation: Administered once daily in combination with the protease inhibitors atazanavir or darunavir

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NOVEL PHARMACEUTICALS 2014

Indication: To increase systemic exposure of atazanavir or darunavir (once-daily dosing regimen) in combination with other antiretroviral agents in the treatment of HIV-1 infection Uceris (new formulation) (Budesonide; Salix Pharmaceuticals) Class/route: Glucocorticosteroid; rectal foam New formulation: Rectal foam; already available in extended-release tablet Indication: For the induction of remission in patients with active mild-to-moderate distal ulcerative colitis extending up to 40 cm from the anal verge Vazculep (new dosages/formulation) (Phenylephrine hydrochloride; Éclat Pharmaceuticals) Class/route: Alpha-1 adrenergic receptor agonist; intravenous New dosages/formulation: 5-mL and 10-mL pharmacy bulk package vials; already available as a 1-mL single-use vial Indication: For the treatment of clinically important hypotension resulting primarily from vasodilation in the setting of anesthesia Vogelxo (new formulation) (Testosterone; Upsher-Smith Laboratories) Class/route: Androgen; topical

New formulation: Gel formulation Indication: For testosterone replacement therapy in males for conditions associated with a deficiency or absence of endogenous testosterone, such as primary hypogonadism (congenital or acquired) and hypogonadotropic hypogonadism (congenital or acquired) Xartemis XR (new formulation) (Oxycodone hydrochloride and acetaminophen; Mallinckrodt Brand Pharmaceuticals) Class/route: Opioid agonist; oral New formulation: Extended-release tablet Indication: For the management of acute pain severe enough to require opioid treatment and for which alternative treatment options are inadequate Approval consideration: Priority review Zubsolv (new dosage) (Buprenorphine and naloxone; Orexo US) Class/route: Partial opioid agonist; sublingual New dosages: 8.6-mg/2.1-mg and 11.4-mg/2.9-mg buprenorphine/naloxone CIII sublingual tablets; already available as 5.7-mg/1.4-mg and 1.4-mg/0.36-mg tablets Indication: For the maintenance treatment of opioid dependence

CFTR indicates cystic fibrosis transmembrane conductance regulator; COPD, chronic obstructive pulmonary disease; GLP-1, glucagon-like peptide-1; NSAID, nonsteroidal anti-inflammatory drug; REMS, Risk Evaluation and Mitigation Strategy.

IV. New Vaccines and New Blood Products Approved in 2014 Alprolix (new blood product) (Coagulation factor IX [recombinant], Fc fusion protein; Biogen Idec) Route: Intravenous Indications: In adults and children with hemophilia B to control and prevent bleeding episodes, for perioperative management, and for routine prophylaxis to prevent or reduce the frequency of bleeding episodes Elocate (new blood product) (Antihemophilic factor [recombinant], Fc fusion protein; Biogen Idec) Route: Intravenous Indications: In adults and children with hemophilia A (congenital factor VIII deficiency) for the control and

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prevention of bleeding episodes, for perioperative management, and for routine prophylaxis to prevent or reduce the frequency of bleeding episodes Fluzone Quadrivalent (new vaccine) (Influenza vaccine; Sanofi Pasteur) Route: Intradermal Indication: For active immunization for the prevention of influenza disease caused by influenza A subtype viruses and influenza type B viruses contained in the vaccine Gardasil 9 (new vaccine) (Human papillomavirus 9-valent vaccine, recombinant; Merck Sharp & Dohme Corporation) Route: Intramuscular

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Indications: For girls and women aged 9-26 years for the prevention of cervical, vulvar, vaginal, and anal cancer caused by HPV types 16, 18, 31, 33, 45, 52, and 58; genital warts caused by HPV types 6 and 11; and precancerous or dysplastic lesions caused by HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58, including CIN grade 2/3 and cervical adenocarcinoma in situ, cervical intraepithelial neoplasia grade 1, vulvar intraepithelial neoplasia grades 2 and 3, vaginal intraepithelial neoplasia grades 2 and 3, and anal intraepithelial neoplasia grades 1, 2, and 3. Also for boys aged 9-15 years for the prevention of anal cancer caused by HPV types 16, 18, 31, 33, 45, 52, and 58; genital warts caused by HPV types 6 and 11; and precancerous or dysplastic lesions caused by HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58; and anal intraepithelial neoplasia grades 1, 2, and 3

Obizur (new blood product) (Antihemophilic factor [recombinant], porcine sequence; Baxter International) Route: Intravenous Indication: Treatment of bleeding episodes in adults with acquired hemophilia A Ruconest (new blood product) (C1 esterase inhibitor [recombinant]; Salix Pharmaceuticals) Route: Intravenous Indication: For the treatment of acute attacks in adult and adolescent patients with hereditary angioedema Trumenba (new vaccine) (Meningococcal group B vaccine; Wyeth Pharmaceuticals) Route: Intramuscular Indication: For active immunization to prevent invasive disease caused by Neisseria meningitidis serogroup B in individuals aged 10-25 years

CIN indicates cervical intraepithelial neoplasia; HPV, human papillomavirus.

V. Drugs Already Marketed Without an FDA-Approved New Drug Application Vasostrict (Vasopressin; Par Pharmaceutical) Class/route: Peripheral vasoconstrictor; intravenous

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Indication: To increase blood pressure in adults with vasodilatory shock (eg, postcardiotomy or sepsis) who remain hypotensive despite fluids and catecholamines

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Introducing the first and FDA-approved treatment

patients with polycythemia vera an inadequate response to or are In a phase 3 trial of Jakafi® (ruxolitinib) vs best available therapy: 21% of patients receiving Jakafi achieved the primary composite end point of hematocrit (Hct) control and spleen volume reduction compared with <1% of patients on best available therapy at week 32 (P < 0.0001)*

Indications and Usage Jakafi is indicated for treatment of patients with polycythemia vera who have had an inadequate response to or are intolerant of hydroxyurea.

Important Safety Information Treatment with Jakafi can cause thrombocytopenia, anemia and neutropenia, which are each dose‐related effects. Perform a pre‐treatment complete blood count (CBC) and monitor CBCs every 2 to 4 weeks until doses are stabilized, and then as clinically indicated Manage thrombocytopenia by reducing the dose or temporarily interrupting Jakafi. Platelet transfusions may be necessary Patients developing anemia may require blood transfusions and/or dose modifications of Jakafi Severe neutropenia (ANC <0.5 X 109/L) was generally reversible by withholding Jakafi until recovery Serious bacterial, mycobacterial, fungal and viral infections have occurred. Delay starting Jakafi until active serious infections have resolved. Observe patients receiving Jakafi for signs and symptoms of infection and manage promptly

Tuberculosis (TB) infection has been reported. Observe patients taking Jakafi for signs and symptoms of active TB and manage promptly. Prior to initiating Jakafi, evaluate patients for TB risk factors and test those at higher risk for latent infection. Consult a physician with expertise in the treatment of TB before starting Jakafi in patients with evidence of active or latent TB. Continuation of Jakafi during treatment of active TB should be based on the overall risk‐benefit determination Progressive multifocal leukoencephalopathy (PML) has occurred with ruxolitinib treatment for myelofibrosis. If PML is suspected, stop Jakafi and evaluate Advise patients about early signs and symptoms of herpes zoster and to seek early treatment When discontinuing Jakafi, myeloproliferative neoplasm-related symptoms may return within one week. After discontinuation, some patients with myelofibrosis have experienced fever, respiratory distress, hypotension, DIC, or multi‐organ failure. If any of these occur after discontinuation or while tapering Jakafi, evaluate and treat any intercurrent

only for

who have had intolerant of hydroxyurea

Visit www.jakafi.com/HCP illness and consider restarting or increasing the dose of Jakafi. Instruct patients not to interrupt or discontinue Jakafi without consulting their physician. When discontinuing or interrupting Jakafi for reasons other than thrombocytopenia or neutropenia, consider gradual tapering rather than abrupt discontinuation Non-melanoma skin cancers including basal cell, squamous cell, and Merkel cell carcinoma have occurred. Perform periodic skin examinations The three most frequent non‐hematologic adverse reactions (incidence >10%) were bruising, dizziness and headache A dose modification is recommended when administering Jakafi with strong CYP3A4 inhibitors or fluconazole or in patients with renal or hepatic impairment. Patients should be closely monitored and the dose titrated based on safety and efficacy Use of Jakafi during pregnancy is not recommended and should only be used if the potential benefit justifies the potential risk to the fetus. Women taking Jakafi should not breast‐feed Please see Brief Summary of Full Prescribing Information for Jakafi on the following page.

to see Full Prescribing Information and learn more about Jakafi for use in PV

* A randomized, open-label, active-controlled phase 3 trial comparing Jakafi with best available therapy in 222 patients. Best available therapy included hydroxyurea (60%), interferon/pegylated interferon (12%), anagrelide (7%), pipobroman (2%), lenalidomide/thalidomide (5%), and observation (15%). The primary end point was the proportion of subjects achieving a response at week 32, with response defined as having achieved both Hct control (the absence of phlebotomy eligibility beginning at the week 8 visit and continuing through week 32) and spleen volume reduction (a ≥35% reduction from baseline in spleen volume at week 32). Phlebotomy eligibility was defined as Hct >45% that is ≥3 percentage points higher than baseline or Hct >48% (lower value). Reference: 1. Jakafi Prescribing Information. Wilmington, DE: Incyte Corporation.

BRIEF SUMMARY: For Full Prescribing Information, see package insert. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Thrombocytopenia, Anemia and Neutropenia Treatment with Jakafi can cause thrombocytopenia, anemia and neutropenia. [see Dosage and Administration (2.1) in Full Prescribing Information]. Manage thrombocytopenia by reducing the dose or temporarily interrupting Jakafi. Platelet transfusions may be necessary [see Dosage and Administration (2.1.1) and Adverse Reactions (6.1) in Full Prescribing Information]. Patients developing anemia may require blood transfusions and/or dose modifications of Jakafi. Severe neutropenia (ANC less than 0.5 X 109/L) was generally reversible by withholding Jakafi until recovery [see Adverse Reactions (6.1)]. Perform a pre-treatment complete blood count (CBC) and monitor CBCs every 2 to 4 weeks until doses are stabilized, and then as clinically indicated. [see Dosage and Administration (2.1.1) and Adverse Reactions (6.1) in Full Prescribing Information]. Risk of Infection Serious bacterial, mycobacterial, fungal and viral infections have occurred. Delay starting therapy with Jakafi until active serious infections have resolved. Observe patients receiving Jakafi for signs and symptoms of infection and manage promptly. Tuberculosis Tuberculosis infection has been reported in patients receiving Jakafi. Observe patients receiving Jakafi for signs and symptoms of active tuberculosis and manage promptly. Prior to initiating Jakafi, patients should be evaluated for tuberculosis risk factors, and those at higher risk should be tested for latent infection. Risk factors include, but are not limited to, prior residence in or travel to countries with a high prevalence of tuberculosis, close contact with a person with active tuberculosis, and a history of active or latent tuberculosis where an adequate course of treatment cannot be confirmed. For patients with evidence of active or latent tuberculosis, consult a physician with expertise in the treatment of tuberculosis before starting Jakafi. The decision to continue Jakafi during treatment of active tuberculosis should be based on the overall risk-benefit determination. PML Progressive multifocal leukoencephalopathy (PML) has occurred with ruxolitinib treatment for myelofibrosis. If PML is suspected, stop Jakafi and evaluate. Herpes Zoster Advise patients about early signs and symptoms of herpes zoster and to seek treatment as early as possible if suspected [see Adverse Reactions (6.1)]. Symptom Exacerbation Following Interruption or Discontinuation of Treatment with Jakafi Following discontinuation of Jakafi, symptoms from myeloproliferative neoplasms may return to pretreatment levels over a period of approximately one week. Some patients with myelofibrosis have experienced one or more of the following adverse events after discontinuing Jakafi: fever, respiratory distress, hypotension, DIC, or multi-organ failure. If one or more of these occur after discontinuation of, or while tapering the dose of Jakafi, evaluate for and treat any intercurrent illness and consider restarting or increasing the dose of Jakafi. Instruct patients not to interrupt or discontinue Jakafi therapy without consulting their physician. When discontinuing or interrupting therapy with Jakafi for reasons other than thrombocytopenia or neutropenia [see Dosage and Administration (2.5) in Full Prescribing Information], consider tapering the dose of Jakafi gradually rather than discontinuing abruptly. Non-Melanoma Skin Cancer Non-melanoma skin cancers including basal cell, squamous cell, and Merkel cell carcinoma have occurred in patients treated with Jakafi. Perform periodic skin examinations. ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling: • Thrombocytopenia, Anemia and Neutropenia [see Warnings and Precautions (5.1)] • Risk of Infection [see Warnings and Precautions (5.2)] • Symptom Exacerbation Following Interruption or Discontinuation of Treatment with Jakafi [see Warnings and Precautions (5.3)] • Non-Melanoma Skin Cancer [see Warnings and Precautions (5.4)]. 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. Clinical Trials Experience in Myelofibrosis The safety of Jakafi was assessed in 617 patients in six clinical studies with a median duration of follow-up of 10.9 months, including 301 patients with myelofibrosis in two Phase 3 studies. In these two Phase 3 studies, patients had a median duration of exposure to Jakafi of 9.5 months (range 0.5 to 17 months), with 89% of patients treated for more than 6 months and 25% treated for more than 12 months. One hundred and eleven (111) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. In patients starting treatment with 15 mg twice daily (pretreatment platelet counts of 100 to 200 X 109/L) and 20 mg twice daily (pretreatment platelet counts greater than 200 X 109/L), 65% and 25% of patients, respectively, required a dose reduction below the starting dose within the first 8 weeks of therapy. In a double-blind, randomized, placebocontrolled study of Jakafi, among the 155 patients treated with Jakafi, the most frequent adverse drug reactions were thrombocytopenia and anemia [see Table 2 ]. Thrombocytopenia, anemia and neutropenia are dose related effects. The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache [see Table 1]. Discontinuation for adverse events, regardless of causality, was observed in 11% of patients treated with Jakafi and 11% of patients treated with placebo. Table 1 presents the most common adverse reactions occurring in patients who received Jakafi in the double-blind, placebo-controlled study during randomized treatment. Table 1: Myelofibrosis: Adverse Reactions Occurring in Patients on Jakafi in the Double-blind, Placebo-controlled Study During Randomized Treatment Jakafi Placebo (N=155) (N=151) Adverse Reactions

a b

c d

e f

Jakafi (N=155) Laboratory Parameter

All Gradesb (%)

Grade 3 (%)

Placebo (N=151) Grade 4 (%)

All Grades (%)

Grade 3 (%)

Grade 4 (%)

Thrombocytopenia

Anemia

Neutropenia

a b

Presented values are worst Grade values regardless of baseline National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0

Additional Data from the Placebo-controlled Study 25% of patients treated with Jakafi and 7% of patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine transaminase (ALT). The incidence of greater than or equal to Grade 2 elevations was 2% for Jakafi with 1% Grade 3 and no Grade 4 ALT elevations. 17% of patients treated with Jakafi and 6% of patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase (AST). The incidence of Grade 2 AST elevations was <1% for Jakafi with no Grade 3 or 4 AST elevations. 17% of patients treated with Jakafi and <1% of patients treated with placebo developed newly occurring or worsening Grade 1 elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was <1% for Jakafi with no Grade 3 or 4 cholesterol elevations. Clinical Trial Experience in Polycythemia Vera In a randomized, open-label, active-controlled study, 110 patients with polycythemia vera resistant to or intolerant of hydroxyurea received Jakafi and 111 patients received best available therapy [see Clinical Studies (14.2) in Full Prescribing Information]. The most frequent adverse drug reaction was anemia. Table 3 presents the most frequent non-hematologic treatment emergent adverse events occurring up to Week 32. Discontinuation for adverse events, regardless of causality, was observed in 4% of patients treated with Jakafi. Table 3: Polycythemia Vera: Treatment Emergent Adverse Events Occurring in ≥ 6% of Patients on Jakafi in the Open-Label, Active-controlled Study up to Week 32 of Randomized Treatment Jakafi (N=110) Adverse Events

Grade 4 (%)

Best Available Therapy (N=111)

All Gradesa (%)

Grade 3-4 (%)

All Grades (%)

Headache

Abdominal Painb

Diarrhea

Dizzinessc

Fatigue

Pruritus

Dyspnead

Muscle Spasms

Nasopharyngitis

Constipation

Cough

Grade 3-4 (%)

All Grades (%)

Grade 3 (%)

Bruisingb

Edemae

Dizzinessc

Arthralgia

Headache

Asthenia

Urinary Tract Infectionsd

Epistaxis

Weight Gaine

Herpes Zosterf

Flatulence

Nausea

Herpes Zosterf

Grade 4 All Grades Grade 3 (%) (%) (%)

Description of Selected Adverse Drug Reactions Anemia In the two Phase 3 clinical studies, median time to onset of first CTCAE Grade 2 or higher anemia was approximately 6 weeks. One patient (<1%) discontinued treatment because of anemia. In patients receiving Jakafi, mean decreases in hemoglobin reached a nadir of approximately 1.5 to 2.0 g/dL below baseline after 8 to 12 weeks of therapy and then gradually recovered to reach a new steady state that was approximately 1.0 g/dL below baseline. This pattern was observed in patients regardless of whether they had received transfusions during therapy. In the randomized, placebo-controlled study, 60% of patients treated with Jakafi and 38% of patients receiving placebo received red blood cell transfusions during randomized treatment. Among transfused patients, the median number of units transfused per month was 1.2 in patients treated with Jakafi and 1.7 in placebo treated patients. Thrombocytopenia In the two Phase 3 clinical studies, in patients who developed Grade 3 or 4 thrombocytopenia, the median time to onset was approximately 8 weeks. Thrombocytopenia was generally reversible with dose reduction or dose interruption. The median time to recovery of platelet counts above 50 X 109/L was 14 days. Platelet transfusions were administered to 5% of patients receiving Jakafi and to 4% of patients receiving control regimens. Discontinuation of treatment because of thrombocytopenia occurred in <1% of patients receiving Jakafi and <1% of patients receiving control regimens. Patients with a platelet count of 100 X 109/L to 200 X 109/L before starting Jakafi had a higher frequency of Grade 3 or 4 thrombocytopenia compared to patients with a platelet count greater than 200 X 109/L (17% versus 7%). Neutropenia In the two Phase 3 clinical studies, 1% of patients reduced or stopped Jakafi because of neutropenia. Table 2 provides the frequency and severity of clinical hematology abnormalities reported for patients receiving treatment with Jakafi or placebo in the placebocontrolled study. Table 2: Myelofibrosis: Worst Hematology Laboratory Abnormalities in the Placebo-Controlled Studya

a b

National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 includes abdominal pain, abdominal pain lower, and abdominal pain upper includes dizziness and vertigo includes dyspnea and dyspnea exertional includes edema and peripheral edema includes herpes zoster and post-herpetic neuralgia

National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 c includes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site d hematoma, increased tendency to bruise, petechiae, purpura e includes dizziness, postural dizziness, vertigo, balance disorder, Meniere’s Disease, labyrinthitis f includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria urine, Other clinically important treatment emergent adverse events observed in less than 6% of patients bacteria urine identified, nitrite urine present treated with Jakafi were: Weight gain, hypertension, and urinary tract infections includes weight increased, abnormal weight gain Clinically relevant laboratory abnormalities are shown in Table 4. includes herpes zoster and post-herpetic neuralgia

Table 4: Polycythemia Vera: Selected Laboratory Abnormalities in the Open-Label, Active-controlled Study up to Week 32 of Randomized Treatmenta Jakafi (N=110) Laboratory Parameter

All Gradesb Grade 3 (%) (%)

Best Available Therapy (N=111) Grade 4 (%)

All Grades (%)

Grade 3 (%)

Grade 4 (%)

Hematology Anemia

Thrombocytopenia

Neutropenia

Chemistry Hypercholesterolemia

Elevated ALT

Elevated AST

Hypertriglyceridemia

a b

Presented values are worst Grade values regardless of baseline National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0

DRUG INTERACTIONS Drugs That Inhibit or Induce Cytochrome P450 Enzymes Ruxolitinib is metabolized by CYP3A4 and to a lesser extent by CYP2C9. CYP3A4 inhibitors: The Cmax and AUC of ruxolitinib increased 33% and 91%, respectively following concomitant administration with the strong CYP3A4 inhibitor ketoconazole in healthy subjects. Concomitant administration with mild or moderate CYP3A4 inhibitors did not result in an exposure change requiring intervention [see Pharmacokinetics (12.3) in Full Prescribing Information]. When administering Jakafi with strong CYP3A4 inhibitors, consider dose reduction [see Dosage and Administration (2.3) in Full Prescribing Information]. Fluconazole: The AUC of ruxolitinib is predicted to increase by approximately 100% to 300% following concomitant administration with the combined CYP3A4 and CYP2C9 inhibitor fluconazole at doses of 100 mg to 400 mg once daily, respectively [see Pharmacokinetics (12.3) in Full Prescribing Information]. Avoid the concomitant use of Jakafi with fluconazole doses of greater than 200 mg daily [see Dosage and Administration (2.3) in Full Prescribing Information]. CYP3A4 inducers: The Cmax and AUC of ruxolitinib decreased 32% and 61%, respectively, following concomitant administration with the strong CYP3A4 inducer rifampin in healthy subjects. No dose adjustment is recommended; however, monitor patients frequently and adjust the Jakafi dose based on safety and efficacy [see Pharmacokinetics (12.3) in Full Prescribing Information]. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: Risk Summary There are no adequate and well-controlled studies of Jakafi in pregnant women. In embryofetal toxicity studies, treatment with ruxolitinib resulted in an increase in late resorptions and reduced fetal weights at maternally toxic doses. Jakafi should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Animal Data Ruxolitinib was administered orally to pregnant rats or rabbits during the period of organogenesis, at doses of 15, 30 or 60 mg/kg/day in rats and 10, 30 or 60 mg/kg/day in rabbits. There was no evidence of teratogenicity. However, decreases of approximately 9% in fetal weights were noted in rats at the highest and maternally toxic dose of 60 mg/kg/day. This dose results in an exposure (AUC) that is approximately 2 times the clinical exposure at the maximum recommended dose of 25 mg twice daily. In rabbits, lower fetal weights of approximately 8% and increased late resorptions were noted at the highest and maternally toxic dose of 60 mg/kg/day. This dose is approximately 7% the clinical exposure at the maximum recommended dose. In a pre- and post-natal development study in rats, pregnant animals were dosed with ruxolitinib from implantation through lactation at doses up to 30 mg/kg/day. There were no drug-related adverse findings in pups for fertility indices or for maternal or embryofetal survival, growth and development parameters at the highest dose evaluated (34% the clinical exposure at the maximum recommended dose of 25 mg twice daily). Nursing Mothers It is not known whether ruxolitinib is excreted in human milk. Ruxolitinib and/or its metabolites were excreted in the milk of lactating rats with a concentration that was 13-fold the maternal plasma. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Jakafi, a decision should be made 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 Jakafi in pediatric patients have not been established. Geriatric Use Of the total number of myelofibrosis patients in clinical studies with Jakafi, 52% were 65Â years of age and older. No overall differences in safety or effectiveness of Jakafi were observed between these patients and younger patients. Renal Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in healthy subjects [CrCl 72-164 mL/min (N=8)] and in subjects with mild [CrCl 53-83 mL/min (N=8)], moderate [CrCl 38-57 mL/min (N=8)], or severe renal impairment [CrCl 15-51 mL/min (N=8)]. Eight (8) additional subjects with end stage renal disease requiring hemodialysis were also enrolled. The pharmacokinetics of ruxolitinib was similar in subjects with various degrees of renal impairment and in those with normal renal function. However, plasma AUC values of ruxolitinib metabolites increased with increasing severity of renal impairment. This was most marked in the subjects with end stage renal disease requiring hemodialysis. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in metabolite exposure. Ruxolitinib is not removed by dialysis; however, the removal of some active metabolites by dialysis cannot be ruled out. When administering Jakafi to patients with myelofibrosis and moderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min) with a platelet count between 50 X 109/L and 150 X 109/L, a dose reduction is recommended. A dose reduction is also recommended for patients with polycythemia vera and moderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min). In all patients with end stage renal disease on dialysis, a dose reduction is recommended [see Dosage and Administration (2.4) in Full Prescribing Information]. Hepatic Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in healthy subjects (N=8) and in subjects with mild [Child-Pugh A (N=8)], moderate [Child-Pugh B (N=8)], or severe hepatic impairment [Child-Pugh C (N=8)]. The mean AUC for ruxolitinib was increased by 87%, 28% and 65%, respectively, in patients with mild, moderate and severe hepatic impairment compared to patients with normal hepatic function. The terminal elimination half-life was prolonged in patients with hepatic impairment compared to healthy controls (4.1-5.0 hours versus 2.8 hours). The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in ruxolitinib exposure except in the severe (Child-Pugh C) hepatic impairment cohort where the pharmacodynamic activity was more prolonged in some subjects than expected based on plasma concentrations of ruxolitinib. When administering Jakafi to patients with myelofibrosis and any degree of hepatic impairment and with a platelet

count between 50 X 109/L and 150 X 109/L, a dose reduction is recommended. A dose reduction is also recommended for patients with polycythemia vera and hepatic impairment [see Dosage and Administration (2.4) in Full Prescribing Information]. OVERDOSAGE There is no known antidote for overdoses with Jakafi. Single doses up to 200 mg have been given with acceptable acute tolerability. Higher than recommended repeat doses are associated with increased myelosuppression including leukopenia, anemia and thrombocytopenia. Appropriate supportive treatment should be given. Hemodialysis is not expected to enhance the elimination of ruxolitinib. Jakafi is a registered trademark of Incyte. All rights reserved. U.S. Patent Nos. 7598257; 8415362; 8722693; 8822481; 8829013 ÂŠ 2011-2014 Incyte Corporation. All rights reserved. Issued: December 2014 RUX-1428

Afrezza (Insulin Human) Inhalation Powder Approved for the Treatment of Patients with Type 1 or Type 2 Diabetes By Loretta Fala, Medical Writer

iabetes is a chronic disease that is often accompanied by multiple comorbidities and health complications.1 In the United States, diabetes affects an estimated 29.1 million people—approximately 9.3% of the US population.1 An additional 37% of adults aged ≥20 years are estimated to have prediabetes, based on 2009-2012 data for fasting glucose or glycated hemoglobin (Hb) A1c.1 Furthermore, with the aging of the US population during the next few decades, the prevalence of diabetes is projected to increase from 1 in 10 adults today to a staggering 1 in 3 adults by 2050.2 In 2010, the American Diabetes Association (ADA) adopted the criterion of HbA1c levels ≥6.5% for a diagnosis of diabetes.3 Approximately 5% of all cases of diabetes are type 1 diabetes mellitus, and 90% to 95% of all cases are type 2 diabetes mellitus.1 Diabetes is the seventh leading cause of mortality in the United States. In fact, the death rate for patients with diabetes is 1.5 times higher than for individuals without diabetes.1 Aside from being a major cause of heart disease and stroke, diabetes is the leading cause of kidney failure, nontraumatic lower-limb amputations, and new cases of blindness among US adults.1 Moreover, patients with diabetes have an increased risk for other complications, including nerve disease, nonalcoholic fatty liver disease, periodontal disease, erectile dysfunction, hearing loss, depression, and pregnancy complications compared with individuals without diabetes.1 The annual US healthcare costs attributed to diabetes totaled $245 billion in 2012, including $176 billion in direct medical costs and $69 billion in reduced productivity (eg, increased absenteeism, reduced productivity, lost productivity resulting from early mortality, and the inability to work resulting from disability).4 These 2012 costs represent a 41% increase from the $174 billion in diabetes-related costs in 2007. Overall, the medical expenses for patients with diabetes are 2.3 times higher than expenses for individuals without diabetes.4 The management of diabetes is complex, generally requiring multiple risk-reduction strategies in addition to glycemic control.2 This demands an ongoing approach that considers the whole patient—glycemic control to prevent or reduce microvascular complications, as well as

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strategies to address obesity and prediabetes as underlying risk factors for diabetes and related macrovascular complications. These approaches often include dietary and other behavioral and lifestyle changes.5 The adequate control of HbA1c levels has been shown to reduce diabetes-associated morbidity and mortality by decreasing chronic complications.6 In fact, a 1% reduction in HbA1c levels is associated with a 35% reduction in diabetes-related microvascular complications, including diabetic neuropathy, nephropathy, and retinopathy.6 The ADA recommends a general target HbA1c level of <7% for adults with diabetes, based on a 2013 position statement on the standards of care for diabetes.6 According to the ADA, the stringency of this goal may need to be adapted based on the patient’s duration of diabetes, comorbidities, age, known cardiovascular or advanced microvascular complications, and other patient-specific factors.6 In a 2013 consensus statement, the American Association of Clinical Endocrinologists (AACE) recommended an HbA1c target goal of <6.5% in the majority of patients with type 2 diabetes, acknowledging that this goal may be too aggressive for some patients and not aggressive enough for others (ie, younger patients for whom a lower target may prevent later complications).5 The AACE also states that the goals of lifestyle modification and antihyperglycemic pharmacotherapy should aim to (1) achieve clinical and biochemical glucose targets, (2) avoid hypoglycemia, (3) reduce or avoid increasing cardiovascular risk, and (4) assist with weight loss and minimize weight gain in patients who are obese.5 Although progress has been made in the number of US patients who achieve the target HbA1c level of <7%, there remains a marked need for improvement.7 Ongoing clinical management, patient engagement, education, and the development of novel therapies may help to improve the achievement of glycemic control targets and outcomes for patients with diabetes.

FDA Approves Insulin Human Inhalation Powder On June 27, 2014, the US Food and Drug Administration (FDA) approved insulin human inhalation powder (Afrezza; MannKind Corporation), a rapid-acting

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inhaled insulin that is used to improve glycemic control in adults with diabetes.8 Insulin human inhalation powder is delivered via an inhaler that can be used for up to 15 days from the date of first use. In patients with type 1 diabetes, insulin human inhalation powder must be used with a long-acting insulin. Insulin human inhalation powder is not recommended for the treatment of diabetic ketoacidosis and is not recommended in patients who smoke.9 “Afrezza is a new treatment option for patients with diabetes requiring mealtime insulin,” said Jean-Marc Guettier, MD, Director of the FDA’s Division of Metabolism and Endocrinology Products. “Today’s approval broadens the options available for delivering mealtime insulin in the overall management of patients with diabetes who require it to control blood sugar levels.” 8

Mechanism of Action The new medication is a rapid-acting inhaled insulin. Insulin lowers HbA1c levels by stimulating peripheral glucose uptake via skeletal muscle and fat and by inhibiting hepatic glucose production. Insulin inhibits lipolysis in adipocytes, inhibits proteolysis, and enhances protein synthesis.9 The insulin contained in this new inhalation powder is regular human insulin. After pulmonary absorption into systemic circulation, the metabolism and elimination of this new insulin powder are comparable with regular human insulin. The peak insulin levels were achieved within 12 to 15 minutes after administration of insulin human inhalation powder, with serum insulin concentrations declining to baseline levels by approximately 180 minutes.9 Dosing and Administration Insulin human inhalation powder is available as single- use cartridges of 4 and 8 units.9 This medication is administered at the beginning of a meal using a single inhalation per cartridge. Dosing must be individualized. Before administering insulin human inhalation powder, a detailed medical history, physical examination, and spirometry (to assess pulmonary function) must be conducted in all patients to identify potential lung disease.9 Clinical Trials The safety and efficacy of insulin human inhalation powder were studied in 3017 adults with diabetes, including 1026 patients with type 1 diabetes and 1991 patients with type 2 diabetes.8,9 Its efficacy in patients with type 1 diabetes was compared with insulin aspart in combination with basal insulin. In patients with type 2 diabetes, insulin inhalation powder was studied in combination with oral antidiabetes drugs; its efficacy in patients with

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type 2 diabetes was compared with placebo inhalation.9 With the approval of insulin human inhalation powder, the FDA requires a Risk Evaluation and Mitigation Strategy program that includes a communication plan informing healthcare professionals about the drug’s association with the serious risk of acute bronchospasm.8 The FDA also requires several postmarketing studies, including a clinical trial to evaluate the drug’s safety and efficacy in pediatric patients; a clinical trial to assess the potential risk of pulmonary malignancy and the cardio vascular risk and long-term effects on pulmonary function; and 2 pharmacokinetic and pharmacodynamic euglycemic glucose clamp clinical trials (ie, 1 clinical trial to assess dose response and 1 clinical trial to assess within-subject variability).8

Type 1 Diabetes A 24-week, open-label, active-controlled study investigated the glucose-lowering effect of mealtime insulin human inhalation powder used in combination with a basal insulin in patients with inadequately controlled type 1 diabetes. After a 4-week basal insulin optimization Mealtime Insulin Human Inhalation Powder plus Basal Table 1 Insulin versus Insulin Aspart plus Basal Insulin in Adults with Type 1 Diabetes: Week 24 Insulin human Insulin inhalation aspart + powder + basal basal insulin insulin Efficacy parameter (N = 174) (N = 170) HbA1c level Baseline, adjusted mean, %

7.94

7.92

hange from baseline, adjusted C mean,a %

–0.21

–0.40

ifference from insulin aspart, D adjusted mean,a %

0.19 (95% CI, 0.02 to 0.36)

Patients achieving HbA1c ≤7%, %b

13.8

27.1

Baseline, adjusted mean, mg/dL

153.9

151.6

Change from baseline, adjusted mean,a mg/dL

–25.3

10.2

Difference from insulin aspart, adjusted mean,a mg/dL

–35.4 (95% CI, –56.3 to –14.6)

Fasting plasma glucose

Data at 24 weeks were available from 131 patients receiving insulin human inhalation powder and 150 patients receiving insulin aspart. b This percentage was calculated based on the number of patients randomized in the clinical trial. CI indicates confidence interval; HbA1c, glycated hemoglobin. Source: Afrezza (insulin human) inhalation powder prescribing information; June 2014. a

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Insulin Human Inhalation Powder versus Placebo in Table 2 Adults with Type 2 Diabetes Inadequately Controlled with Oral Agents: Week 24 Insulin human inhalation powder + Placebo + oral antidiabetic antidiabetic agents agents Efficacy parameter (N = 177) (N = 176) HbA1c level Baseline, adjusted mean, %

8.25

8.27

hange from baseline, C adjusted mean,a %

–0.82

–0.42

ifference from placebo, D adjusted mean,a %

–0.40 (95% CI, 0.57 to –0.23)

atients achieving HbA1c P ≤7%, %b

32.2

15.3

Fasting plasma glucose Baseline, adjusted mean, mg/dL

175.9

175.2

hange from baseline, C adjusted mean,a mg/dL

–11.2

–3.8

ifference from placebo, D adjusted mean,a mg/dL

–7.4 (95% CI, –18.0 to 3.2)

Data at 24 weeks were available from 131 patients receiving insulin human inhalation powder and 150 patients receiving insulin aspart. b This percentage was calculated based on the number of patients randomized in the clinical trial. CI indicates confidence interval; Hb, hemoglobin. Source: Afrezza (insulin human) inhalation powder prescribing information; June 2014. a

period, 344 patients were randomized to receive either insulin human inhalation powder or insulin aspart, administered at each meal of the day. Mealtime insulin doses were titrated to glycemic goals for the first 12 weeks, and were kept stable for the last 12 weeks of the study.9 At week 24, patients who received basal insulin and mealtime insulin human inhalation powder had a mean reduction in HbA1c levels that achieved the prespecified noninferiority margin of 0.4% (Table 1). Patients who received insulin human inhalation powder demonstrated less reduction in HbA1c levels than those receiving insulin aspart, and the difference was significant. In addition, more patients in the insulin aspart group achieved the target HbA1c level of <7% compared with patients who received insulin human inhalation powder (Table 1).9

Type 2 Diabetes A 24-week, double-blind, placebo-controlled study was conducted in 479 adults with type 2 diabetes whose

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disease was inadequately controlled with maximally tolerated doses of metformin only or with ≥2 oral antidiabetes agents. After a 6-week run-in period, 353 patients were randomized to receive either insulin human inhalation powder or an inhaled placebo powder without insulin. For the first 12 weeks, the insulin doses were titrated and were kept stable for the last 12 weeks of the study. The doses of oral antidiabetes agents were kept stable.9 At week 24, treatment with insulin human plus oral antidiabetes agents provided a significantly greater mean reduction in HbA1c levels compared with placebo (Table 2).9

Safety The most common adverse reactions (≥2%) associated with insulin human inhalation powder include hypoglycemia, cough, and throat pain or irritation.9 Contraindications The use of insulin human inhalation powder is contraindicated during episodes of hypoglycemia. It is also contraindicated in patients with chronic lung disease, such as asthma or chronic obstructive pulmonary disease (COPD). In addition, insulin human inhalation powder is contraindicated in patients with hypersensitivity to regular human insulin or any of the insulin human inhalation powder excipients.9 Drug Interactions Drugs that affect glucose metabolism. The adjustment of insulin dosage and an increased frequency of glucose monitoring may be required with insulin human inhalation powder if it is coadministered with drugs that may increase the risk for hypoglycemia, or drugs that may increase or decrease the blood glucose–lowering effect of insulin human inhalation powder.9 Drugs that may affect hypoglycemia. The signs and symptoms of hypoglycemia may be reduced or absent when antiadrenergic drugs (eg, beta-blockers, clonidine, guanethidine, and reserpine) are coadministered with insulin human inhalation powder.9 Warnings and Precautions Boxed warning. The prescribing information for insulin human inhalation powder contains a boxed warning stating that acute bronchospasm has been observed in patients with asthma and COPD who use insulin human inhalation powder. In addition, before initiating therapy with insulin human inhalation powder, a detailed medical history, physical examination, and spirometry should be performed to identify potential lung disease in all patients.9 Acute bronchospasm. Acute bronchospasm has been observed in patients with asthma and COPD. Spirometry should be performed in all patients before initiating

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treatment with insulin human inhalation powder. This medication should not be used in patients with chronic lung disease.9 Change in regimen. Changes in insulin strength, manufacturer, type, or method of administration may affect glycemic control and predispose an individual to hypoglycemia or hyperglycemia. These changes should be made under close medical supervision, and the frequency of blood glucose monitoring should be increased. The co administration of oral antidiabetic agents with insulin human inhalation powder may require adjustment.9 Hypoglycemia. Hypoglycemia may be life-threatening. The frequency of glucose monitoring should be increased with changes to insulin dosage, coadministered glucose-lowering medications, meal pattern, and physical activity, as well as in patients with renal or hepatic impairment and hypoglycemia unawareness.9 Decline in pulmonary function. Pulmonary function should be assessed before initiating therapy with insulin human inhalation powder, after 6 months of therapy, and annually, even in the absence of pulmonary symptoms.9 Lung cancer. Insulin human inhalation powder should not be used in patients with active lung cancer. In patients with a history of lung cancer or those who are at risk for lung cancer, the benefit of insulin human inhalation powder therapy should outweigh this potential risk.9 Diabetic ketoacidosis. More patients using insulin human inhalation powder experienced diabetic ketoacidosis in clinical trials than patients not using insulin human inhalation powder. Patients at risk for diabetic ketoacidosis should be monitored and changed to an alternate route of insulin delivery, if necessary.9 Hypersensitivity reactions. Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products, such as insulin human inhalation powder. The use of this medication should be discontinued, and patients should be monitored and treated, if necessary.9 Hypokalemia. Hypokalemia may be life-threatening. Potassium levels should be monitored in patients at risk for hypokalemia, and these patients should be treated, if necessary.9 Fluid retention and heart failure with the concomitant use of thiazolidinediones. Patients with diabetes should be observed for the signs and symptoms of heart failure; dosage reduction or discontinuation of insulin human inhalation powder should be considered if heart failure occurs.9

Use in Specific Populations Pregnancy. Insulin human inhalation powder should not be used during pregnancy unless the potential benefit to the mother justifies the potential risk to the fetus.9 Nursing mothers. A decision should be made wheth-

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er to discontinue nursing or to suspend the use of insulin human inhalation powder, because it has not been studied in lactating women.9 Pediatric use. Insulin human inhalation powder has not been studied in patients aged <18 years.9 Geriatric use. In clinical studies, no overall differences in safety or efficacy were observed between patients aged ≥65 years.9 Hepatic impairment. The effect of hepatic impairment on the pharmacokinetics of insulin human inhalation powder has not been studied. Frequent glucose monitoring and dose adjustment may be necessary for human insulin inhalation powder in patients with hepatic impairment.9 Renal impairment. The effect of renal impairment on the pharmacokinetics of this insulin has not been studied. Some studies with human insulin have shown increased circulating levels of insulin in patients with renal failure. Frequent glucose monitoring and dose adjustment may be necessary in patients with renal impairment.9

Conclusion The management of diabetes remains a challenge that requires a variety of risk-reduction strategies and different treatment options. The recent FDA approval of insulin human inhalation powder has made available a new treatment option for the treatment of adults with diabetes. In patients with type 1 diabetes, treatment with mealtime insulin human inhalation powder plus basal insulin met the prespecified noninferiority margin of 0.4% compared with treatment with insulin aspart plus basal insulin at 24 weeks. In patients with type 2 diabetes, treatment with insulin human inhalation powder plus oral antidiabetic drugs demonstrated a significantly greater reduction in HbA1c levels versus placebo plus oral antidiabetic drugs at week 24. n References

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Akynzeo (Netupitant and Palonosetron), a Dual-Acting Oral Agent, Approved by the FDA for the Prevention of ChemotherapyInduced Nausea and Vomiting By Lisa A. Raedler, PhD, RPh, Medical Writer

ne of the most fear-inducing side effects of chemotherapy is nausea and vomiting.1 Without appropriate antiemetic prophylaxis, 70% to 80% of all patients with cancer who receive chemotherapy experience nausea and/or vomiting.2 Consequently, preventing and managing chemotherapy-induced nausea and vomiting (CINV) is a crucial part of care planning for patients with cancer. In addition to being a distressing side effect of cancer treatment, CINV has multiple clinical consequences for patients, their families, and the healthcare system, including2-4: • Nonadherence to chemotherapy treatment • Early treatment discontinuation • Problems with appetite and eating, which can lead to nutritional deficits • Impaired daily functioning • Performance status decline3 • Impaired health-related quality of life, as assessed by the Functional Living Index–Emesis • More frequent office visits and emergency department admissions, and higher direct and indirect costs of care compared with patients without CINV. The economic costs associated with CINV are significant. In a study of working-aged adults who were receiving highly or moderately emetogenic chemotherapy, uncontrolled CINV was associated with higher costs; that is, the monthly medical costs for patients with uncontrolled CINV were $1300 higher than the costs for patients without uncontrolled CINV. In addition, the monthly indirect costs, such as lost work time, were $400 higher for patients with uncontrolled CINV than for patients without uncontrolled CINV.4 Given the many potential negative effects of CINV, the use of effective antiemetic therapy is an essential part of treatment planning for patients undergoing chemotherapy and should be initiated at the start of cancer treatment.5 Several factors influence the incidence and severity of CINV. The primary risk factor for CINV is the chemotherapy regimen, including the type of chemotherapy agent,

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the route of administration, and the treatment dosage. Patient-related factors that influence CINV include sex and age. For example, women report CINV and other chemotherapy-associated adverse events more often than do men, and elderly patients report fewer side effects than younger patients.5 History of CINV, emesis during pregnancy, motion sickness, alcohol use, tumor burden, anxiety, concomitant medication and medical conditions, and inadequate hydration are also significant contributors to CINV.2 In practice, CINV is classified into 3 categories— acute onset occurs within 24 hours of the initial administration of chemotherapy; delayed onset occurs 24 hours to several days after the initial treatment; and anticipatory CINV is triggered by senses, thoughts, or anxiety that patients associate with previous chemotherapy.2 Current emesis-related management guidelines focus on the emetogenic potential of chemotherapy drugs and divide agents into 4 risk groups, including high, moderate, low, and minimal. Table 1 summarizes the classification of chemotherapy drugs according to the National Comprehensive Cancer Network (NCCN) guidelines, and provides examples of agents in each risk group.3 Supportive care for patients receiving chemotherapy has dramatically improved during the past 20 years, with combination antiemetic regimens emerging as the standard of care for CINV control.6 Four groups––the NCCN, the Multinational Association of Supportive Care in Cancer (MASCC), the European Society for Medical Oncology (ESMO), and the American Society of Clinical Oncology––have published antiemetic guidelines.3,7,8 These groups broadly agree on the majority of key issues regarding the management of CINV.6 For acute emesis associated with highly emetogenic chemotherapy, as well as with the combination use of anthracycline and cyclophosphamide, antiemesis guidelines recommend triple therapy with a 5-hydroxytrypta mine (5-HT3) receptor antagonist, dexamethasone, and a neurokinin 1 (NK1) receptor agonist.3,7,8 For acute emesis associated with moderately emetogenic regimens, the MASCC/ESMO guidelines recommend double ther-

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apy with a 5-HT3 receptor antagonist (ideally, palonosetron) and dexamethasone. For low emetogenic chemotherapy, dexamethasone monotherapy is adequate, but for minimal emetogenic chemotherapy, prophylaxis for acute emesis is not recommended.6,7 For delayed emesis associated with highly emetogenic chemotherapy, the MASCC/ESMO guidelines recommend the combination of dexamethasone and an NK1 receptor agonist. For delayed emesis associated with moderately emetogenic chemotherapy, such as anthracycline and cyclophosphamide–based regimens, the guidelines recommend aprepitant monotherapy. In other moderately emetogenic regimens, dexamethasone or a 5-HT3 receptor antagonist (presuming the latter was not part of the primary prophylactic treatment) are the preferred agents. For low- and minimal-emetogenic chemotherapy, no prophylaxis for delayed emesis is needed.6,7 Because maintaining dose intensity of chemotherapy is important, particularly in early-stage disease, recommendations for highly emetogenic chemotherapy should be followed when nausea and vomiting are not reduced by the recommended therapy for moderately emetogenic chemotherapy.5 Although the majority of patients with cancer are protected from CINV with these current therapies, other patients still experience nausea and vomiting associated with chemotherapy. Consequently, there remains a need for greater adherence to treatment guidelines and for more effective antiemetic agents.2,5

FDA Approves a Novel Combination Therapy for CINV On October 10, 2014, the US Food and Drug Administration (FDA) approved the combination of netupitant plus palonosetron (Akynzeo; Eisai) for the prevention of acute and delayed nausea and vomiting associated with initial and repeated courses of cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy in patients with cancer.9,10 The fixed combination capsule of netupitant plus palonosetron contains 300 mg of netupitant and 0.5 mg of palonosetron.10 Oral palonosetron was initially approved as a single agent in 2008 for the prevention of acute nausea and vomiting associated with initial and repeated courses of moderately emetogenic chemotherapy in patients with cancer.9,11 Palonosetron prevents nausea and vomiting during the acute phase. Netupitant is a new drug that prevents nausea and vomiting during the acute and the delayed phases after the start of chemotherapy.9,10 “Supportive care products, such as Akynzeo, help ease the nausea and vomiting patients may experience as a side effect of cancer chemotherapy,” said Julie Beitz, MD, Director of the Office of Drug Evaluation III in the FDA’s Center for Drug Evaluation and Research.9

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Mechanism of Action Palonosetron has a strong binding affinity for 5-HT3 receptors, acting as a 5-HT3 antagonist. Acute emesis is known to depend on serotonin and its 5-HT3 receptors.10 Netupitant is a selective antagonist of human substance P and NK1 receptors. These receptors are broadly distributed in the central and the peripheral nervous systems. Delayed emesis is associated with the activation of NK1 receptors by substance P. In vitro and in vivo studies demonstrated that netupitant inhibits substance P–mediated responses.10 Dosing and Administration Netupitant plus palonosetron is a fixed-dose combination capsule containing netupitant (300 mg) and palonosetron (0.5 mg).10 For patients undergoing highly emetogenic chemotherapy, including cisplatin-based chemotherapy, the recommended dosage of netupitant plus palonosetron is 1 capsule given approximately 1 hour before starting chemotherapy, with oral dexamethasone 12 mg administered 30 minutes before the start of chemotherapy on days 1 and dexamethasone 8 mg once daily on days 2 to 4.10 For patients receiving anthracycline and cyclophosphamide or other chemotherapy that is not considered highly emetogenic, the recommended dosage of the new combination is 1 capsule approximately 1 hour before the start of chemotherapy, with dexamethasone 12 mg administered 30 minutes before the start of chemotheraTable 1 Classification of Emetogenic Risk Associated with Some Chemotherapy Agents Proportion of patients experiencing acute emesis without Examples of IV Emetogenic risk prophylaxis, % chemotherapies High

≥90

Cisplatin, high-dose cyclophosphamide, dacarbazine

Moderate

30-90

Carboplatin, high-dose cytarabine, doxorubicin, irinotecan, oxaliplatin

Low

10-30

Cabazitaxel, docetaxel, floxuridine, gemcitabine, pemetrexed, temsirolimus, topotecan

<10

Bevacizumab, fludarabine, vincristine, vinorelbine

Minimal

IV indicates intravenous. Source: National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): antiemesis. Version 2.2014. April 18, 2014.

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py on day 1. The subsequent administration of dexamethasone is not necessary.10 Netupitant plus palonosetron can be taken with or without food.10

Clinical Trials The efficacy and safety of fixed-dose netupitant plus palonosetron in combination with dexamethasone were evaluated in 2 randomized, parallel, double-blind, multicenter, controlled clinical trials––1 clinical trial in patients receiving highly emetogenic chemotherapy and 1 clinical trial in patients receiving moderately emetogenic chemotherapy.10 Study 1: Highly Emetogenic Chemotherapy This multicenter, randomized, parallel, double-blind study enrolled 694 chemotherapy-naïve patients with cancer who were receiving cisplatin-based chemotherapy (median dose, 75 mg/m2).10,12 This trial evaluated 3 oral doses of netupitant (100 mg, 200 mg, and 300 mg) combined with oral palonosetron 0.5 mg and compared it with oral palonosetron 0.5 mg alone, all administered on day 1.10,12 A standard 3-day aprepitant and intravenous ondansetron regimen were included as an exploratory arm. All patients received oral dexamethasone on days 1 through 4.12 Of the 694 patients who enrolled in this clinical trial, 135 patients received netupitant plus palonosetron (netupitant 300 mg and palonosetron 0.5 mg), and 136 patients received oral palonosetron 0.5 mg alone.10 The majority of patients who received netupitant plus palonosetron were male (57%) and white (100%); the patients’ median age was 53 years (range, 19-77 years).10 During the study, 86% of patients who received netupi Study 1: Netupitant plus Palonosetron versus Table 2 Palonosetron Alone in Patients Receiving Highly Emetogenic Chemotherapy Complete response rate Phase after cisplatin chemotherapy Acute phasea b

Delayed phase c

Overall

Netupitant 300 mg + palonosetron 0.5 mg, % (N = 135)

Palonosetron 0.5 mg, % (N = 136)

P value

98.5

89.7

.002

90.4

80.1

.032

89.6

76.5

.003

0-24 hours after treatment. 25-120 hours after treatment. c 0-120 hours after treatment. Source: Akynzeo (netupitant and palonosetron) capsules prescribing information; October 2014. a

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tant plus palonosetron also received a concomitant chemotherapeutic agent in addition to cisplatin, including cyclophosphamide (34%), fluorouracil (24%), etoposide (21%), and doxorubicin (16%).10 The key efficacy end points were the complete response rates (defined as no emetic episode and no use of rescue medication) 0 to 24 hours after cisplatin treatment (acute phase), 25 to 120 hours after cisplatin treatment (delayed phase), and within 120 hours after cisplatin treatment (overall phase).10,12 Table 2 summarizes the efficacy data for netupitant plus palonosetron versus palonosetron alone, which show that the netupitant plus palonosetron combination offers clinically significant improvements in the complete response rates over palonosetron alone.10,12

Study 2: Moderately Emetogenic Chemotherapy In this multicenter, randomized, parallel, double- blind, active-control superiority study, the efficacy and safety of a single oral dose of netupitant plus palonosetron were compared with a single oral dose of palonosetron 0.5 mg in 1450 chemotherapy-naïve patients with cancer who were scheduled to receive anthracycline and cyclophosphamide.10,13 Patients in this clinical trial also received a single oral dose of dexamethasone. After completing their first cycle of anthracycline and cyclophosphamide, patients could participate in a multiple-cycle extension in which they continued the same antiemetic treatment as assigned in cycle 1.10 A total of 725 patients received netupitant plus palonosetron, and 725 patients received palonosetron alone.10,13 Overall, 1438 patients completed cycle 1 of chemotherapy, and the majority (88%) of patients continued treatment in the multiple-cycle extension. A total of 907 (62%) patients finished the multiple-cycle extension for a maximum of 8 treatment cycles.10 The majority of patients who received the netupitant plus palonosetron combination were female (98%) and white (79%); the patients’ median age was 54 years (range, 22-79 years).10 Overall, nearly all patients (99.9%) received cyclophosphamide and an anthracycline; in addition, all patients received either doxorubicin (68%) or epirubicin (32%).10 During the first cycle of chemotherapy, 32% of patients who received netupitant plus palonosetron also received a concomitant chemotherapeutic agent in addition to the protocol-mandated regimens, including fluorouracil (28%) and docetaxel (3%).10 The efficacy end points included the complete response rates for the acute phase, the delayed phase, and the overall phase after chemotherapy with an anthracycline plus cyclophosphamide.10,13 Table 3 summarizes the efficacy data for netupitant plus palonosetron versus

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palonosetron monotherapy, which show that the combination of netupitant plus palonosetron offers significant improvements in complete response rate over palonosetron monotherapy.10,13 Among the patients who participated in the multiple-cycle extension of the study, the antiemetic activity of netupitant plus palonosetron was maintained throughout the repeated cycles of chemotherapy.10

Study 2: Netupitant plus Palonosetron versus Table 3 Palonosetron Alone in Patients Receiving Moderately Emetogenic Chemotherapy Complete response rate Status after Netupitant 300 mg anthracycline/ + palonosetron Palonosetron cyclophosphamide 0.5 mg, % 0.5 mg, % P chemotherapy (N = 724) (N = 725) value Acute phasea

88.4

85.0

.047

76.9

69.5

.001

74.3

66.6

.001

Adverse Reactions The safety of netupitant plus palonosetron was evaluated in clinical trials that included more than 1500 healthy volunteers and patients with cancer.10 More than 1150 patients with cancer have been exposed to netupitant plus palonosetron, receiving at least 1 cycle of cancer chemotherapy in 1 of 3 active-controlled clinical trials, including 782 patients who were exposed to netupitant plus palonosetron for at least 4 cycles, and 321 patients who were exposed to netupitant plus palonosetron for at least 6 cycles, up to a maximum of 12 cycles of chemotherapy.10 All patients received a single oral dose of netupitant plus palonosetron 1 hour before the start of each chemotherapy cycle. In all the studies, dexamethasone was coadministered with netupitant plus palonosetron.10

tron monotherapy, concomitant elevations of total bilirubin and transaminase levels of more than 3 times the upper limit of normal were reported, and the frequency of these elevations was similar with both treatments.10 The combination of netupitant plus palonosetron has no contraindications.10

Cisplatin-Based Highly Emetogenic Chemotherapy In a single-cycle study of patients who received cisplatin-based highly emetogenic chemotherapy, 136 patients received netupitant plus palonosetron.10 Adverse reactions that were reported at an incidence rate of at least 3% and for which the rate with netupitant plus palonosetron exceeded the rate with palonosetron alone included dyspepsia (4%), fatigue (4%), constipation (3%), and ÂÂ erythema (3%).10

Drug Interactions Netupitant plus palonosetron should be used with caution in patients receiving cytochrome (CY) P3A4 substrates (eg, tacrolimus, imatinib, anastrozole, paclitaxel); inhibition of CYP3A4 can result in increased plasma concentrations of the concomitant drug that can last for 4 days or more. The concomitant use of netupitant plus palonosetron with CYP3A4 inducers (eg, rifampin, carbamazepine, phenobarbital, pioglitazone) should be avoided.10,14

Anthracycline and Cyclophosphamideâ&#x20AC;&#x201C;Based Moderately Emetogenic Chemotherapy In a study of patients who received moderately emetogenic chemotherapy, 725 patients received netupitant plus palonosetron during the first cycle, and 635 of these patients continued for up to 8 cycles in a multiple-cycle extension.10 The adverse reactions that were reported at an incidence rate of at least 3% and for which the rate with netupitant plus palonosetron exceeded the rate with palonosetron alone during cycle 1 included headache (9%), asthenia (8%), and fatigue (7%).10 The adverse reactions associated with netupitant plus palonosetron during subsequent cycles of anthracycline and cyclophosphamide were similar to those observed in the first cycle.10 In both treatment arms of the clinical trials that compared netupitant plus palonosetron with oral palonose-

Warnings and Precautions Hypersensitivity. Hypersensitivity reactions, including anaphylaxis, have been reported after the use of other 5-HT3 receptor antagonists.10 Patients experiencing anaphylaxis may or may not have a known hypersensitivity to 5-HT3 receptor antagonists. Patients taking netupitant plus palonosetron should seek immediate medical attention if any signs or symptoms of a hypersensitivity reaction occur.10 Serotonin syndrome. The development of serotonin syndrome has been reported with 5-HT3 receptor antagonists, most often when serotonergic drugs (eg, selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, monoamine oxidase inhibitors, mirtazapine, fentanyl, lithium, tramadol) were used concomitantly; several of the cases were fatal.10

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Delayed phase c

Overall

0-24 hours after treatment. 25-120 hours after treatment. c 0-120 hours after treatment. Source: Akynzeo (netupitant and palonosetron) capsules prescribing information; October 2014. a

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The symptoms associated with serotonin syndrome can include mental status changes (eg, agitation, hallucinations, delirium, coma); autonomic instability (eg, tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia); neuromuscular symptoms (eg, tremor, rigidity, myoclonus, hyperreflexia, incoordination); and seizures, with or without gastrointestinal symptoms (eg, nausea, vomiting, diarrhea). If symptoms of serotonin syndrome occur, netupitant/palonosetron should be discontinued and supportive treatment should be initiated.10

Use in Specific Populations Pregnancy. Netupitant plus palonosetron is listed as pregnancy category C; there are no adequate and well-controlled studies with this combination in pregnant women. Netupitant plus palonosetron should only be used during pregnancy if the potential benefit outweighs the potential risk to the fetus.10 Nursing mothers. It is not known whether the components of netupitant plus palonosetron are present in human breast milk. Nursing or netupitant plus palonosetron therapy should be discontinued on the basis of the importance of the drug to the mother.10 Pediatric use. The safety and efficacy of netupitant plus palonosetron have not been established in pediatric patients aged <18 years.10 Geriatric use. Of the 1169 patients with cancer who received netupitant plus palonosetron in clinical trials, 18% were aged ≥65 years, and 2% were aged ≥75 years.10 The nature and the frequency of adverse events were similar between elderly patients and younger patients. In general, caution should be used when administering netupitant plus palonosetron to elderly patients, because of their higher risk for hepatic, renal, and/or cardiac dysfunction, as well as concomitant diseases and multiple medications.10 Renal impairment. Patients with mild or moderate renal impairment do not require dose adjustment of netupitant plus palonosetron.10 Patients with severe renal impairment or end-stage renal disease should not receive netupitant plus palonosetron.10 Hepatic impairment. No dosage adjustment of netupitant plus palonosetron is recommended for patients with mild or with moderate hepatic impairment. Netupitant plus palonosetron is not recommended for use in patients with severe hepatic impairment.10

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Conclusion The new fixed-dose combination agent that targets 2 antiemetic pathways, netupitant plus palonosetron offers an effective and safe alternative for patients undergoing initial and repeated courses of cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy. This novel dual-acting prophylactic therapy is an important option for patients receiving chemotherapy, in part because adherence to antiemetic consensus guidelines remains low. As an oral single capsule, the use of netupitant plus palonosetron combination therapy may improve the management of patients with cancer who are at high risk for CINV. n References

1. Sun CC, Bodurka DC, Weaver CB, et al. Rankings and symptom assessments of side effects from chemotherapy: insights from experienced patients with ovarian cancer. Support Care Cancer. 2005;13:219-227. 2. Feyer P, Jordan K. Update and new trends in antiemetic therapy: the continuing need for novel therapies. Ann Oncol. 2011;22:30-38. 3. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): antiemesis. Version 2.2014. April 18, 2014. www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf. Accessed February 23, 2015. 4. Tina Shih Y-C, Xu Y, Elting LS. Costs of uncontrolled chemotherapy- induced nausea and vomiting among working-age cancer patients receiving highly or moderately emetogenic chemotherapy. Cancer. 2007;110:678-685. 5. Morrow GR, Navari RM, Rugo HS. Clinical roundtable monograph: new data in emerging treatment options for chemotherapy-induced nausea and vomiting. Clin Adv Hematol Oncol. 2014;12(3 suppl 9):1-14; quiz 15. 6. Hesketh PJ. Chemotherapy-induced nausea and vomiting. N Engl J Med. 2008;358:2482-2494. 7. Roila F, Herrstedt J, Aapro M, et al; for the ESMO/MASCC Guidelines Working Group. Guideline update for MASCC and ESMO in the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting: results of the Perugia consensus conference. Ann Oncol. 2010;21(suppl 5):v232-v243. 8. Basch E, Prestrud AA, Hesketh PJ, et al; for the American Society of Clinical Oncology. Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2011;29:4189-4198. Erratum in: J Clin Oncol. 2014;32:2117. 9. US Food and Drug Administration. FDA approves Akynzeo for nausea and vomiting associated with cancer chemotherapy. Press release. October 10, 2014. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm418375.htm. Accessed February 20, 2015. 10. Akynzeo (netupitant and palonosetron) capsules [prescribing information]. Woodcliff Lake, NJ: Eisai Inc; October 2014. 11. Aloxi (palonosetron HCl) capsules [prescribing information]. Woodcliff Lake, NJ: Eisai Inc; September 2014. 12. Hesketh PJ, Rossi G, Rizzi G, et al. Efficacy and safety of NEPA, an oral combination of netupitant and palonosetron, for prevention of chemotherapy- induced nausea and vomiting following highly emetogenic chemotherapy: a randomized dose-ranging pivotal study. Ann Oncol. 2014;25:1340-1346. 13. Aapro M, Rugo H, Rossi G, et al. A randomized phase III study evaluating the efficacy and safety of NEPA, a fixed-dose combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy. Ann Oncol. 2014;25:13281333. 14. Stenger M. Fixed-combination netupitant/palonosetron for prevention of chemotherapy-induced nausea and vomiting. ASCO Post. 2014;5:119.

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Cyramza (Ramucirumab) Approved for the Treatment of Advanced Gastric Cancer and Metastatic Non–Small-Cell Lung Cancer By Loretta Fala, Medical Writer

astric cancer and lung cancer impose a substantial burden on patients. In light of the high mortality rate and quality-of-life issues associated with these 2 types of cancer, there is a marked need for additional therapeutic options to improve outcomes for patients with gastric or lung cancer.

Gastric Cancer The prevalence of gastric cancer has been on the decline in the United States in the past 80 years.1 Gastric cancer is most common in older people aged >65 years, affecting 6 in 10 people in this age-group. It is estimated that 24,590 new cases of gastric cancer will be diagnosed in the United States in 2015.1 The gastroesophageal junction (GEJ) is the area just beneath the diaphragm, where the esophagus joins the stomach. GEJ adenocarcinoma (or stomach cancer) is a cancer that affects this region of the gastric tract.2 As with other types of cancer, early detection and advances in treatment have improved the outlook for patients with gastric cancer. However, most gastric cancers are diagnosed at advanced stages rather than at early stages, resulting in a low survival rate.3 Overall, the 5-year relative survival rate of all patients with gastric cancer in the United States is approximately 29%.3 The total US expenditures for stomach cancer were estimated to be $1.8 billion in 2010.4 Lung Cancer Lung cancer is the second most common cancer in men and in women in the United States, with an estimated 221,200 new cases projected for 2015.5 Non– small-cell lung cancer (NSCLC) accounts for approximately 85% of all cases of lung cancer.6 Overall, lung cancer claims more lives than any other type of cancer— more than that of colon, breast, and prostate cancers combined—accounting for approximately 27% of all cancer deaths in the United States.5 Although the 5-year survival rate for localized lung cancer is 54%, only 15% of lung cancers are diagnosed at this stage.7 For all lung cancer cases diagnosed between 2003 and 2009, the 1-year relative survival rate was 43%, and the 5-year relative survival rate was 17%.7 Lung

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cancer is the third costliest cancer in the United States, after breast cancer and colorectal cancer, with a total estimated annual cost of $10.3 billion.8

The Vascular Endothelial Growth Factor Pathway Angiogenesis, the formation of new capillaries and blood vessels, is a process involved in tumor growth.9 Vascular endothelial growth factor (VEGF) is a primary mediator of angiogenesis in normal physiology and in certain diseases.9 VEGF and VEGF receptor-2– mediated signaling and angiogenesis may play a key role in the pathogenesis of gastric cancer and lung cancer.10-12 The blockade of VEGF receptor-2 signaling inhibits angiogenesis (ie, blood supply) to t umors.12 A number of small molecule inhibitors and antibody- based agents that target the VEGF pathway have been studied across various cancer types.9 In clinical studies, targeting the VEGF receptor-2 pathway has shown promise as a second-line treatment for patients with gastric or lung cancer.10-12 Ramucirumab Receives Several FDA Approvals in 2014 A New Option for Advanced Stomach Cancer

On April 21, 2014, ramucirumab (Cyramza; Eli Lilly), a human VEGF receptor-2 antagonist, was approved by the US Food and Drug Administration (FDA) as a single agent for the treatment of patients with advanced stomach cancer or GEJ adenocarcinoma that has progressed with or after fluoropyrimidine- or platinum-containing chemotherapy.13 Ramucirumab is a recombinant human immunoglobulin G1 monoclonal antibody, also referred to as an angiogenesis inhibitor (ie, blocking the blood supply to tumors).13 The FDA granted ramucirumab a priority review based on its potential to provide a significant improvement in safety or effectiveness in the treatment of advanced gastric cancer or GEJ adenocarcinoma. The FDA also designated ramucirumab as an orphan drug because it is approved for a rare disease.13 According to Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, “Although the rates of stomach cancer in the United States

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have decreased over the past 40 years, patients require new treatment options, particularly when they no longer respond to other therapies. Ramucirumab is a new treatment option that has demonstrated an ability to extend patients’ lives and slow tumor growth.” 13 Expanded indication. On November 5, 2014, the FDA expanded the initial indication of ramucirumab to be used alone or with paclitaxel for the treatment of patients with advanced stomach cancer that has progressed with or after previous fluoropyrimidine- or platinum- containing chemotherapy.14 A New Option for Non–Small-Cell Lung Cancer

On December 12, 2014, the FDA approved ramucirumab to be used in combination with docetaxel for the treatment of patients with metastatic NSCLC that has progressed with or after platinum-based chemotherapy.15 In patients with lung cancer and the EGFR or ALK genetic mutations, ramucirumab should only be used after their disease has progressed while using FDA- approved therapies for these mutations.16 Dr Pazdur commented, “Today’s approval is the third indication that Cyramza has received in 2014.” 15 He further stated, “The commitment to study Cyramza in a variety of malignancies provides important treatment options to patients.” 15

Mechanism of Action Ramucirumab is a VEGF receptor-2 antagonist that Table 1 The REGARD Trial: Ramucirumab versus Placebo in Gastric Cancer Ramucirumab + Placebo + best best supportive supportive therapy therapy Efficacy measure (N = 238) (N = 117) Overall survival Deaths, N (%) Median, mo Hazard ratio

179 (75)

99 (85)

5.2 (95% CI, 4.4-5.7)

3.8 (95% CI, 2.8-4.7)

0.78 (95% CI, 0.60-0.998)

Stratified log-rank P value

.047

Progression-free survival Events, N (%) Median, mo Hazard ratio Stratified log-rank P value

199 (84)

108 (92)

2.1 (95% CI, 1.5-2.7)

1.3 (95% CI, 1.3-1.4)

0.48 (95% CI, 0.38-0.62) <.001

CI indicates confidence interval. Source: Cyramza (ramucirumab) injection prescribing information; December 2014.

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specifically binds VEGF receptor-2 and blocks the binding of VEGF receptor ligands, VEGF-A, VEGF-C, and VEGF-D. As a result, ramucirumab inhibits ligand-stimulated activation of VEGF receptor-2, thereby inhibiting ligand-induced proliferation and migration of human endothelial cells.16

Dosing and Administration Ramucirumab is administered as an intravenous (IV) infusion only. It should not be administered as an IV push or bolus.16 For patients with advanced gastric cancer, the recommended dose of ramucirumab, either as a single agent or in combination with weekly paclitaxel, is 8 mg/kg every 2 weeks.16 For patients with metastatic NSCLC, the recommended dose of ramucirumab is 10 mg/kg, administered intravenously on day 1 of a 21-day cycle, before the infusion of docetaxel.16 Ramucirumab is available as an injection in single- dose vials in a 100-mg/10-mL (10 mg per mL) solution and in a 500-mg/50-mL (10 mg per mL) solution.16 Clinical Studies

The REGARD Trial: Gastric Cancer

The REGARD trial was a multinational, randomized, double-blind study that evaluated the efficacy of ramucirumab plus best supportive care compared with placebo plus best supportive care and randomized (in a 2:1 ratio) 355 patients with locally advanced or metastatic gastric cancer, including GEJ adenocarcinoma.10,16 The patients (median age, 60 years) received either an IV infusion of ramucirumab 8 mg/kg or placebo every 2 weeks. The primary efficacy end point was overall sur vival (OS), and the supportive outcome measure was progression-free survival (PFS).10,16 The efficacy results from the REGARD trial are shown in Table 1. Patients randomized to receive ramucirumab had significant improvements in OS and PFS compared with patients randomized to placebo.10,16 The median OS was 5.2 months in the ramucirumab group compared with 3.8 months in the placebo group.10,16 Moreover, treatment with ramucirumab was associated with a 52% reduction in the risk for disease progression or death from any cause compared with placebo.10 According to the REGARD study investigators, ramucirumab is the first biologic agent given as a monotherapy to demonstrate survival benefits in patients with advanced gastric cancer or GEJ adenocarcinoma that had progressed after first-line chemotherapy.10 The investigators stated that these findings reinforce the importance of targeting the VEGF receptor-2 pathway when treating patients with advanced gastric cancer.10

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The RAINBOW Trial: Gastric Cancer

The RAINBOW trial, a multinational, randomized, double-blind study of ramucirumab plus paclitaxel versus placebo plus paclitaxel, included 665 patients (randomized in a 1:1 ratio) with locally advanced or metastatic gastric cancer (including GEJ adenocarcinoma) who received platinum- containing and fluoropyrimidine- containing chemotherapy.11,16 The patients (median age, 61 years) were randomized to receive either ramucirumab 8 mg/kg or placebo as an IV infusion on days 1, 8, and 15 of each 28-day cycle. The primary efficacy outcome measure was OS, and the supportive outcome measures were PFS and objective response rate.11,16 As shown in Table 2, treatment with ramucirumab plus paclitaxel showed a significantly longer OS compared with placebo plus paclitaxel (9.6 months vs 7.4 months, respectively).11,16 Moreover, ramucirumab plus paclitaxel demonstrated significant improvements in PFS and objective response rate compared with placebo plus paclitaxel.11,16 The RAINBOW study’s investigators suggested that ramucirumab plus paclitaxel could be considered a standard second-line treatment option for patients with advanced gastric cancer.11 The REVEL Trial: Non–Small-Cell Lung Cancer

The REVEL trial was a multinational, randomized, double-blind study in patients with NSCLC that had progressed while receiving or after receiving 1 platinum- based therapy regimen for locally advanced or metastatic NSCLC.12,16 Patients (median age, 62 years) received either ramucirumab 10 mg/m2 intravenously plus docetaxel 75 mg/m2 intravenously every 21 days or placebo plus docetaxel 75 mg/m2 intravenously every 21 days. The primary end point was OS, and the supportive outcome measures were PFS and objective response rate.12,16 Efficacy results from the REVEL trial are shown in Table 3. Patients in the ramucirumab plus docetaxel group had statistically significant improvements in OS and PFS compared with patients in the placebo plus docetaxel group. Moreover, the objective response rate (complete response or partial response) for patients receiving ramucirumab plus docetaxel was 23% (95% confidence interval, 20-26) compared with 14% (95% confidence interval, 11-17) for patients receiving placebo plus docetaxel (P <.001).16

Safety The most common adverse reactions observed in patients treated with single-agent ramucirumab at a rate of ≥10% and ≥2% higher than placebo were hypertension (16%) and diarrhea (14%).16 In patients treated with ramucirumab plus paclitaxel, the most common adverse reactions observed at a rate of ≥30% and ≥2% higher than placebo plus paclitaxel were

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Table 2 The RAINBOW Trial: Ramucirumab plus Paclitaxel versus Placebo plus Paclitaxel in Gastric Cancer Ramucirumab Placebo + paclitaxel + paclitaxel Efficacy measure (N = 330) (N = 335) Overall survival Deaths, N (%) Median, mo Hazard ratio

256 (78)

260 (78)

9.6 (95% CI, 8.5-10.8)

7.4 (95% CI, 6.3-8.4)

0.81 (95% CI, 0.68-0.96)

Stratified log-rank P value

.017

Progression-free survival Events, N (%) Median, mo Hazard ratio

279 (85)

296 (88)

4.4 (95% CI, 4.2-5.3)

2.9 (95% CI, 2.8-3.0)

0.64 (95% CI, 0.54-0.75)

Stratified log-rank P value

<.001

Objective response rate (complete response plus partial response) Rate, %

28 (95% CI, 23-33)

Stratified CMH P value

16 (95% CI, 13-20)

<.001

CI indicates confidence interval; CMH, Cochran-Mantel-Haenszel. Source: Cyramza (ramucirumab) injection prescribing information; December 2014.

Table 3 The REVEL Trial: Ramucirumab plus Docetaxel versus Placebo plus Docetaxel in Non–Small-Cell Lung Cancer Ramucirumab Placebo + docetaxel + docetaxel Efficacy measure (N = 628) (N = 625) Overall survival Deaths, N (%)

428 (68)

456 (73)

Median, mo

10.5 (95% CI, 9.5-11.2) 9.1 (95% CI, 8.4-10.0)

Hazard ratio

0.86 (95% CI, 0.75-0.98)

Stratified log-rank P value

.024

Progression-free survival Events, N (%) Median, mo Hazard ratio

558 (89)

583 (93)

4.5 (95% CI, 4.2-5.4)

3.0 (95% CI, 2.8-3.9)

0.76 (95% CI, 0.68-0.86)

Stratified log-rank P value

<.001

CI indicates confidence interval. Source: Cyramza (ramucirumab) injection prescribing information; December 2014.

fatigue/asthenia (57%), neutropenia (54%), diarrhea (32%), and epistaxis (31%).16 In patients receiving ramucirumab plus docetaxel, the most common adverse reactions observed at a rate of ≥30% and ≥2% higher than placebo plus docetaxel

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ere neutropenia (55%), fatigue/asthenia (55%), and w stomatitis/mucosal inflammation (37%).16 No pharmacokinetic interactions were observed between ramucirumab and paclitaxel or between ramucirumab and docetaxel.16 There are no contraindications associated with ramucirumab.16

Warnings and Precautions Boxed warning. Ramucirumab was approved with a boxed warning about the increased risk for hemorrhage, including severe and sometimes fatal hemorrhagic events. Ramucirumab should be discontinued in patients who have severe bleeding.16 Arterial thromboembolic events. Serious, sometimes fatal, arterial thromboembolic events occurred in clinical trials. Ramucirumab should be permanently discontinued in patients who experience a severe arterial thromboembolic event.16 Hypertension. An increased incidence of severe hypertension occurred in patients receiving ramucirumab as a single agent and in patients receiving ramucirumab combined with paclitaxel and combined with docetaxel. Hypertension should be controlled before initiating treatment with ramucirumab. Blood pressure should be monitored every 2 weeks or more frequently as indicated during treatment.16 Infusion-related reactions. Patients should be monitored for the signs and symptoms of infusion-related reactions during the infusion of ramucirumab.16 Gastrointestinal perforation. As an antiangiogenic therapy, ramucirumab can increase the risk for gastrointestinal perforation, which can be fatal. Ramucirumab should be permanently discontinued in patients with a gastrointestinal perforation.16 Impaired wound healing. Ramucirumab has not been studied in patients with serious or nonhealing wounds. As an antiangiogenic therapy, ramucirumab has the potential to adversely affect wound healing. Ramucirumab should be withheld before surgery and resumed after surgery based on adequate wound healing. If wound-healing complications develop during treatment, ramucirumab should be discontinued until the wound is fully healed.16 Clinical deterioration of cirrhosis. New-onset or worsening encephalopathy, ascites, or hepatorenal syndrome can occur in patients with Child-Pugh class B or C cirrhosis. Ramucirumab should be only used in patients with Child-Pugh class B or C cirrhosis if the potential benefits of treatment are judged to outweigh the risks of clinical deterioration.16 Reversible posterior leukoencephalopathy syndrome. This syndrome has been reported in clinical studies with

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ramucirumab. If the diagnosis of reversible leukoencephalopathy is confirmed with magnetic resonance imaging, ramucirumab should be discontinued.16

Use in Specific Populations Pregnancy. Based on its mechanism of action, ramucirumab may cause fetal harm. If ramucirumab is used during pregnancy, or if the patient becomes pregnant while taking the drug, assess the potential hazard to the fetus.16 Nursing mothers. It is not known whether ramucirumab is excreted in human milk. Whether the patient should discontinue nursing or discontinue the drug is dependent on the importance of the drug to the mother.16 Pediatric use. The safety and effectiveness of ramucirumab in pediatric patients have not been established.16 Geriatric use. Among patients receiving ramucirumab in the 2 gastric cancer clinical trials, no overall differences in safety or efficacy were observed between patients aged ≥65 years and younger patients.16 Renal impairment. No dose adjustment is recommended for patients with renal impairment.16 Hepatic impairment. No dose adjustment is recommended for patients with mild hepatic impairment.16 Reproductive potential. Ramuciru mab may impair fertility. Females of reproductive potential should be advised to avoid getting pregnant while receiving ramucirumab and for at least 3 months after the last dose.16 Conclusion In 2014, ramucirumab received FDA approval for 3 indications—as a single agent or in combination with paclitaxel for advanced gastric cancer, and in combination with docetaxel for metastatic NSCLC. These FDA approvals mark the availability of an additional second-line treatment option for 2 types of advanced cancer. In patients with advanced stomach cancer or GEJ adenocarcinoma, ramucirumab as a single agent and in combination with paclitaxel demonstrated significant improvements in OS and PFS compared with placebo, and compared with placebo in combination with paclitaxel, based on findings from the REGARD and the RAINBOW clinical trials. In patients with metastatic NSCLC, ramucirumab plus docetaxel showed significant improvements in OS and PFS compared with placebo plus docetaxel, as was demonstrated in the REVEL study. n References

1. American Cancer Society. What are the key statistics about stomach cancer? Revised January 9, 2015. www.cancer.org/cancer/stomachcancer/detailedguide/ stomach-cancer-key-statistics. Accessed February 9, 2015. 2. American Cancer Society. What is stomach cancer? Revised January 9, 2015. www.cancer.org/cancer/stomachcancer/detailedguide/stomach-cancer-what-isstomach-cancer. Accessed February 9, 2015. 3. American Cancer Society. Survival rates for stomach cancer, by stage. Re-

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vised January 9, 2015. www.cancer.org/cancer/stomachcancer/detailedguide/ stomach-cancer-survival-rates. Accessed February 8, 2015. 4. National Cancer Institute. Costs of cancer care. In: Cancer Trends Progress Report—2011/2012 Update. August 2012. http://progressreport.cancer.gov/doc_ detail.asp?pid=1&did=2007&chid=75&coid=726. Accessed February 9, 2015. 5. American Cancer Society. What are the key statistics about lung cancer? Revised January 20, 2015. www.cancer.org/cancer/lungcancer-non-smallcell/detailed guide/non-small-cell-lung-cancer-key-statistics. Accessed February 9, 2015. 6. American Cancer Society. Non-small cell lung cancer. www.cancer.org/ cancer/lungcancer-non-smallcell/. Accessed February 10, 2015. 7. American Cancer Society. Cancer facts & figures 2014. 2014. www.cancer. org/acs/groups/content/@research/documents/webcontent/acspc-042151.pdf. Accessed February 10, 2015. 8. Hardison BL. The financial burden of cancer. NCI Benchmarks. April 23, 2010. http://benchmarks.cancer.gov/2010/04/the-financial-burden-of-cancer/. Accessed February 9, 2015. 9. Sullivan LA, Brekken RA. The VEGF family in cancer and antibody-based strategies for their inhibition. MAbs. 2010;2:165-175. 10. Fuchs CS, Tomasek J, Yong CJ, et al; for the REGARD Trial Investigators. Ramucirumab monotherapy for previously treated advanced gastric or gastro- oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2014;383:31-39.

11. Wilke H, Muro K, Van Cutsem E, et al; for the RAINBOW Study Group. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014;15:1224-1235. 12. Garon EB, Ciuleanu TE, Arrieta O, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet. 2014;384:665-673. 13. US Food and Drug Administration. FDA approves Cyramza for stomach cancer. Press release. April 21, 2014. www.fda.gov/NewsEvents/Newsroom/ PressAnnouncements/ucm394107.htm. Accessed February 9, 2015. 14. Eli Lilly and Company. Lilly’s Cyramza (ramucirumab) in combination with paclitaxel granted FDA approval for advanced gastric cancer after prior chemotherapy. Press release. November 5, 2014. https://investor.lilly.com/release detail.cfm?releaseid=880745. Accessed February 6, 2015. 15. US Food and Drug Administration. FDA expands approved use of Cyramza to treat aggressive non-small cell lung cancer. Press release. December 12, 2014. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm426720.htm. Accessed February 9, 2015. 16. Cyramza (ramucirumab) injection [prescribing information]. Indianapolis, IN: Eli Lilly and Company; December 2014.

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Once-a-Day Harvoni (Ledipasvir plus Sofosbuvir), a New Oral Combination for the Treament of Patients with Genotype 1 Chronic Hepatitis C Infection By Lisa A. Raedler, PhD, RPh, Medical Writer

epatitis C virus (HCV) infection is the most common blood-borne disease; approximately 3.2 million Americans and 130 million to 170 million individuals worldwide are infected with HCV.1,2 Chronic HCV infection has been called a silent epidemic; the disease can remain quiescent for decades before clinically significant symptoms appear.3 Because many Americans who are currently living with HCV were infected before blood screening testing for HCV was performed, the prevalence of HCV complications is likely to rise as these individuals enter their 50s and 60s.4 Research indicates that by 2015, more than 3 million individuals will have HCV infection that has been present for 20 years or more.5 This will result in a significant increase in the incidence of advanced liver disease, including cirrhosis, decompensated cirrhosis, and liver cancer.5,6 In addition to causing substantial morbidity and mortality, HCV is associated with significant financial consequences.3 A 2000 study estimated that between 2010 and 2019, the direct medical expenditures for HCV- related conditions will reach nearly $11 billion, the cost of morbidity from disability related to decompensated cirrhosis and hepatocellular carcinoma would reach approximately $21 billion, and the societal cost of premature mortality for patients aged <65 years will exceed $54 billion (in 1999 US dollars).7 In the early 1990s, single-agent interferon was the standard of care for patients with HCV infection. Single- agent interferon represented a significant therapeutic advancement, because until then there was no treatment available for HCV infection; however, single-agent interferon offered a sustained virologic response (SVR) rate of less than 10% in patients with HCV genotype 1, the most common HCV subtype.8 Interferon was then used in combination with ribavirin, increasing the SVR rate by another 14% to 22%.8 In the early 2000s, pegylated forms of interferon dosed once weekly were introduced. The combination of pegylated interferon with ribavirin increased SVR rates to more than 50% in patients with HCV genotype 1.9,10 However, HCV genotype 1 was less responsive than HCV genotype 2 and

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genotype 3.9,10 Because of this variability in HCV response, low response rates in common HCV subpopulations (ie, black patients, patients with cirrhosis), and side effects associated with interferon and ribavirin, there remained a need to develop novel antiviral therapies.8 The treatment options for patients with HCV have evolved significantly in the past few years. HCV is currently the only chronic viral infection that can be cured with antiviral therapy.8 Although the prevention of infection should be the primary goal of treatment for HCV, no HCV vaccine is available. Therefore, the goals of current anti-HCV approaches are to cure infection, to prevent complications, and to prevent the spread of this disease to other individuals.8 In 2011, 2 first-generation protease inhibitors, telaprevir (Incivek) and boceprevir (Victrelis), also known as direct-acting antiviral drugs, were approved by the US Food and Drug Administration (FDA) for HCV genotype infection; both agents offer significant efficacy as measured by the SVR rates.11,12 In December 2013, the FDA approved sofosbuvir (Sovaldi) in combination with ribavirin—the first interferon-free, all-oral regimen—for the treatment of patients with HCV genotype 2 and genotype 3. In addition, sofosbuvir in combination with interferon and ribavirin is approved for the treatment of patients with HCV genotype 1 and genotype 4.13,14 Candidates for sofosbuvir therapy include patients with hepatocellular carcinoma who meet Milan criteria (ie, awaiting liver transplantation) and patients with HCV/human immunodeficiency virus 1 coinfection.13,14 In contrast to older combination regimens, sofosbuvir regimens require less treatment time: 12 weeks for patients with HCV genotype 1, genotype 2, and genotype 4; and 24 weeks for patients with HCV genotype 3.14 Interest and investment in novel therapies for HCV remain strong in light of the increasing incidence of HCV (and its costly complications), unmet patient needs, and the identification of new drug targets through clinical research and discovery.15 Efforts continue, with the goals of improving the pharmacokinetics and the

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tolerability of these agents, as well as determining treatment strategies––interferon-containing and interferon- free (all oral) regimens––that optimize outcomes.16

First Combination Tablet for Chronic Hepatitis C Genotype 1 Infection On October 10, 2014, the FDA approved the fixeddose combination capsule of ledipasvir plus sofosbuvir (Harvoni; Gilead Sciences) for the treatment of patients with chronic HCV genotype 1 infection.17,18 Ledipasvir plus sofosbuvir is the first combination tablet approved for the treatment of patients with chronic HCV genotype 1 infection, as well as the first approved regimen that does not require the use of interferon or ribavirin.17 Ledipasvir and sofosbuvir interfere with the enzymes that HCV needs to be able to multiply.17 Ledipasvir was a new agent that was approved for use in combination with sofosbuvir.17,18 Ledipasvir plus sofosbuvir combination therapy was reviewed under the FDA’s priority review program, which expedites the review of drugs that treat serious conditions and that, if approved, would provide significant improvement in the safety or efficacy of the treatment.17 “With the development and approval of new treatments for hepatitis C virus, we are changing the treatment paradigm for Americans living with the disease,” said Edward Cox, MD, MPH, Director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research.17 “Until last year, the only available treatments for hepatitis C virus required administration with interferon and ribavirin. Now, patients and health care professionals have multiple treatment options, including a combination pill to help simplify treatment regimens.” 17 Mechanism of Action The combination pill contains a fixed-dose of ledipasvir and sofosbuvir, 2 direct-acting antiviral agents against HCV.18 Ledipasvir is an inhibitor of the NS5A protein, which is required for HCV replication. Sofosbuvir inhibits the HCV NS5B RNA-dependent RNA polymerase, which is also required for viral replication. Sofosbuvir is a nucleotide prodrug that undergoes intracellular metabolism to form a pharmacologically active triphosphate that can incorporate into the HCV RNA.18 Dosing and Administration The 2-drug, fixed-dose combination contains 90 mg of ledipasvir and 400 mg of sofosbuvir in a single tablet.18 The recommended dosage is 1 tablet taken orally once daily with or without food. Table 1 describes the recommended treatment durations for the specific subsets of patients with HCV genotype 1 infection.18

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Recommended Treatment Duration for Table 1 Ledipasvir/Sofosbuvir in Patients with Chronic HCV Genotype 1 Infection Recommended treatment duration

Patient population Treatment-naïve with or without cirrhosis

12 weeksa

Treatment-experiencedb without cirrhosis

12 weeks

Treatment-experienced with cirrhosis

24 weeks

Ledipasvir/sofosbuvir for 8 weeks can be considered in treatment-naïve patients without cirrhosis who have pretreatment HCV RNA <6 million IU/mL. b Treatment-experienced patients whose disease has failed treatment with peginterferon alfa plus ribavirin or with an HCV protease inhibitor plus peginterferon alfa plus ribavirin. HCV indicates hepatitis C virus. Source: Harvoni (ledipasvir and sofosbuvir) tablets prescribing information; October 2014. a

Clinical Trials The efficacy of ledipasvir-sofosbuvir combination therapy was evaluated in 3 clinical trials that enrolled patients with HCV genotype 1, including patients with or without cirrhosis.18-20 In each clinical trial, patients were randomly assigned to receive ledipasvir-sofosbuvir with or without ribavirin. The primary end point of the studies was the SVR rate, defined as the inability to detect HCV in the blood at least 12 weeks after finishing treatment, indicating that HCV infection has been cured.17,18 The 3 trials are: • Study ION-1: 865 treatment-naïve patients with or without cirrhosis • Study ION-2: 440 treatment-experienced patients with or without cirrhosis who failed previous therapy with an interferon-based regimen, including regimens containing an HCV protease inhibitor • Study ION-3: 647 treatment-naïve patients without cirrhosis. ION-1 Clinical Trial (Study 0102): TreatmentNaïve Adults with or without Cirrhosis ION-1 enrolled 865 treatment-naïve patients with genotype 1 HCV, regardless of cirrhosis status.18,19 This randomized study was designed to evaluate 12 weeks and 24 weeks of treatment with ledipasvir-sofosbuvir, used with or without ribavirin.18,19 The patients were randomized to receive 1 of 4 treatment regimens: ledipasvir- sofosbuvir for 12 weeks, ledipasvir-sofosbuvir plus ribavirin for 12 weeks, ledipasvir-sofosbuvir for 24 weeks, or ledipasvir-sofosbuvir plus ribavirin for 24 weeks.18,19 The patients were stratified based on the presence or absence of cirrhosis and on their HCV genotype (1a vs 1b).18

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ION-1 Clinical Trial: Response Rates After 12 Weeks of Table 2 Treatment in Treatment-Naïve Patients with Chronic HCV Genotype 1 with or without Cirrhosis Ledipasvir/sofosbuvir Patient population 12 weeks, % (n/N) SVRa

99 (210/213)

SVR by genotypeb Genotype 1a Genotype 1b

98 (142/145) 100 (67/67)

SVR by cirrhosisc No Yes

99 (176/177) 94 (32/34)

Excluding 1 patient with genotype 4 infection. One patient without a confirmed subtype for genotype 1 infection and 1 patient with genotype 4 infection were excluded from this subgroup analysis. c Patients with missing cirrhosis status were excluded from this subgroup analysis. HCV indicates hepatitis C virus; SVR, sustained virologic response. Source: Harvoni (ledipasvir and sofosbuvir) tablets prescribing information; October 2014. a

ION-2 Trial: Response Rates at 12 and 24 Weeks of Table 3 Treatment in Treatment-Experienced Patients with Chronic HCV Genotype 1 and with or without Cirrhosis Ledipasvir/ Ledipasvir/ sofosbuvir sofosbuvir 12 weeks, 24 weeks, Patient population % (n/N) % (n/N) 94 (102/109) 99 (108/109) SVR SVR by genotype Genotype 1a 95 (82/86) 99 (84/85) Genotype 1b 87 (20/23) 100 (24/24) SVR by cirrhosisa No 95 (83/87) 99 (85/86) Yes 86 (19/22) 100 (22/22) SVR by previous HCV therapy Pegylated interferon + ribavirin 93 (40/43) 100 (58/58) HCV protease inhibitor + 94 (62/66) 98 (49/50) pegylated interferon + ribavirin SVR by response to previous HCV therapy Relapse or breakthrough 95 (57/60) 100 (60/60) Nonresponder 92 (45/49) 98 (48/49) Patients with missing cirrhosis status were excluded from this subgroup analysis. HCV indicates hepatitis C virus; SVR, sustained virologic response. Source: Harvoni (ledipasvir and sofosbuvir) tablets prescribing information; October 2014.

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In ION-1, the demographics and the baseline characteristics were balanced among the treatment groups.18 The patients’ median age was 54 years (range, 18-80 years), and 59% of patients were male. Overall, 85% of patients were white, 12% were black, and 12% were Hispanic or Latino.18 The patients’ mean body mass index (BMI) was 27 kg/m2 (range, 18-48 kg/m2). The majority of patients had baseline HCV RNA levels ≥800,000 IU/mL (79%), genotype 1a HCV infection (67%), and non-C/C IL28B alleles (70%). Overall, 16% of patients had cirrhosis.18 The SVR rates for the 12-week treatment groups in the ION-1 clinical trial are summarized in Table 2. Ribavirin did not increase the response rates with ledipasvir-sofosbuvir.18 Virologic failure was rare in the ION-1 patient population, occurring in 0.3% of 865 patients.19 No clinical or virologic predictors of virologic failure were identified in these patients, with the exception of suspected nonadherence to therapy.19

ION-2 Clinical Trial (Study 0109): Previously Treated Adults with or without Cirrhosis In ION-2, a randomized, open-label clinical trial, investigators evaluated 12 weeks and 24 weeks of treatment with ledipasvir-sofosbuvir, with or without ribavirin.18 The study included 440 patients with HCV genotype 1 and with or without cirrhosis whose disease did not respond to previous therapy with an interferon-based treatment regimen, including treatment regimens that contained an HCV protease inhibitor. Patients were randomized to 1 of 4 treatment regimens: ledipasvir-sofosbuvir for 12 weeks, ledipasvir-sofosbuvir plus ribavirin for 12 weeks, ledipasvir-sofosbuvir for 24 weeks, or ledipasvir-sofosbuvir plus ribavirin for 24 weeks. Patients were stratified based on the presence or the absence of cirrhosis, HCV genotype (1a vs 1b), and the response to previous HCV therapy (ie, relapse or breakthrough vs nonresponse).18 The demographics and the baseline characteristics were balanced among the treatment groups.18 The patients’ median age was 57 years (range, 24-75 years), and 65% of patients were male. Overall, 81% of patients were white, 18% were black, and 9% were Hispanic or Latino. The patients’ mean BMI was 28 kg/m2 (range, 19-50 kg/m2). The majority of patients had baseline HCV RNA levels ≥800,000 IU/mL (89%), genotype 1a HCV infection (79%), and non-C/C IL28B alleles (88%); in addition, 20% of patients had cirrhosis.18 Overall, there were 47% of patients whose disease did not respond to previous therapy with pegylated interferon plus ribavirin.18 In addition, there were 53% of patients whose disease failed previous therapy with pegylated interferon plus ribavirin and a protease inhibitor.18

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The SVR rates for the treatment groups in the ION-2 clinical trial are summarized in Table 3. Ribavirin did not increase the response rates with ledipasvir-sofosbuvir.18

ION-3 Clinical Trial (Study 0108): TreatmentNaïve Adults without Cirrhosis ION-3, a randomized, open-label clinical trial, was conducted in 647 treatment-naïve patients with HCV genotype 1 and without cirrhosis.18,20 Patients were stratified by the HCV genotype (1a vs 1b) and were randomized to 1 of 3 treatment groups: ledipasvir-sofosbuvir for 8 weeks, ledipasvir-sofosbuvir for 12 weeks, or ledipasvir- sofosbuvir plus ribavirin for 8 weeks.18,20 The demographics and the baseline characteristics were balanced among the treatment groups.18 The patients’ median age was 55 years (range, 20-75 years), and 58% of the patients were male. Overall, 78% of patients were white, 19% were black, and 6% were Hispanic or Latino. The patients’ mean BMI was 28 kg/m2 (range, 18-56 kg/m2). In addition, 81% of patients had baseline HCV RNA levels ≥800,000 IU/mL, 80% had genotype 1a HCV infection, and 73% had non-C/C IL28B alleles.18 In all 3 treatment groups, the SVR rates were significantly higher than the adjusted historical control rate of 60% (P <.001).20 Ribavirin was not shown to increase the response rates with ledipasvir-sofosbuvir.18,20 The SVR rates after 8 weeks and 12 weeks of treatment with ledipasvir-sofosbuvir are summarized in Table 4. The SVR rates in patients with characteristics that are historically associated with a poor response to interferon-based treatment, such as high viral load at baseline, black race, and HCV genotype 1a infection, were similar to patients without these characteristics.20 The treatment difference between the 8-week and 12-week course of ledipasvir-sofosbuvir was –2.3% (97.5% confidence interval, –7.2% to 2.5%).18 Among patients with a lower baseline HCV RNA (ie, <6 million IU/mL), the SVR rate was 97% with 8 weeks of treatment and 96% with 12 weeks of treatment with ledipasvir-sofosbuvir.18 Safety The safety assessment of ledipasvir-sofosbuvir was based on the pooled data from the 3 phase 3 clinical trials of patients with HCV genotype 1 with compensated liver disease (with or without cirrhosis). These 3 studies evaluated ledipasvir-sofosbuvir combination therapy for 8 weeks, 12 weeks, or 24 weeks and included 215 patients, 539 patients, and 326 patients, respectively.18 Adverse reactions that occurred in ≥10% of patients who received ledipasvir-sofosbuvir (8 weeks, 12 weeks, or 24 weeks) were fatigue and headache.18 Nausea, diar-

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ION-3 Trial: Response Rates at 8 and 12 Weeks of Table 4 Treatment in Treatment-Naïve Patients with HCV Genotype 1 and without Cirrhosis Ledipasvir/ Ledipasvir/s sofosbuvir ofosbuvir 8 weeks, % 12 weeks, % Patient population (n/N) (n/N) SVR

94 (202/215)

96 (208/216)

SVR by genotypea Genotype 1a Genotype 1b

93 (159/171) 98 (42/43)

96 (165/172) 98 (43/44)

One patient without a confirmed subtype for genotype 1 infection was excluded from this subgroup analysis. HCV indicates hepatitis C virus; SVR, sustained virologic response. Source: Harvoni (ledipasvir and sofosbuvir) tablets prescribing information; October 2014.

rhea, and insomnia were also reported at rates between 5% and 10%18; the majority of these adverse reactions were categorized as grade 1.18 The percentage of patients who permanently discontinued 8 weeks, 12 weeks, or 24 weeks of ledipasvir-sofosbuvir treatment as a result of adverse events was 0%, <1%, and 1%, respectively. Ledipasvir-sofosbuvir has no contraindications.18

Warnings and Precautions Reduced therapeutic effect with P-glycoprotein inducers. The use of ledipasvir-sofosbuvir together with P-glycoprotein inducers, such as rifampin and St. John’s wort, may significantly decrease plasma concentrations of ledipasvir and sofosbuvir, potentially reducing the combination’s therapeutic effect; therefore, the use of ledipasvir-sofosbuvir with P-glycoprotein inducers is not recommended.18 Related drugs. Ledipasvir-sofosbuvir combination therapy should not be used with other drugs that contain sofosbuvir.18 Specific Populations Pregnancy. Ledipasvir-sofosbuvir is listed as pregnancy category B.18 No adequate studies with ledipasvir-sofosbuvir were conducted in pregnant women. Ledipasvir-sofosbuvir should only be used during pregnancy if the potential benefits justify the potential risk to the fetus.18 Nursing mothers. It is not known whether ledipasvir-sofosbuvir combination therapy and its metabolites are present in human breast milk.18 The developmental and the health benefits of breastfeeding, as well as the mother’s clinical need for ledipasvir-sofosbuvir and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition, should be considered.18

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Pediatric use. The safety and efficacy of ledipasvir-sofosbuvir have not been established in pediatric patients.18 Geriatric use. The clinical trials of ledipasvir-sofosbuvir included 117 patients aged ≥65 years.18 No overall differences in safety or efficacy were observed between older and younger patients. Dose adjustment of ledipasvir-sofosbuvir is not recommended for geriatric patients.18 Renal impairment. Patients with mild or moderate renal impairment do not require dosage adjustment of ledipasvir-sofosbuvir. Because the combination drug’s

Once-daily ledipasvir-sofosbuvir combination therapy is a highly active and safe oral option for patients with HCV genotype 1 infection. As the first combination pill approved for the treatment of this patient population, ledipasvir-sofosbuvir combination therapy represents a significant therapeutic advancement. safety and efficacy have not been established in patients with severe renal impairment or end-stage renal disease requiring hemodialysis, no dosage adjustment for ledipasvir-sofosbuvir can be recommended.18 Hepatic impairment. No dosage adjustment of ledipasvir-sofosbuvir is required for patients with mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, or C). The safety and efficacy have not been established in patients with decompensated cirrhosis.18

Conclusion Once-daily ledipasvir-sofosbuvir combination therapy is a highly active and safe oral option for patients with HCV genotype 1 infection. Based on the 3 phase 3 clinical trials that demonstrated high response rates in all patient subgroups, this combination drug is effective in previously treated or untreated patients with HCV geno type 1 infection. As the first combination pill approved

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for the treatment of this patient population, as well as the first approved treatment regimen that does not require administration with interferon or ribavirin, ledipasvir-sofosbuvir combination therapy represents a significant therapeutic advancement for the treatment of patients with HCV genotype 1 infection. n

References

1. Centers for Disease Control and Prevention. Hepatitis C FAQs for health professionals. Updated November 17, 2014. www.cdc.gov/hepatitis/HCV/HCVfaq.htm# section1. Accessed November 20, 2014. 2. Lavanchy D. The global burden of hepatitis C. Liver Int. 2009;29(suppl s1):74-81. 3. US Department of Health & Human Services. Action plan for the prevention, care, & treatment of viral hepatitis. February 2014. Updated 2014-2016. http://aids. gov/pdf/viral-hepatitis-action-plan.pdf. Accessed March 2, 2015. 4. Davis GL, Alter MJ, El-Serag H, et al. Aging of hepatitis C virus (HCV)-infected persons in the United States: a multiple cohort model of HCV prevalence and disease progression. Gastroenterology. 2010;138:513-521; 521.e1-521.e6. 5. McHutchison JG, Bacon BR. Chronic hepatitis C: an age wave of disease burden. Am J Manag Care. 2005;11(10 suppl):S286-S295. 6. Zalesak M, Francis K, Gedeon A, et al. Current and future disease progression of the chronic HCV population in the United States. PLoS ONE. 2013;8:e63959. 7. Wong JB, McQuillan GM, McHutchison JG, Poynard T. Estimating future hepatitis C morbidity, mortality, and costs in the United States. Am J Public Health. 2000;90:1562-1569. 8. Poordad F, Dieterich D. Treating hepatitis C: current standard of care and emerging direct-acting antiviral agents. J Viral Hepat. 2012;19:449-464. 9. Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975-982. 10. Manns MP, McHutchison JG, Gordon SC, et al; for the International Hepatitis Interventional Therapy Group. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358:958-965. 11. Incivek (telaprevir) tablets [prescribing information]. Cambridge, MA: Vertex Pharmaceuticals Inc; October 2013. 12. Victrelis (boceprevir) capsules [prescribing information]. Whitehouse Station, NJ: Merck Sharp & Dohme Corp; July 2014. 13. Sovaldi (sofosbuvir) tablets [prescribing information]. Foster City, CA: Gilead Sciences, Inc; November 2014. 14. US Food and Drug Administration. FDA approves Sovaldi for chronic hepatitis C: drug is third with breakthrough therapy designation to receive FDA approval. Press release. December 6, 2013. www.fda.gov/NewsEvents/Newsroom/PressAnnounce ments/ucm377888.htm. Accessed November 20, 2014. 15. Stedman CA. Current prospects for interferon-free treatment of hepatitis C in 2012. J Gastroenterol Hepatol. 2013;28:38-45. 16. Kiser JJ, Flexner C. Direct-acting antiviral agents for hepatitis C virus infection. Annu Rev Pharmacol Toxicol. 2013;53:427-449. 17. US Food and Drug Administration. FDA approves first combination pill to treat hepatitis C. Press release. October 10, 2014. www.fda.gov/NewsEvents/Newsroom/ PressAnnouncements/ucm418365.htm. Accessed November 20, 2014. 18. Harvoni (ledipasvir and sofosbuvir) tablets [prescribing information]. Foster City, CA: Gilead Sciences, Inc; October 2014. 19. Afdhal N, Zeuzem S, Kwo P, et al; for the ION-1 Investigators. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med. 2014;370:18891898. 20. Kowdley KV, Gordon SC, Reddy KR, et al; for the ION-3 Investigators. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med. 2014;370:1879-1888.

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For patients with metastatic squamous non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapyâ&#x20AC;Ś

What if You Could Do More?

Expect More. Do More.

Proven Superior Survival With the Only Immuno-Oncology Therapy in Previously Treated Metastatic Squamous NSCLC INDICATION OPDIVO速 (nivolumab) is indicated for the treatment of patients with metastatic squamous non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy.

SELECT IMPORTANT SAFETY INFORMATION OPDIVO is associated with the following Warnings and Precautions including immune-mediated: pneumonitis, colitis, hepatitis, nephritis and renal dysfunction, hypothyroidism, hyperthyroidism, other adverse reactions; and embryofetal toxicity.

For patients with metastatic squamous non-small cell lung cancer with progression on or after platinum-based chemotherapy

OPDIVO Demonstrated Superior Survival vs Standard of Care1-5 100

MEDIAN OS 9.2 MONTHS vs 6.0 MONTHS

Probability of Survival (% of Patients)

(95% CI: 7.3-13.3 vs 5.1-7.3) HR=0.59; 95% CI: 0.44-0.79; P=0.00025

70 60 50 40 30 20 10 0 0

Number at risk OPDIVO 135 137 DOCETAXEL

31 14

15 7

7 2

0 0

OS (Months) 113 103

86 68

69 45

52 30

Refer to Figure 1 in the Full Prescribing Information for data on censored patients. CI=confidence interval; HR=hazard ratio; IV=intravenous; OS=overall survival; PD-1=programmed death-1; PD-L1=programmed death ligand 1.

Study design: OPDIVO was evaluated in a randomized (1:1), open-label, phase 3 study of OPDIVO 3 mg/kg IV every 2 weeks (n=135) vs docetaxel 75 mg/m2 IV every 3 weeks (n=137). The primary endpoint of the study was overall survival.1,6 Results were based on the prespecified interim analysis conducted when 199 events (86% of the planned number of events for final analysis) were observed (86 in the OPDIVO arm and 113 in the docetaxel arm).1 ■

This study included patients regardless of PD-L1 status; PD-L1 testing is not required for a treatment decision

Based on the unprecedented results, OPDIVO achieved the benchmark goal of improving overall survival in metastatic squamous NSCLC The safety of OPDIVO (3 mg/kg IV over 60 minutes every 2 weeks) was evaluated in CHECKMATE 063 (Trial 3), a singlearm study of 117 patients with metastatic squamous NSCLC who had progressed after receiving a platinum-based therapy and at least one additional systemic treatment regimen.1,7 Twenty-nine percent of patients receiving OPDIVO had a drug delay for an adverse reaction.

Serious Adverse Reactions ■

In Trial 3, serious adverse reactions occurred in 59% of patients receiving OPDIVO. The most frequent serious adverse drug reactions reported in ≥2% of patients were dyspnea, pneumonia, chronic obstructive pulmonary disease exacerbation, pneumonitis, hypercalcemia, pleural effusion, hemoptysis, and pain.

Common Adverse Reactions ■

The most common adverse reactions (≥20%) reported with OPDIVO in Trial 3 were fatigue (50%), dyspnea (38%), musculoskeletal pain (36%), decreased appetite (35%), cough (32%), nausea (29%), and constipation (24%).

Please see additional Important Safety Information on the following page.

Responding to Your Needs in 24 Hours or Less

IMPORTANT SAFETY INFORMATION Immune-Mediated Pneumonitis

Severe pneumonitis or interstitial lung disease, including fatal

cases, occurred with OPDIVO treatment. Across the clinical trial experience in 691 patients with solid tumors, fatal immunemediated pneumonitis occurred in 0.7% (5/691) of patients receiving OPDIVO; no cases occurred in Trial 3. In Trial 3, immunemediated pneumonitis occurred in 6% (7/117) of patients receiving OPDIVO including five Grade 3 and two Grade 2 cases. Monitor patients for signs and symptoms of pneumonitis. Administer corticosteroids for Grade 2 or greater pneumonitis. Permanently discontinue OPDIVO for Grade 3 or 4 and withhold OPDIVO until resolution for Grade 2.

Immune-Mediated Colitis

In Trial 3, diarrhea occurred in 21% (24/117) of patients receiving

OPDIVO. Grade 3 immune-mediated colitis occurred in 0.9% (1/117) of patients. Monitor patients for immune-mediated colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. Withhold OPDIVO for Grade 2 or 3. Permanently discontinue OPDIVO for Grade 4 colitis or recurrent colitis upon restarting OPDIVO.

Immune-Mediated Hepatitis In Trial 3, the incidences of increased liver test values were AST (16%), alkaline phosphatase (14%), ALT (12%), and total bilirubin (2.7%). Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. Withhold OPDIVO for Grade 2 and permanently discontinue OPDIVO for Grade 3 or 4 immunemediated hepatitis. Immune-Mediated Nephritis and Renal Dysfunction In Trial 3, the incidence of elevated creatinine was 22%. Immunemediated renal dysfunction (Grade 2) occurred in 0.9% (1/117) of patients. Monitor patients for elevated serum creatinine prior to and periodically during treatment. For Grade 2 or 3 serum creatinine elevation, withhold OPDIVO and administer corticosteroids; if worsening or no improvement occurs, permanently discontinue OPDIVO. Administer corticosteroids for Grade 4 serum creatinine elevation and permanently discontinue OPDIVO. Immune-Mediated Hypothyroidism and Hyperthyroidism

In Trial 3, hypothyroidism occurred in 4.3% (5/117) of patients

receiving OPDIVO. Hyperthyroidism occurred in 1.7% (2/117) of patients including one Grade 2 case. Monitor thyroid function prior to and periodically during treatment. Administer hormone replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism.

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse

administered at doses 3 mg/kg and 10 mg/kg, additional clinically significant, immune-mediated adverse reactions were identified: hypophysitis, diabetic ketoacidosis, hypopituitarism, GuillainBarré syndrome, and myasthenic syndrome. Based on the severity of adverse reaction, withhold OPDIVO, administer high-dose corticosteroids, and, if appropriate, initiate hormone-replacement therapy. Embryofetal Toxicity

Based on its mechanism of action, OPDIVO can cause fetal harm

when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and for at least 5 months after the last dose of OPDIVO.

Lactation

It is not known whether OPDIVO is present in human milk. Because many drugs, including antibodies, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from OPDIVO, advise women to discontinue breastfeeding during treatment.

Serious Adverse Reactions

In Trial 3, serious adverse reactions occurred in 59% of patients

receiving OPDIVO. The most frequent serious adverse drug reactions reported in ≥2% of patients were dyspnea, pneumonia, chronic obstructive pulmonary disease exacerbation, pneumonitis, hypercalcemia, pleural effusion, hemoptysis, and pain.

Common Adverse Reactions

The most common adverse reactions (≥20%) reported

with OPDIVO in Trial 3 were fatigue (50%), dyspnea (38%), musculoskeletal pain (36%), decreased appetite (35%), cough (32%), nausea (29%), and constipation (24%).

Please see brief summary of Full Prescribing Information on the following pages. References: 1. OPDIVO [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2015. 2. Taxotere [package insert]. Bridgewater, NJ: sanofi-aventis U.S. LLC; 2014. 3. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Non-Small Cell Lung Cancer V.4.2015. ©2015 National Comprehensive Cancer Network, Inc. All rights reserved. Accessed February 3, 2015. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 4. Garassino MC, Martelli O, Broggini M, et al; on behalf of the TAILOR trialists. Erlotinib versus docetaxel as second-line treatment of patients with advanced non-small-cell lung cancer and wild-type EGFR tumours (TAILOR): a randomised controlled trial. Lancet Oncol. 2013;14(10):981-988. 5. Kawaguchi T, Ando M, Asami K, et al. Randomized phase III trial of erlotinib versus docetaxel as second- or third-line therapy in patients with advanced nonsmall-cell lung cancer: Docetaxel and Erlotinib Lung Cancer Trial (DELTA). J Clin Oncol. 2014;32(18):19021908. 6. Bristol-Myers Squibb. Study of BMS-936558 (nivolumab) compared to docetaxel in previously treated advanced or metastatic squamous cell non-small cell lung cancer (NSCLC) (CheckMate 017). Identifier: NCT01642004. https://clinicaltrials.gov/ct2/show/NCT01642004. Updated December 31, 2014. Accessed February 5, 2015. 7. Rizvi NA, Mazières J, Planchard D, et al. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol. 2015;16:257-265.

reactions occurred in <2% of OPDIVO-treated patients: adrenal insufficiency, uveitis, pancreatitis, facial and abducens nerve paresis, demyelination, autoimmune neuropathy, motor dysfunction and vasculitis. Across clinical trials of OPDIVO OPDIVO® and the related logo are trademarks of Bristol-Myers Squibb Company. ©2015 Bristol-Myers Squibb Company. All rights reserved. Printed in USA. 1506US15BR00482-01-01 03/15

OPDIVO® (nivolumab) injection, for intravenous use Brief Summary of Prescribing Information. For complete prescribing information consult official package insert. INDICATIONS AND USAGE OPDIVO® (nivolumab) is indicated for the treatment of patients with metastatic squamous non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy [see Clinical Studies (14.2) in full Prescribing Information]. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Immune-Mediated Pneumonitis Severe pneumonitis or interstitial lung disease, including fatal cases, occurred with OPDIVO treatment. Across the clinical trial experience in 691 patients with solid tumors, fatal immune-mediated pneumonitis occurred in 0.7% (5/691) of patients receiving OPDIVO. No cases of fatal pneumonitis occurred in Trial 3; all five fatal cases occurred in a dose-finding study with OPDIVO doses of 1 mg/kg (two patients), 3 mg/kg (two patients), and 10 mg/kg (one patient). In Trial 3, pneumonitis occurred in 6% (7/117) of patients receiving OPDIVO, including five Grade 3 and two Grade 2 cases, all immune-mediated. The median time to onset was 3.3 months (range: 1.4 to 13.5 months). All seven patients discontinued OPDIVO for pneumonitis or another event and all seven patients experienced complete resolution of pneumonitis following receipt of high-dose corticosteroids (at least 40 mg prednisone equivalents per day). Monitor patients for signs and symptoms of pneumonitis. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents for Grade 2 or greater pneumonitis, followed by corticosteroid taper. Permanently discontinue OPDIVO for severe (Grade 3) or life-threatening (Grade 4) pneumonitis and withhold OPDIVO until resolution for moderate (Grade 2) pneumonitis [see Dosage and Administration (2.2) in full Prescribing Information]. Immune-Mediated Colitis In Trial 3, diarrhea occurred in 21% (24/117) of patients. Immune-mediated colitis (Grade 3) occurred in 0.9% (1/117) of patients. The time to onset in this patient was 6.7 months. The patient received high-dose corticosteroids and was permanently discontinued from OPDIVO (nivolumab). Complete resolution occurred. Monitor patients for immune-mediated colitis. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents followed by corticosteroid taper for severe (Grade 3) or life-threatening (Grade 4) colitis. Administer corticosteroids at a dose of 0.5 to 1 mg/kg/day prednisone equivalents followed by corticosteroid taper for moderate (Grade 2) colitis of more than 5 days duration; if worsening or no improvement occurs despite initiation of corticosteroids, increase dose to 1 to 2 mg/kg/day prednisone equivalents. Withhold OPDIVO for Grade 2 or 3 immune-mediated colitis. Permanently discontinue OPDIVO for Grade 4 colitis or for recurrent colitis upon restarting OPDIVO [see Dosage and Administration (2.2) in full Prescribing Information]. Immune-Mediated Hepatitis In Trial 3, the incidences of increased liver test values were AST (16%), alkaline phosphatase (14%), ALT (12%), and total bilirubin (2.7%). No cases of immunemediated hepatitis occurred in this trial. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents for Grade 2 or greater transaminase elevations, with or without concomitant elevation in total bilirubin. Withhold OPDIVO for moderate (Grade 2) and permanently discontinue OPDIVO for severe (Grade 3) or life-threatening (Grade 4) immune-mediated hepatitis [see Dosage and Administration (2.2) in full Prescribing Information and Adverse Reactions]. Immune-Mediated Nephritis and Renal Dysfunction In Trial 3, the incidence of elevated creatinine was 22%. Immune-mediated renal dysfunction (Grade 2) occurred in 0.9% (1/117) of patients. The time to onset in this patient was 0.8 months. The patient received high-dose corticosteroids. OPDIVO was withheld, and the patient discontinued due to disease progression prior to receiving additional OPDIVO. Immune-mediated renal dysfunction was ongoing. Monitor patients for elevated serum creatinine prior to and periodically during treatment. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents followed by corticosteroid taper for life-threatening (Grade 4) serum creatinine elevation and permanently discontinue OPDIVO. For severe (Grade 3) or moderate (Grade 2) serum creatinine elevation, withhold OPDIVO and administer

corticosteroids at a dose of 0.5 to 1 mg/kg/day prednisone equivalents followed by corticosteroid taper; if worsening or no improvement occurs, increase dose of corticosteroids to 1 to 2 mg/kg/day prednisone equivalents and permanently discontinue OPDIVO (nivolumab) [see Dosage and Administration (2.2) in full Prescribing Information and Adverse Reactions]. Immune-Mediated Hypothyroidism and Hyperthyroidism In Trial 3, patients were evaluated for thyroid function at baseline, first day of treatment, and every 6 weeks. Hypothyroidism occurred in 4.3% (5/117) of patients. The median time to onset for these five cases was 4.1 months (range: 1.4 to 4.6 months). All five patients with hypothyroidism received levothyroxine. Complete resolution of hypothyroidism occurred in one patient allowing discontinuation of levothyroxine. Interruption of OPDIVO did not occur in these five patients. Hyperthyroidism occurred in 1.7% (2/117) of patients. One patient experienced Grade 2 hyperthyroidism 5.2 months after the first dose of OPDIVO, requiring treatment with high-dose corticosteroids and methimazole. Thyroid laboratory tests returned to normal 4.7 months later. Monitor thyroid function prior to and periodically during treatment. Administer hormone replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism. There are no recommended dose adjustments of OPDIVO for hypothyroidism or hyperthyroidism. Other Immune-Mediated Adverse Reactions Other clinically significant immune-mediated adverse reactions can occur. Immune-mediated adverse reactions may occur after discontinuation of OPDIVO therapy. The following clinically significant, immune-mediated adverse reactions occurred in less than 2% of OPDIVO-treated patients (n=385): adrenal insufficiency, uveitis, pancreatitis, facial and abducens nerve paresis, demyelination, autoimmune neuropathy, motor dysfunction, and vasculitis. Across clinical trials of OPDIVO administered at doses of 3 mg/kg and 10 mg/kg the following additional clinically significant, immune-mediated adverse reactions were identified: hypophysitis, diabetic ketoacidosis, hypopituitarism, GuillainBarré syndrome, and myasthenic syndrome. For any suspected immune-mediated adverse reactions, exclude other causes. Based on the severity of the adverse reaction, withhold OPDIVO, administer highdose corticosteroids, and if appropriate, initiate hormone-replacement therapy. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider restarting OPDIVO after completion of corticosteroid taper based on the severity of the event [see Dosage and Administration (2.2) in full Prescribing Information]. Embryofetal Toxicity Based on its mechanism of action and data from animal studies, OPDIVO can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of nivolumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in increased abortion and premature infant death. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and for at least 5 months after the last dose of OPDIVO [see Use in Specific Populations]. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling. • Immune-Mediated Pneumonitis [see Warnings and Precautions] • Immune-Mediated Colitis [see Warnings and Precautions] • Immune-Mediated Hepatitis [see Warnings and Precautions] • Immune-Mediated Nephritis and Renal Dysfunction [see Warnings and Precautions] • Immune-Mediated Hypothyroidism and Hyperthyroidism [see Warnings and Precautions] • Other Immune-Mediated Adverse Reactions [see Warnings and Precautions] 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 clinical practice. The data described in the WARNINGS and PRECAUTIONS section and below reflect exposure to OPDIVO in Trial 3, a single-arm trial in patients with metastatic squamous non-small cell lung cancer (NSCLC).

Clinically significant adverse reactions were evaluated in a total of 691 patients enrolled in Trials 1, 3, or an additional dose finding study (n=306) administering OPDIVO (nivolumab) at doses of 0.1 to 10 mg/kg every 2 weeks [see Warnings and Precautions]. Metastatic Squamous Non-Small Cell Lung Cancer The safety of OPDIVO was evaluated in Trial 3, a single-arm multinational, multicenter trial in 117 patients with metastatic squamous NSCLC and progression on both a prior platinum-based therapy and at least one additional systemic therapy [see Clinical Studies (14.2) in full Prescribing Information]. Patients received 3 mg/kg of OPDIVO administered intravenously over 60 minutes every 2 weeks. The median duration of therapy was 2.3 months (range: 1 day to 16.1+ months). Patients received a median of 6 doses (range: 1 to 34). Trial 3 excluded patients with active autoimmune disease, symptomatic interstitial lung disease, or untreated brain metastasis. The median age of patients was 65 years (range: 37 to 87) with 50% ≥65 years of age and 14% ≥75 years of age. The majority of patients were male (73%) and white (85%). All patients received two or more prior systemic treatments. Baseline disease characteristics of the population were recurrent Stage IIIb (6%), Stage IV (94%), and brain metastases (1.7%). Baseline ECOG performance status was 0 (22%) or 1 (78%). OPDIVO was discontinued due to adverse reactions in 27% of patients. Twenty-nine percent of patients receiving OPDIVO had a drug delay for an adverse reaction. Serious adverse reactions occurred in 59% of patients receiving OPDIVO. The most frequent serious adverse reactions reported in at least 2% of patients were dyspnea, pneumonia, chronic obstructive pulmonary disease exacerbation, pneumonitis, hypercalcemia, pleural effusion, hemoptysis, and pain. Table 1 summarizes adverse reactions that occurred in at least 10% of patients. The most common adverse reactions (reported in at least 20% of patients) were fatigue, dyspnea, musculoskeletal pain, decreased appetite, cough, nausea, and constipation. Table 1:

Adverse Reactions Occurring in ≥10% of Patients for All NCI CTCAE* Grades or ≥5% for Grades 3-4 (Trial 3)

Table 1: (Continued)

Adverse Reactions Occurring in ≥10% of Patients for All NCI CTCAE* Grades or ≥5% for Grades 3-4 (Trial 3) OPDIVO (nivolumab) (n=117)

Adverse Reaction

All Grades

Investigations Decreased weight Infections and Infestations Pneumoniag

0.9

*a National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0. Includes face edema, peripheral edema, local swelling, localized edema, lymphoedema. b Includes chest discomfort and noncardiac chest pain. c Includes back pain, bone pain, musculoskeletal chest pain, myalgia, neck pain, pain in extremity, spinal pain. d Includes arthritis and osteoarthritis. e Includes abdominal pain lower, abdominal pain upper, gastrointestinal pain. f Includes maculopapular rash, rash erythematous, erythema, dermatitis, dermatitis exfoliative, and dermatitis acneiform. g Includes lung infection and pneumonia aspiration. Other clinically important adverse reactions in less than 10% of patients in Trial 3 were: General Disorders and Administration Site Conditions: stomatitis Nervous System Disorders: peripheral neuropathy Infections and Infestations: bronchitis, upper respiratory tract infection Table 2:

Laboratory Abnormalities Worsening from Baseline Occurring in ≥10% of Patients for all NCI CTCAE Grades or ≥2% for Grades 3-4 (Trial 3) Percentage of Patients with Worsening Laboratory Test from Baselinea

Grades 3-4

Percentage (%) of Patients General Disorders and Administration Site Conditions Fatigue Asthenia Edemaa Pyrexia Chest painb Pain Respiratory, Thoracic, and Mediastinal Disorders Dyspnea Cough Musculoskeletal and Connective Tissue Disorders Musculoskeletal painc Arthralgiad Metabolism and Nutrition Disorders Decreased appetite Gastrointestinal Disorders Nausea Constipation Vomiting Diarrhea Abdominal paine Skin and Subcutaneous Tissue Disorders Rashf Pruritus

Grades 3-4

Percentage (%) of Patients

OPDIVO (n=117) Adverse Reaction

All Grades

50 19 17 17 13 10

7 1.7 1.7 0 0 2.6

38 32

9 1.7

36 13

6 0

2.6

29 24 19 18 16

1.7 0 0.9 2.6 1.7

16 11

0.9 0.9 (Continued)

Test Chemistry Hyponatremia Increased creatinine Hypercalcemia Hypokalemia Hypomagnesemia Hypocalcemia Hyperkalemia Increased AST Increased alkaline phosphatase Increased ALT Hematology Lymphopenia Anemia Thrombocytopenia a

All Grades

Grades 3-4

38 22 20 20 20 18 18 16 14 12

10 0 2.6 2.6 0 1.8 4.4 0.9 0 0

47 28 14

16 2.6 0

Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available (range 111 to 114 patients).

Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. Of 281 patients who were treated with OPDIVO 3 mg/kg every 2 weeks and evaluable for the presence of anti-product antibodies, 24 patients (8.5%) tested positive for treatment-emergent anti-product antibodies by an electrochemiluminescent (ECL) assay. Neutralizing antibodies were detected in two patients (0.7%). There was no evidence of altered pharmacokinetic profile or toxicity profile with anti-product binding antibody development based on the population pharmacokinetic and exposure-response analyses. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample

collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to OPDIVO (nivolumab) with the incidences of antibodies to other products may be misleading. DRUG INTERACTIONS No formal pharmacokinetic drug-drug interaction studies have been conducted with OPDIVO. USE IN SPECIFIC POPULATIONS

Hepatic Impairment Based on a population pharmacokinetic analysis, no dose adjustment is recommended for patients with mild hepatic impairment. OPDIVO (nivolumab) has not been studied in patients with moderate or severe hepatic impairment [see Clinical Pharmacology (12.3) in full Prescribing Information]. OVERDOSAGE There is no information on overdosage with OPDIVO.

Pregnancy

PATIENT COUNSELING INFORMATION

Risk Summary Based on its mechanism of action [see Clinical Pharmacology (12.1) in full Prescribing Information] and data from animal studies, OPDIVO can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) in full Prescribing Information]. In animal reproduction studies, administration of nivolumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in increased abortion and premature infant death [see Data]. Human IgG4 is known to cross the placental barrier and nivolumab is an immunoglobulin G4 (IgG4); therefore, nivolumab has the potential to be transmitted from the mother to the developing fetus. The effects of OPDIVO are likely to be greater during the second and third trimesters of pregnancy. There are no available human data informing the drug-associated risk. Advise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown; however, the background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies. Data

Advise the patient to read the FDA-approved patient labeling (Medication Guide). Inform patients of the risk of immune-mediated adverse reactions that may require corticosteroid treatment and interruption or discontinuation of OPDIVO, including: • Pneumonitis: Advise patients to contact their healthcare provider immediately for any new or worsening cough, chest pain, or shortness of breath [see Warnings and Precautions]. • Colitis: Advise patients to contact their healthcare provider immediately for diarrhea or severe abdominal pain [see Warnings and Precautions]. • Hepatitis: Advise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, pain on the right side of abdomen, lethargy, or easy bruising or bleeding [see Warnings and Precautions]. • Nephritis and Renal Dysfunction: Advise patients to contact their healthcare provider immediately for signs or symptoms of nephritis including decreased urine output, blood in urine, swelling in ankles, loss of appetite, and any other symptoms of renal dysfunction [see Warnings and Precautions]. • Hypothyroidism and Hyperthyroidism: Advise patients to contact their healthcare provider immediately for signs or symptoms of hypothyroidism and hyperthyroidism [see Warnings and Precautions]. Advise patients of the importance of keeping scheduled appointments for blood work or other laboratory tests [see Warnings and Precautions]. Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions, Use in Specific Populations]. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and for at least 5 months following the last dose of OPDIVO [see Use in Specific Populations]. Advise women not to breastfeed while taking OPDIVO [see Use in Specific Populations].

Animal Data A central function of the PD-1/PD-L1 pathway is to preserve pregnancy by maintaining maternal immune tolerance to the fetus. Blockade of PD-L1 signaling has been shown in murine models of pregnancy to disrupt tolerance to the fetus and to increase fetal loss. The effects of nivolumab on prenatal and postnatal development were evaluated in monkeys that received nivolumab twice weekly from the onset of organogenesis through delivery, at exposure levels of between 9 and 42 times higher than those observed at the clinical dose of 3 mg/kg of nivolumab (based on AUC). Nivolumab administration resulted in a non-doserelated increase in spontaneous abortion and increased neonatal death. Based on its mechanism of action, fetal exposure to nivolumab may increase the risk of developing immune-mediated disorders or altering the normal immune response and immune-mediated disorders have been reported in PD-1 knockout mice. In surviving infants (18 of 32 compared to 11 of 16 vehicle-exposed infants) of cynomolgus monkeys treated with nivolumab, there were no apparent malformations and no effects on neurobehavioral, immunological, or clinical pathology parameters throughout the 6-month postnatal period. Lactation Risk Summary It is not known whether OPDIVO is present in human milk. Because many drugs, including antibodies are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from OPDIVO, advise women to discontinue breastfeeding during treatment with OPDIVO. Females and Males of Reproductive Potential Contraception Based on its mechanism of action, OPDIVO can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations]. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and for at least 5 months following the last dose of OPDIVO. Pediatric Use The safety and effectiveness of OPDIVO have not been established in pediatric patients. Geriatric Use Clinical studies of OPDIVO did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients. Of the 117 patients treated with OPDIVO in Trial 3, 50% of patients were 65 years or older and 14% were 75 years or older. Renal Impairment Based on a population pharmacokinetic analysis, no dose adjustment is recommended in patients with renal impairment [see Clinical Pharmacology (12.3) in full Prescribing Information].

Manufactured by: Bristol-Myers Squibb Company Princeton, NJ 08543 USA U.S. License No. 1713 1321663A1

Revised: March 2015 1506US15BR00210-02-01

Imbruvica (Ibrutinib), First-in-Class Bruton’s Tyrosine Kinase Inhibitor, Receives Expanded Indications for Patients with Relapsed Chronic Lymphocytic Leukemia By Lisa A. Raedler, PhD, RPh, Medical Writer

hronic lymphocytic leukemia (CLL), the most common type of leukemia in adults, is a cancer of B-cell lymphocytes, which originate in the bone marrow, develop in the lymph nodes, and normally fight infection by producing an immune response.1,2 In CLL, excess B-cells accumulate in the bone marrow and blood, where they crowd out healthy blood cells.2 The Leukemia & Lymphoma Society has estimated that more than 15,500 Americans were diagnosed with CLL in 2013.3 The incidence of CLL increases significantly among people aged ≥50 years; only a small fraction of adults are diagnosed in their 30s or 40s.3 The majority of patients who are diagnosed with CLL are asymptomatic, and the diagnosis is made as a result of a routine blood test that shows a high white blood cell count.4 As it advances, CLL can cause swollen lymph nodes, an enlarged spleen, anemia, and infections.2 The prognosis for patients with CLL varies significantly based on their disease subtype and risk status, with survival duration ranging from approximately 1 year to more than 20 years.5 According to the American Society of Clinical Oncology, the 5-year overall survival rate for patients with CLL of all stages is approximately 79%.5 Early-stage CLL is typically not treated, whereas patients with symptomatic intermediate- or high-risk CLL are usually receiving chemotherapy combined with a targeted monoclonal antibody drug, either rituximab or another CD-20 targeted agent.6 Studies comparing treatment with chemotherapy, such as fludarabine or the combination of fludarabine and cyclophosphamide, with chemoimmunotherapy (fludarabine and rituximab) have shown that rituximab-containing combinations significantly improve complete response rates, remission duration, and overall survival of previously untreated patients with CLL.7 In November 2013, the US Food and Drug Administration (FDA) approved obinutuzumab (Gazyva) in combination with chlorambucil for the treatment of patients with previously untreated CLL.8 Obinutuzumab is a humanized monoclonal antibody that targets CD20 on the surface of CLL cells.9 There is no consensus regarding the management of

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patients with relapsed and refractory CLL. Treatment decisions are based on several factors, including the timing of relapse, the patient’s age, disease extent, overall health status, and previous therapies.10 Agents that are frequently used (either alone or in combination) in the relapsed and/or refractory CLL setting include alem tuzumab, bendamustine, chlorambucil, fludarabine, ofatumumab, and rituximab.11 As a chronic illness, the cost burden associated with CLL is significant. A recent published cost analysis was conducted in Germany using both the direct and indirect costs of CLL.12 European investigators found that the total per-patient cost for patients with CLL was €9753 (approximately $13,500) annually compared with €4807 (approximately $6600) annually for individuals in the control group with the same age and sex. In this study, the economic burden associated with CLL was primarily driven by inpatient and pharmaceutical costs. From a societal perspective, productivity loss was the highest cost driver associated with a diagnosis of CLL.12

Ibrutinib Receives New Indications for Previously Treated Patients with CLL and for CLL with del 17p On February 12, 2014, the FDA accelerated the approval of an expanded indication for ibrutinib (Imbruvica; Pharmacyclics) for patients with CLL who have received at least 1 previous therapy.13 A few months earlier (in November 2013), the FDA accelerated its approval of ibrutinib for the treatment of patients with mantle-cell lymphoma who had received at least 1 previous therapy.13 Ibrutinib is the first FDA-approved drug designed to target Bruton’s tyrosine kinase (BTK), a protein necessary for the growth and survival of B-cells.14 On July 28, 2014, the FDA approved an expanded indication for ibrutinib for the treatment of patients with CLL who have a deletion in chromosome 17 (del 17p), a genetic mutation associated with poor response to standard therapy. The approval of ibrutinib for patients with CLL and del 17p was based on results of a clinical trial with 391

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previously treated patients, 127 of whom had CLL with del 17p. Results of an interim analysis showed a 78% reduction of progression-free survival in patients with CLL and del 17p who received ibrutinib. John C. Byrd, MD, Director of the Division of Hematology at the Ohio State University Comprehensive Cancer Center in Columbus, and a principal investigator in the ibrutinib CLL trial, stated, “Rarely does a drug come along with so much potential to help CLL patients….I have been impressed with the promising and durable response rates we have seen in patients.” 16 In January 2015, ibrutinib received yet another new FDA indication. See page 69.

Mechanism of Action Ibrutinib is a small-molecule inhibitor of BTK, a signaling molecule of the B-cell antigen receptor and cytokine receptor pathways.15 As an irreversible covalent inhibitor, ibrutinib continues to inhibit BTK even after the drug is metabolized.17 Preclinical studies have demonstrated that ibrutinib prevents the activation of downstream pathways affected by BTK, promotes cancer-cell apoptosis, and inhibits cell proliferation.18 Dosing and Administration In patients with CLL who have received at least 1 previous therapy, the recommended dose and schedule for ibrutinib is 420 mg orally once daily. Ibrutinib should be administered at the same time each day, and should be swallowed whole with water. The capsules should not be opened, broken, or chewed.15 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.15 Because ibrutinib is primarily metabolized by the cytochrome (CY) P450 enzyme 3A, it should not be coadministered with strong or moderate CYP3A inhibitors. The concomitant use of strong CYP3A inhibitors that are taken on a long-term basis (eg, ritonavir, indinavir, nelfinavir, saquinavir, boceprevir, telaprevir, nefazodone) is not recommended.15 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.15 Less than 1% of the ibrutinib dose is excreted renally.15 Exposure to ibrutinib is not altered in patients with creatinine clearance (CrCl) of >25 mL/min. No data exist for patients with severe renal impairment (CrCl <25 mL/min) or for patients on dialysis.15

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Clinical Trials Pivotal Phase 2 Study The safety and efficacy of ibrutinib for the treatment of patients with CLL were demonstrated in a phase 1b/2 open-label, multicenter trial. This trial included 48 patients with CLL who had previously received multiple therapies.15 In this study, ibrutinib was given orally, 420 mg daily, in continuous 28-day cycles until disease progression.15 The primary end point of this phase 2 study was overall response rate, which was defined as partial response and complete response. Tumor response was evaluated by an Independent Review Committee using a modified version of the International Workshop on CLL criteria.15 Patient population The median age of the 48 patients with CLL evaluated for this trial was 67 years (range, 37-82 years).15 Most patients were male (71%) and Caucasian (94%). All of the patients had an Eastern Cooperative Oncology Group performance status of 0 or 1. The patients’ median time since the diagnosis of CLL exceeded 6 years (80 months). These patients had received 1 to 12 (median, 4) previous therapies for CLL.15 Efficacy In this phase 2 study of ibrutinib in patients with relapsed CLL, the overall response rate was 58.3% (95% confidence interval, 43.2%-72.4%).15 All were partial responses. The duration of response for these patients with CLL ranged from 5.6 months to 24.2+ months. The median duration of response was not reached at the time of the FDA’s approval of the drug for CLL.15 An increase in lymphocyte counts, defined as a ≥50% increase from baseline and above absolute lymphocyte count of 5000/mcL, was observed in 77% of patients with CLL who received ibrutinib in this phase 2 study. Isolated lymphocytosis occurred during the first 4 weeks of ibrutinib therapy and resolved after a median of 23 weeks (range, 1-104+ weeks).15 Table 1 Ibrutinib for CLL Dose Modifications for Adverse Reactions Nonhematologic Dose modification postrecovery in patients toxicity event with CLL, starting dose, 420 mg First

Restart at 420 mg daily

Second

Restart at 280 mg daily

Third

Restart at 140 mg daily

Fourth

Discontinue ibrutinib therapy

CLL indicates chronic lymphocytic leukemia. Source: Imbruvica (ibrutinib) prescribing information; February 2014.

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Table 2 Selected Adverse Events of Patients with CLL Receiving Ibrutinib System organ class/ All grades, % Grade 3 or 4, % adverse events (N = 48) (N = 48) Blood disorders 71 10 Thrombocytopenia 54 27 Neutropenia Infections/infestations 21 6 Sinusitis 17 6 Skin infection 10 8 Pneumonia Vascular disorders 17 8 Hypertension Musculoskeletal/connective tissue disorders Musculoskeletal pain

CLL indicates chronic lymphocytic leukemia. Source: Imbruvica (ibrutinib) prescribing information; February 2014.

RESONATE: Phase 3 Study As a condition for the accelerated approval of ibrutinib for patients with CLL, the FDA instructed the drug manufacturer to submit the results of phase 3 randomized clinical trials to the FDA. In January 2014, the manufacturer of the drug notified the FDA that based on the favorable results of a planned interim analysis, the phase 3 RESONATE clinical trial that compared ibrutinib and ofatumumab for patients with CLL was ended early.16,19 This phase 3 clinical trial randomized patients with previously treated CLL or with small lymphocytic lymphoma who were not considered candidates for treatment with purine analog-based treatments to receive either ibrutinib or the anti-CD20 monoclonal antibody ofatumumab.19 The results of this interim analysis showed significant improvements in progression-free survival and overall survival with ibrutinib compared with ofatumumab for patients with previously treated CLL in this phase 3 trial.16,19 Adverse Events The 48 previously treated CLL patients who received ibrutinib in the phase 2 clinical trial received 420 mg daily for a median of 15.6 months.15 Adverse reactions that occurred at a frequency of â&#x2030;Ľ20% included thrombocytopenia (71%, all grades), diarrhea (63%), bruising (54%), neutropenia (54%), upper respiratory tract infection (48%), anemia (44%), 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%).15 The most common grade 3 or grade 4 nonhematologic adverse reactions were pneumonia (8%), hypertension (8%), atrial fibrillation (6%), sinusitis (6%), skin infec-

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tion (6%), dehydration (6%), and musculoskeletal pain (6%; Table 2).15,16 Of the 48 patients with CLL, 5 discontinued ibrutinib as a result of adverse reactions in the phase 2 trial: 3 patients with infections and 2 patients with subdural hematomas.15 Of the patients with CLL who received ibrutinib, 13% experienced adverse reactions that led to dose reduction. In 38% of patients, uric acid levels shifted from normal to elevated during the study, including 4% of patients with values >10 mg/dL.15 Ibrutinib has no contraindications.15

Warnings and Precautions Hemorrhage. Bleeding events, including bruising of any grade, were observed in 63% of patients with CLL who received 420 mg of ibrutinib daily.15 Of the patients with CLL, 6% had grade â&#x2030;Ľ3 bleeding events, including subdural hematoma, gastrointestinal bleeding, and hematuria. Clinicians should consider the benefit-risk of ibrutinib in patients who require antiplatelet or anticoagulant therapies, and the benefit-risk of withholding ibrutinib for at least 3 to 7 days before and after surgery depending on the procedure and the risk of bleeding.15 Infections. Fatal and nonfatal infections occurred in the clinical trial of ibrutinib in patients with CLL.15 At least 35% of patients with CLL had grade â&#x2030;Ľ3 infections. Clinicians should regularly monitor patients who are receiving ibrutinib for signs of fever and infections and should evaluate the patients promptly.15 Myelosuppression. Grade 3 or 4 cytopenias, including neutropenia (27%) and thrombocytopenia (10%; Table 2), were reported in the patients with CLL receiving ibrutinib.15 Patients should undergo monthly complete blood cell counts while taking ibrutinib.15 Renal toxicity. Serious and even fatal cases of renal failure have occurred with ibrutinib.15 Increases in creatinine levels up to 1.5 times the upper limit of normal (ULN) occurred in 23% of patients with CLL receiving ibrutinib and from 1.5 to 3 times the ULN in 4% of patients with CLL. Patients receiving ibrutinib should undergo periodic creatinine level monitoring and should maintain hydration.15 Secondary primary malignancies. Other malignancies, including skin cancers (8%) and other types of carcinomas (2%), have been observed in patients with CLL who have received ibrutinib.15 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.15 Specific Populations Pregnant women. Ibrutinib has been assigned Preg-

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nancy Category D. Based on animal data, ibrutinib can cause fetal harm when administered to a pregnant woman.15 Nursing mothers. Ibrutinib has not been studied in nursing mothers. It is not known whether this agent is excreted in human breast milk. Because many drugs are excreted in human milk and because of the potential for serious adverse events with ibrutinib, a decision should be made to discontinue nursing or to discontinue taking ibrutinib, with the importance of the drug to the mother kept in mind.15 Pediatric patients. The safety and efficacy of ibrutinib in pediatric patients have not been established. Older patients. In the clinical trial of ibrutinib for the treatment of patients with CLL, 52% of patients were aged ≥65 years. When older and younger patients were compared, no overall differences in efficacy were observed. However, a higher number of adverse events were reported in older patients (aged ≥65 years). Specifically, grade ≥3 adverse events occurred more often among older patients compared with among younger patients (80% vs 61%, respectively).15

Imbruvica Receives New FDA Indication in 2015 for Waldenström’s Macroglobulinemia On January 29, 2015, the FDA approved a new indication for ibrutinib for the treatment of patients with Waldenström’s macroglobulinemia, a rare, indolent type of non-Hodgkin lymphoma. Ibrutinib received a breakthrough therapy designation by the FDA for this use, as well as an orphan drug designation for the treatment of this rare disease. Waldenström’s macroglobulinemia progresses slowly, often with no symptoms, resulting in overproduction of B lymphocytes (B-cells) within the bone marrow, lymph nodes, liver, and spleen. These B-cells also overproduce immunoglobulin M that may lead to bleeding, excessive fatigue, as well as vision and central nervous system problems. Ibrutinib works by inhibiting the abnormal activity of the B-cells. This new FDA indication for Waldenström’s macroglobulinemia was based on a clinical study of 63 previously treated patients with Waldenström’s macroglobulinemia. Ibrutinib led to a 62% overall response rate, with a response duration lasting between 2.8 and approximately 18.8 months.20 Conclusion Ibrutinib, the first FDA-approved BTK inhibitor, offers clinicians and previously treated patients with CLL an effective and safe treatment option. This once-daily oral agent has demonstrated a high response rate, as well as a favorable toxicity profile, in patients with relapsed

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CLL. Because ibrutinib has a favorable therapeutic index, its use in combination with other agents for the treatment of patients with CLL and other hematologic malignancies is currently being explored.16,21 Examples include an ongoing study combining ibrutinib with bendamustine and rituximab for patients with relapsed or refractory CLL and a study combining ibrutinib with rituximab for patients with relapsed or refractory mantle-cell lymphoma.22 The new indication approved by the FDA for ibrutinib for the treatment of patients with Waldenström’s macroglobulinemia adds a new treatment options for patients with this rare disease and few treatment options. n

References

1. Leukemia & Lymphoma Society. Chronic lymphocytic leukemia. www.lls.org/#/ diseaseinformation/leukemia/chroniclymphocyticleukemia/. Accessed March 3, 2014. 2. Leukemia & Lymphoma Society. Chronic lymphocytic leukemia: causes and risk factors. www.lls.org/diseaseinformation/leukemia/chroniclymphocyticleukemia/causes riskfactors/. Accessed March 3, 2014. 3. Leukemia & Lymphoma Society. Incidence: how common is CLL? www.lls.org/#/ diseaseinformation/leukemia/chroniclymphocyticleukemia/incidence/. Accessed March 3, 2014. 4. Leukemia & Lymphoma Society. Chronic lymphocytic leukemia: signs and symptoms. www.lls.org/diseaseinformation/leukemia/chroniclymphocyticleukemia/signs symptoms/. Accessed March 3, 2014. 5. Cancer.net. Leukemia–chronic lymphocytic–CLL: statistics. Updated February 18, 2014. www.cancer.net/cancer-types/leukemia-chronic-lymphocytic-cll/statistics. Accessed March 4, 2014. 6. Cancer.net. Leukemia–chronic lymphocytic–CLL: treatment options. www.cancer. net/cancer-types/leukemia-chronic-lymphocytic-cll/treatment-options. Accessed March 4, 2014. 7. Leukemia & Lymphoma Society. Chronic lymphocytic leukemia: clinical trials. www. lls.org/diseaseinformation/leukemia/chroniclymphocyticleukemia/clinicaltrials/. Accessed March 3, 2014. 8. 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. 9. Gazyva (obinutuzumab) injection [prescribing information]. South San Francisco, CA: Genentech, Inc; November 2013. 10. Leukemia & Lymphoma Society. Chronic lymphocytic leukemia: before treatment. www.lls.org/#/diseaseinformation/leukemia/chroniclymphocyticleukemia/before treatment/. Accessed March 3, 2014. 11. Leukemia & Lymphoma Society. Chronic lymphocytic leukemia: chemotherapy and drug therapy. www.lls.org/#/diseaseinformation/leukemia/chroniclymphocyticleukemia/ treatment/chemotherapydrugtherapy/. Accessed March 3, 2014. 12. Blankart CR, Koch T, Linder R, et al. Cost of illness and economic burden of chronic lymphocytic leukemia. Orphanet J Rare Dis. 2013;8:32. 13. US Food and Drug Administration. FDA approves Imbruvica to treat chronic lymphocytic leukemia. Press release. February 12, 2014. www.fda.gov/NewsEvents/ Newsroom/PressAnnouncements/ucm385764.htm. Accessed March 14, 2014. 14. Lymphoma Research Foundation. Breakthrough therapy ibrutinib effective in CLL and MCL lymphomas. August 2013. www.lymphoma.org/site/pp.asp?c=bkLTKa OQLmK8E&b=8756085. Accessed March 11, 2014. 15. Imbruvica (ibrutinib) capsules [prescribing information]. Sunnyvale, CA: Pharmacyclics; February 2014. 16. Inman S. FDA approves ibrutinib for chronic lymphocytic leukemia. OncLive. February 12, 2014. www.onclive.com/web-exclusives/FDA-Approves-Ibrutinib-forCLL#sthash.bNUKV3Wo.dpuf. Accessed March 11, 2014. 17. Woyach J. BTK inhibition and the mechanism of action of ibrutinib. Targeted Oncology. August 20, 2013. www.targetedonc.com/targeted-communications/DrWoyach-on-BTK-Inhibition-and-the-Mechanism-of-Action-of-Ibrutinib. Accessed December 16, 2013. 18. Akinleye A, Chen Y, Mukhi N, et al. Ibrutinib and novel BTK inhibitors in clinical development. J Hematol Oncol. 2013;6:59. 19. US Food and Drug Administration. Ibrutinib (Imbruvica). Updated February 13, 2014. www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm385878.htm. Accessed March 11, 2014. 20. US Food and Drug Administration. FDA expands approved use of Imbruvica for rare form of non-Hodgkin lymphoma. Press release. January 29, 2015. www.fda.gov/ NewsEvents/Newsroom/PressAnnouncements/ucm432123.htm. Accessed February 28, 2015. 21. Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369:32-42. 22. ClinicalTrials.gov. Ibrutinib combination. Search results. http://clinicaltrials.gov/ ct2/results?term= ibrutinib+combination+&Search=Search. Accessed March 11, 2014.

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Invokamet (Canagliflozin plus Metformin HCl): First Fixed-Dose Combination with an SGLT2 Inhibitor Approved for the Treatment of Patients with Type 2 Diabetes By Loretta Fala, Medical Writer

iabetes is a chronic disease that affects an estimated 29.1 million individuals in the United States—approximately 9.3% of the US population.1 In addition, a staggering 37% of US adults have prediabetes, placing them at a high risk for 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 in 10 adults today to approximately 1 in 3 adults by 2050.2 Approximately 90% to 95% of all cases of diabetes are type 2 diabetes mellitus, a disease that is characterized by insulin resistance and a gradual decline in the ability of the pancreas to produce insulin.1 Diabetes is associated with multiple comorbidities, as well as microvascular, macrovascular, and neuropathic complications that impact the quality of life.1 The seventh leading cause of mortality in the United States, diabetes is a major cause of stroke and heart disease and is the leading cause of kidney failure, new cases of blindness, and nontraumatic lower-limb amputations. Furthermore, individuals with diabetes are at an increased risk for nerve disease, nonalcoholic fatty liver disease, periodontal disease, erectile dysfunction, hearing loss, depression, and pregnancy complications compared with individuals without diabetes.1 In 2012, diabetes accounted for $245 billion in total US healthcare costs, including $176 billion in direct medical costs and $69 billion in indirect costs (eg, increased absenteeism, reduced productivity, lost productivity, and disability).3 These estimated economic costs of diagnosed diabetes represent a 41% increase from the estimated medical expenditures in 2007.3 Overall, the medical expenditures for individuals with diabetes are approximately 2.3 times higher than the medical expenditures for individuals without diabetes. In fact, more than 1 in 5 US healthcare dollars is spent on the care of patients with diabetes.3 The management of diabetes requires glycemic control, as well as multiple risk-reduction strategies, including lifestyle and behavioral changes, ongoing medical care, patient education and self-management, and ongoing patient monitoring and support.4 Improvements in glycemic control have been shown

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to reduce the morbidity and mortality associated with type 2 diabetes mellitus by decreasing chronic complications. Lowering hemoglobin (Hb) A1c levels to ≤7% is associated with a reduction in diabetes-related microvascular complications (ie, diabetic neuropathy, nephropathy, and retinopathy).4 In its 2013 position statement, the American Diabetes Association (ADA) recommends a general HbA1c target goal of <7% for adult patients with diabetes, acknowledging that more stringent or less stringent goals may be appropriate for individual patients.4 According to the ADA, 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.4 The American Association of Clinical Endocrinologists recommends an HbA1c target goal of <6.5% for the majority of patients with type 2 diabetes mellitus, acknowledging that this goal may be too aggressive for some patients and not aggressive enough for other patients (ie, younger patients for whom a lower target may prevent subsequent complications).5 Although the number of individuals in the United States who achieve the target HbA1c levels of <7% has been increasing in recent years, further strategies are needed to improve the achievement of glycemic-control targets and overall outcomes for individuals with diabetes or those at risk for diabetes.4

The New SGLT2 Inhibitors The kidney plays a key role in maintaining glucose homeostasis. 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.6 In hyperglycemia, excess glucose is reabsorbed by the kidneys—a process that increases the renal glucose threshold and c reates a cycle of chronic hyperglycemia, along with associated microvascular complications.6 The sodium-glucose cotransporter 2 (SGLT2), a cotransporter that is expressed in the proximal renal tubules, mediates the active transport of glucose

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against a concentration g radient via cotransport with sodium. SGLT2 is responsible for reabsorbing 90% of the glucose that is filtered at the glomerulus.6 SGLT2 inhibitors represent a novel class of drugs that lower the renal threshold for glucose, thereby increasing urinary glucose excretion.6,7 Combined with diet and exercise, these agents have a promising role in improving glycemic control in patients with type 2 diabetes mellitus.

Fixed-Dose Combination for Type 2 Diabetes On August 8, 2014, the combination of canagliflozin (Invokana) plus metformin hydrochloride (Invokamet; Janssen Pharmaceuticals) in a single tablet was approved by the US Food and Drug Administration (FDA) for the treatment of patients with type 2 diabetes mellitus.8 The combination of canagliflozin, an SGLT2 inhibitor, and metformin hydrochloride (metformin), a biguanide, is not indicated for the treatment of type 1 diabetes or for the treatment of diabetic ketoacidosis. Canagliflozin plus metformin is the first fixed-dose combination of an SGLT2 inhibitor with metformin to receive FDA approval in the United States.8 Canagliflozin, the first SGLT2 inhibitor available in the United States, was approved by the FDA in 2013 for type 2 diabetes.9 Metformin, often prescribed in the early treatment of type 2 diabetes mellitus, has been available in the United States for nearly 20 years. Richard B. Aguilar, MD, Medical Director of Diabetes Nation, said, “InvokametTM combines, in one tablet, two complementary therapeutic approaches proven effective for managing type 2 diabetes. Canagliflozin works with the kidney to promote the loss of glucose in the urine, whereas metformin decreases the production of glucose in the liver and improves the body’s response to insulin.” 8 Mechanism of Action Canagliflozin plus metformin combines 2 oral antihyperglycemic agents with complementary mechanisms of action to improve glycemic control in patients with type 2 diabetes mellitus—canagliflozin, an SGLT2 inhibitor, and metformin, a member of the biguanide class.10 SGLT2, expressed in the proximal renal tubules, is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen. By inhibiting SGLT2, canagliflozin reduces reabsorption of filtered glucose and lowers the renal threshold for glucose, thereby increasing urinary glucose excretion.10 Metformin is an antihyperglycemic agent that improves glucose tolerance in patients with type 2 diabetes by 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.10

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Dosing The dosing of canagliflozin plus metformin is individualized based on the patient’s current antidiabetes drug regimen.10 The combination of canagliflozin plus metformin is taken twice daily with meals, with gradual dose escalation to reduce metformin-related gastrointestinal side effects.10 The daily dose of metformin should not exceed 2000 mg, and the daily dose of canagliflozin should not exceed 300 mg in patients with an estimated glomerular filtration rate (eGFR) of ≥60 mL/min/1.73 m2. Canagliflozin plus metformin is limited to canagliflozin 50 mg twice daily in patients with an eGFR of 45 mL/min/1.73 m2 to <60 mL/min/1.73 m2.10 Before starting treatment with canagliflozin plus metformin, renal function should be assessed.10 Canagliflo zin plus metformin should not be initiated or continued if creatinine levels are ≥1.5 mg/dL for males or 1.4 mg/dL for females, or if eGFR is <45 mL/min/1.73 m2. The combination of canagliflozin plus metformin is available as film-coated tablets in 4 strengths—canagliflozin 50 mg/metformin 500 mg, canagliflozin 50 mg/ metformin 1000 mg, canagliflozin 150 mg/metformin 500 mg, and canagliflozin 150 mg/metformin 1000 mg.10 Clinical Trials Although no clinical efficacy studies have been conducted on the combination of canagliflozin plus metformin, the bioequivalence of canagliflozin plus metformin to canagliflozin and metformin coadministered as individual tablets has been demonstrated in healthy individuals.10 Treatment with canagliflozin plus metformin demonstrated clinically significant improvements in HbA1c levels compared with placebo in patients with type 2 diabetes. These reductions were observed across subgroups, including age, sex, race, and baseline body mass index.7,10,11 Studies have been conducted on canagliflozin in combination with metformin alone, metformin and sulfonylurea, metformin and a thiazolidinedione (ie, pioglitazone), and metformin and insulin (with or without other antihyperglycemic agents).10 In addition, the efficacy of canagliflozin was compared with a dipeptidyl peptidase-4 inhibitor (sitagliptin) and with a sulfonylurea (glimepiride).7,10,11 Canagliflozin as Add-On to Metformin A 26-week, double-blind, placebo-controlled phase 3 clinical trial evaluated the efficacy and safety of canagliflozin in combination with metformin.7 This study included 1284 patients with type 2 diabetes mellitus that was inadequately controlled with metformin monotherapy (≥2000 mg daily or ≥1500 mg daily if a higher dose was not tolerated). The patients’ mean age was 55 years; 47% were men, and the mean baseline eGFR was 89 mL/min/1.73 m2.10 The primary end point of this study was the change

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from baseline in HbA1c levels at 26 weeks. The secondary end points included changes in HbA1c levels, fasting plasma glucose (FPG) levels at 52 weeks, body weight, and systolic blood pressure at 26 and 52 weeks.7,10 A total of 1009 patients who were already receiving the required metformin dose were randomized after completing a 2-week, single-blind, placebo run-in period. In addition, 275 patients who were taking less than the required metformin dose or who were receiving metformin in combination with another antihyperglycemic agent were switched to metformin monotherapy for at least 8 Table 1 Canagliflozin plus Metformin: Results from a 26-Week, Placebo-Controlled Clinical Trial Canagliflozin Canagliflozin Placebo + 100 mg + 300 mg + metformin metformin metformin Efficacy parameter (N = 183) (N = 368) (N = 367) HbA1c level Baseline, mean, %

7.96

7.94

7.95

Change from baseline, adjusted mean, %

–0.17

–0.79

–0.94

Difference from placebo, adjusted mean,a % Patients achieving HbA1c <7%, %

–0.62b (95% CI, –0.77b (95% CI, –0.76 to –0.48) –0.91 to –0.64) 30

46b

58b

Baseline, mean, mg/dL

164

169

173

Change from baseline, adjusted mean, mg/dL

–27

–38

–30b (95% CI, –36 to –24)

–40b (95% CI, –46 to –34)

Fasting plasma glucose

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

249

258

262

Change from baseline, adjusted mean, mg/dL

–10

–48

–57

–38b (95% CI, –49 to –27)

–47b (95% CI, –58 to –36)

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

86.7

88.7

85.4

Change from baseline, adjusted mean, %

–1.2

–3.7

–4.2

–2.5b (95% CI, –3.1 to –1.9)

–2.9b (95% CI, –3.5 to –2.3)

Difference from placebo, adjusted mean,a kg

Least squares mean adjusted for baseline value and stratification factors. b P <.001. CI indicates confidence interval. Source: Invokamet (canagliflozin and metformin hydrochloride) tablets prescribing information; August 2014. a

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weeks before entering the 2-week, single-blind, placebo run-in period. After the placebo run-in period, all patients were randomized to canagliflozin 100 mg, canagliflozin 300 mg, sitagliptin 100 mg, or to placebo, administered once daily as add-on therapy to metformin.10 At the end of the 26-week treatment period, 100-mg and 300-mg doses of canagliflozin administered once daily as add-on therapy to metformin demonstrated a significant improvement in HbA1c levels (P <.001 for both doses) compared with placebo (Table 1). Furthermore, canagliflozin 100 mg and canagliflozin 300 mg once daily also resulted in a greater proportion of patients who achieved HbA1c levels of <7%, a significant reduction in FPG levels, improved postprandial glucose, and greater percent body weight reduction compared with placebo when added to metformin. The mean changes from baseline in systolic blood pressure compared with placebo were significant: –5.4 mm Hg for canagliflozin 100 mg and –6.6 mm Hg for canagliflozin 300 mg (P <.001 for both doses).10 At week 52, canagliflozin 100 mg was noninferior to sitagliptin at lowering HbA1c levels, and canagliflozin 300 mg was superior to sitagliptin at lowering HbA1c levels. Canagliflozin 100 mg and canagliflozin 300 mg also showed a significant reduction in body weight compared with sitagliptin at 52 weeks (P <.001).7

Canagliflozin versus Glimepiride In a 52-week, double-blind, active-controlled study, the efficacy and safety of canagliflozin plus metformin versus glimepiride plus metformin were evaluated in 1450 patients with type 2 diabetes that was inadequately controlled with metformin monotherapy (≥2000 mg daily or ≥1500 mg daily if a higher dose was not tolerated).11 The patients’ mean age was 56 years; 56% were men, and the mean baseline eGFR was 90 mL/min/1.73 m2.10 The primary end point was the change from baseline in HbA1c levels at 52 weeks (0.3% noninferiority margin for comparing each of the canagliflozin doses vs glimepiride).11 The secondary end point was changes in percent body weight at week 52.11 A total of 928 patients who tolerated the maximally required metformin dose were randomized after completing a 2-week, single-blind, placebo run-in period. In addition, 522 patients were switched to metformin monotherapy for at least 10 weeks, and then completed a 2-week single-blind run-in period. After the 2-week run-in period, all the patients were randomized to receive canagliflozin 100 mg, canagliflozin 300 mg, or glimepiride (6 mg or 8 mg, allowed throughout the 52-week study period), administered once daily as add-on therapy to metformin.10 At the end of the treatment period, canagliflozin 100 mg demonstrated similar reductions in HbA1c levels from baseline compared with glimepiride when added to

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metformin therapy (Table 2).10 Furthermore, canagliflozin 300 mg demonstrated a greater reduction from baseline in HbA1c levels compared with glimepiride, and the relative treatment difference was –0.12% (95% confidence interval, –0.22 to –0.02). Treatment with canagliflozin 100 mg and canagliflozin 300 mg daily also demonstrated greater reductions in percent body weight than treatment with glimepiride.10

Table 2 Canagliflozin plus Metformin versus Glimepiride plus Metformin: Results from a 52-Week Clinical Trial Canagliflozin Canagliflozin Glimepiride 100 mg + 300 mg + (titrated) + metformin metformin metformin Efficacy parameter (N = 483) (N = 485) (N = 482) HbA1c level Baseline, mean, %

7.78

7.79

7.83

Safety The most common adverse reactions (≥5%) associated with the use of canagliflozin are female genital mycotic infections, urinary tract infection, and increased uri nation. The most common adverse reactions (≥5%) associated with the use of metformin are diarrhea, nausea, vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache.10

Change from baseline, adjusted mean, %

–0.82

–0.93

–0.81

Contraindications The combination of canagliflozin plus metformin is contraindicated in patients with renal impairment (eg, serum creatinine levels ≥1.5 mg/dL for males or 1.4 mg/ dL for females, or eGFR <45 mL/min/1.73 m2), which may also result from conditions such as cardiovascular collapse, acute myocardial infarction, or septicemia; endstage renal disease; or patients on dialysis.10 Canagliflozin plus metformin is also contraindicated in patients with acute or chronic metabolic acidosis, including diabetic ketoacidosis, or in patients with a history of a hypersensitivity reaction to canagliflozin or to metformin.10 Drug Interactions Cationic drugs. Cationic drugs (eg, amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, or vancomycin) may compete with metformin for common renal tubular transport systems and may inhibit metformin elimination.10 Uridine 5’-diphospho-glucoronosyltransferase (UGT) enzyme inducers. The concomitant use of a UGT inducer (eg, rifampin, phenytoin, phenobarbital, ritonavir) with canagliflozin plus metformin may reduce the exposure of canagliflozin; consider increasing the canagliflo zin dose from 50 mg to 150 mg twice daily.10 Digoxin. Canagliflozin increases digoxin exposure. Patients who take canagliflozin plus metformin with concomitant digoxin should be monitored for a need to adjust the dose of either drug.10 Warnings and Precautions Boxed warning. The prescribing information for canagliflozin plus metformin contains a boxed warning stating that lactic acidosis can occur as a result of metformin accumulation. This risk increases in patients with renal

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Difference from glimepiride, adjusted mean,a %

–0.01b (95% CI, –0.12b (95% CI, –0.11 to 0.09) –0.22 to –0.02)

Patients achieving HbA1c <7%, %

Baseline, mean, mg/dL

165

164

166

Change from baseline, adjusted mean, mg/dL

–24

–28

–18

–6 (95% CI, –10 to –2)

–9 (95% CI, –13 to –5)

Baseline, mean, kg

86.8

86.6

Change from baseline, adjusted mean, %

–4.2

–4.7

1.0

–5.2c (95% CI, –5.7 to –4.7)

–5.7c (95% CI, –6.2 to –5.1)

Fasting plasma glucose

Difference from glimepiride, adjusted mean,a mg/dL Body weight

Difference from glimepiride, adjusted mean,a kg

Least squares mean adjusted for baseline value and stratification factors. b Canagliflozin plus metformin is considered noninferior to glimepiride plus metformin, because the upper limit of this confidence interval is less than the prespecified noninferiority margin of <0.3%. c P <.001. CI indicates confidence interval. Source: Invokamet (canagliflozin and metformin hydrochloride) tablets prescribing information; August 2014. a

impairment, sepsis, dehydration, excess alcohol intake, hepatic impairment, and acute congestive heart failure.10 The symptoms associated with lactic acidosis include malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. Laboratory abnormalities include low pH levels, increased anion gap, and elevated blood lactate levels. If lactic acidosis is suspected, the combination of canagliflozin plus metformin should be discontinued, and the patient should be hospitalized immediately. Lactic acidosis. Patients should be cautioned against excessive alcohol use. The use of canagliflozin plus metformin is not recommended in patients with hepatic

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impairment or with hypoxic states. Patients should be checked for normal renal function before treatment is initiated and at least annually thereafter.10 Hypotension. Before the combination of canagliflozin plus metformin combination treatment is initiated, the volume status and correct hypovolemia should be assessed in patients with renal impairment; the elderly; patients with low systolic blood pressure; or those receiving diuretics, angiotensin-converting enzyme inhibitors, or angiotensin receptor blockers. Patients should be monitored for signs and symptoms of hypotension during therapy.10 Renal function. Potential impairment in renal function should be monitored during therapy.10 Radiologic studies/surgical procedures. Canagliflozin plus metformin should be temporarily discontinued for radiologic studies with intravascular administration of iodinated contrast materials or any surgical procedures that necessitate the restricted intake of food and fluids.10 Hyperkalemia. Potassium levels should be monitored in patients with impaired renal function and in patients who are predisposed to hyperkalemia.10 Hypoglycemia. When used in combination with canagliflozin plus metformin, a lower dose of insulin or the insulin secretagogue should be considered to reduce the risk of developing hypoglycemia.10 Genital mycotic infections. Patients should be monitored and treated for genital mycotic infections.10 Hypersensitivity reactions. Canagliflozin plus metformin should be discontinued in patients with hypersensitivity reactions, and patients should be monitored until the signs and symptoms of hypersensitivity resolve.10 Vitamin B12 deficiency. Metformin may lower vitamin B12 levels; hematologic parameters should be measured annually.10 Increased low-density lipoprotein cholesterol (LDL-C) levels. Dose-related increases in LDL-C levels may occur with canagliflozin. LDL-C levels should be monitored and treated per standard of care after the combination of canagliflozin plus metformin is initiated.10

Use in Specific Populations Pregnancy. Canagliflozin plus metformin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.10 Nursing mothers. A decision should be made whether to discontinue nursing or to suspend the use of canagliflozin plus metformin, taking into account the importance of the drug to the mother.10 Geriatric use. Because renal function abnormalities

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can occur after initiating canagliflozin, metformin is substantially excreted by the kidney, and aging can be as sociated with reduced renal function, renal function should be monitored more frequently after initiating canagliflozin plus metformin in the elderly, and the dose should be adjusted based on renal function.10 Renal impairment. The efficacy and safety of canagliflozin were evaluated in a study that included patients with moderate renal impairment. These patients had a higher incidence of adverse reactions that were related to reduced intravascular volume and renal function compared with patients with mild renal impairment or patients with normal renal function.10

Conclusion The recent FDA approval of the combination of canagliflozin plus metformin marks the availability of a novel SGLT2 and biguanide combination therapy in a single tablet for the treatment of patients with type 2 diabetes. Phase 3 studies demonstrated that this new combination improved HbA1c levels in patients with type 2 diabetes. In addition, canagliflozin plus metformin resulted in greater reductions in body weight and systolic blood pressure compared with metformin alone. n References

1. Centers for Disease Control and Prevention. National diabetes statistics report: estimates of diabetes and its burden in the United States, 2014. 2014. www.cdc.gov/ diabetes/pubs/statsreport14/national-diabetes-report-web.pdf. Accessed August 25, 2014. 2. Boyle JP, Thompson TJ, Gregg EW, et al. Projection of the year 2050 burden of diabetes in the US adult 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. Erratum in: Diabetes Care. 2013;36:1797. 4. American Diabetes Association. Standards of medical care in diabetes—2013. Diabetes Care. 2013;36(suppl 1):S11-S66. 5. Garber AJ, Abrahamson MJ, Barzilay JI, et al. American Association of Clinical Endocrinologists’ comprehensive diabetes management algorithm 2013 consensus statement. Endocr Pract. 2013;19(suppl 2):1-48. 6. Triplitt CL. Understanding the kidneys’ role in blood glucose regulation. Am J Manag Care. 2012;18(1 suppl):S11-S16. 7. Lavalle-González FJ, Januszewicz A, Davidson J, et al. Efficacy and safety of canagliflozin compared with placebo and sitagliptin in patients with type 2 diabetes on background metformin monotherapy: a randomised trial. Diabetologia. 2013;56:25822592. 8. Johnson & Johnson. U.S. FDA approves Invokamet (canagliflozin/metformin HCl) for the treatment of adults with type 2 diabetes: in phase 3 studies, Invokana plus metformin lowered blood sugar and reduced secondary endpoints of body weight and systolic blood pressure to a greater degree than metformin alone. Press release. August 8, 2014. www.investor.jnj.com/releasedetail.cfm?releaseid=865927. Accessed August 28, 2014. 9. US Food and Drug Administration. FDA approves Invokana to treat type 2 diabetes. Press release. March 29, 2013. www.fda.gov/NewsEvents/Newsroom/PressAn nouncements/ucm345848.htm. Accessed August 28, 2014. 10. Invokamet (canagliflozin and metformin hydrochloride) tablets [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc; August 2014. 11. Cefalu WT, Leiter LA, Yoon K-H, et al. Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomised, double-blind, phase 3 non-inferiority trial. Lancet. 2013;382:941-950.

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Jakafi (Ruxolitinib): First FDA-Approved Medication for the Treatment of Patients with Polycythemia Vera By Lisa A. Raedler, PhD, RPh, Medical Writer

imilar to myelofibrosis and essential thrombocythemia, polycythemia vera is a Philadelphia chromosomeâ&#x20AC;&#x201C;negative myeloproliferative neoplasm.1 Polycythemia vera is characterized by the clonal stem-cell proliferation of red blood cells, white blood cells, and platelets.2,3 Increased red blood cell mass results in the hyperviscosity of the blood, an increased risk for thrombosis, poor quality of life, and a shortened life expectancy.4 Polycythemia vera is a rare condition. The incidence rate of polycythemia vera for all races and ethnicities is higher among men than among women: approximately 2.8 per 100,000 men and approximately 1.3 per 100,000 women.3 Based on several small studies, approximately 22 in 100,000 individuals are affected by polycythemia vera.3 The condition is typically diagnosed in older adults aged 60 to 65 years, and is uncommon in younger people aged <30 years.3 Approximately 96% of patients with polycythemia vera have a mutation of the Janus-associated kinase (JAK) 2 gene.5 In the polycythemia vera progenitor cells, JAK2 is directly involved in the intracellular signaling that occurs after exposure to specific cytokines.5,6 The course of the disease varies.3 Some patients with polycythemia vera have few symptoms, and the condition is discovered only after blood work is performed during a periodic health examination. In others, the signs, symptoms, and complications result from the high red blood cell count and platelet count.3 In addition, polycythemia vera evolves to postpolycythemia vera myelofibrosis in up to 10% of patients by year 10.7 Transformation to acute myeloid leukemia has been observed in up to 15% of patients with polycythemia vera after 10 years of the disease.8 The symptoms of polycythemia vera are primarily related to thrombi that result from increased blood viscosity and high platelet counts. The thrombotic complications are divided into microvascular and macrovascular complications. The microvascular complications result from thrombi in small blood vessels and can cause a variety of signs and symptoms, including headaches, dizziness, and paresthesia (Table 1).9 The macrovascular complications, often referred to as major thrombotic events, are serious events that are secondary to thrombi in large arteries or

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veins, including myocardial infarction (Table 1).10 Cardiovascular events are the primary cause of mortality in patients with polycythemia vera, accounting for 45% of deaths.11 Other major causes of death in this patient population include solid tumors (20%) and hematologic transformations (13%).11 Although polycythemia vera is incurable, it can be managed effectively for long periods.3 The treatment of patients with polycythemia vera is designed to reduce the hematocrit and platelet concentrations, control polycythemia vera symptoms, decrease the risk for thrombotic events and other complications, and avoid leukemic transformation.3,12,13 The need for treatment is determined after assessing the patientâ&#x20AC;&#x2122;s risk status, based on age and thrombosis history. Patients aged >60 years or those with a history of thrombosis have high-risk polycythemia vera, whereas younger patients aged <60 years or those with no history of thrombosis have low-risk disease.3,13 Patients with lowrisk polycythemia vera are often phlebotomized and receive low-dose aspirin. Conversely, patients with highTable 1 T hrombotic Complications in Polycythemia Vera Microvascular complications Erythromelalgia Headache Dizziness Visual disturbances Paresthesia Transient ischemic attack Macrovascular complications Arterial thrombotic events Myocardial infarction Unstable angina Stroke Peripheral arterial occlusion Venous thrombotic events Deep vein thrombosis Pulmonary embolism Intra-abdominal vein thrombosis Cerebral vein thrombosis Sources: Michiels JJ, et al. Semin Thromb Hemost. 2006;32:174-207; Falanga A, Marchetti M. Hematology Am Soc Hematol Educ Program. 2012;2012:571-581; Marchioli R, et al. J Clin Oncol. 2005;23:22242232.

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risk disease require medical therapy to lower their hematocrit concentration permanently (ie, <45% in men and <42% in women), eliminate the need for phlebotomy, and decrease the risk for clotting.3,13 Cytoreductive therapy is recommended to control red blood cell volume in patients for whom phlebotomy is poorly tolerated, in patients with a high thrombotic risk, and in those with symptomatic splenomegaly.3 Among the available cytoreductive medication options, hydroxyurea is currently the treatment of choice for pa-

“The approval of Jakafi for polycythemia vera underscores the importance of developing drugs matched to our increasing knowledge of the mechanisms of diseases. The trial used to evaluate Jakafi confirmed clinically meaningful reductions in spleen size and the need for phlebotomies to control the disease.” tients with polycythemia vera who are older than 40 years.12-14 Although it effectively improves myelosuppression and reduces the risk for thrombosis compared with phlebotomy alone, hydroxyurea’s utility is limited by its risk for secondary leukemia.14,15 Patients who are intolerant of or are resistant to hyTable 2 RESPONSE: Patients with Polycythemia Vera Reaching Primary and Key Secondary End Points Patients achieving primary/secondary end points

Ruxolitinib, N (%) (N = 110)

Best available therapy, N (%) (N = 112) P value

Responsea at week 32

23 (21)

1 (<1)

<.001

Durable response at week 48

21 (19)

1 (<1)

<.001

Complete hematologic remissionb at week 32

26 (24)

10 (9)

.003

Hematocrit control at week 32

66 (60)

22 (20)

—

Spleen volume reduction ≥35% from baseline at week 32

42 (38)

1 (<1)

—

Defined as hematocrit control and a ≥35% reduction from baseline in spleen volume at week 32. b Defined as hematocrit control, platelet count ≤400 × 109/L, and white blood cell count ≤10 × 109/L at week 32. Sources: Jakafi (ruxolitinib) tablets prescribing information; December 2014; Vannucchi AM, et al. N Engl J Med. 2015;372: 426-435. a

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droxyurea can be effectively managed with pegylated interferon (IFN)-alpha or with busulfan.16 A 2011 article recommends the use of IFN-alpha for the treatment of patients with polycythemia vera aged <65 years, and the use of busulfan in older patients, although no other evidence is available to validate this recommendation.16 Data regarding the economic burden of polycythemia vera and other myeloproliferative neoplasms are sparse. However, a study presented at the 2011 annual meeting of the American Society of Hematology demonstrated that the medical costs for patients with myeloproliferative neoplasms are significant and are up to 6 times higher than the medical costs incurred by patients with other noncancer conditions.17 The investigators assessed the medical costs of more than 25,000 patients with myeloproliferative neoplasms using claims data from approximately 100 US-based payers. Patients with myelofibrosis incurred the highest total annual costs, averaging $34,690, with outpatient costs accounting for the ma jority of the costs. The total medical costs for patients with essential thrombocythemia averaged $19,672, and $11,927 for patients with polycythemia vera.17

Ruxolitinib First Therapy Approved by the FDA for Polycythemia Vera On December 4, 2014, the US Food and Drug Administration (FDA) approved ruxolitinib (Jakafi; Incyte Corporation), an oral kinase inhibitor, for the treatment of patients with polycythemia vera who have had an inadequate response to or are intolerant of hydroxyurea.18,19 Ruxolitinib is the first drug approved by the FDA for the treatment of polycythemia vera.18 “The approval of Jakafi for polycythemia vera underscores the importance of developing drugs matched to our increasing knowledge of the mechanisms of diseases,” said Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “The trial used to evaluate Jakafi confirmed clinically meaningful reductions in spleen size and the need for phlebotomies to control the disease.” 18 The FDA approved ruxolitinib under its priority review program, because the medication demonstrated the potential to provide significant improvement in safety or efficacy over the other available therapy for polycythemia vera at the time its application was submitted. In addition, ruxolitinib received an orphan drug designation.18 Polycythemia vera is the second indication for ruxolitinib. Ruxolitinib was first approved by the FDA in November 2011 for the treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, postpolycythemia vera myelofibrosis, and postessential thrombocythemia myelofibrosis.18,20

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Mechanism of Action Polycythemia vera is associated with dysregulated JAK1 and JAK2 signaling. Ruxolitinib inhibits JAK1 and JAK2; these kinases mediate the signaling of cytokines and growth factors that are important for hematopoiesis and for immune function. JAK signaling involves the recruitment of signal transducers and activators of transcription (STATs) to cytokine receptors, as well as the activation and the subsequent localization of STATs to the cell nucleus. This process results in the modulation of gene expression.19 Dosing and Administration The starting dose of ruxolitinib is 10 mg taken orally twice daily with or without food. The doses of ruxolitinib can be altered based on the drug’s safety and efficacy.19 The drug labeling provides detailed recommendations for dose reduction and dose reinitiation after interruption of treatment with ruxolitinib.19 Clinical Trials The approval of ruxolitinib for the treatment of patients with polycythemia vera was based on a randomized, open-label, active-controlled phase 3 clinical trial known as the RESPONSE trial.18,19,21 In this clinical trial, ruxolitinib (10 mg twice daily) was compared with best available care in patients with polycythemia vera who had unacceptable side effects from or who had an inadequate response to hydroxyurea.19,21 The primary end point of the RESPONSE study included hematocrit control and a spleen volume reduction of ≥35% by week 32.19,21 The secondary end points included the proportion of randomized patients who reached the primary end point and maintained their response 48 weeks after randomization, and the proportion of patients who reached complete hematologic remission at week 32.19,21 A total of 222 phlebotomy-dependent patients with splenomegaly received ruxolitinib (N = 110) or best available therapy (N = 112), which was determined by the investigators on an individualized basis19,21; patients in the best available therapy group typically received hydroxyurea, IFN-alpha, or no medication.21 The doses of ruxolitinib were individualized based on tolerability and efficacy, with a maximum dose of 25 mg twice daily.19,21 The majority of patients in the RESPONSE trial had been diagnosed with polycythemia vera for 8 years or longer (range, 0.5-36 years).21 Approximately 95% of patients had the JAK2 V617F mutation.21 The patients’ median age was 61 years (range, 33-90 years), with 30% of patients aged >65 years.19,21 Overall, 66% of patients were male.19 The median spleen volume was 1272 cm3 (range, 254 cm3-5147 cm3), and the median palpable spleen length below the costal margin was 7 cm.19,21

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Table 3 RESPONSE: Treatment Emergent Adverse Events in ≥6% of Patients Receiving Ruxolitinib Up to Week 32 Patients receiving ruxolitinib (N = 110)

Patients receiving best available therapy (N = 111)

All grades,a Grade 3-4,a All grades,a Grade 3-4,a % % % %

Adverse events Headache

Abdominal pain

Diarrhea

Dizziness + vertigo

Fatigue

Dyspnea

Muscle spasms

Nasopharyngitis

Constipation

Cough

Edema + peripheral edema

Arthralgia

Asthenia

Epistaxis

Herpes zoster + postherpetic neuralgia

Nausea

Pruritus c

National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0. b Including lower and upper abdominal pain. c Including dyspnea exertional. Source: Jakafi (ruxolitinib) tablets prescribing information; December 2014. a

As shown in Table 2, 21% of patients who received ruxolitinib reached the primary end point compared with <1% of patients who received best available therapy.19,21 The majority (77%) of patients in the ruxolitinib group reached at least 1 component of the primary end point by week 32.21 The results of the secondary end point analyses also favored ruxolitinib.19,21 The likelihood that the response to therapy was maintained 48 weeks after randomization was higher in patients who received ruxolitinib compared with patients who received best available therapy. In addition, a significantly larger proportion of patients who received ruxolitinib reached complete hematologic remission at week 32 compared with patients who received best available therapy.19,21

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Safety The safety of ruxolitinib has been assessed in 617 patients who participated in 1 of 6 clinical trials.19 The median duration of follow-up was 10.9 months.19 This cohort included 110 patients with polycythemia vera whose disease was resistant to or who were intolerant of hydroxyurea in the RESPONSE clinical trial19; in this study, the most frequent adverse drug reaction was anemia.19 Table 3 lists the most common nonhematologic treatment-emergent adverse events that occurred up to week 32 in the RESPONSE trial, which included headaches, abdominal pain, and diarrhea.19 Other clinically important treatment-emergent adverse events that were noted in <6% of patients who received ruxolitinib were weight gain, hypertension, and urinary tract infections.19 Of the patients who received ruxolitinib in the RESPONSE trial, 4% discontinued the use of the drug as a result of adverse events.19 Ruxolitinib has no contraindications.

Ruxolitinib is the first medication to receive FDA approval for the treatment of patients with polycythemia vera. This medication demonstrated superior efficacy in controlling hematocrit levels, reducing spleen size, and improving disease-related symptoms. Warnings and Precautions Thrombocytopenia, anemia, and neutropenia. Thrombocytopenia, anemia, and neutropenia can occur after treatment with ruxolitinib. Thrombocytopenia should be managed by reducing the dose of ruxolitinib or by temporarily interrupting its use; platelet transfusions may be required. If anemia occurs, blood transfusions and/or dose modification of ruxolitinib may be necessary. Severe neutropenia is generally reversible after the discontinuation of ruxolitinib therapy. Patients should undergo a complete blood count before starting treatment with ruxolitinib, followed by every 2 to 4 weeks until the doses are stabilized.19 Risk for infection. Ruxolitinib has been associated with serious bacterial, mycobacterial, fungal, and viral infections. Ruxolitinib therapy should not be started until active serious infections have resolved. Patients who receive ruxolitinib should be observed for the signs and symptoms of infection and should be managed promptly.19 Tuberculosis has been reported in patients who received ruxolitinib. Patients should be evaluated for tuberculosis risk before starting ruxolitinib therapy. Patients at high risk for tuberculosis should be tested for

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latent infection. If evidence of active or latent tuberculosis is found, a physician with expertise in the treatment of tuberculosis should be consulted before starting ruxolitinib therapy. The decision to continue ruxolitinib therapy while active tuberculosis is being treated should be based on the overall risk–benefit determination.19 Progressive multifocal leukoencephalopathy (PML) has occurred with ruxolitinib in the treatment of patients with myelofibrosis. The use of ruxolitinib therapy should be discontinued if PML is suspected.19 Patients who receive ruxolitinib should be advised about the early signs and symptoms of herpes zoster and should seek treatment if it is suspected.19 Symptom exacerbation after ruxolitinib discontinuation. Symptoms associated with myeloproliferative neoplasms may return to pretreatment levels approximately 1 week after ruxolitinib therapy is discontinued.19 If symptoms occur, patients should be evaluated and treated for any intercurrent illness; in addition, restarting ruxolitinib therapy or increasing its dose should be considered.19 Patients should not interrupt or discontinue ruxolitinib therapy without consulting their physician. If therapy is stopped for reasons other than thrombocytopenia, the dose of ruxolitinib should be tapered.19 Nonmelanoma skin cancer. Skin cancers, including basal-cell, squamous-cell, and Merkel-cell carcinoma, have occurred in patients receiving ruxolitinib. Therefore, the skin should be examined periodically while taking ruxolitinib.19

Use in Specific Populations Pregnancy. Ruxolitinib is a pregnancy category C teratogen; there are no adequate and well-controlled studies with ruxolitinib in pregnant women. Ruxolitinib should only be used during pregnancy if the potential benefit outweighs the potential risk to the fetus.19 Nursing mothers. It is not known whether the components of ruxolitinib are present in human breast milk. Nursing or ruxolitinib should be discontinued on the basis of the importance of ruxolitinib to the mother.19 Pediatric use. The safety and efficacy of ruxolitinib have not been established in patients aged <18 years.19 Geriatric use. Overall, 52% of patients with myelo fibrosis in clinical studies of ruxolitinib were aged ≥65 years. No overall differences in safety or efficacy were observed between older and younger patients.19 Renal impairment. The dose of ruxolitinib should be reduced in patients with moderate or severe renal impairment, or in patients with end-stage renal disease (ESRD) who are on dialysis. Ruxolitinib should not be used by patients with ESRD who are not on dialysis.19 Hepatic impairment. A dose reduction is recommended in patients with hepatic impairment; ruxolitinib

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should be started at 5 mg twice daily in patients with mild, moderate, or severe hepatic impairment.19

Conclusion Ruxolitinib is the first medication to receive FDA approval for the treatment of patients with polycythemia vera. This medication demonstrated superior efficacy in controlling hematocrit levels, reducing spleen size, and improving disease-related symptoms in a randomized clinical trial that compared oral ruxolitinib with best available therapies, including hydroxyurea, for the treatment of patients with polycythemia vera. By contrast, best available therapies offered little to no benefit. This novel kinase inhibitor represents an important new, and the only FDA-approved, option for the treatment of patients with polycythemia vera. Clinical trials continue to explore the potential role of ruxolitinib in myeloproliferative neoplasms, as well as in other hematologic malignancies, such as acute myeloid leukemia and chronic myeloid leukemia, as well as in solid tumors, such as metastatic pancreatic cancer.22 n References

1. Tefferi A, Vardiman JW. Classification and diagnosis of myeloproliferative neoplasms: the 2008 World Health Organization criteria and point-of-care 足diagnostic algorithms. Leukemia. 2008;22:14-22. 2. Spivak JL. Polycythemia vera: myths, mechanisms, and management. Blood. 2002;100:4272-4290. 3. Leukemia & Lymphoma Society. Polycythemia vera facts. No. 13. Revised June 2012. www.lls.org/content/nationalcontent/resourcecenter/freeeducation materials/mpd/pdf/polycythemiavera.pdf. Accessed March 2, 2015. 4. Kumar C, Purandare AV, Lee FY, Lorenzi MV. Kinase drug discovery approaches in chronic myeloproliferative disorders. Oncogene. 2009;28:2305-2313. 5. Passamonti F, Rumi E, Pietra D, et al. Relation between JAK2 (V617F) mutation status, granulocyte activation, and constitutive mobilization of CD34+ cells into peripheral blood in myeloproliferative disorders. Blood. 2006; 107:3676-3682. 6. Vannucchi AM, Antonioli E, Guglielmelli P, et al. Clinical correlates of JAK2V617F presence or allele burden in myeloproliferative neoplasms: a criti-

cal reappraisal. Leukemia. 2008;22:1299-1307. 7. Tefferi A. Essential thrombocythemia, polycythemia vera, and myelofibrosis: current management and the prospect of targeted therapy. Am J Hematol. 2008; 83:491-497. 8. Finazzi G, Caruso V, Marchioli R, et al; for the ECLAP Investigators. Acute leukemia in polycythemia vera: an analysis of 1638 patients enrolled in a prospective observational study. Blood. 2005;105:2664-2670. 9. Michiels JJ, Berneman Z, Van Bockstaele D, et al. Clinical and laboratory features, pathobiology of platelet-mediated thrombosis and bleeding complications, and the molecular etiology of essential thrombocythemia and polycythemia vera: therapeutic implications. Semin Thromb Hemost. 2006;32:174-207. 10. Falanga A, Marchetti M. Thrombotic disease in the myeloproliferative neoplasms. Hematology Am Soc Hematol Educ Program. 2012;2012:571-581. 11. Marchioli R, Finazzi G, Landolfi R, et al. Vascular and neoplastic risk in a large cohort of patients with polycythemia vera. J Clin Oncol. 2005;23:2224-2232. 12. Barbui T, Barosi G, Birgegard G, et al; for the European LeukemiaNet. Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet. J Clin Oncol. 2011;足29:761-770. 13. Finazzi G, Barbui T. Evidence and expertise in the management of polycythemia vera and essential thrombocythemia. Leukemia. 2008;22:1494-1502. 14. Weinfeld A, Swolin B, Westin J. Acute leukaemia after hydroxyurea therapy in polycythaemia vera and allied disorders: prospective study of efficacy and leukaemogenicity with therapeutic implications. Eur J Haematol. 1994;52:134-139. 15. Fruchtman SM, Mack K, Kaplan ME, et al. From efficacy to safety: a Polycythemia Vera Study Group report on hydroxyurea in patients with polycythemia vera. Semin Hematol. 1997;34:17-23. 16. Tefferi A. Annual clinical updates in hematological malignancies: a continuing medical education series: polycythemia vera and essential thrombocythemia: 2011 update on diagnosis, risk-stratification, and management. Am J Hematol. 2011;86:足292-301. 17. Price GL, Pohl GM, Xie J, Walgren RA. A retrospective observational study of annual healthcare costs for patients with forms of myeloproliferative neoplasms (MPN). Blood (ASH Annual Meeting Abstracts). 2011;118. Abstract 2060. 18. US Food and Drug Administration. FDA approves Jakafi to treat patients with a chronic type of bone marrow disease: first FDA-approved drug for polycythemia vera. Press release. December 4, 2014. www.fda.gov/NewsEvents/ Newsroom/PressAnnouncements/ucm425677.htm. Accessed March 2, 2015. 19. Jakafi (ruxolitinib) tablets [prescribing information]. Wilmington, DE: Incyte Corporation; December 2014. 20. US Food and Drug Administration. FDA approves first drug to treat a rare bone marrow disease. Press release. November 16, 2011. www.fda.gov/NewsEvents/足 Newsroom/PressAnnouncements/ucm280102.htm. Accessed March 2, 2015. 21. Vannucchi AM, Kiladjian JJ, Griesshammer M, et al. Ruxolitinib versus standard therapy for the treatment of polycythemia vera. N Engl J Med. 2015; 372:426-435.

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REVLIMID® (lenalidomide) in combination with dexamethasone (dex) is indicated for the treatment of patients with multiple myeloma (MM). REVLIMID is not indicated and is not recommended for the treatment of patients with chronic lymphocytic leukemia (CLL) outside of controlled clinical trials

NOW FOR NEWLY DIAGNOSED MULTIPLE MYELOMA

SHAPE PROGRESSION-FREE SURVIVAL WITH CONTINUOUS TREATMENT Continuous REVLIMID + dex until progression showed a PFS and OS benefit in patients with newly diagnosed multiple myeloma vs MPT WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS and ARTERIAL THROMBOEMBOLISM See full prescribing information for complete boxed warning. EMBRYO-FETAL TOXICITY • Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study similar to birth defects caused by thalidomide in humans. If lenalidomide is used during pregnancy, it may cause birth defects or embryo-fetal death. • Pregnancy must be excluded before start of treatment. Prevent pregnancy during treatment by the use of two reliable methods of contraception. REVLIMID is available only through a restricted distribution program called the REVLIMID REMS® program (formerly known as the “RevAssist® program”). HEMATOLOGIC TOXICITY. REVLIMID can cause significant neutropenia and thrombocytopenia. • For patients with del 5q myelodysplastic syndromes, monitor complete blood counts weekly for the first 8 weeks and monthly thereafter. VENOUS AND ARTERIAL THROMBOEMBOLISM • Significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as risk of myocardial infarction and stroke in patients with multiple myeloma receiving REVLIMID with dexamethasone. Anti-thrombotic prophylaxis is recommended.

REVLIMID is only available through a restricted distribution program, REVLIMID REMS®. Please see additional Important Safety Information and Brief Summary, including Boxed WARNINGS, on the following pages. Learn more at www.REVLIMID.com

Median Progression-Free Survival (PFS) Rd Continuous (n=535) 25.5 mo (95% CI 20.7, 29.4) Rd18 (n=541) 20.7 mo (95% CI 19.4, 22.0) MPT (n=547) 21.2 mo (95% CI 19.3, 23.2)

100

Survival Probability (%)

HR (95% CI) Rd Continuous vs MPT 0.72 (0.61, 0.85) Rd Continuous vs Rd18 0.70 (0.60, 0.82) Rd18 vs MPT 1.03 (0.89, 1.20)

Logrank P value (2-sided) P<0.0001

Planned duration of treatment in the Rd18 40 and MPT arms was 18 months 20

Progression-Free Survival (Years) • PFS Events: Rd Continuous=278/535 (52.0%), Rd18=348/541 (64.3%), MPT=334/547 (61.1%)

Study design: The MM-020 (FIRST) trial compared REVLIMID + low-dose dexamethasone (Rd) Continuous until progression, fixed-cycle MPT, and fixed-cycle Rd18. MM-020 was a Phase 3, randomized, multicenter, open-label, 3-arm study enrolling 1623 newly diagnosed patients who did not receive a stem cell transplant (SCT). REVLIMID was given 25 mg once daily orally on Days 1 to 21 of 28-day cycles, and dex was dosed once daily orally on Days 1, 8, 15, and 22 of each 28-day cycle (40 mg for patients ≤75 years and 20 mg for patients >75 years). The primary endpoint in the trial was progression-free survival (PFS), as the time from randomization to the first documentation of disease progression as determined by Independent Response Adjudication Committee (IRAC), based on International Myeloma Working Group (IMWG) criteria, or death due to any cause, whichever occurred first during the study until the end of the PFS follow-up phase. For the efficacy analysis of all endpoints, the primary comparison was between Rd Continuous and MPT arms.

58.9 months median overall survival (OS) with Rd Continuous until progression in an interim analysis, compared with 48.5 months with MPT (HR 0.75 [95% CI 0.62, 0.90]) and 56.7 months with Rd18 (HR 0.91 [95% CI 0.75, 1.09]) • At median follow-up of 45.5 months, only 78% of prespecified events had occurred (697/896 of the final OS events) • OS is defined as the time from randomization to death from any cause ADVERSE REACTIONS Multiple Myeloma • In newly diagnosed patients the most frequently reported Grade 3 or 4 adverse reactions in Arm Rd Continuous included neutropenia (27.8%), anemia (18.2%), thrombocytopenia (8.3%), pneumonia (11.3%), asthenia (7.7.%), fatigue (7.3%), back pain (7%), hypokalemia (6.6%), rash (7.3%), cataract (5.8%), dyspnea (5.6%), DVT (5.6%), hyperglycemia (5.3%), lymphopenia and leukopenia. The frequency of infections in Arm Rd Continuous was 75% Adverse reactions reported in ≥20% of NDMM patients in Arm Rd Continuous: diarrhea (45.5%), anemia (43.8%), neutropenia (35%), fatigue (32.5%), back pain (32%), insomnia (27.6%), asthenia (28.2%), rash (26.1%), decreased appetite (23.1%), cough (22.7%), pyrexia (21.4%), muscle spasms (20.5%), and abdominal pain (20.5%). The frequency of onset of cataracts increased over time with 0.7% during the first 6 months and up to 9.6% by the second year of treatment with Arm Rd Continuous CONTRAINDICATIONS Pregnancy: REVLIMID can cause fetal harm when administered to a pregnant female 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 the fetus Allergic Reactions: REVLIMID is contraindicated in patients who have demonstrated hypersensitivity (e.g., angioedema, StevensJohnson syndrome, toxic epidermal necrolysis) to lenalidomide

Treatment is a science. Patient care is your art.

REVLIMID® (lenalidomide) in combination with dexamethasone (dex) is indicated for the treatment of patients with multiple myeloma (MM) REVLIMID is not indicated and is not recommended for the treatment of patients with chronic lymphocytic leukemia (CLL) outside of controlled clinical trials

Important Safety Information

WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS and ARTERIAL 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 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 and Arterial Thromboembolism REVLIMID has demonstrated a significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as risk of myocardial infarction and stroke in patients with MM who were treated with REVLIMID and dexamethasone therapy. Monitor for and advise patients about signs and symptoms of thromboembolism. Advise patients to seek immediate medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. Thromboprophylaxis is recommended and the choice of regimen should be based on an assessment of the patient’s underlying risks. CONTRAINDICATIONS Pregnancy: REVLIMID can cause fetal harm when administered to a pregnant female 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 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 indicates that lenalidomide produced malformations in offspring of female monkeys who received 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. 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. Monitor patients with neutropenia for signs of infection. Advise patients to observe for bleeding or bruising, especially with use of concomitant medications that may increase risk of bleeding. MM: Patients taking REVLIMID/dex should have their complete blood counts (CBC) assessed every 7 days for the first 2 cycles, on days 1 and 15 of cycle 3, and every 28 days thereafter. Venous and Arterial Thromboembolism: Venous thromboembolic events (DVT and PE) and arterial thromboses are increased in patients treated with REVLIMID. A significantly increased risk of DVT (7.4%) and PE (3.7%) occurred in patients with MM after at least one prior therapy, treated with REVLIMID/dex compared to placebo/dex (3.1% and 0.9%) in clinical trials with varying use of anticoagulant therapies. In NDMM study, in which nearly all patients received antithrombotic prophylaxis, DVT (3.6%) and PE (3.8%) were reported in the Rd continuous arm. Myocardial infarction (MI, 1.7%) and stroke (CVA, 2.3%) are increased in patients with MM after at least 1 prior therapy who were treated with REVLIMID/dex therapy compared with placebo/dex (0.6%, and 0.9%) in clinical trials. In NDMM study, MI (including acute) was reported (2.3%) in the Rd Continuous arm. Frequency of serious adverse reactions of CVA was (0.8%) in the Rd Continuous arm. Patients with known risk factors, including prior thrombosis, may be at greater risk and actions should be taken to try to minimize all modifiable factors (e.g. hyperlipidemia, hypertension, smoking). In controlled clinical trials that did not use concomitant thromboprophylaxis, 21.5% overall thrombotic events occurred in patients with refractory and relapsed MM who were treated with REVLIMID/dex compared to 8.3% thrombosis in the placebo/dex group. Median time to first thrombosis event was 2.8 months. In NDMM study, which nearly all patients received antithrombotic prophylaxis, overall frequency of thrombotic events was 17.4% in combined Rd Continuous and Rd18 arms. Median time to first thrombosis event was 4.37 months. Thromboprophylaxis is recommended and regimen is based on patients underlying risks. ESAs and estrogens may further increase the risk of thrombosis and their use should be based on a benefit-risk decision. See Boxed WARNINGS 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

WARNINGS AND PRECAUTIONS (continued) treatment arm. REVLIMID is not indicated and not recommended for use in CLL outside of controlled clinical trials Second Primary Malignancies: In clinical trials in patients with MM receiving REVLIMID, an increase of invasive second primary malignancies (SPM) notably AML and MDS have been observed. The increase of AML and MDS occurred predominantly in NDMM patients receiving REVLIMID in combination with oral melphalan (5.3%) or immediately following high dose intravenous melphalan and ASCT (up to 5.2%). The frequency of AML and MDS cases in the REVLIMID/dex arms was observed to be 0.4%. Cases of B-cell malignancies (including Hodgkin’s Lymphomas) were observed in clinical trials where patients received REVLIMID in the post-ASCT setting. Patients who received REVLIMID-containing therapy until disease progression did not show a higher incidence of invasive SPM than patients treated in the fixed duration REVLIMID-containing arms. Monitor patients for the development of second primary malignancies. Take into account both the potential benefit of REVLIMID and risk of second primary malignancies when considering treatment Hepatotoxicity: Hepatic failure, including fatal cases, has occurred in patients treated with REVLIMID in combination with dex. 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) 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. Impaired Stem Cell Mobilization: A decrease in the number of CD34+ cells collected after treatment (> 4 cycles) with REVLIMID has been reported. In patients who are autologous stem cell transplant (ASCT) candidates, referral to a transplant center should occur early in treatment to optimize timing of the stem cell collection ADVERSE REACTIONS Multiple Myeloma • In newly diagnosed patients the most frequently reported Grade 3 or 4 adverse reactions in Arm Rd Continuous included neutropenia (27.8%), anemia (18.2%), thrombocytopenia (8.3%), pneumonia (11.3%), asthenia (7.7.%), fatigue (7.3%), back pain (7%), hypokalemia (6.6%), rash (7.3%), cataract (5.8%), dyspnea (5.6%), DVT (5.6%), hyperglycemia (5.3%), lymphopenia and leukopenia. The frequency of infections in Arm Rd Continuous was 75%

Adverse reactions reported in ≥20% of NDMM patients in Arm Rd Continuous: diarrhea (45.5%), anemia (43.8%), neutropenia (35%), fatigue (32.5%), back pain (32%), insomnia (27.6%), asthenia (28.2%), rash (26.1%), decreased appetite (23.1%), cough (22.7%), pyrexia (21.4%), muscle spasms (20.5%), and abdominal pain (20.5%). The frequency of onset of cataracts increased over time with 0.7% during the first 6 months and up to 9.6% by the second year of treatment with Arm Rd Continuous • After at least one prior therapy most adverse reactions and Grade 3 or 4 adverse reactions were more frequent in MM patients who received the combination of REVLIMID/dex compared to placebo/dex. Grade 3 or 4 adverse reactions included neutropenia 33.4% vs 3.4%, febrile neutropenia 2.3% vs 0%, DVT 8.2% vs 3.4% and PE 4% vs 0.9% respectively Adverse reactions reported in ≥15% of MM patients (REVLIMID/dex vs dex/placebo): fatigue (44% vs 42%), neutropenia (42% vs 6%), constipation (41% vs 21%), diarrhea (39% vs 27%), muscle cramp (33% vs 21%), anemia (31% vs 24%), pyrexia (28% vs 23%), peripheral edema (26% vs 21%), nausea (26% vs 21%), back pain (26% vs 19%), upper respiratory tract infection (25% vs 16%), dyspnea (24% vs 17%), dizziness (23% vs 17%), thrombocytopenia (22% vs 11%), rash (21% vs 9%), tremor (21% vs 7%), weight decreased (20% vs 15%), nasopharyngitis (18% vs 9%), blurred vision (17% vs 11%), anorexia (16% vs 10%), and dysgeusia (15% vs 10%) 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. It is not known whether there is an interaction between dex and warfarin. Close monitoring of PT and INR is recommended in MM patients taking concomitant warfarin. Erythropoietic agents, or other agents, that may increase the risk of thrombosis, such as estrogen containing therapies, should be used with caution after making a benefit-risk assessment in patients receiving 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 patients below the age of 18 have not been established 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 Please see Brief Summary of full Prescribing Information, including Boxed WARNING, on the following pages.

REVLIMID is only available through a restricted distribution program, REVLIMID REMS®.

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REVLIMID [lenalidomide] capsules, for oral use

Table 1: Dose Adjustments for Hematologic Toxicities for MM

The following is a Brief Summary; refer to full Prescribing Information for complete product information.

Platelet counts

1 INDICATIONS AND USAGE 1.1 Multiple Myeloma REVLIMID in combination with dexamethasone is indicated for the treatment of patients with multiple myeloma (MM). 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. 2.1 Multiple Myeloma Multiple Myeloma The recommended starting dose of REVLIMID is 25 mg orally once daily on Days 1-21 of repeated 28-day cycles in combination with dexamethasone. Refer to Section 14.1 for specific dexamethasone dosing. For patients > 75 years old, the starting dose of dexamethasone may be reduced. Treatment should be continued until disease progression or unacceptable toxicity. In patients who are not eligible for autologous stem cell transplantation (ASCT), treatment should continue until disease progression or unacceptable toxicity. For patients who are ASCT-eligible, hematopoietic stem cell mobilization should occur within 4 cycles of a REVLIMID-containing therapy [see Warnings and Precautions (5.11)]. Dose Adjustments for Hematologic Toxicities During Multiple Myeloma Treatment Dose modification guidelines, as summarized in Table 1 below, are recommended to manage Grade 3 or 4 neutropenia or thrombocytopenia or other Grade 3 or 4 toxicity judged to be related to REVLIMID.

When Platelets

Recommended Course

Fall to <30,000/mcL

Interrupt REVLIMID treatment, follow CBC weekly Resume REVLIMID at next lower dose. Do not dose below 2.5 mg daily

Return to ≥30,000/mcL For each subsequent drop <30,000/mcL Return to ≥30,000/mcL

Interrupt REVLIMID treatment Resume REVLIMID at next lower dose. Do not dose below 2.5 mg daily

Absolute Neutrophil counts (ANC) Neutropenia in MM When Neutrophils

Recommended Course

Fall to <1000/mcL Return to ≥1,000/mcL and neutropenia is the only toxicity

Interrupt REVLIMID treatment, follow CBC weekly Resume REVLIMID at 25 mg daily or initial starting dose

Return to ≥1,000/mcL and if other toxicity

Resume REVLIMID at next lower dose. Do not dose below 2.5 mg daily

For each subsequent drop <1,000/mcL Return to ≥1,000/mcL

Interrupt REVLIMID treatment Resume REVLIMID at next lower dose. Do not dose below 2.5 mg daily

Other Toxicities in MM 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 MM: [See Dosage and Administration (2.4)]. 2.4 Starting Dose for Renal Impairment in MM 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. The recommendations for initial starting doses for patients with MM are as follows: Table 3: Starting Dose Adjustments for Patients with Renal Impairment in MM Category

Renal Function (Cockcroft-Gault)

Dose in MM

Moderate Renal Impairment

CLcr 30-50 mL/min

10 mg Every 24 hours

Severe Renal Impairment

CLcr < 30 mL/min (not requiring dialysis)

15 mg Every 48 hours

End Stage Renal Disease

CLcr < 30 mL/min (requiring dialysis)

5 mg Once daily. On dialysis days, administer the dose following dialysis.

Moderate renal impairment for MM: Consider escalating the dose to 15 mg after 2 cycles if the patient tolerates the 10 mg dose of lenalidomide without dose-limiting toxicity. After initiation of REVLIMID therapy, subsequent REVLIMID dose increase or decrease is based on individual patient treatment tolerance, as described elsewhere [See Dosage and Administration (2.1-2.3)]. 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)].

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Venous and Arterial Thromboembolism REVLIMID has demonstrated a significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as risk of myocardial infarction and stroke in patients with multiple myeloma who were treated with REVLIMID and dexamethasone therapy. Monitor for and advise patients about signs and symptoms of thromboembolism. Advise patients to seek immediate medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. Thromboprophylaxis is recommended and the choice of regimen should be based on an assessment of the patient’s underlying risks [see Warnings and Precautions (5.4)].

Thrombocytopenia in MM

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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)].

5.2 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-Physician 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. Monitor patients with neutropenia for signs of infection. Advise patients to observe for bleeding or bruising, especially with use of concomitant medication that may increase risk of bleeding. Patients taking REVLIMID should have their complete blood counts assessed periodically as described below [see Dosage and Administration (2.1, 2.2, 2.3)]. Patients taking REVLIMID in combination with dexamethasone for MM should have their complete blood counts (CBC) assessed every 7 days (weekly) for the first 2 cycles, on Days 1 and 15 of Cycle 3, and every

Patients taking REVLIMID for MDS should have their complete blood counts monitored weekly for the first 8 weeks and at least monthly thereafter. 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)]. 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. 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 and Arterial Thromboembolism Venous thromboembolic events (deep venous thrombosis and pulmonary embolism) and arterial thromboses are increased in patients treated with REVLIMID. A significantly increased risk of DVT (7.4%) and of PE (3.7%) occurred in patients with multiple myeloma after at least one prior therapy who were treated with REVLIMID and dexamethasone therapy compared to patients treated in the placebo and dexamethasone group (3.1% and 0.9%) in clinical trials with varying use of anticoagulant therapies. In the newly diagnosed multiple myeloma (NDMM) study in which nearly all patients received antithrombotic prophylaxis, DVT was reported as a serious adverse reaction (3.6%, 2.0%, and 1.7%) in the Rd Continuous, Rd18, and MPT Arms, respectively. The frequency of serious adverse reactions of PE was similar between the Rd Continuous, Rd18, and MPT Arms (3.8%, 2.8%, and 3.7%, respectively) [see Boxed Warning and Adverse Reactions (6.1)]. Myocardial infarction (1.7%) and stroke (CVA) (2.3%) are increased in patients with multiple myeloma after at least one prior therapy who were treated with REVLIMID and dexamethasone therapy compared to patients treated with placebo and dexamethasone (0.6%, and 0.9%) in clinical trials. In the NDMM study, myocardial infarction (including acute) was reported as a serious adverse reaction (2.3%, 0.6%, and 1.1%) in the Rd Continuous, Rd18, and MPT Arms, respectively. The frequency of serious adverse reactions of CVA was similar between the Rd Continuous, Rd18, and MPT Arms (0.8%, 0.6 %, and 0.6%, respectively) [see Adverse Reactions (6.1)]. Patients with known risk factors, including prior thrombosis, may be at greater risk and actions should be taken to try to minimize all modifiable factors (e.g. hyperlipidemia, hypertension, smoking). In controlled clinical trials that did not use concomitant thromboprophylaxis, 21.5% overall thrombotic events (Standardized MedDRA Query Embolic and Thrombotic events) occurred in patients with refractory and relapsed multiple myeloma who were treated with REVLIMID and dexamethasone compared to 8.3% thrombosis in patients treated with placebo and dexamethasone. The median time to first thrombosis event was 2.8 months. In the NDMM study in which nearly all patients received antithrombotic prophylaxis, the overall frequency of thrombotic events was 17.4% in patients in the combined Rd Continuous and Rd18 Arms, and was 11.6% in the MPT Arm. The median time to first thrombosis event was 4.37 months in the combined Rd Continuous and Rd18 Arms. Thromboprophylaxis is recommended. The regimen of thromboprophylaxis should be based on an assessment of the patient’s underlying risks. Instruct patients to report immediately any signs and symptoms suggestive of thrombotic events. ESAs and estrogens may further increase the risk of thrombosis and their use should be based on a benefit-risk decision in patients receiving REVLIMID [see Drug Interactions (7.2)]. 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.

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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 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.

28 days (4 weeks) thereafter. A dose interruption and/or dose reduction may be required [see Dosage and Administration (2.1)].

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5.6 Second Primary Malignancies In clinical trials in patients with multiple myeloma receiving REVLIMID an increase of invasive second primary malignancies notably AML and MDS have been observed. The increase of cases of AML and MDS occurred predominantly in NDMM patients receiving REVLIMID in combination with oral melphalan (frequency of 5.3%) or immediately following high dose intravenous melphalan and ASCT (frequency of up to 5.2%). The frequency of AML and MDS cases in the REVLIMID / dexamethasone arms was observed to be 0.4%. Cases of B-cell malignancies (including Hodgkin’s Lymphomas) were observed in clinical trials where patients received lenalidomide in the post-ASCT setting. Patients who received REVLIMID-containing therapy until disease progression did not show a higher incidence of invasive SPM than patients treated in the fixed duration REVLIMID-containing arms. Monitor patients for the development of second primary malignancies. Take into account both the potential benefit of REVLIMID and the risk of second primary malignancies when considering treatment with REVLIMID. 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.

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 antiinflammatory drugs (NSAIDs) and/or narcotic analgesics for management of TFR symptoms. In patients with Grade 3 or 4 TFR, it is recommended to 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. 5.11 Impaired Stem Cell Mobilization A decrease in the number of CD34+ cells collected after treatment (> 4 cycles) with REVLIMID has been reported. In patients who are ASCT candidates, referral to a transplant center should occur early in treatment to optimize the timing of the stem cell collection. In patients who received more than 4 cycles of a REVLIMID-containing treatment or for whom inadequate numbers of CD 34+ cells have been collected with G-CSF alone, G-CSF with cyclophosphamide or the combination of G-CSF with a CXCR4 inhibitor may be considered.

Grade 3/4 Adverse Reactionsb

All Adverse Reactionsa

Rd Rd System organ class Continuous Rd18 MPT Continuous Rd18 MPT Preferred term (N = 532) (N = 540) (N = 541) (N = 532) (N = 540) (N = 541) General disorders and administration site conditions Fatigue%

173 (32.5) 177 (32.8) 154 (28.5) 39 (7.3)

46 (8.5)

31 (5.7)

Asthenia

150 (28.2) 123 (22.8) 124 (22.9) 41 (7.7)

33 (6.1)

32 (5.9)

Pyrexiac

114 (21.4) 102 (18.9) 76 (14.0) 13 (2.4)

7 (1.3)

< 1%

18 (3.3)

8 (1.5)

Non-cardiac chest pain f

29 (5.5)

31 (5.7)

18 (3.3)

<1%

Gastrointestinal disorders Diarrhea

242 (45.5) 208 (38.5) 89 (16.5) 21 (3.9)

Abdominal pain%f 109 (20.5) 78 (14.4) 60 (11.1) Dyspepsia f

57 (10.7)

28 (5.2)

7 (1.3)

9 (1.7)

< 1%

<1%

< 1%

0 (0.0)

36 (6.7)

(continued)

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REVLIMID capsules contain lactose. Risk-benefit of REVLIMID treatment should be evaluated in patients with lactose intolerance.

6 ADVERSE REACTIONS The following adverse reactions are described in detail in other sections of the prescribing information: • Embryo-Fetal Toxicity [see Boxed Warnings, Warnings and Precautions (5.1, 5.2)] • Neutropenia and thrombocytopenia [see Boxed Warnings, Warnings and Precautions (5.3)] • Venous and arterial thromboembolism [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)] • Impaired Stem Cell Mobilization [see Warnings and Precautions (5.11)] 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. 6.1 Clinical Trials Experience Specific Populations Newly Diagnosed Multiple Myeloma: Data were evaluated from 1613 patients in a large phase 3 study who received at least one dose of REVLIMID with low dose dexamethasone (Rd) given for 2 different durations of time (i.e., until progressive disease [Arm Rd Continuous; N=532] or for up to eighteen 28-day cycles [72 weeks, Arm Rd18; N=540] or who received melphalan, prednisone and thalidomide (Arm MPT; N=541) for a maximum of twelve 42-day cycles (72 weeks). The median treatment duration in the Rd Continuous arm was 80.2 weeks (range 0.7 to 246.7) or 18.4 months (range 0.16 to 56.7). In general, the most frequently reported adverse reactions were comparable in Arm Rd Continuous and Arm Rd18, and included diarrhea, anemia, constipation, peripheral edema, neutropenia, fatigue, back pain, nausea, asthenia, and insomnia. The most frequently reported Grade 3 or 4 reactions included neutropenia, anemia, thrombocytopenia, pneumonia, asthenia, fatigue, back pain, hypokalemia, rash, cataract, lymphopenia, dyspnea, DVT, hyperglycemia, and leukopenia. The highest frequency of infections occurred in Arm Rd Continuous (75%) compared to Arm MPT (56%). There were more grade 3 and 4 and serious adverse reactions of infection in Arm Rd Continuous than either Arm MPT or Rd18. In the Rd Continuous arm, the most common adverse reactions leading to dose interruption of REVLIMID were infection events (28.8%); overall, the median time to the first dose interruption of REVLIMID was 7 weeks. The most common adverse reactions leading to dose reduction of REVLIMID in the Rd Continuous arm were hematologic events (10.7%); overall, the median time to the first dose reduction of REVLIMID was 16 weeks. In the Rd Continuous arm, the most common adverse reactions leading to discontinuation of REVLIMID were infection events (3.4%). In both Rd arms, the frequencies of onset of adverse reactions were generally highest in the first 6 months of treatment and then the frequencies decreased over time or remained stable throughout treatment, except for cataracts. The frequency of onset of cataracts increased over time with 0.7% during the first 6 months and up to 9.6% by the 2nd year of treatment with Rd Continuous. Table 4 summarizes the adverse reactions reported for the Rd Continuous, Rd18, and MPT treatment arms. Table 4: All Adverse Reactions in ≥5.0% and Grade 3/4 Adverse Reactions in ≥ 1.0% of Patients in the Rd Continuous or Rd18 Arms*

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Table 4: All Adverse Reactions in ≥5.0% and Grade 3/4 Adverse Reactions in ≥ 1.0% of Patients in the Rd Continuous or Rd18 Arms* All Adverse Reactionsa

Table 4: All Adverse Reactions in ≥5.0% and Grade 3/4 Adverse Reactions in ≥ 1.0% of Patients in the Rd Continuous or Rd18 Arms*

Grade 3/4 Adverse Reactionsb

All Adverse Reactionsa

Grade 3/4 Adverse Reactionsb

Rd Rd System organ class Continuous Rd18 MPT Continuous Rd18 MPT Preferred term (N = 532) (N = 540) (N = 541) (N = 532) (N = 540) (N = 541)

Musculoskeletal and connective tissue disorders

Psychiatric disorders

Back painc

170 ( 32) 145 (26.9) 116 (21.4)

37 (7)

34 (6.3)

28 (5.2)

Muscle spasms f

109 (20.5) 102 (18.9) 61 (11.3)

< 1%

Arthralgia f

101 (19.0) 71 (13.1) 66 (12.2)

9 (1.7)

8 (1.5)

Bone pain f

87 (16.4) 77 (14.3) 62 (11.5) 16 (3.0)

15 (2.8)

14 (2.6)

Pain in extremity f 79 (14.8) 66 (12.2) 61 (11.3)

8 (1.5)

7 (1.3)

Musculoskeletal pain f

67 (12.6) 59 (10.9)

36 (6.7)

< 1%

Musculoskeletal chest pain f

60 (11.3)

51 (9.4)

39 (7.2)

6 (1.1)

< 1%

Muscular weakness f

43 (8.1)

35 (6.5)

29 (5.4)

< 1%

8 (1.5)

< 1%

Neck pain f

40 (7.5)

19 (3.5)

10 (1.8)

< 1%

90 (16.9) 59 (10.9)

43 (7.9)

9 (1.7)

6 (1.1)

3 (0.6)

33 (6.1)

0 (0.0)

Infections and infestations Bronchitisc Nasopharyngitis f Urinary tract infection f

80 (15)

54 (10)

76 (14.3) 63 (11.7)

41 (7.6)

8 (1.5)

< 1%

Upper respiratory tract infectionc% f

69 (13.0)

Pneumoniac@

93 (17.5) 87 (16.1) 56 (10.4) 60 (11.3) 57 (10.5) 41 (7.6)

53 (9.8)

31 (5.7)

< 1%

8 (1.5)

< 1%

Respiratory tract infection%

35 (6.6)

25 (4.6)

21 ( 3.9)

7 ( 1.3)

4 ( 0.7)

1 ( 0.2)

Influenza f

33 (6.2)

23 (4.3)

15 (2.8)

< 1%

0 (0.0)

Gastroenteritis f

32 (6.0)

17 (3.1)

13 (2.4)

0 (0.0)

< 1%

29 (5.5)

14 (2.6)

16 (3.0)

10 (1.9)

3 (0.6)

Rhinitis f

29 ( 5.5)

24 ( 4.4) 14 ( 2.6)

0 (0.0)

Cellulitisc

< 5%

8 (1.5)

3 ( 0.6)

2 ( 0.4)

Sepsisc@

33 (6.2)

26-(4.8)

18 (3.3)

26 (4.9)

20 (3.7)

13 (2.4)

Nervous system disorders Headache f

75 (14.1)

52 (9.6)

56 (10.4)

< 1%

Dysgeusia f

39 (7.3)

45 (8.3)

22 (4.1)

< 1%

0 (0.0)

< 1%

Blood and lymphatic system disordersd Anemia

233 (43.8) 193 (35.7) 229 (42.3) 97 (18.2) 85 (15.7) 102 (18.9)

Neutropenia

186 (35.0) 178 (33) 328 (60.6) 148 (27.8) 143 (26.5) 243 (44.9)

Thrombocytopenia 104 (19.5) 100 (18.5) 135 (25.0) 44 (8.3)

43 (8.0)

60 (11.1)

Febrile neutropenia

7 (1.3)

17 (3.1)

15 (2.8)

6 (1.1)

16 (3.0)

14 (2.6)

Pancytopenia

5 (0.9)

6 (1.1)

7 (1.3)

1 (0.2)

3 (0.6)

5 (0.9)

Respiratory, thoracic and mediastinal disorders Cough f

121 (22.7) 94 (17.4) 68 (12.6)

Dyspneac,e

117 (22.0) 89 (16.5) 113 (20.9) 30 (5.6)

< 1%

22 (4.1)

18 (3.3)

Epistaxis f

32 (6.0)

31 (5.7)

17 (3.1)

< 1%

0 (0.0)

Oropharyngeal pain f

30 (5.6)

22 (4.1)

14 (2.6)

0 (0.0)

Dyspnea exertional e

27 (5.1)

29 (5.4)

< 5%

6 (1.1)

2 (0.4)

0 (0.0)

Metabolism and nutrition disorders Decreased appetite

123 (23.1) 115 (21.3) 72 (13.3) 14 (2.6)

7 (1.3)

5 (0.9)

Hypokalemia%

91 ( 17.1) 62 (11.5)

20 (3.7)

11 (2.0)

38 ( 7)

35 (6.6)

Hyperglycemia

62 (11.7)

52 (9.6)

19 (3.5)

28 (5.3)

23 (4.3)

9 (1.7)

Hypocalcemia

57 (10.7) 56 (10.4)

31 (5.7)

23 (4.3)

19 (3.5)

8 (1.5)

Dehydration%

25 ( 4.7)

29 ( 5.4)

17 ( 3.1)

8 (1.5)

13 (2.4)

9 (1.7)

Gout e

< 5%

8 (1.5)

0 (0.0)

Diabetes mellitus% e

< 5%

8 (1.5)

4 (0.7)

2 (0.4)

Hypophosphatemia e

< 5%

7 (1.3)

3 (0.6)

1 (0.2)

Hyponatremia% e

< 5%

7 (1.3)

13 (2.4)

6 (1.1)

139 (26.1) 151 (28.0) 105 (19.4) 39 (7.3)

38 (7.0)

33 (6.1)

Skin and subcutaneous tissue disorders Rash Pruritus f

47 (8.8)

49 (9.1)

24 (4.4)

< 1%

< 1% (continued)

147 (27.6) 127 (23.5) 53 (9.8)

4 (0.8)

6 (1.1)

0 (0.0)

Depression

58 (10.9)

10 (1.9)

4 (0.7)

1 (0.2)

46 (8.5)

30 (5.5)

Vascular disorders Deep vein thrombosisc%

55 (10.3)

39 (7.2)

22 (4.1)

30 (5.6)

20 (3.7)

15 (2.8)

Hypotensionc%

51 (9.6)

35 (6.5)

36 (6.7)

11 (2.1)

8 (1.5)

6 (1.1)

Injury, Poisoning, and Procedural Complications Fall f

43 (8.1)

25 (4.6)

< 1%

6 (1.1)

Contusion f

33 (6.2)

24 (4.4)

15 (2.8)

< 1%

0 (0.0)

73 (13.7)

31 (5.7)

5 (0.9)

31 (5.8)

14 (2.6)

3 (0.6)

< 5%

7 (1.3)

0 (0.0)

48 (8.9)

11 (2.1)

4 (0.7)

Eye disorders Cataract Cataract subcapsular e Investigations Weight decreased 72 (13.5) 78 (14.4) Cardiac disorders Atrial fibrillationc Myocardial infarction (including acute)c ,e

37 (7.0)

25 (4.6)

13 (2.4)

9 (1.7)

6 (1.1)

< 5%

10 (1.9)

3 (0.6)

5 (0.9)

54 (10.0)

37 (6.8)

28 (5.3)

33 (6.1)

29 (5.4)

Renal and Urinary disorders Renal failure (including acute)c@,f 49 (9.2)

Neoplasms benign, malignant and unspecified (Incl cysts and polyps) Squamous cell carcinomac e

< 5%

8 (1.5)

4 (0.7)

0 (0.0)

Basal cell carcinomac e,f

< 5%

< 1%

0 (0.0)

Note: System organ classes (SOC) and preferred terms (PTs) reflect coding of adverse reactions using MedDRA. A subject with multiple occurrences of an adverse reaction is counted only once under the applicable SOC/PT. a All treatment-emergent adverse reactions in at least 5.0% of subjects in the Rd Continuous or Rd18 Arms and at least a 2.0% higher frequency (%) in either the Rd Continuous or Rd18 Arms compared to the MPT Arm. b All grade 3 or 4 treatment-emergent adverse reactions in at least 1.0% of subjects in the Rd Continuous or Rd18 Arms and at least a 1.0% higher frequency (%) in either the Rd Continuous or Rd18 Arms compared to the MPT Arm. c Serious treatment-emergent adverse reactions in at least 1.0% of subjects in the Rd Continuous or Rd18 Arms and at least a 1.0% higher frequency (%) in either the Rd Continuous or Rd18 Arms compared to the MPT Arm. d Preferred terms for the blood and lymphatic system disorders SOC were included by medical judgment as known adverse reactions for Rd Continuous/Rd18, and have also been reported as serious. e Footnote “a” not applicable f Footnote “b” not applicable. @ - adverse reactions in which at least one resulted in a fatal outcome % - adverse reactions in which at least one was considered to be life threatening (if the outcome of the reaction was death, it is included with death cases) *PTs for combined adverse reaction terms: Abdominal Pain: Abdominal pain, abdominal pain upper, abdominal pain lower, gastrointestinal pain Pneumonias: Pneumonia, lobar pneumonia, pneumonia pneumococcal, bronchopneumonia, pneumocystis jiroveci pneumonia, pneumonia legionella, pneumonia staphylococcal, pneumonia klebsiella, atypical pneumonia, pneumonia bacterial, pneumonia escherichia, pneumonia streptococcal, pneumonia viral Sepsis: Sepsis, septic shock, urosepsis, escherichia sepsis, neutropenic sepsis, pneumococcal sepsis, staphylococcal sepsis, bacterial sepsis, meningococcal sepsis, enterococcal sepsis, klebsiella sepsis, pseudomonal sepsis Rash: Rash, rash pruritic, rash erythematous, rash maculo-papular, rash generalised, rash papular, exfoliative rash, rash follicular, rash macular, drug rash with eosinophilia and systemic symptoms, erythema multiforme, rash pustular Deep Vein Thrombosis: Deep vein thrombosis, venous thrombosis limb, venous thrombosis

After At Least One Prior Therapy for MM Data were evaluated from 703 patients in two studies who received at least one dose of REVLIMID/dexamethasone (353 patients) or placebo/dexamethasone (350 patients). In the REVLIMID/dexamethasone treatment group, 269 patients (76%) had at least one dose interruption with or without a dose reduction of REVLIMID compared to 199 patients (57%) in the placebo/dexamethasone treatment group. Of these patients who had one dose interruption with or Cosmos Communications K

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Lower respiratory tract infection

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without a dose reduction, 50% in the REVLIMID/dexamethasone treatment group had at least one additional dose interruption with or without a dose reduction compared to 21% in the placebo/dexamethasone treatment group. Most adverse reactions and Grade 3/4 adverse reactions were more frequent in patients who received the combination of REVLIMID/dexamethasone compared to placebo/dexamethasone.

Tables 5, 6, and 7 summarize the adverse reactions reported for REVLIMID/dexamethasone and placebo/dexamethasone groups.

Metabolism and nutrition disorders Anorexia Hypokalemia Hypocalcemia Appetite Decreased Dehydration Hypomagnesemia Investigations Weight Decreased Eye disorders Blurred vision Vascular disorders Deep vein thrombosis% Hypertension Hypotension

55 (15.6) 48 (13.6) 31 (8.8) 24 (6.8) 23 (6.5) 24 (6.8)

34 (9.7) 21 (6.0) 10 (2.9) 14 (4.0) 15 (4.3) 10 (2.9)

69 (19.5)

52 (14.9)

61 (17.3)

40 (11.4)

33 (9.3) 28 (7.9) 25 (7.1)

15 (4.3) 20 (5.7) 15 (4.3)

Table 6: Grade 3/4 Adverse Reactions Reported in ≥2% Patients and With a ≥1% Difference in Proportion of Patients Between the REVLIMID/dexamethasone and Placebo/dexamethasone groups System Organ Class/ Preferred Term REVLIMID/Dex# Placebo/Dex# (N=353) (N=350) n (%) n (%) Blood and lymphatic system disorders Neutropenia% 118 (33.4) 12 (3.4) Thrombocytopenia@ 43 (12.2) 22 (6.3) Anemia@ 35 (9.9) 20 (5.7) Leukopenia 14 (4.0) 1 (0.3) Lymphopenia 10 (2.8) 4 (1.1) Febrile Neutropenia% 8 (2.3) 0 (0.0) General disorders and administration site conditions Fatigue 23 (6.5) 17 (4.9) Vascular disorders Deep vein thrombosis% 29 (8.2) 12 (3.4) Infections and infestations Pneumonia@ 30 (8.5) 19 (5.4) Urinary Tract Infection 5 (1.4) 1 (0.3) Metabolism and nutrition disorders Hypokalemia 17 (4.8) 5 (1.4) Hypocalcemia 13 (3.7) 6 (1.7) Hypophosphatemia 9 (2.5) 0 (0.0) Respiratory, thoracic and mediastinal disorders Pulmonary embolism@ 14 (4.0) 3 (0.9) Respiratory Distress@ 4 (1.1) 0 (0.0) Musculoskeletal and connective tissue disorders Muscle weakness 20 (5.7) 10 (2.9) Gastrointestinal disorders Diarrhea@ 11 (3.1) 4 (1.1) Constipation 7 (2.0) 1 (0.3) Nausea@ 6 (1.7) 2 (0.6) Cardiac disorders Atrial fibrillation@ 13 (3.7) 4 (1.1) Tachycardia 6 (1.7) 1 (0.3) Cardiac Failure Congestive@ 5 (1.4) 1 (0.3) Nervous System disorders Syncope 10 (2.8) 3 (0.9) Dizziness 7 (2.0) 3 (0.9) (continued)

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Table 5: Adverse Reactions Reported in ≥5% of Patients and with a ≥2% Difference in Proportion of Patients Between the REVLIMID/dexamethasone and Placebo/dexamethasone Groups System Organ Class/ Preferred Term REVLIMID/Dex* Placebo/Dex * (N=353) (N=350) n (%) n (%) Blood and lymphatic system disorders Neutropenia % 149 (42.2) 22 (6.3) Anemia@ 111 (31.4) 83 (23.7) Thrombocytopenia@ 76 (21.5) 37 (10.6) Leukopenia 28 (7.9) 4 (1.1) Lymphopenia 19 (5.4) 5 (1.4) General disorders and administration site conditions Fatigue 155 (43.9) 146 (41.7) Pyrexia 97 (27.5) 82 (23.4) Peripheral edema 93 (26.3) 74 (21.1) Chest Pain 29 ( 8.2) 20 (5.7) Lethargy 24 ( 6.8) 8 (2.3) Gastrointestinal disorders Constipation 143 (40.5) 74 (21.1) Diarrhea@ 136 (38.5) 96 (27.4) Nausea@ 92 (26.1) 75 (21.4) Vomiting@ 43 (12.2) 33 (9.4) Abdominal Pain@ 35 (9.9) 22 (6.3) Dry Mouth 25 (7.1) 13 (3.7) Musculoskeletal and connective tissue disorders Muscle cramp 118 (33.4) 74 (21.1) Back pain 91 (25.8) 65 (18.6) Bone Pain 48 (13.6) 39 (11.1) Pain in Limb 42 (11.9) 32 (9.1) Nervous system disorders Dizziness 82 (23.2) 59 (16.9) Tremor 75 (21.2) 26 (7.4) Dysgeusia 54 (15.3) 34 (9.7) Hypoaesthesia 36 (10.2) 25 (7.1) Neuropathyª 23 (6.5) 13 (3.7) Respiratory, Thoracic and Mediastinal Disorders Dyspnea 83 (23.5) 60 (17.1) Nasopharyngitis 62 (17.6) 31 (8.9) Pharyngitis 48 (13.6) 33 (9.4) Bronchitis 40 (11.3) 30 (8.6) Infectionsb and infestations Upper respiratory tract infection 87 (24.6) 55 (15.7) Pneumonia@ 48 (13.6) 29 (8.3) Urinary Tract Infection 30 (8.5) 19 (5.4) Sinusitis 26 (7.4) 16 (4.6) Skin and subcutaneous system disorders Rashc 75 (21.2) 33 (9.4) Sweating Increased 35 (9.9) 25 (7.1) Dry Skin 33 (9.3) 14 (4.0) Pruritus 27 (7.6) 18 (5.1) (continued)

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Venous and Arterial Thromboembolism [see Boxed Warning, Warnings and Precautions (5.4)] Deep vein thrombosis (DVT) was reported as a serious (7.4%) or severe (8.2%) adverse drug reaction at a higher rate in the REVLIMID/dexamethasone group compared to 3.1 % and 3.4% in the placebo/dexamethasone group, respectively in the 2 studies in patients with at least 1 prior therapy with discontinuations due to DVT adverse reactions reported at comparable rates between groups. In the NDMM study, DVT was reported as an adverse reaction (all grades: 10.3%, 7.2%, 4.1%), as a serious adverse reaction (3.6%, 2.0%, 1.7%), and as a Grade 3/4 adverse reaction (5.6%, 3.7%, 2.8%) in the Rd Continuous, Rd18, and MPT Arms, respectively. Discontinuations and dose reductions due to DVT adverse reactions were reported at comparable rates between the Rd Continuous and Rd18 Arms (both <1%). Interruption of REVLIMID treatment due to DVT adverse reactions was reported at comparable rates between the Rd Continuous (2.3%) and Rd18 (1.5%) arms. Pulmonary embolism (PE) was reported as a serious adverse drug reaction (3.7%) or Grade 3/4 (4.0%) at a higher rate in the REVLIMID/dexamethasone group compared to 0.9% (serious or grade 3/4) in the placebo/dexamethasone group in the 2 studies in patients with, at least 1 prior therapy, with discontinuations due to PE adverse reactions reported at comparable rates between groups. In the NDMM study, the frequency of adverse reactions of PE was similar between the Rd Continuous, Rd18, and MPT Arms for adverse reactions (all grades: 3.9%, 3.3%, and 4.3%, respectively), serious

Myocardial infarction was reported as a serious (1.7%) or severe (1.7%) adverse drug reaction at a higher rate in the REVLIMID/dexamethasone group compared to 0.6 % and 0.6% respectively in the placebo/ dexamethasone group. Discontinuation due to MI (including acute) adverse reactions was 0.8% in REVLIMID/dexamethasone group and none in the placebo/dexamethasone group. In the NDMM study, myocardial infarction (including acute) was reported as an adverse reaction (all grades: 2.4%, 0.6%, and 1.1%), as a serious adverse reaction, (2.3%, 0.6%, and 1.1%), or as a severe adverse reaction (1.9%, 0.6%, and 0.9%) in the Rd Continuous, Rd18, and MPT Arms, respectively. Stroke (CVA) was reported as a serious (2.3%) or severe (2.0%) adverse drug reaction in the REVLIMID/dexamethasone group compared to 0.9% and 0.9% respectively in the placebo/dexamethasone group. Discontinuation due to stroke (CVA) was 1.4% in REVLIMID/dexamethasone group and 0.3% in the placebo/dexamethasone group. In the NDMM study, CVA was reported as an adverse reaction (all grades: 0.8%, 0.6%, and 0.6%), as a serious adverse reaction (0.8%, 0.6 %, and 0.6%), or as a severe adverse reaction (0.6%, 0.6%, 0.2%) in the Rd Continuous, Rd18, and MPT arms respectively. Other Adverse Reactions: After At Least One Prior Therapy for MM In these 2 studies, the following adverse drug reactions (ADRs) not described above that occurred at ≥1% rate and of at least twice of the placebo percentage rate were reported: Blood and lymphatic system disorders: pancytopenia, autoimmune hemolytic anemia Cardiac disorders: bradycardia, myocardial infarction, angina pectoris Endocrine disorders: hirsutism Eye disorders: blindness, ocular hypertension Gastrointestinal disorders: gastrointestinal hemorrhage, glossodynia General disorders and administration site conditions: malaise Investigations: liver function tests abnormal, alanine aminotransferase increased Nervous system disorders: cerebral ischemia Psychiatric disorders: mood swings, hallucination, loss of libido Reproductive system and breast disorders: erectile dysfunction Respiratory, thoracic and mediastinal disorders: cough, hoarseness Skin and subcutaneous tissue disorders: exanthem, skin hyperpigmentation 6.2 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 (5.7 to 5.10)]. Cases of hypothyroidism and hyperthyroidism have also been reported. Optimal control of thyroid function is recommended before start of 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. 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 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 after making a benefit-risk assessment in patients receiving REVLIMID [see Warnings and Precautions (5.4)].

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Table 7: Serious Adverse Reactions Reported in ≥1% Patients and With a ≥1% Difference in Proportion of Patients Between the REVLIMID/dexamethasone and Placebo/dexamethasone Groups System Organ Class/ Preferred Term REVLIMID/Dex& Placebo/Dex& (N=353) (N=350) n (%) n (%) Blood and lymphatic system disorders Febrile Neutropenia% 6 (1.7) 0 (0.0) Vascular disorders Deep vein thrombosis% 26 (7.4) 11 (3.1) Infections and infestations Pneumonia@ 33 (9.3) 21 (6.0) Respiratory, thoracic, and mediastinal disorders Pulmonary embolism@ 13 (3.7) 3 (0.9) Cardiac disorders Atrial fibrillation@ 11 (3.1) 2 (0.6) Cardiac Failure Congestive@ 5 (1.4) 0 (0.0) Nervous system disorders Cerebrovascular accident@ 7 (2.0) 3 (0.9) Gastrointestinal disorders Diarrhea @ 6 (1.7) 2 (0.6) Musculoskeletal and connective tissue disorders Bone Pain 4 (1.1) 0 (0.0) For Tables 5, 6 and 7 above: @ - adverse reactions in which at least one resulted in a fatal outcome % - adverse reactions in which at least one was considered to be life threatening (if the outcome of the reaction was death, it is included with death cases) Median duration of exposure among patients treated with REVLIMID/dexamethasone was 44 weeks while median duration of exposure among patients treated with placebo/dexamethasone was 23 weeks. This should be taken into consideration when comparing frequency of adverse reactions between two treatment groups REVLIMID/dexamethasone vs. placebo/dexamethasone.

adverse reactions (3.8%, 2.8%, and 3.7%, respectively), and grade 3/4 adverse reactions (3.8%, 3.0%, and 3.7%, respectively).

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7.3 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. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category X [see Boxed Warnings and Contraindications (4.1).]

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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-FDA-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 91 years of age. After At Least One Prior Therapy: 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.

NDMM: Overall, of the 1613 patients in the NDMM study who received study treatment, 94% (1521 /1613) were 65 years of age or older, while 35% (561/1613) were over 75 years of age. The percentage of patients over age 75 was similar between study arms (Rd Continuous: 33%; Rd18: 34%; MPT: 33%). Overall, across all treatment arms, the frequency in most of the AE categories (eg, all AEs, grade 3/4 AEs, serious AEs) was higher in older (> 75 years of age) than in younger (≤ 75 years of age) subjects. Grade 3 or 4 AEs in the General Disorders and Administration Site Conditions SOC were consistently reported at a higher frequency (with a difference of at least 5%) in older subjects than in younger subjects across all treatment arms. Grade 3 or 4 TEAEs in the Infections and Infestations, Cardiac Disorders (including cardiac failure and congestive cardiac failure), Skin and Subcutaneous Tissue Disorders, and Renal and Urinary Disorders (including renal failure) SOCs were also reported slightly, but consistently, more frequently (<5% difference), in older subjects than in younger subjects across all treatment arms. For other SOCs (e.g., Blood and Lymphatic System Disorders, Infections and Infestations, Cardiac Disorders, Vascular Disorders), there was a less consistent trend for increased frequency of grade 3/4 AEs in older vs younger subjects across all treatment arms Serious AEs were generally reported at a higher frequency in the older subjects than in the younger subjects across all treatment arms. 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.

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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 with MM, MDS, or MCL. In dose-ranging studies in healthy subjects, some were exposed to up to 200 mg (administered 100 mg BID) and in single-dose studies, some subjects were exposed to up to 400 mg. Pruritus, urticaria, rash, and elevated liver transaminases were the primary reported AEs. In clinical trials, the dose-limiting toxicity was neutropenia and thrombocytopenia. 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.

17 PATIENT COUNSELING INFORMATION See FDA-approved Patient labeling (Medication Guide) Embryo-Fetal Toxicity Advise patients that REVLIMID is contraindicated in pregnancy [see Contraindications (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)].

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. Pat. www.celgene.com/therapies ©2005-2015 Celgene Corporation, All Rights Reserved. REV_MM_HCP_BS_v020 02_2015

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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.

• 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-Physician 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 and Arterial Thromboembolism Inform patients of the risk of thrombosis including DVT, PE, MI, and stroke and to report immediately any signs and symptoms suggestive of these events for evaluation [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 [see Warnings and Precautions (5.6)]. 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 [see Warnings and Precautions (5.7)]. 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 [see Warnings and Precautions (5.8)]. 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 [see Warnings and Precautions (5.9)]. 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 [see Warnings and Precautions (5.10)]. 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.

Jardiance (Empagliflozin), an SGLT2 Inhibitor, Receives FDA Approval for the Treatment of Patients with Type 2 Diabetes By Loretta Fala, Medical Writer

iabetes is on the rise at an alarming rate in the United States. An estimated 9.3% of the US population, or 29.1 million people, are affected by diabetes.1 Furthermore, approximately 37% of all US adults (51% of people aged ≥65 years) have prediabetes, a condition that greatly increases their risk for developing diabetes.1 The prevalence of diabetes is projected to increase from 1 in 10 adults today to 1 in 3 adults by 2050, based on current trends and the aging of the population over the next few decades.2 Type 2 diabetes mellitus, a type of diabetes characterized by insulin resistance and the gradual decline in the ability of the pancreas to produce insulin, accounts for an estimated 90% to 95% of all cases of diabetes.1 Associated with serious comorbidities, diabetes is the seventh leading cause of mortality and a major cause of stroke, heart disease, kidney failure, blindness, and other conditions.1 Moreover, diabetes is associated with microvascular, macrovascular, and neuropathic complications that impact health and quality of life.1 The annual healthcare costs attributable to diabetes in the United States totaled $245 billion in 2012, including $176 billion in direct medical costs and $69 billion in indirect costs (ie, absenteeism, reduced or lost productivity, and disability).3 Overall, the medical costs for people with diabetes are more than twice as high as costs for people without diabetes, and more than 1 in 5 US healthcare dollars is spent on diabetes care.3 Diabetes management is complex, requiring multiple considerations beyond glycemic control.4 Approaches include incorporating lifestyle changes and self-management, providing appropriate education, minimizing the risk of weight gain, minimizing the risk of hypoglycemia, and targeting the patient’s hemoglobin (Hb) A1c goal on an individual basis, which is based on factors such as age, comorbid conditions, disease duration, adherence, and others.5 Patients must be monitored on an ongoing basis, and the effectiveness of their therapies must be evaluated until stable results are achieved.5 Improvements in glycemic control are associated with improved outcomes for patients with type 2 diabetes. Lowering the HbA1c level to ≤7% in appropriate patients is associated with a reduction in diabetes-related

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microvascular complications (ie, diabetic neuropathy, nephropathy, and retinopathy).6 Pharmacologic treatments include metformin, sulfonylureas, meglitinides, thiazolidinediones, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, insulin, and sodium glucose cotransporter-2 (SGLT2) inhibitors— the most recent class of antidiabetic agents.7

SGLT2 Inhibitors: The Newest Diabetes Drug Class The kidney, which plays a key role in maintaining glucose homeostasis, has emerged as a therapeutic target in the treatment of type 2 diabetes.8,9 In hyperglycemia, excess glucose is reabsorbed by the kidney, a process that increases the renal glucose threshold and creates a cycle of chronic hyperglycemia.8,10 The SGLT2, located in the proximal tubule of the kidney, is responsible for reabsorbing 90% of renal glucose.8 Inhibition of the SGLT2 reduces glucose reabsorption and lowers the renal threshold for glucose, leading to increased urinary glucose excretion and improved glycemic control.8,10 The SGLT2 inhibitors may have a promising role, combined with diet and exercise, in improving glycemic control in patients with type 2 diabetes. Empagliflozin: Another Option for Type 2 Diabetes On August 1, 2014, empagliflozin (Jardiance; Boehringer Ingelheim), an SGLT2 inhibitor, was approved by the US Food and Drug Administration (FDA) as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.11 Empagliflozin is an oral tablet taken once daily.11 Empagliflozin is not indicated for the treatment of patients with type 1 diabetes mellitus or with diabetic ketoacidosis.12 According to Curtis J. Rosebraugh, MD, MPH, Director of the Office of Drug Evaluation II in the FDA’s Center for Drug Evaluation and Research, “Jardiance provides an additional treatment option for the care of patients with type 2 diabetes. It can be used alone or added to existing treatment regimens to control blood sugar levels in the overall management of diabetes.” 11 Several postmarketing studies have been required by the FDA for empagliflozin, including the completion of an ongoing cardiovascular outcomes trial, a pediatric pharmacokinetic and pharmacodynamic study, a pediat-

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ric safety and efficacy study, and a nonclinical (animal) juvenile toxicity study with a particular focus on renal development, bone development, and growth.11

patients with type 2 diabetes mellitus with mild or moderate renal impairment.12 Based on these studies, treatment with empagliflozin was shown to reduce HbA1c compared with placebo in patients with type 2 diabetes.12

Mechanism of Action Empagliflozin is an inhibitor of SGLT2, the predominant transporter responsible for the reabsorption of glucose from the glomerular filtrate back into the circulation. By inhibiting SGLT2, empagliflozin reduces the renal reabsorption of filtered glucose and lowers the renal threshold for glucose, thereby increasing urinary glucose excretion.12

Empagliflozin Monotherapy: EMPA-REGMONO In the EMPA-REGMONO trial, a total of 986 patients with type 2 diabetes participated in this double- blind, placebo-controlled study to evaluate the efficacy and safety of monotherapy with empagliflozin.13 Treatment-naïve patients with inadequately controlled type 2 diabetes entered an open-label placebo run-in phase for 2 weeks. At the end of the run-in period, patients who were still inadequately controlled and had an HbA1c level between 7% and 10% were randomized to placebo, empagliflozin 10 mg, empagliflozin 25 mg, or a reference comparator.12,13 The results of this study are shown in Table 1. At week 24, monotherapy with empagliflozin 10 mg or 25 mg daily provided significant reductions in HbA1c (P <.001), fasting plasma glucose (FPG), and body weight compared with placebo.12,13

Dosage and Administration The recommended dose of empagliflozin is 10 mg once daily, taken in the morning, with or without food. This dose may be increased to 25 mg once daily.12 Before initiating therapy with empagliflozin, renal function should be assessed. Treatment with empagliflo zin should be discontinued if the estimated glomerular filtration rate (eGFR) falls persistently below 45 mL/min/1.73 m2.12 Empagliflozin is available in 10-mg and 25-mg tablets.12 Clinical Studies Empagliflozin has been studied as monotherapy and in combination with metformin, sulfonylurea, pioglitazone, and insulin. In addition, empagliflozin has been studied in

Add-On Combination Therapy with Metformin: The EMPA-REG MET Trial A total of 637 patients with type 2 diabetes participat-

Table 1 E mpagliflozin Monotherapy versus Placebo: Results from the EMPA-REGMONO Trial at Week 24 Empagliflozin 10 mg Empagliflozin 25 mg Placebo Efficacy results (N = 224) (N = 224) (N = 228) HbA1c levela Baseline, mean, %

7.9

Change from baseline, adjusted mean, %

–0.7

–0.8

0.1

Difference from placebo, adjusted mean, %

–0.7 (97.5% CI, –0.9 to –0.6)

–0.9 (97.5% CI, –1.0 to –0.7)

—

Patients achieving an HbA1c <7%, N (%)

72 (35)

88 (44)

25 (12)

Baseline, mean, mg/dL

153

155

Change from baseline, adjusted mean, mg/dL

–19

–25

–31 (95% CI, –37 to –26)

–36 (95% CI, –42 to –31)

—

Fasting plasma glucoseb

Difference from placebo, adjusted mean, mg/dL Body weight Baseline, mean, kg Change from baseline, adjusted mean, % Difference from placebo, adjusted mean, kg

–2.8

–3.2

–0.4

–2.5 (95% CI, –3.1 to –1.9)

–2.8 (95% CI, –3.4 to –2.2)

—

Modified intent-to-treat population. N = 223 for empagliflozin 10 mg, N = 223 for empagliflozin 25 mg, and N = 226 for placebo. CI indicates confidence interval; FPG, fasting plasma glucose; HbA1c, glycated hemoglobin. Sources: Jardiance (empagliflozin) tablets prescribing information; August 2014; Roden M, et al; for the EMPA-REGMONO Trial Investigators. Lancet Diabetes Endocrinol. 2013;1:208-219. a

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Table 2 Empagliflozin in Combination with Metformin versus Placebo plus Metformin: Results from the EMPA-REG MET Trial at Week 24 Empagliflozin 10 mg Empagliflozin 25 mg + metformin + metformin Placebo Efficacy results (N = 217) (N = 213) (N = 207) HbA1c levela Baseline, mean, %

7.9

Change from baseline, adjusted mean, %

–0.7

–0.8

–0.1

Difference from placebo plus metformin, adjusted mean, %

–0.6 (97.5% CI, –0.7 to –0.4)

–0.6 (97.5% CI, –0.8 to –0.5)

—

75 (38)

74 (39)

23 (13)

Baseline, mean, mg/dL

155

149

156

Change from baseline, adjusted mean, mg/dL

–20

–22

Difference from placebo, adjusted mean, mg/dL

–26

–29

—

Patients achieving an HbA1c <7%, N (%) Fasting plasma glucose

Body weight Baseline, mean, kg

–2.5

–2.9

–0.5

–2.0 (95% CI, –2.6 to –1.4)

–2.5 (95% CI, –3.1 to –1.9)

—

Change from baseline, adjusted mean, % Difference from placebo, adjusted mean, kg

Modified intent-to-treat population. N = 216 for empagliflozin 10 mg, N = 213 for empagliflozin 25 mg, and N = 207 for placebo. CI indicates confidence interval; FPG, fasting plasma glucose; HbA1c, glycated hemoglobin. Sources: Jardiance (empagliflozin) tablets prescribing information; August 2014; Häring H-U, et al; for the EMPA-REG MET Trial Investigators. Diabetes Care. 2014;37:1650-1659. a

ed in the EMPA-REG MET trial, a placebo-controlled study to evaluate the efficacy and safety of empagliflozin in combination with metformin.9 Patients with type 2 diabetes who were inadequately controlled with ≥1500 mg of metformin daily entered an open-label, 2-week, placebo run-in phase. At the end of the run-in period, patients who were still inadequately controlled and had an HbA1c level between 7% and 10% were randomized to placebo, empagliflozin 10 mg, empagliflozin 25 mg, or a reference comparator.9,12 Findings from this study are shown in Table 2. At week 24, treatment with empagliflozin 10 mg or 25 mg daily demonstrated significant reductions in HbA1c (P <.001), FPG, and body weight compared with placebo.9,12

Other Studies Treatment with empagliflozin showed significant reductions in HbA1c compared with placebo in several other clinical trials, including in combination with metformin and sulfonylurea; as add-on combination therapy with pioglitazone (with or without metformin); as addon combination therapy with insulin (with or without metformin and/or sulfonylureas); and in patients with type 2 diabetes and renal impairment.12 In addition, empagliflozin 25 mg was shown to be noninferior to glimep

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iride (at week 52) at lowering HbA1c and FPG levels in an active controlled study versus glimepiride in combination with metformin.12

Safety In clinical trials, the most common adverse reactions associated with empagliflozin 10 mg (≥5% incidence) were urinary tract infections (9.3%) and female genital mycotic infections (5.4%).12 The most common adverse reactions associated with empagliflozin 25 mg (≥5% incidence) were urinary tract infections (7.6%) and female genital mycotic infections (6.4%).12 Discontinuation from clinical studies as a result of genital infection occurred in none of the patients receiving placebo and in 0.2% of patients receiving either empagliflozin 10 mg or 25 mg. The rates of treatment discontinuation as a result of urinary tract infections were 0.1%, 0.2%, and 0.1% for placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively.12 Contraindications The use of empagliflozin is contraindicated in patients with a history of serious hypersensitivity reaction to empagliflozin and in patients with severe renal impairment, end-stage renal disease, or those on dialysis.12

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Warnings and Precautions Hypotension. Empagliflozin causes intravascular volume contraction. Before initiating treatment with empagliflozin, volume status should be assessed and corrected in patients with renal impairment, in the elderly, in patients with low systolic blood pressure, and in patients receiving diuretics. Patients should also be monitored for the signs and symptoms of hypotension during therapy.12 Impairment in renal function. Empagliflozin increases serum creatinine and decreases eGFR. Renal function should be monitored during therapy. More frequent monitoring is recommended in patients with an eGFR <60 mL/min/1.73 m2.12 Hypoglycemia. Insulin and insulin secretagogues are known to cause hypoglycemia. The risk for hypoglycemia is increased when empagliflozin is used in combination with insulin secretagogues (eg, sulfonylurea) or insulin. Consideration should be given to lowering the dose of insulin secretagogue or insulin to reduce the risk for hypoglycemia when initiating empagliflozin therapy.12 Genital mycotic infections. Empagliflozin increases the risk for genital mycotic infections. Patients with a history of chronic or recurrent genital mycotic infections were more likely to develop mycotic genital infections. Patients should be monitored and treated as appropriate.12 Urinary tract infections. Empagliflozin increases the risk for urinary tract infections. Patients should be monitored and treated as appropriate.12 Increased low-density lipoprotein cholesterol. Increases in low-density lipoprotein cholesterol can occur with empagliflozin. Patients should be monitored.12 Macrovascular outcomes. There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with empagliflozin.12 Use in Specific Populations Pregnancy. There are no adequate and well-controlled studies in pregnant women. Empagliflozin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.12 Nursing mothers. Empagliflozin should be discontinued in nursing mothers or nursing should be discontinued.12 Geriatric patients. In geriatric patients aged ≥75 years, there was a higher incidence of adverse reactions related to volume depletion and reduced renal function and a higher risk for urinary tract infections.12 Renal impairment. In patients with renal impairment, there was a higher incidence of adverse reactions related to reduced renal function.12 Hepatic impairment. Empagliflozin may be used in patients with hepatic impairment.12

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Conclusion The FDA approval of empagliflozin in August 2014 provides another treatment option for patients with type 2 diabetes as an adjunct to diet and exercise. Empagliflo zin, an SGLT2 inhibitor, improves glycemic control by blocking the reabsorption of glucose by the kidney, increasing glucose secretion, and lowering blood glucose levels in patients with type 2 diabetes. Treatment with empagliflozin provided significant reductions in HbA1c levels compared with placebo across multiple studies—as monotherapy, combined with metformin, as add-on combination therapy with metformin and sulfonylurea, as add-on combination therapy with pioglitazone (with or without metformin), as add-on combination therapy with insulin (with or without metformin and/or sulfonylureas), in combination with insulin (with or without metformin and/or sulfonylureas), and in patients with type 2 diabetes and renal impairment. The reduction in HbA1c levels shown with empagliflozin versus placebo was observed across various subgroups, including sex, race, geographic region, baseline body mass index, and disease duration.12 n References

1. Centers for Disease Control and Prevention. National diabetes statistics report: estimates of diabetes and its burden in the United States, 2014. 2014. www.cdc. gov/diabetes/pubs/statsreport14/national-diabetes-report-web.pdf. Accessed February 26, 2015. 2. Boyle JP, Thompson TJ, Gregg EW, et al. Projection of the year 2050 burden of diabetes in the US adult 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. Erratum in: Diabetes Care. 2013;36:1797. 4. American Diabetes Association. Standards of medical care in diabetes—2013. Diabetes Care. 2013;36(suppl 1):S11-S66. 5. Garber AJ, Abrahamson MJ, Barzilay JI, et al; for the American Association of Clinical Endocrinologists. AACE comprehensive diabetes management algorithm 2013. Endocr Pract. 2013;19:327-336. 6. American Diabetes Association. Executive summary: standards of medical care in diabetes—2013. Diabetes Care. 2013;36(suppl 1):S4-S10. 7. Mayo Clinic staff. Diseases and conditions: type 2 diabetes. July 24, 2014. www. mayoclinic.org/diseases-conditions/type-2-diabetes/basics/treatment/con-20031902. Accessed February 26, 2015. 8. DeFronzo RA, Davidson JA, Del Prato S. The role of the kidneys in glucose homeostasis: a new path towards normalizing glycaemia. Diabetes Obes Metab. 2012;14:5-14. 9. Häring H-U, Merker L, Seewaldt-Becker E, et al; for the EMPA-REG MET Trial Investigators. Empagliflozin as add-on to metformin in patients with type 2 diabetes: a 24-week, randomized, double-blind, placebo-controlled trial. Diabetes Care. 2014;37:1650-1659. 10. Triplitt CL. Understanding the kidneys’ role in blood glucose regulation. Am J Manag Care. 2012;18(1 suppl):S11-S16. 11. US Food and Drug Administration. FDA approves Jardiance to treat type 2 diabetes. Press release. August 1, 2014. www.fda.gov/NewsEvents/Newsroom/ PressAnnouncements/ucm407637.htm. Accessed February 25, 2015. 12. Jardiance (empagliflozin) tablets [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; August 2014. 13. Roden M, Weng J, Eilbracht J, et al; for the EMPA-REGMONO Trial Investigators. Empagliflozin monotherapy with sitagliptin as an active comparator in patients with type 2 diabetes: a randomised, double-blind, placebo- controlled, phase 3 trial. Lancet Diabetes Endocrinol. 2013;1:208-219.

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Keytruda (Pembrolizumab): First PD-1 Inhibitor Approved for Previously Treated Unresectable or Metastatic Melanoma By Lisa A. Raedler, PhD, RPh, Medical Writer

elanoma, although not the most common skin cancer in the United States, is the most deadly.1 Based on data collected between 2004 and 2010, the 5-year survival rate for Americans with metastatic melanoma remains very low—only 16%—for all ages and races, and both sexes.2 The National Cancer Institute has estimated that 21.3 in 100,000 people will be diagnosed with melanoma of the skin in the United States in 2014.2 More than 9700 patients are estimated to die from melanoma in the same time frame.2 The incidence of melanoma is increasing in the United States, particularly among children and adolescents.2,3 An analysis of first-time melanoma diagnoses in patients aged 18 to 39 years 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 analyzing data from 1973 to 2009 documented an average increase of 2% annually in melanoma in children aged between 0 and 19 years, particularly in girls and those aged between 15 and 19 years.4 These trends in melanoma diagnosis rates are concerning in light of their potential impact on healthcare resource consumption. An assessment 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 consumed an average of more than $11,000 monthly in total healthcare costs, the majority of which was related to inpatient hospital services.5 Of note, this cost analysis was conducted before the new targeted therapies for metastatic melanoma became available. Because tumor cells can spread to distant lymph nodes and to other organs, metastatic melanoma can be difficult to cure.6 Surgery and radiation therapy can be considered for tumors on the skin or for tumors that are localized to the lymph nodes. Metastases in internal organs can be surgically removed, depending on their number and location.6 The development of novel agents has significantly altered the management of patients with advanced disease. Today’s armamentarium of systemic treatments for metastatic melanoma includes immunotherapies, BRAF

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inhibitors (ie, vemurafenib, dabrafenib, trametinib), and chemotherapy.6 Many of these newer agents offer superior efficacy compared with chemotherapy.6 Specifically, immune checkpoint blockade with immuno-oncology agents that are directed toward cytotoxic T-lymphocyte antigen (CTLA)-4 (eg, ipilimumab), as well as programmed death (PD)-1 and PD-ligand 1 (PDL1), has emerged as a successful treatment approach.7 Ipilimumab was the first CTLA-4 inhibitor to demonstrate an overall survival benefit and durable objective responses in patients with metastatic melanoma.7 In patients with metastatic melanoma and BRAF V600 mutation, a striking contrast has been observed between BRAF inhibition, which offers higher response rates with limited response durability, and CTLA-4 inhibition, which offers a relatively low response rate but very durable responses.7 To increase the number of patients with melanoma who benefit from durable responses with immunotherapy, researchers are exploring potential synergies between immune checkpoint inhibitors that target CTLA-4, PD-1, and PD-L1, and kinase-targeted therapies, as well as the concurrent and sequential use of CTLA-4 and PD-1/PD-L1 inhibitors.7 Pembrolizumab a New Option for Metastatic Melanoma On September 4, 2014, the US Food and Drug Administration (FDA) approved pembrolizumab (Keytruda; Merck Sharp & Dohme Corp) for the treatment of patients with unresectable or metastatic melanoma and disease progression after receiving ipilimumab and, in patients with BRAF V600 mutation melanoma, a BRAF inhibitor.8 Pembrolizumab is the first human PD-1– blocking antibody approved for use in the United States.9 Pembrolizumab, which is administered via intravenous infusion, was approved under the accelerated approval program based on surrogate end points of confirmed overall response rate (ORR) and duration of response.8 Improvements in survival or disease-related symptoms have not yet been established.10 According to Jeffrey S. Weber, MD, PhD, Director of the Donald A. Adam Comprehensive Melanoma Research Center of Excellence at the Moffitt Cancer Cen-

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ter, Tampa, FL, “Pembrolizumab is…a clearly effective drug that will prolong survival for many patients with metastatic melanoma. This approval is a real advance and a major milestone in the treatment of the disease.”11 As a condition for this accelerated approval, the manufacturer is required to conduct a multicenter, randomized trial to establish the superiority of pembrolizumab over standard therapy and to verify its clinical benefit in patients with metastatic melanoma.8 Currently, 2 ongoing multicenter, randomized, controlled, therapeutic confirmatory trials are under way in patients with metastatic melanoma: Trial P002 in ipilimumab-refractory patients and Trial P006 in ipilimumab-naïve patients. In both trials, the coprimary end points are progression-free survival and overall survival.8 Mechanism of Action Pembrolizumab is a monoclonal antibody that binds to the PD-1 receptor and blocks interaction with its ligands, PD-L1 and PD-L2. This binding results in the activation of T-cell–mediated immune responses against tumor cells. Blocking PD-1 activity resulted in decreased tumor growth in genetically identical mouse tumor models.10 Dosing and Administration The recommended dosage of pembrolizumab is 2 mg/ kg administered as an intravenous infusion over 30 minutes every 3 weeks; it should be reconstituted and diluted before infusion. Pembrolizumab should be used until disease progression or until unacceptable toxicity.10 No dose adjustment of pembrolizumab is needed for patients with renal impairment or for patients with mild hepatic impairment, defined as a total bilirubin of the upper limit of normal or less, and aspartate aminotransferase (AST) of more than the upper limit of normal, or a total bilirubin of >1 to 1.5 times the upper limit of normal and any AST. Pembrolizumab has not been studied in patients with moderate or severe hepatic impairment.10 KEYNOTE-001 Clinical Trial: Relapsed Metastatic Melanoma The accelerated approval of pembrolizumab was based on the results of a multicenter, open-label, randomized, dose-comparative, activity-estimating cohort conducted within the phase 1b KEYNOTE-001 trial (Trial P001).10 Of the 411 patients with treatment-naïve or with previously treated unresectable or metastatic melanoma who enrolled in the KEYNOTE-001 trial, 173 had disease progression within 24 weeks of the last dose of ipilimu mab and, in those with BRAF V600 mutation melanoma, after previous treatment with a BRAF inhibitor. These 173 patients were randomized to receive 2 mg/kg (N = 89) or 10 mg/kg (N = 84) of intravenous pembroliz

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umab once every 3 weeks until disease progression or until unacceptable toxicity.10 The primary efficacy end points were confirmed ORR according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as assessed by a blinded independent central review and duration of response.10,11 The patients’ tumor status was assessed every 12 weeks.10 The secondary outcome measures included investigator- assessed immune-related response criteria.11 The KEYNOTE-001 trial excluded patients with autoimmune disease, medical conditions that required immunosuppression, or a history of severe immune-mediated adverse events with ipilimumab. The latter was defined as any grade 4 toxicity requiring treatment with corticosteroids or grade 3 toxicity requiring corticosteroid treatment for ≥12 weeks.10 Among the 173 patients with previously treated unresectable or metastatic melanoma in KEYNOTE-001, 61% were aged <65 years.10 Most patients were male (60%) and white (97%). All of the patients in the trial had an Eastern Cooperative Oncology Group performance status of 0 or 1. The patients’ disease characteristics included stage M1c (82%), having had ≥2 previous therapies for advanced or metastatic disease (73%), elevated lactate dehydrogenase (39%), BRAF V600 mutation (17%), and brain metastases (9%).10 The ORR associated with 2-mg/kg pembrolizumab was 24% (95% confidence interval, 15%-34%) in patients with unresectable or metastatic melanoma who were previously treated with ipilimumab and, if relevant, a BRAF inhibitor.10 Of the 21 patients with an objective response to pembrolizumab, 1 patient achieved a complete response and 20 patients achieved a partial response.10 Of these 21 patients, 3 (14%) patients had disease progressions 2.8 months, 2.9 months, and 8.2 months (respectively) after the initial response to pembrolizumab therapy. The remaining 18 (86%) patients had ongoing responses after the initial response to therapy, with response duration ranging from ≥1.4 months to ≥8.5 months; this group included 8 patients with ongoing responses of ≥6 months. Objective responses were observed in patients with and without BRAF V600 mutation melanoma.10 The ORR associated with 10-mg/kg pembrolizumab was similar (26%) to the ORR with 2-mg/kg pembrolizumab.10,12 Safety The cohort of 89 patients with previously treated unresectable or metastatic melanoma in KEYNOTE-001 who received pembrolizumab (2 mg/kg) had a median of 9 doses (range, 1-23 doses).10 The median duration of exposure for this cohort was 6.2 months (range, 1 day15.3 months). Of these 89 patients, 51% were exposed to

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dverse Reactions in ≥10% of Patients with Unresectable Table A or Metastatic Melanoma Receiving Pembrolizumab 2 mg/kg Pembrolizumab 2 mg/kg every 3 weeks (N = 89) All grades, % Grade 3,a % General disorders and administration site conditions Fatigue

Peripheral edema

Chills

Pyrexia

Nausea

Constipation

Diarrhea

Vomiting

Abdominal pain

Gastrointestinal disorders

Respiratory, thoracic, and mediastinal disorders Cough

Dyspnea

Pruritus

Rash

Vitiligo

Skin and subcutaneous tissue disorders

Metabolism and nutrition disorders Decreased appetite

Musculoskeletal and connective tissue disorders Arthralgia

Pain in extremity

Myalgia

Back pain

Headache

Dizziness

Nervous system disorders

Blood and lymphatic system disorders Anemia Psychiatric disorders Insomnia Infections and infestations Upper respiratory tract infection

No grade 5 adverse reactions were reported. Of the ≥10% adverse reactions, none was grade 4. Source: Keytruda (pembrolizumab) for injection prescribing information; September 2014.

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pembrolizumab for >6 months, and 21% were exposed for >1 year.10 The Table summarizes the adverse reactions that occurred in ≥10% of patients in this cohort. Among the 411 patients who received pembrolizumab in KEYNOTE-001, serious adverse reactions occurred in 36%. The most common serious adverse drug reactions reported in ≥2% of the 411 patients receiving pembro lizumab were renal failure, dyspnea, pneumonia, and cellulitis.10,12 Pembrolizumab was discontinued because of adverse reactions in 9% of the 411 patients receiving 2-mg/kg or 10-mg/kg doses in KEYNOTE-001. Among the 89 patients with unresectable or metastatic melanoma who received 2 mg/kg of pembrolizumab, the discontinuation rate associated with adverse reactions was 6%. The adverse reactions that led to the discontinuation of pembrolizumab included pneumonitis, renal failure, and pain.10 Pembrolizumab has no contraindications. Warnings and Precautions Immune-mediated pneumonitis. Pneumonitis occurred in 12 of the 411 patients with unresectable or metastatic melanoma who received pembrolizumab in the KEYNOTE-001 trial. The median time to the development of pneumonitis was 5 months (range, 2 days-9.9 months), and the median duration of pneumonitis was 4.9 months (range, 1 week-14.4 months). In 5 of the 8 patients with grade 2 pneumonitis and 1 patient with grade 3 pneumonitis, initial treatment with high-dose systemic corticosteroids (≥40 mg prednisone or equivalent daily) was required and was followed by a corticosteroid taper. Pembrolizumab was discontinued in 3 patients with pneumonitis. In 7 of the 9 patients with grade 2 or 3 pneumonitis, the condition completely resolved.10 Patients receiving pembrolizumab should be monitored for signs and symptoms of pneumonitis and should undergo radiographic imaging if pneumonitis is suspected. Corticosteroids are appropriate if grade ≥2 pneumonitis is detected. Pembrolizumab should be withheld for moderate (grade 2) pneumonitis, and should be permanently discontinued for severe (grade 3) or life-threatening (grade 4) pneumonitis.10 Immune-mediated colitis. Colitis, including microscopic colitis, occurred in 4 of the 411 patients in the KEYNOTE-001 trial. Grades 2 and 3 colitis were observed in 1 and 2 patients, respectively. The median time to onset of colitis was 6.5 months (range, 2.3-9.8 months). All 3 patients with grade 2 or 3 colitis were treated with high-dose corticosteroids followed by a corticosteroid taper. One patient permanently discontinued pembro lizumab as a result of colitis. All 4 patients with colitis experienced complete resolution of the condition.10

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Patients receiving pembrolizumab should be monitored for signs and symptoms of colitis. Corticosteroids should be used for grade ≥2 colitis. Pembrolizumab should be withheld for moderate (grade 2) or severe (grade 3) colitis, and should be permanently discontinued for life-threatening (grade 4) colitis.10 Immune-mediated hepatitis. In the KEYNOTE-001 trial, hepatitis, including autoimmune hepatitis, occurred in 2 of the 411 patients, including 1 patient with grade 4 hepatitis. The time to onset was 22 days after initiating pembrolizumab for the patient with grade 4 hepatitis. This patient permanently discontinued pembrolizumab and was treated with high-dose systemic corticosteroids followed by a corticosteroid taper. Both patients with hepatitis experienced complete resolution of the event.10 Patients receiving pembrolizumab should be monitored for changes in liver function. Corticosteroids should be administered for grade ≥2 hepatitis. Pembro lizumab should be withheld or discontinued based on the severity of liver enzyme elevations.10 Immune-mediated hypophysitis. Inflammation of the pituitary gland (hypophysitis) occurred in 2 of the 411 patients in the KEYNOTE-001 trial. One of these events was grade 2 and 1 was grade 4. The time to onset was 1.3 months for the patient with grade 2 hypophysitis and 1.7 months for the patient with grade 4 hypophysitis. Both patients were treated with high-dose corticosteroids followed by a corticosteroid taper and continued receiving physiologic replacement doses of glucocorticoids.10 Patients receiving pembrolizumab should be monitored for signs of hypophysitis. Corticosteroids should be used for grade ≥2 hypophysitis. Pembrolizumab should be withheld for moderate (grade 2) hypophysitis, withheld or discontinued for severe (grade 3) hypophysitis, and permanently discontinued for life-threatening (grade 4) hypophysitis.10 Renal failure and immune-mediated nephritis. In the KEYNOTE-001 trial, nephritis occurred in 3 of the 411 patients, including 1 case of grade 2 autoimmune nephritis and 2 cases of interstitial nephritis with renal failure (1 case of grade 3 and 1 case of grade 4). In the patient with autoimmune nephritis, the time to onset was 11.6 months after the first dose of pembrolizumab and 5 months after the last dose. This patient did not undergo a kidney biopsy. Acute interstitial nephritis was confirmed by biopsy in 2 patients with grade 3 or 4 renal failure.10 All 3 patients with nephritis fully recovered their kidney function after treatment with high-dose corticosteroids followed by a corticosteroid taper.10 Patients receiving pembrolizumab should be monitored for changes in renal function. Corticosteroids should be administered for grade ≥2 nephritis. Pembro lizumab should be withheld for moderate (grade 2) ne-

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phritis and should be permanently discontinued for severe (grade 3) or life-threatening (grade 4) nephritis.10 Immune-mediated hyperthyroidism and hypothyroidism. Hyperthyroidism occurred in 5 of the 411 patients (2 patients with grade 1, 2 with grade 2, and 1 with grade 3) receiving pembrolizumab. The median time to onset was 1.5 months (range, 0.5-2.1 months) after pembrolizumab initiation, and the median duration was 2.8 months (range, 0.9-6.1 months). One of the 2 patients with grade 2 hyperthyroidism and the patient with grade 3 hyperthyroidism required treatment with high-dose corticosteroids followed by a corticosteroid taper. Only 1 patient permanently discontinued pembrolizumab as a result of hyperthyroidism. Hyperthyroidism resolved completely in all 5 patients.10 Hypothyroidism occurred in 34 (8.3%) of the 411 patients who received pembrolizumab in the KEYNOTE-001 trial. The median time to the onset of hypothyroidism was 3.5 months (range, 5 days-19 months). All but 2 patients with hypothyroidism were treated with long-term thyroid hormone replacement therapy. The other 2 patients required short-term thyroid hormone replacement therapy. None of the patients received corticosteroids or discontinued pembrolizumab secondary to hypothyroidism.10 Because thyroid disorders can occur at any time during treatment with pembrolizumab, patients should be monitored for changes in thyroid function at the initiation of treatment, periodically during treatment, and as indicated based on clinical evaluation.10 Isolated hypothyroidism can be managed with thyroid hormone replacement therapy without treatment interruption and without corticosteroids. Corticosteroids should be administered for grade ≥3 hyperthyroidism. Pembrolizumab should be withheld for severe (grade 3) hyperthyroidism and should be permanently discontinued for life-threatening (grade 4) hyperthyroidism.10 Other immune-mediated adverse reactions. Other clinically important immune-mediated adverse reactions can occur while patients with unresectable or metastatic melanoma are receiving pembrolizumab.10 Clinically significant, immune-mediated adverse reactions that occurred in <1% of the 411 patients treated with pembrolizumab in the KEYNOTE-001 trial included exfoliative dermatitis, uveitis, arthritis, myositis, pancreatitis, hemolytic anemia, partial seizures arising in a patient with inflammatory foci in brain parenchyma, and adrenal insufficiency.10 In clinical studies of 2000 patients with various diagnoses who received pembrolizumab, other clinically significant immune-mediated adverse reactions included myasthenic syndrome, optic neuritis, and rhabdomyolysis.10 If an immune-mediated adverse reaction is suspected,

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patients receiving pembrolizumab must be evaluated to exclude other causes. Pembrolizumab should be withheld and corticosteroids should be administered based on the severity of the reaction. Upon improvement of the reaction to grade ≤1, a corticosteroid taper can be initiated and continued for at least 1 month.10 Pembrolizumab can be restarted if the adverse reaction remains at grade ≤1. Pembrolizumab should be permanently discontinued for any severe or grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.10 Embryofetal toxicity. Pembrolizumab may cause fetal harm when administered to a pregnant woman. If pembrolizumab is used during pregnancy, or if a patient becomes pregnant while taking the drug, she should be made aware of the potential hazard to the fetus. Women of childbearing age should use effective contraception during treatment with pembrolizumab and for at least 4 months after the last dose of the drug.10

Pembrolizumab, the first FDA-approved PD-1 inhibitor, is a safe and effective immunotherapy for patients with unresectable or metastatic melanoma and disease progression after ipilimumab and, if BRAF V600 mutation melanoma, after a BRAF inhibitor. Specific Populations Pediatric patients. The safety and efficacy of pembro lizumab in pediatric patients have not been established.10 Geriatric use. Of the 411 patients with relapsed unresectable or metastatic melanoma who received pembro lizumab, 39% were aged ≥65 years. No meaningful differences in efficacy were observed among the age cohorts.10 Pregnancy. Pembrolizumab has been assigned pregnancy category D. Women should avoid becoming pregnant while being treated with pembrolizumab.10 Nursing mothers. Nursing should be discontinued during treatment with pembrolizumab.10 Conclusion Pembrolizumab, the first FDA-approved PD-1 inhibitor, is a safe and effective immunotherapy for patients with unresectable or metastatic melanoma and

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disease progression after ipilimumab and, if BRAF V600 mutation melanoma, after a BRAF inhibitor. The FDA approved pembrolizumab under its accelerated approval program based on tumor response rate and duration of response data. As a condition of this accelerated approval, the FDA required that a multicenter, randomized trial be conducted to establish pembrolizu mab’s survival superiority over standard therapy, and to verify its clinical benefit in patients with metastatic melanoma.8 The 2 ongoing trials of pembrolizumab, Trial P002 in ipilimumab-refractory patients and Trial P006 in ipilimumab-naïve patients, are currently investigating the potential survival benefit with pembrolizumab in patients with advanced melanoma. The safety and efficacy of pembrolizumab are also being evaluated in other solid and liquid tumors, including advanced non–small-cell lung cancer, renal-cell carcinoma, recurrent head and neck cancer, and multiple myeloma.13 n

References

1. Skin Cancer Foundation. Melanoma. www.skincancer.org/skin-cancer-information/ melanoma. Accessed October 17, 2014. 2. National Cancer Institute. SEER stat fact sheets: melanoma of the skin. http://seer. cancer.gov/statfacts/html/melan.html. Accessed October 17, 2014. 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. American Cancer Society. Treatment of melanoma skin cancer by stage. Revised September 5, 2014. www.cancer.org/cancer/skincancer-melanoma/detailedguide/ melanoma-skin-cancer-treating-by-stage. Accessed October 17, 2014. 7. Ott PA, Hodi FS, Robert C. CTLA-4 and PD-1/PD-L1 blockade: new immunotherapeutic modalities with durable clinical benefit in melanoma patients. Clin Cancer Res. 2013;19:5300-5309. 8. US Food and Drug Administration. Drugs: pembrolizumab. Updated September 5, 2014. www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm412861.htm. Accessed October 17, 2014. 9. Loftus P. FDA approves Merck’s new-wave cancer drug: new treatment, which costs $150,000 a year, is aimed at bolstering the body’s immune system. Wall Street Journal. Updated September 4, 2014. http://online.wsj.com/articles/fda-approvesmercks-cancer-drug-1409856320. Accessed October 17, 2014. 10. Keytruda (pembrolizumab) for injection [prescribing information]. Whitehouse Station, NJ: Merck Sharp & Dohme Corp; September 2014. 11. Inman S. FDA approves pembrolizumab for advanced melanoma. OncLive. September 4, 2014. www.onclive.com/web-exclusives/FDA-Approves-Pembrolizumabfor-Advanced-Melanoma#sthash.hAnbLPqJ.dpuf. Accessed October 17, 2014. 12. National Cancer Institute. Melanoma treatment (PDQ®): unresectable stage III, stage IV, and recurrent melanoma treatment. Updated September 19, 2014. www. cancer. gov/cancertopics/pdq/treatment/melanoma/HealthProfessional/Page9# Section_896. Accessed October 20, 2014. 13. ClinicalTrials.gov. Pembrolizumab. Search results. http://clinicaltrials.gov/ct2/ results?term=pembrolizumab&Search=Search. Accessed October 21, 2014.

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Ofev (Nintedanib): First Tyrosine Kinase Inhibitor Approved for the Treatment of Patients with Idiopathic Pulmonary Fibrosis By Loretta Fala, Medical Writer

diopathic pulmonary fibrosis, a debilitating lung disease, affects approximately 128,100 patients in the United States, with 48,000 new cases diagnosed annually.1 Idiopathic pulmonary fibrosis is defined as a specific form of chronic, progressive fibrosing interstitial pneumonia of unknown cause that occurs primarily in older adults (ie, aged 50-75 years).2 The disease is characterized by progressive worsening of dyspnea (shortness of breath) and lung function, as well as a poor prognosis.2 In fact, the median survival for patients with idiopathic pulmonary fibrosis in the United States is 2.5 to 3.5 years after diagnosis, with the disease claiming an estimated 40,000 lives annually.3 The course and severity of idiopathic pulmonary fibrosis varies from person to person. Symptoms include dyspnea, dry cough, fatigue, unexplained weight loss, and aching muscles and joints.4 An estimated 9 in 10 patients with idiopathic pulmonary fibrosis also have gastroesophageal reflux disease.5 The symptoms of idiopathic pulmonary fibrosis can have a profound impact on an individual’s physical activity, independence, and quality of life.4,6 Complications of idiopathic pulmonary fibrosis include pulmonary hypertension, right-sided heart failure (cor pulmonale), respiratory failure, and lung cancer.4 Acute exacerbations are associated with increased morbidity and mortality rates.6 According to a retrospective 2001-2008 claims database analysis, the total direct medical costs for people with idiopathic pulmonary fibrosis were $26,378 per person annually; furthermore, these costs were $12,124 higher than the costs incurred by age- and sex-matched control patients.7 During this same period, the all-cause hospital admission rates and the all-cause outpatient visits for patients with idiopathic pulmonary fibrosis were twice that of the control group.7 Patients with idiopathic pulmonary fibrosis may receive oxygen therapy and/or pulmonary rehabilitation. For some patients with severe disease, a lung transplantation may be a last-resort option if other treatment options fail.4 In the past, conventional medications for patients with idiopathic pulmonary fibrosis included glucocorticosteroids (ie, prednisone) or immunosuppressants.8 A

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2-drug combination regimen of prednisone and azathioprine or a 3-drug regimen of prednisone, azathioprine, and N-acetylcysteine were used to treat the disease.8 However, based on the findings from the PANTHER-IPF study that was funded by the National Heart, Lung, and Blood Institute and published in 2012, treatment with the triple combination of prednisone, azathioprine, and N-acetylcysteine was shown to increase the rate of mortality and hospitalization compared with placebo.8 Until October 2014, no medications were approved by the US Food and Drug Administration (FDA) for the treatment of patients with idiopathic pulmonary fibrosis.9 Approaches that reduce the decline in forced vital capacity may slow the progression of this devastating disease and improve outcomes for affected patients.10

Nintedanib: A Novel Treatment for Idiopathic Pulmonary Fibrosis On October 15, 2014, nintedanib (Ofev; Boehringer Ingelheim), a tyrosine kinase inhibitor, received FDA approval for the treatment of patients with idiopathic pulmonary fibrosis, a rare disease. Nintedanib was granted a fast-track, priority review by the FDA and was designated as a breakthrough therapy, based on the substantial improvement it demonstrated over the existing therapies.11 It was also granted an orphan drug designation, for the treatment of a rare disease. Nintedanib, taken as 1 capsule twice daily, is the first and only tyrosine kinase inhibitor that is FDA approved for the treatment of patients with idiopathic pulmonary fibrosis.12,13 According to Mary Parks, MD, Deputy Director of the Office of Drug Evaluation II in the FDA’s Center for Drug Evaluation and Research, “Today’s Ofev approval expands the available treatment options for patients with idiopathic pulmonary fibrosis, a serious, chronic condition. Providing health care professionals and patients with additional treatment options helps enable appropriate care decisions based on a patient’s need.” 11 Also on October 15, 2014, the FDA approved pirfenidone (Esbriet; InterMune), a pyridone, for the treatment of patients with idiopathic pulmonary fibrosis.11 Together, nintedanib and pirfenidone are the first 2 therapies to receive FDA approval for this life-threatening disease.

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Mechanism of Action Nintedanib is a small molecule that inhibits multiple receptor tyrosine kinases and nonreceptor tyrosine kinases. Specifically, nintedanib inhibits the platelet-derived growth factor (PDGF) receptor-alpha and -beta, fibroblast growth factor (FGF) receptor 1-3, vascular endothelial growth factor (VEGF) receptor 1-3, and fms-like tyrosine kinase-3. Of these tyrosine kinase receptors, FGF, PDGF, and VEGF have been implicated in the pathogenesis of idiopathic pulmonary fibrosis.12 Nintedanib binds competitively to the adenosine triphosphate-binding pocket of these receptors and blocks the intracellular signaling, which is crucial for the pro liferation, migration, and transformation of fibroblasts, representing essential mechanisms of the idiopathic pulmonary fibrosis pathology.12 Dosing and Administration Nintedanib is available in 150-mg and 100-mg capsules. The recommended dosage of nintedanib is 150 mg twice daily administered approximately 12 hours apart. Nintedanib capsules should be taken with food and swallowed whole with liquid. Liver function tests should be conducted before starting treatment with nintedanib.12 Nintedanib capsules should not be chewed or crushed because of a bitter taste. The effect of chewing or crushing the drug capsule on the pharmacokinetics of nintedanib is not known.12 If a dose of nintedanib is missed, the next dose should be taken at the next scheduled time. The patient should be advised not to make up for a missed dose. The recommended maximum daily dose of nintedanib should not exceed 300 mg.12 A temporary dose reduction to 100 mg, treatment interruption, or treatment discontinuation may be required to manage the adverse reactions of nintedanib therapy.12 TOMORROW Clinical Trial: Annual Rate of Decline in Table 1 FVC in Patients with Idiopathic Pulmonary Fibrosis Receiving Nintedanib or Placebo Patients receiving nintedanib 150 mg Patients twice daily receiving placebo Primary end point (N = 84) (N = 83) –60 –191 Ratea of decline in FVC during 52 weeks, mL 131 (95% CI, 27-235) Comparison vs placebo difference,b mL a Randomized set. b Estimated based on a random coefficient regression model. CI indicates confidence interval; FVC, forced vital capacity. Sources: Ofev (nintedanib) capsules prescribing information; October 2014; Richeldi L, et al. N Engl J Med. 2011;365:1079-1087.

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Clinical Trials The clinical efficacy of nintedanib has been evaluated in 1231 patients in 3 studies, including 1 phase 2 clinical trial and 2 phase 3 trials.6,10,12 All 3 clinical trials were randomized, double-blind, placebo-controlled studies that compared the treatment of nintedanib 150 mg twice daily with placebo for 52 weeks. In all 3 studies, patients had to have a diagnosis of idiopathic pulmonary fibrosis for <5 years. Patients were aged ≥40 years and had a forced vital capacity ≥50% of predicted value and a carbon monoxide diffusing capacity of the lung for carbon monoxide (corrected for hemoglobin) that was 30% to 79% of the predicted value.12 The TOMORROW Trial In the TOMORROW clinical trial, patients (mean age, 65 years) were randomized in a 1:1 ratio to receive nintedanib 150 mg or placebo twice daily for 52 weeks.6 The primary end point was the annual rate of decline in forced vital capacity.6 This study also evaluated several other doses of nintedanib, including 50 mg and 100 mg.6,12 Table 1 shows the primary end point results from the TOMORROW clinical trial. The adjusted annual rate of change in forced vital capacity was –60 mL in the nintedanib group versus –191 mL in the placebo group, representing a difference of 131 mL annually6,12; patients who received nintedanib had a significant reduction (68%) in the annual rate of decline of forced vital capacity compared with patients who received placebo, based on the random coefficient regression model that was adjusted for gender, height, and age.6,12 The INPULSIS-1 and INPULSIS-2 Trials INPULSIS-1 and INPULSIS-2 were 52-week, randomized, double-blind, phase 3 clinical trials in 1066 patients (mean age, 67 years) who were randomized in a 3:2 ratio to receive nintedanib or placebo.10 These 2 studies were identical in design. The primary end point in both studies was the annual rate of decline in forced vital capacity.10,12 The primary end point results from the INPULSIS-1 and INPULSIS-2 studies are shown in Table 2. In both studies, the adjusted annual rate of change in forced vital capacity was significantly lower in patients who received nintedanib than in those who received placebo; a difference of 125 mL annually was demonstrated in the INPULSIS-1 clinical trial, and a difference of 94 mL annually was demonstrated in the INPULSIS-2 clinical trial.10,12 Safety The safety of nintedanib was evaluated in more than 1000 patients with idiopathic pulmonary fibrosis; more than 200 patients were exposed to nintedanib for more than 2 years in the clinical studies. The most common

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Table 2 I NPULSIS-1 and INPULSIS-2 Clinical Trials: Annual Rate of Decline in FVC in Patients with Idiopathic Pulmonary Fibrosis Receiving Nintedanib or Placebo INPULSIS-1 INPULSIS-2 Nintedanib 150 mg Nintedanib 150 mg twice daily Placebo twice daily Placebo Primary end point (N = 309) (N = 204) (N = 329) (N = 219) Ratea of decline in FVC during 52 weeks, mL Comparison vs placebo difference,b mL

–115

–240

–114

125 (95% CI, 78-173)

–207

94 (95% CI, 45-143)

Treated set. Estimated based on a random coefficient regression model. CI indicates confidence interval; FVC, forced vital capacity. Sources: Ofev (nintedanib) capsules prescribing information; October 2014; Richeldi L, et al. N Engl J Med. 2014;370:2071-2082.

adverse reactions (≥5%) with nintedanib therapy included diarrhea (62%), nausea (24%), abdominal pain (15%), vomiting (12%), liver enzyme elevation (14%), decreased appetite (11%), headache (8%), weight loss (10%), and hypertension (5%).12 Overall, 21% of patients who received nintedanib and 15% of patients who received placebo discontinued treatment because of an adverse event.12 The most frequent adverse reactions leading to the discontinuation of nintedanib were diarrhea (5%), nausea (2%), and decreased appetite (2%). Nintedanib has no known contraindications.12

Drug Interactions The coadministration of P-glycoproteins and cytochrome P3A4 inhibitors, including ketoconazole, may increase the exposure to nintedanib. Patients should be monitored closely for tolerability of nintedanib.12 Because nintedanib may increase the risk for bleeding, patients who are receiving full anticoagulation therapy should be monitored closely for bleeding, and anticoagulation treatment should be adjusted as necessary.12 Warnings and Precautions Elevated liver enzymes. Nintedanib therapy is associated with elevated levels of liver enzymes, including alanine transaminase (ALT), aspartate transaminase (AST), and bilirubin. Liver function tests should be conducted before starting treatment with nintedanib. ALT, AST, and bilirubin levels should be monitored before and during treatment; temporary dosage reductions or discontinuation of nintedanib therapy may be required.12 Gastrointestinal disorders. Diarrhea, nausea, and vomiting have occurred with nintedanib. At first signs of these gastrointestinal symptoms, patients should receive adequate hydration and antidiarrheal medicine (eg, lo peramide) or antiemetics. Nintedanib therapy should be

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discontinued if severe diarrhea, nausea, or vomiting persists despite symptomatic treatment.12 Embryofetal toxicity. Nintedanib can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised of the potential hazard of nintedanib to the fetus; they should also be advised to avoid becoming pregnant while receiving nintedanib, and to use adequate contraception during treatment and at least 3 months after the last dose of nintedanib.12 Arterial thromboembolic events. Arterial thromboembolic events have been reported in patients who received nintedanib therapy. Caution should be used when treating patients with nintedanib who are at a higher risk for cardiovascular events, including known coronary artery disease.12 Bleeding risk. Bleeding events have been reported with nintedanib. In patients with known bleeding risk, nintedanib should only be used if the anticipated benefit outweighs the potential risk.12 Gastrointestinal perforation. Gastrointestinal perforation has been reported with nintedanib. Nintedanib should be used with caution in patients who recently underwent abdominal surgery. In patients with a known risk for gastrointestinal perforation, nintedanib should only be used if the anticipated benefit outweighs the potential risk.12

Use in Specific Populations Pregnancy. Nintedanib is listed as pregnancy category D. Because nintedanib can cause harm to the fetus, women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with nintedanib. Nursing mothers. The excretion of nintedanib and/ or its metabolites into human milk is probable. Because of the potential for serious adverse reactions in nursing

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infants from nintedanib, a decision should be made whether to discontinue nursing or to discontinue nintedanib, taking into account the importance of the drug to the mother.12 Geriatric use. No overall differences in the safety of nintedanib were observed between individuals aged ≥65 years or individuals aged ≥75 years and younger individuals, but greater sensitivity of some older individuals cannot be ruled out.12 Pediatric use. The safety and efficacy of nintedanib in pediatric patients have not been established.12 Hepatic impairment. Patients should be monitored for adverse reactions with nintedanib therapy; a dose modification or discontinuation of nintedanib should be

The FDA approval of nintedanib welcomes the availability of a much needed treatment option for patients with idiopathic pulmonary fibrosis, a serious, progressive disease with a high mortality rate. Nintedanib is 1 of the first 2 agents to receive FDA approval specifically for patients with idiopathic pulmonary fibrosis. considered for patients with mild hepatic impairment. Nintedanib is not recommended for use in patients with moderate or severe hepatic impairment.12 Renal impairment. The safety and efficacy of nintedanib have not been studied in patients with severe renal impairment and with end-stage renal disease.12 Smokers. Smoking was associated with decreased exposure to nintedanib, which may alter the efficacy profile of nintedanib. Patients should be encouraged to stop smoking before starting treatment with nintedanib and to avoid smoking during treatment with nintedanib.12

Conclusion The FDA approval of nintedanib welcomes the availability of a much needed treatment option for patients with idiopathic pulmonary fibrosis, a serious, progressive

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disease with a high mortality rate. Nintedanib is 1 of the first 2 agents to receive FDA approval specifically for patients with idiopathic pulmonary fibrosis. Treatment with nintedanib, a tyrosine kinase inhibitor that blocks pathways thought to be involved in the scarring of lung tissue, demonstrated a significant reduction in the adjusted annual rate of decline of forced vital capacity in patients with idiopathic pulmonary fibrosis compared with placebo. This beneficial treatment effect of nintedanib on forced vital capacity was consistent across 3 clinical trials. n

References

1. Coalition for Pulmonary Fibrosis. Facts about idiopathic pulmonary fibrosis. Updated March 10, 2015. www.coalitionforpf.org/facts-about-idiopathic-pulmon ary-fibrosis/. Accessed March 13, 2015. 2. Raghu G, Collard HR, Egan JJ, et al; for the ATS/ERS/JRS/ALAT Committee on Idiopathic Pulmonary Fibrosis. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. 2011;183:788-824. 3. Blackwell TS, Tager AM, Anstrom KJ, et al; for the NHLBI Workshop participants. Strategic planning for idiopathic pulmonary fibrosis research: NHLBI Workshop executive summary—November 27-28, 2012. www.nhlbi.nih. gov/ research/reports/strategic-planning-idiopathic-pulmonary-fibrosis-research. Accessed February 12, 2015. 4. Mayo Clinic staff. Diseases and conditions: pulmonary fibrosis. March 18, 2014. www.mayoclinic.org/diseases-conditions/pulmonary-fibrosis/basics/definition/ con-20029091. Accessed February 15, 2015. 5. National Heart, Lung, and Blood Institute. What causes idiopathic pulmonary fibrosis? September 20, 2011. www.nhlbi.nih.gov/health/health-topics/topics/ipf/ causes#. Accessed February 12, 2015. 6. Richeldi L, Costabel U, Selman M, et al. Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. N Engl J Med. 2011;365:1079-1087. 7. Collard HR, Ward AJ, Lanes S, et al. Burden of illness in idiopathic pulmonary fibrosis. J Med Econ. 2012;15:829-835. 8. Idiopathic Pulmonary Fibrosis Clinical Research Network. Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. N Engl J Med. 2012;366: 1968-1977. 9. Chowdhury BA. Two FDA drug approvals for idiopathic pulmonary fibrosis (IPF). FDA Voice. October 15, 2014. http://blogs.fda.gov/fdavoice/index.php/ 2014/10/two-fda-drug-approvals-for-idiopathic-pulmonary-fibrosis-ipf/. Accessed February 18, 2015. 10. Richeldi L, du Bois RM, Raghu G, et al; for the INPULSIS Trial Investigators. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370:2071-2082. 11. US Food and Drug Administration. FDA approves Ofev to treat idiopathic pulmonary fibrosis. Press release. October 15, 2014. www.fda.gov/NewsEvents/ Newsroom/PressAnnouncements/ucm418994.htm. Accessed February 12, 2015. 12. Ofev (nintedanib) capsules [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; October 2014. 13. Boehringer Ingelheim. Boehringer Ingelheim’s Ofev™ (nintedanib) approved by the FDA for the treatment of idiopathic pulmonary fibrosis. Press release. October 16, 2014. www.boehringer-ingelheim.com/news/news_releases/ press_releases/2014/16_october_2014.html. Accessed February 15, 2015.

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Otezla (Apremilast), an Oral PDE-4 Inhibitor, Receives FDA Approval for the Treatment of Patients with Active Psoriatic Arthritis and Plaque Psoriasis By Loretta Fala, Medical Writer

soriatic arthritis and psoriasis, often referred to as psoriatic diseases, are autoimmune diseases characterized by chronic inflammation, tissue and organ involvement, and the accelerated growth cycle of skin cells. Both psoriatic arthritis and psoriasis impose a substantial physical, emotional, and economic burden on the millions of individuals in the United States who are affected by these conditions.

Psoriatic Arthritis Psoriatic arthritis, a progressive, potentially debilitating type of arthritic inflammation, affects approximately 7 million people in the United States.1,2 The symptoms of psoriatic arthritis, like the symptoms of psoriasis, may flare and subside, varying from person to person.3 In some cases, the arthritis precedes skin disorders. Psoriatic arthritis can affect any joint in the body; it may affect 1 or more joints (eg, 1 or both knees), and it may affect fingers and toes.3 Some patients also develop dactylitis, a condition in which the fingers and toes swell profusely or enthesitis, which is characterized by inflammation of sites at which tendons and ligaments attach to the bone.3 Many patients with psoriatic arthritis are affected by the joint disease and the psoriasis that often accompanies it.4 The chronic pain, fatigue, limitations in physical function, and work disability associated with psoriatic arthritis can have a profound effect on the patient’s health-related quality of life.5 Furthermore, the risk for cardiovascular disease and other comorbidities is greater in patients with psoriatic arthritis and other inflammatory diseases than in individuals without these diseases.2,4 Psoriatic arthritis can also have a substantial impact on a patient’s psychological well-being, because of the itching, pain, and potential for social rejection encountered by many patients.2,4 Psoriatic arthritis imposes a considerable economic burden on patients and society. Based on a 2010 review of the literature, in the United States, direct annual medical costs associated with psoriatic arthritis total nearly $1.9 billion.4 In this review of 49 studies, patients with psoriatic arthritis had a lower health-related quality of life com-

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pared with the general population.4 Moreover, the direct and indirect costs associated with psoriatic arthritis, including lost productivity and disability, increase with worsening disease activity (ie, joint involvement and psoriatic skin lesions) and worsening physical function.4 Evidence shows that persistent inflammation associated with psoriatic arthritis causes joint damage over time. Consequently, early diagnosis of psoriatic arthritis is essential, because early detection and treatment may prevent further damage to the joints.3 The therapeutic goals for patients with psoriatic arthritis are to alleviate symptoms, control inflammation in affected joints, and prevent joint pain and disability.6 Treatment depends on the severity of the disease, the number of joints involved, and the associated skin symptoms.1 During the early stages of psoriatic arthritis, nonsteroidal anti-inflammatory drugs (NSAIDs) and cortisone may be used to manage mild inflammation. For patients with erosive disease or for those in whom NSAIDs fail to work, the disease-modifying antirheumatic drugs (DMARDs), including methotrexate, sulfasalazine, leflunomide, and a number of biologic agents may be used to slow the progression of psoriatic arthritis and spare the joints and other tissues from permanent damage.1,6 Until recently, the US Food and Drug Administration (FDA)-approved treatments for psoriatic arthritis included corticosteroids, several tumor necrosis factor blockers (adalimumab, certolizumab, etanercept, golimumab, infliximab), and an interleukin-12/interleukin-23 inhibitor (ustekinumab).7

Plaque Psoriasis Psoriasis is a chronic, relapsing disease that is characterized by thick patches of inflamed, scaly skin resulting from excessive proliferation of skin cells.8 Affecting an estimated 7.5 million Americans, psoriasis is the most prevalent autoimmune disease in the United States. In many cases, psoriasis can be disfiguring and disabling.8 Psoriasis is categorized as moderate when it involves 3% to 10% of the body and severe when it involves more than 10% of the body.9

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Plaque psoriasis is the most common form of psoriasis and is characterized by raised, red patches covered with a silvery white buildup of dead skin cells or scale. These plaques typically appear on the scalp, knees, elbows, and lower back. They are often painful, and they can crack and bleed.10 Patients with psoriasis have a higher risk for developing psoriatic arthritis, eye disorders, obesity, type 2 diabetes, and hypertension compared with individuals without psoriasis.11 An estimated 15% to 30% of patients with psoriasis will develop psoriatic arthritis.1,3 In addition, patients with psoriasis have a higher risk for cardiovascular disease, Parkinson’s disease, kidney disease, and other autoimmune diseases compared with individuals without psoriasis.11 Psoriasis can have a dramatic impact on patients’ quality of life and self-esteem, and can lead to depression, social isolation, and work-related problems.11 Furthermore, psoriasis imposes a considerable financial burden on patients and on the US healthcare system as a whole. In 2008, the total annual US costs attributed to psoriasis reached $11.25 billion.8 The therapeutic goals for psoriasis include (1) slowing the speed of skin growth to reduce inflammation and plaque formation, and (2) smoothing the skin.11 Topical treatments for psoriasis include topical corticosteroids, vitamin D analogues, anthralin, topical retinoids, calcineurin inhibitors, salicylic acid, and coal tar. Phototherapy with artificial ultraviolet A or ultraviolet B light is sometimes used alone or in combination with other medications. Oral or injectable therapies include methotrexate, retinoids, cyclosporine, and the biologic immunomodulator agents, including several tumor necrosis factor-alpha inhibitors (eg, adalimumab, etanercept, infliximab) and the interleukin-12/interleukin-23 inhibitor (ie, ustekinumab).11,12

Oral Therapy for Psoriatic Arthritis and Plaque Psoriasis On March 21, 2014, the FDA approved apremilast (Otezla; Celgene) for the treatment of adults with active psoriatic arthritis.7 Apremilast, an oral inhibitor of phosphodiesterase (PDE)-4, is the first oral therapy to receive FDA approval for the treatment of adults with active psoriatic arthritis.7,13 According to Curtis Rosebraugh, MD, MPH, Director of the Office of Drug Evaluation II at the FDA Center for

Drug Evaluation and Research, “Relief of pain and inflammation and improving physical function are impor tant treatment goals for patients with active psoriatic arthritis. Otezla provides a new treatment option for patients suffering from this disease.” 7 On September 23, 2014, apremilast received a new indication by the FDA for the treatment of patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy. Apremilast is the first and the only PDE-4 agent approved for the treatment of patients with plaque psoriasis.14 M. Shane Chapman, MD, Section Chief of Dermatology at Dartmouth-Hitchcock Medical Center, stated, “OTEZLA offers an important new treatment option for patients whose symptoms are not adequately improving with their current treatments. In clinical trials, OTEZLA reduced redness, thickness, and scaliness of plaques in patients with moderate or severe plaque psoriasis.” Dr Chapman further commented, “Because the product labeling does not require routine laboratory monitoring, oral OTEZLA may be a welcome new option for patients and physicians looking for a different treatment experience.” 14

Mechanism of Action Apremilast is a small-molecule inhibitor of PDE-4 specific for cyclic adenosine monophosphate (cAMP). Inhibition of PDE-4 results in increased intracellular cAMP levels. The specific mechanism by which apremilast exerts its therapeutic effect in patients with psoriatic arthritis and psoriasis is not well-defined.13 Dosing and Administration To reduce the risk of gastrointestinal symptoms, it is recommended that apremilast be titrated to the recommended dose of 30 mg twice daily, to be taken orally starting on day 6. The recommended initial dosage titration of apremilast from day 1 to day 5 (for both psoriatic arthritis and psoriasis) is shown in Table 1.13 Coadministration of apremilast with food does not alter the extent of absorption of this drug.13 The recommended dose for patients with severe renal impairment is 30 mg once daily. For initial dose titration in these patients, titration should follow the morning schedule in Table 1; the afternoon doses should be skipped.13

Table 1 Apremilast Dosage Titration Schedule for Patients with Psoriatic Arthritis and Psoriasis Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 and beyond am 10 mg

10 mg

20 mg

30 mg

Source: Otezla (apremilast) tablets prescribing information; September 2014.

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Table 2 Apremilast versus Placebo: Patients with Psoriatic Arthritis and ACR Response at Week 16 in 3 Clinical Trials PALACE-1 study PALACE-2 study PALACE-3 study Patients achieving ACR Placebo ± Apremilasta ± Placebo ± Apremilasta ± Placebo ± Apremilasta ± response at DMARDs DMARDs DMARDs DMARDs DMARDs DMARDs week 16 (N = 168) (N = 168) (N = 159) (N = 162) (N = 169) (N = 167) ACR20, %

38b

32b

41b

ACR50, %

ACR70, %

Apremilast 30 mg twice daily. Significantly different from placebo (P <.05). ACR indicates American College of Rheumatology; DMARD, disease-modifying antirheumatic drug. Sources: Otezla (apremilast) tablets prescribing information; September 2014; Kavanaugh A, et al. Ann Rheum Dis. 2014;73:1020-1026; Husni ME. June 14, 2014. a

Apremilast is available in 10-mg, 20-mg, and 30-mg tablets.13

Clinical Trials Psoriatic Arthritis The safety and efficacy of apremilast for the treatment of patients with psoriatic arthritis were demonstrated in 3 multicenter, randomized, double-blind, placebo- controlled clinical trials of similar design.13 In these studies (ie, PALACE-1, PALACE-2, and PALACE-3), a total of 1493 adult patients with active psoriatic arthritis (≥3 swollen joints and ≥3 tender joints) despite previous or current treatment with DMARD therapy were randomized to receive placebo, apremilast 20 mg twice daily, or apremilast 30 mg twice daily.13,15,16 Enrolled patients had a diagnosis of psoriatic arthritis for at least 6 months. The primary end point was the percentage of patients who achieved American College of Rheumatology (ACR) 20 response at week 16.13 An ACR20 is defined as a 20% improvement in tender and swollen joint counts and a 20% improvement in 3 of the 5 remaining ACR core set measures (ie, patient and physician global assessments, pain, disability, others).17 An ACR50 represents a 50% improvement in both measures; an ACR70, a 70% improvement in both measures.17 In these studies, placebo-controlled efficacy data were also collected and analyzed through week 24.13 If patients’ tender and swollen joint counts had not improved by at least 20%, they were considered nonresponders at week 16. Placebo nonresponders were rerandomized 1:1 in a blinded fashion to either apremilast 20 mg twice daily or 30 mg twice daily, after titration. Patients receiving apremilast continued their initial treatment. At week 24, all remaining patients receiving placebo were rerandomized to either 20 mg twice daily or to 30 mg twice daily.13 Patients enrolled across the 3 clinical studies had a median duration of psoriatic arthritis disease of 5 years, with a variety of psoriatic arthritis subtypes, including

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symmetric polyarthritis (62%), asymmetric oligoarthritis (27%), distal interphalangeal joint arthritis (6%), arthritis mutilans (3%), and predominant spondylitis (2.1%).13 Patients received concomitant therapy with at least 1 DMARD (65%), methotrexate (55%), sulfasalazine (9%), leflunomide (7%), low-dose oral corticosteroids (14%), and NSAIDs (71%). Previous treatment with small-molecule DMARDs was reported in only 76% of patients, and previous treatment with biologic DMARDs was reported in 22% of patients, including 9% who failed previous biologic DMARD treatment.13 The proportion of patients who achieved a clinical response (ie, ACR20, ACR50, or ACR70 responses) in the PALACE 1, PALACE 2, and PALACE 3 studies are shown in Table 2.13 Patients receiving apremilast with or without DMARDs showed a greater improvement in signs and symptoms of psoriatic arthritis compared with placebo with or without DMARDs as demonstrated by the proportion of patients who achieved an ACR20 response at week 16.13 Apremilast 30 mg twice daily also demonstrated improvement for each ACR component versus placebo at week 16 in the PALACE-1 study, as shown in Table 3.15 These results from the PALACE-1 trial were consistent with those observed in the PALACE-2 and PALACE-3 trials.13 In the PALACE-1 study, apremilast 30 mg twice daily also showed a greater improvement in mean change from baseline for the health assessment questionnaire disability index (HAQ-DI) score at week 16 compared with the placebo group. The proportions of HAQ-DI responders (≥0.3 improvement from baseline) at week 16 were 38% for the apremilast (30 mg twice daily) group compared with 27% for the placebo group. Consistent results were observed in studies PALACE-2 and PALACE-3.13,15 Treatment with apremilast demonstrated improvement in dactylitis and enthesitis in patients with preexisting dactylitis or enthesitis.13

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Patients with Psoriatic Arthritis: Mean Change in Table 3 ACR Components with Apremilast, at Week 16 of the PALACE-1 Study Placebo Apremilast 30 mg ACR component (N = 168) twice daily (N = 168) Number of tender jointsa Sample size, N Baseline

Mean change at week 16

166

164

–2

–7

166

164

Number of swollen joints

Sample size, N Baselinec Mean change at week 16

–2

–5

Patient’s assessment of pain (VAS)

Sample size, N

165

Baseline

Mean change at week 16

159

–6

–14

Patient’s global assessment of disease activity (VAS)d Sample size, N Baseline

Mean change at week 16

165

159

–3

–10

Physician’s global assessment of disease activity

Sample size, N

158

159

Baseline

Mean change at week 16b

–8

–19

165

159

1.2

–0.09

–0.2

Sample size, N

166

167

Baselinef

1.1

0.8

Mean change at week 16a

0.1

–0.1

HAQ-DI scoree Sample size, N Baseline

Mean change at week 16

C-reactive protein

Scale, 0-78. Mean changes from baseline are least square means from analyses of covariance. c Scale, 0-76. d 0 = best; 100 = worst. e 0 = best; 3 = worst; the HAQ-DI measures the subject’s ability to perform daily activities. f Reference range, 0-0.5 mg/dL. ACR indicates American College of Rheumatology; HAQ-DI, health assessment questionnaire disability index; VAS, visual analog scale. Sources: Otezla (apremilast) tablets prescribing information; September 2014; Kavanaugh A, et al. Ann Rheum Dis. 2014;73:1020-1026. a

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Psoriasis The safety and efficacy of apremilast for the treatment of patients with plaque psoriasis were evaluated in 2 multicenter, randomized, double-blind, placebo- controlled clinical trials—ESTEEM-1 and ESTEEM-2.18,19 These studies included a total of 1257 patients aged ≥18 years with moderate to severe plaque psoriasis, as determined by body surface area involvement of ≥10%; static Physicians’ Global Assessment (sPGA) score of ≥3 (moderate or severe disease); Psoriasis Area and Severity Index (PASI) score ≥12; and candidates for phototherapy or systemic therapy. Patients were allowed to use low- potency topical corticosteroids on the face, axilla, and groin; patients with scalp psoriasis were allowed to use coal tar shampoo and/or salicylic acid scalp preparations on scalp lesions.13 In both studies, patients were randomized in a 2:1 ratio to apremilast 30 mg twice daily or to placebo for 16 weeks. Both studies assessed the proportion of patients who achieved PASI-75 at week 16 and those who achieved an sPGA score of clear (0) or almost clear (1) at week 16.13 Across both studies, the patients’ median was 46 years (range, 18-83 years).13 The mean baseline body surface area involvement was 25.19% (median, 21.0%), the mean baseline PASI score was 19.07 (median, 16.80), and the proportions of patients with sPGA score of 3 (moderate) and 4 (severe) at baseline were 70.0% and 29.8%, respectively. A total of 18% of patients had a history of psoriatic arthritis. Approximately 30% of all patients had received previous phototherapy, and 54% of patients had received previous conventional systemic and/or biologic therapy for the treatment of psoriasis (ie, 37% received previous conventional systemic therapy, and 30% received previous biologic therapy). Approximately 33% of patients had not received previous phototherapy, conventional systemic or biologic therapy.13 The proportion of patients who achieved PASI-75 responses and sPGA score of clear or almost clear are presented in Table 4.13 ESTEEM-1 clinical trial. A total of 844 patients were enrolled in the ESTEEM-1 clinical trial.18 At 16 weeks, significantly more patients who received apremilast achieved a PASI-75 compared with placebo (33.1% vs 5.3%, respectively; P <.001).18 Furthermore, significantly more patients who received apremilast (21.7%) achieved an sPGA score of clear or almost clear compared with placebo (3.9%).13 ESTEEM-2 clinical trial. A total of 411 patients were enrolled in the ESTEEM-2 clinical trial.19 At week 16, significantly more patients who received apremilast achieved a PASI-75 compared with placebo (28.8% vs

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premilast versus Placebo: Clinical Response in Patients with Plaque Psoriasis at Week 16 in the ESTEEM-1 Table 4 A and ESTEEM-2 Clinical Trials ESTEEM-1 ESTEEM-2 Apremilast 30 mg Apremilast 30 mg Placebo, N (%) twice daily, N (%) Placebo, N (%) twice daily, N (%) Clinical response (N = 282) (N = 562) (N = 137) (N = 274) PASI -75

15 (5.3)

186 (33.1)

8 (5.8)

79 (28.8)

sPGA of clear or almost clear

11 (3.9)

122 (21.7)

6 (4.4)

56 (20.4)

PASI indicates Psoriasis Area and Severity Index; sPGA, static Physician Global Assessment. Sources: Otezla (apremilast) tablets prescribing information; September 2014; Papp K, et al. J Am Acad Dermatol. 2014;70 (5 suppl 1). Abstract P8359; Paul C, et al. J Am Acad Dermatol. 2014;70(5 suppl 1). Abstract P8412.

5.8%, respectively; P <.001).19 In addition, significantly more patients who received apremilast achieved an sPGA of clear or almost clear compared with placebo (20.4% vs 4.4%, respectively; P <.001).19 The median time to loss of PASI-75 response among the patients who were rerandomized to placebo at week 32 during the randomized treatment withdrawal phase was 5.1 weeks.13

Safety In the psoriatic arthritis clinical trials, the most common adverse reactions associated with apremilast and occurring in ≥5% of patients were nausea (8.9%), diarrhea (7.7%), and headache (5.9%). In addition, upper respiratory tract infections were reported in 3.9% of patients and vomiting in 3.2%.13 The most common reasons leading to treatment discontinuation with apremilast among patients with psoriatic arthritis were diarrhea (1.8%), nausea (1.8%), and headache (1.2%).13 In clinical trials, the proportion of patients with psoriatic arthritis who discontinued treatment because of any adverse reaction was 4.6% for patients taking apremilast 30 mg twice daily and 1.2% for patients who received a placebo.13 In the plaque psoriasis clinical trials, the most common adverse reactions associated with apremilast (occurring in ≥5% of patients) were diarrhea (17%), nausea (17%), upper respiratory tract infection (9%), tension headache (8%), and headache (6%).13 The most frequently reported reasons for the discontinuation of apremilast were nausea (1.6%), diarrhea (1.0%), and headache (0.8%).13 Contraindications Apremilast is contraindicated in patients with a known hypersensitivity to apremilast or to any of the excipients in the formulation.13 Drug Interactions Use of apremilast with strong cytochrome P450 en-

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zyme inducers (eg, rifampin, phenobarbital, carbamazepine, phenytoin) is not recommended, because it may result in a loss of efficacy of apremilast.13

Warnings and Precautions Depression. Patients should be advised of the potential emergence or worsening of depression, suicidal thoughts, or other mood changes. The risks and benefits of treatment with apremilast should be weighed carefully in patients with a history of depression and/or suicidal thoughts or behavior.13 Weight loss. The patient’s weight should be monitored regularly. If unexplained or clinically significant weight loss occurs, discontinuation of apremilast should be considered.13 Use in Specific Populations Pregnancy. Adequate and well-controlled studies with apremilast have not been conducted in pregnant women. Apremilast should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus.13 Nursing mothers. It is not known whether apremilast or its metabolites are present in human milk. However, because many drugs are present in human milk, use caution when apremilast is administered to a nursing woman.13 Pediatric use. The safety and efficacy of apremilast in patients aged <18 years have not been established.13 Geriatric use. In the psoriatic arthritis clinical trials and in the plaque psoriases clinical trials, no overall differences were observed between older patients (aged ≥65 years) and younger patients.13 Severe renal impairment. Increased systemic exposure of apremilast has been observed in patients with severe renal impairment; the dose of apremilast should be reduced to 30 mg once daily in patients with severe renal impairment.13 Hepatic impairment. No dose adjustment is necessary in patients with hepatic impairment.13

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Conclusion The FDA approval of apremilast marks the availability of the first oral option for the treatment of patients with active psoriatic arthritis and the first PDE-4 inhibitor for the treatment of patients with moderate to severe plaque psoriasis. The option of an oral therapy adds convenience for patients and can also be important for patients who are unable or unwilling to use other treatment options. The safety and efficacy of apremilast for the treatment of patients with psoriatic arthritis were demonstrated in 3 randomized, double-blind, placebo-controlled clinical trials. In all 3 studies, significantly more patients who received apremilast achieved an ACR20 response at

The FDA approval of apremilast marks the availability of the first oral option for the treatment of patients with active psoriatic arthritis and the first PDE-4 inhibitor for the treatment of patients with moderate to severe plaque psoriasis. week 16 compared with those receiving a placebo. Treatment with apremilast 30 mg twice daily also resulted in improvement for each ACR component, including tender joints, swollen joints, and physical function. Patients with plaque psoriasis who received apremilast showed significant and clinically meaningful improvements in PASI scores at week 16. In addition, these studies demonstrated clinical improvement, as measured by sPGA scores of clear to almost clear. n

References

1. Cleveland Clinic Foundation. Psoriatic arthritis. http://my.clevelandclinic. org/orthopaedics-rheumatology/diseases-conditions/hic-psoriatic-arthritis.aspx. Accessed October 29, 2014. 2. National Institutes of Health. Psoriasis. Fact sheet. Updated October 2010.

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http://report.nih.gov/NIHfactsheets/Pdfs/Psoriasis%28NIAMS%29.pdf. Accessed October 29, 2014. 3. Emery P, Ash Z; for the American College of Rheumatology. Psoriatic arthritis. Updated September 2012. www.rheumatology.org/Practice/Clinical/Patients/ Diseases_And_Conditions/Psoriatic_Arthritis/. Accessed November 5, 2014. 4. 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. 5. Armstrong AW, Schupp C, Wu J, Bebo B. Quality of life and work productivity impairment among psoriasis patients: findings from the National Psoriasis Foundation survey data 2003–2011. PLoS One. 2012;7:e52935. 6. Mayo Clinic staff. Diseases and conditions: psoriatic arthritis: treatment and drugs. January 29, 2014. www.mayoclinic.org/diseases-conditions/psoriatic- arthritis/basics/treatment/con-20015006. Accessed May 1, 2014. 7. US Food and Drug Administration. FDA approves Otezla to treat psoriatic arthritis. Press release. March 21, 2014. www.fda.gov/newsevents/newsroom/ pressannouncements/ucm390091.htm. Accessed October 29, 2014. 8. National Psoriasis Foundation. Psoriasis and comorbid conditions issue brief: executive summary. January 2012. www.psoriasis.org/document.doc?id=793. Accessed October 30, 2014. 9. National Psoriasis Foundation. Psoriasis severity. www.psoriasis.org/about- psoriasis/treatments/severity. Accessed November 6, 2014. 10. National Psoriasis Foundation. Plaque psoriasis. www.psoriasis.org/about- psoriasis/types/plaque. Accessed March 6, 2015. 11. Mayo Clinic staff. Diseases and conditions: psoriasis. April 11, 2014. www. mayoclinic.org/diseases-conditions/psoriasis/basics/definition/con-20030838. Accessed November 5, 2014. 12. National Psoriasis Foundation. Moderate to severe psoriasis: biologic drugs. www.psoriasis.org/about-psoriasis/treatments/biologics. Accessed November 5, 2014. 13. Otezla (apremilast) tablets [prescribing information]. Summit, NJ: Celgene Corporation; September 2014. 14. Celgene Corporation. Oral Otezla (apremilast) approved by the U.S. Food and Drug Administration for the treatment of patients with moderate to severe plaque psoriasis. Press release. September 23, 2014. http://ir.celgene.com/release detail.cfm?releaseid=872240. Accessed October 29, 2014. 15. Kavanaugh A, Mease PJ, Gomez-Reino JJ, et al. Treatment of psoriatic arthritis in a phase 3 randomised, placebo-controlled trial with apremilast, an oral phosphodiesterase 4 inhibitor. Ann Rheum Dis. 2014;73:1020-1026. 16. Husni ME. American College of Rheumatology. Apremilast for the treatment of psoriatic arthritis. June 14, 2014. www.rheumatology.org/Publications/Hot line/Apremilast_for_the_Treatment_of_Psoriatic_Arthritis/. Accessed October 30, 2014. 17. 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. 18. Papp K, Griffiths C, Leonardi C, et al. Apremilast, an oral phosphodiesterase 4 inhibitor, in patients with moderate to severe psoriasis: results from the randomized treatment withdrawal phase of a phase 3, randomized, controlled trial (ESTEEM 1). J Am Acad Dermatol. 2014;70(5 suppl 1). Abstract P8359. 19. Paul C, Crowley J, Cather J, et al. Apremilast, an oral phosphodiesterase 4 inhibitor, in patients with moderate to severe psoriasis: 16-week results of a phase 3, randomized, controlled trial (ESTEEM 2). J Am Acad Dermatol. 2014;70 (5 suppl 1). Abstract P8412.

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Sivextro (Tedizolid Phosphate) Approved for the Treatment of Adults with Acute Bacterial Skin and SkinStructure Infections By Loretta Fala, Medical Writer

n acute bacterial skin and skin-structure infection (ABSSSI) is a bacterial infection of the skin with a lesion size of ≥75 cm2, which is measured by the area of redness, edema, or induration.1 The types of infections that comprise ABSSSIs include cellulitis or erysipelas, major cutaneous abscesses, and wound infections1; these infections can be life-threatening and may require hospitalization and surgery.2 Streptococcus pyogenes and Staphylococcus aureus, including methicillin-resistant S aureus (MRSA), are the most common bacterial pathogens responsible for ABSSSIs. The less common ABSSSI-causing pathogens include other Streptococcus species, Enterococcus faecalis, and gram-negative bacteria.1 In the United States, more than 2 million individuals are infected with antibiotic-resistant bacteria annually, and at least 23,000 die annually as a direct result of these infections.3 Cellulitis, a skin infection that is primarily attributed to streptococci, is most often caused by Streptococcus and Staphylococcus; however, the incidence of MRSA as the cause of cellulitis is increasing.4 The prevalence rate of leg erysipelas or cellulitis, which can occur anywhere on the body but usually affects the lower leg, is estimated to be more than 1 per 1000 persons annually.5 S aureus, particularly MRSA, is associated with major health complications and mortality. Furthermore, S aureus infections are particularly challenging to treat because of their potential for resistance to antimicrobial drugs.6 In addition, S aureus imposes a substantial economic burden on patients and on hospitals. In intensive care units, an estimated 59.5% to 64.4% of S aureus strains are methicillin-resistant.6 A study sponsored by the Centers for Disease Control and Prevention (CDC) showed that S aureus–related hospitalizations increased 62% between 1999 and 2005, and MRSA-related hospitalizations more than doubled during this period.6 Furthermore, S aureus–related deaths averaged 10,800 and MRSA-related deaths averaged 5500 annually.6 Most MRSA infections involve ABSSSI.7 MRSA continues to be a major public health concern in the United

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States. According to the CDC, an estimated 75,309 individuals in the United States are infected with invasive MRSA infections annually.8 Despite its high incidence, life-threatening, hospital-acquired MRSA infections declined 54% between 2005 and 2011, with 9000 fewer MRSA-associated deaths among hospitalized patients in 2011 than in 2005.8 Recent evidence indicates that community-acquired MRSA strains are spreading into healthcare institutions.9 Consequently, there is an urgent need to reduce the inappropriate use of antimicrobial agents and to increase awareness about MRSA in the community setting, including in daycare centers, schools, and environments with at-risk individuals (eg, the elderly, immunodeficient persons).6,9 More expensive to treat than susceptible infections, antimicrobial drug-resistant infections are associated with a 30% to 100% increase in mortality, illness, and direct costs.10 In a study that assessed 1,472,965 hospitalization episodes, of which 23,026 had skin and skin-structure infections as a secondary diagnosis, patients with skin and skin-structure infections had significantly (5 days) longer hospital stays, a higher mortality rate (5.4% vs 3.5%, respectively), and higher (excess of >$21,000) hospital costs compared with matched controls.11 The management of ABSSSIs presents several challenges. For example, aside from its link to drugresistant gram-positive pathogens, an ABSSSI often requires antimicrobial or antibiotic therapy. Antibiotic resistance and adverse effects may limit the use of some antibiotic agents—factors that underscore the need for novel therapies to help combat drug-resistant pathogens.2,7

Tedizolid Phosphate: A New Treatment Option for ABSSSIs On June 20, 2014, the US Food and Drug Administration (FDA) approved tedizolid phosphate (Sivextro; Cubist Pharmaceuticals) for the treatment of adults with an ABSSSI that is caused by designated susceptible bacteria.12 To reduce the development of drug-resistant bacteria

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and maintain the effectiveness of tedizolid phosphate and other antibacterial drugs, tedizolid phosphate should only be used to treat or to prevent infections that are proved or strongly suspected to be caused by bacteria.12,13 According to Edward Cox, MD, MPH, Director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research, “Today’s approval provides physicians and patients with a new treatment option for serious skin infections.”12 Barbara Murray, MD, Professor and Director of the Division of Infectious Diseases, University of Texas Health Science Center Medical School, Houston, and President of the Infectious Diseases Society of America, commented that this news is “encouraging.” She added,

Based on its designation as a qualified infectious disease drug for the treatment of serious or life-threatening infections, tedizolid phosphate was also granted an additional 5-year exclusivity period in addition to its currently specified exclusivity period. “We still have a great deal more work to do to combat antibiotic resistance and ensure we have the tools necessary to help the patients who need it the most.”14 Tedizolid phosphate was approved by the FDA under its expedited review process. Based on its designation as a qualified infectious disease drug for the treatment of serious or life-threatening infections, tedizolid phosphate was also granted an additional 5-year exclusivity period in addition to its currently specified exclusivity period.12

Dosing and Administration Tedizolid phosphate is available in 2 dosage forms—as a 200-mg, sterile, lyophilized powder in a single-use vial for reconstitution for intravenous (IV) infusion, and as a 200-mg tablet.13 The oral tablet of tedizolid phosphate is administered once daily for 6 days, and the IV infusion is administered once daily for 1 hour for a duration of 6 days.13 Mechanism of Action Tedizolid phosphate is the prodrug of tedizolid, which is a member of the oxazolidinone class of antibacterial agents.13 Tedizolid’s antibacterial activity is mediated by binding to the 50S subunit of the bacterial ribosome, resulting in the inhibition of protein synthesis. Tedizolid inhibits bacterial protein synthesis through a mechanism of action different from that of other nonoxazolidinone classes of antibacterial drugs; therefore, cross-resistance

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between tedizolid and other classes of antibacterial drugs is unlikely. The results of in vitro time-kill studies show that tedizolid is bacteriostatic against enterococci, staphylococci, and streptococci.13

Key Clinical Studies The safety and efficacy of tedizolid phosphate were evaluated in 2 multicenter, multinational, double-blind, noninferiority clinical trials that involved 1315 adults with ABSSSIs.2,15 In both studies, tedizolid 200 mg once daily for 6 days was compared with linezolid 600 mg every 12 hours for 10 days. Patients with cellulitis or erysipelas, major cutaneous abscess, or wound infection were enrolled in the clinical trials. Patients with wound infections could have received aztreonam and/or metronidazole as adjunctive therapy for gram-negative bacterial coverage, if needed. The intent-to-treat (ITT) patient population included all randomized patients.2,15 The ESTABLISH-1 Clinical Trial The ESTABLISH-1 clinical trial (Trial 1) showed that tedizolid phosphate 200 mg once daily for 6 days was noninferior to linezolid 600 mg every 12 hours for 10 days in early clinical response (ie, 48-72 hours after initial treatment for an ABSSSI), indicating that tedizolid phosphate may be a useful alternative to linezolid for appropriate patients.2,13 In Trial 1, patients received oral tedizolid phosphate. A total of 323 patients with ABSSSI were randomized to tedizolid phosphate, and 326 patients were randomized to linezolid. The majority (91%) of the patients who received tedizolid phosphate were aged <65 years; the median age was 43 years. In these patients, the overall median surface area of infection was 190 cm2.2,13 The infection types included cellulitis or erysipelas (40%), wound infection (30%), and major cutaneous abscess (30%). In addition to the local signs and symptoms of infection, patients were also required to have at least 1 regional or systemic sign of infection at baseline, defined as lymphadenopathy (87% of patients), a temperature of ≥38°C (16%), a white blood cell (WBC) count of >10,000 cells/mm3 or <4000 cells/mm3 (43%), or ≥10% band forms on a WBC differential (4%).2,13 The primary end point of the study was early clinical response, defined as no increase from the baseline lesion area at 48 to 72 hours after the first dose of tedizo lid phosphate and an oral temperature of ≤37.6°C, to be confirmed by a second temperature measurement within 24 hours in the ITT population.2,13 The key findings from Trial 1 are shown in Table 1. The ESTABLISH-2 Clinical Trial In the ESTABLISH-2 clinical trial (Trial 2), tedizolid

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Table 1 E arly Clinical Response in the ITT Patient Population: Tedizolid Phosphate versus Linezolid (Trials 1 and 2) Tedizolid Treatment difference Patients/responders phosphate 200 mg Linezolid 1200 mg (2-sided 95% CI) No increase in lesion surface area from baseline and oral temperature of ≤37.6°C, confirmed by a second temperature measurement within 24 hrs at 48-72 hrsa Trial 1, N • Responders, N (%) Trial 2, N • Responders, N (%)

323

326

256 (79.3)

258 (79.1)

332

334

286 (86.1)

281 (84.1)

0.1 (–6.2 to 6.3)

2.0 (–3.5 to 7.3)

≥20% decrease from baseline in lesion area at 48-72 hrs

Trial 1, N • Responders, N (%) Trial 2, N • Responders, N (%)

323

326

252 (78.0)

246 (75.5)

332

334

283 (85.2)

276 (82.6)

2.6 (–4.0 to 9.1)

2.6 (–3.0 to 8.2)

Primary end point for Trial 1; sensitivity analysis for Trial 2. Primary end point for Trial 2; sensitivity analysis for Trial 1. CI indicates confidence interval; ITT, intent-to-treat. Source: Sivextro (tedizolid phosphate) prescribing information; June 2014. a

Table 2 C linical Response at Posttherapy Evaluation: Tedizolid Phosphate versus Linezolid (Trials 1 and 2) Tedizolid phosphate Linezolid Treatment difference Patient population, by trial 200 mg, n/N (%) 1200 mg, n/N (%) (2-sided 95% CI) Trial 1 Intent-to-treat

277/323 (85.8)

279/326 (85.6)

0.2 (–5.3 to 5.6)

Clinically evaluable

257/270 (95.2)

260/273 (95.2)

–0.0 (–3.9 to 3.7)

Intent-to-treat

292/332 (88.0)

293/334 (87.7)

0.3 (–4.8 to 5.3)

Clinically evaluable

268/290 (92.4)

269/280 (96.1)

–3.7 (–7.7 to 0.2)

Trial 2

CI indicates confidence interval. Source: Sivextro (tedizolid phosphate) prescribing information; June 2014.

phosphate 200 mg for 6 days was shown to be noninferior to twice-daily linezolid 600 mg for 10 days, demonstrating that tedizolid phosphate may be a useful therapeutic option for the treatment of an ABSSSI in the hospital and the outpatient settings.13,15 In Trial 2, patients could have received oral tedizolid phosphate therapy after a minimum of 1 day of IV tedizolid phosphate therapy. A total of 332 patients with an ABSSSI were randomized to tedizolid phosphate, and 334 patients were randomized to linezolid. The majority (87%) of the patients who received tedizolid phosphate were aged <65 years; the median age was 46 years. The patients’ overall median surface area of infection was 231 cm2.13,15 The infection types included cellulitis or erysip elas (50%), wound infection (30%), and major cutaneous ab-

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scess (20%). In addition to the local signs and symptoms of infection, patients were also required to have at least 1 regional or systemic sign of infection at baseline, defined as lymphadenopathy (71% of patients), temperature of ≥38°C (31%), WBC count of >10,000 cells/mm3 or <4000 cells/mm3 (53%), or ≥10% band forms on a WBC differential (16%).13,15 The primary end point of this study was early clinical response, which was defined as a ≥20% decrease from the baseline lesion area at 48 to 72 hours after the first dose in the ITT population.13,15 The key findings from Trial 2 are also shown in Table 1.

Investigator Assessment of Clinical Response An investigator assessment of clinical response was conducted at the posttherapy evaluation (ie, 7-14 days

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Table 3 Early Clinical Response by Baseline Pathogen in the MITT Population: Tedizolid Phosphate versus Linezolid (Trials 1 and 2) No increase in lesion surface area from baseline and oral temperature of ≤37.6°Ca

≥20% decrease from baseline in lesion areab

Tedizolid phosphate 200 mg, n/N (%)c

Linezolid 1200 mg, n/N (%)

Tedizolid phosphate 200 mg, n/N (%)c

Linezolid 1200 mg, n/N (%)

Staphylococcus aureus

274/327 (83.8)

276/339 (81.4)

279/327 (85.3)

273/339 (80.5)

• MRSA

111/140 (79.3)

112/144 (77.8)

114/140 (81.4)

109/144 (75.7)

• Methicillin-susceptible S aureus

163/187 (87.2)

166/197 (84.3)

165/187 (88.2)

166/197 (84.3)

Streptococcus pyogenes

27/33 (81.8)

18/20 (90.0)

25/33 (75.8)

16/20 (80.0)

Streptococcus anginosus

22/30 (73.3)

26/28 (92.9)

22/30 (73.3)

25/28 (89.3)

Streptococcus agalactiae

6/9 (66.7)

8/10 (80.0)

6/9 (66.7)

7/10 (70.0)

Enterococcus faecalis

7/10 (70.0)

3/4 (75.0)

6/10 (60.0)

1/4 (24.0)

Baseline pathogen

NOTE: Pooled analysis: n = number of patients in the specific category; N = number of patients with the specific pathogen isolated from the ABSSSI population. a Primary end point of Trial 1. b Primary end point of Trial 2. c Baseline bacteremia in the tedizolid arm with relevant pathogens included 2 patients with MRSA, 4 patients with methicillin-sensitive S aureus, 2 patients with S pyogenes, and 1 patient with Streptococcus constellatus; all of these patients were responders at 48 to 72 hours. ABSSSI indicates acute bacterial skin and skin-structure infection; MITT, microbiologic intent-to-treat; MRSA, methicillinresistant S aureus. Source: Sivextro (tedizolid phosphate) prescribing information; June 2014.

after the end of therapy) in the ITT population and in the clinically evaluable population. Clinical success was defined as the resolution or near resolution of most disease-specific signs and symptoms; the absence or near resolution of systemic signs of infection if present at baseline (eg, lymphadenopathy, fever, >10% immature neutrophils, abnormal neutrophils, abnormal WBC count); and no new signs, symptoms, or complications attributable to an ABSSSI that would require further treatment of the primary lesion (Table 2).2,13,15

Clinical Success, by Baseline Pathogens Early clinical response by baseline pathogens from the primary infection site or blood cultures for the microbiologic ITT patient population in Trials 1 and 2 are shown in Table 3.2,13,15 Adverse Events The most common (≥2%) adverse reactions associated with tedizolid phosphate are nausea, headache, diarrhea, vomiting, and dizziness.13 Tedizolid phosphate has no contraindications. Warnings and Precautions Patients with neutropenia. The safety and efficacy of tedizolid phosphate in patients with neutropenia (ie,

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neutrophil counts of <1000 cells/mm3) have not been adequately evaluated. In an animal model of infection, the antibacterial activity of tedizolid was reduced in the absence of granulocytes. An alternative therapy should be considered in patients with neutropenia.13 Clostridium difficile–associated diarrhea. Treatment with antibacterial agents can alter the normal flora of the colon and may permit overgrowth of C difficile, which contributes to the development of C difficile– associated diarrhea (CDAD). Patients who present with diarrhea after taking antibiotics should be evaluated for CDAD. If CDAD is suspected or confirmed, antibacterial medications not directed against C difficile should be discontinued, if possible. Appropriate measures should be instituted as clinically indicated.13

Use in Specific Populations Pregnancy. No adequate and well-controlled studies were conducted with tedizolid phosphate in pregnant women. Tedizolid phosphate should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.13 Nursing mothers. It is not known whether tedizolid phosphate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when tedizolid phosphate is administered to a

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nursing woman.13 Pediatric use. The safety and effectiveness of tedizo lid phosphate in pediatric patients aged <18 years have not been established.13 Geriatric use. Clinical studies of tedizolid phosphate did not include sufficient numbers of patients aged ≥65 years to determine whether they respond different from younger patients. No overall differences in pharmacokinetics were observed between elderly patients and younger patients.13

Based on its early and sustained clinical response, tedizolid phosphate was shown to be as effective as linezolid for the treatment of an ABSSSI. Tedizolid phosphate is available as an injection for IV use and in tablet form for oral administration. Conclusion A new treatment option for ABSSSIs became available in June 2014 when the FDA approved tedizolid phosphate. The safety and efficacy of tedizolid phosphate were evaluated in 2 clinical trials that involved 1315 patients with an ABSSSI. Based on its early and sustained clinical response, tedizolid phosphate was shown to be as effective as linezolid for the treatment of an ABSSSI. Tedizolid phosphate is available as an injection for IV use and in tablet form for oral administration. The most common adverse reactions

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associated with tedizolid treatment include nausea, headache, diarrhea, vomiting, and dizziness. n

References

1. Center for Drug Evaluation and Research. Guidance for industry. Acute bacterial skin and skin structure infections: developing drugs for treatment. October 2013. www.fda.gov/downloads/Drugs/.../Guidances/ucm071185.pdf. Accessed July 22, 2014. 2. Prokocimer P, De Anda C, Fang E, et al. Tedizolid phosphate vs linezolid for treatment of acute bacterial skin and skin structure infections: the ESTABLISH-1 randomized trial. JAMA. 2013;309:559-569. 3. Centers for Disease Control and Prevention. Antibiotic resistance threats in the United States, 2013. Updated June 2, 2014. www.cdc.gov/drugresistance/threat- report-2013/pdf/ar-threats-2013-508.pdf. Accessed July 22, 2013. 4. Mayo Clinic staff. Diseases and conditions: cellulitis. February 23, 2012. www.mayo clinic.org/diseases-conditions/cellulitis/basics/causes/con-20023471?p=1. Accessed July 23, 2014. 5. Gabillot-Carré M, Roujeau J-C. Acute bacterial skin infections and cellulitis. Curr Opin Infect Dis. 2007;20:118-123. 6. Klein E, Smith DL, Laxminarayan R. Hospitalizations and deaths caused by methicillin-resistant Staphylococcus aureus, United States, 1999-2005. Emerg Infect Dis. 2007;13:1840-1846. 7. O’Riordan W, Green S, Mehra P, et al. Tedizolid phosphate for the management of acute bacterial skin and skin structure infections: efficacy summary. Clin Infect Dis. 2014;58(suppl 1):S43-S50. 8. Centers for Disease Control and Prevention. Methicillin-resistant Staphylococcus aureus (MRSA) infections: MRSA tracking. Updated April 30, 2014. www.cdc.gov/ mrsa/tracking/index.html. Accessed July 22, 2014. 9. Carleton HA, Diep BA, Charlebois ED, et al. Community-adapted methicillin- resistant Staphylococcus aureus (MRSA): population dynamics of an expanding community reservoir of MRSA. J Infect Dis. 2004;190:1730-1738. 10. Cosgrove SE, Carmeli Y. The impact of antimicrobial resistance on health and economic outcomes. Clin Infect Dis. 2003;36:1433-1437. 11. Hatoum HT, Akhras KS, Lin S-J. The attributable clinical and economic burden of skin and skin structure infections in hospitalized patients: a matched cohort study. Diagn Microbiol Infect Dis. 2009;64:305-310. 12. US Food and Drug Administration. FDA approves Sivextro to treat skin infections. Press release. June 20, 2014. www.fda.gov/NewsEvents/Newsroom/PressAnnounce ments/ucm402174.htm. Accessed July 3, 2014. 13. Sivextro (tedizolid phosphate) tablet or for injection [prescribing information]. Lexington, MA: Cubist Pharmaceuticals US; June 2014. 14. Smith M. FDA OKs tedizolid for skin infections. June 21, 2014. MedPage Today. www.medpagetoday.com/InfectiousDisease/GeneralInfectiousDisease/46430. Accessed July 22, 2014. 15. Moran GJ, Fang E, Corey GR, et al. Tedizolid for 6 days versus linezolid for 10 days for acute bacterial skin and skin-structure infections (ESTABLISH-2): a randomised, double-blind, phase 3, non-inferiority trial. Lancet Infect Dis. 2014;14:696-705.

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DISCOVERING HOW FAR THERAPY CAN GO IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS Hemorrhage - Fatal bleeding events have occurred in patients treated with IMBRUVICA®. Grade 3 or higher bleeding events (subdural hematoma, gastrointestinal bleeding, hematuria, and post-procedural hemorrhage) have occurred in up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, occurred in approximately half of patients treated with IMBRUVICA®. 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. Grade 3 or greater infections occurred in 14% to 26% of patients. Cases of progressive multifocal leukoencephalopathy (PML) have occurred in patients treated with IMBRUVICA®. Monitor patients for fever and infections and evaluate promptly.

Cytopenias - Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 19 to 29%), thrombocytopenia (range, 5 to 17%), and anemia (range, 0 to 9%) occurred in patients treated with IMBRUVICA®. Monitor complete blood counts monthly. Atrial Fibrillation - Atrial fibrillation and atrial flutter (range, 6 to 9%) have occurred in patients treated with IMBRUVICA®, particularly in patients with cardiac risk factors, acute infections, and a previous history of atrial fibrillation. Periodically monitor patients clinically for atrial fibrillation. Patients who develop arrhythmic symptoms (eg, palpitations, lightheadedness) or newonset dyspnea should have an ECG performed. If atrial fibrillation persists, consider the risks and benefits of IMBRUVICA® treatment and dose modification. Second Primary Malignancies - Other malignancies (range, 5 to 14%) including non-skin carcinomas (range, 1 to 3%) have occurred in patients treated with IMBRUVICA®. The most frequent second primary malignancy was non-melanoma skin cancer (range, 4 to 11%).

IMBRUVICA® (ibrutinib) is the first and only FDA-approved therapy for use in patients with Waldenström’s macroglobulinemia (WM) IMBRUVICA® is approved for use in 4 indications IMBRUVICA® is indicated for the treatment of patients with Mantle cell lymphoma (MCL) who have received at least one prior therapy.

Accelerated approval was granted for this indication based on overall response rate. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials.

Chronic lymphocytic leukemia (CLL) who have received at least one prior therapy. Chronic lymphocytic leukemia with 17p deletion. Waldenström’s macroglobulinemia (WM).

Tumor Lysis Syndrome - Tumor lysis syndrome has been reported with IMBRUVICA® therapy. Monitor patients closely and take appropriate precautions in patients at risk for tumor lysis syndrome (e.g. high tumor burden).

DRUG INTERACTIONS

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.

CYP3A Inducers - Avoid co-administration with strong CYP3A inducers.

ADVERSE REACTIONS The most common adverse reactions (≥25%) in patients with B-cell malignancies (MCL, CLL, WM) were thrombocytopenia, neutropenia, diarrhea, anemia, fatigue, musculoskeletal pain, bruising, nausea, upper respiratory tract infection, and rash. Seven percent of patients receiving IMBRUVICA® discontinued treatment due to adverse events.

CYP3A Inhibitors - Avoid co-administration with strong and moderate CYP3A inhibitors. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA® dose.

SPECIFIC POPULATIONS Hepatic Impairment - Avoid use in patients with moderate or severe baseline hepatic impairment. In patients with mild impairment, reduce IMBRUVICA® dose. Please review the Brief Summary of full Prescribing Information on the following page.

To learn more, visit

www.IMBRUVICA.com © Pharmacyclics, Inc. 2015 © Janssen Biotech, Inc. 2015 1/15 PRC-00770

Brief Summary of Prescribing Information for IMBRUVICA® (ibrutinib) IMBRUVICA® (ibrutinib) capsules, for oral use See package insert for Full Prescribing Information INDICATIONS AND USAGE Mantle Cell Lymphoma: IMBRUVICA is indicated for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. Accelerated approval was granted for this indication based on overall response rate. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials [see Clinical Studies (14.1) in Full Prescribing Information]. Chronic Lymphocytic Leukemia: IMBRUVICA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy [see Clinical Studies (14.2) in Full Prescribing Information]. Chronic Lymphocytic Leukemia with 17p deletion: IMBRUVICA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion [see Clinical Studies (14.2) in Full Prescribing Information]. Waldenström’s Macroglobulinemia: IMBRUVICA is indicated for the treatment of patients with Waldenström’s macroglobulinemia (WM) [see Clinical Studies (14.3) in Full Prescribing Information]. CONTRAINDICATIONS None WARNINGS AND PRECAUTIONS Hemorrhage: Fatal bleeding events have occurred in patients treated with IMBRUVICA. Grade 3 or higher bleeding events (subdural hematoma, gastrointestinal bleeding, hematuria and post procedural hemorrhage) have occurred in up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, occurred in approximately half of patients treated with IMBRUVICA. 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. Grade 3 or greater infections occurred in 14% to 26% of patients. [See Adverse Reactions]. Cases of progressive multifocal leukoencephalopathy (PML) have occurred in patients treated with IMBRUVICA. Monitor patients for fever and infections and evaluate promptly. Cytopenias: Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 19 to 29%), thrombocytopenia (range, 5 to 17%), and anemia (range, 0 to 9%) occurred in patients treated with IMBRUVICA. Monitor complete blood counts monthly. Atrial Fibrillation: Atrial fibrillation and atrial flutter (range, 6 to 9%) have occurred in patients treated with IMBRUVICA, particularly in patients with cardiac risk factors, acute infections, and a previous history of atrial fibrillation. Periodically monitor patients clinically for atrial fibrillation. Patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness) or new onset dyspnea should have an ECG performed. If atrial fibrillation persists, consider the risks and benefits of IMBRUVICA treatment and dose modification [see Dosage and Administration (2.3) in Full Prescribing Information]. Second Primary Malignancies: Other malignancies (range, 5 to 14%) including non-skin carcinomas (range, 1 to 3%) have occurred in patients treated with IMBRUVICA. The most frequent second primary malignancy was non-melanoma skin cancer (range, 4 to 11 %). Tumor Lysis Syndrome: Tumor lysis syndrome has been reported with IMBRUVICA therapy. Monitor patients closely and take appropriate precautions in patients at risk for tumor lysis syndrome (e.g. high tumor burden). 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 or WM, 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] • Cytopenias [see Warnings and Precautions] • Atrial Fibrillation [see Warnings and Precautions] • Second Primary Malignancies [see Warnings and Precautions] • Tumor Lysis Syndrome [see Warnings and Precautions]

IMBRUVICA® (ibrutinib) capsules 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. Clinical Trials Experience: 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. 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. Fatal and serious cases of renal failure have occurred with IMBRUVICA therapy. Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 9% of patients. 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 MCL (N=111) System Organ Class Gastrointestinal disorders

Infections and infestations

General disorders and administrative site conditions Skin and subcutaneous tissue disorders Musculoskeletal and connective tissue disorders Respiratory, thoracic and mediastinal disorders Metabolism and nutrition disorders Nervous system disorders

Preferred Term Diarrhea Nausea Constipation Abdominal pain Vomiting Stomatitis Dyspepsia Upper respiratory tract infection Urinary tract infection Pneumonia Skin infections Sinusitis Fatigue Peripheral edema Pyrexia Asthenia Bruising Rash Petechiae Musculoskeletal pain Muscle spasms Arthralgia Dyspnea Cough Epistaxis Decreased appetite Dehydration Dizziness Headache

All Grades (%) 51 31 25 24 23 17 11

Grade 3 or 4 (%) 5 0 0 5 0 1 0

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

0 3 7 5 1 5 3 1 3 0 3 0 1 0 0 4 0 0 2 4 0 0

Table 2: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Patients with MCL (N=111)

Platelets Decreased Neutrophils Decreased Hemoglobin Decreased

Percent of Patients (N=111) All Grades Grade 3 or 4 (%) (%) 57 17 47 29 41 9

* 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.

IMBRUVICA® (ibrutinib) capsules

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 an open label clinical trial (Study 1) that included 48 patients with previously treated CLL and a randomized clinical trial (Study 2) that included 391 randomized patients with previously treated CLL or SLL. The most commonly occurring adverse reactions in Study 1 and Study 2 (≥ 20%) were thrombocytopenia, neutropenia, diarrhea, anemia, fatigue, musculoskeletal pain, upper respiratory tract infection, rash, nausea, and pyrexia. Approximately five percent of patients receiving IMBRUVICA in Study 1 and Study 2 discontinued treatment due to adverse events. These included infections, subdural hematomas and diarrhea. Adverse events leading to dose reduction occurred in approximately 6% of patients. Study 1: Adverse reactions and laboratory abnormalities from the CLL trial (N=48) using single agent IMBRUVICA 420 mg daily occurring at a rate of ≥ 10% are presented in Tables 3 and 4. Table 3: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with CLL (N=48) in Study 1 System Organ Class Gastrointestinal disorders

Infections and infestations

General disorders and administrative site conditions Skin and subcutaneous tissue disorders Respiratory, thoracic and mediastinal disorders Musculoskeletal and connective tissue disorders Nervous system disorders Metabolism and nutrition disorders Neoplasms benign, malignant, unspecified Injury, poisoning and procedural complications Psychiatric disorders Vascular disorders

Preferred Term

All Grades (%)

Grade 3 or 4 (%)

Diarrhea Constipation Nausea Stomatitis Vomiting Abdominal pain Dyspepsia Upper respiratory tract infection Sinusitis Skin infection Pneumonia Urinary tract infection Fatigue Pyrexia Peripheral edema Asthenia Chills Bruising Rash Petechiae Cough Oropharyngeal pain Dyspnea Musculoskeletal pain Arthralgia Muscle spasms Dizziness Headache Peripheral neuropathy Decreased appetite

63 23 21 21 19 15 13

4 2 2 0 2 0 0

48 21 17 10 10 31 25 23 13 13 54 27 17 19 15 10 27 23 19 21 19 10 17

2 6 6 8 0 4 2 0 4 0 2 0 0 0 0 0 6 0 2 0 2 0 2

Second malignancies*

10*

Laceration

Anxiety Insomnia Hypertension

10 10 17

0 0 8

*One patient death due to histiocytic sarcoma.

Table 4: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Patients with CLL (N=48) in Study 1 Percent of Patients (N=48) All Grades Grade 3 or 4 (%) (%) Platelets Decreased 71 10 Neutrophils Decreased 54 27 Hemoglobin Decreased 44 0 * Based on laboratory measurements per IWCLL criteria and adverse reactions Study 2: Adverse reactions and laboratory abnormalities described below in Tables 5 and 6 reflect exposure to IMBRUVICA with a median duration of 8.6 months and exposure to ofatumumab with a median of 5.3 months in Study 2. Table 5: Non-Hematologic Adverse Reactions ≥ 10% Reported in Study 2

System Organ Class ADR Term Gastrointestinal disorders Diarrhea Nausea Stomatitis* Constipation Vomiting General disorders and administration site conditions Fatigue Pyrexia Infections and infestations Upper respiratory tract infection Pneumonia* Sinusitis* Urinary tract infection Skin and subcutaneous tissue disorders Rash* Petechiae Bruising* Musculoskeletal and connective tissue disorders Musculoskeletal Pain* Arthralgia Nervous system disorders Headache Dizziness Injury, poisoning and procedural complications Contusion Eye disorders Vision blurred

IMBRUVICA (N=195) All Grade Grades 3 or 4 (%) (%)

Ofatumumab (N=191) All Grade Grades 3 or 4 (%) (%)

48 26 17 15 14

4 2 1 0 0

18 18 6 9 6

2 0 1 0 1

28 24

2 2

30 15

2 1

16 15 11 10

1 10 1 4

11 13 6 5

2 9 0 1

24 14 12

3 0 0

13 1 1

0 0 0

28 17

2 1

18 7

1 0

14 11

1 0

6 5

0 0

Subjects with multiple events for a given ADR term are counted once only for each ADR term. The system organ class and individual ADR terms are sorted in descending frequency order in the IMBRUVICA arm. * Includes multiple ADR terms

IMBRUVICA® (ibrutinib) capsules

Table 6: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Study 2

Neutrophils Decreased Platelets Decreased Hemoglobin Decreased

IMBRUVICA (N=195) Grade All 3 or 4 Grades (%) (%) 51 23 52 5 36 0

Ofatumumab (N=191) Grade All 3 or 4 Grades (%) (%) 57 26 45 10 21 0

* Based on laboratory measurements per IWCLL criteria Waldenström’s Macroglobulinemia The data described below reflect exposure to IMBRUVICA in an open label clinical trial that included 63 patients with previously treated WM. The most commonly occurring adverse reactions in the WM trial (≥ 20%) were neutropenia, thrombocytopenia, diarrhea, rash, nausea, muscle spasms, and fatigue. Six percent of patients receiving IMBRUVICA in the WM trial discontinued treatment due to adverse events. Adverse events leading to dose reduction occurred in 11% of patients. Adverse reactions and laboratory abnormalities described below in Tables 7 and 8 reflect exposure to IMBRUVICA with a median duration of 11.7 months in the WM trial. Table 7: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with Waldenström’s Macroglobulinemia (N=63) System Organ Class Gastrointestinal disorders

Skin and subcutaneous tissue disorders General disorders and administrative site conditions Musculoskeletal and connective tissue disorders Infections and infestations

Respiratory, thoracic and mediastinal disorders Nervous system disorders Neoplasms benign, malignant, and unspecified (including cysts and polyps)

All Grades (%) 37 21 16

Grade 3 or 4 (%) 0 0 0

13 22 16 11 21

0 0 0 0 0

Muscle spasms Arthropathy

21 13

0 0

Upper respiratory tract infection Sinusitis Pneumonia* Skin infection* Epistaxis Cough

19 19 14 14 19 13

0 0 6 2 0 0

Dizziness Headache Skin cancer*

14 13 11

0 0 0

Preferred Term Diarrhea Nausea Stomatitis* Gastroesophageal reflux disease Rash* Bruising* Pruritus Fatigue

The system organ class and individual ADR terms are sorted in descending frequency order. * Includes multiple ADR terms. Table 8: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Patients with WM (N=63)

Platelets Decreased Neutrophils Decreased Hemoglobin Decreased

Percent of Patients (N=63) All Grades (%) Grade 3 or 4 (%) 43 13 44 19 13 8

* Based on laboratory measurements.

Postmarketing Experience: The following adverse reactions have been identified during post-approval use of IMBRUVICA. 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. Hypersensitivity reactions including anaphylactic shock (fatal), urticaria, and angioedema have been reported. 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 rifampin, a strong CYP3A inducer, decreased ibrutinib Cmax and AUC by approximately 13- and 10-fold, respectively. 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]. 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 or WM 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 391 patients randomized in Study 2, 61% were ≥ 65 years of age. No overall differences in effectiveness were observed between age groups. Grade 3 or higher adverse events occurred more frequently among elderly patients treated with IMBRUVICA (61% of patients age ≥ 65 versus 51% of younger patients) [see Clinical Studies (14.2) in Full Prescribing Information]. Of the 63 patients treated for WM, 59% 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), and infections (pneumonia and urinary tract infection) occurred more frequently among elderly 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].

IMBRUVICA® (ibrutinib) capsules Hepatic Impairment: Ibrutinib is metabolized in the liver. In a hepatic impairment study, data showed an increase in ibrutinib exposure. Following single dose administration, the AUC of ibrutinib increased 2.7-, 8.2- and 9.8-fold in subjects with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment compared to subjects with normal liver function. The safety of IMBRUVICA has not been evaluated in patients with hepatic impairment. Monitor patients for signs of IMBRUVICA toxicity and follow dose modification guidance as needed. It is not recommended to administer IMBRUVICA to patients with moderate or severe hepatic impairment (Child-Pugh classes B and C) [see Dosage and Administration (2.5) and 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]. Plasmapheresis: Management of hyperviscosity in patients with WM may include plasmapheresis before and during treatment with IMBRUVICA. Modifications to IMBRUVICA dosing are not required. 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, weakness, confusion) suggestive of infection [see Warnings and Precautions]. • Atrial Fibrillation: Counsel patients to report any signs of palpitations, lightheadedness, dizziness, fainting, shortness of breath, and chest discomfort [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]. • Tumor lysis syndrome: Inform patients of the potential risk of tumor lysis syndrome and report any signs and symptoms associated with this event to their healthcare provider for evaluation [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. Advise patients to maintain adequate hydration. 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 registered trademark owned by Pharmacyclics, Inc. © Pharmacyclics, Inc. 2015 © Janssen Biotech, Inc. 2015 PRC-00786

Soolantra (Ivermectin) 1% Cream: A Novel, Antibiotic-Free Agent Approved for the Treatment of Patients with Rosacea By Lisa A. Raedler, PhD, RPh, Medical Writer

osacea is a chronic and progressive skin condition characterized by episodes of remission and exacer bations of its many cutaneous symptoms, including flushing, facial erythema, telangiectasia, edema, papules, pustules, ocular lesions, and rhinophyma.1 Approximately 16 million individuals in the United States are affected by rosacea.2 The incidence of rosacea is increasing with aging.2 Rosacea is more frequently observed in women than in men; however, men with rosacea often have more disfiguring skin changes than women.3 An expert committee of the National Rosacea Soci ety described the 4 clinical subtypes of the disease as (1) erythematotelangiectatic, (2) papulopustular, (3) phy matous, and (4) ocular rosacea.1 Erythematotelangiectat ic rosacea includes flushing and persistent central facial erythema. Papulopustular rosacea is characterized by persistent central facial erythema with transient papules, pustules, or both in a central facial distribution; papulo pustular rosacea is one of the more common subtypes of rosacea and resembles acne vulgaris, without comedones. Phymatous rosacea is characterized by thickening skin, irregular surface nodularities, and enlargement. Ocular rosacea is characterized by symptoms specific to the eye, including watery or bloodshot eyes, foreign body sensa tion in the eye, burning, stinging, dryness, itching, light sensitivity, or lid and periocular erythema.1 The diagnosis of rosacea can be challenging, because it is based on the clinical signs and symptoms; no con firmatory laboratory test is available.3 Furthermore, the etiology of rosacea is not fully understood; the condition is believed to be an inflammatory disorder in the context of an altered immune response.4 The causative elements of rosacea include genetic and environmental factors, such as heat, sunlight, and stress. Digestive tract diseases, infestation with the Demodex mites, epidermal barrier defect, and childhood stye are also believed to affect the immune response and to trig ger the inflammation seen in patients with rosacea.5-7 Various types of Demodex mites may infest the skin of the host, depending on the area of the skin. Human skin may be affected by 2 species of Demodex mites: Demodex folliculorum and Demodex brevis.5 D folliculorum is a para site that resides in the hair follicles, and is especially

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prevalent in papulopustular rosacea. D brevis inhabits the deep part of the skin.5,8 Because the main food sourc es for these mites are epidermal cells and sebum compo nents, they occupy areas that are rich in sebaceous glands, such as the face (especially the nose, cheeks, forehead, and chin).5 The clinical signs and symptoms of rosacea occur pre dominantly in the face.9 The impact of rosacea on the physical appearance of patients has been shown to nega tively affect patients’ emotional well-being, resulting in psychosocial comorbidities such as anxiety disorders, so cial phobias, and depression.10,11 In one National Rosacea Society survey of more than 400 patients with rosacea, 75% of respondents reported that their rosacea had low ered their self-esteem, and approximately 70% reported that rosacea made them feel embarrassed and frustrated.12 Furthermore, more than 50% of the respondents reported they had felt robbed of pleasure or happiness because of their rosacea.12 These findings underline the serious psy chosocial impact of rosacea on patients’ well-being and for the need for treatment of this dermatologic condition. Similar to other chronic skin diseases with variable symptomatology, rosacea requires long-term treatment, and drug selection is often based on anecdotal evidence.7 The topical treatment options for papulopustular rosacea include azelaic acid, benzoyl peroxide, metronidazole, and sodium sulfacetamide/sulfur.7,13 Systemic interven tions include tetracycline and azithromycin. A 2011 Cochrane Review showed that only topical metronida zole, azelaic acid, and doxycycline (40 mg) had some evidence to support their effectiveness in the treatment of patients with moderate-to-severe rosacea.7 In practice, mild cases of papulopustular rosacea are often managed with topical medications alone, whereas moderate-to-severe disease may require systemic therapy to achieve clearance of inflammatory skin lesions.3,14 The inflammatory changes in the skin usually respond to medical therapies and heal without scarring. Conversely, telangiectasias and phymatous changes may require laser or surgical interventions.3 All patients with rosacea should be advised to protect their skin from heat and cold, and to avoid factors that trigger disease exacerba tions and cause skin irritation.3

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Because antibiotics are consistently available and ef fective for many skin conditions, they are susceptible to overuse in the dermatologic setting.15 The potential for antibiotic resistance is an important concern for clini cians who treat patients with rosacea, as well as other conditions, including acne and skin infections.15 Topical rosacea agents offer an alternative to systemic antibiot ics, but vehicle selection can be critical; the choice of a lotion, a cream, a gel, or a foam can influence the medi cation’s efficacy, and the patient’s adherence to and tol erability of the therapeutic agent.4 The cost and efficacy rates of topical and oral thera pies for rosacea vary widely.16 Using published clinical trial data, researchers calculated the cost associated with successful management for 6 different rosacea therapies. The drug cost was combined with office visit costs to estimate the total treatment cost for a 15-week period. Published in 2009, this study showed that metronidazole 1% gel once daily was considerably less expensive than the other 5 branded and generic alternatives.16 The medication cost per treatment success of topical regimens ranged from $60.90 ($205.40 total, including office visits) for metronidazole 1% gel to $152.25 ($296.75 total) for azelaic acid 20% cream twice daily.16 Tetracycline 250 mg daily was the least expensive oral medication for the treatment of patients with rosacea, at $6.30 ($150.80 total) per treatment success.16

FDA Approves Ivermectin 1% Cream for Patients with Rosacea On December 23, 2014, the US Food and Drug Admin istration (FDA) approved ivermectin 1% cream (Sool antra; Galderma Laboratories) for the once-daily treatment of patients with inflammatory lesions of rosacea.17 The FDA approval of ivermectin 1% cream for this indication was based on the results of 2 phase 3 randomized, dou ble-blind, 12-week trials comparing ivermectin 1% cream with vehicle-controlled studies of patients with moder ate-to-severe papulopustular rosacea.17,18 In both studies, ivermectin 1% cream was superior to the vehicle cream. Responding to the FDA’s approval of this new agent, Linda Stein Gold, MD, Director of Clinical Research, Dermatology, Henry Ford Hospital, Detroit, MI, and clinical investigator for the phase 3 clinical trials of iver mectin 1% cream, said, “While some rosacea treatments for the common bumps and pimples of the condition may take more than four weeks to show effect, Soolantra Cream may provide initial results as early as week two.” 17 Mechanism of Action The exact mechanism of action of ivermectin 1% cream in treating rosacea lesions is not known.19 One of the features of this topical agent is that it is not

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an antibiotic, thereby removing the concern of antibiotic resistance that is often associated with antibiotic creams.18,20 Ivermectin 1% cream is a member of the aver mectin class of drugs, and has been used in veterinary medicine as a parenteral parasiticide.21 Ivermectin is also administered orally for the treatment of patients with onchocerciasis (river blindness), and ivermectin has demonstrated efficacy against other worm infestations, indicating that ivermectin has antiparasitic properties.18,22 In immunopharmacologic studies, ivermectin demon strated anti-inflammatory properties, specifically the in hibition of inflammatory cytokine production and the upregulation of interleukin-10 production, an anti- inflammatory cytokine.23

Dosing and Administration Ivermectin 1% cream should be applied once daily to the areas of the face and neck affected by rosacea.19 A pea-size amount should be used for each area with rosa cea lesions, including the forehead, chin, nose, and each cheek. The cream should be spread in a thin layer, taking special precaution to avoid the lips and the eyes.19 Each gram of ivermectin 1% cream contains 10 mg of ivermectin. The drug is supplied in 30-g, 45-g, and 60-g tubes.19 Clinical Trials Two randomized, double-blind, vehicle-controlled clinical trials were conducted to assess the efficacy and safety of ivermectin 1% cream for the treatment of pa tients with inflammatory lesions of rosacea.18,19 These clinical trials were identical in design. A total of 1371 adults (aged ≥18 years) with moderate-to-severe papulo pustular rosacea were randomized to receive once-daily ivermectin 1% cream or a vehicle cream for 12 weeks.18,19 Both clinical trials had 2 coprimary efficacy end points, including (1) success rate according to the Investigator Global Assessment (IGA) scale, which was defined as the percentage of patients whose disease is categorized as clear (IGA = 0) and almost clear (IGA = 1); and (2) the abso lute change in inflammatory lesion counts from baseline to week 12.18,19 Other assessments comprised patient- reported outcomes, including quality-of-life ratings and patients’ assessments of rosacea improvement.18,19 Patient Population In the 2 clinical trials of ivermectin 1% cream, the majority of patients with papulopustular rosacea were white (96%) and female (67%), and the patients’ mean age was 50 years.18,19 Based on the 5-point IGA scale, 79% of patients had moderate papulopustular rosacea (IGA = 3), and 21% of patients had severe papulopustular rosacea (IGA = 4)

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Table 1 Ivermectin Cream versus Vehicle Cream: Coprimary Efficacy Results at Week 12 Study 1 Efficacy end point

Ivermectin 1% cream (N = 451) 173 (38)

Study 2

Vehicle cream (N = 232)

Ivermectin 1% cream (N = 459)

Vehicle cream (N = 229)

27 (12)

184 (40)

43 (19)

Investigator Global Assessment Patients categorized as clear or almost clear, N (%) P value

<.001

Inflammatory lesion counts Mean absolute change from baseline, N (%)

20.5 (65)

12.0 (42)

P value

22.2 (66)

13.4 (43)

<.001

Source: Soolantra (ivermectin) 1% cream prescribing information; December 2014.

Table 2 Patient-Reported Outcomes: Ratings of Rosacea Improvement at Week 12 Study 1 Ivermectin 1% cream, % (N = 451)

Excellent

Study 2

Vehicle cream, % (N = 232)

Ivermectin 1% cream, % (N = 459)

Vehicle cream, % (N = 229)

Good

Moderate

No improvement

Worse

Patient ratings of rosacea improvement

P value

<.001

NOTE: The totals of each study arm may not equal 100% because of rounding. Source: Stein Gold L, Kircik L, Fowler J, et al. Efficacy and safety of ivermectin 1% cream in treatment of papulopustular rosacea: results of two randomized, double-blind, vehicle-controlled pivotal studies. J Drugs Dermatol. 2014;13:316-323.

upon randomization into the study.18,19 The patients’ average inflammatory lesion count at baseline ranged from 31 to 33.18

Efficacy Both randomized clinical trials demonstrated that ivermectin 1% cream was more effective than the vehi cle cream based on the coprimary efficacy end points— IGA and absolute change in inflammatory lesion counts (P <.001; Table 1).18,19 Significant differences in the 2 coprimary end points were observed after 4 weeks of treatment with ivermec tin 1% cream.18 At week 12, significant improvements were seen in the 2 coprimary end points, as well as in secondary end points, including patient assessments (ie, general and rosacea-specific quality-of-life measures, patient assessments of rosacea improvement).

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Table 2 summarizes patient-reported outcomes at week 12.18 After receiving ivermectin cream, 38% of patients in Study 1 and 40% of patients in Study 2 were categorized as clear or almost clear versus 12% of patients in Study 1 and 19% of patients in Study 2 who received the vehicle cream (Table 1).18,19 At week 12, more than 60% of patients who received ivermectin 1% cream in the 2 studies rated the improve ment in their rosacea as excellent or very good compared with less than 40% of patients who received the vehicle cream in both studies (Table 2).18

Adverse Events and Safety Overall, 2047 patients with inflammatory type of ro sacea received once-daily ivermectin 1% cream in clini cal trials; of these, 1555 patients used the cream for more

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than 12 weeks, and 519 patients used it for approximate ly 1 year.19 Ivermectin 1% cream was well tolerated and safe during the 12-week study period.18,19 Skin irritation and sensation of skin burning were reported in ≤1% of patients who re ceived ivermectin 1% cream for 3 months or longer.19 Adverse events led to the discontinuation of ivermec tin 1% cream in 1.3% of patients in Study 1 and in 0.2% of patients in Study 2, compared with a discontinuation rate of 1.7% among patients who received the vehicle cream in each study.18 Ivermectin 1% cream has no contraindications.19

“While some rosacea treatments for the common bumps and pimples of the condition may take more than four weeks to show effect, Soolantra Cream may provide initial results as early as week two.“ Warnings and Precautions The oral, ophthalmic, or intravaginal use of ivermec tin 1% cream is not recommended.19 Use in Specific Populations Pediatric patients. The safety and efficacy of ivermec tin cream in pediatric patients have not been established.19 Geriatric use. Ivermectin cream has been studied in a total of 1371 patients with rosacea, of whom 12% were aged ≥65 years. There were no meaningful differences in the efficacy or the safety of ivermectin cream among the age cohorts.19 Pregnancy. Ivermectin cream should only be used during pregnancy if its potential benefit justifies its po tential risk to the fetus. Adequate and well-controlled studies with ivermectin cream have not been conducted in pregnant women.19 Nursing mothers. Because of the potential for serious adverse reactions from ivermectin cream in nursing in fants, the use of ivermectin cream or nursing should be discontinued, taking into account the importance of the drug to the mother.19 Conclusion Because papulopustular rosacea is a common and challenging subtype of rosacea, basic and clinical re search continue to focus on elucidating its etiology and its optimal management. Patients with this inflammatory cutaneous disorder are believed to have an altered im mune response that is affected by multiple triggers, in

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cluding environmental factors, genetic factors, and mi crobe challenges by pathogens such as D folliculorum. Based on the results of 2 phase 3 clinical trials, iver mectin 1% cream demonstrated efficacy and safety in the treatment of patients with inflammatory lesions of rosa cea. Administered once daily, this antibiotic-free treat ment option possesses unique anti-inflammatory and antiparasitic properties. The FDA’s approval of ivermec tin 1% cream offers an innovative, convenient, and ef fective treatment option for patients with this debilitat ing condition. n

References

1. Wilkin J, Dahl M, Detmar M, et al. Standard classification of rosacea: report of the National Rosacea Society Expert Committee on the Classification and Staging of Rosacea. J Am Acad Dermatol. 2002;46:584-587. 2. National Rosacea Society. Rosacea riddle now threatens more than 16 million Americans. Press release. April 1, 2010. www.rosacea.org/press/archive/20100401.php. Accessed January 14, 2015. 3. Powell FC. Rosacea. N Engl J Med. 2005;352:793-803. 4. Fallen RS, Gooderham M. Rosacea: update on management and emerging thera pies. Skin Therapy Lett. 2012;17:1-4. 5. Jarmuda S, O’Reilly N, Zaba R, et al. Potential role of Demodex mites and bac teria in the induction of rosacea. J Med Microbiol. 2012;61(pt 11):1504-1510. 6. National Rosacea Society. The ecology of your face: Demodex, rosacea and you. www.rosacea.org/patients/demodex. Accessed January 19, 2015. 7. van Zuuren EJ, Kramer S, Carter B, et al. Interventions for rosacea. Cochrane Database Syst Rev. 2011:CD003262. 8. Georgala S, Katoulis AC, Kylafis GD, et al. Increased density of Demodex follic ulorum and evidence of delayed hypersensitivity reaction in subjects with papulo pustular rosacea. J Eur Acad Dermatol Venereol. 2001;15:441-444. 9. Huynh TT. Burden of disease: the psychosocial impact of rosacea on a patient’s quality of life. Am Health Drug Benefits. 2013;6:348-354. 10. Su D, Drummond PD. Blushing propensity and psychological distress in people with rosacea. Clin Psychol Psychother. 2012;19:488-495. 11. Gupta MA, Gupta AK, Chen SJ, Johnson AM. Comorbidity of rosacea and depression: an analysis of the National Ambulatory Medical Care Survey and Na tional Hospital Ambulatory Care Survey—Outpatient Department data collected by the US National Center for Health Statistics from 1995 to 2002. Br J Dermatol. 2005;153:1176-1181. 12. National Rosacea Society. Coping with rosacea: managing psychosocial aspects of rosacea. www.rosacea.org/patients/materials/coping/managing.php#Managing. Accessed July 24, 2013. 13. Baldwin HE. Diagnosis and treatment of rosacea: state of the art. J Drugs Dermatol. 2012;11:725-730. 14. Del Rosso JQ. Medical treatment of rosacea with emphasis on topical therapies. Expert Opin Pharmacother. 2004;5:5-13. 15. Chon SY, Doan HQ, Mays RM, et al. Antibiotic overuse and resistance in dermatology. Dermatol Ther. 2012;25:55-69. 16. Thomas K, Yelverton CB, Yentzer BA, et al. The cost-effectiveness of rosacea treatments. J Dermatolog Treat. 2009;20:72-75. 17. Galderma. Galderma receives FDA approval of novel treatment option for rosa cea patients. Press release. December 24, 2014. www.galderma.com/Media/Press- releases/articleType/ArticleView/articleId/75/Galderma-Receives-FDA-Approval-of- Novel-Treatment-Option-for-Rosacea-Patients. Accessed January 29, 2015. 18. Stein Gold L, Kircik L, Fowler J, et al. Efficacy and safety of ivermectin 1% cream in treatment of papulopustular rosacea: results of two randomized, double- blind, vehicle-controlled pivotal studies. J Drugs Dermatol. 2014;13:316-323. 19. Soolantra (ivermectin) cream, 1%, for topical use [prescribing information]. Fort Worth, TX: Galderma Laboratories, LP; December 2014. 20. National Rosacea Society. Novel treatment Soolantra® (ivermectin) cream, 1%, now approved. December 23, 2014. www.rosacea.org/weblog/novel-treatment-soolantra %C2%AE-ivermectin-cream-1-now-approved. Accessed January 29, 2015. 21. Drugs.com. IVOMEC 1% injection for cattle and swine. www.drugs.com/vet/ ivomec-1-injection-for-cattle-and-swine.html. Accessed January 16, 2015. 22. Centers for Disease Control and Prevention. Onchocerciasis FAQs. Updated May 21, 2013. www.cdc.gov/parasites/onchocerciasis/gen_info/faqs.html. Accessed January 16, 2015. 23. Ci X, Li H, Yu Q, et al. Avermectin exerts anti-inflammatory effect by down regulating the nuclear transcription factor kappa-B and mitogen-activated protein kinase activation pathway. Fundam Clin Pharmacol. 2009;23:449-455.

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Tanzeum (Albiglutide): A Once-Weekly GLP-1 Receptor Agonist Subcutaneous Injection Approved for the Treatment of Patients with Type 2 Diabetes By Loretta Fala, Medical Writer

iabetes affects 25.8 million individuals in the United States, an estimated 8.3% of the US population.1 Furthermore, approximately 79 million US adults aged >20 years have prediabetes.1 Based on the aging of the US population and its projected increasing incidence in the coming decades, diabetes is estimated to affect 1 in 3 US adults by 2050.2 Effective preventive strategies, particularly in high-risk individuals, may reduce the projected increase in the prevalence of diabetes.2 Diabetes is a chronic disease that is associated with multiple comorbidities, including microvascular, macrovascular, and neuropathic complications that impact the patient’s quality of life.1,2 Diabetes is the seventh leading cause of death in the United States and is a major cause of stroke and heart disease, as well as the leading cause of kidney failure, new cases of blindness, and nontraumatic lower-limb amputations.1 Patients with diabetes are also at an increased risk for hypertension and depression.1 In 2012, diabetes accounted for $245 billion in total healthcare costs in the United States3; of this total, direct medical costs accounted for $176 billion, and indirect costs (eg, increased absenteeism, reduced productivity, lost productivity, and disability) accounted for $69 billion.3 Overall, the medical expenses for patients with diabetes are approximately 2.3 times higher than for individuals without diabetes.3 In fact, more than $1 in $5 of US healthcare dollars is spent on the care of patients with diagnosed diabetes; more than 50% of that expenditure is directly attributable to diabetes.3 Approximately 90% to 95% of all cases of diabetes are type 2 diabetes mellitus, a disease that is characterized by insulin resistance and the gradual decline in the ability of the pancreas to produce insulin.1 Diabetes management is complex and requires multiple risk-reduction strategies beyond glycemic control, according to the American Diabetes Association (ADA).4 The management of diabetes demands ongoing medical care in addition to patient self-management, education, and support to prevent and to reduce long-term compli-

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cations.4 Lifestyle and behavioral changes are crucial aspects of diabetes care.1 The therapeutic goals for type 2 diabetes include achieving clinical and biochemical glucose targets, mitigating hypoglycemia, avoiding weight gain and/or assisting with weight loss in individuals who are obese, and reducing increasing complications, particularly cardiovascular risks.5 Glycemic control has been shown to be an effective strategy to decreasing the morbidity and mortality associated with type 2 diabetes by reducing complications. Every 1% reduction in glycated hemo globin (HbA1c) is associated with a 40% reduction in diabetes-related microvascular complications, including diabetic nephropathy, neuropathy, and retinopathy.1,4 The ADA recommends a general target goal of <7% HbA1c level for adults with diabetes, acknowledging that this goal is subject to adjustment, depending on the patient’s duration of disease, comorbid conditions, age, known cardiovascular complications or advanced microvascular complications, and other patient factors.4 The American Association of Clinical Endocrinologists recommends a target HbA1c level of <6.5%, recognizing that this goal may be too aggressive for some patients and not aggressive enough for others (ie, younger patients for whom a lower target may prevent subsequent complications).5 Although progress is being made in the number of patients who achieve a target HbA1c level of <7%, there remains a pressing need for different strategies to help to improve glycemic control and outcomes for patients with diabetes and prediabetes.6 Novel therapies may provide clinicians with additional treatment options to improve glycemic control in patients with type 2 diabetes. The glucagon-like peptide (GLP)-1 receptor agonists represent a relatively recent class of antihyperglycemic drugs. Several GLP-1 receptor agonists with a longer duration of action than exenatide twice daily include liraglutide once daily and exenatide once weekly. A new once-weekly GLP-1 option was recently added to this drug class.

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Albiglutide: A New GLP-1 Receptor Agonist Option On April 15, 2014, the US Food and Drug Admin istration (FDA) approved albiglutide (Tanzeum; GlaxoSmithKline), a GLP-1 receptor agonist subcutaneous injection, as an adjunct to diet and exercise to improve glycemic control in adult patients with type 2 diabetes mellitus.8 Commenting on the approval of albiglutide, Curtis Rosebraugh, MD, MPH, Director of the Office of Drug Evaluation II in the FDA’s Center for Drug Evaluation and Research, said, “Tanzeum is a new treatment option for the millions of Americans living with type 2 diabetes. It can be used alone or added to existing treatment regimens to control blood sugar levels in the overall management of diabetes.” 8 With the approval of albiglutide, the FDA required the manufacturer to conduct postmarketing studies, including a clinical trial to assess the dosing, efficacy, and safety of albiglutide in pediatric patients; a case registry for at least 15 years to identify any increased incidence of medullary thyroid carcinoma cases associated with albiglutide; and a cardiovascular outcomes clinical trial to evaluate albiglutide-associated cardiovascular risk in patients with a high baseline risk for cardiovascular disease.8 In addition, the FDA requires a Risk Evaluation and Mitigation Strategy program for albiglutide, which includes a communication plan to notify healthcare providers about the serious risks associated with this agent.8 Albiglutide is not recommended as a first-line treatment for patients whose diabetes is inadequately controlled with diet and exercise.9 In addition, albiglutide is not indicated for the treatment of type 1 diabetes, diabetic ketoacidosis, or for patients with diabetes and preexisting severe gastrointestinal disease. Albiglutide has not been studied in patients with a history of pancreatitis or in combination with prandial insulin.9 Dosing and Administration Albiglutide is administered once weekly at any time of the day, with or without food, via subcutaneous injection (ie, injection pen) in the abdomen, thigh, or upper arm; the initial dose is 30 mg.9 The dose can be increased to 50 mg once weekly in patients who require additional glycemic control. If a dose of albiglutide is missed, it should be administered within 3 days of the missed dose. The lyophilized powder that is contained in the injection pen must be reconstituted before administration.9 Mechanism of Action Albiglutide is an agonist of the GLP-1 receptor that augments glucose-dependent insulin secretion. In addition, albiglutide slows gastric emptying.9

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Clinical Trials Albiglutide has been studied as monotherapy and in combination with metformin, metformin and a sulfonyl urea, thiazolidinedione (with and without metformin), and insulin glargine (with or without oral antidiabetic drugs). The efficacy of albiglutide was also evaluated in comparative studies with placebo, glimepiride, pioglitazone, liraglutide, sitagliptin, insulin lispro, and insulin glargine.9 Overall, albiglutide 30 mg and 50 mg were evaluated in a series of 8 phase 3 clinical trials, collectively known as the Harmony program that involved more than 5000 patients, 2000 of whom had received albiglutide.9,10 In 5 of the 8 studies, the optional uptitration of albiglutide from 30 mg to 50 mg was allowed if glycemic response with 30 mg was inadequate.9 In these studies, albiglutide demonstrated clinically relevant reductions from baseline in HbA1c levels compared with placebo.9 No overall differences in glycemic effectiveness or body weight were observed across the demographic subgroups with respect to age, sex, race, ethnicity, or the duration of diabetes.9 Albiglutide as Monotherapy Albiglutide as monotherapy was evaluated in a 52week, randomized, double-blind, placebo-controlled clinical trial in 296 patients with type 2 diabetes that was Table 1 Albiglutide Monotherapy versus Placebo: Results at Week 52 Albiglutide Albiglutide 50 mg Placebo 30 mg weekly weekly Efficacy parameter (N = 99) (N = 100) (N = 97) HbA1c level Baseline, mean, %

8.0

8.1

8.2

+0.2

–0.7

–0.9

–0.8 (95% CI, –1.1 to –0.6)a

–1.0 (95% CI, –1.3 to –0.8)a

Baseline, mean, mg/dL

163

164

171

Change at week 52, mg/dL

+18

–16

–25

–34 (95% CI, –46 to –22)a

–43 (95% CI, –55 to –31)a

Change at week 52, % Difference from placebo, % Patients achieving HbA1c <7%, % Fasting plasma glucose

Difference from placebo, mg/dL

P <.001. CI indicates confidence interval; HbA1c, glycated hemoglobin. Source: Tanzeum (albiglutide) for injection prescribing information; April 2014.

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Table 2 A lbiglutide in Combination with Metformin: Results at Week 104 Albiglutide + metformin (N = 297)

Efficacy parameter

Placebo + Sitagliptin + Glimepiride metformin metformin + metformin (N = 100) (N = 300) (N = 302)

HbA1c level Baseline, mean, %

8.1

Change at week 104, %

–0.6

+0.3

–0.3

–0.4

Baseline, mean, mg/dL

165

162

165

168

Change at week 104, mg/dL

–18

+10

–2

–8

–1.2

–1.0

–0.9

+1.2

Difference from placebo + metformin, %

–0.9 (95% CI, –1.16 to –0.65)a

Difference from sitagliptin + metformin, %

–0.4 (95% CI, –0.53 to –0.17)a

Difference from glimepiride + metformin, %

–0.3 (95% CI, –0.45 to –0.09)a

Patients achieving HbA1c <7%, % Fasting plasma glucose

Difference from placebo + metformin, mg/dL

–28 (95% CI, –39 to –16)

Difference from sitagliptin + metformin, mg/dL

–16 (95% CI, –24 to –8)a

Difference from glimepiride + metformin, mg/dL

–10 (95% CI, –18 to –2)a

Body weight Baseline, mean, kg Change at week 104, kg Difference from placebo + metformin, kg

–0.2 (95% CI, –1.1 to 0.7)

Difference from sitagliptin + metformin, kg

–0.4 (95% CI, –1.0 to 0.3)

Difference from glimepiride + metformin, kg

–2.4 (95% CI, –3.0 to –1.7)a

P <.0137. CI indicates confidence interval; HbA1c, glycated hemoglobin. Source: Tanzeum (albiglutide) for injection prescribing information; April 2014.

inadequately controlled with diet and exercise.9,11 Patients (mean age, 53 years) were randomized to receive albiglutide 30 mg subcutaneously once weekly, albiglutide 30 mg subcutaneously once weekly uptitrated to 50 mg once weekly at week 12, or placebo.9,11 The primary and secondary efficacy results of the monotherapy clinical trial are shown in Table 1.9 Patients who received albiglutide 30 mg or 50 mg showed a significant reduction in HbA1c levels from baseline at week 52 compared with placebo. More than twice as many patients in the albiglutide 30-mg group achieved a <7% HbA1c level compared with the placebo group (49% vs 21%, respectively), and nearly twice as many patients in the albiglutide 50-mg group achieved a <7% HbA1c level compared with placebo (40% vs 21%, respectively). The adjusted mean change in weight from baseline did not differ significantly between albiglutide and placebo at week 52.9,11

Albiglutide as Combination Therapy Add-on to metformin. Albiglutide was evaluated as a

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combination therapy in a 104-week randomized, double- blind clinical trial in 999 patients (mean age, 55 years) with type 2 diabetes that was inadequately controlled with background metformin therapy (≥1500 mg daily).9,12 In this study, albiglutide 30 mg was administered subcutaneously weekly (with optional uptitration to 50 mg weekly after a minimum of 4 weeks) and compared with placebo, sitagliptin 100 mg daily, or glimepiride 2 mg daily (with optional titration to 4 mg daily).9,12 Table 2 summarizes the results of the primary and secondary analyses. Patients who received albiglutide had a significantly greater reduction from baseline in HbA1c levels compared with placebo, sitagliptin, and glimepiride at week 104. The change in body weight from baseline was significantly better with albiglutide than with glimepiride at week 104 (P <.0137).9,12 Add-on to pioglitazone. In a 52-week, randomized, double-blind clinical trial, albiglutide was evaluated in 299 patients with type 2 diabetes that was inadequately controlled with pioglitazone ≥30 mg daily (with or without metformin ≥1500 mg daily). Patients (mean age, 55

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years) were randomized to receive albiglutide 30 mg or placebo weekly.9,13 The results from the primary and secondary analyses are shown in Table 3. Treatment with albiglutide resulted in a significant reduction in HbA1c levels from baseline at week 52 compared with placebo. In this study, 44% of patients in the albiglutide group achieved HbA1c levels of <7% compared with 15% of patients in the placebo group. The adjusted mean change from baseline in weight did not differ significantly between albiglutide (+0.3 kg) and placebo (+0.5 kg) at week 52.9,13

Adverse Events The most common adverse reactions reported in ≥10% of patients who received albiglutide and were more common than in patients who received placebo included upper respiratory tract infection, diarrhea, nausea, and injection-site reaction.9 Drug Interactions Albiglutide delays gastric emptying and may impact the absorption of concomitantly administered oral medications.9 Contraindications Albiglutide is contraindicated in patients with a personal history or a family history of medullary thyroid carcinoma or in patients with multiple endocrine neoplasia syndrome type 2. Albiglutide is also contraindicated in patients with a history of serious hypersensitivity to albiglutide or to any albiglutide drug components.9 Warnings and Precautions Boxed warning. The prescribing information for albiglutide carries a boxed warning about the risk for thyroid C-cell tumors, which have been observed in studies of rodents who received GLP-1 receptor agonists at clinically relevant exposures. It is not known whether albiglutide causes thyroid C-cell tumors, including medullary thyroid carcinoma, in humans.9 Pancreatitis. Albiglutide should be discontinued promptly if pancreatitis is suspected. In patients with confirmed pancreatitis, albiglutide should not be started or restarted. Other antidiabetes therapies should be considered in patients with a history of pancreatitis.9 Hypoglycemia. Hypoglycemia can occur when albiglutide is used in combination with insulin secretagogues (eg, sulfonylureas) or with insulin. Lowering the sulfonyl urea or insulin dosage should be considered when starting albiglutide therapy.9 Hypersensitivity reactions. Albiglutide should be discontinued if a hypersensitivity reaction is suspected. The patient should be monitored and treated promptly

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per standard of care until the signs and symptoms of hypersensitivity resolve.9 Renal impairment. Renal function should be monitored in patients with renal impairment and severe adverse gastrointestinal reactions.9 Macrovascular outcomes. Conclusive evidence of macrovascular risk reduction with albiglutide or any other antidiabetic drug has not been established.9

Use in Specific Populations Pregnancy. Albiglutide may cause fetal harm and should only be used if the potential benefit justifies the potential risk to the fetus.9 Nursing mothers. It is not known whether albiglutide is excreted into human milk during lactation. Therefore, either nursing or albiglutide should be discontinued, taking into account the importance of the drug to the mother.9 Geriatric use. A total of 19% of patients in the 8 phase 3 clinical trials who received albiglutide were aged ≥65 years, and <3% were aged ≥75 years. No difference in safety or efficacy was observed between older and younger patients, but greater sensitivity of some older individuals cannot be ruled out.9 Conclusion The FDA approval of albiglutide has added a new once-weekly treatment option as an adjunct to diet and Table 3 Albiglutide in Combination with Pioglitazone: Results at Week 52 Albiglutide + Placebo + pioglitazone pioglitazone (with or without (with or without metformin) metformin) Efficacy parameter (N = 150) (N = 149) HbA1c level Baseline, mean, %

8.1

Change at week 52, %

–0.8

–0.1

Difference from placebo + pioglitazone, % Patients achieving HbA1c <7%, %

–0.8 (95% CI, –0.95 to –0.56)a 44

Baseline, mean, mg/dL

165

167

Change at week 52, mg/dL

–23

Fasting plasma glucose

Difference from placebo + pioglitazone, mg/dL

–30 (95% CI, –39 to –20)a

P <.001. CI indicates confidence interval; HbA1c, glycated hemoglobin. Source: Tanzeum (albiglutide) for injection prescribing information; April 2014.

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exercise for the treatment of patients with type 2 diabetes. Albiglutide is a GLP-1 receptor agonist administered via an injection pen once weekly. The safety and efficacy of albiglutide were evaluated in the Harmony clinical trials––a series of 8 phase 3 clinical trials that involved more than 5000 patients, 2000 of whom had received albiglutide.

This new drug therapy provides patients a treatment option with a longer duration of action, which may offer patients the added convenience of fewer dosing versus treatment regimens with more frequent dosing. This new drug therapy provides patients a treatment option with a longer duration of action, which may offer patients the added convenience of fewer dosing versus treatment regimens with more frequent dosing. Albiglutide was studied as monotherapy and in combination with metformin and other frequently used antidiabetic medications. It was also investigated versus placebo, glimepiride, pioglitazone, liraglutide, sitagliptin, insulin glargine, and insulin lispro. In clinical trials, albiglutide was shown to produce clinically relevant reductions from baseline in HbA1c levels versus placebo in patients with type 2 diabetes. The most common adverse reactions reported with

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albiglutide were upper respiratory tract infection, diarrhea, nausea, and injection-site reaction. 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 March 7, 2014. 2. Boyle JP, Thompson TJ, Gregg EW, et al. Projection of the year 2050 burden of diabetes in the US adult 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. Standards of medical care in diabetes—2013. Diabetes Care. 2013;36(suppl 1):S11-S66. 5. Garber AJ, Abrahamson MJ, Barzilay JI, et al. American Association of Clinical Endocrinologists’ comprehensive diabetes management algorithm 2013 consensus statement. Endocr Pract. 2013;19(suppl 2):1-48. 6. 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. 7. Garber AJ. Novel GLP-1 receptor agonists for diabetes. Expert Opin Investig Drugs. 2012;21:45-57. 8. US Food and Drug Administration. FDA approves Tanzeum to treat type 2 diabetes. Press release. April 15, 2014. www.fda.gov/newsevents/newsroom/pressannounce ments/ucm393289.htm. Accessed May 12, 2014. 9. Tanzeum (albiglutide) for injection [prescribing information]. Research Triangle Park, NC: GlaxoSmithKline; April 2014. 10. GlaxoSmithKline. GSK receives US approval for once-weekly type 2 diabetes treatment, Tanzeum™ (albiglutide). Press release. April 15, 2014. www.gsk.com/ media/press-releases/2014/gsk-receives-us-approval-for-once-weekly-type-2-diabetes- treatme.html. Accessed May 13, 2014. 11. Reinhardt R, Nauck MA, Stewart M, et al. Harmony 2 results at week 52 primary endpoint: once-weekly albiglutide monotherapy for patients with type 2 diabetes mellitus inadequately controlled with diet and exercise. Poster presented at the 49th Annual Meeting of the European Association for the Study of Diabetes; September 23-27, 2013; Barcelona, Spain. 12. Ahrén B, Johnson SL, Stewart M, et al. HARMONY 3: 104-week randomized, double-blind, placebo- and active-controlled trial assessing the efficacy and safety of albiglutide compared with placebo, sitagliptin, and glimepiride in patients with type 2 diabetes taking metformin. Diabetes Care. 2014;37:2141-2148. 13. Reusch J, Stewart MW, Perkins CM, et al. Efficacy and safety of once-weekly glucagon-like peptide 1 receptor agonist albiglutide (HARMONY 1 trial): 52-week primary endpoint results from a randomized, double-blind, placebo-controlled trial in patients with type 2 diabetes mellitus not controlled on pioglitazone, with or without metformin. Diabetes Obes Metab. 2014;16:1257-1264.

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Trulicity (Dulaglutide): A New GLP-1 Receptor Agonist Once-Weekly Subcutaneous Injection Approved for the Treatment of Patients with Type 2 Diabetes By Loretta Fala, Medical Writer

iabetes, a chronic disease that is often accompanied by multiple comorbidities and health complications, is the seventh leading medical cause of death in the United States. In fact, the mortality rate for patients with diabetes is 1.5 times higher than for individuals without diabetes.1 Diabetes affects an estimated 29.1 million individuals in the United States—an alarming 9.3% of the US population.1 In addition, an estimated 37% of US adults aged ≥20 years have prediabetes, according to the 2009-2012 National Health and Nutrition Examination Survey data.1 The prevalence of diabetes is projected to increase from 1 in 10 adults today to 1 in 3 adults by 2050, coinciding with the aging of the baby boom generation during the next few decades.2 Type 2 diabetes mellitus accounts for approximately 90% to 95% of all cases of diabetes. Diabetes is a major cause of heart disease and stroke. In addition, diabetes is the leading cause of kidney failure, nontraumatic lower-limb amputations, and new cases of blindness in US adults.1 Furthermore, patients with diabetes are at an increased risk for other complications, including nerve disease, nonalcoholic fatty liver disease, periodontal disease, erectile dysfunction, hearing loss, depression, and pregnancy complications.1 The total estimated cost for patients with diagnosed diabetes in 2012 totaled $245 billion, including $176 billion in direct medical costs and $69 billion in indirect costs (ie, increased absenteeism, reduced productivity, lost productivity as a result of early mortality, and the inability to work resulting from disability).3 These 2012 costs represent a 41% increase from diabetes-related costs of $174 billion in 2007. Overall, the medical expenses for patients with diabetes are 2.3 times higher than for individuals without diabetes.3 According to the American Diabetes Association (ADA), diabetes management is complex, generally requiring multiple risk reduction strategies in addition to glycemic control.4 Diabetes management demands an ongoing, patient-tailored approach that considers the whole patient—glycemic control to prevent or reduce

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microvascular complications, as well as strategies to address obesity and prediabetes as the underlying risk factors for diabetes and for related macrovascular complications. These approaches generally include dietary and other behavioral and lifestyle changes, which are impor tant aspects of diabetes care.4 Adequate glycemic control has been shown to reduce the morbidity and mortality of diabetes by decreasing chronic complications.4 Lowering the hemoglobin (Hb) A1c levels to 7% or below reduces microvascular complications, and, if reached soon after the diagnosis of diabetes, is associated with a long-term reduction in macrovascular disease.4 The ADA’s 2013 position statement on the standards of care for diabetes recommends a target HbA1c level of <7% for the majority of adult patients with diabetes.4 The ADA acknowledges that the stringency of this goal may need to be modified based on the patient’s duration of diabetes, comorbidities, age, known cardiovascular or advanced microvascular complications, and other patient-specific factors.4 In a 2013 consensus statement, the American Association of Clinical Endocrinologists (AACE) recommended an HbA1c target goal of <6.5% in the majority of patients with type 2 diabetes, with the caveat that this goal may be too aggressive for some patients and not aggressive enough for other patients (ie, younger patients for whom a lower target may prevent later complications).5 The AACE also states that lifestyle modification and antihyperglycemic pharmacotherapy should aim to reach clinical and biochemical glucose targets, avoid hypoglycemia, assist with weight loss and minimize weight gain in obese individuals, and reduce or avoid increasing cardiovascular disease risk.5 Despite the progress made in the number of US adults who reach the target HbA1c level of <7%, there is room for more improvement.6 Ongoing clinical management, patient engagement, education, and the development of novel therapies may help to improve glycemic control and outcomes for patients with diabetes.6 The ADA recommends metformin as the initial therapy for type 2 diabetes; if another treatment or a com

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bination therapy is warranted, available agents include sulfonylureas, thiazolidinediones, dipeptidyl peptidase (DPP)-4 inhibitors, glucagon-like peptide (GLP)-1 receptor agonists, insulin, and other agents.7 The development of the GLP-1 receptor agonist and the DPP-4 inhibitor classes, both of which target the incretin system, represents an important advancement in the management of type 2 diabetes.8 The long-acting GLP-1 receptor agonists improve glycemic control and help to promote weight loss. Furthermore, based on their glucose-dependent mechanism of action, the GLP-1 receptor agonists have a low risk for hypoglycemia.8

Dulaglutide: A New Once-Weekly Option On September 18, 2014, dulaglutide (Trulicity; Eli Lilly), a once-weekly subcutaneous injection, was approved by the US Food and Drug Administration (FDA) as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.9 Dulaglutide is a GLP-1 receptor agonist that was shown to reduce fasting and postprandial glucose after a single dose.10 Dulaglutide is not recommended as first-line therapy for patients whose diabetes is inadequately controlled with diet and exercise.10 In addition, dulaglutide is not recommended in patients with type 1 diabetes, diabetic ketoacidosis, or a preexisting severe gastrointestinal disease. DuTable 1 AWARD-3 Clinical Trial: Dulaglutide Monotherapy versus Metformin, at Week 26 Metformin Dulaglutide Dulaglutide 15000.75 mg 1.5 mg 2000 mg Efficacy parameter (N = 270)a (N = 269)a (N = 268)a Mean HbA1c level Baseline, %

7.6

Change from baseline (adjusted mean), %

–0.7

–0.8

–0.6

Baseline, mg/dL

161

164

161

Change from baseline (adjusted mean), mg/dL

–26

–29

–24

92.7

92.4

–1.4b

–2.3

–2.2

Mean fasting serum glucose

Mean body weight Baseline, kg Change from baseline (adjusted mean), kg

Patients included in the analysis are a subset of the intent-to-treat population who had at least 1 postbaseline assessment; the primary analysis included 265 patients in each of the treatment arms. b Umpierrez G, et al. Diabetes Care. 2014;37:2168-2176. HbA1c indicates glycated hemoglobin. Source: Trulicity (dulaglutide) injection prescribing information; September 2014. a

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laglutide has not been studied in patients with a history of pancreatitis or in combination with basal insulin.10 According to Mary Parks, MD, Deputy Director, Office of Drug Evaluation II in the FDA Center for Drug Evaluation and Research, “Type 2 diabetes is a serious chronic condition that causes blood glucose levels to rise higher than normal. Trulicity is a new treatment option, which can be used alone or added to existing treatment regimens to control blood sugar levels in the overall management of type 2 diabetes.” 9 The FDA requires a Risk Evaluation and Mitigation Strategy program for dulaglutide to inform healthcare professionals about dulaglutide’s serious associated risks.9 The FDA also requires several postmarketing studies to be conducted on dulaglutide, including a clinical trial to evaluate the dosing, efficacy, and safety of dulaglutide in pediatric patients; a study to assess the potential effects on sexual maturation, reproduction, and central nervous system in immature rats; a case registry for at least 15 years to investigate the incidence of medullary thyroid carcinoma in relation to dulaglutide; a trial comparing dulaglutide and insulin glargine in patients with type 2 diabetes and renal impairment; and a cardiovascular outcomes clinical trial in relation to dulaglutide.9

Dosing and Administration Dulaglutide is administered once weekly at any time of the day via subcutaneous injection into the abdomen, thigh, or upper arm.10 The initial dose of dulaglutide is 0.75 mg administered subcutaneously once weekly. This dose can be increased to 1.5 mg once weekly for additional glycemic control. If a dose is missed, dulaglutide should be administered within 3 days of the missed dose. The day of the weekly administration can be changed if necessary, as long as the last dose was administered ≥3 days before. Dulaglutide can be administered with or without food.10 Dulaglutide is available in 2 single-dose pen solutions and in 2 single-dose prefilled syringe solutions for injection—0.75 mg/0.5 mL and 1.5 mg/0.5 mL.10 Mechanism of Action Dulaglutide is a human GLP receptor agonist with 90% amino acid sequence homology to the endogenous human GLP-1 fragment 7-37.10 Dulaglutide activates the GLP-1 receptor, a membrane-bound cell-surface receptor that is coupled to adenylyl cyclase in pancreatic beta cells. By increasing intracellular cyclic adenosine monophosphate in beta cells, dulaglutide leads to glucose- dependent insulin release. Dulaglutide also decreases glucagon secretion and slows gastric emptying.10 Clinical Studies Dulaglutide has been studied as monotherapy and in

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combination with several antihyperglycemic medications, including metformin, metformin and sulfonylurea, metformin and thiazolidinedione, and prandial insulin with or without metformin.11,12 These studies evaluated treatment with dulaglutide 0.75 mg and dulaglutide 1.5 mg. Uptitration was not performed in any of the clinical trials. Patients were initiated with dulaglutide 0.75 mg or dulaglutide 1.5 mg, and these doses were maintained for the duration of the clinical trials.11,12 In patients with type 2 diabetes, dulaglutide was shown to reduce HbA1c levels from baseline compared with placebo.10 No overall differences in glycemic effectiveness were observed across the demographic subgroups, including age, sex, race and ethnicity, and the duration of diabetes.10

AWARD-3: Dulaglutide versus Metformin The safety and efficacy of dulaglutide monotherapy versus metformin were evaluated in the AWARD-3 trial, a 52-week, double-blind study (26-week primary end point) with 807 patients: the median age was 56 years, and the mean duration of type 2 diabetes was 3 years.11 All the patients had inadequate glycemic control with diet and exercise, or with diet and exercise and 1 antidiabetic agent used at the submaximal dose.11 The patients were randomized to receive dulaglutide 0.75 mg once weekly, dulaglutide 1.5 mg once weekly, or metformin 1500 mg to 2000 mg daily after a 2-week washout period.11 Approximately 90% of patients who had previously received an antidiabetic agent were receiving metformin at a median dose of 1000 mg daily, and approximately 10% of patients were receiving sulfonylurea.11 As shown in Table 1, treatment with dulaglutide 0.75 mg or 1.5 mg once weekly resulted in the reduction of HbA1c levels from baseline at the 26-week primary time point. The decrease from baseline in fasting serum glucose levels was similar with dulaglutide 0.75 mg, with dulaglutide 1.5 mg, and with metformin.11 The decrease in body weight from baseline was similar with dulaglutide 1.5 mg and with metformin, but it was smaller with dulaglutide 0.75 mg compared with metformin. A greater percentage of patients who received dulaglutide 0.75 mg or dulaglutide 1.5 mg reached HbA1c levels of <7.0% and ≤6.5% compared with patients who received metformin (P <.05, all comparisons).11 AWARD-5 Trial: Dulaglutide versus Sitagliptin This 104-week, double-blind, placebo-controlled study (with a 52-week end point) evaluated the safety and efficacy of dulaglutide versus sitagliptin as an add-on therapy to metformin.10,12 This study included 972 patients; the patients’ mean age was 54 years and the mean duration of type 2 diabetes was 7 years. Patients were randomized to receive placebo (after 26 weeks, patients in the placebo

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Table 2 AWARD-5 Clinical Trial: Dulaglutide versus Sitagliptin as Add-On Therapy to Metformin, at Week 52 Dulaglutide Dulaglutide Sitagliptin 0.75 mg 1.5 mg 100 mg Efficacy parameter (N = 281) (N = 279) (N = 273) Mean HbA1c level 8.2 Baseline, % –0.9 Change from baseline (adjusted mean), % –0.5 (95% CI, Difference from –0.7 to –0.3)a sitagliptin, % 49b Patients reaching HbA1c <7%, % Mean fasting plasma glucose 174 Baseline, mg/dL –30 Change from baseline (adjusted mean), mg/dL –15 (95% CI, Difference from –22 to –9) sitagliptin, mg/dL Mean body weight 85.5 Baseline, kg –2.7 Change from baseline (adjusted mean), kg –1.2 (95% CI, Difference from –1.8 to –0.6) sitagliptin, kg

8.1

8.0

–1.1

–0.4

–0.7 (95% CI, –0.9 to –0.5)a 59b

33b

173

171

–41

–14

–27 (95% CI, –33 to –20) 86.5

85.8

–3.1

–1.5

–1.5 (95% CI, –2.1 to –0.9)

Multiplicity adjusted 1-sided P <.001. P <.002 dulaglutide compared with sitagliptin. CI indicates confidence interval; HbA1c, glycated hemoglobin. Source: Trulicity (dulaglutide) injection prescribing information; September 2014. a

treatment group received blinded sitagliptin 100 mg daily for the remainder of the study), dulaglutide 0.75 mg once weekly, dulaglutide 1.5 mg once weekly, or sitagliptin 100 mg daily, all as add-on therapies to metformin. Randomization occurred after an 11-week lead-in period to allow for a metformin titration period, followed by a 6-week glycemic stabilization period.10 Treatment with dulaglutide 0.75 mg and with dulaglutide 1.5 mg once weekly, in combination with metformin, demonstrated a significant reduction in HbA1c levels compared with placebo at 26 weeks, and compared with sitagliptin at 26 weeks and at 52 weeks (Table 2).10,12 At 26 weeks, the percentage of patients who reached <7.0% HbA1c levels was significantly higher in patients who received dulaglutide 1.5 mg (61%) or dulaglutide 0.75 mg (55%) compared with patients who received sitagliptin (38%; P <.001, for both comparisons).12 At 52 weeks, the least squares mean changes from baseline in fasting plasma glucose levels were significantly greater with dulaglutide 1.5 mg and with dulaglutide 0.75 mg compared with sitagliptin (P <.001, for both compari-

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sons).12 Furthermore, dulaglutide 0.75 mg and dulaglutide 1.5 mg showed a significantly greater mean change in body weight from baseline at 52 weeks compared with sitagliptin (P <.001, for both comparisons).12

Adverse Events The most common adverse reactions reported in ≥5% of patients who received dulaglutide are nausea, diarrhea, vomiting, abdominal pain, and decreased appetite.10 Contraindications Dulaglutide is contraindicated in patients with a personal history or a family history of medullary thyroid carcinoma or in patients with multiple endocrine neoplasia syndrome type 2. Dulaglutide should not be used if the patient has a history of serious hypersensitivity to dulaglutide or any of its drug components.10 Drug Interactions Dulaglutide slows gastric emptying and may affect the absorption of concomitantly administered oral drugs.10 Warnings and Precautions Boxed warning. In rodent studies, dulaglutide caused an increase in the incidence of thyroid C-cell tumors after lifetime exposure.10 It is not known whether dulaglutide causes thyroid C-cell tumors in humans.10 Thyroid C-cell tumors in animals. Patients should be counseled about the risk for medullary thyroid carcinoma with the use of dulaglutide.10 Pancreatitis. Pancreatitis-related adverse reactions were reported with dulaglutide. Dulaglutide should be promptly discontinued if pancreatitis is suspected and should not be restarted if pancreatitis is confirmed.10 Hypoglycemia. Lowering the dose of the sulfonylurea or insulin may be warranted when dulaglutide is used with an insulin secretagogue (eg, sulfonylurea) or insulin to reduce the risk for hypoglycemia.10 Hypersensitivity reactions. Dulaglutide should be discontinued if a hypersensitivity reaction is suspected. Patients should be monitored and treated promptly until the signs and symptoms of hypersensitivity resolve.10 Renal impairment. Renal impairment should be monitored in patients with renal impairment who report severe adverse gastrointestinal reactions.10 Use in Specific Populations Pregnancy. There are no adequate and well-controlled studies of dulaglutide in pregnant women.10 Nursing mothers. It is not known whether dulaglutide is excreted in human milk.10 Pediatric use. The safety and efficacy of dulaglutide have not been established in pediatric patients. It is not

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recommended in young patients aged <18 years. Geriatric use. No overall differences in the safety or efficacy of dulaglutide were detected between patients aged ≥65 years and younger patients, but greater sensitivity of some older individuals cannot be ruled out.10 Hepatic impairment. There is limited experience with dulaglutide in patients with any hepatic impairment.10 Renal impairment. No dosage adjustment is recommended for patients with renal impairment. Renal function should be monitored in patients with renal impairment and severe adverse gastrointestinal reactions.10 Gastroparesis. Dulaglutide slows gastric emptying.10

Conclusion With the recent FDA approval of dulaglutide, a new, once-weekly subcutaneous injection became available as an adjunct to diet and exercise for adult patients with type 2 diabetes. Dulaglutide, a GLP-1 receptor agonist, provides a once-weekly treatment option that can be used as monotherapy or as an add-on therapy to existing treatment regimens. A once-weekly treatment may provide an attractive option for patients with diabetes. In 6 clinical studies that included a total of 3342 patients with type 2 diabetes, treatment with dulaglutide resulted in greater reductions from baseline in HbA1c levels compared with placebo, with no overall differences in glycemic reductions across age, sex, race/ethnicity, or duration of disease. n References

1. Centers for Disease Control and Prevention. National diabetes statistics report: estimates of diabetes and its burden in the United States, 2014. 2014. www.cdc. gov/diabetes/pubs/statsreport14/national-diabetes-report-web.pdf. Accessed August 5, 2014. 2. Boyle JP, Thompson TJ, Gregg EW, et al. Projection of the year 2050 burden of diabetes in the US adult 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. Erratum in: Diabetes Care. 2013;36:1797. 4. American Diabetes Association. Standards of medical care in diabetes—2013. Diabetes Care. 2013;36(suppl 1):S11-S66. 5. Garber AJ, Abrahamson MJ, Barzilay JI, et al. American Association of Clinical Endocrinologists’ comprehensive diabetes management algorithm 2013 consensus statement. Endocr Pract. 2013;19(suppl 2):1-48. 6. 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. 7. Inzucchi SE, Bergenstal RM, Buse JB, et al. 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. 8. Garber AJ. Long-acting glucagon-like peptide 1 receptor agonists: a review of their efficacy and tolerability. Diabetes Care. 2011;34(suppl 2):S279-S284. 9. US Food and Drug Administration. FDA approves Trulicity to treat type 2 diabetes. Press release. September 18, 2014. www.fda.gov/NewsEvents/Newsroom/Press Announcements/ucm415180.htm. Accessed September 22, 2014. 10. Trulicity (dulaglutide) injection [prescribing information]. Indianapolis, IN: Eli Lilly and Company; September 2014. 11. Umpierrez G, Tofé Povedano S, Pérez Manghi F, et al. Efficacy and safety of dulaglutide monotherapy versus metformin in type 2 diabetes in a randomized controlled trial (AWARD-3). Diabetes Care. 2014;37:2168-2176. 12. Nauck M, Weinstock RS, Umpierrez GE, et al. Efficacy and safety of dulaglutide versus sitagliptin after 52 weeks in type 2 diabetes in a randomized controlled trial (AWARD-5). Diabetes Care. 2014;37:2149-2158.

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Velcade (Bortezomib) Receives 2 New FDA Indications: For Retreatment of Patients with Multiple Myeloma and for First-Line Treatment of Patients with Mantle-Cell Lymphoma By Lisa Raedler, PhD, RPh, Medical Writer

ultiple myeloma, also referred to as myeloma, is a malignant neoplasm of plasma cells in the bone marrow that leads to bone destruction and bone marrow failure.1,2 According to the American Cancer Society, an estimated 26,850 new cases of myeloma will be diagnosed in 2015, and 11,240 deaths will be attributed to myeloma.3 Relatively uncommon, myeloma represents approximately 1% of all cancers. Nevertheless, myeloma is the second most common hematologic malignancy after non-Hodgkin lymphoma (NHL).4 Although the overall incidence of myeloma has increased nearly 1% annually since 1975, the mortality rates associated with myeloma have declined during the past 2 decades.1 Myeloma is more common in men than in women. Middle-aged or older individuals, those with a family history of myeloma, or with a personal history of monoclonal gammopathy of undetermined significance are at an increased risk for myeloma.1 The complications associated with myeloma include back pain, kidney dysfunction, bone loss, impaired immunity, and anemia.5 Based on one study, the annual US costs attributed to metastatic bone disease, including myeloma, were an estimated $12.6 billion.6 The median cost for patients with metastatic bone disease was $75,329 annually compared with $31,382 annually for cancers that are not associated with metastatic bone disease. The regression-adjusted incremental costs were highest for patients with myeloma; that is, $63,455 for myeloma versus $44,442 across all cancer types (P <.001).6 The treatment of patients with myeloma has evolved substantially in recent years. The introduction of novel drugs, including thalidomide, lenalidomide, and bortezomib, as well as a better understanding of the bone marrow microenvironment, have led to new combination therapies and new anticancer drugs.7 In fact, the use of novel agents for first-line treatment of myeloma has 足improved outcomes, including overall responses, for pa-

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tients with relapsed or refractory myeloma.7 Nevertheless, despite strides in the treatment of myeloma, there remains a marked need for additional therapeutic options and approaches for this patient population.8 Current therapies for myeloma include chemotherapy, corticosteroids, angiogenesis inhibitors, targeted therapies, biologic therapies, radiation therapy, stem-cell transplantation, and supportive care.1 Because patients with myeloma will experience disease relapse after initial treatment, multiple lines of therapy may be required. The therapeutic considerations for patients with relapsed myeloma include the duration of response to previous treatment, as well as the toxicity profile of a specific treatment and patient-specific factors.7

Mantle-Cell Lymphoma Mantle-cell lymphoma (MCL) is a rare malignancy, comprising approximately 5% of all NHL cases.9 MCL, which can be an aggressive cancer, most often affects men aged >60 years.9,10 The median overall survival is approximately 5 to 7 years, making MCL one of the poorest prognosis B-cell lymphomas.11 The survival outcomes are poor in part because MCL is typically diagnosed in later stages, such that the gastrointestinal tract and bone marrow are involved.9 Although data suggest a possible increase in the incidence of MCL during the past 20 years, this may be the result of improved diagnostic methods.11 In clinical practice, combinations of chemotherapy agents with anti-CD20 monoclonal antibody therapy, high-dose chemotherapy followed by autologous stemcell transplantation, and radioimmunotherapy are relevant options for treatment-na誰ve patients with MCL.9 MCL typically responds to initial treatment, but the disease relapses within a few years or becomes refractory to therapy, requiring subsequent lines of therapy.10 There is no consensus regarding the management of patients with relapsed or refractory MCL. Treatment

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decisions are based on several factors, including timing of disease relapse, disease extent, patient age, overall health, and previous therapies.10 Currently, bortezomib, lenalidomide, and ibrutinib are approved by the US Food and Drug Administration (FDA) for the treatment of patients with MCL. Bortezomib was initially indicated for use in patients with MCL who have received at least 1 previous therapy.12 Lenalidomide is approved for use in patients with MCL whose disease had relapsed or progressed after 2 previous therapies, 1 of which included bortezomib.13 Most recently, ibrutinib was granted accelerated approval by the FDA for the treatment of patients with MCL who have received at least 1 previous therapy.14 Other novel options under investigation for MCL include phosphoinositide 3-kinase inhibitors, cell-cycle inhibitors, monoclonal antibodies, and mTOR inhibitors.15 There are few assessments of the cost burden associated with MCL. A 2012 cost-effectiveness study based on US payer data showed that the total per-patient costs for patients with MCL exceeded $100,000.16 In this study, which compared the combination of bendamustine plus rituximab with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in treatment-naïve patients with MCL, the calculated average per-patient costs exceeded $115,000 and $100,200 for bendamustine plus rituximab and R-CHOP, respectively.16

Bortezomib Receives 2 New Indications in 2014 In 2014, the FDA approved bortezomib (Velcade; Millennium Pharmaceuticals [Takeda]) for 2 new indications. On August 8, 2014, bortezomib was approved for the retreatment of adult patients with myeloma whose disease had previously responded to bortezomib therapy and relapsed at least 6 months after the completion of that therapy with bortezomib.17,18 (The initial FDA approval of bortezomib was in 2003 for the treatment of patients with myeloma.19) The new indication for retreatment with bortezomib was based on findings from the phase 2 clinical trial known as RETRIEVE, as well as other supportive data.17,18 The revised drug labeling now includes dosing guidelines and safety and efficacy data on bortezomib therapy as a single agent or in combination with dexamethasone in patients who had previously received treatment with bortezomib.19 According to Michael Vasconcelles, MD, Global Head, Oncology Therapeutic Area Unit, Takeda Pharmaceuticals, “For the past 11 years, Velcade has played an impor tant role as the only therapy proven to extend overall survival for patients with newly diagnosed and relapsed multiple myeloma.” Dr Vasconcelles added, “With these

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newly approved dosing guidelines, physicians will be able to provide their patients, who have previously received Velcade, with an effective treatment extending Velcade use across the continuum of care of multiple myeloma.” 18 On October 9, 2014, the FDA approved bortezomib for the treatment of treatment-naïve patients with MCL, making it the first US treatment to receive FDA approval for this setting.20 This approval extends the use of bortezomib beyond relapsed or refractory MCL, for which it has been indicated since 2006. The approval for treatment-naïve patients with MCL was based on the results of a phase 3 clinical trial comparing the regimen of bortezomib plus rituximab, cyclophosphamide, doxorubicin, and prednisone (VcR-CAP) with the R-CHOP regimen.19,20 According to Andrew Evens, DO, MSc, Director, Tufts Cancer Center; Chief, Division of Hematology/ Oncology; and Director, Lymphoma Program, Tufts School of Medicine, “There are several new targeted drugs approved by the FDA for patients with relapsed or refractory, but up to this point, there had been none approved for the treatment of patients with previously untreated disease. Velcade, when used in the VcR-CAP regimen, has demonstrated improved outcomes for patients, making it an important advance for the treatment of newly diagnosed patients with MCL.” 20

Mechanism of Action Bortezomib is a reversible inhibitor of the chymo trypsin-like activity of the 26S proteasome in mammalian cells. The 26S proteasome is a large protein complex that degrades ubiquitinated proteins. The ubiquitin- proteasome pathway plays an essential role in regulating the intracellular concentration of specific proteins, thereby maintaining homeostasis within cells. Inhibition of the 26S proteasome prevents this targeted proteolysis, which can affect multiple signaling cascades within the cell. The disruption of the normal homeostatic mechanisms on the cellular level can lead to cell death.19 In vitro experiments have demonstrated that bortezomib is cytotoxic to a variety of cancer cell types. In nonclinical tumor models, bortezomib therapy causes a delay in tumor growth in vivo.19 Dosing and Administration Bortezomib is available as a single-use vial containing 3.5 mg of bortezomib as lyophilized powder. The recommended starting dose is 1.3 mg/m2. Bortezomib may also be administered intravenously at a concentration of 1 mg/ mL, or subcutaneously at a concentration of 2.5 mg/mL.19 Retreatment with bortezomib may be considered for patients with myeloma whose disease had previously responded to treatment with bortezomib and had relapsed at least 6 months after completing previous bortezomib

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therapy. Retreatment with bortezomib may be started at the last tolerated dose.19 The updated labeling for bortezomib is consistent with the National Comprehensive Cancer Network Clinical Practice Guidelines for the treatment of patients with relapsed myeloma, which state that if disease relapse occurs more than 6 months after the completion of the initial primary therapy, patients may be retreated with the same primary regimen.2 In patients with MCL, bortezomib 1.3 mg/m2 is administered intravenously in combination with VcRCAP.19 Bortezomib should be administered first, followed by rituximab. Bortezomib is administered twice weekly for 2 weeks on days 1, 4, 8, and 11, followed by a 10-day rest period. At least 72 hours should elapse between consecutive bortezomib doses.19 Six 3-week treatment cycles of VcR-CAP are recommended for patients with MCL.19 Two additional VcRCAP cycles should be administered to patients whose first documented response occurs at the end of 6 cycles.19 When administered intravenously, bortezomib is given as a 3- to 5-second bolus injection. Bortezomib is indicated for intravenous or subcutaneous administration only; it should not be administered by any other route. Because each route of administration has a different reconstituted concentration, caution should be used when calculating the required administration volume.19

Clinical Trials Pivotal Phase 2 Clinical Trial: Bortezomib Retreatment in Relapsed Myeloma The efficacy and safety of bortezomib retreatment of patients with relapsed myeloma were evaluated in the RETRIEVE study, an international, single-arm, open-label, phase 2 clinical trial.7 In this study, 130 patients (aged ≥18 years) with myeloma who previously had at least a partial response after receiving a bortezomib-based regimen (median of 2 previous lines of therapy) were retreated with intravenous bortezomib at disease progression.7 Patients were excluded from this trial if they had peripheral neuropathy or neuropathic pain of grade ≥2.7 At least 6 months after the completion of previous bortezomib therapy, patients restarted bortezomib therapy at the last tolerated dose of 1.3 mg/m2 (N = 93) or ≤1.0 mg/m2 (N = 37), which was administered on days 1, 4, 8, and 11 every 3 weeks for a maximum of 8 cycles, as a single agent or in combination with dexamethasone in accordance with the standard of care. Dexamethasone was administered in combination with bortezomib to 83 patients during cycle 1; 11 additional patients received dexamethasone during subsequent bortezomib retreatment cycles.7,19

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Table 1 Patients Receiving Previous Therapies in the RETRIEVE Study Patients receiving Type of previous nonbortezomib therapy this therapy,a N Steroids

115

Alkylating agents

100

Anthracyclines

Thalidomide

Other Previous high-dose therapy/stem-cell transplant

Previous bortezomib treatment Bortezomib single-agent

Bortezomib plus other agents

Among the 130 patients with relapsed myeloma in the study. Source: Petrucci MT, et al. Br J Haematol. 2013;160:649-659.

Table 2 Response to Bortezomib Retreatment in Patients with Relapsed Myeloma Patients achieving response, N Best confirmed responsea (N = 130) Partial response or better

50b

• Complete response

• Partial response

Overall response rate, %

38.5 (95% CI, 30.1-47.4)

As assessed by the European Group for Blood and Marrow Transplantation criteria. b In the 50 patients who responded, the median duration of response was 6.5 months (range, 0.6-19.3 months). CI indicates confidence interval. Source: Velcade (bortezomib) for injection prescribing information; October 2014. a

The patients’ median age was 67 years (range, 38-86 years), and the median time from myeloma diagnosis was 4.5 years (range, 0.8-13.9 years).7,19 Table 1 lists the various previous therapies used by the 130 patients in the RETRIEVE trial. The primary end point of this clinical trial was the best confirmed response to bortezomib retreatment as assessed by the European Group for Blood and Marrow Transplantation criteria. Retreatment with bortezomib demonstrated a 38.5% overall response rate (Table 2), with a median duration of response of 6.5 months (range, 0.6-19.3 months).19

Open-Label Phase 3 Clinical Trial: Bortezomib Therapy in Untreated Mantle-Cell Lymphoma The approval of bortezomib in patients with previous-

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ly untreated MCL was based on an open-label phase 3 clinical trial.19,20 In this trial, 487 adults with stage II to IV MCL who were ineligible or not considered for bone marrow transplantation received VcR-CAP (N = 243) or R-CHOP (N = 244).19 The VcR-CAP regimen consisted of bortezomib at 1.3 mg/m2 administered intravenously on days 1, 4, 8, and 11 (rest period, days 12-21), rituximab at 375 mg/m2 on day 1, cyclophosphamide at 750 mg/m2 on day 1, doxorubicin at 50 mg/m2 on day 1, and prednisone at 100 mg/m2 on days 1 to 5 every 21 days for 6 cycles. In both groups, patients whose response was first documented at cycle 6 could receive 2 additional cycles of therapy.19 The patients’ median age was 66 years; 74% were male, 66% were white, and 32% were Asian.19 The majority of these patients had stage IV disease (76%), positive bone marrow aspirate and/or biopsy (69%), and an International Prognostic Index score ≥3 (54%).19 The primary end point of this trial was median progression-free survival, which was based on independent radiographic assessment. The progression-free survival results demonstrated a significant advantage of the VcRCAP regimen over the R-CHOP regimen—25 months with the VcR-CAP regimen versus 14 months with the R-CHOP regimen (Table 3).19 The overall response rate was 88% in the VcR-CAP group versus 85% in the R-CHOP group, with complete response of 44% in the VcR-CAP group versus 34% in the R-CHOP group.19

Adverse Events Bortezomib Retreatment in Relapsed Myeloma The most frequently reported adverse reactions (incidence ≥20%) associated with bortezomib therapy in clinical studies included nausea, diarrhea, thrombocytoTable 3 VcR-CAP versus R-CHOP: Progression-Free Survival in Previously Untreated Mantle-Cell Lymphoma VcR-CAP R-CHOP Efficacy end point (N = 243) (N = 244) Progression-free survivala Events, N (%) Median, mo Hazard ratio

133 (55)

165 (68)

25 (95% CI, 20-32)

14 (95% CI, 12-17)

0.63 (95% CI, 0.50-0.79) P <.001

By independent radiographic assessment. CI indicates confidence interval; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; VcR-CAP, bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone. Source: Velcade (bortezomib) for injection prescribing information; October 2014.

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penia, neutropenia, peripheral neuropathy, fatigue, neuralgia, anemia, leukopenia, constipation, vomiting, lymphopenia, rash, pyrexia, and anorexia.19 In the RETRIEVE trial, the safety profile was consistent with the known safety profile of patients with relapsed myeloma who received bortezomib therapy. No cumulative toxicities were observed upon retreatment.19 The most common adverse reaction was thrombocytopenia, which occurred in 52% of the patients (grade ≥3, 24% of the patients). Peripheral neuropathy occurred in 28% of the patients (grade ≥3, 6% of the patients).19 The incidence of serious adverse reactions was 12.3%; the most common serious adverse reactions were thrombocytopenia (3.8%), diarrhea (2.3%), herpes zoster (1.5%), and pneumonia (1.5%).19 Adverse reactions leading to discontinuation of bor tezomib therapy occurred in 13% of patients.19 The reasons for treatment discontinuation included peripheral neuropathy (5%) and diarrhea (3%).19 Overall, 2 deaths were attributed to bortezomib therapy and occurred within 30 days of the last bortezomib dose; 1 death occurred in a patient with a cerebrovascular accident, and the other in a patient with sepsis.7,19

Bortezomib in Patients with Untreated MantleCell Lymphoma The safety of the VcR-CAP regimen was assessed in 240 patients with previously untreated MCL.19 Adverse reactions led to the discontinuation of VcR-CAP in 8% of these patients and in 6% of patients who received R-CHOP in this phase 3 clinical trial.19 Among patients receiving VcR-CAP, the most common adverse reaction that led to treatment discontinuation was peripheral neuropathy (1%).19 The most common adverse reaction that led to the discontinuation of R-CHOP was febrile neutropenia (<1%).19 The rates of peripheral neuropathy (all severity grades) were higher among patients receiving VcR-CAP (30%) than in patients receiving R-CHOP (27%). In addition, the incidence of grade 3 peripheral neuropathy was higher in the VcR-CAP group (7%) compared with the R-CHOP group (4%).19 The rate of thrombocytopenia (all grades) was substantially higher among patients who received the VcRCAP regimen (72%) compared with those receiving R-CHOP (17%). Overall, 3 patients who received VcRCAP and 1 patient who received R-CHOP had a bleeding event of grade ≥3.19 Neutropenia (all grades) was more common in the VcR-CAP group (87%) compared with the R-CHOP group (71%).19 Grade ≥3 febrile neutropenia occurred in 15% of patients in the VcR-CAP group and in 13% of patients in the R-CHOP group.19

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Drug Interactions Coadministration of bortezomib with strong cytochrome (CY) P3A4 inhibitors (eg, ketoconazole) can increase the exposure of bortezomib. Patients receiving bortezomib in combination with strong CYP3A4 inhibitors should be closely monitored.19 The coadministration of strong CYP3A4 inducers (eg, rifampin) can decrease the exposure of bortezomib. The use of strong CYP3A4 inducers should be avoided.19 Contraindications Bortezomib is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. Bortezomib therapy is also contraindicated for intrathecal administration.19 Warnings and Precautions Peripheral neuropathy. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain, or weakness. Patients experiencing new or worsening peripheral neuropathy during bortezomib therapy may require a decrease in dose and/or a less dose-intense schedule, or a discontinuation of bortezomib. Patients with preexisting severe neuropathy should receive bortezomib only after a careful risk–benefit assessment.19 Hypotension. Caution should be exercised when treating patients with a history of syncope, patients receiving antihypertensive agents, or patients experiencing dehydration.19 Cardiac toxicity. The worsening and development of cardiac failure have occurred during bortezomib therapy. Patients with existing heart disease or with risk factors for heart disease should be closely monitored.19 Pulmonary toxicity. Acute respiratory syndromes have occurred during bortezomib therapy. Patients should be closely monitored for new or worsening symptoms of pulmonary toxicity.19 Posterior reversible encephalopathy. Magnetic resonance imaging should be considered for an onset of visual or neurologic symptoms; bortezomib therapy should be discontinued if posterior reversible encephalopathy syndrome is suspected.19 Gastrointestinal toxicity. Nausea, diarrhea, constipation, and vomiting may require the use of antiemetic and antidiarrheal medications or fluid replacement.19 Thrombocytopenia or neutropenia. The cyclical pattern of platelet and neutrophil decreases and recovery that is associated with bortezomib use were also observed in studies of retreatment for myeloma and in untreated MCL, with no evidence of cumulative thrombocytope-

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nia or neutropenia. Complete blood counts should be monitored regularly during treatment with bortezomib.19 Tumor lysis syndrome. Patients with a high tumor burden should be monitored closely for tumor lysis syndrome.19 Hepatic toxicity. Hepatic enzymes should be monitored in patients receiving bortezomib therapy.19 Embryofetal risk. Women of reproductive potential should avoid becoming pregnant while receiving bor tezomib therapy. Pregnant women should be advised of the potential for embryofetal harm.19

Use in Specific Populations Pregnancy. No adequate studies were conducted with bortezomib in pregnant women. Women who are pregnant while receiving bortezomib should be informed of the potential hazards to the fetus.19 Nursing mothers. It is not known whether bortezomib is excreted in human milk. A decision whether to discontinue nursing or to discontinue bortezomib therapy should be based on the importance of this drug to the mother.19 Pediatric use. The safety and efficacy of bortezomib in children have not been established.19 Geriatric use. No overall differences in the safety or efficacy of bortezomib were observed between patients aged ≥65 years and younger patients; however, greater sensitivity of some older individuals cannot be ruled out.19 Renal impairment. Dosing adjustments are not necessary for patients with renal insufficiency. Because dialysis may reduce bortezomib concentrations, bortezomib should be administered after the dialysis procedure.19 Hepatic impairment. The exposure of bortezomib is increased in patients with moderate (ie, bilirubin ≥1.5-3 times the upper limit of normal [ULN]) or severe (ie, bilirubin >3 times ULN) hepatic impairment. The starting dose of bortezomib should be reduced in patients with moderate or severe hepatic impairment.19 Patients with diabetes. In clinical studies, hypoglycemia and hyperglycemia were reported in patients with diabetes who were receiving oral hypoglycemic therapy. Patients with diabetes who receive bortezomib therapy may require close monitoring of their blood glucose levels and dose adjustment of antidiabetic medications.19 Conclusions Retreatment with bortezomib is now an FDA-approved option for patients with myeloma whose disease had previously responded to bortezomib therapy and relapsed at least 6 months after the completion of previous bor tezomib therapy. The safety profile of bortezomib retreatment was consistent with the known safety profile of bortezomib in patients with relapsed myeloma, with no cumulative toxicities. Bortezomib is the first treatment to be approved in the

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United States for use in patients with previously untreated MCL. A large randomized clinical trial demonstrated improved progression-free survival and superior response rates with the VcR-CAP regimen compared with the R-CHOP regimen, a frequently used first-line regimen in this setting. Clinical studies are under way to evaluate the use of bortezomib in combination with other regimens that are used in previously untreated and relapsed MCL.21 n

References

1. National Cancer Institute. A snapshot of myeloma. November 5, 2014. www. cancer.gov/researchandfunding/snapshots/myeloma. Accessed January 8, 2015. 2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): multiple myeloma. Version 1.2015. August 13, 2014. www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf. Accessed August 19, 2014. 3. American Cancer Society. Multiple myeloma: what are the key statistics about multiple myeloma? Revised January 23, 2015. www.cancer.org/cancer/ multiplemyeloma/detailedguide/multiple-myeloma-key-statistics. Accessed January 8, 2015. 4. Multiple Myeloma Research Foundation. Newly diagnosed patients: what is multiple myeloma. www.themmrf.org/multiple-myeloma/what-is-multiple- myeloma/. Accessed March 20, 2015. 5. Mayo Clinic staff. Diseases and conditions: multiple myeloma: treatments and drugs. September 11, 2014. www.mayoclinic.org/diseases-conditions/multiple- myeloma/basics/treatment/con-20026607. Accessed March 20, 2015. 6. Schulman KL, Kohles J. Economic burden of metastatic bone disease in the U.S. Cancer. 2007;109:2334-2342. 7. Petrucci MT, Giraldo P, Corradini P, et al. A prospective, international phase 2 study of bortezomib retreatment in patients with relapsed multiple myeloma. Br J Haematol. 2013;160:649-659. 8. Munshi NC, Anderson KC. New strategies in the treatment of multiple myeloma. Clin Cancer Res. 2013;19:3337-3344. 9. Lymphoma Research Foundation. Getting the facts: mantle cell lymphoma. Updated January 2013. www.lymphoma.org/atf/cf/%7Baaf3b4e5-2c43-404cafe5-fd903c87b254%7D/LRF_FACTSHEET_MCL_2013.PDF. Accessed January 6, 2015. 10. Lymphoma Research Foundation. Mantle cell lymphoma: relapsed/refrac-

tory. Updated January 2013. www.lymphoma.org/atf/cf/%7BAAF3B4E5-2C43404C-AFE5-FD903C87B254%7D/LRF_FACTSHEET_MCL_RR_2013.PDF? auid=12730367. Accessed January 6, 2015. 11. Smedby KE, Hjalgrim H. Epidemiology and etiology of mantle cell lymphoma and other non-Hodgkin lymphoma subtypes. Semin Cancer Biol. 2011;21: 293-298. 12. 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/Centers Offices/OfficeofMedicalProductsandTobacco/CDER/ucm094929.htm. Accessed March 20, 2015. 13. US Food and Drug Administration. Drugs: lenalidomide. Updated June 5, 2013. www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm355438. htm. Accessed March 20, 2015. 14. US Food and Drug Administration. Drugs: ibrutinib. Updated November 13, 2013. www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm374857. htm. Accessed March 20, 2015. 15. Leukemia & Lymphoma Society. Mantle cell lymphoma facts. Revised November 2014. www.lls.org/content/nationalcontent/resourcecenter/freeeducation materials/lymphoma/pdf/mantlecelllymphoma.pdf. Accessed January 6, 2015. 16. 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. 17. Takeda Pharmaceutical Company Limited. FDA approves Velcade® (bortezomib) retreatment in patients with multiple myeloma. Press release. August 11, 2014. www.takeda.com/news/2014/20140811_6663.html. Accessed September 3, 2014. 18. Business Wire. FDA approves Velcade® (bortezomib) retreatment in patients with multiple myeloma. Press release. August 8, 2014. www.businesswire. com/news/home/20140808005774/en/FDA-Approves-VELCADE%C2%AEbortezomib-Retreatment-Patients-Multiple#.U_ekJ2Onn6M. Accessed August 16, 2014. 19. Velcade (bortezomib) for injection [prescribing information]. Cambridge, MA: Millennium Pharmaceuticals [Takeda]; October 2014. 20. Takeda Pharmaceutical Company Limited. FDA approves Velcade (bortez omib) for injection for previously untreated patients with mantle cell lymphoma. Press release. October 10, 2014. www.takeda.com/news/2014/20141010_ 6789.html. Accessed January 7, 2015. 21. ClinicalTrials.gov. Bortezomib mantle cell lymphoma. Search results. https:// clinicaltrials.gov/ct2/results?term=bortezomib+mantle+cell+lymphoma&Search= Search. Accessed January 8, 2015.

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Viekira Pak (Ombitasvir, Paritaprevir, and Ritonavir Tablets; Dasabuvir Tablets): All-Oral Fixed Combination Approved for Genotype 1 Chronic Hepatitis C Infection By Lisa A. Raedler, PhD, RPh, Medical Writer

pproximately 130 million to 170 million individuals worldwide, including 3.2 million Americans, are infected with chronic hepatitis C virus (HCV), making it the most common blood-borne disease.1,2 Chronic HCV infection is a silent epidemic; the disease can remain quiescent for decades before clinically significant symptoms appear.3 The prevalence of HCV and its complications are expected to rise as Americans who are currently living with HCV enter their 50s and 60s.4 Research indicates that by 2015, more than 3 million individuals will have HCV infection that has been present for 20 years or more, which will result in a significant increase in the incidence of advanced liver disease, including cirrhosis, decompensated cirrhosis, and liver cancer.5,6 The Centers for Disease Control and Prevention estimates that for every 100 individuals infected with HCV, 1 to 5 will die from liver cancer or cirrhosis.1 In addition to causing substantial morbidity and mortality, HCV is associated with significant financial consequences.3,7 A 2000 study estimated that between 2010 and 2019, the direct medical expenditures for HCV- related conditions will reach nearly $11 billion, the cost of morbidity from disability related to decompensated cirrhosis and hepatocellular carcinoma would reach approximately $21 billion, and the societal cost of premature mortality for patients aged <65 years will exceed $54 billion (in 1999 US dollars).7 HCV is currently the only chronic viral infection that is curable with antiviral therapy. The goals of current anti- HCV approaches are to eradicate infection, to avoid complications, and to prevent the spread of HCV to others.8 In the early 1990s, single-agent interferon was the standard of care for patients with HCV infection. Single- agent interferon represented a significant therapeutic advancement, because until then there was no treatment available for HCV infection; however, single-agent interferon offered a sustained virologic response (SVR) rate of less than 10% in patients with HCV genotype 1, the most common HCV subtype.8 Interferon was then

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used in combination with ribavirin, increasing the SVR rate by another 14% to 22%.8 In the early 2000s, once-weekly pegylated forms of interferon were introduced. The combination of pegylated interferon with ribavirin increased SVR rates to more than 50% in patients with HCV genotype 1. However, HCV genotype 1 was less responsive than HCV genotype 2 or 3.9,10 Because of this variability in HCV response, low response rates in common HCV subpopulations (ie, black patients, patients with cirrhosis), and side effects associated with interferon and ribavirin, there remained a need to develop novel antiviral therapies.8 The treatment options for patients with HCV have evolved significantly in the past several years. In 2011, 2 first-generation protease inhibitors, telaprevir and bo ceprevir (also known as direct-acting antiviral drugs), were approved by the US Food and Drug Administration (FDA).11,12 Both agents offered significant efficacy in patients with HCV genotype 1 infection as measured by SVR rates.11,12 In December 2013, the FDA approved sofosbuvir (Sovaldi) in combination with ribavirin—the first interferon- free, all-oral regimen—for the treatment of patients with HCV genotype 2 or 3.13,14 In addition, sofosbuvir in combination with interferon and ribavirin is approved for the treatment of patients with HCV genotype 1 and genotype 4.13,14 Candidates for sofosbuvir therapy include patients with hepatocellular carcinoma who meet Milan criteria (ie, awaiting liver transplantation) and patients with HCV/HIV-1 coinfection.13,14 Sofosbuvir regimens require less treatment time than older combination regimens—12 weeks for patients with HCV genotype 1, 2, or 4; and 24 weeks for patients with HCV genotype 3.14 In October 2014, the FDA approved the fixed-dose combination capsule of ledipasvir and sofosbuvir (Harvoni) for the treatment of patients with HCV genotype 1 infection.15 This once-daily combination tablet was the first regimen approved for HCV genotype 1 without interferon or ribavirin.15 Interest in novel therapies for HCV remain strong in

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light of the increasing incidence of HCV (and its costly complications), unmet patient needs, and the identification of new drug targets.16 Efforts continue, with the goals of improving the pharmacokinetics and the tolerability of these agents, as well as determining treatment strategies––interferon-containing and interferon-free (all oral) regimens––that optimize outcomes.17

Novel Oral Regimen Approved for Genotype 1 Chronic HCV Infection On December 19, 2014, the FDA approved the combination of ombitasvir, paritaprevir, and ritonavir tablets copacked with dasabuvir tablets (Viekira Pak; AbbVie) for use with or without ribavirin for the treatment of patients with genotype 1 chronic HCV infection, including patients with compensated cirrhosis.18 This combination includes 3 new drugs (ombitasvir, paritaprevir, and dasabuvir) and an older drug (ritonavir) that are copackaged for oral use; ombitasvir is an HCV NS5A inhibitor; paritaprevir, an HCV NS3/4A protease inhibitor; ritonavir, a cytochrome (CY) P3A inhibitor; and dasabuvir, an HCV nonnucleoside NS5B palm polymerase inhibitor. Overall, 3 of these medications target HCV at multiple steps in the viral lifecycle.19 Ombitasvir, paritaprevir, and ritonavir plus dasabuvir combination is the eleventh new drug with breakthrough therapy designation to receive FDA approval.18 This new regimen was reviewed under the FDA’s priority review program, which expedites the assessment of medications for serious conditions that offer a significant improvement in the safety or efficacy.18 “The new generation of therapeutics for hepatitis C virus is changing the treatment paradigm for Americans living with the disease,” said Edward Cox, MD, MPH, Director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research. “We continue to see the development of new all-oral treatments with very high virologic response rates and improved safety profiles compared to some of the older interferon-based drug regimens.” 18 Mechanism of Action The 3 direct-acting HCV antiviral agents––ombitasvir, paritaprevir, and dasabuvir––have distinct mechanisms of action and nonoverlapping resistance profiles.19 This combination is designed to target multiple steps in the HCV lifecycle. The fourth drug, ritonavir, is not active against HCV; it is a potent CYP3A inhibitor that enhances plasma drug concentrations of paritaprevir and overall drug exposure.19 Dosing and Administration The drug includes fixed-dose combination tablets of

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ombitasvir (12.5 mg), paritaprevir (75 mg), and ritonavir (50 mg) copackaged with dasabuvir (250 mg).19 The recommended oral dosage of the combination drug is 2 ombitasvir, paritaprevir, and ritonavir tablets once daily in the morning, and 1 dasabuvir tablet twice daily (ie, morning and evening). The drug should be taken with a meal without regard to fat or caloric content.19 Table 1 summarizes the recommended treatment regimens and duration of therapy for specific subsets of patients with HCV genotype 1 infection.19

Clinical Trials The efficacy and safety of the new 4-drug oral combination were evaluated in 6 randomized, multicenter, clinical trials (Table 2).19-23 A total of 2308 patients with genotype 1 chronic HCV infection received the drug, including patients with cirrhosis or with mild hepatic impairment (ie, Child-Pugh A).19 In the 6 clinical trials, the ombitasvir, paritaprevir, and ritonavir dose was 25/150/100 mg once daily, and the dasabuvir dose was 250 mg twice daily; the dose was not adjusted. For patients who received ribavirin, the ribavirin dose was 1000 or 1200 mg daily, based on the patient’s weight (<75 kg or ≥75 kg, respectively).19 Chronic HCV Genotype 1a Infection without Cirrhosis Patients with HCV genotype 1a infection without Table 1 T reatment Regimen and Duration in Patients with Genotype 1 HCV Infection Patient population

Recommended regimena

Recommended treatment duration

Genotype 1a, no cirrhosis

Ombitasvir, paritaprevir, ritonavir, plus dasabuvir, with ribavirin

12 wks

Genotype 1a, cirrhosis

Ombitasvir, paritaprevir, ritonavir, plus dasabuvir, with ribavirin

24 wksb

Genotype 1b, no cirrhosis

Ombitasvir, paritaprevir, ritonavir, plus dasabuvir

12 wks

Genotype 1b, cirrhosis

Ombitasvir, paritaprevir, ritonavir, plus dasabuvir, with ribavirin

12 wks

Follow the genotype 1a dosing recommendations in patients with an unknown genotype 1 subtype or with mixed genotype 1 infection. b A 12-week treatment may be considered for some patients based on their treatment history. HCV indicates hepatitis C virus. Source: Viekira Pak (ombitasvir, paritaprevir, and ritonavir tablets; dasabuvir tablets), copackaged, prescribing information; February 2015. a

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andomized, Multicenter Trials with Ombitasvir, Paritaprevir, Ritonavir, plus Dasabuvir, with/without Table 2 R Ribavirin in Patients with Genotype 1 Chronic HCV Infection Ombitasvir, paritaprevir, ritonavir, plus dasabuvir, with/without Clinical trial Trial design Patient cohort ribavirin (sample size) SAPPHIRE-I

Double-blind, placebo-controlled

Without cirrhosis, treatment-naïve,a genotype 1a and 1b

With ribavirin (N = 473) Placebo (N = 158)

SAPPHIRE-II

Double-blind, placebo-controlled

Without cirrhosis, treatment-experienced,b genotype 1a and 1b

With ribavirin (N = 297) Placebo (N = 97)

PEARL-II

Open-label

Without cirrhosis, treatment-experienced, genotype 1b

With ribavirin (N = 88) Without ribavirin (N = 91)

PEARL-III

Double-blind

Without cirrhosis, treatment-naïve, genotype 1b

With ribavirin (N = 210) Without ribavirin (N = 209)

PEARL-IV

Double-blind

Without cirrhosis, treatment-naïve, genotype 1a

With ribavirin (N = 100) Without ribavirin (N = 205)

Open-label

With cirrhosis, treatment-naïve and treatment-experienced, genotype 1a and 1b

With ribavirin for 12 wks (N = 208) With ribavirin for 24 wks (N = 172)

TURQUOISE-II

Treatment-naïve was defined as receiving no previous therapy for HCV infection. Treatment-experienced was defined as patients whose disease previously relapsed, previous partial responders, or previous null responders to pegylated interferon plus ribavirin treatment. HCV indicates hepatitis C virus. Source: Viekira Pak (ombitasvir, paritaprevir, and ritonavir tablets; dasabuvir tablets), copackaged, prescribing information; February 2015. a

cirrhosis received ombitasvir, paritaprevir, and ritonavir plus dasabuvir, with ribavirin, for 12 weeks in 3 studies: SAPPHIRE-I, SAPPHIRE-II, and PEARLIV.19,21-23 The patients’ median age was 53 years (range, 18-70 years).19 The majority of patients were male (63%) and white (90%), with baseline HCV RNA levels ≥800,000 IU/mL (85%). In these studies, 7% of patients were black or African American, 8% were Hispanic or Latino, and 19% had a body mass index (BMI) ≥30 kg/m2.19 Table 3 presents the SVR outcomes for treatment- naïve and treatment-experienced patients who received ombitasvir, paritaprevir, and ritonavir plus dasabuvir, with ribavirin, for 12 weeks in these clinical trials.

Chronic HCV Genotype 1b Infection without Cirrhosis Patients with HCV genotype 1b infection without cirrhosis received ombitasvir, paritaprevir, and ritonavir plus dasabuvir, with or without ribavirin, for 12 weeks in 2 studies: PEARL-II and PEARL-III.19 The patients’ median age was 52 years (range, 22-70 years). The majority of patients were female (53%) and white (93%), with baseline HCV RNA levels ≥800,000 IU/mL (77%).19 Overall, 5% of patients were black or African American, and 2% were Hispanic or Latino. In addition, 21% of patients had a BMI ≥30 kg/m2.19 Table 4 summarizes the SVR outcomes for the treatment-naïve and treatment-experienced patients who

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received ombitasvir, paritaprevir, and ritonavir plus dasabuvir for 12 weeks in these clinical trials.

Chronic HCV Genotype 1a or 1b Infection with Compensated Cirrhosis A total of 380 treatment-naïve or treatment-experienced patients with HCV genotype 1a or genotype 1b, with cirrhosis, and with mild hepatic impairment (ChildPugh A) enrolled in TURQUOISE-II, an open-label randomized clinical trial.19,20 This clinical trial compared the SVR rates after treatment with ombitasvir, paritaprevir, and ritonavir plus dasabuvir, with ribavirin, for 12 or 24 weeks in patients who were treatment-naïve or who did not reach SVR with previous pegylated interferon therapy.19 The patients’ median age was 58 years (range, 21-71 years).19 The majority of patients were male (70%) and white (95%), with baseline HCV RNA levels ≥800,000 IU/mL (86%). Overall, 3% of patients were black or African American, 12% were Hispanic or Latino, and 28% had a BMI ≥30 kg/m2.19 Treatment outcomes for treatment-naïve and treatment-experienced patients with cirrhosis who received ombitasvir, paritaprevir, and ritonavir plus dasabuvir, with ribavirin, for 12 or 24 weeks are summarized in Table 5. Durability of Response In an open-label clinical trial, 92% of patients (526 of 571) who received various combinations of the direct-

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acting antiviral agents that are included in the ombitasvir, paritaprevir, and ritonavir plus dasabuvir combination, with or without ribavirin, reached an SVR after 12 weeks of treatment (ie, SVR12).19 Among patients who reached SVR12, 99% maintained their response through 48 weeks posttreatment.19

Safety The pooled data from more than 2000 patients with chronic HCV infection who participated in 6 phase 3 clinical trials were used for the safety assessment of ombitasvir, paritaprevir, and ritonavir plus dasabuvir.19 These studies evaluated the combination tablets given for 12 or 24 weeks (with or without ribavirin).19 The safety of ombitasvir, paritaprevir, and ritonavir plus dasabuvir, with ribavirin, was assessed in 770 patients with chronic HCV infection in 2 placebo-controlled clinical trials known as SAPPHIRE-I and -II.19 Adverse events that occurred more frequently in patients who received the 4-drug combination plus ribavirin compared with placebo included fatigue, nausea, pruritus, other skin reactions, insomnia, and asthenia. Overall, 2% of patients in SAPPHIRE-I and SAPPHIRE-II experienced a serious adverse event, and less than 1% of patients permanently discontinued treatment as a result of adverse events.19 The safety of ombitasvir, paritaprevir, and ritonavir plus dasabuvir, with and without ribavirin, was assessed in 401 patients and in 509 patients with chronic HCV infection, respectively, in 3 clinical trials known as PEARL-II, PEARL-III, and PEARL-IV.19 Adverse events that occurred more frequently in patients who received ombitasvir, paritaprevir, and ritonavir plus dasabuvir with ribavirin compared with the 4-drug combination without ribavirin were pruritus, nausea, insomnia, and asthenia.19 The majority of adverse events were mild to moderate. Less than 1% of patients permanently discontinued treatment because of adverse events after receiving the 4-drug combination, with or without ribavirin.19 The safety of the 4-drug combination plus ribavirin was assessed in 380 patients with compensated cirrhosis who received treatment for 12 or 24 weeks in TURQUOISE-II.19 The type and the severity of adverse events in these patients were comparable to those in patients without cirrhosis who participated in other phase 3 clinical trials. Fatigue, skin reactions, and dyspnea occurred at least 5% more frequently in patients who received ombitasvir, paritaprevir, and ritonavir plus dasabuvir with ribavirin for 24 weeks.19 The majority of adverse events occurred during the first 12 weeks of dosing in the 12-week and 24-week treatment arms, and were mild to moderate.19 Serious adverse events were reported by 6% and 5% of patients who received treat-

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ment with the new combination plus ribavirin for 12 and 24 weeks, respectively.19 In each study arm, 2% of patients permanently discontinued the new regimen plus ribavirin as a result of adverse events.19

Drug Interactions The concomitant use of ombitasvir, paritaprevir, and ritonavir plus dasabuvir and certain other drugs can result in known and potentially significant drug interactions.19 Drug interactions may lead to the loss of therapeutic effect of the new regimen, the development of resistance, and clinically significant adverse events from greater exposure to concomitant drugs or to components of ombitasvir, paritaprevir, and ritonavir plus dasabuvir.19 Contraindications If the combination pack of ombitasvir, paritaprevir, and ritonavir tablets plus dasabuvir tablets is administered with ribavirin, the contraindications to ribavirin also apply.19 Because of the risk for toxicity, the ombitasvir, paritaprevir, and ritonavir plus dasabuvir regimen is contrain SVR Rates at 12 Weeks of Ombitasvir, Paritaprevir, Table 3 Ritonavir, plus Dasabuvir, with Ribavirin, in Patients with HCV Genotype 1a without Cirrhosis Outcome at 12 weeks of ombitasvir, paritaprevir, SAPPHIRE-I SAPPHIRE-II PEARL-IV ritonavir, plus treatmenttreatmenttreatmentdasabuvir, na誰ve experienced na誰ve with ribavirin (N = 322) (N = 173) (N = 100) SVR12, %

HCV indicates hepatitis C virus; SVR, sustained virologic response. Adapted from Viekira Pak (ombitasvir, paritaprevir, and ritonavir tablets; dasabuvir tablets), copackaged, prescribing information; February 2015.

SVR Rates at 12 Weeks of Ombitasvir, Paritaprevir, Table 4 Ritonavir, plus Dasabuvir, in Patients with Genotype 1b HCV without Cirrhosis Outcome at 12 weeks of ombitasvir, paritaprevir, PEARL-II PEARL-III ritonavir, plus treatment-足experienced treatment-na誰ve dasabuvir (N = 91) (N = 209) SVR12, %

100

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esponse Rates at 12 and 24 Weeks of Treatment with Ombitasvir, Paritaprevir, Ritonavir, plus Dasabuvir, Table 5 R with Ribavirin, in Patients with Genotype 1 Chronic HCV with Cirrhosis HCV genotype 1a ombitasvir, paritaprevir, ritonavir, and dasabuvir plus ribavirin

HCV genotype 1b ombitasvir, paritaprevir, ritonavir, and dasabuvir plus ribavirin

Outcome

12 weeks

24 weeks

12 weeks

Sustained virologic response 12, % (n/N)

89 (124/140)

95 (115/121)

99 (67/68)

92 (59/64)

95 (53/56)

100 (22/22)

Sustained virologic response 12 for treatment-naïve patients, % (n/N)

Sustained virologic response 12 by previous pegylated interferon treatment Null responder, % (n/N)

80 (40/50)

93 (39/42)

100 (25/25)

Partial responder, % (n/N)

100 (11/11)

100 (10/10)

86 (6/7)

Relapsed, % (n/N)

93 (14/15)

100 (13/13)

100 (14/14)

HCV indicates hepatitis C virus. Adapted from Viekira Pak (ombitasvir, paritaprevir, and ritonavir tablets; dasabuvir tablets), copackaged, prescribing information; February 2015.

dicated in patients with severe hepatic impairment.19 The combination is also contraindicated with: • Drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events • Drugs that are strong inducers of CYP3A and CYP2C8, which may lead to reduced efficacy of the combination of ombitasvir, paritaprevir, and ritonavir plus dasabuvir • Drugs that are strong inhibitors of CYP2C8, which may increase dasabuvir plasma concentrations and the risk for QT prolongation.19

Warnings and Precautions Increased risk for alanine aminotransferase (ALT) elevations. In clinical trials of ombitasvir, paritaprevir, and ritonavir plus dasabuvir, with or without ribavirin, elevations of ALT levels to >5 times the upper limit of normal (ULN) were observed in approximately 1% of all patients.19 These ALT elevations were typically asymptomatic, occurred during the first 4 weeks of treatment and declining within 2 to 8 weeks of continued dosing.19 Evaluations of hepatic function should be performed during the first 4 weeks after starting treatment, and as clinically indicated thereafter. If elevated ALT levels are observed, close monitoring is recommended.19 Patients should consult a healthcare professional if they experience signs of liver problems, including the onset of fatigue, weakness, lack of appetite, nausea and vomiting, jaundice, or discolored feces. The discontinuation of ombitasvir, paritaprevir, and ritonavir plus dasabuvir should be considered if ALT levels remain >10 times the ULN. The 4-drug combination should be permanently discontinued if elevation in ALT levels is

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accompanied by the signs or symptoms of liver inflammation or increasing conjugated bilirubin, alkaline phosphatase, or international normalized ratio.19 Risks associated with ribavirin combination treatment. The warnings and precautions for ribavirin, including the pregnancy avoidance warning, apply when ombitasvir, paritaprevir, and ritonavir plus dasabuvir tablets are administered with ribavirin.19 Risk for HIV-1 protease inhibitor drug resistance. Ritonavir is an HIV-1 protease inhibitor. To reduce the risk for HIV-1 protease inhibitor drug resistance, patients who are HCV/HIV-1 coinfected and who receive treatment with ombitasvir, paritaprevir, and ritonavir plus dasabuvir should also receive a suppressive antiretroviral drug regimen.19

Specific Populations Pregnancy. Ombitasvir, paritaprevir, and ritonavir plus dasabuvir is assigned pregnancy category B; there are no adequate and well-controlled studies with this regimen in pregnant women. It should therefore only be used during pregnancy if clearly needed.19 The combination of ombitasvir, paritaprevir, and ritonavir plus dasabuvir, with ribavirin, is contraindicated in pregnant women and in men whose female partners are pregnant.19 Nursing mothers. It is not known whether the components of ombitasvir, paritaprevir, and ritonavir plus dasabuvir and its metabolites are present in human breast milk.19 The developmental and health benefits of breastfeeding, as well as the mother’s clinical need for this combination and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition, should be considered.19

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Pediatric use. The safety and efficacy of ombitasvir, paritaprevir, and ritonavir plus dasabuvir have not been established in pediatric patients aged <18 years.19 Geriatric use. No dosage adjustment is recommended for geriatric patients.19 Renal impairment. Patients with mild, moderate, or severe renal impairment do not require dose adjustment of ombitasvir, paritaprevir, and ritonavir plus dasabuvir.19 When managing patients with renal impairment who

Ombitasvir, paritaprevir, and ritonavir tablets plus dasabuvir tablets represents a novel, multitargeted treatment option for patients with genotype 1 HCV infection. require combination therapy with ribavirin, the prescribing information for ribavirin should be consulted.19 Hepatic impairment. No dosage adjustment is recommended for patients with mild hepatic impairment (Child-Pugh A). Ombitasvir, paritaprevir, and ritonavir plus dasabuvir is not recommended in patients with HCV and moderate hepatic impairment (Child-Pugh B), and is contraindicated in patients with severe hepatic impairment (Child-Pugh C).19

Conclusion Twice-daily ombitasvir, paritaprevir, and ritonavir plus dasabuvir is a very active and safe oral option for patients with genotype 1 HCV infection. Overall, 6 phase 3 studies have demonstrated high rates of response in all patient subgroups, suggesting that this copacked oral combination of 3 new antiviral drugs plus a CYP3A inhibitor is effective across a broad range of treatment-naïve and treatment-experienced patients with HCV genotype 1 infection. Ombitasvir, paritaprevir, and ritonavir tablets plus dasabuvir tablets represents a novel, multitargeted treatment option for patients with genotype 1 HCV infection. n

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References

1. Centers for Disease Control and Prevention. Hepatitis C FAQs for health professionals. Updated March 6, 2015. www.cdc.gov/hepatitis/HCV/HCVfaq. htm#section1. Accessed February 9, 2015. 2. Lavanchy D. The global burden of hepatitis C. Liver Int. 2009;29(suppl 1): 74-81. 3. US Department of Health & Human Services. Action plan for the prevention, care, & treatment of viral hepatitis: updated: 2014-2016. February 2014. http://aids.gov/pdf/viral-hepatitis-action-plan.pdf. Accessed March 24, 2015. 4. Davis GL, Alter MJ, El-Serag H, et al. Aging of hepatitis C virus (HCV)- infected persons in the United States: a multiple cohort model of HCV prevalence and disease progression. Gastroenterology. 2010;138:513-521, 521.e1-521.e6. 5. McHutchison JG, Bacon BR. Chronic hepatitis C: an age wave of disease burden. Am J Manag Care. 2005;11(10 suppl):S286-S295; quiz S307-S311. 6. Zalesak M, Francis K, Gedeon A, et al. Current and future disease progression of the chronic HCV population in the United States. PLoS One. 2013; 8:e63959. 7. Wong JB, McQuillan GM, McHutchison JG, Poynard T. Estimating future hepatitis C morbidity, mortality, and costs in the United States. Am J Public Health. 2000;90:1562-1569. 8. Poordad F, Dieterich D. Treating hepatitis C: current standard of care and emerging direct-acting antiviral agents. J Viral Hepat. 2012;19:449-464. 9. Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975-982. 10. Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358:958-965. 11. Incivek (telaprevir) tablets [prescribing information]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; October 2013. 12. Victrelis (boceprevir) capsules [prescribing information]. Whitehouse Station, NJ: Merck & Co, Inc; July 2014. 13. US Food and Drug Administration. FDA approves Sovaldi for chronic hepatitis C: drug is third with breakthrough therapy designation to receive FDA approval. Press release. December 6, 2013. www.fda.gov/NewsEvents/Newsroom/ PressAnnouncements/ucm377888.htm. Accessed February 9, 2015. 14. Sovaldi (sofosbuvir) tablets [prescribing information]. Foster City, CA: Gilead Sciences, Inc; November 2014. 15. Harvoni (ledipasvir and sofosbuvir) tablets [prescribing information]. Foster City, CA: Gilead Sciences, Inc; October 2014. 16. Stedman CAM. Current prospects for interferon-free treatment of hepatitis C in 2012. J Gastroenterol Hepatol. 2013;28:38-45. 17. Kiser JJ, Flexner C. Direct-acting antiviral agents for hepatitis C virus infection. Annu Rev Pharmacol Toxicol. 2013;53:427-449. 18. US Food and Drug Administration. FDA approves Viekira Pak to treat hepatitis C. Press release. December 19, 2014. www.fda.gov/NewsEvents/Newsroom/ PressAnnouncements/ucm427530.htm. Accessed February 9, 2015. 19. Viekira Pak (ombitasvir, paritaprevir, and ritonavir tablets; dasabuvir tablets), copackaged [prescribing information]. North Chicago, IL: AbbVie Inc; February 2015. 20. Poordad F, Hezode C, Trinh R, et al. ABT-450/r–ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis. N Engl J Med. 2014;370:1973-1982. 21. Feld JJ, Kowdley KV, Coakley E, et al. Treatment of HCV with ABT-450/r– ombitasvir and dasabuvir with ribavirin. N Engl J Med. 2014;370:1594-1603. 22. Zeuzem S, Jacobson IM, Baykal T, et al. Retreatment of HCV with ABT450/r–ombitasvir and dasabuvir with ribavirin. N Engl J Med. 2014;370:16041614. 23. Ferenci P, Bernstein D, Lalezari J, et al; for the PEARL-III Study and PEARL-IV Study. ABT-450/r–ombitasvir and dasabuvir with or without ribavirin for HCV. N Engl J Med. 2014;370:1983-1992.

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Zontivity (Vorapaxar), First-in-Class PAR-1 Antagonist, Receives FDA Approval for Risk Reduction of Heart Attack, Stroke, and Cardiovascular Death By Loretta Fala, Medical Writer

n the United States, heart disease is the number one cause of death, claiming the lives of approximately 600,000 people annually—a staggering 1 in every 4 deaths.1,2 Coronary heart disease (CHD) alone accounts for nearly 380,000 deaths yearly.2 Myocardial infarction (MI) is a common type of CHD affecting 720,000 Americans every year. Of these total MIs, 515,000 are first MIs, and 205,000 are recurrent MIs.2 Stroke is the fourth leading cause of mortality in the United States, accounting for 1 of every 19 deaths annually.1,3 In fact, every 4 minutes someone dies of a stroke. Overall, stroke affects an estimated 795,000 Americans annually; of this total, 610,000 are first strokes, and 185,000 are recurrent strokes. In addition, stroke is a leading cause of disability, particularly in individuals aged ≥65 years.3 Peripheral arterial disease (PAD), a condition characterized by plaque buildup in the legs, increases the risk for MI and stroke.4 It is estimated that 1 in every 20 Americans aged >50 years has PAD.4 CHD accounts for $108.9 billion total costs annually in the United States.2 Stroke alone accounts for $38.6 billion annually in healthcare costs and lost productivity.3 Adequate control of hypertension and high low-density lipoprotein cholesterol (LDL-C) has been shown to reduce the risk for stroke and CHD.5-7 Other factors that may reduce the risk for cardiovascular (CV) disease include exercising, refraining from smoking, and maintaining a healthy diet and weight.1 Pharmacologic approaches for patients at risk for CV disease include therapies that control hypertension and reduce high LDL-C and/or antithrombotic therapies.8 Patients at high risk for thrombotic events may be managed with an antithrombotic drug—either an anticoagulant or an antiplatelet.8 Many patients who have an MI undergo thrombolysis, a procedure with a clot-dissolving agent, to restore coronary artery blood flow.9 Other patients may need an urgent coronary revascularization procedure, including a coronary artery bypass graft surgery or a percutaneous intervention to improve blood flow.9 For patients with acute coronary syndromes, the use of platelet inhibitors was shown to reduce the rate of

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thrombotic events; however, these agents are associated with a risk of bleeding.10 Recently, research has focused on the efficacy and safety of intensifying antiplatelet therapy in patients with established atherosclerosis by adding an agent with a different pharmacologic pathway.11 One of these pathways targets thrombin, a serine protease that facilitates thrombosis through the selective inhibition of protease-activated receptor (PAR)-1, the main thrombin receptor on human platelets.11

Vorapaxar: A Novel Antiplatelet Treatment Option On May 8, 2014, the US Food and Drug Administration (FDA) approved vorapaxar (Zontivity; Merck)— the first-in-class PAR-1 antagonist––for the reduction of thrombotic CV events in patients with a history of MI or with PAD.12 Vorapaxar has been shown to reduce the rate of a combined end point of CV death, MI, stroke, and urgent coronary revascularization.11 The FDA approval of vorapaxar was based on the TRA 2P-TIMI 50 (Thrombin Receptor Antagonist in the Secondary Prevention of Atherothrombotic Ischemic Events-Thombolysis in Myocardial Infarction) clinical trial, a double-blind, placebo-controlled, phase 3 study that included more than 26,000 patients.11,13 The FDA’s labeling requires vorapaxar to be dispensed with a patient medication guide that includes instructions for its use and important safety information. This guide directs healthcare professionals to inform patients about the increased risk for bleeding and bruising associated with this medication and to instruct patients to report any unanticipated, prolonged, or excessive bleeding or blood in the stool or urine.12 According to Ellis Unger, MD, Director of the Office of Drug Evaluation in the FDA’s Center for Drug Evaluation and Research, “In patients who have had a heart attack or who have peripheral arterial disease, this drug will lower the risk of heart attack, stroke, and cardiovascular death. In the study that supported the drug’s approval, Zontivity lowered this risk from 9.5 percent to 7.9 percent over a 3-year period—about 0.5 percent per year.”12

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Dosing and Administration Vorapaxar is available as a 2.08-mg tablet (equivalent to 2.5 mg of vorapaxar sulfate) and is administered orally once daily, with or without food. The use of vorapaxar with aspirin and/or clopidogrel should follow the indications or standards of care for these medications. There is limited clinical experience with other antiplatelet drugs or with vorapaxar as the only administered antiplatelet agent.13

clots.9 Vorapaxar is a reversible antagonist of PAR-1 expressed on platelets, but its long half-life makes it effectively irreversible. In in vitro studies, vorapaxar has been shown to inhibit thrombin-induced and thrombin receptor agonist peptide-induced platelet aggregation.13

The Pivotal TRA 2P-TIMI 50 Clinical Trial The efficacy of vorapaxar is supported by clinical evidence from the pivotal TRA 2P-TIMI 50 clinical trial, a randomized, double-blind, placebo-controlled phase 3 clinical trial in patients with evidence or a history of atherosclerosis involving the coronary system (ie, spon-

Mechanism of Action Vorapaxar reduces the risk for MI and stroke by decreasing the tendency of platelets to form blood

Table 1 V orapaxar versus Placebo: Event Rates for Primary and Secondary End Points in the TRA 2P-TIMI 50 Study 3-yr Kaplan-Meier event rate

Placebo, % (N = 13,224)

Vorapaxar, % (N = 13,225)

Hazard ratioa

Primary: composite of CV death, MI, stroke, and UCR

12.4

11.2

0.88 (95% CI, 0.82-0.95)

.001

Secondary: composite of CV death, MI, and stroke

10.5

9.3

0.87 (95% CI, 0.80-0.94)

<.001

End points

P value

Vorapaxar group versus placebo group. CI indicates confidence interval; CV, cardiovascular; MI, myocardial infarction; UCR, urgent coronary revascularization. Source: Zontivity (vorapaxar) tablets prescribing information; May 2014.

Table 2 V orapaxar versus Placebo: Time to First Event in Patients with Post-MI or PAD and No History of Stroke or TIA in the TRA 2P-TIMI 50 Study Placebo Vorapaxar (N = 10,090) (N = 10,080) Patients KaplanPatients Kaplanwith events,a Meier,b with events,a Meier,b Efficacy end points N (%) % N (%) % Hazard ratioc P value Primary: composite of CV death, MI, stroke, UCRa

—

12.4

11.2

0.88 (95% CI, 0.82-0.95)

.001

Secondary: composite of CV death, MI, strokea

—

10.5

9.3

0.87 (95% CI, 0.80-0.94)

<.001

Other secondary efficacy end points (first specified event at any time)d CV death

239 (2.4)

2.8

205 (2.0)

2.4

0.86 (95% CI, 0.71-1.03)

569 (5.6)

6.4

470 (4.7)

5.4

0.82 (95% CI, 0.73-0.93)

Stroke

145 (1.4)

1.6

98 (1.0)

1.2

0.67 (95% CI, 0.52-0.87)

UCR

283 (2.8)

249 (2.5)

2.8

0.88 (95% CI, 0.74-1.04)

Each patient was counted only once in the component of the primary efficacy end point. Kaplan-Meier estimate at 1080 days. c Vorapaxar group versus placebo group. d Including patients who could have had other nonfatal events or subsequently died. CI indicates confidence interval; CV, cardiovascular; MI, myocardial infarction; NR, not reported; PAD, peripheral arterial disease; TIA, transient ischemic attack; UCR, urgent coronary revascularization. Source: Zontivity (vorapaxar) tablets prescribing information; May 2014. a

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taneous MI ≥2 weeks but ≤12 months before the study), the cerebral system (ie, ischemic stroke), or the peripheral vascular system (ie, documented PAD).11,13 The patients were randomized to receive daily treatment with vorapaxar (N = 13,225) or placebo (N = 13,224) in addition to the standard of care. The primary end point was a composite of CV death, MI, stroke, or recurrent ischemia leading to urgent coronary revascularization. The secondary end point was a composite of CV death, MI, or stroke. The median follow-up time was 2.5 years (up to 4 years).11,13 Table 1 describes the findings for the primary and secondary efficacy end points. Table 2 shows the findings in patients with post-MI or PAD and without a history of stroke or transient ischemic attack (TIA). The effect of long-term treatment with vorapaxar on the primary and key secondary end points was maintained for the duration of the trial (median follow-up of 2.5 years, up to 4 years).11,13 Among patients with post-MI or PAD who survived an on-study event, the incidence of subsequent events was lower with vorapaxar. The time from the previous MI to randomization had no relationship to the treatment benefit for the primary study outcome.11,13

Adverse Events The safety of vorapaxar was evaluated in the TRA 2P-TIMI 50 study, and included 13,186 patients––2187 of whom received treatment with this medication for more than 3 years. The patients randomized to vorapaxar received treatment for a median of 2.3 years. The most common adverse reactions reported in patients receiving vorapaxar were bleeding, including life-threatening and fatal bleeding.11,13 The results for the bleeding end points in patients with post-MI or PAD and without a history of stroke or TIA are shown in Table 3. Vorapaxar was associated with a 55% increase in moderate or severe bleeding as measured by GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries).11,13 GUSTO severe bleeding was defined as fatal, intracranial, or bleeding with hemodynamic compromise requiring intervention. GUSTO moderate bleeding was defined as bleeding requiring transfusion of whole blood or packed red blood cells without hemodynamic compromise. Although this study was not designed to evaluate the relative benefits and risks of vorapaxar in individual patient subgroups, patients with a history of stroke, TIA, or

on–CABG-Related Bleeding Events in Patients with Post-MI or PAD and No History of Stroke or TIA (First Table 3 N Dose to Last Dose + 30 Days) in the TRA 2P-TIMI 50 Study Placebo Vorapaxar (N = 10,049) (N = 10,059) Patients with KaplanPatients with Kaplanbleeding events, Meier,a bleeding events, Meier,a % N (%) % Hazard ratiob,c Bleeding events N (%) GUSTO bleeding categories Severe

100 (1.0)

1.3

1.24 (95% CI, 0.92-1.66)

199 (2.0)

2.4

303 (3.0)

3.7

1.55 (95% CI, 1.30-1.86)

1769 (17.6)

19.8

2518 (25.0)

27.7

1.52 (95% CI, 1.43-1.61)

Fatal bleeding

14 (0.1)

0.2

16 (0.2)

0.2

1.15 (95% CI, 0.56-2.36)

Intracranial hemorrhage

31 (0.3)

0.4

45 (0.4)

0.6

1.46 (95% CI, 0.92-2.31)

Clinically significant bleedingb

950 (9.5)

10.9

1349 (13.4)

15.5

1.47 (95% CI, 1.35-1.60)

Gastrointestinal bleeding

297 (3.0)

3.5

400 (4.0)

4.7

1.37 (95% CI, 1.18-1.59)

Moderate or severe Any GUSTO bleeding (severe, moderate, mild)

82 (0.8)

Kaplan-Meier estimate at 1080 days. Clinically significant bleeding includes any bleeding requiring medical attention, including intracranial hemorrhage, or clinically significant overt signs of hemorrhage associated with a drop in hemoglobin (Hb) of ≥3 g/dL (or, when Hb is not available, an absolute drop in hematocrit of ≥15% or a fall in hematocrit of 9 to <15%). c Vorapaxar group versus placebo group. CABG indicates coronary artery bypass graft surgery; CI, confidence interval; GUSTO, Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries; MI, myocardial infarction; PAD, peripheral arterial disease; TIA, transient ischemic attack. Source: Zontivity (vorapaxar) tablets prescribing information; May 2014. a

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intracranial hemorrhage (ICH) showed an increased risk for ICH events.11,13

Contraindications The use of vorapaxar is contraindicated in patients with a history of stroke, TIA, or ICH, because of an increased risk for ICH in this patient population. Vorapaxar is also contraindicated in patients with pathologic bleeding, such as ICH or peptic ulcer.13 Warnings and Precautions Boxed warning. The prescribing information for vorapaxar includes a boxed warning about the risk for bleeding. Vorapaxar should not be used in patients with a history of stroke, TIA, ICH, or active pathologic bleeding. Furthermore, antiplatelet agents, including vorapaxar, increase the risk for bleeding, including ICH and fatal bleeding.13 General risk for bleeding. Antiplatelet agents, including vorapaxar, increase the risk for bleeding, including ICH and fatal bleeding. Vorapaxar increases a patient’s risk for bleeding in proportion to the patient’s underlying bleeding risk. Before initiating vorapaxar therapy, the underlying risk for bleeding should be considered.13 Strong cytochrome P3A inhibitors or inducers. Vorapaxar is eliminated primarily by metabolism, with contributions from cytochrome (CY) P3A4 and CYP2J2. Strong CYP3A inhibitors increase vorapaxar exposure. Vorapaxar should not be used with strong CYP3A inhibitors (eg, ketoconazole, itraconazole, posaconazole, cla rithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, boceprevir, telaprevir, telithromycin, and conivaptan). Strong CYP3A inducers decrease vorapaxar exposure. Vorapaxar should not be used with strong inducers of CYP3A (eg, rifampin, carbamazepine, St. John’s Wort, and phenytoin).13 Use in Specific Populations Pregnancy. There are no adequate and well-controlled studies of vorapaxar use in pregnant women. Vorapaxar should only be used during pregnancy if the potential benefit to the mother justifies the potential risk to the fetus.13 Nursing mothers. Nursing should be discontinued in patients receiving vorapaxar, or vorapaxar should be discontinued in a nursing mother.13 Renal impairment. No dose adjustment is needed in patients with renal impairment.13 Hepatic impairment. In patients with mild and moderate hepatic impairment, no dose adjustment is required. Based on the increased risk for bleeding in pa-

Vol 8

Special Feature

March 2015

tients with severe hepatic impairment, vorapaxar is not recommended in these patients.13 Overdose. There is no known treatment to reverse the antiplatelet effect of vorapaxar; if bleeding occurs after a vorapaxar overdose, neither dialysis nor platelet transfusion can be expected to be beneficial. The inhibition of platelet aggregation can be expected for weeks after the discontinuation of normal dosing. There is no standard test available to assess the risk for bleeding in an overdose situation.13

Conclusion Vorapaxar, the first-in-class PAR-1 antagonist to receive FDA approval, represents a new antiplatelet treatment option for patients at high risk for MI, stroke, or CV death, namely, patients with a history of MI or with PAD. In a clinical trial involving more than 26,000 patients, treatment with vorapaxar, in addition to the standard of care, was shown to reduce the rate of a composite end point of CV death, MI, stroke, and the need for urgent coronary revascularization procedures. The most common adverse reaction reported in patients receiving vorapaxar is bleeding, including life- threatening and fatal bleeding. n References

1. Centers for Disease Control and Prevention. CDC health disparities and inequalities report—United States, 2013. MMWR Morb Mortal Wkly Rep. 2013;62(suppl 3):157-160. 2. Centers for Disease Control and Prevention. Heart disease facts. Updated July 7, 2014. www.cdc.gov/heartdisease/facts.htm. Accessed June 3, 2014. 3. Centers for Disease Control and Prevention. Stroke fact sheet. Updated July 26, 2013. www.cdc.gov/dhdsp/data_statistics/fact_sheets/fs_stroke.htm. Accessed June 3, 2014. 4. National Institutes of Health. Facts about peripheral arterial disease (PAD). August 2006. www.nhlbi.nih.gov/health/public/heart/pad/docs/pad_extfctsht_general_ 508.pdf. Accessed June 3, 2014. 5. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastat in Survival Study (4S). Lancet. 1994;344:1383-1389. 6. Sacks FM, Pfeffer MA, Moye LA, et al; for the Cholesterol and Recurrent Events Trial Investigators. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med. 1996;335:1001-1009. 7. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med. 1998;339:1349-1357. 8. National Cholesterol Education Program. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III): Final Report. NIH Publication No. 02-5215. September 2002. www.nhlbi.nih.gov/files/ docs/resources/heart/atp3full.pdf. Accessed August 15, 2014. 9. American Heart Association. Cardiac procedures and surgeries. Updated June 27, 2014. www.heart.org/HEARTORG/Conditions/HeartAttack/PreventionTreatment ofHeartAttack/Cardiac-Procedures-and-Surgeries_UCM_303939_Article.jsp. Accessed August 15, 2014. 10. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361:1045-1057. 11. Morrow DA, Braunwald E, Bonaca MP, et al; for the TRA 2P–TIMI 50 Steering Committee and Investigators. Vorapaxar in the secondary prevention of atherothrombotic events. N Engl J Med. 2012;366:1404-1413. 12. US Food and Drug Administration. FDA approves Zontivity to reduce the risk of heart attacks and stroke in high-risk patients. Press release. May 8, 2014. www. fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm396585.htm. Accessed May 20, 2014. 13. Zontivity (vorapaxar) tablets [prescribing information]. Whitehouse Station, NJ: Merck Sharp & Dohme Corp; May 2014.

www.AHDBonline.com

American Health & Drug Benefits

151

Consider once-weekly TANZEUM for formulary inclusion

• The lowest Wholesale Acquisition Cost (WAC) in the GLP-1 receptor agonist class1,a — WAC comparison does not imply comparable safety or effectiveness and does not imply identical indications — No Phase III clinical trial data are available comparing the efficacy of TANZEUM to Bydureon® (exenatide extended-release for injectable suspension), Byetta® (exenatide) Injection, or Trulicity™ (dulaglutide) injection, for subcutaneous use. In a head-to-head trial of TANZEUM vs Victoza, TANZEUM provided less HbA1c reduction than Victoza® (liraglutide [rDNA origin] injection), solution for subcutaneous use and the treatment difference was statistically significant • Available in 2 dosage strengths at the same WAC price1,2: 30-mg and 50-mg, single-dose pens • The safety and efficacy for TANZEUM have been evaluated in a clinical trial program comprising 8 Phase III studies and 2365 patients who received TANZEUM2 a

WAC is the listed price to wholesalers and warehousing chains, not including prompt pay, stocking or distribution allowances, or other discounts, rebates, or chargebacks. The listed price may not represent prices charged to other customers, including specialty distributors. WAC does not reflect the price paid by consumers.1

Indications and Usage for TANZEUM TANZEUM is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Limitations of Use: • TANZEUM is not recommended as first-line therapy for patients inadequately controlled on diet and exercise. • TANZEUM has not been studied in patients with a history of pancreatitis. Consider other antidiabetic therapies in patients with a history of pancreatitis. • TANZEUM is not indicated in the treatment of patients with type 1 diabetes mellitus or for the treatment of patients with diabetic ketoacidosis. TANZEUM is not a substitute for insulin in these patients. • TANZEUM has not been studied in patients with severe gastrointestinal disease, including severe gastroparesis. The use of TANZEUM is not recommended in patients with pre-existing severe gastrointestinal disease. • TANZEUM has not been studied in combination with prandial insulin.

Important Safety Information for TANZEUM WARNING: RISK OF THYROID C-CELL TUMORS Thyroid C-cell tumors have been observed in rodent studies with glucagon-like peptide-1 (GLP-1) receptor agonists at clinically relevant exposures. It is unknown whether TANZEUM causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans. TANZEUM is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Routine serum calcitonin or thyroid ultrasound monitoring is of uncertain value in patients treated with TANZEUM. Patients should be counseled regarding the risk and symptoms of thyroid tumors.

CONTRAINDICATIONS Hypersensitivity: TANZEUM is contraindicated in patients with a prior serious hypersensitivity reaction to albiglutide or to any of the product components. Continued on next page

Important Safety Information for TANZEUM (contâ&#x20AC;&#x2122;d) WARNINGS AND PRECAUTIONS Risk of Thyroid C-cell Tumors: Counsel patients regarding the risk for MTC with the use of TANZEUM and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Patients with thyroid nodules noted on physical examination or neck imaging should be referred to an endocrinologist for further evaluation. Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with TANZEUM. If serum calcitonin is measured and found to be elevated, the patient should be referred to an endocrinologist for further evaluation. Acute Pancreatitis: In clinical trials, acute pancreatitis has been reported in association with TANZEUM. After initiation of TANZEUM, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied by vomiting). If pancreatitis is suspected, promptly discontinue TANZEUM. If pancreatitis is confirmed, TANZEUM should not be restarted. TANZEUM has not been studied in patients with a history of pancreatitis to determine whether these patients are at increased risk for pancreatitis. Consider other antidiabetic therapies in patients with a history of pancreatitis. Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin: The risk of hypoglycemia is increased when TANZEUM is used in combination with insulin secretagogues (e.g., sulfonylureas) or insulin. Therefore, patients may require a lower dose of sulfonylurea or insulin to reduce the risk of hypoglycemia in this setting. Hypersensitivity Reactions: Across 8 Phase III clinical trials, a serious hypersensitivity reaction with pruritus, rash, and dyspnea occurred in a patient treated with TANZEUM. If hypersensitivity reactions occur, discontinue use of TANZEUM; treat promptly per standard of care and monitor until signs and symptoms resolve. Renal Impairment: In patients treated with GLP-1 receptor agonists, there have been postmarketing reports of acute renal failure and worsening of chronic renal failure, which may sometimes require hemodialysis. Some of these events were reported in patients without known underlying renal disease. A majority of reported events occurred in patients who had experienced nausea, vomiting, diarrhea, or dehydration. In a trial of TANZEUM in patients with renal impairment, the frequency of such gastrointestinal reactions increased as renal function declined. Because these reactions may worsen renal function, use caution when initiating or escalating doses of TANZEUM in patients with renal impairment. Monitor renal function in patients with renal impairment reporting severe adverse gastrointestinal reactions. Macrovascular Outcomes: There have been no clinical trials establishing conclusive evidence of macrovascular risk reduction with TANZEUM or any other antidiabetic drug.

ADVERSE REACTIONS The most common adverse reactions, excluding hypoglycemia, reported in â&#x2030;Ľ5% of patients treated with TANZEUM and more commonly than in patients treated with placebo, are: upper respiratory tract infection (14.2 vs 13.0); diarrhea (13.1 vs 10.5); nausea (11.1 vs 9.6); injection site reaction (10.5 vs 2.1); cough (6.9 vs 6.2); back pain (6.7 vs 5.8); arthralgia (6.6 vs 6.4); sinusitis (6.2 vs 5.8); influenza (5.2 vs 3.2).

DRUG INTERACTIONS TANZEUM delays gastric emptying and may impact absorption of concomitantly administered oral medications. Caution should be exercised when oral medications are concomitantly administered with TANZEUM.

USE IN SPECIFIC PATIENT POPULATIONS Pediatric Use: Safety and effectiveness of TANZEUM have not been established in pediatric patients (younger than 18 years). A1C = glycosylated hemoglobin; GLP-1 = glucagon-like peptide-1. References: 1. Data on file. GSK. 2. Prescribing Information for TANZEUM.

Please see Brief Summary of Prescribing Information, including Boxed Warning, for TANZEUM on the following pages. www.GSKSource.com Bydureon and Byetta are registered trademarks of the AstraZeneca group of companies. Trulicity is a trademark of Eli Lilly and Company. Victoza is a registered trademark of Novo Nordisk A/S.

TANZEUM

™

BRIEF SUMMARY

(albiglutide) for injection, for subcutaneous use

The following is a brief summary only; see full prescribing information for complete product information. WARNING: RISK OF THYROID C-CELL TUMORS • Thyroid C-cell tumors have been observed in rodent studies with glucagon-like peptide-1 (GLP-1) receptor agonists at clinically relevant exposures. It is unknown whether TANZEUM™ causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans [see Warnings and Precautions (5.1)]. • TANZEUM is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Routine serum calcitonin or thyroid ultrasound monitoring is of uncertain value in patients treated with TANZEUM. Patients should be counseled regarding the risk and symptoms of thyroid tumors [see Contraindications (4.1), Warnings and Precautions (5.1)]. 1 INDICATIONS AND USAGE TANZEUM is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus [see Clinical Studies (14) of full prescribing information]. Limitations of Use: TANZEUM is not recommended as first-line therapy for patients inadequately controlled on diet and exercise [see Warnings and Precautions (5.1)]. TANZEUM has not been studied in patients with a history of pancreatitis [see Warnings and Precautions (5.2)]. Consider other antidiabetic therapies in patients with a history of pancreatitis. TANZEUM is not indicated in the treatment of patients with type 1 diabetes mellitus or for the treatment of patients with diabetic ketoacidosis. TANZEUM is not a substitute for insulin in these patients. TANZEUM has not been studied in patients with severe gastrointestinal (GI) disease, including severe gastroparesis. The use of TANZEUM is not recommended in patients with pre-existing severe gastrointestinal disease [see Adverse Reactions (6.1)]. TANZEUM has not been studied in combination with prandial insulin. 4 CONTRAINDICATIONS 4.1 Medullary Thyroid Carcinoma: TANZEUM is contraindicated in patients with a personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) [see Warnings and Precautions (5.1)]. 4.2 Hypersensitivity: TANZEUM is contraindicated in patients with a prior serious hypersensitivity reaction to albiglutide or to any of the product components [see Warnings and Precautions (5.4)]. 5 WARNINGS AND PRECAUTIONS 5.1 Risk of Thyroid C-cell Tumors: Nonclinical studies in rodents of clinically relevant doses of GLP-1 receptor agonists showed dose-related and treatment-duration-dependent increases in the incidence of thyroid C-cell tumors (adenomas and carcinomas). Carcinogenicity studies could not be conducted with TANZEUM because drug-clearing, anti-drug antibodies develop in animals used for these types of studies [see Nonclinical Toxicology (13.1)]. It is unknown whether GLP-1 receptor agonists are associated with thyroid C-cell tumors, including MTC in humans [see Boxed Warning, Contraindications (4.1)]. Across 8 Phase III clinical trials [see Clinical Studies (14) of full prescribing information], MTC was diagnosed in 1 patient receiving TANZEUM and 1 patient receiving placebo. Both patients had markedly elevated serum calcitonin levels at baseline. TANZEUM is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2. Counsel patients regarding the risk for MTC with the use of TANZEUM and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness). The clinical value of routine monitoring of serum calcitonin to diagnose MTC in patients at risk for MTC has not been established. Elevated serum calcitonin is a biological marker of MTC. Patients with MTC usually have calcitonin values >50 ng/L. Patients with thyroid nodules noted on physical examination or neck imaging should be referred to an endocrinologist for further evaluation. Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with TANZEUM. Such monitoring may increase the risk of unnecessary procedures, due to the low specificity of serum calcitonin testing for MTC and a high background incidence of thyroid disease. If serum calcitonin is measured and found to be elevated, the patient should be referred to an endocrinologist for further evaluation. 5.2 Acute Pancreatitis: In clinical trials, acute pancreatitis has been reported in association with TANZEUM. Across 8 Phase III clinical trials [see Clinical Studies (14) of full prescribing information], pancreatitis adjudicated as likely related to therapy occurred more frequently in patients receiving TANZEUM (6 of 2,365 [0.3%]) than in patients receiving placebo (0 of 468 [0%]) or active comparators (2 of 2,065 [0.1%]). After initiation of TANZEUM, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied by vomiting). If pancreatitis is suspected, promptly discontinue TANZEUM. If pancreatitis is confirmed, TANZEUM should not be restarted. TANZEUM has not been studied in patients with a history of pancreatitis to

determine whether these patients are at increased risk for pancreatitis. Consider other antidiabetic therapies in patients with a history of pancreatitis. 5.3 Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin: The risk of hypoglycemia is increased when TANZEUM is used in combination with insulin secretagogues (e.g., sulfonylureas) or insulin. Therefore, patients may require a lower dose of sulfonylurea or insulin to reduce the risk of hypoglycemia in this setting [see Adverse Reactions (6.1)]. 5.4 Hypersensitivity Reactions: Across 8 Phase III clinical trials [see Clinical Studies (14) of full prescribing information], a serious hypersensitivity reaction with pruritus, rash, and dyspnea occurred in a patient treated with TANZEUM. If hypersensitivity reactions occur, discontinue use of TANZEUM; treat promptly per standard of care and monitor until signs and symptoms resolve [see Contraindications (4.2)]. 5.5 Renal Impairment: In patients treated with GLP-1 receptor agonists, there have been postmarketing reports of acute renal failure and worsening of chronic renal failure, which may sometimes require hemodialysis. Some of these events were reported in patients without known underlying renal disease. A majority of reported events occurred in patients who had experienced nausea, vomiting, diarrhea, or dehydration. In a trial of TANZEUM in patients with renal impairment [see Clinical Studies (14.3) of full prescribing information], the frequency of such gastrointestinal reactions increased as renal function declined [see Use in Specific Populations (8.6)]. Because these reactions may worsen renal function, use caution when initiating or escalating doses of TANZEUM in patients with renal impairment [see Dosage and Administration (2.3) of full prescribing information, Use in Specific Populations (8.6)]. 5.6 Macrovascular Outcomes: There have been no clinical trials establishing conclusive evidence of macrovascular risk reduction with TANZEUM or any other antidiabetic drug. 6 ADVERSE REACTIONS The following serious reactions are described below or elsewhere in the labeling: Risk of Thyroid C-cell Tumors [see Warnings and Precautions (5.1)], Acute Pancreatitis [see Warnings and Precautions (5.2)], Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin [see Warnings and Precautions (5.3)], Hypersensitivity Reactions [see Warnings and Precautions (5.4)], Renal Impairment [see Warnings and Precautions (5.5)]. 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. Pool of Placebo-Controlled Trials: The data in Table 1 are derived from 4 placebo-controlled trials. TANZEUM was used as monotherapy in 1 trial and as add-on therapy in 3 trials [see Clinical Studies (14) of full prescribing information]. These data reflect exposure of 923 patients to TANZEUM and a mean duration of exposure to TANZEUM of 93 weeks. The mean age of participants was 55 years, 1% of participants were 75 years or older and 53% of participants were male. The population in these studies was 48% white, 13% African/African American, 7% Asian, and 29% Hispanic/Latino. At baseline, the population had diabetes for an average of 7 years and had a mean HbA1c of 8.1%. At baseline, 17% of the population in these studies reported peripheral neuropathy and 4% reported retinopathy. Baseline estimated renal function was normal or mildly impaired (eGFR >60 mL/min/1.73 m2) in 91% of the study population and moderately impaired (eGFR 30 to 60 mL/min/1.73 m2) in 9%. Table 1 shows common adverse reactions excluding hypoglycemia associated with the use of TANZEUM in the pool of placebo-controlled trials. These adverse reactions were not present at baseline, occurred more commonly on TANZEUM than on placebo, and occurred in at least 5% of patients treated with TANZEUM. Table 1. Adverse Reactions in Placebo-controlled Trials Reported in ≥5% of Patients Treated with TANZEUMa Placebo TANZEUM Adverse Reaction (N=468) (N=923) % % Upper respiratory tract infection 13.0 14.2 Diarrhea

10.5

13.1

Nausea

9.6

11.1

Injection site reaction

2.1

10.5

Cough

6.2

6.9

Back pain

5.8

6.7

Arthralgia

6.4

6.6

Sinusitis

5.8

6.2

Influenza

3.2

5.2

Adverse reactions reported includes adverse reactions occurring with the use of glycemic rescue medications which included metformin (17% for placebo and 10% for TANZEUM) and insulin (24% for placebo and 14% for TANZEUM). b See below for other events of injection site reactions reported. a

Continued on next page

Adverse Reactions (cont’d) Gastrointestinal Adverse Reactions: In the pool of placebo-controlled trials, gastrointestinal complaints occurred more frequently among patients receiving TANZEUM (39%) than patients receiving placebo (33%). In addition to diarrhea and nausea (see Table 1), the following gastrointestinal adverse reactions also occurred more frequently in patients receiving TANZEUM: vomiting (2.6% versus 4.2% for placebo versus TANZEUM), gastroesophageal reflux disease (1.9% versus 3.5% for placebo versus TANZEUM), and dyspepsia (2.8% versus 3.4% for placebo versus TANZEUM). Constipation also contributed to the frequently reported reactions. In the group treated with TANZEUM, investigators graded the severity of GI reactions as “mild” in 56% of cases, “moderate” in 37% of cases, and “severe” in 7% of cases. Discontinuation due to GI adverse reactions occurred in 2% of individuals on TANZEUM or placebo. Injection Site Reactions: In the pool of placebo-controlled trials, injection site reactions occurred more frequently on TANZEUM (18%) than on placebo (8%). In addition to the term injection site reaction (see Table 1), the following other types of injection site reactions also occurred more frequently on TANZEUM: injection site hematoma (1.9% versus 2.1% for placebo versus TANZEUM), injection site erythema (0.4% versus 1.7% for placebo versus TANZEUM), injection site rash (0% versus 1.4% for placebo versus TANZEUM), injection site hypersensitivity (0% versus 0.8% versus for placebo versus TANZEUM), and injection site hemorrhage (0.6% versus 0.7% for placebo versus TANZEUM). Injection site pruritus also contributed to the frequently reported reactions. The majority of injection site reactions were judged as “mild” by investigators in both groups (73% for TANZEUM versus 94% for placebo). More patients on TANZEUM than on placebo: discontinued due to an injection site reaction (2% versus 0.2%), experienced more than 2 reactions (38% versus 20%), had a reaction judged by investigators to be “moderate” or “severe” (27% versus 6%) and required local or systemic treatment for the reactions (36% versus 11%). Pool of Placebo- and Active-controlled Trials: The occurrence of adverse reactions was also evaluated in a larger pool of patients with type 2 diabetes participating in 7 placebo- and active-controlled trials. These trials evaluated the use of TANZEUM as monotherapy, and as add-on therapy to oral antidiabetic agents, and as add-on therapy to basal insulin [see Clinical Studies (14) of full prescribing information]. In this pool, a total of 2,116 patients with type 2 diabetes were treated with TANZEUM for a mean duration of 75 weeks. The mean age of patients treated with TANZEUM was 55 years, 1.5% of the population in these studies was 75 years or older and 51% of participants were male. Forty-eight percent of patients were white, 15% African/African American, 9% Asian, and 26% were Hispanic/Latino. At baseline, the population had diabetes for an average of 8 years and had a mean HbA1c of 8.2%. At baseline, 21% of the population reported peripheral neuropathy and 5% reported retinopathy. Baseline estimated renal function was normal or mildly impaired (eGFR >60 mL/min/1.73 m2) in 92% of the population and moderately impaired (eGFR 30 to 60 mL/min/1.73 m2) in 8% of the population. In the pool of placebo- and active-controlled trials, the types and frequency of common adverse reactions excluding hypoglycemia were similar to those listed in Table 1. Other Adverse Reactions: Hypoglycemia: The proportion of patients experiencing at least one documented symptomatic hypoglycemic episode on TANZEUM and the proportion of patients experiencing at least one severe hypoglycemic episode on TANZEUM in clinical trials [see Clinical Studies (14) of full prescribing information] is shown in Table 2. Hypoglycemia was more frequent when TANZEUM was added to sulfonylurea or insulin [see Warnings and Precautions (5.3)]. Table 2. Incidence (%) of Hypoglycemia in Clinical Trials of TANZEUMa TANZEUM Monotherapyb Placebo 30 mg Weekly N = 101 (52 Weeks) N = 101 Documented symptomaticc Severed In Combination with Metformin Trial (104 Weeks)e Documented symptomatic Severe In Combination with Pioglitazone ± Metformin (52 Weeks) Documented symptomatic Severe In Combination with Metformin and Sulfonylurea (52 Weeks) Documented symptomatic Severe In Combination with Insulin Glargine (26 Weeks) Documented symptomatic Severe

2% Placebo N = 101 4% Placebo N = 151 1% Placebo N = 115 7% Insulin Lispro N = 281 30% 0.7%

2% TANZEUM N = 302 3% TANZEUM N = 150 3% 1% TANZEUM N = 271 13% 0.4% TANZEUM N = 285 16% -

Table 2. Incidence (%) of Hypoglycemia in Clinical Trials of TANZEUMa (cont’d) Insulin In Combination with TANZEUM Glargine N = 504 Metformin ± Sulfonylurea (52 Weeks) N = 241 Documented symptomatic Severe In Combination with OADs in Renal Impairment (26 Weeks) Documented symptomatic Severe

27% 0.4%

17% 0.4%

Sitagliptin N = 246

TANZEUM N = 249

6% 0.8%

10% -

OAD = Oral antidiabetic agents. Data presented are to the primary endpoint and include only events occurring on-therapy with randomized medications and excludes events occurring after use of glycemic rescue medications (i.e., primarily metformin or insulin). bIn this trial, no documented symptomatic or severe hypoglycemia were reported for TANZEUM 50 mg and these data are omitted from the table. cPlasma glucose concentration ≤70 mg/dL and presence of hypoglycemic symptoms. dEvent requiring another person to administer a resuscitative action. eRate of documented symptomatic hypoglycemia for active controls 18% (glimepiride) and 2% (sitagliptin).

Pneumonia: In the pool of 7 placebo- and active-controlled trials, the adverse reaction of pneumonia was reported more frequently in patients receiving TANZEUM (1.8%) than in patients in the all-comparators group (0.8%). More cases of pneumonia in the group receiving TANZEUM were serious (0.4% for TANZEUM versus 0.1% for all comparators). Atrial Fibrillation/Flutter: In the pool of 7 placebo- and active-controlled trials, adverse reactions of atrial fibrillation (1.0%) and atrial flutter (0.2%) were reported more frequently for TANZEUM than for all comparators (0.5% and 0%, respectively). In both groups, patients with events were generally male, older, and had underlying renal impairment or cardiac disease (e.g., history of arrhythmia, palpitations, congestive heart failure, cardiomyopathy, etc.). Appendicitis: In the pool of placebo- and active-controlled trials, serious events of appendicitis occurred in 0.3% of patients treated with TANZEUM compared with 0% among all comparators. Immunogenicity: In the pool of 7 placebo- and active-controlled trials, 116 (5.5%) of 2,098 patients exposed to TANZEUM tested positive for anti-albiglutide antibodies at any time during the trials. None of these antibodies were shown to neutralize the activity of albiglutide in an in vitro bioassay. Presence of antibody did not correlate with reduced efficacy as measured by HbA1c and fasting plasma glucose or specific adverse reactions. Consistent with the high homology of albiglutide with human GLP-1, the majority of patients (approximately 79%) with anti-albiglutide antibodies also tested positive for anti-GLP-1 antibodies; none were neutralizing. A minority of patients (approximately 17%) who tested positive for anti-albiglutide antibodies also transiently tested positive for antibodies to human albumin. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, the incidence of antibodies to albiglutide cannot be directly compared with the incidence of antibodies of other products. Liver Enzyme Abnormalities: In the pool of placebo- and active-controlled trials, a similar proportion of patients experienced at least one event of alanine aminotransferase (ALT) increase of 3-fold or greater above the upper limit of normal (0.9% and 0.9% for all comparators versus TANZEUM). Three subjects on TANZEUM and one subject in the all-comparator group experienced at least one event of ALT increase of 10-fold or greater above the upper limit of normal. In one of the 3 cases an alternate etiology was identified to explain the rise in liver enzyme (acute viral hepatitis). In one case, insufficient information was obtained to establish or refute a drug-related causality. In the third case, elevation in ALT (10 times the upper limit of normal) was accompanied by an increase in total bilirubin (4 times the upper limit of normal) and occurred 8 days after the first dose of TANZEUM. The etiology of hepatocellular injury was possibly related to TANZEUM but direct attribution to TANZEUM was confounded by the presence of gallstone disease diagnosed on ultrasound 3 weeks after the event. Gamma Glutamyltransferase (GGT) Increase: In the pool of placebo-controlled trials, the adverse event of increased GGT occurred more frequently in the group treated with TANZEUM (0.9% and 1.5% for placebo versus TANZEUM). Heart Rate Increase: In the pool of placebo-controlled trials, mean heart rate in patients treated with TANZEUM was higher by an average of 1 to 2 bpm compared with mean heart rate in patients treated with placebo across study visits. The long-term clinical effects of the increase in heart rate have not been established [see Warnings and Precautions (5.6)].

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7 DRUG INTERACTIONS TANZEUM did not affect the absorption of orally administered medications tested in clinical pharmacology studies to any clinically relevant degree [see Clinical Pharmacology (12.3) of full prescribing information]. However, TANZEUM causes a delay of gastric emptying, and thereby has the potential to impact the absorption of concomitantly administered oral medications. Caution should be exercised when oral medications are concomitantly administered with TANZEUM.

50 mg/kg/day (39 times clinical exposure based on AUC). In pregnant mice given SC doses of 1, 5, or 50 mg/kg/day from gestation Day 6 through 15 (organogenesis), embryo-fetal lethality (post-implantation loss) and bent (wavy) ribs were observed at 50 mg/kg/day (39 times clinical exposure based on AUC), a dose associated with maternal toxicity (body weight loss and reduced food consumption). Pregnant mice were given SC doses of 1, 5, or 50 mg/kg/day from gestation Day 6 to 17. Offspring of pregnant mice given 50 mg/kg/day (39 times clinical exposure based on AUC), a dose associated with maternal toxicity, had reduced body weight pre-weaning, dehydration and coldness, and a delay in balanopreputial separation. Pregnant mice were given SC doses of 1, 5, or 50 mg/kg/day from gestation Day 15 to lactation day 10. Increased mortality and morbidity were seen at all doses (≥1 mg/kg/ day) in lactating females in mouse pre- and postnatal development studies. Mortalities have not been observed in previous toxicology studies in nonlactating or non-pregnant mice, nor in pregnant mice. These findings are consistent with lactational ileus syndrome which has been previously reported in mice. Since the relative stress of lactation energy demands is lower in humans than mice and humans have large energy reserves, the mortalities observed in lactating mice are of questionable relevance to humans. The offspring had decreased pre-weaning body weight which reversed post-weaning in males but not females at ≥5 mg/kg/day (2.2 times clinical exposure based on AUC) with no other effects on development. Low levels of albiglutide were detected in plasma of offspring. Lactating mice were given SC doses of 1, 5, or 50 mg/kg/day from lactation day 7 to 21 (weaning) under conditions that limit the impact of lactational ileus (increased caloric intake and culling of litters). Doses ≥1 mg/kg/day (exposures below clinical AUC) caused reduced weight gain in the pups during the treatment period.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy: Pregnancy Category C: There are no adequate and wellcontrolled studies of TANZEUM in pregnant women. Nonclinical studies have shown reproductive toxicity, but not teratogenicity, in mice treated with albiglutide at up to 39 times human exposure resulting from the maximum recommended dose of 50 mg/week, based on area under the time-concentration curve (AUC) [see Nonclinical Toxicology (13.1,13.3)]. TANZEUM should not be used during pregnancy unless the expected benefit outweighs the potential risks. Due to the long washout period for TANZEUM, consider stopping TANZEUM at least 1 month before a planned pregnancy. There are no data on the effects of TANZEUM on human fertility. Studies in mice showed no effects on fertility [see Nonclinical Toxicology (13.1)]. The potential risk to human fertility is unknown. 8.3 Nursing Mothers: There are no adequate data to support the use of TANZEUM during lactation in humans. It is not known if TANZEUM is excreted into human milk during lactation. Given that TANZEUM is an albumin-based protein therapeutic, it is likely to be present in human milk. Decreased body weight in offspring was observed in mice treated with TANZEUM during gestation and lactation [see Nonclinical Toxicology (13.3)]. A decision should be made whether to discontinue nursing or to discontinue TANZEUM, taking into account the importance of the drug 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide and Instructions for to the mother and the potential risks to the infant. 8.4 Pediatric Use: Safety Use). The Medication Guide is contained in a separate leaflet that accompanies and effectiveness of TANZEUM have not been established in pediatric patients the product. Inform patients about self-management practices, including the (younger than 18 years). 8.5 Geriatric Use: Of the total number of patients importance of proper storage of TANZEUM, injection technique, timing of dosage (N = 2,365) in 8 Phase III clinical trials who received TANZEUM, 19% (N = of TANZEUM and concomitant oral drugs, and recognition and management of 444) were 65 years and older, and <3% (N = 52) were 75 years and older. hypoglycemia. Inform patients that thyroid C-cell tumors have been observed No overall differences in safety or effectiveness were observed between in rodents treated with some GLP-1 receptor agonists, and the human these patients and younger patients, but greater sensitivity of some older relevance of this finding is unknown. Counsel patients to report symptoms of individuals cannot be ruled out. 8.6 Renal Impairment: Of the total number thyroid tumors to their physician [see Warnings and Precautions (5.1)]. Advise of patients (N = 2,365) in 8 Phase III clinical trials who received TANZEUM, patients that persistent, severe abdominal pain that may radiate to the back 54% (N = 1,267) had mild renal impairment (eGFR 60 to 89 mL/min/1.73 and which may (or may not) be accompanied by vomiting is the hallmark m2), 12% (N = 275) had moderate renal impairment (eGFR 30 to 59 mL/ symptom of acute pancreatitis. Instruct patients to discontinue TANZEUM min/1.73 m2) and 1% (N = 19) had severe renal impairment (eGFR 15 to <30 promptly and to contact their physician if persistent, severe abdominal pain mL/min/1.73 m2). No dosage adjustment is required in patients with mild occurs [see Warnings and Precautions (5.2)]. The risk of hypoglycemia is (eGFR 60 to 89 mL/min/1.73 m2), moderate (eGFR 30 to 59 mL/min/1.73 m2), increased when TANZEUM is used in combination with an agent that induces or severe (eGFR 15 to <30 mL/min/1.73 m2) renal impairment. Efficacy of hypoglycemia, such as sulfonylurea or insulin. Instructions for hypoglycemia TANZEUM in patients with type 2 diabetes and renal impairment is described should be reviewed with patients and reinforced when initiating therapy with elsewhere [see Clinical Studies (14.3) of full prescribing information]. There TANZEUM, particularly when concomitantly administered with a sulfonylurea or is limited clinical experience in patients with severe renal impairment (19 insulin [see Warnings and Precautions (5.3)]. Advise patients on the symptoms subjects). The frequency of GI events increased as renal function declined. of hypersensitivity reactions and instruct them to stop taking TANZEUM and For patients with mild, moderate, or severe impairment, the respective seek medical advice promptly if such symptoms occur [see Warnings and event rates were: diarrhea (6%, 13%, 21%), nausea (3%, 5%,16%), and Precautions (5.4)]. Instruct patients to read the Instructions for Use before vomiting (1%, 2%, 5%). Therefore, caution is recommended when initiating starting therapy. Instruct patients on proper use, storage, and disposal of or escalating doses of TANZEUM in patients with renal impairment [see the pen [see How Supplied/Storage and Handling (16.2) of full prescribing Dosage and Administration (2.3) of full prescribing information, Warnings and information, Patient Instructions for Use of full prescribing information]. Precautions (5.5), Clinical Pharmacology (12.3) of full prescribing information]. Instruct patients to read the Medication Guide before starting TANZEUM and to 10 OVERDOSAGE read again each time the prescription is renewed. Instruct patients to inform No data are available with regard to overdosage in humans. Anticipated their doctor or pharmacist if they develop any unusual symptom, or if any symptoms of an overdose may be severe nausea and vomiting. In the event known symptom persists or worsens. Inform patients not to take an extra of an overdose, appropriate supportive treatment should be initiated as dose of TANZEUM to make up for a missed dose. If a dose is missed, instruct dictated by the patient’s clinical signs and symptoms. A prolonged period of patients to take a dose as soon as possible within 3 days after the missed observation and treatment for these symptoms may be necessary, taking into dose. Instruct patients to then take their next dose at their usual weekly time. account the half-life of TANZEUM (5 days). If it has been longer than 3 days after the missed dose, instruct patients to wait and take TANZEUM at the next usual weekly time. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility: As albiglutide TANZEUM is a trademark of the GSK group of companies. is a recombinant protein, no genotoxicity studies have been conducted. Carcinogenicity studies have not been performed with albiglutide because such studies are not technically feasible due to the rapid development of drug-clearing, anti-drug antibodies in rodents. Thyroid C-cell tumors were observed in 2-year rodent carcinogenicity studies with some GLP-1 receptor agonists. The clinical relevance of rodent thyroid findings observed with GLP-1 Manufactured by GlaxoSmithKline LLC receptor agonists is unknown. In a mouse fertility study, males were treated Wilmington, DE 19808 with subcutaneous (SC) doses of 5, 15, or 50 mg/kg/day for 7 days prior to U.S. Lic. No. 1727 cohabitation with females, and continuing through mating. In a separate fertility Marketed by GlaxoSmithKline study, females were treated with SC doses of 1, 5, or 50 mg/kg/day for 7 days Research Triangle Park, NC 27709 prior to cohabitation with males, and continuing through mating. Reductions ©2014, the GSK group of companies. All rights reserved. in estrous cycles were observed at 50 mg/kg/day, a dose associated with August 2014, TNZ:2BRS maternal toxicity (body weight loss and reduced food consumption). There were no effects on mating or fertility in either sex at doses up to 50 mg/kg/ ©2014 GSK group of companies. day (up to 39 times clinical exposure based on AUC). 13.3 Reproductive All rights reserved. Printed in USA. BIG159R0 November 2014 and Developmental Toxicity: In order to minimize the impact of the drug-clearing, anti-drug antibody response, reproductive and developmental toxicity assessments in the mouse were partitioned to limit the dosing period to no more than approximately 15 days in each study. In pregnant mice given SC doses of 1, 5, or 50 mg/kg/day from gestation Day 1 to 6, there were no adverse effects on early embryonic development through implantation at

Zydelig (Idelalisib): First-in-Class PI3 Kinase Inhibitor Approved for the Treatment of 3 Hematologic Malignancies By Lisa A. Raedler, PhD, RPh, Medical Writer

hronic lymphocytic leukemia (CLL), a cancer of B-cell lymphocytes, is the most common type of leukemia in Western adult patients.1 According to the Leukemia and Lymphoma Society, more than 15,600 Americans were diagnosed with CLL in 2013.2 CLL is a disease of the elderly.3 The incidence of CLL increases significantly among individuals aged ≥50 years, with only a small fraction of patients diagnosed in their 30s and 40s.2 The majority of patients with CLL are diagnosed without symptoms, and typically learn that they have CLL after routine blood work.4 As it advances, CLL can cause severe fatigue, swollen lymph nodes, enlarged spleen, shortness of breath, a nd infections.4 The clinical course of CLL is heterogeneous. Although some patients with CLL live for decades with no treatment, others have disease that is rapidly aggressive.3 The survival of patients with CLL ranges from approximately 1 year to more than 20 years.5 According to the American Society of Clinical Oncology, the 5-year overall survival (OS) rate for patients with CLL of all stages is approximately 79%.5 The cost burden associated with CLL is significant. Based on a recent cost analysis conducted in Germany, the total per-patient costs for patients with CLL is €9753 (approximately $12,202) annually compared with €4807 (approximately $6014) annually for individuals in a control group of the same age and sex.6 In this study, the economic burden of CLL was primarily driven by inpatient costs and by drug costs. From a societal perspective, productivity loss was the highest cost associated with a CLL diagnosis.6

Small Lymphocytic Lymphoma According to the World Health Organization, CLL and small lymphocytic lymphoma (SLL) are different clinical manifestations of the same disease.7 The term CLL is used when there is a leukemic component in peripheral blood, whereas SLL is used when lymph nodes or other tissues are infiltrated by CLL cells that appear to be without the leukemic component.2,7 Only 5% of patients present with clinical features of SLL.2 CLL and SLL affect people of the same age-groups, have common signs and symptoms, and are generally

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slow-growing conditions.8 The treatment for both malignancies is also similar.8

Follicular Lymphoma Follicular lymphoma is the second most common subtype of non-Hodgkin lymphoma (NHL), comprising approximately 20% of all NHL cases.8 Follicular lymphoma is characterized by a translocation between chromosome 14 and chromosome 18, which causes the overexpression of BCL-2 and increased resistance to treatment.8 Although an indolent NHL, follicular lymphoma can transform into an aggressive phenotype, at which point it should be managed using therapies that are appropriate for aggressive forms of NHL, including combinations of chemotherapy and anti-CD20 monoclonal antibodies.9 Evolving Treatments for Chronic Lymphocytic Leukemia In the past several years, major advances have been made in understanding the pathophysiology of CLL, including biologic factors that influence its clinical course. As a result, treatment approaches have evolved to target the underlying disease pathology.3 The International Workshop on CLL recommends treating CLL if patients present with active progressive disease manifested as bulky progressive adenopathy or bone marrow failure.2,10 Initial treatment of patients with symptomatic CLL typically includes chemotherapy combined with a targeted drug––either rituximab or another CD20-targeted monoclonal antibody.2,11 Medications that can be used for the treatment of patients with relapsed and/or refractory CLL include alemtuzumab, bendamustine, chlorambucil, fludarabine, ibrutinib, lenalidomide, obinutuzumab (in combination with chlorambucil), ofatumumab, and rituximab.12 Several of these are new therapies that were approved in 2013 and 2014 for use in patients with previously untreated CLL and in relapsed or refractory CLL; these include ibrutinib, obinutuzumab, and ofatumumab.13-15 Idelalisib: First-in-Class PI3 Kinase Inhibitor Approved by the FDA On July 23, 2014, the US Food and Drug Ad ministration (FDA) approved idelalisib (Zydelig;

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Gilead Sciences), an oral phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor, for the treatment of 3 types of hematologic malignancies, including patients with relapsed CLL, to be used in combination with rituximab when rituximab can be used alone because of the presence of comorbidities, as well as patients with relapsed follicular lymphoma or patients with relapsed SLL after 2 previous systemic therapies.16 The FDA approved idelalisib for the treatment of CLL under the prescheduled review process, and used its accelerated approval program to approve the indications for the treatment of patients with relapsed follicular lymphoma and for patients with relapsed SLL, based on the surrogate end points of tumor response rate and duration of response. An improvement in survival or disease-related symptoms has not been established for idelalisib in these 2 malignancies.16 Idelalisib was approved with a Risk Evaluation and Mitigation Strategy program to ensure that healthcare providers who prescribe idelalisib are informed of the risk for fatal and serious toxicities associated with idelalisib.16

Mechanism of Action Idelalisib is a potent and selective inhibitor of the PI3Kδ, an enzyme that is expressed in normal and malignant B-cells.17,18 Idelalisib inhibits several cell-signaling pathways, including B-cell receptor signaling and CXCR4 and CXCR5 signaling, which are involved in trafficking and homing of B-cells to the lymph nodes and to the bone marrow.18 In cell lines derived from malignant B-cells and in primary tumor cells, idelalisib induced apoptosis and inhibited proliferation. Inhibition of chemotaxis and adhesion, and reduced cell viability have been observed in lymphoma cells that were treated with idelalisib.18 Dosing and Administration The recommended dosage of idela lisib for all 3 indications is 150 mg administered orally twice daily. Idelalisib tablets can be taken with or without food and should be swallowed whole.18 Treatment with idelalisib should be continued until disease progression or unacceptable toxicity. The optimal and safe dosing regimen for patients who take idelalisib for more than several months is unknown.18 Key Clinical Trials Study 116: Phase 3 Clinical Trial in Relapsed CLL The approval of idelalisib in combination with rituximab for the treatment of patients with relapsed CLL was based on Study 116, a randomized, double-blind, placebo-controlled phase 3 clinical trial.17 This clinical trial enrolled 220 patients with relapsed CLL who

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required treatment and were unable to tolerate standard chemoimmunotherapy as a result of coexisting medical conditions, reduced renal function, or significant neutropenia or thrombocytopenia resulting from previous therapy with cytotoxic agents.17,18 Patients received idelalisib plus rituximab or placebo plus rituximab until disease progression or unacceptable toxicity. Idelalisib was administered orally at 150 mg twice daily.17,18 Patients in both arms received 8 doses of rituximab (first dose, 375 mg/m2; subsequent doses, 500 mg/m2 every 2 weeks for 4 infusions, and every 4 weeks for 4 infusions). The median duration of exposure to idelalisib was 5 months.17,18 The primary end point was progression-free survival (PFS), which was defined as the interval from randomization to disease progression or death from any cause (whichever came first), using the Kaplan-Meier method.17 The primary end point was assessed by an Independent Review Committee. The secondary end points included overall response rate (ORR) and complete response rates, lymph-node response, and OS. Study 116 was stopped for efficacy following the first prespecified interim analysis.17,18 Patient population. The patients’ median age was 71 years, with 78% of patients aged ≥65 years. The majority of patients were male (66%), and Caucasian (90%). The median time since CLL diagnosis was 8.5 years.17,18 Overall, 40% of patients in Study 116 had moderate-to-severe renal dysfunction, defined as creatinine clearance <60 mL per minute, and 35% of patients had poor bone marrow function, defined as grade ≥3 anemia, thrombocytopenia, or neutropenia. Almost two-thirds of the patients had advanced-stage CLL, and more than 40% had 17p deletion or TP53 gene mutations.17,18 Patients in both arms had received a median of 3 previous therapies, including regimens containing rituximab, fludarabine, cyclophosphamide, and bendamustine.17,18 Efficacy. At 24 weeks, the PFS rate was 93% in patients receiving idelalisib plus rituximab compared with 46% in patients receiving placebo plus rituximab (Table 1).17 The adjusted hazard ratio (HR) for progression or death in the idelalisib plus rituximab group was 0.15 (95% confidence interval [CI], 0.08-0.28; unadjusted P <.001).17,18 Study 116 was stopped for efficacy following the first prespecified interim analysis.17,18 Results of a second interim analysis continued to show a significant PFS alisib plus rituximab over plaimprovement for idel cebo plus rituximab (HR, 0.18; 95% CI, 0.10-0.32; P <.001; Table 1). In the idelalisib plus rituximab group, the median duration of PFS was not reached; in the

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placebo plus rituximab group, the median duration of PFS was 5.5 months. The PFS benefit for idelalisib and rituximab was similarly favorable in all prespecified subgroups, including those that were stratified according to the presence or absence of the 17p deletion or TP53 gene mutation and immunoglobulin heavy chain variable mutational status.17,18 At 12 months, the OS rate in the idelalisib plus ri tuximab group (92%) was significantly higher than the OS rate in the placebo plus rituximab group (80%; HR for death, 0.28; 95% CI, 0.09-0.86; P = .02). In the idel alisib plus rituximab group, the ORR was 81% (95% CI, 71%-88%) compared with 13% (95% CI, 6%-21%) in the placebo plus rituximab group (P <.001). All responses were partial responses (Table 1).17

DELTA Study: Phase 2 Clinical Trial in Relapsed Follicular Lymphoma The safety and efficacy of idelalisib in patients with relapsed follicular lymphoma were evaluated in the DELTA clinical trial, a single-arm, multicenter clinical trial that included 72 patients with relapsed follicular lymphoma.18,19 In this clinical trial, idelalisib was administered orally at 150 mg twice daily until evidence of disease progression or unacceptable toxicity. The study’s primary end point was Independent Review Committee– assessed ORR. Tumor response was assessed using revised response criteria for malignant lymphoma, as recommended by the International Working Group.18,19 Patient population. The patients’ median age was 62 years.18,19 The majority of the patients were male (54%), Caucasian (90%), and had a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (92%). The patients’ median time since diagnosis was 4.7 years. The patients had received at least 2 previous treatments and experienced disease relapse within 6 months after treatment with rituximab and an alkylating agent. The median number of previous treatments was 4 (range, 2-12) and included rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP); bendamustine and rituximab; and rituximab plus cyclophosphamide, vincristine, and prednisone. At baseline, 33% of patients had extranodal disease, and 26% of patients had bone marrow involvement.18,19 Efficacy. Among the 72 patients with relapsed follicular lymphoma who received idelalisib, the ORR was 54% (95% CI, 42%-66%), including 6 complete responses (8%) and 33 partial responses (46%) (Table 2). The median duration of response was not evaluable (range, 0+ to 14.8+ months). The median time to response was 1.9 months (range, 1.6-8.3 months).18

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Table 1 Idelalisib versus Placebo: Survival and Response Results in Patients with Relapsed CLL in Study 116 Idelalisib plus Placebo plus rituximab rituximab Efficacy parameter (N = 110) (N = 110) P value Median PFS, months

NR (95% CI, 10.7-NR)

5.5 (95% CI, 3.8-7.1)

<.001

PFS, %

<.001

Overall survival, %

.02

Overall response, %

<.001

CI indicates confidence interval; CLL, chronic lymphocytic leukemia; NR, not reached; PFS, progression-free survival. Sources: Zydelig (idelalisib) tablets prescribing information; 2014; Furman RR, et al. N Engl J Med. 2014;370:997-1007.

Table 2 DELTA Trial: Response Rate in Patients with Relapsed FL or SLL Receiving Idelalisib Response

Idelalisib 150 mg twice daily, N (%)

Relapsed FL (N = 72) Overall response

39 (54)

Complete response

42 (8)

Partial response

33 (46)

Relapsed SLL (N = 26) Overall response

15 (58)

Complete response Partial response

0 15 (58)

FL indicates follicular lymphoma; SLL, small lymphocytic lymphoma. Source: Zydelig (idelalisib) tablets prescribing information; 2014.

An improvement in survival or disease-related symptoms has not been established for idelalisib in patients with relapsed follicular lymphoma.16,18 The continued approval of idelalisib for the treatment of patients with relapsed follicular lymphoma may be contingent on the verification of clinical benefit in confirmatory clinical trials.18

DELTA Study: Phase 2 Clinical Trial in Relapsed Small Lymphocytic Lymphoma The safety and efficacy of idelalisib in patients with relapsed SLL were also evaluated in the DELTA clinical trial.18,19 Overall, 26 patients with relapsed SLL received 150 mg of idelalisib orally twice daily until evidence of disease progression or unacceptable toxicity. The primary end point was Independent Review Committee– assessed ORR. Tumor response was assessed using revised response criteria for malignant lymphoma, as recommended by the International Working Group.18,19

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Patient population. The patients’ median age was 65 years.18 The majority of patients were male (73%), Caucasian (81%), and had a baseline ECOG performance status of 0 or 1 (96%). The patients had received at least 2 previous treatments, and their disease had relapsed within 6 months after treatment with rituximab and an alkylating agent. The patients’ median time since SLL diagnosis was 6.7 years. The median number of previous treatments was 4 (range, 2-9) and included bendamustine plus rituximab; fludarabine, cyclophosphamide, and rituximab; and R-CHOP. At baseline, 27% of patients had extranodal disease.18,19 Efficacy. Among the 26 patients with relapsed SLL who received idelalisib, the ORR was 58% (95% CI, 37%-77%), and all responses were partial responses (Table 2). The median duration of response was 11.9 months (range, 0+ to 14.7+ months). The median time to response was 1.9 months (range, 1.6-8.3 months).18,19 An improvement in survival or disease-related symptoms has not been established for idelalisib in relapsed SLL. The continued approval of idelalisib for the treatment of patients with relapsed SLL may be contingent on the verification of clinical benefit in confirmatory clinical trials.16,19

included pneumonia, pyrexia, sepsis, febrile neutropenia, and diarrhea (Table 3). Adverse reactions leading to the discontinuation of idelalisib therapy occurred in 10% of the patients; the most common of these reactions included hepatotoxicity and diarrhea or colitis.17,18 Dose interruption of idelalisib was required in 35% of patients with relapsed CLL.18 Overall, 15% of the patients needed dose reductions as a result of adverse events or laboratory abnormalities; the most common reasons for dose reductions included elevated transaminase levels, diarrhea or colitis, and rash.18 The safety data for idelalisib also reflect drug exposure in 146 adult patients with indolent NHL who received idelalisib 150 mg twice daily in clinical trials. The patients’ median duration of exposure to idelalisib was 6.1 months (range, 0.3-26.4 months). Overall, 50% of these patients experienced serious adverse events, including pneumonia, diarrhea, and pyrexia.18 In addition, dose interruption or discontinuation of idelalisib occurred in 53% of the patients with indolent NHL; the most common reasons for interruption or discontinuation of idelalisib included diarrhea, pneumonia, and elevated transaminase levels.18

Adverse Events The majority of adverse events among patients receiving idelalisib plus rituximab were consistent with those expected for patients with relapsed CLL who had received extensive previous therapy.17 In Study 116, serious adverse events were reported in 49% of the patients who received idelalisib plus rituximab.17,18 The most frequent serious adverse events

Contraindications Idelalisib is contraindicated in patients with a history of serious allergic reactions, including anaphylaxis and toxic epidermal necrolysis.18

Table 3 Grade ≥3 Adverse Reactions Reported with Idelalisib versus Placebo in Patients with CLL Idelalisib plus rituximab, N (%) (N = 110)

Placebo plus rituximab, N (%) (N = 108)

18 (16)

14 (13)

Sepsis

8 (7)

4 (4)

Diarrhea

6 (5)

Rash

4 (4)

1 (1)

Pyrexia

3 (3)

1 (1)

Chills

2 (2)

Stomatitis

2 (2)

Bronchitis

1 (1)

Headache

1 (1)

Adverse event Pneumonia

CLL indicates chronic lymphocytic leukemia. Source: Zydelig (idelalisib) tablets prescribing information; July 2014.

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Warnings and Precautions Boxed warning. Idelalisib carries a boxed warning indicating that the drug may cause fatal and/or serious intestinal perforation, hepatoxicity, diarrhea or colitis, and pneumonitis. Patients should be monitored for the development of these adverse events, and idelalisib therapy should be discontinued if intestinal perforation is suspected.18 Hepatotoxicity. In clinical trials, 14% of patients who received idelalisib experienced fatal and/or serious hepatotoxicity. In addition, elevations in transaminase levels greater than 5 times the upper limit of normal have been observed. These findings were typically noted within the first 12 weeks of treatment with idel alisib and were reversible with dose interruption.18 After resuming idelalisib treatment at a lower dose, 26% of patients experienced recurrence of alanine aminotransferase (ALT) and aspartate aminotrans ferase (AST) elevations. Idelalisib treatment should be discontinued if recurrent hepatotoxicity occurs.18 The use of idelalisib concurrently with other drugs that may cause liver toxicity is not recommended.18 Transaminase levels should be monitored in all idel alisib recipients according to the following schedule18:

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• Every 2 weeks for months 1 to 3 • Every 4 weeks for months 4 to 6 • Every 1 to 3 months thereafter. Weekly monitoring is appropriate if ALT or AST levels rise above 3 times the upper limit of normal until liver toxicity resolves. Idelalisib should be withheld if ALT or AST levels are greater than 5 times the upper limit of normal. Total bilirubin, AST, and ALT levels should be monitored weekly until abnormalities resolve.18 Severe diarrhea or colitis. Across clinical trials, severe diarrhea or colitis (grade ≥3) occurred in 14% of patients receiving idelalisib. Diarrhea can occur at any time and responds poorly to antimotility agents. Concurrent use of idelalisib and other medications that cause diarrhea should be avoided.18 After interruption of idelalisib therapy and, in some instances, the use of corticosteroids, the median time to resolution of diarrhea ranged from 1 week to 4 weeks.18 Pneumonitis. Patients taking idelalisib have experienced fatal and serious pneumonitis. Pneumonitis should be suspected in patients who are taking idelalisib and present with pulmonary symptoms, including cough, dyspnea, hypoxia, interstitial infiltrates on a radiologic examination, or a decline of >5% in oxygen saturation.18 For patients with possible pneumonitis, idelalisib should be interrupted until an etiology for lung symptoms has been determined. Patients with pneumonitis that is believed to be caused by idelalisib have discontinued idelalisib therapy and received corticosteroids.18 Intestinal perforation. In clinical trials, fatal and serious intestinal perforations have occurred in patients taking idelalisib. Some patients had moderate-to-severe diarrhea at the time of perforation. Patients should immediately report new or worsening abdominal pain, chills, fever, nausea, or vomiting. Idelalisib should be permanently discontinued in patients who experience intestinal perforation.18 Severe cutaneous reactions. Overall, 1 case of toxic epidermal necrolysis was reported in a study of idel alisib plus bendamustine and rituximab. Patients receiving idelalisib have also reported other severe or life-threatening (grade ≥3) cutaneous reactions, including exfoliative dermatitis, rash, rash erythematous, rash generalized, rash macular, rash maculopapular, rash papular, rash pruritic, exfoliative rash, and skin disorders. Patients should be monitored for the development of severe cutaneous reactions, and idelalisib should be discontinued if they occur.18 Anaphylaxis. Serious allergic reactions, including anaphylaxis, have been reported in patients taking idel alisib. Idelalisib should be permanently discontinued if this occurs, and appropriate supportive measures should be instituted.18

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Neutropenia. Across clinical trials, 31% of patients receiving idelalisib experienced treatment-emergent grade 3 or 4 neutropenia. Blood counts should be monitored a minimum of every 2 weeks for the first 3 months of therapy and at least weekly in patients whose neutrophil counts are <1.0 Gi/L.18 Embryofetal toxicity. Idelalisib may cause fetal harm when administered to a pregnant woman.18 If idela lisib is used during pregnancy, or if a patient becomes pregnant while taking this drug, she should be made aware of the potential hazard to the fetus. While taking idelalisib, women of reproductive potential should avoid becoming pregnant. Effective contraception can be used during idelalisib treatment and for at least 1 month after the last dose.18

Use in Specific Populations Pregnancy. Idelalisib is a pregnancy category D teratogen and may cause teratogenicity and/or embryofetal lethality. Women should avoid becoming pregnant while taking idelalisib.18 Nursing mothers. Because many drugs are excreted in human milk and because of the potential for idel alisib-related adverse events in nursing infants from idelalisib, nursing or idelalisib should be discontinued based on the importance of the drug to the mother.18 Pediatric use. The safety and efficacy of idelalisib in pediatric patients have not been established.18 Geriatric use. In clinical trials of idel alisib for relapsed CLL, relapsed follicular lymphoma, and relapsed SLL, 63% of patients receiving the agent (131 of 208) were aged ≥65 years. No meaningful differences in efficacy were observed among age cohorts.18 When patients aged ≥65 years with relpased CLL were compared with younger patients, older patients had a higher incidence of discontinuation as a result of an adverse reaction (11% vs 5%), higher incidence of serious adverse events (51% vs 43%), and higher incidence of death (3% vs 0%).18 When patients aged ≥65 years with indolent NHL were compared with younger patients, older patients had a higher incidence of discontinuation as a result of an adverse event (28% vs 20%). In addition, older patients had a higher incidence of serious adverse reactions (64% vs 37%) and a higher incidence of death (11% vs 5%).18 Hepatic impairment. Safety and efficacy data are not available in patients with baseline ALT or AST values greater than 2.5 times the upper limit of normal, or bilirubin values greater than 1.5 times the upper limit of normal. Patients with baseline hepatic impairment should be monitored for signs of idelalisib toxicity.18

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Conclusion Idelalisib, the first FDA-approved PI3Kδ inhibitor, is an effective and safe treatment option for patients with relapsed CLL, relapsed follicular lymphoma, or relapsed SLL. Based on a significant PFS benefit, idela lisib joins ibrutinib as an FDA-approved oral agent for use in patients with relapsed CLL. In relapsed follicular lymphoma and relapsed SLL, idelalisib was approved

Idelalisib, the first FDA-approved PI3Kδ inhibitor, is an effective and safe treatment option for patients with relapsed CLL, relapsed follicular lymphoma, or relapsed SLL. Based on a significant PFS benefit, idelalisib joins ibrutinib as an FDA-approved oral agent for use in patients with relapsed CLL. under the accelerated approval program based on ORR data. Clinical trials to collect data verifying the clinical benefit of idelalisib in these 2 indolent lymphomas are under way.20 Additional clinical trials are evaluating the combination of idelalisib plus ofatumumab and idelalisib plus obinutuzumab for the treatment of patients with previously untreated CLL. Idelalisib is also being studied in combination with bendamustine and rituximab for the treatment of patients with previously untreated and relapsed hematologic malignancies.20 n

References

1. Leukemia & Lymphoma Society. Chronic lymphocytic leukemia. www.lls. org/#/diseaseinformation/leukemia/chroniclymphocyticleukemia/. Accessed Sep tember 11, 2014. 2. Leukemia & Lymphoma Society. Chronic lymphocytic leukemia: incidence.

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www.lls.org/#/diseaseinformation/leukemia/chroniclymphocyticleukemia/incidence/. Accessed September 11, 2014. 3. Gribben JG. How I treat CLL up front. Blood. 2010;115:187-197. 4. Leukemia & Lymphoma Society. Chronic lymphocytic leukemia: signs and symptoms. www.lls.org/#/diseaseinformation/leukemia/chroniclymphocyticleu kemia/signssymptoms/. Accessed September 11, 2014. 5. Cancer.net. Leukemia—chronic lymphocytic—CLL: statistics. Reviewed July 2014. www.cancer.net/cancer-types/leukemia-chronic-lymphocytic-cll/statistics. Accessed September 11, 2014. 6. Blankart CR, Koch T, Linder R, et al. Cost of illness and economic burden of chronic lymphocytic leukemia. Orphanet J Rare Dis. 2013;8:32. 7. Harris NL, Jaffe ES, Diebold J, et al. World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting—Airlie House, Virginia, November 1997. J Clin Oncol. 1999;17:3835-3849. 8. Leukemia & Lymphoma Society. Non-Hodgkin lymphoma: treating specific indolent subtypes. www.lls.org/#/diseaseinformation/lymphoma/nonhodgkin lymphoma/treatment/indolentnhlsubtypes/specificindolentsubtypes/. Accessed September 11, 2014. 9. Leukemia & Lymphoma Society. Treatment for aggressive NHL subtypes. www.lls.org/#/diseaseinformation/lymphoma/nonhodgkinlymphoma/treatment/ aggressivenhlsubtypes/. Accessed September 11, 2014. 10. Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute– Working Group 1996 guidelines. Blood. 2008;111:5446-5456. Erratum in: Blood. 2008;112:5259. 11. Leukemia & Lymphoma Society. Chronic lymphocytic leukemia: treatment: chemotherapy and drug therapy. www.lls.org/#/diseaseinformation/ leukemia/chroniclymphocyticleukemia/treatment/chemotherapydrugtherapy/. Accessed September 11, 2014. 12. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): non-Hodgkin’s lymphomas. Version 4.2014. August 22, 2014. www.nccn.org/professionals/physician_gls/ pdf/nhl.pdf. Accessed October 3, 2014. 13. Gazyva (obinutuzumab) injection [prescribing information]. South San Francisco, CA: Genentech, Inc; June 2014. 14. Imbruvica (ibrutinib) capsules [prescribing information]. Sunnyvale, CA: Pharmacyclics, Inc; July 2014. 15. Arzerra (ofatumumab) injection [prescribing information]. Research Triangle Park, NC: GlaxoSmithKline; April 2014. 16. US Food and Drug Administration. FDA approves Zydelig for three types of blood cancers. Press release. July 23, 2014. www.fda.gov/newsevents/newsroom/ pressannouncements/ucm406387.htm. Accessed September 11, 2014. 17. Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014;370:997-1007. 18. Zydelig (idelalisib) tablets [prescribing information]. Foster City, CA: Gilead Sciences, Inc; July 2014. 19. Gopal AK, Kahl BS, de Vos S, et al. PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med. 2014;370:1008-1018. 20. ClinicalTrials.gov. Idelalisib. Search results. http://clinicaltrials.gov/ct2/results ?term=idelalisib&Search=Search. Accessed September 11, 2014.

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Zykadia (Ceritinib) Approved for Patients with Crizotinib-Resistant ALK-Positive Non–Small-Cell Lung Cancer 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 According to the American Cancer Society, more than 159,000 Americans will die from lung cancer in 2014, representing approximately 27% of all cancer deaths.1 Non–small-cell lung cancer (NSCLC), the most common form of lung cancer, accounts for 85% to 90% of all cases.2 NSCLC comprises a number of histologies, including adenocarcinoma, squamous-cell carcinoma, nonsquamous carcinoma, large-cell carcinoma, sarcomatoid carcinoma, and adenosquamous carcinoma.2 A recent analysis of claims data from an oncology registry associated with a large US commercial health plan has demonstrated the substantial cost burden associated with NSCLC.3 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.3 The average total healthcare costs ranged from approximately $19,000 to $167,000 for first-line NSCLC management, and from approximately $35,000 to $135,000 for second-line management.3 In this analysis, systemic therapy represented 20% to 55% of first-line total costs, and 22% to 68% of second-line total costs.3 Traditionally, patients with metastatic NSCLC have been managed with combinations of cytotoxic agents. Although the use of platinum-based doublets has improved the median overall survival for patients with advanced NSCLC from 4 to 5 months to 8 to 10 months (in treatment-naïve patients), these chemotherapy combinations are limited by significant toxicities, including myelosuppression, nausea and vomiting, and severe fatigue.4-6 As knowledge of tumor-cell biology in lung cancer evolves, small molecules that target specific genetic mutations offer the opportunity to manage patients with NSCLC using a personalized approach.6 In NSCLC, multiple driver oncogenes have been identified, including EGFR, ALK, and KRAS.6 Among North American patients with advanced NSCLC, approximately 10% express mutations in EGFR,7 approximately 23% express mutations in KRAS,8 and up to 13% express activating mutations or translocations of ALK.9

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Identifying EGFR and ALK mutations can help to decide whether a given patient with NSCLC can benefit from today’s targeted therapies, including erlotinib and afatinib (EGFR inhibitors) or crizotinib (an ALK inhibitor). Granted an accelerated approval by the US Food and Drug Administration (FDA) in 2011, crizotinib was the first treatment available for patients with metastatic NSCLC whose tumors are ALK-positive.10 An open-label, active-controlled, multinational, randomized clinical trial demonstrated prolonged progression-free survival with crizotinib compared with chemotherapy in ALK-positive, metastatic NSCLC. Vision disorders, nausea, diarrhea, vomiting, constipation, edema, elevated transaminases, and fatigue were the most common adverse reactions observed among recipients of crizotinib in this trial.10 To overcome the documented resistance to crizotinib, researchers continue to investigate medications that target ALK mutations.6 Novel kinase inhibitors currently being investigated in clinical trials for patients with ALK mutation NSCLC include alectinib, ganetespib, and AP26113.6,11

Ceritinib: New Treatment Option for ALK-Positive NSCLC On April 29, 2014, the FDA approved ceritinib (Zykadia; Novartis Pharmaceuticals), a kinase inhibitor, for the treatment of patients with metastatic ALK-positive NSCLC who are intolerant of, or whose disease progressed during therapy with, crizotinib.12 This approval was granted under the FDA’s accelerated process based on unpublished clinical trial data demonstrating significant tumor response rate and duration of response.12 Improvements in survival or disease-related symptoms have not been demonstrated.13 The approval of ceritinib was based on the results of a multicenter, single-arm, open-label clinical trial that enrolled 163 patients with ALK-positive metastatic NSCLC that had progressed with crizotinib or who were intolerant of that drug.12,13 Ceritinib was administered at a dose of 750 mg once daily.12,13 “Zykadia represents an important treatment option for ALK-positive NSCLC patients who relapse after starting initial therapy with crizotinib,” noted lead investigator Alice T. Shaw, MD, PhD, of Massachusetts Gen-

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Table 1 Response Rate and Duration of Response with Crizotinib in Patients with ALK-Positive NSCLC Investigator assessment BIRC assessment Efficacy end point (N = 163) (N = 163) 54.6 (95% CI, 47-62)

43.6 (95% CI, 36-52)

Complete response, %

1.2

2.5

Partial response, %

53.4

41.1

7.4 (95% CI, 5.4-10.1)

7.1 (95% CI, 5.6-not estimable)

Overall response rate, %

Duration of response, median, months

BIRC indicates Blinded Independent Review Committee; CI, confidence interval. Source: Zykadia (ceritinib) capsules prescribing information; April 2014.

eral Hospital Cancer Center in Boston.14 “This approval will affect the way we manage and monitor patients with this type of lung cancer, as we will now be able to offer them the opportunity for continued treatment response with a new ALK inhibitor.”14

Mechanism of Action In vitro and in vivo assays demonstrate that ceritinib, a kinase inhibitor, hinders the proliferation of ALK- dependent cancer cells by blocking the autophosphorylation of ALK, as well as ALK-mediated phosphorylation of STAT3, a downstream signaling protein. Ceritinib also targets insulin-like growth factor 1 receptor, insulin receptor, and ROS1.13 Dosing and Administration Ceritinib should be administered at a dose of 750 mg orally once daily until disease progression or until unacceptable toxicity. It should be taken on an empty stomach, but not within 2 hours of a meal. If a dose of ceritinib is missed, it should be administered only if the next dose is not due within 12 hours.13 Single-Arm Phase 2 Trial The multicenter, single-arm, open-label trial of ceritinib enrolled 163 patients with the ALK-mutation NSCLC whose disease progressed while receiving crizotinib or those who were intolerant of crizotinib.13 Objective response rate (ORR) according to the Response Evaluation Criteria in Solid Tumors version 1.0 was the primary end point of this study. This parameter was evaluated by the investigators and by a central Blinded Independent Review Committee.13 Most patients with ALK-positive NSCLC were female (54%), Caucasian (66%), aged <65 years (87%), and never or former smokers (97%).13 The majority (87%)

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had an Eastern Cooperative Oncology Group performance status of 0 or 1.13 Overall, 91% of patients had progressed with previous treatment of crizotinib, 84% had received ≥2 previous therapies, and 93% had adenocarcinoma histology.13 Common sites of extrathoracic metastases included the brain (60%), liver (42%), and bone (42%).13 Retrospective verification of ALK positivity was performed by review of local test results for 99% of patients.13 The phase 2 study demonstrated that ceritinib is active in patients with ALK-positive NSCLC, with an ORR of 54.6% by investigator assessment and a median duration of response of 7.4 months. All participants received ceritinib at an initial dose of 750 mg daily. The median duration of exposure to ceritinib was 6 months.13 The findings of the Blinded Independent Review Committee were similar to those of the investigators. Table 1 lists the findings on ORR and duration of response from this study.13

Safety and Adverse Events The safety of ceritinib was established based on data from 255 patients with ALK-positive disease in the phase 2 study—246 patients with NSCLC and 9 patients with other cancer types.13 A total of 59% of the patients receiving ceritinib required dose reductions as a result of adverse reactions.13 The adverse reactions that led to dose reductions or interruptions were reported in ≥10% of patients and included increased alanine aminotransferase (ALT; 29%), nausea (20%), increased aspartate aminotransferase (AST; 16%), diarrhea (16%), and vomiting (16%).13 Serious adverse drug reactions that were reported in ≥2% of patients receiving ceritinib included convulsion, pneumonia, interstitial lung disease/pneumonitis, dyspnea, dehydration, hyperglycemia, and nausea.13 Of the patients receiving ceritinib, 5% had fatal adverse reactions, including pneumonia, respiratory failure, interstitial lung disease/pneumonitis, pneumothorax, gastric hemorrhage, general physical health deterioration, pulmonary tuberculosis, cardiac tamponade, and 1 case of sepsis.13 Overall, 10% of patients receiving ceritinib discontinued therapy as a result of adverse reactions.13 Pneumonia, interstitial lung disease/pneumonitis, and decreased appetite were the most common adverse drug reactions that led to discontinuation in ≥1% of patients.13 Of note, ceritinib should be discontinued in patients who do not tolerate 300 mg daily dosing.13 Table 2 lists the common adverse reactions and Table 3 lists the laboratory abnormalities reported in patients treated with ceritinib.13 Additional adverse reactions occurring in ≥2% of the patients receiving ceritinib include neuropathy (17%), manifested as paresthesia, muscular weakness, gait disturbance, peripheral neuropathy, hypoesthesia, periph-

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eral sensory neuropathy, dysesthesia, neuralgia, peripheral motor neuropathy, hypotonia, or polyneuropathy; vision disorder (9%), including vision impairment, blurred vision, photopsia, accommodation disorder, presbyopia, or reduced visual acuity; prolonged QT interval (4%); and bradycardia (3%).13 Ceritinib has no contraindications.

Warnings and Precautions Severe/persistent gastrointestinal toxicity. Of the 255 patients receiving ceritinib in the phase 2 study, 96% had diarrhea, nausea, vomiting, or abdominal pain; severe cases were reported in 14% of the patients. Dose modification was required in 38% of patients as a result of diarrhea, nausea, vomiting, or abdominal pain. Patients should be managed using standards of care, as needed. Based on the severity of the adverse drug reaction, ceritinib should be withheld and then resumed with a 150-mg dose reduction.13 Hepatotoxicity. Of the 255 patients in the phase 2 study, 27% had elevations in ALT that were greater than 5 times the upper limit of normal. Permanent discontinuation resulting from elevated transaminases and jaundice was required in 1 (0.4%) patient. Patients should undergo laboratory tests, including ALT, AST, and total bilirubin, once monthly and as clinically indicated. More frequent testing is warranted in patients who develop transaminase elevations. Ceritinib should be withheld, dose reduced, or should be permanently discontinued based on the severity of the hepatotoxicity reaction.13 Interstitial lung disease/pneumonitis. Severe, life- threatening, or fatal interstitial lung disease/pneumonitis has occurred in patients receiving ceritinib. Pneumonitis was reported in 4% of the 255 patients in the phase 2 study. In all, 3% of patients had grade 3 or 4 disease, and 1 patient died. Ceritinib was discontinued in 1% of patients because of interstitial lung disease/pneumonitis. If symptoms indicative of interstitial lung disease/pneumonitis are observed, exclude other potential causes. If interstitial lung disease/pneumonitis is deemed to be treatment- related, discontinue ceritinib therapy permanently.13 QT interval prolongation. In the phase 2 study and across the development program of ceritinib, 3% of patients had corrected QT (QTc) interval increase from a baseline of >60 msec.13 Across the development program of ceritinib, 1 patient using doses ranging from 50 mg to 750 mg had a QTc of >500 msec.13 Ceritinib should be avoided in patients with congenital long QT syndrome. Patients with congestive heart failure, bradyarrhythmias, or electrolyte abnormalities, and those taking medications known to prolong the QTc interval should undergo periodic electrocardiograms (ECGs) and electrolyte monitoring.13

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dverse Reactions Reported with Ceritinib in >10% Table 2 A of Patients for All Grades or ≥2% for Grades 3/4 Ceritinib (N = 255) All grades, Grade 3/4, Adverse reaction % % Gastrointestinal events Diarrhea

Nausea

Vomiting

Abdominal pain/discomfort, epigastric discomfort

Constipation

Esophageal disorder: dyspepsia, gastroesophageal reflux disease, dysphagia

Fatigue/asthenia

Decreased appetite

Rash, maculopapular rash, acneiform dermatitis

Other events

Source: Zykadia (ceritinib) capsules prescribing information; April 2014.

Table 3 Key Laboratory Abnormalities in >10% (All Grades) of Patients Receiving Ceritinib Ceritinib (N = 255) All grades, Grade 3/4, Laboratory abnormality % % Hemoglobin decreased

Alanine transaminase increased

Aspartate transaminase increased

Creatinine increased

Glucose increased

Phosphate decreased

Lipase increased

Bilirubin (total) increased

Source: Zykadia (ceritinib) capsules prescribing information; April 2014.

Ceritinib should be withheld in patients who develop a QTc interval of >500 msec on at least 2 separate ECGs. Ceritinib can be resumed with a 150-mg dose reduction if the QTc interval is <481 msec or on recovery to baseline if the QTc interval is ≥481 msec.13 Ceritinib should be permanently discontinued in patients who develop QTc interval prolongation in combination with torsades de pointes, polymorphic ventricular tachycardia, or signs or symptoms of serious arrhythmia.13 Hyperglycemia. Grade 3 or 4 hyperglycemia based on

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laboratory values occurred in 13% of patients in the phase 2 study of ceritinib. The risk for grade 3 or 4 hyperglycemia in patients with diabetes or glucose intolerance was increased 6-fold. There was a 2-fold increase in the risk for grade 3 or 4 hyperglycemia in patients taking corticosteroids. Serum glucose levels should be monitored, and antihyperglycemic medications should be used as indicated. Ceritinib should be withheld until hyperglycemia is controlled and then resumed with a 150-mg dose reduction. If adequate hyperglycemic control cannot be achieved, ceritinib should be discontinued.13 Bradycardia. Sinus bradycardia was observed as a new finding in 1% of patients and was reported as an adverse drug reaction in 3% of patients in the phase 2 study of ceritinib.13 Ceritinib should be avoided in patients taking other agents known to cause bradycardia (eg, beta-blockers, nondihydropyridine calcium channel blockers, clonidine, and digoxin) if possible. Heart rate and blood pressure should be monitored regularly.13 If symptomatic bradycardia is not life-threatening, ceritinib should be withheld until recovery or until the heart rate is ≥60 beats per minute (bpm). Concomitant medication use should be evaluated, and ceritinib dose should be adjusted. If bradycardia is associated with a medication known to cause bradycardia or hypotension, ceritinib can be withheld until recovery or to a heart rate of ≥60 bpm. If the concomitant medication can be adjusted or discontinued, ceritinib can be restarted at a 150-mg dose reduction on recovery to asymptomatic bradycardia or to a heart rate of ≥60 bpm, with frequent monitoring. Ceritinib should be discontinued if life-threatening bradycardia is observed and no concomitant medication use is identified.13 Embryofetal toxicity. Based on its mechanism of action, ceritinib may cause fetal harm when administered to a pregnant woman.13

Specific Populations Pregnancy. Ceritinib has a pregnancy Category D. Women of reproductive potential should be made aware of the potential hazard to a fetus, as well as the need to use effective contraception during treatment with ceritinib and for at least 2 weeks after the completion of therapy.13 Nursing mothers. Whether ceritinib or its metabolites are excreted in human milk is not known. Nursing mothers who take ceritinib should discontinue breastfeeding.13 Pediatric use. The safety and effectiveness of ceritinib have not been established in pediatric patients.13 Geriatric use. Clinical studies of ceritinib did not include sufficient numbers of patients aged ≥65 years to assess its effect on older patients. Of the 255 patients in the phase 2 study, 40 (16%) were aged ≥65 years.13 Hepatic impairment. Because ceritinib is eliminated

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primarily in the liver, patients with hepatic impairment may have increased exposure. Based on a pharmacokinetic analysis, dose adjustment is not recommended for patients with mild hepatic impairment. A recommended dose has not been determined for patients with moderate-to-severe hepatic impairment.13

Conclusion NSCLC remains the main cause of death from cancer in the United States for men and women. The disease is still diagnosed mainly at advanced stages; therefore, prognosis is poor, and long-term survival is rare. Ceritinib, the second oral kinase inhibitor approved for the initial treatment of ALK-positive metastatic NSCLC, has demonstrated efficacy with manageable side effects. Ceritinib joins crizotinib as the second FDA-approved agent for this subset of patients with NSCLC, offering an effective alternative to cytotoxic therapy. Ceritinib may confer clinical value in other cancers in which ALK mutations are present. Clinical studies are evaluating ceritinib in pediatric malignancies and other tumors characterized by genetic abnormalities of ALK.15 n References

1. American Cancer Society. What are the key statistics about lung cancer? Revised April 30, 2014. www.cancer.org/cancer/lungcancer-non-smallcell/detailedguide/nonsmall-cell-lung-cancer-key-statistics. Accessed May 15, 2014. 2. American Cancer Society. What is non-small cell lung cancer? Revised April 30, 2014. www.cancer.org/cancer/lungcancer-non-smallcell/detailedguide/non-smallcell-lung-cancer-what-is-non-small-cell-lung-cancer. Accessed May 15, 2014. 3. 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. 4. Azzoli CG, Giaccone G, Temin S. American Society of Clinical Oncology Clinical Practice Guideline Update on Chemotherapy for Stage IV Non–Small-Cell Lung Cancer. J Oncol Pract. 2010;6:39-43. 5. American Cancer Society. Chemotherapy for non-small cell lung cancer. Revised April 30, 2014. www.cancer.org/cancer/lungcancer-non-smallcell/detailedguide/ non-small-cell-lung-cancer-treating-chemotherapy. Accessed May 15, 2014. 6. Villaflor VM, Salgia R. Targeted agents in non-small cell lung cancer therapy: what is there on the horizon? J Carcinog. 2013;12:7. 7. 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. 8. Massarelli E, Varella-Garcia M, Tang X, et al. KRAS mutation is an important predictor of resistance to therapy with epidermal growth factor receptor tyrosine kinase inhibitors in non–small-cell lung cancer. Clin Cancer Res. 2007;13:2890-2896. 9. Shaw AT, Yeap BY, Mino-Kenudson M, et al. Clinical features and outcome of patients with non–small-cell lung cancer who harbor EML4-ALK. J Clin Oncol. 2009;27:4247-4253. 10. US Food and Drug Administration. Drugs: crizotinib. www.fda.gov/drugs/infor mationondrugs/approveddrugs/ucm376058.htm. Accessed May 17, 2014. 11. Iwama E, Okamoto I, Harada T, et al. Development of anaplastic lymphoma kinase (ALK) inhibitors and molecular diagnosis in ALK rearrangement-positive lung cancer. Onco Targets Ther. 2014;7:375-385. 12. US Food and Drug Administration. FDA approves Zykadia for late-stage lung cancer: breakthrough therapy drug approved four months ahead of review completion goal date. Press release. April 29, 2014. www.fda.gov/newsevents/newsroom/press announcements/ucm395299.htm. Accessed July 24, 2014. 13. Zykadia (ceritinib) capsules [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; April 2014. 14. Novartis. Novartis gains FDA approval for Zykadia(TM), first therapy for patients with ALK+ NSCLC previously treated with the ALK inhibitor crizotinib. April 29, 2014. www.novartis.com/newsroom/media-releases/en/2014/1776962.shtml. Accessed May 17, 2014. 15. ClinicalTrials.gov. LDK378. Search results. http://clinicaltrials.gov/ct2/results? term=LDK378&Search= Search. Accessed May 17, 2014.

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Once-Fatal Conditions Have Become Chronic: Early Trends in the FDA’s 2015 Approvals By Gary Branning, MBA Adjunct Professor, Rutgers Graduate School of Business, Guest Lecturer, Blanche and Irwin Lerner Center for Pharmaceutical Management Studies, Newark, NJ, and President of Managed Market Resources, Mt Olive, NJ

or patients, newly approved drugs represent exciting opportunities to treat serious disease states, many of which have had few treatment options available. New therapies have enabled physicians to initiate treatment earlier and to continue treatment throughout the disease progression. The goal of early therapy is to alleviate the long-term effects of chronic or life-threatening conditions, but when treatment occurs earlier and lasts longer, the cost of therapy also increases.1 In early 2015, new vaccines, treatments for HIV/ AIDS, and oncology medications have been prominent among new approvals by the US Food and Drug Administration (FDA). Thanks to advances in treatment, all 3 of these therapeutic categories have either prevented once-fatal diseases or have begun to transform them into sustainable, chronic conditions. The Table lists the new drugs in all clinical categories approved by the FDA by March 10, 2015.

Vaccines Despite a recent heated public debate sparked by an outbreak of measles, vaccines are widely regarded as one of the greatest public health advances in the United States. Through the use of vaccines, we have eradicated, or nearly eliminated, previously devastating conditions, such as smallpox, and have dramatically reduced the number of patients suffering from preventable conditions, such as measles, diphtheria, and whooping cough.2 As the importance of vaccine safety continues to grow, the development and licensure of new vaccines will add to the already robust list of currently available vaccines. One of those new vaccines, Bexsero (meningococcal group B vaccine), was approved in January 2015, and was the second to receive FDA approval for the prevention of invasive meningococcal disease caused by Neisseria meningitidis serogroup B in individuals aged 10 to 25 years. The first vaccine for the prevention of serogroup B meningococcal disease was Trumenba, which was approved 3 months earlier.

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Before these 2 approvals, the existing FDA-approved vaccines only covered 4 of the 5 main serogroups of N meningitidis bacteria that cause meningococcal disease A, C, Y, and W. The FDA used the accelerated approval regulatory pathway to approve Bexsero as well as Trumenba.3

HIV/AIDS An estimated 1.1 million people are living with HIV in the United States, and approximately 50,000 new cases are diagnosed annually.4 Although many patients have been diagnosed with HIV and are undergoing treatment, only 25% are virally suppressed, reflecting the continued need for new and innovative treatments to help patients achieve viral suppression.4 In January 2015, the FDA approved the combination of atazanavir and cobicistat (Evotaz) for the treatment of adults with HIV-1 infection. This drug is indicated for use in combination with other antiretroviral drugs,5 and is the first and only protease inhibitor that is pharmacoenhanced by cobicistat (Tybost) and is supported by comparative phase 3 trial data.4

One of those new vaccines, Bexsero (meningococcal group B vaccine), was approved in January 2015, and was the second to receive FDA approval for the prevention of invasive meningococcal disease caused by Neisseria meningitidis serogroup B. Also in January, the FDA approved the combination of darunavir and cobicistat (Prezcobix) for the treatment of patients with HIV. This combination is indicated for use with other antiretroviral agents for treatment-naïve and treatment-experienced adults with HIV-1 infection who have no darunavir resistance–associated mutations.6

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Table New 2015 FDA-Approved Drugs, as of March 10 Approval date

Drug name

Manufacturer

Indication/class/route

Rytary (carbidopa/ levodopa)a

Impax Laboratories

Parkinson’s disease; extended-release aromatic amino acid decarboxylation inhibitor and aromatic amino acid combination; oral

1/7/2015

Savaysa (edoxaban)

Daiichi Sankyo

For risk reduction of stroke and systemic embolism in patients with nonvalvular atrial fibrillation; factor Xa inhibitor; oral

1/8/2015

Duopa (carbidopa/ levodopa)a

AbbVie

To control motor fluctuations in patients with advanced Parkinson’s disease; aromatic amino acid decarboxylation inhibitor and aromatic amino acid combination; enteral suspension

1/12/2015

Cosentyx (secukinumab)

Novartis

For moderate-to-severe plaque psoriasis; human interleukin-17A antagonist; subcutaneous

1/21/2015

Bexsero (meningococcal group B vaccine)

Novartis

Vaccine for invasive meningococcal disease caused by Neisseria meningitidis serogroup B; intramuscular

1/23/2015

Triferic (ferric pyrophosphate citrate)

Rockwell Medical

For treatment of anemia in patients with chronic renal failure; iron replacement; solution

1/23/2015

Natpara (parathyroid hormone)

NPS Pharmaceuticals

To control hypocalcemia in patients with hypoparathyroidism; parathyroid hormone; subcutaneous

1/23/2015

Prestalia (perindopril arginine and amlodipine besylate)a

Symplmed Pharmaceuticals

Fixed-dose combination for the treatment of hypertension; dihydropyridine calcium channel blocker + angiotensinconverting enzyme inhibitor; oral

1/26/2015

Evotaz (atazanavir/ cobicistat)a

Bristol-Myers Squibb

For HIV-1 infection; antiretroviral combination; oral

1/29/2015

Prezcobix (darunavir/ cobicistat)a

Janssen

For HIV-1 infection; antiretroviral combination; oral

1/29/2015

Imbruvica (ibrutinib)b

Pharmacyclics

For Waldenström’s macroglobulinemia; BTK inhibitor; oral

1/29/2015

Glyxambi (empagliflozin and linagliptin)

Boehringer For adults with type 2 diabetes; SGLT2 and DPP-4 Ingelheim/Eli Lilly combination; oral

1/30/2015

Vyvanse (lisdexamfetamine dimesylate)

Shire

For binge-eating disorder in adults; central nervous system stimulant; oral

1/30/2015

Pazeo (olopatadine hydrochloride)

Alcon Laboratories

For allergic conjunctivitis; mast-cell stabilizer; ophthalmic solution

1/30/2015

Ibrance (palbociclib)

Pfizer

For metastatic breast cancer; cyclin-dependent kinase inhibitor; oral

2/3/2015

Lucentis (ranibizumab)

Genentech

For diabetic retinopathy in patients with diabetic macular edema; antiangiogenic ophthalmic agent; intravitreal injection

2/6/2015

Dutrebis (lamivudine and raltegravir)

Merck

For HIV infection; fixed-dose antiretroviral combination; oral

2/6/2015

Banzel (rufinamide)

Eisai

As adjunctive treatment for pediatric patients with seizures associated with Lennox-Gastaut syndrome; oral suspension

2/12/2015

Lenvima (lenvatinib)

Eisai

For differentiated thyroid cancer that has progressed despite radioactive iodine therapy; tyrosine kinase receptor inhibitor; oral

2/13/2015

Revlimid (lenalidomide)b

Celgene

For newly diagnosed multiple myeloma; antineoplastic immunosuppressant; oral

2/17/2015

Farydak (panobinostat)

Novartis

For multiple myeloma; HDAC inhibitor; oral

2/23/2015

Continued

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Table New 2015 FDA-Approved Drugs, as of March 10 (Continued) Approval date

Drug name

Manufacturer

Indication/class/route

Avycaz (ceftazidime/ avibactam)a

Actavis

For complicated intra-abdominal infections, in combination 2/25/2015 with metronidazole, and complicated urinary tract infections with limited or no treatment options; antibacterial combination; IV

Toujeo (insulin glargine [rDNA origin] injection)

Sanofi

To improve glycemic control in adults with type 1 or xtype 2 diabetes; long-acting basal insulin; injection

2/25/2015

Elepsia XR (levetriacetam)

Sun Pharma

Extended-release formulation for partial-onset seizures; oral

3/2/2015

Opdivo (nivolumab)

Bristol-Myers Squibb

For metastatic squamous non–small-cell lung cancer; PD-1–blocking antibody; IV

3/4/2015

Zarxio (filgrastim-sndz)c

Sandoz

For chemotherapy-associated neutropenia, and for the same indications as filgrastim (Neupogen); leukocyte growth factor biosimilar to Neupogen

3/6/2015

Cresemba (isavuconazonium sulfate)

Astellas Pharma

For adults with invasive aspergillosis and invasive mucormycosis; azole antifungal; oral/IV

3/6/2015

Unituxin (dinutuximab)

United Therapeutics

For pediatric patients with high-risk neuroblastoma; GD2-binding monoclonal antibody; IV

3/10/2015

New combination, with a new molecular entity. New indication. c First biosimilar approved by the FDA. BTK indicates Bruton’s tyrosine kinase; DPP-4, dipeptidyl peptidase-4; FDA, US Food and Drug Administration; HDAC, histone deacetylase; IV, intravenous; PD-1, programmed-death receptor-1; SGLT2, sodium glucose cotransporter-2. a

Oncology According to an article by de Moor and colleagues, within the next decade, the number of Americans who live at least 5 years with cancer is projected to grow by 37% to 11.9 million.7 This growing population of cancer survivors has brought about an interesting dilemma: although treatments for cancer have saved their lives, the therapies often result in severe side effects that may linger for years, including heart damage and radiation syndrome. The emotional effects are also serious, including depression, anxiety, and body image disorders. A consistent, medical response strategy to these longterm side effects has yet to be determined, but survivorship will become increasingly important as the generation of baby boomers (born between 1946 and 1964) reach an age when some of them are likely to have cancer and other chronic conditions.8 A new drug for the treatment of patients with breast cancer, palbociclib (Ibrance), was granted accelerated approval by the FDA in February 2015, 2 months ahead of schedule.9 Palbociclib is indicated for use with letrozole, an aromatase inhibitor, as first-line treatment in postmenopausal women with metastatic breast cancer that is estrogen receptor–positive and human epidermal growth factor receptor 2–negative. Its unique mechanism of action allows palbociclib to serve as an inhibitor of cy-

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clin-dependent kinases 4 and 6, which promote the growth of cancer cells. The FDA granted this cancer drug a breakthrough therapy designation and a priority review.9 Another cancer medication, panobinostat (Farydak), was approved under the FDA’s accelerated approval program for drugs that show promise in treating a serious disease in February 2015, despite a setback in November 2014, when an FDA advisory committee voted against

A new drug for the treatment of patients with breast cancer, palbociclib (Ibrance), was granted accelerated approval by the FDA in February 2015, 2 months ahead of schedule. Its unique mechanism of action allows palbociclib to serve as an inhibitor of cyclin-dependent kinases 4 and 6, which promote the growth of cancer cells. approving panobinostat for patients with multiple myeloma, because of concerns that the benefits of the drug did not outweigh its risks. Since then, the manufacturer submitted additional information to support the use of panobinostat in patients who have already tried at least 2 other

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A 2015 PIPELINE PREVIEW

therapies, including the chemotherapy drug bortezomib (Velcade) and the immunotherapy drug dexamethasone.10 Also in February 2015, the FDA approved an expanded indication for lenalidomide (Revlimid), in combination with dexamethasone, for the treatment of newly diagnosed patients with multiple myeloma.11 This combination was approved in 2006 for patients with myeloma who had previously tried at least 1 other therapy.11

The FDA also granted accelerated approval in February 2015 to lenvatinib (Lenvima) for the treatment of the most common strain of thyroid cancer. It is currently being studied for liver, kidney, lung, and endometrial cancers as well. The FDA also granted accelerated approval in February 2015 to lenvatinib (Lenvima) for the treatment of the most common strain of thyroid cancer.12 Lenvatinib is a tyrosine kinase receptor inhibitor that blocks the growth agents that tumors need to proliferate. It is currently being studied for liver, kidney, lung, and endometrial cancers as well. The manufacturer anticipates that lenvatinib could become a blockbuster drug by 2020.12

Conclusion As patients live longer and manage their potentially life-threatening diseases, healthcare costs are likely to continue to rise. Among other influential drugs, the medications approved by the FDA for vaccination against meningococcal disease, for cancer treatment, and for the management of the symptoms of HIV/AIDS will offer patients alternative therapies that have the potential to improve their quality of life and/or extend their lives.

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Although 2015 has just begun, it is already a momentous year for new pharmaceuticals coming to market. n Author Disclosure Statement Mr Branning reported no conflicts of interest.

References

1. Spatz I, McGee N. Health policy brief: specialty pharmaceuticals: complex new drugs hold great promise for people with chronic and life-threatening conditions. The drugs are also a driver of spending growth. Health Aff. November 25, 2013. www.healthaffairs.org/healthpolicybriefs/brief.php?brief_id=103. Accessed January 23, 2015. 2. Centers for Disease Control and Prevention. Vaccine safety: history of vaccine safety. Updated November 4, 2014. www.cdc.gov/vaccinesafety/Vaccine_ Monitoring/history.html. Accessed March 9, 2015. 3. US Food and Drug Administration. FDA approves a second vaccine to prevent serogroup B meningococcal disease. Press release. January 23, 2015. www. fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm431370.htm. Accessed March 9, 2015. 4. Bristol-Myers Squibb. U.S. Food and Drug Administration approves Bristol-Myers Squibbâ&#x20AC;&#x2122;s Evotaz (atazanavir and cobicistat) for the treatment of HIV-1 infection in adults. Press release. January 29, 2015. http://news.bms.com/ press-release/financial-news/us-food-and-drug-administration-approves-bristolmyers-squibbs-evotaz-a. Accessed March 9, 2015. 5. Brown T. Evotaz combo pill approved for HIV-1 in adults. Medscape Medical News. January 29, 2015. www.medscape.com/viewarticle/838958. Accessed March 9, 2015. 6. Brooks M. Darunavir/cobicistat (Prezcobix) combo pill clears FDA. Medscape Medical News. January 30, 2015. www.medscape.com/viewarticle/839016. Accessed March 9, 2015. 7. de Moor JS, Mariotto AB, Parry C, et al. Cancer survivors in the United States: prevalence across the survivorship trajectory and implications for care. Cancer Epidemiol Biomarkers Prev. 2013;22:561-570. 8. Lopatto E. Cancer no longer death sentence brings care gap: health. Bloomberg Business. June 4, 2013. www.bloomberg.com/news/articles/2013-0604/cancer-no-longer-death-sentence-brings-care-gap-health. Accessed March 9, 2015. 9. Chustecka Z. Novel drug approved for breast cancer: palbociclib (Ibrance). Medscape Medical News. February 3, 2015. www.medscape.com/viewarticle/ 839171. Accessed March 9, 2015. 10. Simon S. FDA approves Farydak (panobinostat) for multiple myeloma. American Cancer Society. February 25, 2015. www.cancer.org/cancer/news/ news/fda-approves-farydak-panobinostat-for-multiple-myeloma. Accessed March 9, 2015. 11. Nelson R. Lenalidomide now for newly diagnosed multiple myeloma patients. Medscape Medical News. February 25, 2015. www.medscape.com/view article/840390. Accessed March 9, 2015. 12. Garde D. Eisai wins an early FDA nod for its self-described cancer blockbuster. FierceBiotech. February 13, 2015. www.fiercebiotech.com/story/eisaiwins-early-fda-nod-self-described-cancer-blockbuster/2015-02-13. Accessed March 9, 2015.

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Glyxambi (Empagliflozin/Linagliptin): A DualActing Oral Medication Approved for the Treatment of Patients with Type 2 Diabetes By Lisa A. Raedler, PhD, RPh, Medical Writer

ore than 29 million individuals in the United States have diabetes; of these, approximately 21 million people are diagnosed, and 8 million individuals remain undiagnosed and untreated.1 Type 2 diabetes, which accounts for the large majority of new diagnoses of diabetes, is a leading cause of morbidity, including cardiovascular disease, blindness, renal failure, amputations, and hospitalizations.1,2 Type 2 diabetes is also associated with an increased risk for cancer, psychiatric illness, cognitive decline, chronic liver disease, arthritis, and other disabling conditions.2 Type 2 diabetes is a disorder in which the cells in the muscles, liver, and fat tissue are unable to use insulin effectively.1 As the body’s need for insulin increases, the beta cells in the pancreas lose their ability to produce sufficient quantities of the hormone. The relative role of insulin resistance compared with beta-cell dysfunction varies; some individuals are primarily insulin resistant, and others use insulin effectively but have low insulin secretion.1 The risk for type 2 diabetes increases with older age, obesity, family history of diabetes, history of gestational diabetes, impaired glucose metabolism, and physical inactivity.1 The prevalence and the incidence of type 2 diabetes continue to escalate worldwide, resulting in a significant economic burden for healthcare systems.2 The American Diabetes Association (ADA) estimates that the total (direct and indirect) cost of diabetes in the United States was $245 billion in 2012; the direct medical costs were $176 billion, and the indirect costs, including disability, work loss, and premature death, totaled approximately $69 billion.3 The treatment goals for patients with type 2 diabetes include the elimination of symptoms and the prevention of complications. Dietary and exercise modifications, as well as patient education, remain the cornerstones of initial treatment of patients with type 2 diabetes.2 Antidiabetic medications are considered when these interventions are insufficient to maintain near-normal blood glucose levels and the patient’s target hemoglobin (Hb) A1c level.2 In recent years, glycemic management of patients with type 2 diabetes has become increasingly complex and even controversial.2 New pharmacologic agents for type

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2 diabetes have been introduced at a rapid rate, each with potential adverse effects. In addition, the benefits of intensive glucose control in preventing macrovascular complications remain uncertain. According to a joint position statement issued by the ADA and the European Association for the Study of Diabetes, metformin monotherapy represents the standard treatment for patients with diabetes at diagnosis, unless explicitly contraindicated.2 If a patient’s HbA1c target level is not reached after approximately 3 months, one of several drugs can be combined with metformin.2 Drug classes and drugs that can be considered for adjunctive use with metformin include2: •S ulfonylureas (glipizide, glimepiride, glyburide) hiazolidinediones (pioglitazone) •T ipeptidyl peptidase (DPP)-4 inhibitors (alogliptin, •D linagliptin, saxagliptin, sitagliptin, vildagliptin) •G lucagon-like peptide (GLP)-1 receptor agonists (albiglutide, dulaglutide, exenatide, liraglutide) • I nsulins (glargine, lispro) odium-glucose transporter (SGLT)2 inhibitors •S (canagliflozin, empagliflozin). Typically, the choice of treatment should be made on the basis of patient and medication characteristics, with the primary goal of improving glycemic control and minimizing the side effects.2

Glyxambi: A Novel Fixed-Dose Combination Agent for Type 2 Diabetes On February 2, 2015, the US Food and Drug Administration (FDA) approved empagliflozin plus linagliptin (Glyxambi; Boehringer Ingelheim/Eli Lilly) tablets as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes when treatment with empagliflozin and linagliptin is appropriate.4 This fixed-dose combination contains 10 mg or 25 mg of empagliflozin and 5 mg of linagliptin, combining the properties of an SGLT2 and a DPP-4 in a single tablet.5 “Both of these classes of medications are safe and effective to lower the blood glucose, each through a different mechanism of action,” said J. Michael Gonzalez- Campoy, MD, PhD, FACE, Medical Director and Chief Executive Officer of the Minnesota Center for Obesity,

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Metabolism and Endocrinology. “Any time combination therapy is used, it is superior to monotherapy. Whenever two medications are combined into 1 pill, adherence improves, and usually the cost decreases.” 6 Empagliflozin and linagliptin are each FDA approved in single-ingredient oral formulations. Linagliptin was approved by the FDA in 2011 for the treatment of adults with type 2 diabetes, and empagliflozin was approved in August 2014.7,8 The empagliflozin plus linagliptin combination is not indicated for the treatment of patients with type 1 diabetes or those with diabetic ketoacidosis.5 No studies of

empagliflozin plus linagliptin combination have been conducted in patients with a history of pancreatitis; these patients may be at a high risk for pancreatitis while taking this fixed-dose combination.5

Mechanism of Action Empagliflozin plus linagliptin therapy combines 2 medications with complementary mechanisms of action; empagliflozin is an SGLT2 inhibitor, and linagliptin is a DPP-4 inhibitor.5 SGLT2 is a protein that facilitates the reabsorption of glucose from the kidney into the blood. By inhibiting SGLT2, empagliflozin lowers blood glucose

Table 1 Glycemic Parameters at 24 Weeks: Comparing Empagliflozin plus Linagliptin versus Each Drug Alone as Add-On Therapy in Patients Inadequately Controlled with Metformin Empagliflozin/ Empagliflozin/ linagliptin linagliptin Empagliflozin Empagliflozin Linagliptin Efficacy parameter 10 mg/5 mg 25 mg/5 mg 10 mg 25 mg 5 mg HbA1c level Patients, N

135

133

137

139

128

Baseline, mean, %

8.0

7.9

8.0

Change in HbA1c from baseline, adjusted mean, %

–1.1

–1.2

–0.7

–0.6

–0.7

Comparison vs empagliflozin 25 mg or 10 mg, adjusted mean, %

–0.4 (95% CI, –0.6 to –0.2)

–0.6 (95% CI, –0.7 to –0.4)

—

Comparison vs linagliptin 5 mg, adjusted mean, %

–0.4 (95% CI, –0.6 to –0.2)

–0.6 (95% CI, –0.7 to –0.3)

—

74 (58)

76 (62)

35 (28)

43 (33)

43 (36)

Patients, N

133

131

136

137

125

Baseline, mean, mg/dL

157

155

162

160

156

Change from baseline, adjusted mean, mg/dL

–33

–36

–21

–13

Comparison vs empagliflozin 25 mg or 10 mg, adjusted mean, mg/dL

–12 (95% CI, –18 to –5)

–15 (95% CI, –22 to –9)

—

Comparison vs linagliptin 5 mg, adjusted mean, mg/dL

–20 (95% CI, –27 to –13)

–23 (95% CI, –29 to –16)

—

Patients, N

135

134

137

140

128

Baseline, mean, kg

–3.1

–3.4

–3.0

–3.5

–0.7

Comparison vs empagliflozin 25 mg or 10 mg, adjusted mean, kg

0.0 (95% CI, –0.9 to 0.8)

0.1 (95% CI, –0.8 to 0.9)

—

Comparison vs linagliptin 5 mg, adjusted mean, kg

–2.4 (95% CI, –3.3 to –1.5)

–2.7 (95% CI, –3.6 to –1.8)

—

Patients achieving HbA1c <7%,a N (%) Fasting plasma glucose

Body weight

Percent change in weight from baseline

a Number of patients with HbA1c levels >7% at baseline: empagliflozin 25 mg/linagliptin 5 mg, N = 123; empagliflozin 10 mg/ linagliptin 5 mg, N = 128; empagliflozin 25 mg, N = 132; empagliflozin 10 mg, N = 125; linagliptin 5 mg, N = 119. CI indicates confidence interval; HbA1c, glycated hemoglobin. Adapted from Glyxambi (empagliflozin and linagliptin) tablets prescribing information; January 2015.

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levels and increases glucose excretion.5 DPP-4 is an enzyme that cleaves GLP-1 and glucose-dependent insulinotropic polypeptide, 2 intestinal hormones that regulate the postprandial production of insulin and glucagon by the pancreas.5 As an inhibitor of DPP-4, linagliptin increases the concentrations of these incretin hormones, which stimulates the release of insulin in a glucose-dependent manner and decreases glucagon levels in the blood. GLP-1 also reduces glucagon secretion from the pancreas, which results in lowered glucose production by the liver.5

Dosing and Administration Empagliflozin plus linagliptin fixed-dose combination should be started at 10 mg empagliflozin/5 mg linagliptin, taken once daily in the morning, with or without food. The higher dose of empagliflozin plus linagliptin (25 mg empagliflozin/5 mg linagliptin) once daily may be considered if the initial dose is well-tolerated.5 No data are available regarding the safety and efficacy of empagliflozin plus linagliptin in patients who previously received other oral antihyperglycemic agents and switched to empagliflozin plus linagliptin.5 Clinical Trials The approval of empagliflozin plus linagliptin was based on a double-blind, phase 3 clinical trial that compared the safety and efficacy of empagliflozin plus linagliptin with the individual drugs, empagliflozin (10 mg or 25 mg) and linagliptin (5 mg), in adults with inadequately controlled type 2 diabetes despite taking at least 1500 mg of metformin.4,5,9 After a single-blind, placebo run-in period of 2 weeks, 686 patients with type 2 diabetes whose disease remained inadequately controlled (HbA1c levels, 7.0%-10.5%) were randomized to 1 of 5 active-treatment arms.5,9 The study’s primary end point was the change from baseline in HbA1c levels at week 24. The secondary end points included the change from baseline in fasting plasma glucose levels at week 24, the change from baseline in body weight at week 24, and the proportion of patients with baseline HbA1c levels ≥7% who reached HbA1c levels <7% at week 24.9 After 24 weeks of treatment, the combination of empagliflozin plus linagliptin demonstrated a significant improvement in the HbA1c levels (P <.001) and fasting plasma glucose levels (P <.001) compared with empagliflozin monotherapy and linagliptin monotherapy (Table 1).5,9 Although not approved for lowering weight, daily treatment with both formulations of empagliflozin plus linagliptin also resulted in a significant reduction in body weight compared with linagliptin alone (P <.001)4,5,9; no

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Adverse Reactions in ≥2% of Patients Receiving Table 2 Empagliflozin and More Often Than in Patients Receiving Placebo Empagliflozin Empagliflozin Placebo, Adverse reaction 10 mg, % 25 mg, % % Urinary tract infection

9.3

7.6

Female genital mycotic infections

5.4

6.4

1.5

Upper respiratory tract infections

3.1

4.0

3.8

Increased urination

3.4

3.2

1.0

Dyslipidemia

3.9

2.9

3.4

Arthralgia

2.4

2.3

2.2

Male genital mycotic infections

3.1

1.6

0.4

Nausea

2.3

1.1

1.4

Adapted from Glyxambi (empagliflozin and linagliptin) tablets prescribing information; January 2015.

Adverse Reactions in ≥2% of Patients Receiving Table 3 Linagliptin and More Often Than in Patients Receiving Placebo Adverse reaction Linagliptin 5 mg, % Placebo, % Nasopharyngitis

7.0

6.1

Diarrhea

3.3

3.0

Cough

2.1

1.4

Adapted from Glyxambi (empagliflozin and linagliptin) tablets prescribing information; January 2015.

significant differences in body weight were observed when empagliflozin plus linagliptin was compared with empagliflozin alone (Table 1).5,9

Safety The safety of empagliflozin plus linagliptin (empagliflozin 10 or 25 mg/linagliptin 5 mg) was evaluated in 1363 patients with type 2 diabetes who received treatment for a maximum of 52 weeks in active-controlled clinical trials.5 Based on pooled analyses of these studies, the most common adverse reactions associated with empagliflozin plus linagliptin therapy included urinary tract infection (a predefined adverse event grouping that also includes asymptomatic bacteriuria and cystitis), nasopharyngitis, and upper respiratory tract infection.5 Table 2 summarizes the adverse events that occurred in ≥2% of patients who received empagliflozin and that occurred more frequently than in patients who received placebo.5 Because empagliflozin causes osmotic diuresis,

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intravascular volume contraction and side effects related to volume depletion can occur.5 Table 3 lists the adverse events that occurred in â&#x2030;Ľ2% of patients who received linagliptin and that occurred more frequently than in patients who received placebo.5 Hypersensitivity and myalgia were also reported in clinical studies of linagliptin monotherapy.5 Hypoglycemia was reported among patients taking empagliflozin plus linagliptin during a period of 52 weeks (Table 4).5

Warnings and Precautions Pancreatitis. Acute pancreatitis, including fatal pancreatitis, has been reported in patients taking linagliptin.5 If pancreatitis is suspected, empagliflozin plus linagliptin should be discontinued and appropriate management should be initiated. This combination has not been studied in patients with a history of pancreatitis.5 Hypotension. Because empagliflozin causes intravascular volume contraction, symptomatic hypotension can occur, particularly in patients with renal impairment, with low systolic blood pressure, in elderly patients, and in patients taking diuretic agents. Before starting empagliflozin plus linagliptin therapy, the volume status should be assessed and corrected as needed. Patients should be monitored for the signs and symptoms of hypotension, particularly in clinical situations in which volume contraction is expected.5 Impairment in renal function. Empagliflozin is known to increase serum creatinine levels and to decrease estimated glomerular filtration rate (eGFR).5 Elderly patients and patients with moderate renal impairment are at an increased risk for renal function impairment while taking empagliflozin. Renal function should be evaluated before starting empagliflozin plus linagliptin and frequently thereafter.5 Hypoglycemia with concomitant use with insulin and insulin secretagogues. In a placebo-controlled clinTable 4 I ncidence of Overall and Severe Hypoglycemic Adverse Reactions with Empagliflozin plus Linagliptin Add-on to Empagliflozin 10 mg/ Empagliflozin 25 mg/ metformin after linagliptin 5 mg, % linagliptin 5 mg, % 52 weeks (N = 136) (N = 137) Hypoglycemic events, overalla

2.2

3.6

Hypoglycemic events, severeb

Plasma or capillary glucose of â&#x2030;¤70 mg/dL or requiring assistance. Requiring assistance regardless of blood glucose. Adapted from Glyxambi (empagliflozin and linagliptin) tablets prescribing information; January 2015. a

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ical trial, the rates of hypoglycemia were higher when empagliflozin or linagliptin was used in combination with an insulin secretagogue (eg, sulfonylurea) or with insulin. When used in combination with empagliflozin plus linagliptin therapy, a lower dose of the insulin secretagogue or insulin may be required.5 Genital mycotic infections. Genital mycotic infections have been reported by patients who received empagliflozin. Patients with a history of chronic or recurrent genital mycotic infections are more likely to develop these infections while taking empagliflozin plus linagliptin compared with patients without these characteristics; these patients should be monitored appropriately.5 Urinary tract infections. Patients receiving empagliflozin are at a higher risk for urinary tract infections, and should be monitored appropriately.5 Hypersensitivity reactions. During postmarketing surveillance, serious hypersensitivity reactions (eg, anaphylaxis, angioedema, exfoliative skin conditions) were reported in patients who received linagliptin. These reactions typically occurred within the first 3 months after starting linagliptin treatment, with some reactions occurring after the first linagliptin dose.5 If a serious hypersensitivity reaction is suspected, empagliflozin plus linagliptin therapy should be discontinued and alternative treatment for diabetes should be started.5 Because angioedema has been reported with other DPP-4 inhibitors, caution should be taken when considering empagliflozin plus linagliptin for patients who have experienced angioedema after taking another DPP-4 inhibitor.5 Increased low-density lipoprotein cholesterol (LDLC) levels. Increases in LDL-C levels can occur with empagliflozin. Lipid levels should be monitored and treated as needed.5 Macrovascular outcomes. No clinical studies have demonstrated conclusive evidence of the reduction in macrovascular risk with empagliflozin plus linagliptin therapy or with any other antidiabetic drug.5

Use in Specific Populations Pregnancy. Empagliflozin plus linagliptin combination has been assigned pregnancy category C; there are no adequate and well-controlled studies with this drug in pregnant women. This combination should only be used during pregnancy if the potential benefit outweighs the potential risk to the fetus.5 Nursing mothers. It is not known whether the components of empagliflozin plus linagliptin are present in human breast milk. Either nursing or empagliflozin plus linagliptin therapy should be discontinued on the basis of the importance of the drug to the mother.5 Pediatric use. The safety and efficacy of empagliflozin

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plus linagliptin have not been established in pediatric patients aged <18 years.5 Geriatric use. Empagliflozin is associated with osmotic diuresis, which could affect hydration in patients aged ≥75 years.5 The efficacy of empagliflozin is diminished in elderly patients with renal impairment. In addition, the risk for urinary tract infections increased among patients aged ≥75 years who received empagliflozin. No dosage adjustment of empagliflozin or linagliptin is recommended in elderly patients.5

For patients whose type 2 diabetes is inadequately controlled with high-dose metformin, this novel combination drug, with a combined mechanism of action, may enhance drug adherence and glycemic control. Renal impairment. Empagliflozin plus linagliptin is contraindicated in patients with severe renal impairment (eg, eGFR <30 mL/min/1.73 m2) or with endstage renal disease, and in patients undergoing dialysis.5 The risks for renal impairment, volume depletion, and urinary tract infections are higher among patients with renal dysfunction compared with patients without renal dysfunction.5 Hepatic impairment. No dosage adjustment of empagliflozin plus linagliptin is necessary for patients with mild, moderate, or severe hepatic impairment.5

Conclusion Control of glucose and HbA1c levels is key to preventing complications of diabetes. Some experts have suggested that reaching and maintaining glucose control

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early in patients with type 2 diabetes may result in benefits that persist beyond the treatment period.10 Empagliflozin plus linagliptin, a dual-acting oral tablet, has demonstrated superior efficacy and acceptable safety in a large phase 3 clinical trial of patients with poorly controlled type 2 diabetes compared with patients who received empagliflozin or linagliptin monotherapy. For patients whose type 2 diabetes is inadequately controlled with high-dose metformin, this novel combination drug, with a combined mechanism of action, may enhance drug adherence and glycemic control. n

References

1. Centers for Disease Control and Prevention. National diabetes statistics report: estimates of diabetes and its burden in the United States, 2014. 2014. www.cdc.gov/diabetes/pubs/statsreport14/national-diabetes-report-web.pdf. Accessed February 27, 2015. 2. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2015;38:140-149. 3. American Diabetes Association. Economic costs of diabetes in the U.S. in 2012. Diabetes Care. 2013;36:1033-1046. 4. Eli Lilly and Company. U.S. FDA approves first-in-class Glyxambi (empagliflozin/linagliptin) tablets for adults with type 2 diabetes. Press release. February 2, 2015. http://lilly.mediaroom.com/index.php?s=9042&item=137386. Accessed February 25, 2015. 5. Glyxambi (empagliflozin and linagliptin) tablets [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; January 2015. 6. Gonzalez-Campoy JM; for Endocrineweb. Glyxambi approved as first dual SGLT2 and DDP-4 inhibitor for type 2 diabetes. February 11, 2015. www.endo crineweb.com/professional/type-2-diabetes/glyxambi-approved-first-dual-sglt2- ddp-4-inhibitor-type-2-diabetes. Accessed February 25, 2015. 7. US Food and Drug Administration. FDA approves new treatment for type 2 diabetes. Press release. May 2, 2011. www.fda.gov/NewsEvents/Newsroom/Press Announcements/ucm253501.htm. Accessed February 25, 2015. 8. US Food and Drug Administration. FDA approves Jardiance to treat type 2 diabetes. Press release. August 1, 2014. www.fda.gov/NewsEvents/Newsroom/ PressAnnouncements/ucm407637.htm. Accessed February 25, 2015. 9. DeFronzo RA, Lewin A, Patel S, et al. Combination of empagliflozin and linagliptin as second-line therapy in subjects with type 2 diabetes inadequately controlled on metformin. Diabetes Care. 2015;38:384-393. 10. Holman RR, Paul SK, Bethel MA, et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359:1577-1589.

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Lenvima (Lenvatinib), a Multireceptor Tyrosine Kinase Inhibitor, Approved by the FDA for the Treatment of Patients with Differentiated Thyroid Cancer By Loretta Fala, Medical Writer

hyroid cancer, cancer that starts in the thyroid gland, accounts for 3.8% of all cancer cases in the United States.1 There were an estimated 62,980 new cases of thyroid cancer and 1890 deaths resulting from thyroid cancer in 2014.1 Thyroid cancer is most common in people aged 45 to 54 years (median age, 50 years),1 and it occurs 2 to 3 times more often in women than in men.2 The incidence of thyroid cancer has risen steadily in recent years.3 Although this increasing rate can be attributed largely to disease detection at an earlier stage, the incidence of larger tumors has also increased.3 Thyroid cancer is classified into 3 types—differentiated (includes papillary, follicular, and Hürthle tumors); medullary tumors; and anaplastic (aggressive undifferentiated tumors).2 Differentiated thyroid cancer accounts for more than 90% of all cases of thyroid carcinoma.2 An estimated 566,708 patients were living with thyroid cancer in the United States in 2011.1 Approximately 68.2% of patients are diagnosed at the local stage of thyroid cancer; for patients with localized thyroid cancer, the 5-year survival rate is currently 99.9%.1 However, 10% to 30% of patients who are thought to be disease-free after the initial treatment will have disease recurrence and/or metastases.4 For patients with differentiated thyroid cancer that is refractory to radioactive iodine [131-isotope, also known as 131I] therapy, the 10-year survival rate is only 10% from the time that metastatic disease is detected.5,6 According to a recent study, the estimated annual US healthcare costs (undiscounted) for thyroid cancer were $1.4 billion in 2010; these costs are projected to reach $2.1 billion in 2015 and to exceed $3.1 billion by 2019.7 The authors noted that thyroid cancer is a major public health issue, particularly for women, given the increasing incidence (especially of papillary carcinoma) of the disease among women.7 According to another study, differentiated thyroid cancer accounted for total societal costs of approximately $1.6 billion annually in the United States in 2013.8 Furthermore, the annual costs attributable to differentiated thyroid cancer were projected to approach $3.5 billion by 2030 in that study.8

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The treatment of differentiated thyroid cancer generally includes surgery, when possible, followed by radioactive iodine treatment in appropriate patients, and thyroxine therapy. Systemic therapy, including the recently approved tyrosine kinase inhibitors, may be used for patients with significant disease progression, nonresectable tumors, or tumors that are nonresponsive to radioactive iodine therapy.2 The multitargeted tyrosine kinase inhibitors have demonstrated a clinical benefit in locally recurrent, unresectable and metastatic medullary thyroid cancer and in radioactive iodine–refractory differentiated thyroid cancer.2 Optimal management of the side effects associated with tyrosine kinase inhibitor therapy and/or dose modification are key considerations when managing thyroid cancer with this class of drugs.2 The tyrosine kinase inhibitors represent an important advancement in the treatment of thyroid cancer, because they target multiple molecular pathways that are involved in the pathogenesis of thyroid tumors.5

Lenvatinib: A New Oral Option for Differentiated Thyroid Cancer On February 13, 2015, lenvatinib (Lenvima; Eisai), an oral, multireceptor tyrosine kinase inhibitor, was approved by the US Food and Drug Administration (FDA) to treat patients with locally recurrent or metastatic, progressive, radioactive iodine–refractory differentiated thyroid cancer.9 Lenvatinib was granted an expedited review by the FDA, using its priority review process, based on the drug’s potential to provide a significant improvement in safety or effectiveness in treating a serious condition over available medications. In addition, lenvatinib received an orphan drug designation, because it is designated to treat a rare condition.9 Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said, “The development of new therapies to assist patients with refractory disease is of high importance to the FDA. Today’s approval

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gives patients and healthcare professionals a new therapy to help slow the progression of DTC [differentiated thyroid cancer].” 9 Steven I. Sherman, MD, Associate Vice Provost, Clinical Research, M.D. Anderson Cancer Center, and principal investigator of a pivotal phase 3 study on lenvatinib led by researchers at the University of Texas M.D. Anderson Cancer Center, noted that advances in thyroid cancer treatment have been made in recent years, particularly for patients with metastatic disease who do not respond to radioactive iodine therapy.10 Dr Sherman stated, “For decades, in this patient population, the treatment was often to repeat ineffective doses of radioactive iodine, and possibly salvage therapy with chemotherapy.” He added, “About 10 years ago, with the growing availability of novel targeted agents and multi-targeted kinase inhibitors, we began to recognize potential for treating this subgroup of patients with antiangiogenic therapy and sought to enroll those with refractory disease in clinical trials.” 10

Mechanism of Action Lenvatinib is a multireceptor tyrosine kinase inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). Lenvatinib also inhibits other receptor tyrosine kinases that have been implicated in pathogenic angiogenesis, tumor growth, and cancer progression in addition to their normal cellular functions, including the fibroblast growth factor receptors FGFR1, 2, 3, and 4; and the platelet-derived growth factor receptor alpha, KIT, and RET.11 Dosing and Administration The recommended dose of lenvatinib is 24 mg orally, once daily. In patients with severe renal or hepatic impairment, the dose is reduced to 14 mg once daily.11 Lenvatinib is available in a 4-mg and a 10-mg capsule.11

received cumulative radioactive iodine activity of >600 mCi (22 GBq) with the last dose administered at least 6 months before study entry.11 In this study, patients were randomized to receive lenvatinib 24 mg once daily (N = 261) or placebo (N = 131) until disease progression. Randomization was stratified by geographic region, previous VEGF/VEGFR-targeted therapy, and age. The median age of the patients was 63 years. Overall, 99% of the patients had metastatic disease.11 The primary efficacy outcome measure was progression-free survival, as determined by a blinded IRR using Table 1 E fficacy Results in the SELECT Study: Lenvatinib versus Placebo in Patients with Progressive Thyroid Cancer Lenvatinib cohort Placebo cohort Efficacy variable (N = 261) (N = 131) Progression-free survivala Events, N (%)

107 (41)

113 (86)

Progressive disease

93 (36)

109 (83)

Death

14 (5)

4 (3)

18.3 (95% CI, 15.1-NE)

3.6 (95% CI, 2.2-3.7)

Median progressionfree survival, mo Hazard ratiob

0.21 (95% CI, 0.16-0.28) P <.001c

Objective response ratea Objective response rate, %

65 (95% CI, 59%-71%)

2 (95% CI, 0%-4%)

Complete response, %

Partial response, %

63 P <.001

Overall survival

Deaths, N (%) Median overall survival

Hazard ratio

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71 (27)

47 (36)

0.73 (95% CI, 0.50-1.07)

Clinical Studies The SELECT Trial The safety and efficacy of lenvatinib were evaluated in the SELECT trial, a multicenter, randomized (in a 2:1 ratio), double-blind, placebo-controlled study.5 The study included 392 patients with locally recurrent or metastatic radioactive iodine–refractory differentiated thyroid cancer and radiographic evidence of disease progression within 12 months before study randomization, as confirmed by an Independent Radiologic Review (IRR).5,11 Radioactive iodine–refractory was defined as (1) ≥1 measurable lesions with no iodine uptake on radioactive iodine scan, (2) iodine uptake with progression within 12 months of radioactive iodine therapy, or (3) having

2 d

P = .10b

Independent radiologic review. Estimated with Cox proportional hazard model stratified by region (Europe vs North America vs other), age-group (≤65 vs >65 years), and previous VEGF/VEGFR-targeted therapy (0 vs 1). c Log-rank test stratified by region (Europe vs North America vs other), age-group (≤65 vs >65 years), and previous VEGF/VEGFR-targeted therapy (0 vs 1). d Cochran-Mantel-Haenszel chi-square test. e Not estimable. CI indicates confidence interval; NE, not estimable; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor. Source: Lenvima (lenvatinib) capsules prescribing information; February 2015. a

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Table 2 L envatinib versus Placebo: Adverse Events (All Grades Incidence â&#x2030;Ľ30%) Lenvatinib 24 mg Placebo (N = 261) (N = 131) All Grades All Grades Adverse reaction grades, % 3-4, % grades, % 3-4, % Hypertensiona

Fatigue

Diarrhea

Arthralgia/myalgiac

Decreased appetite

Weight decreased

Nausea

Stomatitis (inflammation of the mouth and lips)

Headache

Vomiting

Proteinuria

Palmar-plantar erythrodysesthesia (hand-foot) syndrome

Abdominal paine

Dysphonia (voice impairment)

Includes hypertension, hypertensive crisis, increased blood pressure diastolic, and increased blood pressure. b Includes asthenia, fatigue, and malaise. c Includes musculoskeletal pain, back pain, pain in extremity, arthralgia, and myalgia. d Includes aphthous stomatitis, stomatitis, glossitis, mouth ulceration, and mucosal inflammation. e Includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, abdominal tenderness, epigastric discomfort, and gastrointestinal pain. Source: Lenvima (lenvatinib) capsules prescribing information; February 2015. a

Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1).11,12 Secondary efficacy outcome measures included objective response rate and overall survival. Patients in the placebo group could receive lenvatinib after an independent review confirmation of disease progression.11 As shown in Table 1, a significant prolongation in progression-free survival was demonstrated in patients receiving lenvatinib compared with patients who received placebo. Patients in the lenvatinib group had a 14.7-month longer median progression-free survival than patients in the placebo group. Moreover, 65% of patients

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in the lenvatinib group had an objective response compared with 2% of patients in the placebo group. Overall survival was not estimable in either group.5,11

Safety The most common adverse reactions (with an incidence of â&#x2030;Ľ30%) associated with lenvatinib are shown in Table 2. The most common serious adverse reactions (at least 2%) were pneumonia (4%), hypertension (3%), and dehydration (3%).11 The most common adverse reactions (at least 1%) resulting in discontinuation of lenvatinib were hypertension (1%) and asthenia (1%).11 Lenvatinib has no known contraindications.11 Drug Interactions Effect of other drugs on lenvatinib. CYP3A is one of the main metabolic enzymes of lenvatinib. No dose adjustment of lenvatinib is recommended when coadministered with CYP3A, P-glycoprotein (P-gp), and breast cancer resistance protein inhibitors and CYP3A and P-gp inducers.11 Warnings and Precautions Hypertension. Blood pressure should be controlled prior to treatment with lenvatinib. Lenvatinib should be withheld for grade 3 hypertension despite optimal hypertensive therapy. For patients with life-threatening hypertension, lenvatinib should be discontinued.11 Cardiac failure. Patients should be monitored for clinical symptoms or signs of cardiac decompensation. Lenvatinib should be withheld for grade 3 cardiac dysfunction. For patients with grade 4 cardiac dysfunction, lenvatinib should be discontinued.11 Arterial thromboembolic events. Lenvatinib should be discontinued following an arterial thromboembolic event.11 Hepatotoxicity. Before initiation of lenvatinib and periodically throughout treatment, liver function tests should be monitored. For patients with grade 3 or greater liver impairment, lenvatinib should be withheld. Lenvatinib should be discontinued for patients with hepatic failure.11 Proteinuria. Before initiating lenvatinib therapy and periodically through treatment with lenvatinib, patients should be monitored for proteinuria. Lenvatinib should be withheld in patients with â&#x2030;Ľ2 g of proteinuria for 24 hours. Lenvatinib should be discontinued in patients with nephritic syndrome.11 Renal failure and impairment. Lenvatinib should be withheld for grade 3 or 4 renal failure or impairment.11 Gastrointestinal perforation and fistula formation. Lenvatinib should be discontinued in patients who develop gastrointestinal perforation or life-threatening fistula.11 QT interval prolongation. Electrolyte abnormalities should be monitored and corrected in all patients. For

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patients who develop grade ≥3 QT interval prolongation, lenvatinib should be withheld.11 Hypocalcemia. Blood calcium levels should be monitored at least monthly and calcium should be replaced as necessary during treatment with lenvatinib.11 Reversible posterior leukoencephalopathy syndrome (RPLS). Lenvatinib should be withheld for patients with RPLS until the RPLS is fully resolved.11 Hemorrhagic events. Lenvatinib should be discontinued for patients with grade 3 hemorrhage. Lenvatinib should be discontinued for patients with grade 4 hemorrhage.11 Impairment of thyroid-stimulating hormone (TSH) suppression. TSH levels should be monitored monthly and thyroid replacement medication should be adjusted as needed in patients with differentiated thyroid cancer.11 Embryofetal toxicity. Lenvatinib can cause fetal harm. Women of reproductive potential should be advised about the potential risk to the fetus and the use of effective contraception.11

Use in Specific Populations Lactation. It is not known whether lenvatinib is present in human milk. Because of the potential for serious adverse reactions in nursing infants from lenvatinib, women should be advised to discontinue breastfeeding during treatment with lenvatinib.11 Pregnancy. Lenvatinib can cause fetal harm when administered to a pregnant woman. Pregnant women should be advised of the potential risk to the fetus.11 Females and males of reproductive potential. Lenvatinib may result in reduced fertility in women of reproductive potential. Lenvatinib may result in damage to male reproductive tissues leading to reduced fertility of unknown duration.11 Pediatric use. The safety and effectiveness of lenvatinib in pediatric patients have not been established.11 Geriatric use. In clinical studies, no overall differences in safety or effectiveness were observed between patients aged ≥65 years and those aged <65 years.11 Renal impairment. No dose adjustment is recommended in patients with mild or moderate renal impairment. In patients with severe renal impairment, the recommended dose of lenvatinib is 14 mg taken once daily. Patients with end-stage renal disease were not studied.11 Hepatic impairment. No dose adjustment is recommended in patients with mild or moderate hepatic impairment. In patients with severe hepatic impairment, the recommended dose of lenvatinib is 14 mg taken once daily.11

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Conclusion With the FDA approval of lenvatinib, a new, once-daily oral treatment option became available to help slow the progression of differentiated thyroid cancer, the most common type of thyroid cancer, in patients with locally recurrent or metastatic, radioactive iodine–refractory disease.9

With the FDA approval of lenvatinib, a new, once-daily oral treatment option became available to help slow the progression of differentiated thyroid cancer, the most common type of thyroid cancer. Treatment with lenvatinib, a multitargeted tyrosine k inase inhibitor, demonstrated a statistically significant prolongation in progression-free survival in patients with progressive, radioactive iodine–refractory differentiated thyroid cancer. In the SELECT clinical study, the median progression-free survival in the lenvatinib group was 18.3 months versus 3.6 months in the placebo group (P <.001).5,11 n

References

1. National Cancer Institute. SEER stat fact sheets: thyroid cancer. http://seer. cancer.gov/statfacts/html/thyro.html. Accessed March 10, 2015. 2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): thyroid carcinoma. Version 2.2014. August 12, 2014. www.nccn.org/store/login/login.aspx?ReturnURL=http://www. nccn.org/professionals/physician_gls/pdf/thyroid.pdf. Accessed March 10, 2015. 3. American Cancer Society. What are the key statistics about thyroid cancer? Revised February 13, 2015. www.cancer.org/cancer/thyroidcancer/detailedguide/ thyroid-cancer-key-statistics. Accessed March 11, 2015. 4. National Cancer Institute. Thyroid cancer treatment (PDQ®). Updated February 25, 2015. www.cancer.gov/cancertopics/pdq/treatment/thyroid/Health Professional/page9. Accessed March 13, 2015. 5. Schlumberger M, Tahara M, Wirth LJ, et al. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med. 2015;372:621-630. 6. Durante C, Haddy N, Baudin E, et al. Long-term outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma: benefits and limits of radioiodine therapy. J Clin Endocrinol Metab. 2006;91:2892-2899. 7. Aschebrook-Kilfoy B, Schechter RB, Shih Y-C, et al. The clinical and economic burden of a sustained increase in thyroid cancer incidence. Cancer Epidemiol Biomarkers Prev. 2013;22:1252-1259. 8. Lubitz CC, Kong CY, McMahon PM, et al. Annual financial impact of well-differentiated thyroid cancer care in the United States. Cancer. 2014;120:1345-1352. 9. US Food and Drug Administration. FDA approves Lenvima for a type of thyroid cancer. Press release. February 13, 2015. www.fda.gov/NewsEvents/ Newsroom/PressAnnouncements/ucm434288.htm. Accessed March 14, 2015. 10. M.D. Anderson. Lenvatinib shows promise for patients with radioiodine- refractory thyroid cancer. Press release. February 11, 2015. www.mdanderson. org/newsroom/news-releases/2015/lenvatinib-promise-radioiodine-refractory- thyroid-cancer.html. Accessed March 13, 2015. 11. Lenvima (lenvatinib) capsules [prescribing information]. Woodcliff Lake, NJ: Eisai Inc; February 2015. 12. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228-247.

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Opdivo (Nivolumab): Second PD-1 Inhibitor Receives FDA Approval for Unresectable or Metastatic Melanoma By Lisa A. Raedler, PhD, RPh, Medical Writer

lthough less common than other skin cancers, melanoma is the most dangerous form of skin cancer.1 According to data collected between 2004 and 2010, the 5-year relative survival rate for Americans with distant melanoma is only 16% for all ages, races, and sexes.2 The National Cancer Institute estimated that there were 76,100 new cases of skin melanoma in 2014, and more than 9700 patients died from this disease during the same period.2 The incidence of melanoma continues to rise, particularly among children and adolescents.3 Analysis of first-time melanoma diagnoses between 1970 and 2009 in patients aged 18 to 39 years showed that the number of new cases of skin melanoma increased 8-fold among young women and 4-fold among young men.3 Using data from 1973 to 2009, another study documented an average increase in melanoma of 2% annually in individuals aged between 0 and 19 years.4 The potential effect on healthcare resource use is just one reason for concern regarding these trends. Based on an assessment of Medicare administrative claims data between 1991 and 2005, patients with melanoma, particularly those with metastatic disease, accrued an average of more than $11,000 monthly in total healthcare costs5; the majority of these costs were related to inpatient hospital services.5 This cost analysis was conducted in 2009, before the approval of novel targeted therapies for metastatic melanoma. As evidenced by its low 5-year survival rates, metastatic melanoma is difficult to cure.6 Surgery and radiation therapy are feasible options for tumors that are localized to the skin or to the lymph nodes. Depending on their number and location, the surgical removal of melanoma metastases in internal organs is also an option.6 In the past, the management of patients with advanced stages of melanoma was very challenging. Today, however, the development and the introduction of targeted agents have significantly changed the treatment landscape. The current armamentarium of systemic treatments for metastatic melanoma features immunotherapy agents (ie, ipilimumab, pembrolizumab) and BRAF inhibitors (ie, vemurafenib, dabrafenib, trametinib), in addition to traditional chemotherapy.6 Several of these novel agents offer superior efficacy compared with older cytotoxic drugs.6 Immune checkpoint blockade with monoclonal anti-

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bodies that are directed toward cytotoxic T-lymphocyte antigen (CTLA)-4, such as ipilimumab, as well as programmed-cell death (PD)-1 and PD ligand 1 (PD-L1), have emerged as successful treatment options in the treatment of patients with melanoma.7 Ipilimumab was the first CTLA-4 inhibitor to demonstrate an overall survival benefit and highly durable objective tumor responses in patients with advanced melanoma.7 In September 2014, the US Food and Drug Administration (FDA) approved pembrolizumab, the first PD-1 inhibitor for the treatment of patients with unresectable or metastatic melanoma.8 This agent demonstrated objective and durable responses in a large phase 1b study that involved patients with unresectable or metastatic melanoma and disease progression after treatment with ipilimumab and, if the patient had the BRAF V600 mutation, after treatment with a BRAF inhibitor.8,9 To increase the proportion of patients with metastatic melanoma who achieve durable responses with immunotherapy, researchers are exploring potential synergies between immune checkpoint inhibitors that target CTLA-4, PD-1, PD-L1, and kinase-targeted therapies, as well as the concurrent and sequential use of CTLA-4, PD-1, and PD-L1 inhibitors.7

A Novel PD-1 Inhibitor for Advanced Melanoma On December 22, 2014, the FDA approved nivolumab (Opdivo; Bristol-Myers Squibb) for the treatment of patients with unresectable or metastatic melanoma and disease progression after ipilimumab therapy and, if the patient is positive for a BRAF V600 mutation, after treatment with a BRAF inhibitor.10,11 Nivolumab is a monoclonal antibody that blocks PD-1 and is administered via intravenous infusion. This agent was approved under the accelerated approval program based on the surrogate end points, overall response rate, and duration of response.10,11 When discussing data supporting the efficacy of nivolu mab in relapsed metastatic melanoma, Jeffrey S. Weber, MD, PhD, Director of the Donald A. Adam Comprehensive Melanoma Research Center of Excellence at Moffitt Cancer Center, stated, “These data are important as they mark the first presentation of results from a phase 3 randomized study for the PD-1 immune checkpoint inhibitor class. The response rate and duration of response in pa-

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tients treated with Opdivo are consistent with findings from the early phase 1 trial in previously treated advanced melanoma.” 12 In March 2015, nivolumab received a new FDA indication for lung cancer. See page 183.

Dosing and Administration The recommended dosage of nivolumab is 3 mg/kg administered as an intravenous infusion for 60 minutes every 2 weeks. Nivolumab should be administered until disease progression or until unacceptable toxicity.11 No dose adjustment of nivolumab is required for patients with renal impairment or for patients with mild hepatic impairment, defined as total bilirubin upper limit of normal or less and aspartate aminotransferase (AST) more than upper limit of normal or total bilirubin <1 to 1.5 times upper limit of normal and any AST.11 Mechanism of Action Nivolumab is a monoclonal antibody that binds to the PD-1 receptor and blocks interaction with its ligands, PD-L1 and PD-L2. This binding releases PD-1 pathway-mediated immune responses against tumor cells. Blocking PD-1 activity resulted in decreased tumor growth in syngeneic mouse tumor models.11 Clinical Trial: Checkmate-037 The approval of nivolumab was based on the results of Checkmate-037, a phase 3 randomized, controlled, open-label study of nivolumab versus investigator’s choice chemotherapy in patients with advanced melanoma who previously received ipilimumab.11 A total of 370 patients with previously treated unresectable or metastatic melanoma enrolled in the Checkmate-037 clinical trial.11 All patients’ disease had progressed after previous therapy with ipilimumab and, if the patients were positive for a BRAF V600 mutation, after treatment with a BRAF inhibitor.11 These patients were randomized to receive nivolumab 3 mg/kg (N = 268) or investigator’s choice chemotherapy (N = 102) with dacarbazine 1000 mg/m2 every 3 weeks or with carboplatin (area under the curve, 6 mg•min/mL) plus paclitaxel 175 mg/m2 every 3 weeks until disease progression or until unacceptable toxicity.11 The efficacy of nivolumab was evaluated in a single- arm, noncomparative, planned interim analysis of the first 120 patients who received nivolumab in the Checkmate-037 clinical trial and in whom the minimum duration of follow-up was 6 months.11 The primary efficacy end points were confirmed overall response rate according to the Response Evaluation Criteria in Solid Tumors, as assessed by a blinded independent review committee, and duration of response. Tumor assessments were conducted 9 weeks after randomization, followed by every 6 weeks for the first year, and then every 12 weeks.11

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The trial excluded patients with an autoimmune disease, medical conditions requiring systemic immunosuppression, ocular melanoma, active brain metastasis, or a history of grade 4 ipilimumab-related adverse reactions (except for endocrinopathies) or grade 3 ipilimumab-related adverse reactions that had not resolved or were inadequately controlled after 12 weeks.11 Among the 120 patients who received nivolumab, the median age was 58 years.11 The majority of the patients were male (65%) and white (96%). All the patients had an Eastern Cooperative Oncology Group performance status of 0 or 1. The patients’ disease characteristics included stage M1c disease (76%), 2 or more previous therapies for advanced or metastatic disease (68%), elevated lactate dehydrogenase (56%), positive for a BRAF V600 mutation (22%), and a history of brain metastases (18%).11 The planned interim analysis of the Checkmate-037 clinical trial documented a 32% overall response rate for nivolumab 3 mg/kg in patients with unresectable or metastatic melanoma who previously received ipilimumab therapy and, if relevant, a BRAF inhibitor (95% confidence interval, 23%-41%).11 Of the 38 patients whose disease responded to nivolumab therapy, 4 patients achieved complete responses and 34 patients achieved partial responses.11 The majority (87%) of patients responding to nivolumab had ongoing responses with durations ranging from 2.6+ to 10+ months, including 13 patients with ongoing responses of at least 6 months.11

Adverse Events The cohort of 268 patients with previously treated unresectable or metastatic melanoma in Checkmate-037 received a median of 8 doses (range, 1-31 doses) of nivolumab (3 mg/kg).11 The patients’ median duration of exposure to nivolumab was 5.3 months (range, 1 day-9.6 months).11 Overall, 24% of patients were exposed to nivolumab for more than 6 months, and 3% of patients were exposed to nivolumab for more than 1 year.11 The Table summarizes the adverse reactions that occurred in ≥10% of patients and at a higher incidence rate compared with patients who received chemotherapy.11 Grade 3 and 4 adverse reactions occurred in 42% of nivolumab recipients.11 These events included abdominal pain, hyponatremia, elevated AST levels, and increased lipase levels; these adverse reactions occurred at rates ranging from 2% to <5%.11 Nivolumab was discontinued as a result of adverse reactions in 9% of patients, and 26% of patients who received nivolumab experienced a drug delay for an adverse reaction.11 Nivolumab has no contraindications. Warnings and Precautions Immune-mediated pneumonitis. Overall, 5 (0.9%)

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fatal cases of pneumonitis occurred among 574 patients with solid tumors who received nivolumab in clinical trials.11 Pneumonitis, including interstitial lung disease, occurred in 3.4% of patients who received nivolumab in the Checkmate-037 clinical trial.11 Immune-mediated pneumonitis, which requires the use of corticosteroids and has no clear alternate etiology, occurred in 6 (2.2%) patients who received nivolumab. Grade 2 pneumonitis led to discontinuation of nivolumab in 4 patients. The other 2 patients discontinued nivolumab for other reasons. In all 6 patients, immune-mediated pneumonitis improved to grade 0 or 1 with corticosteroids.11 Patients should be monitored for pneumonitis. Corticosteroids should be administered if grade 2 or higher pneumonitis is detected.11 Nivolumab should be withheld for moderate (grade 2) pneumonitis, and permanently discontinued for severe (grade 3) or life-threatening (grade 4) pneumonitis.11 Immune-mediated colitis. Colitis or diarrhea occurred in 21% of patients who received nivolumab, and in 18% of patients who received chemotherapy.11 Immune-mediated colitis was observed in 6 patients who received nivolumab. Patients should be monitored for colitis. Corticosteroids should be administered for grade 2 or higher colitis. Nivolumab should be withheld for grade 2 or grade 3 colitis, and permanently discontinued for grade 4 colitis or recurrent colitis upon restarting nivolumab therapy.11 Immune-mediated hepatitis. An increased incidence Selected Adverse Reactions in ≥10% of Patients Table Receiving Nivolumab (and at a Higher Incidence than in the Chemotherapy Arm) Nivolumab 3 mg/kg every 2 weeks Chemotherapy (N = 268) (N = 102) Adverse All Grade All Grade reaction grades, % 3-4, % grades, % 3-4, % Skin and subcutaneous tissue disorders Rasha

0.4

Pruritus

3.9

2.0

Respiratory, thoracic, and mediastinal disorders Cough

Infections and infestations Upper respiratory tract infectionb

General disorders and administration site conditions Peripheral edema

Including maculopapular, erythematous, pruritic, follicular, macular, papular, pustular, or vesicular rash, and dermatitis acneiform. b Including rhinitis, pharyngitis, and nasopharyngitis. Source: Opdivo (nivolumab) injection prescribing information; December 2014. a

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of liver test abnormalities was observed in the nivolumab group compared with the chemotherapy group, including increases in AST levels (28% vs 12%, respectively), alkaline phosphatase levels (22% vs 13%, respectively), alanine aminotransferase levels (16% vs 5%, respectively), and total bilirubin levels (9% vs 0%, respectively).11 Overall, 1.1% of patients who received nivolumab had immune-mediated hepatitis, which requires the use of corticosteroids and has no clear alternate etiology.11 Nivolumab should be withheld if grade 2 hepatitis is observed, and discontinued for grade 3 and grade 4 immune-mediated hepatitis.11 Immune-mediated nephritis/renal dysfunction. An increased incidence of elevated creatinine levels was observed in patients who received nivolumab compared with patients who received chemotherapy (13% vs 9%) in the Checkmate-037 clinical trial.11 Grade 2 or 3 immune-mediated nephritis or renal dysfunction, defined as grade 2 or higher increased creatinine levels, need for corticosteroids, and no clear etiology, occurred in 0.7% of patients after 3.5 months and 6 months of nivolumab therapy, respectively.11 Patients should be monitored for elevated serum creatinine levels before and during treatment with nivolu mab.11 If grade 4 elevation in serum creatinine levels is observed, corticosteroid therapy should be tapered and nivolumab should be permanently discontinued. Nivolu mab therapy should be withheld if grade 2 or 3 elevation in serum creatinine levels is observed.11 Immune-mediated hypothyroidism and hyperthyroidism. Grade 1 or 2 hypothyroidism occurred in 8% of patients who received nivolumab and was not observed among patients who received chemotherapy. The median time to onset was 2.5 months (range, 24 days-11.7 months). The majority of patients with hypothyroidism received levothyroxine and restarted nivolumab therapy.11 Grade 1 or 2 hyperthyroidism occurred in 3% of patients who received nivolumab and in 1% of patients who received chemotherapy. The median time to onset in patients who received nivolumab was 1.6 months (range, 0-3.3 months).11 Thyroid function should be monitored before and during treatment with nivolumab. Hormone replacement therapy for hypothyroidism should be administered as needed, and hyperthyroidism should be controlled. There are n o recommended dose adjustments for nivolumab.11 Other immune-mediated adverse r eactions. Other clinically important immune-mediated adverse reactions can occur while patients with unresectable or metastatic melanoma are receiving nivolumab.11 Clinically significant, immune-mediated adverse reactions that were observed in <1% of patients who received nivolumab included pancreatitis, uveitis, demyelination, autoimmune neuropathy, adrenal insufficiency, and facial and abducens nerve paresis.11

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When nivolumab was administered at doses of 3 mg/kg and 10 mg/kg, clinically significant, immune-mediated adverse reactions were observed, including hypophysitis, diabetic ketoacidosis, hypo pituitarism, Guillain- Barré syndrome, and myasthenic syndrome.11 If an immune-mediated adverse reaction is suspected, patients who receive nivolumab must be evaluated to exclude other causes.11 Embryofetal toxicity. Nivolumab therapy may cause fetal harm when it is administered to a pregnant woman.11 Women of reproductive potential should use effective contraception during nivolumab therapy and for at least 5 months after the last dose. Women who become pregnant while taking nivolumab should be made aware of the potential risk of nivolumab to the fetus.11

Use in Specific Populations Pediatric patients. The safety and efficacy of nivolu mab in pediatric patients have not been established.11 Geriatric use. The clinical studies of nivolumab did not include sufficient numbers of patients aged ≥65 years to determine whether they respond differently compared with younger patients.11 Pregnancy. There are no human data to describe the risk associated with nivolumab use during pregnancy. Pregnant women should be advised of the potential risk of nivolumab therapy to the fetus.11 Nursing mothers. It is not known whether nivolumab is present in human milk. Because many drugs, including antibodies, are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from nivolumab, women should be advised to discontinue breastfeeding during treatment with nivolumab.11 Conclusion Nivolumab is the second PD-1 inhibitor approved by the FDA for the treatment of patients with unresectable or metastatic melanoma. Based on an interim analysis of phase 3 clinical data, this novel agent is an effective and safe alternative for patients with unresectable or metastatic melanoma and disease progression after ipilimumab therapy, and if the patient is positive for a BRAF V600 mutation, after treatment with a BRAF inhibitor. As a condition of its accelerated approval, the FDA requires confirmatory trials to verify the agent’s clinical benefit. The new indication for nivolumab approved by the FDA for the treatment of patients with metastatic NSCLC adds a new treatment options for patients with this hard-to-treat disease. The efficacy and safety of nivolumab are being evaluated in several other tumors; these include metastatic breast cancer, metastatic colon cancer, follicular lymphoma, Hodgkin lymphoma, and non-Hodgkin lymphoma.13 n

Vol 8

Special Feature

March 2015

Nivolumab Approved for Metastatic Lung Cancer On March 4, 2015, the FDA approved a new indication for nivolumab for the treatment of patients with metastatic squamous non–small-cell lung cancer (NSCLC) that had progressed with platinum-based chemotherapy. “This approval will provide patients and health care providers knowledge of the survival advantage associated with Opdivo,” said Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. The efficacy of nivolumab in squamous NSCLC was demonstrated in a clinical trial of 272 patients with squamous NSCLC who were randomized to nivolumab (N = 135) or to docetaxel (N = 137). The overall survival was an average of 3.2 months longer with nivolumab than with docetaxel. The safety and efficacy of nivolumab for the treatment of squamous NSCLC were further seen in a single-arm trial of 117 patients with squamous NSCLC that had progressed after platinum-based therapy and ≥1 additional systemic regimens. The objective response rate was 15%, all partial responses. At the time of the analysis, 10 of the 17 responding patients (59%) had a response duration lasting ≥6 months. References

1. Skin Cancer Foundation. What is melanoma? www.skincancer.org/skin-cancer- information/melanoma. Accessed January 23, 2015. 2. National Cancer Institute. SEER stat fact sheets: melanoma of the skin. http://seer. cancer.gov/statfacts/html/melan.html. Accessed January 23, 2015. 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. American Cancer Society. Treatment of melanoma skin cancer by stage. Revised December 23, 2014. www.cancer.org/cancer/skincancer-melanoma/detailedguide/ melanoma-skin-cancer-treating-by-stage. Accessed January 23, 2015. 7. Ott PA, Hodi FS, Robert C. CTLA-4 and PD-1/PD-L1 blockade: new immunotherapeutic modalities with durable clinical benefit in melanoma patients. Clin Cancer Res. 2013;19:5300-5309. 8. US Food and Drug Administration. FDA approves Keytruda for advanced melanoma. Press release. September 4, 2014. www.fda.gov/NewsEvents/Newsroom/Press Announcements/ucm412802.htm. Accessed January 29, 2015. 9. Keytruda (pembrolizumab) for injection [prescribing information]. Whitehouse Station, NJ: Merck & Co; January 2015. 10. US Food and Drug Administration. FDA approves Opdivo for advanced melanoma. Press release. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm 427716.htm. Accessed January 29, 2015. 11. Opdivo (nivolumab) injection [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; December 2014. 12. Bristol-Myers Squibb. Positive phase 3 data for Opdivo (nivolumab) in advanced melanoma patients previously treated with Yervoy (ipilimumab) presented at the ESMO 2014 Congress; first phase 3 results presented for a PD-1 immune checkpoint inhibitor. September 29, 2014. http://news.bms.com/press-release/rd-news/positive- phase-3-data-opdivo-nivolumab-advanced-melanoma-patients-previously-t. Accessed January 27, 2015. 13. ClinicalTrials.gov. Nivolumab. Search results. http://clinicaltrials.gov/ct2/ results?term=nivolumab&Search=Search. Accessed January 27, 2015.

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