Urology Practice Management - April 2015

FOR UROLOGISTS, PRACTICE MANAGERS, FINANCIAL COUNSELORS, AND REIMBURSEMENT SPECIALISTS™

April 2015

www.UroPracticeManagement.com

Volume 4 • Number 2

Urology History of Testicular Cancer Association Increases Risk for Aggressive Presses for Prostate Cancer Later On Delaying Transition By Phoebe Starr to ICD-10 revious studies have shown that a sium shows, for

P

history of testicular cancer increases the risk for developing prostate cancer. A new study presented at the 2015 Genitourinary Cancers Sympo-

By Ellen Martin

Mohummad Minhaj Siddiqui, MD

the first time ever, a link between a history of testicular cancer and an increased likelihood of intermediate- and high-risk prostate Continued on page 25

William J. Terry, Sr, MD

T

Jonathan Rubenstein, MD

he American Urological Association (AUA) is continuing to put pressure on the US government to postpone an imminent transition to the International Classification of Diseases, Tenth Revision (ICD-10) until more practices have time to adjust to the new set of billing codes. In his testimony to a US Continued on page 9

FDA Issues Safety Communication About Cardiovascular Risks of Testosterone Replacement

By Rosemary Frei, MSc

T

he FDA has announced that it will require prescription testosterone product labels to include a warning about a possible increased risk of heart attacks and strokes in patients using the medication, as well as require manufacturers of these products to

change the labeling so that approved uses of the medications are clear. The agency is also encouraging healthcare professionals to prescribe testosterone therapy only for men whose low testosterone levels are caused by certain medical conditions and confirmed with Continued on page 8

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© 2015 Engage Healthcare Communications, LLC

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Your Patients, Your Practice…

Helping Your Practice This comprehensive financial assistance program offers ongoing support across the reimbursement spectrum to help you help your patients.

Complete Provider Assistance Benefits verification Prior authorization tracking Regionally dedicated case managers Local access and reimbursement specialists Denied claims assistance Indication XTANDI (enzalutamide) capsules is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC).

Important Safety Information Contraindications XTANDI (enzalutamide) capsules can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. XTANDI is not indicated for use in women. XTANDI is contraindicated in women who are or may become pregnant.

Warnings and Precautions In Study 1, conducted in patients with metastatic castration-resistant prostate cancer (CRPC) who previously received docetaxel, seizure occurred in 0.9% of patients who were treated with XTANDI and 0% treated with placebo. In Study 2, conducted in patients with chemotherapy-naïve metastatic CRPC, seizure occurred in 0.1% of patients who were treated with XTANDI and 0.1% treated with placebo. Patients experiencing a seizure were permanently discontinued from therapy and all seizure events resolved. There is no clinical trial experience re-administering XTANDI to patients who experienced a seizure, and limited clinical trial experience in patients with predisposing factors for seizure. Study 1 excluded the use of concomitant medications that may lower threshold, whereas Study 2 permitted the use of these medications.

Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity during which sudden loss of consciousness could cause serious harm to themselves or others. Permanently discontinue XTANDI in patients who develop a seizure during treatment.

Adverse Reactions The most common adverse reactions (≥ 10%) reported from the two combined clinical trials that occurred more commonly (≥ 2% over placebo) in the XTANDI-treated patients were asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight decreased, headache, hypertension, and dizziness/ vertigo.

Other Adverse Reactions include: • Laboratory Abnormalities: In the two studies, Grade 1-4 neutropenia occurred in 15% of patients treated with XTANDI (1% Grade 3-4) and in 6% of patients treated with placebo (0.5% Grade 3-4). The incidence of Grade 1-4 thrombocytopenia was 6% of patients treated with XTANDI (0.3% Grade 3-4) and 5% of patients on placebo (0.5% Grade 3-4). Grade 1-4 elevations in ALT occurred in 10% of patients treated with XTANDI (0.2% Grade 3-4) and 16% of patients treated with placebo (0.2% Grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of patients treated with XTANDI

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(0.1% Grade 3-4) and 2% of patients treated with placebo (no Grade 3-4).

• Infections: In Study 1, 1% of XTANDI versus 0.3% of placebo patients and in Study 2, 1 patient in each treatment group (0.1%) had an infection resulting in death.

• Falls: In the two studies, falls including fall-related injuries occurred in 9% of XTANDI patients vs 4% treated with placebo. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in XTANDI patients and included non-pathologic fractures, joint injuries, and hematomas.

• Hypertension: In the two studies, hypertension was reported in 11% of patients receiving XTANDI and 4% of patients receiving placebo. No patients experienced hypertensive crisis. Medical history of hypertension was balanced between arms. Hypertension led to study discontinuation in < 1% of XTANDI or placebo treated patients.

Drug Interactions • Effect of Other Drugs on XTANDI – Administration of strong CYP2C8 inhibitors can increase the plasma exposure to XTANDI. Co-administration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible.

If co-administration of XTANDI cannot be avoided,

XTANDISupportSolutions.com

reduce the dose of XTANDI. Co-administration of XTANDI with strong or moderate CYP3A4 and CYP2C8 inducers may alter the plasma exposure of XTANDI and should be avoided if possible.

• Effect of XTANDI on Other Drugs – XTANDI is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. Avoid CYP3A4, CYP2C9 and CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the plasma exposures of these drugs. If XTANDI is co-administered with warfarin (CYP2C9 substrate), conduct additional INR monitoring.

PLEASE SEE BRIEF SUMMARY OF COMPLETE PRESCRIBING INFORMATION ON FOLLOWING PAGES.

XTANDI Support SolutionsSM, a component of Astellas Access ServicesSM 1-855-8XTANDI (1-855-898-2634); Fax 1-855-982-6341; XTANDISupportSolutions.com ©2014 Astellas Pharma US, Inc. All rights reserved. 076-0329-PM 9/14 Printed in USA XTANDI, Astellas, and the flying star logo are trademarks of Astellas Pharma, Inc.

XTANDI® (enzalutamide) capsules for oral use Initial U.S. Approval: 2012 BRIEF SUMMARY OF PRESCRIBING INFORMATION The following is a brief summary. Please see the package insert for full prescribing information.

INDICATIONS AND USAGE

Grade 3 and higher adverse reactions were reported among 47% of XTANDI-treated patients and 53% of placebo-treated patients. Discontinuations due to adverse events were reported for 16% of XTANDI-treated patients and 18% of placebo-treated patients. The most common adverse reaction leading to treatment discontinuation was seizure, which occurred in 0.9% of the XTANDI-treated patients compared to none (0%) of the placebo-treated patients. Table 1 shows adverse reactions reported in Study 1 that occurred at a ≥ 2% higher frequency in the XTANDI arm compared to the placebo arm.

Table 1. Adverse Reactions in Study 1 (cont.)

Respiratory Disorders

Table 1. Adverse Reactions in Study 1

Seizure In Study 1, which enrolled patients who previously received docetaxel, 7 of 800 (0.9%) patients treated with XTANDI experienced a seizure and no patients treated with placebo experienced a seizure. Seizure occurred from 31 to 603 days after initiation of XTANDI. In Study 2, 1 of 871 (0.1%) chemotherapy-naive patients treated with XTANDI and 1 of 844 (0.1%) patients treated with placebo experienced a seizure. Patients experiencing seizure were permanently discontinued from therapy and all seizure events resolved. There is no clinical trial experience readministering XTANDI to patients who experienced seizure.

Limited safety data are available in patients with predisposing factors for seizure because these patients were generally excluded from the trials. These exclusion criteria included a history of seizure, underlying brain injury with loss of consciousness, transient ischemic attack within the past 12 months, cerebral vascular accident, brain metastases, and brain arteriovenous malformation. Study 1 excluded the use of concomitant medications that may lower the seizure threshold, whereas Study 2 permitted the use of these medications.

Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Permanently discontinue XTANDI in patients who develop a seizure during treatment.

ADVERSE REACTIONS Clinical Trial 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.

Two randomized clinical trials enrolled patients with metastatic prostate cancer that has progressed on androgen deprivation therapy (GnRH therapy or bilateral orchiectomy), a disease setting that is also defined as metastatic CRPC. In both studies, patients received XTANDI 160 mg orally once daily in the active treatment arm or placebo in the control arm. All patients continued androgen deprivation therapy. Patients were allowed, but not required, to take glucocorticoids.

The most common adverse reactions (≥ 10%) that occurred more commonly (≥ 2% over placebo) in the XTANDI-treated patients from the two randomized clinical trials were asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight decreased, headache, hypertension, and dizziness/vertigo.

Study 1: Metastatic Castration-Resistant Prostate Cancer Following Chemotherapy Study 1 enrolled 1199 patients with metastatic CRPC who had previously received docetaxel. The median duration of treatment was 8.3 months with XTANDI and 3.0 months with placebo. During the trial, 48% of patients on the XTANDI arm and 46% of patients on the placebo arm received glucocorticoids.

0.1

1.3

0.3

26.4

5.3

24.3

4.0

Arthralgia 20.5 Musculoskeletal 15.0 Pain Muscular 9.8 Weakness Musculoskeletal 2.6 Stiffness Gastrointestinal Disorders

2.5

17.3

1.8

1.3

11.5

0.3

Table 2. Adverse Reactions in Study 2

1.5

6.8

1.8

0.3

0.3

0.0

21.8

1.1

17.5

0.3

Hot Flush

20.3

0.0

10.3

0.0

Hypertension

6.4

2.1

2.8

1.3

Grade 1-4a (%)

CONTRAINDICATIONS

WARNINGS AND PRECAUTIONS

3.3

CTCAE v4 Includes asthenia and fatigue.

Includes dizziness and vertigo.

Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention. e Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis. f Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection.

Study 2: Chemotherapy-naive Metastatic CastrationResistant Prostate Cancer Study 2 enrolled 1717 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy, of whom 1715 received at least one dose of study drug. The median duration of treatment was 17.5 months with XTANDI and 4.6 months with placebo. Grade 3-4 adverse reactions were reported in 44% of XTANDItreated patients and 37% of placebo-treated patients.

Discontinuations due to adverse events were reported for 6% of XTANDI-treated patients and 6% of placebo-treated patients. The most common adverse reaction leading to treatment discontinuation was fatigue/asthenia, which occurred in 1% of patients on each treatment arm. Table 2 includes adverse reactions reported in Study 2 that occurred at a ≥ 2% higher frequency in the XTANDI arm compared to the placebo arm.

XTANDI N = 800

XTANDI is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC).

Pregnancy XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. XTANDI is not indicated for use in women. XTANDI is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss [see Use in Specific Populations (8.1)].

Epistaxis a b c d

General Disorders Asthenic Conditionsb Peripheral Edema

Placebo N = 399

Grade Grade Grade 3-4 1-4 3-4 (%) (%) (%)

50.6

9.0

44.4

9.3

15.4

1.0

13.3

0.8

Musculoskeletal And Connective Tissue Disorders Back Pain

Diarrhea Vascular Disorders

Nervous System Disorders Headache

12.1

0.9

5.5

0.0

Dizzinessc Spinal Cord Compression and Cauda Equina Syndrome Paresthesia Mental Impairment Disordersd Hypoesthesia

9.5

0.5

7.5

0.5

XTANDI N = 871 Grade 1-4a (%)

Grade 3-4 (%)

Placebo N = 844 Grade 1-4 (%)

Grade 3-4 (%)

General Disorders Asthenic 46.9 3.4 33.0 2.8 Conditionsb Peripheral 11.5 0.2 8.2 0.4 Edema Musculoskeletal And Connective Tissue Disorders Back Pain

28.6

2.5

22.4

3.0

Arthralgia

21.4

1.6

16.1

1.1

Gastrointestinal Disorders 7.4

6.6

4.5

3.8

6.6

0.0

4.5

0.0

4.3

0.3

1.8

0.0

4.0

0.3

1.8

0.0

0.0

6.5

0.3

Infections And Infestations Upper Respiratory Tract 10.9 Infectione Lower Respiratory 8.5 Tract And Lung Infectionf Psychiatric Disorders

2.4

4.8

1.3

Insomnia

8.8

0.0

6.0

0.5

Anxiety

6.5

0.3

4.0

0.0

Renal And Urinary Disorders Hematuria

6.9

1.8

4.5

1.0

Pollakiuria

4.8

0.0

2.5

0.0

Injury, Poisoning And Procedural Complications Fall 4.6 0.3 1.3 Non-pathologic 4.0 1.4 0.8 Fractures Skin And Subcutaneous Tissue Disorders

0.0 0.3

Pruritus

3.8

0.0

1.3

0.0

Dry Skin

3.5

0.0

1.3

0.0

Constipation

23.2

0.7

17.3

0.4

Diarrhea

16.8

0.3

14.3

0.4

Vascular Disorders Hot Flush

18.0

0.1

7.8

0.0

Hypertension

14.2

7.2

4.1

2.3

Nervous System Disorders Dizzinessc

11.3

0.3

7.1

0.0

Headache

11.0

0.2

7.0

0.4

Dysgeusia

7.6

0.1

3.7

0.0

5.7

0.0

1.3

0.1

2.1

0.1

0.4

0.0

0.6

8.5

0.6

10.5

0.0

4.7

1.1

5.7

0.0

Mental Impairment Disordersd Restless Legs Syndrome

Respiratory Disorders Dyspneae

11.0

Infections And Infestations Upper Respiratory 16.4 0.0 Tract Infectionf Lower Respiratory Tract And 7.9 1.5 Lung g Infection Psychiatric Disorders Insomnia

8.2

0.1

Table 2. Adverse Reactions in Study 2 (cont.)

Renal And Urinary Disorders Hematuria

8.8

1.3

5.8

1.3

Injury, Poisoning And Procedural Complications Fall

12.7

1.6

5.3

NonPathological 8.8 2.1 3.0 Fracture Metabolism and Nutrition Disorders Decreased 18.9 0.3 16.4 Appetite

0.7 1.1

0.7

Investigations Weight Decreased

12.4

0.8

8.5

0.2

Reproductive System and Breast Disorders Gynecomastia

3.4

0.0

1.4

0.0

a b c d

CTCAE v4 Includes asthenia and fatigue.

Includes dizziness and vertigo.

Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention. e Includes dyspnea, exertional dyspnea, and dyspnea at rest. f Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis. g Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection.

Laboratory Abnormalities In the two randomized clinical trials, Grade 1-4 neutropenia occurred in 15% of patients treated with XTANDI (1% Grade 3-4) and in 6% of patients treated with placebo (0.5% Grade 3-4).

The incidence of Grade 1-4 thrombocytopenia was 6% of patients treated with XTANDI (0.3% Grade 3-4) and 5% of patients treated with placebo (0.5% Grade 3-4). Grade 1-4 elevations in ALT occurred in 10% of patients treated with XTANDI (0.2% Grade 3-4) and 16% of patients treated with placebo (0.2% Grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of patients treated with XTANDI (0.1% Grade 3-4) and 2% of patients treated with placebo (no Grade 3-4).

Infections In Study 1, 1% of patients treated with XTANDI compared to 0.3% of patients treated with placebo died from infections or sepsis. In Study 2, 1 patient in each treatment group (0.1%) had an infection resulting in death.

Falls and Fall-related Injuries In the two randomized clinical trials, falls including fall-related injuries, occurred in 9% of patients treated with XTANDI compared to 4% of patients treated with placebo. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in patients treated with XTANDI and included non-pathologic fractures, joint injuries, and hematomas.

Hypertension In the two randomized trials, hypertension was reported in 11% of patients receiving XTANDI and 4% of patients receiving placebo. No patients experienced hypertensive crisis. Medical history of hypertension was balanced between arms. Hypertension led to study discontinuation in < 1% of patients in each arm.

DRUG INTERACTIONS Drugs that Inhibit or Induce CYP2C8 Co-administration of a strong CYP2C8 inhibitor (gemfibrozil) increased the composite area under the plasma concentration-time curve (AUC) of enzalutamide plus N-desmethyl enzalutamide by 2.2-fold in healthy volunteers. Co-administration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If co-administration of XTANDI with a strong CYP2C8 inhibitor cannot be avoided, reduce the dose of XTANDI [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].

The effects of CYP2C8 inducers on the pharmacokinetics of enzalutamide have not been evaluated in vivo.

Co-administration of XTANDI with strong or moderate CYP2C8 inducers (e.g., rifampin) may alter the plasma exposure of XTANDI and should be avoided if possible.

Selection of a concomitant medication with no or minimal CYP2C8 induction potential is recommended [see Clinical Pharmacology (12.3)].

Drugs that Inhibit or Induce CYP3A4 Co-administration of a strong CYP3A4 inhibitor (itraconazole) increased the composite AUC of enzalutamide plus N-desmethyl

enzalutamide by 1.3-fold in healthy volunteers [see Clinical Pharmacology (12.3)].

The effects of CYP3A4 inducers on the pharmacokinetics of enzalutamide have not been evaluated in vivo.

Co-administration of XTANDI with strong CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine) may decrease the plasma exposure of XTANDI and should be avoided if possible.

Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Moderate CYP3A4 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin) and St. John’s Wort may also reduce the plasma exposure of XTANDI and should be avoided if possible [see Clinical Pharmacology (12.3)].

Effect of XTANDI on Drug Metabolizing Enzymes Enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. At steady state, XTANDI reduced the plasma exposure to midazolam (CYP3A4 substrate), warfarin (CYP2C9 substrate), and omeprazole (CYP2C19 substrate). Concomitant use of XTANDI with narrow therapeutic index drugs that are metabolized by CYP3A4 (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus and tacrolimus), CYP2C9 (e.g., phenytoin, warfarin) and CYP2C19 (e.g., S-mephenytoin) should be avoided, as enzalutamide may decrease their exposure. If co-administration with warfarin cannot be avoided, conduct additional INR monitoring [see Clinical Pharmacology (12.3)].

USE IN SPECIFIC POPULATIONS Pregnancy - Pregnancy Category X [see Contraindications (4)].

Risk Summary XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. While there are no human data on the use of XTANDI in pregnancy and XTANDI is not indicated for use in women, it is important to know that maternal use of an androgen receptor inhibitor could affect development of the fetus. Enzalutamide caused embryofetal toxicity in mice at exposures that were lower than in patients receiving the recommended dose. XTANDI is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with XTANDI. Animal Data In an embryo-fetal developmental toxicity study in mice, enzalutamide caused developmental toxicity when administered at oral doses of 10 or 30 mg/kg/day throughout the period of organogenesis (gestational days 6-15). Findings included embryo-fetal lethality (increased post-implantation loss and resorptions) and decreased anogenital distance at ≥ 10 mg/kg/day, and cleft palate and absent palatine bone at 30 mg/kg/day. Doses of 30 mg/kg/day caused maternal toxicity. The doses tested in mice (1, 10 and 30 mg/kg/day) resulted in systemic exposures (AUC) approximately 0.04, 0.4 and 1.1 times, respectively, the exposures in patients. Enzalutamide did not cause developmental toxicity in rabbits when administered throughout the period of organogenesis (gestational days 6-18) at dose levels up to 10 mg/kg/day (approximately 0.4 times the exposures in patients based on AUC).

Nursing Mothers XTANDI is not indicated for use in women. It is not known if enzalutamide 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 XTANDI, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother.

Pediatric Use Safety and effectiveness of XTANDI in pediatric patients have not been established.

Geriatric Use Of 1671 patients who received XTANDI in the two randomized clinical trials, 75% were 65 and over, while 31% were 75 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients. Other reported clinical

experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Patients with Renal Impairment A dedicated renal impairment trial for XTANDI has not been conducted.

Based on the population pharmacokinetic analysis using data from clinical trials in patients with metastatic CRPC and healthy volunteers, no significant difference in enzalutamide clearance was observed in patients with pre-existing mild to moderate renal impairment (30 mL/min ≤ creatinine clearance [CrCL] ≤ 89 mL/min) compared to patients and volunteers with baseline normal renal function (CrCL ≥ 90 mL/min). No initial dosage adjustment is necessary for patients with mild to moderate renal impairment. Severe renal impairment (CrCL < 30 mL/min) and end-stage renal disease have not been assessed [see Clinical Pharmacology (12.3)].

Patients with Hepatic Impairment A dedicated hepatic impairment trial compared the composite systemic exposure of enzalutamide plus N-desmethyl enzalutamide in volunteers with baseline mild or moderate hepatic impairment (Child-Pugh Class A and B, respectively) versus healthy controls with normal hepatic function.

The composite AUC of enzalutamide plus N-desmethyl enzalutamide was similar in volunteers with mild or moderate baseline hepatic impairment compared to volunteers with normal hepatic function. No initial dosage adjustment is necessary for patients with baseline mild or moderate hepatic impairment. Baseline severe hepatic impairment (Child-Pugh Class C) has not been assessed [see Clinical Pharmacology (12.3)].

OVERDOSAGE In the event of an overdose, stop treatment with XTANDI and initiate general supportive measures taking into consideration the half-life of 5.8 days. In a dose escalation study, no seizures were reported at < 240 mg daily, whereas 3 seizures were reported, 1 each at 360 mg, 480 mg, and 600 mg daily. Patients may be at increased risk of seizure following an overdose.

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been conducted to evaluate the carcinogenic potential of enzalutamide.

Enzalutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in either the in vitro mouse lymphoma thymidine kinase (Tk) gene mutation assay or the in vivo mouse micronucleus assay.

Based on nonclinical findings in repeat-dose toxicology studies, which were consistent with the pharmacological activity of enzalutamide, male fertility may be impaired by treatment with XTANDI. In a 26-week study in rats, atrophy of the prostate and seminal vesicles was observed at ≥ 30 mg/kg/day (equal to the human exposure based on AUC). In 4-, 13-, and 39-week studies in dogs, hypospermatogenesis and atrophy of the prostate and epididymides were observed at ≥ 4 mg/kg/day (0.3 times the human exposure based on AUC).

Manufactured by: Catalent Pharma Solutions, LLC, St. Petersburg, FL 33716 Manufactured for and Distributed by: Astellas Pharma US, Inc., Northbrook, IL 60062 Marketed by: Astellas Pharma US, Inc., Northbrook, IL 60062 Medivation, Inc., San Francisco, CA 94105 Revised: September 2014 14B006-XTA-BRFS Rx Only © 2014 Astellas Pharma US, Inc. XTANDI® is a registered trademark of Astellas Pharma Inc.

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FEATURES Urology Association Presses for Delaying Transition to ICD-10....................…1

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History of Testicular Cancer Increases Risk for Aggressive Prostate Cancer Later On.................................................................................................. 1

By Phoebe Starr

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FDA Issues Safety Communication About Cardiovascular Risks of Testosterone Replacement................................................................................. 1

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Prostate Cancer Therapies Included in New Oncology Care Model......... 12 ASCO Shares Concerns Regarding CMS Model.........................................…12

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SGR Formula, Medicare Reimbursements in Limbo....................................…14

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AR-V7 Predicts Chemotherapy Sensitivity in Metastatic Prostate Cancer..............................................................................................…24

By Phoebe Starr

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April 2015

In This Issue

Urology Practice Management™, ISSN 2374-0752 (print); 2374-0760 (online), is published 6 times a year by Engage Healthcare Communications, LLC, 1249 South River Road, Cranbury, NJ 08512. Copyright © 2015 by Engage Healthcare Communications, LLC. All rights reserved. Urology Practice Management™ is a trademark 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.

The ideas and opinions expressed in Urology Practice Management™ do not necessarily reflect those of the editorial board, the editors, or the publisher. Publication of an advertisement or other product mentioned in Urology Practice Management™ 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 responsibil­ ity for any injury and/or damage to persons or property arising out of or related to any use of the material mentioned in this publication.

FOR UROLOGISTS, PRACTICE MANAGERS, FINANCIAL COUNSELORS, AND REIMBURSEMENT SPECIALISTS™

Caution: Active Surveillance Ill Advised in Men with Intermediate-Risk Prostate Cancer................................................................................................. 27

By Phoebe Starr

Trials Under Way for Patients with Benign Prostatic Hyperplasia.................. 28 Bringing the Oncology Care Model into Focus….......................................... 31

By Leah Ralph

Why You Need Disability Insurance: A Doctor’s Story................................... 32

By Stuart E. Lowenkron, MD

Disability Insurance: Deciphering the COLA Rider........................................ 34

By Lawrence B. Keller, CFP®, CLU®, ChFC®, RHU®, LUTCF

Editorial Advisory Board Neil Baum, MD Practicing Urologist New Orleans, LA Cheris Craig, MBA, CMPE Chief Administrative Officer Urology of Greater Atlanta, LLC Atlanta, GA Michael deWitt Clayton, MD, FACS Urology Associates of San Luis Obispo, CA Rick Janss, MBA, CMPE Practice Administrator Clinical Urology Associates Gadsden, AL

John McMann, MS Administrator Advanced Urology Specialists, LLC Oxford, FL

James A. Sylora, MD Urologist AUS–Midwest Urology Evergreen Park, IL

Jonathan Oppenheimer, MD, FCAP Medical Director, Chief Pathologist Oppenheimer Urologic Reference Laboratory Nashville, TN

Sean M. Weiss, CCP-P, CCA-P, ACS-EM, CPC, CPC-P Vice President & Chief Compliance Officer DecisionHealth/Professional Services Gaithersburg, MD

Jonathan Rubenstein, MD Director of Coding and Compliance Chesapeake Urology Baltimore, MD

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Coding and Billing

FDA Issues Safety Communication... Continued from the cover appropriate laboratory testing.1 According to the FDA announcement, testosterone replacement therapy is approved for men with low testosterone levels caused by disorders of the testicles, pituitary gland, or brain, which cause hypogonadism.

Genetic problems, chemotherapy, or infection may be at the root of some of these disorders.1 The agency cautioned against testosterone replacement therapy to treat age-related low testosterone. “[The] FDA has become aware that testosterone is being used extensively in attempts to relieve symptoms in men who have low testosterone for no apparent reason other than aging,” the announcement indicates. “The benefits and safety of this use have not been established.”

“Based on our findings, we are requiring labeling changes for all prescription testosterone products to reflect the possible increased risk of heart attacks and strokes associated with testosterone use,” the announcement continues. “Healthcare professionals should make patients aware of this possible risk when deciding whether to start or continue a patient on testosterone therapy.”

It goes on to say that patients should seek medical attention if, while using testosterone, they experience heart attack or stroke symptoms. Manufacturers of approved testosterone products will be required

to conduct well-designed clinical trials that address more clearly the question of whether users of these medications are at an increased risk of heart attack or stroke.

Testosterone replacement therapy is approved for men with low testosterone levels caused by disorders of the testicles, pituitary gland, or brain, which cause hypogonadism.

In 2013, 2.3 million people in the United States received a prescription for testosterone, up considerably from the 1.3 million in 2009.2 Further, the most common diagnostic code related to testosterone therapy is the nonspecific diagnosis of “testicular hypofunction, not elsewhere classified”; however, only 72% of men prescribed testosterone had testosterone-level testing prior to being prescribed the hormone.2 The agency’s announcement, dated March 3, 2015, follows on the heels of a nearly unanimous September 2014 vote of 2 of its advisory committees that supported labeling to clarify medical indications for

Key Points n Prescription testosterone product labels will be required to include a warning about a possible increased risk of heart attacks and strokes n Healthcare professionals will be encouraged to prescribe therapy only for men whose low testosterone levels are caused by certain medical conditions n Manufacturers of prescription testosterone products will be required to make approved uses clear on medication labeling n Responses to the safety communication have been mixed within the urology community.

testosterone therapy, as well as a June 2014 joint statement by the FDA and the Center for Drug Eval­ uation and Research.2-4 The joint statement outlined a requirement for manufacturers to include in testosterone product labeling that there is a risk of venous thromboembolism, including deep vein thrombosis and pulmonary embolism.

After hearing from medical, corporate, and government experts, as well as from the general public, members of the 2 committees voted 20 to 1 in favor of label changes stating that testosterone is only indicated in men with valid medical conditions that cause testicular dysfunction rather than men with normal, age-related hypogonadism.4 The decision was not binding, but in this case, the FDA acceded to the strength of the vote and to the precautionary principle.

The committees were charged with examining the cardiovascular safety of testosterone therapy after a paper was published showing an increased risk of stroke, heart attack, and death in older hypogonadal men.5 Other studies and meta-analyses have demonstrated both an increased and decreased risk of cardiovascular disease and/or death rate associated with testosterone. One meta-analysis demonstrated a connection between funding sources and study outcomes, stating, “in trials not funded by the pharmaceutical industry the risk of a cardiovascular-related event on testosterone therapy was greater…than in pharmaceutical industry funded trials.”6 Response to the announcement from the urology community has been mixed. Daniel Shoskes, MD, Professor of Surgery, Department of Surgery, Cleveland Lerner College of Medicine of Case Western Reserve University, and Director, Novick Center for Clinical and Translational Continued on page 10

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Coding and Billing

Urology Association Presses for Delaying... Continued from the cover House of Representatives subcommittee as a member of the AUA, William J. Terry, Sr, MD, outlined the organization’s concerns with ICD-10 implementation.

Released earlier this year, the transcript of Dr Terry’s testimony in February demonstrates the association’s concerns with an implementation date for the new codes of October 1, 2015, including increased administrative and financial burdens that urology practices may incur.

“This is what I always discuss with my patients when sharing in the decision on various treatment options; ‘Do the benefits outweigh the risks?’”

—William J. Terry, Sr, MD

“I hope that you will keep in mind the concerns of practicing physicians—particularly those in small practices—balanced with proven advantages of ICD-10 on direct patient care and weighed against the consequences of a poorly executed implementation,” Dr Terry said in his testimony. “This is what I always discuss with my patients when sharing in the decision on various treatment

options; ‘Do the benefits outweigh the risks?’ ” The association is also asking the Centers for Medicare & Medicaid Services (CMS) to release the results of testing it has done on some practices in order to shed light on the ease or difficulty of using ICD-10.

“We urge CMS to release the details of its end-to-end testing, as well as its contingency plans should providers not be prepared on October 1, 2015. We urge Congress to delay implementation of the ICD-10 code set and appoint a committee to better study the ‘risks and benefits,’ ” Dr Terry stated, according to a summary of his testimony.

In the summary, he said that if a delay is impossible, Congress should consider legislating a period during which physicians can use ICD-10 or keep using ICD-9. Similar sentiments were voiced in a March 2015 letter to CMS Acting Administrator Andrew Slavitt from the AUA and more than 50 other national medical associations, including the American Medical Association, as well as 47 state medical associations. They stated that the ICD-10 transition is “one of the largest technical, operational, and business implementations in the healthcare industry in the past several decades.” The signatory organizations urged the following: • Because only 89% of claims were accepted in the March 2014 endto-end test and 76% in the November 2014 test, and the number of practices tested was very small, CMS should release more detailed end-to-end testing results, including the type and size of providers who tested use of ICD-10, the number of claims tested by each practice, the percentage of claims processed successfully, details about problems that occurred, and what steps need to be taken to correct the problems

• The Physician Quality Reporting System and Meaningful Use quality reporting periods straddle October 1, and CMS has not dis-

“While there is controversy on the exact financial burden this will place on providers and practices, we know the burden will be great.”

—Jonathan Rubenstein, MD

cussed how it plans to address the reporting of these metrics after the transition to ICD-10. The organizations urged CMS to clarify how it plans to ensure that the measure calculations for these programs are not adversely impacted by the transition, ensure that crosswalks do not attribute increased costs to a physician’s Value-Based Modifier score when switching to ICD-10, and that the changes in measure specifications will be stable and budget-neutral for providers • CMS should commit to providing advance payments to physicians who are experiencing a severe financial hardship as a result of the change to ICD-10, particularly if the issue originates on Medicare’s Continued on page 10

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Coding and Billing

FDA Issues Safety Communication... Continued from page 8 Research, Glickman Urological & Kidney Institute, Cleveland Clinic, is among those who are concerned. He noted concerns with the paper used

“I certainly sympathize with the FDA in seeing that there are a large portion of the men who are getting testosterone therapy in the United

The joint statement outlined a requirement for manufacturers to include in testosterone product labeling that there is a risk of venous thromboembolism, including deep vein thrombosis and pulmonary embolism. as the basis for the ruling, as well as evidence that having low testosterone is a risk factor for cardiovascular health problems. Testosterone replacement therapy could mitigate that risk, he said.

States without getting their testosterone levels checked first and are not being monitored according to guidelines,” said Dr Shoskes. “But I am surprised and deeply disappointed in the FDA’s ruling.” l

References

1. US Food and Drug Administration. FDA Drug Safety Communication: FDA cautions about using testosterone products for low testosterone due to aging; requires labeling change to inform of possible increased risk of heart attack and stroke with use. www.fda.gov/ Drugs/DrugSafety/ucm436259.htm. Published March 3, 2015. Accessed April 6, 2015.

2. US Food and Drug Administration. Testosterone replacement therapy. www.fda.gov/downloads/Advisory Committees/CommitteesMeetingMaterials/Drugs/ ReproductiveHealthDrugsAdvisoryCommittee/ UCM416461.pdf. Published September 17, 2014. Accessed April 6, 2015.

3. US Food and Drug Administration. Testosterone Products: FDA/CDER statement - risk of venous blood clots. www.fda.gov/safety/medwatch/safetyinformation/ safetyalertsforhumanmedicalproducts/ucm402054.htm.

Published June 20, 2014. Accessed April 6, 2015.

4. US Food and Drug Administration. FDA News. FDA advisory panel rejects testosterone replacement therapy. www.fdanews.com/articles/167396-fda-advisory-panelsreject-testosterone-replacement-therapy. Published September 26, 2014. Accessed April 6, 2015.

5. Vigen R, O’Donnell CI, Barón AE. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. J Am Med Assoc. 2013;310:1829-1836.

6. Xu L, Freeman G, Cowling BJ, Schooling CM. Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials. BMC Med. 2013;11:108.

Urology Association Presses for Delaying... Continued from page 9

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end, and should work with the Office of the National Coordinator for Health Information Technology to provide information about electronic health record–vendor readiness for ICD-10 codes • CMS should ensure that it will not audit claims simply for code specificity.

The actual financial cost for practices to implement ICD-10 has been a source of study and debate. An article published in the Journal of the American Health Information Management Association pegged the cost of implementation for small practices at $1960 to $5900.1 A paper released in February 2014 that was prepared by Nachimson Advisors for the American Medical Association, however, suggested a range of costs to providers depending on the size of the practice: $56,639 to $226,105 for a small group practice

(3 providers, 2 administrators); $213,364 to $824,735 for a medium group practice (10 providers, 1 coder, 6 administrators); and $2 million to $8 million for a large group practice (100 providers, 64 coding staff). This 2014 report was an update of a study on the same topic that Nachimson Advisors first released in 2008.2,3 Dr Terry said that physicians are resigned to implementation of ICD10 but hope that CMS will put in place measures to mitigate some of the potentially devastating effects on healthcare practices. Jonathan Rubenstein, MD, Director of Coding and Compliance with Chesapeake Urology, Baltimore, MD, and a member of the AUA Coding & Reimbursement Committee, echoed some of Dr Terry’s concerns, and noted that the AUA will work hard to help its members prepare for this transition.

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“While there is controversy on the exact financial burden this will place on providers and practices, we know the burden will be great,” Dr Rubenstein said. “The AUA will continue to support its members and assist them in their preparations for this transition to ICD-10.”

CMS declined to comment for this story. l

References

1. Kravis TC, Belley S, Smith DM, Averill RF. Cost of converting small physician offices to ICD-10 much lower than previously reported. J AHIMA website. http://journal.ahima.org/wp-content/uploads/Week-3_ PDFpost.FINAL-Estimating-the-Cost-of-Conversionto-ICD-10_-Nov-12.pdf. Published November 12, 2014.

Accessed April 2, 2014.

2. Nachimson Advisors, LLC. The cost of implementing ICD-10 for physician practices – updating the 2008 Nachimson Advisors Study. A report to the American Medical Association. February 12, 2014.

3. The impact of implementing ICD-10 on physician practices and clinical laboratories: a report to the ICD-10 coalition. Nachimson Advisors, LLC. Nachimson Advisors website. www.nachimsonadvisors.com/Documents/ ICD-10%20Impacts%20on%20Providers.pdf. Published October 8, 2008. Accessed April 2, 2015.

Managed Care Payers and Pharmaceutical Oncology Trends

John Fox, MD, MHA Senior Medical Director Associate Vice President Medical Affairs Priority Health

Alex Jung Principal, Global Strategic Advisory Services Ernst & Young LLP

Omni Shoreham Hotel • Washington, DC TH

AN

ANNUAL CONFERENCE

RSARY VE NI

AGENDA

*

MAY 4, 2015

7:00 am – 8:00 am

Meet the Experts Breakfast

8:00 am – 8:15 am

Introduction to Conference and Opening Remarks John Fox, MD, MHA, Priority Health Alex Jung, Ernst & Young LLP

8:15 am – 9:00 am

Session 1 - The Emerging Role of Personal Medicine – the Business Case Vince Miller, MD, Foundation Medicine

9:00 am – 9:45 am

Session 2 - Pathways versus Personalized Medicine – Never the Twain Shall Meet Michael Kolodziej, MD, Aetna

9:45 am – 10:00 am

Break

10:00 am – 10:45 am

Session 3 - The CMMI Multipayer Oncology Care Model Heidi Schumacher, MD, CMMI

10:45 am – 11:30 am

Session 4 - Practice Accreditation as Oncology Medical Homes Ted Okon, Community Oncology Alliance (Invited) David Eagle, Community Oncology Alliance (Invited)

11:30 am – 12:15 pm

12:15 pm – 1:15 pm

Session 5 - How to Measure Quality in Cancer Michael Kolodziej, MD, Aetna Heidi Schumacher, MD, CMMI David Eagle, Community Oncology Alliance (Invited) Ted Okon, Community Oncology Alliance (Invited) Lunch Presentation - Financial Toxicity Speaker TBD

1:15 pm – 2:00 pm

Session 6 - Keynote Session – IMS Oncology Drug Trends Report Doug Long, IMS Health Inc

2:00 pm – 2:45 pm

Session 7 - Pharma and Defining Value in Cancer Care Sanjeev Wadhwa, Biologist/Life Sciences Consultant for R&D

2:45 pm – 3:30 pm

Session 8 - Comparative Effectiveness and Measuring Value of Drug Therapeutic Options in Cancer Care Robert Bilkovski, MD, Abbott Pharmaceuticals

3:30 pm – 4:15 pm

Session 9 - Perspective on the Future of Oncology Drug and Disease Management Grant Lawless, RPh, MD, FACP, University of Southern California

4:15 pm – 5:00 pm

Session 10 - Limited Distribution Oncology Drug Networks and the Value of Controlled Distribution Alex Jung, Ernst & Young LLP

5:00 pm – 5:45 pm

Session 11 - Specialized Pharmacy and Adding Value of Disease and Patient’s Support in Cancer Care Speaker TBD

5:45 pm – 6:00 pm

Poster Award Q & A

6:00 pm – 6:15 pm

Closing Remarks

6:15 pm – 8:15 pm

Welcome Reception/Exhibit Hall

*Agenda subject to change.

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AVBCConline.org/conference

Payment Reform

Prostate Cancer Therapies Included in New Oncology Care Model

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new payment model announced by the US Department of Health & Human Services offers providers the potential to receive at least $160 per month for patients who are undergoing chemotherapy treatment. The per-beneficiary, per-month (PBPM) allocation is part of a 2-pronged approach that also includes a performance-based payment to incentivize practices to reduce costs and improve care for this patient population. Hormonal therapies, including antiandrogen therapy used for the treatment of prostate cancer, are among the therapeutic regimens eligible for inclusion under this model.

The goal of this new model, known as the Oncology Care Model (OCM) and developed by the Centers for Medicare & Medicaid Services (CMS) Innovation Center, is to provide high-quality, well-coordinated, appropriately incentivized oncology care while controlling expenses and reducing costs, according to information provided by CMS. It also aligns with the US Department of Health & Human Services’ goal of moving toward provider payments that are based on quality of care, rather than quantity. It is estimated that more than 1.6 million people are diagnosed with cancer annually, the majority of whom are at least 65 years old and Medicare beneficiaries.

“Based on feedback from the medical, consumer and business communities, we are launching this new model of care to support clinicians’ work with their patients,” Patrick Conway, MD, CMS Chief Medical Officer and Deputy Administrator for Innovation and Quality, stated in a release announcing the new care model. “We aim to provide Medicare beneficiaries struggling with cancer with high-quality care around the

clock and to reward doctors for the value, not volume, of care they provide. Improving the way we pay providers and deliver care to patients will result in healthier people.”

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Hormonal therapies, including antiandrogen therapy used for the treatment of prostate cancer, are among the therapeutic regimens eligible for inclusion under this model.

Through this model, CMS will provide qualifying providers with the $160 PBPM care management pay-

ment for each eligible beneficiary receiving chemotherapy and the care related to it. Payments will be made for the duration of a 6-month episode, hinged on the initiation of treatment with a preset list of chemotherapy drugs. Medications on this list include antiandrogen therapies that are used in the treatment of prostate cancer, as well as other hormone therapies related to treating this disease. A complete list of eligible drugs is provided in the program application, which is available by visiting the CMS website.

The PBPM payment will remain constant for OCM’s designated 5-year performance period, and comes in addition to fee-for-service payments. Eligible practices can be physician groups or solo practitioners who administer cancer chemothera-

ASCO Shares Concerns Regarding CMS Model

By Rosemary Frei, MSc

T

he announcement in February of a new Oncology Care Model has brought a lukewarm response by the American Society of Clinical Oncology (ASCO). Developed by the Centers for Medicare & Medicaid Services (CMS) Innovation Center and announced through the US Department of Health & Human Services, the new care delivery model encompasses a multipayer structure as well as incentivized and monthly per beneficiary payments to participating practices (see article on this page).

In August 2014, the Innovation Center, known officially as the Center for Medicare & Medicaid

April 2015

Innovation (CMMI) posted and sought comments online for the proposed model, titled “Preliminary Design for an Oncology-­ Focused Model.” The new model was announced February 12, 2015.

That same day, ASCO issued a news release outlining what its officials see as challenges with the new model. ASCO Chief Medical Officer Richard L. Schilsky, MD, FACP, FASCO, echoed these concerns when reached by Urology Practice Management.

“While CMS is to be commended for seeking new approaches to payment, we are disappointed they have chosen to pursue only one model—and one that continues to

Payment Reform

py and who are enrolled in Medicare.

They must also meet the following requirements to participate in OCM and receive payment: • Provide core functions of patient navigation • Document a care plan that encompasses the Institute of Medicine Care Management Plan • Give patients around-the-clock access to an appropriate clinician who has real-time access to patient medical records • Treat patients according to nationally recognized clinical guidelines • Use data to drive quality improvement • Use electronic health records and attest to stage 2 of Meaningful Use by the third year of participation.

As part of their participation, practices must also report data quarterly to the CMS Innovation Center on eligible, participating beneficiaries. The Innovation Center will monitor participating practices to rely on a broken fee-for-service system,” Dr Schilsky stated in an e-mail to the journal. “ASCO looks forward to working with both public and private payers to explore new payment strategies that better reflect modern oncology practice and support high-value, patient-centered care.”

During the period for comments on the proposal, ASCO Chief Executive Officer Allen S. Lichter, MD, FASCO, submitted a letter to CMS detailing the organization’s concerns with the proposal. He took issue with most aspects of it.

With respect to the calculation of performance-based payments, Dr Lichter wrote that, “CMMI should provide a transition period where it does not calculate and retain a discount on the target cost of per­ formance period episodes,” and “CMMI should defer implementing any hold-back retained by Medi-

ensure that patients are accessing and receiving high-quality care, practices have the necessary infrastructure in place to deliver comprehensive care, and practices are submitting required data. Monitoring by the Innovation Center may include site visits, tracking and analysis of data, patient surveys, and medical record audits.

Payments may be billed to Medicare for the entire 6-month chemotherapy episode, whether or not the patient receives chemotherapy treatment for the full 6 months; payments cannot be billed to Medicare once the patient enters hospice. After an episode ends, another 6-month episode may be started if chemotherapy treatment is still active and being billed. Management of patients who are not receiving chemotherapy will not be eligible for this model.

The program is voluntary for oncology practices and payers, and CMS is asking for nonbinding letters

of intent to gauge interest, due April 9 for payers and May 7 for practices.

Those who submit completed, timely letters of intent will be eligible to submit final applications (due June 18). CMS is also encouraging participation from other payers, including commercial insurers, state Medicaid agencies, and other government payers. The agency will publicly post a list of payers who have submitted letters of intent and agreed to the posting; the agency will also post a list of practices, based on the same conditions.

Payers and practices will then have an opportunity to discuss and coordinate collaboration within the OCM. Provider applications will be evaluated using a process that favors those who are partnering with approved payers. The program is slated to begin in spring 2016, and applicants will be notified of their selection status within 6 months from the date they submit their application. l

care until after the first 2 performance periods are completed.”

He noted, in addition, that ASCO has been developing its Consolidated Payments for Oncology Care (CPOC) model. He concluded that CPOC, which ASCO released in May 2014, “shares a number of important policy goals with the [Oncology Care Model] framework, and our model is designed to provide Medicare and other payers with the flexibility to incorporate its key components into a variety of reform approaches. We would very much like to work with you to explore ways that we can leverage our respective efforts to build a better payment system in oncology.”

CMS declined Urology Practice Management’s requests for comment regarding ASCO’s concerns.

The Oncology Care Model developed through CMMI offers eligible practitioners a $160 per-bene-

April 2015

ficiary, per-month payment for a 6-month episode of chemotherapy care, as well as the potential for an incentivized, performance-based payment for care episodes. Participating practices must adhere to specified guidelines and requirements, and demonstrate the capabilities to provide and document care as outlined in the Oncology Care Model (OCM) Request for Applications (RFA) February 2015.

CMS is also soliciting participation from other payers, including commercial insurers, state agencies, and government payers.

For more information, interested practices can download the application from http://innovation.cms. gov/Files/x/ocmrfa.pdf. Practices that are interested in participating are required to submit a nonbinding letter of intent by May 7; interested payers must submit letters of intent by April 9. l

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Payment Reform

SGR Formula, Medicare Reimbursements in Limbo

By Gail Thompson

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nce again, providers and practice administrators are in limbo about the status of Medicare payments. In late March, Congress moved closer than they ever had before, but stopped just short of repealing and replacing Medicare’s sustainable growth rate (SGR) physician payment formula.

The $200-billion deal up for consideration would stave off a 21.2% cut to Medicare payment rates and extend the Children’s Health Insurance Program (CHIP) while repealing the nearly 20-year-old formula.

After the US House of Representatives passed the surprise bipartisan SGR legislation, pressure then mounted on members of the US Senate to sign and approve the deal as well before leaving on spring break.

The March 31 deadline to pass the bill came and went, however, with members of Congress heading home for a 2-week holiday recess. Prominent senators have shared their optimism that the issue will be addressed upon their April 13 return, although concerns of filibusters and opposition are surfacing. Practice managers and administrators, wary from past experience, are remaining cautious, and have been urged to prepare a contingency plan for whatever may come next until a final bill is approved.

“There is still time to work out a product that, in its entirety, is something members of both parties in both chambers can support,” said Sen Ron Wyden (D, Oregon), the ranking member of the Senate Finance Committee, in a written statement on March 19, 2015. “This involves major issues of health policy and we are just not there yet.”

Without a signed deal, the patch enacted in 2014 to the SGR formula

expired on March 31, and the Centers for Medicare & Medicaid Services (CMS) must proceed as if the 21.2% cuts to Medicare payments have taken effect. Under current law, however, it does not actually have to pay out April 1 claims under any fee schedule until April 14 at the earliest. In the past, CMS has held claims for longer than the 14 days in anticipation of congressional action on the SGR formula, and that might well happen again. Practices should expect to receive updates from CMS regarding the status of their claims, when to expect payment, and under what fee schedule.

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“There is still time to work out a product that, in its entirety, is something members of both parties in both chambers can support.”

—Sen Ron Wyden (D, Oregon), Ranking Member, Senate Finance Committee

Next Steps Medicare is required to annually publish each November the actual Medicare conversion factor, the SGR update, and allowed expenditures for physicians’ services for the upcoming year. For years, the rise in physician services expenditures has resulted in an ever-increasing SGR correction against the targeted expenditures, and an annual announcement of a double-digit reduction in physician services rates—21.2% this year—scheduled for each April 1.

Each year, the medical community

April 2015

rises up, decrying the unsustainability of double-digit rate reductions in the physician fee schedule, and each year, at the last minute, Congress has passed a patch that modifies the actual fee schedule adjustment from what is required under the actual SGR formula.

With the recent bipartisan legislation passed in the House, providers who would like to see Medicare’s SGR payment formula repealed must wait and see what happens when the Senate returns from recess. In the meantime, though, there are a few steps providers can take to stay informed and ensure their practices are prepared for potential reimbursement delays: • Prepare for delayed Medicare reimbursements for claims dating from April 1 forward; expect, at a minimum, the usual 14-day delay for electronic claims • Prepare for the possibility that CMS may hold payments for a further period of time in anticipation of some modifying action by Congress; this may require practices to obtain a line of credit to offset the loss in cash flow for several weeks as they wait for Medicare payments • Watch for updates from CMS, the medical community, and the press; even if Congress does take action, CMS may delay payments a few extra days to allow for fee schedule updates in its system.

Having come this far, it would seem as though the long-awaited repeal of the SGR formula may actually happen this year. However, a number of issues and concerns could affect action by the Senate, and nothing is guaranteed. Providers should continue to stay informed, and prepared, for whatever the outcome might be. l

In mCRPC therapy…

Is there more to the story?

INDICATION ZYTIGA® (abiraterone acetate) in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC).

IMPORTANT SAFETY INFORMATION Contraindications—ZYTIGA® is not indicated for use in women. ZYTIGA® can cause fetal harm (Pregnancy Category X) when administered to a pregnant woman and is contraindicated in women who are or may become pregnant.

Adverse Reactions—The most common adverse reactions (≥10%) are fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection, and contusion.

The most common laboratory abnormalities (>20%) are anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT, and hypokalemia.

Increased ZYTIGA® Exposures With Food—ZYTIGA® must be taken on an empty stomach. No food should be eaten for at least two hours before the dose of ZYTIGA® is taken and for at least one hour after the dose of ZYTIGA® is taken.

Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state.

Adrenocortical Insufficiency (AI)—AI was reported in patients receiving ZYTIGA® in combination with prednisone, after an interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of AI if prednisone is stopped or withdrawn, if prednisone dose is reduced, or if the patient experiences unusual stress. Symptoms and signs of AI may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA®. Perform appropriate tests, if indicated, to confirm AI. Increased dosages of corticosteroids may be used before, during, and after stressful situations.

Hypertension, Hypokalemia, and Fluid Retention Due to Mineralocorticoid Excess—Use with caution in patients with a history of cardiovascular disease or with medical conditions that might be compromised by increases in blood pressure, hypokalemia, or fluid retention. ZYTIGA® may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition. Safety has not been established in patients with LVEF <50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in Study 2) because these patients were excluded from these randomized clinical trials.

Control hypertension and correct hypokalemia before and during treatment. Monitor blood pressure, serum potassium, and symptoms of fluid retention at least monthly. mCRPC=metastatic castration-resistant prostate cancer; AST=aspartate aminotransferase; ALT=alanine aminotransferase.

Please see additional Important Safety Information on the next page.

Please see brief summary of full Prescribing Information on subsequent pages.

For men with mCRPC who progressed on ADT

In a clinical trial, patients had a median overall survival on ZYTIGA® (abiraterone acetate) of…*

More than 1,000 days.

And every day tells a story.

35.3 IMPROVEMENT IN MEDIAN OVERALL SURVIVAL 5.2 MONTHS compared with placebo plus prednisone.

MONTHS MEDIAN OVERALL SURVIVAL FOR ZYTIGA® plus prednisone† vs 30.1 MONTHS with placebo plus prednisone (active compound).‡

Co-primary end point—overall survival: hazard ratio (HR)=0.792; 95% CI: 0.655, 0.956; P=0.0151; prespecified value for statistical significance not reached.

Co-primary end point—radiographic progression-free survival: median not reached for ZYTIGA® plus prednisone vs a median of 8.28 months for placebo plus prednisone. HR=0.425; 95% CI: 0.347, 0.522; P<0.0001.

IMPORTANT SAFETY INFORMATION (cont) Increased ZYTIGA® Exposures With Food—ZYTIGA® must be taken on an empty stomach. No food should be eaten for at least two hours before the dose of ZYTIGA® is taken and for at least one hour after the dose of ZYTIGA® is taken.

Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state.

Hepatotoxicity—Monitor liver function and modify, withhold, or discontinue ZYTIGA® dosing as recommended (see Prescribing Information for more information). Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA®, every two weeks for the first three months of treatment, and monthly thereafter.

Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop.

Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the upper limit of normal (ULN) or the bilirubin rises above three times the ULN, interrupt ZYTIGA® treatment and closely monitor liver function. *Study Design: ZYTIGA®, in combination with prednisone, was evaluated in a phase 3, randomized, double-blind, placebo-controlled, multicenter trial in patients with mCRPC who had not received prior chemotherapy (N=1,088). Patients were using a luteinizing hormone-releasing hormone (LHRH) agonist or were previously treated with orchiectomy. In the ZYTIGA® arm, patients received ZYTIGA® 1,000 mg orally once daily + prednisone 5 mg orally twice daily. In the placebo arm, patients received placebo orally once daily + prednisone 5 mg orally twice daily. In this study, the co-primary efficacy end points were overall survival (OS) and radiographic progression-free survival.

ADT=androgen-deprivation therapy.

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2014 6/14 016819-140612

Please see brief summary of full Prescribing Information on subsequent pages.

003307-130924

Drug Interactions—Based on in vitro data, ZYTIGA® is a substrate of CYP3A4. In a drug interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%. Avoid concomitant strong CYP3A4 inducers during ZYTIGA® treatment. If a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA® dosing frequency only during the co-administration period [see Dosage and Administration (2.3)]. In a dedicated drug interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone.

ZYTIGA® is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. Avoid co-administration with CYP2D6 substrates with a narrow therapeutic index. If alternative treatments cannot be used, exercise caution and consider a dose reduction of the CYP2D6 substrate drug. In vitro, ZYTIGA® inhibits CYP2C8. There are no clinical data on the use of ZYTIGA® with drugs that are substrates of CYP2C8. Patients should be monitored closely for signs of toxicity related to the CYP2C8 substrate if used concomitantly with abiraterone acetate.

Use in Specific Populations—Do not use ZYTIGA® in patients with baseline severe hepatic impairment (Child-Pugh Class C). †At a prespecified interim analysis for OS, 37% (200/546) of patients treated with ZYTIGA® plus prednisone compared with 43% (234/542) of patients treated with placebo plus prednisone had died. ‡Prednisone, as a single agent, is not approved for the treatment of prostate cancer.

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ZYTIGA® (abiraterone acetate) Tablets Brief Summary of Prescribing Information.

INDICATIONS AND USAGE ZYTIGA is a CYP17 inhibitor indicated in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer.

CONTRAINDICATIONS Pregnancy: ZYTIGA can cause fetal harm when administered to a pregnant woman. ZYTIGA is not indicated for use in women. ZYTIGA is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss [see Use in Specific Populations].

WARNINGS AND PRECAUTIONS Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess: ZYTIGA may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see Clinical Pharmacology (12.1) in full Prescribing Information].

In the two randomized clinical trials, grade 3 to 4 hypertension occurred in 2% of patients, grade 3 to 4 hypokalemia in 4% of patients, and grade 3 to 4 edema in 1% of patients treated with ZYTIGA [see Adverse Reactions].

Co-administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in the incidence and severity of these adverse reactions. Use caution when treating patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia or fluid retention, e.g., those with heart failure, recent myocardial infarction or ventricular arrhythmia. Use ZYTIGA with caution in patients with a history of cardiovascular disease. The safety of ZYTIGA in patients with left ventricular ejection fraction <50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in Study 2) was not established because these patients were excluded from these randomized clinical trials [see Clinical Studies (14) in full Prescribing Information]. Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment with ZYTIGA. Adrenocortical Insufficiency: Adrenal insufficiency occurred in the two randomized clinical studies in 0.5% of patients taking ZYTIGA and in 0.2% of patients taking placebo. Adrenocortical insufficiency was reported in patients receiving ZYTIGA in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations [see Warnings and Precautions].

Hepatotoxicity: In the two randomized clinical trials, grade 3 or 4 ALT or AST increases (at least 5X ULN) were reported in 4% of patients who received ZYTIGA, typically during the first 3 months after starting treatment. Patients whose baseline ALT or AST were elevated were more likely to experience liver test elevation than those beginning with normal values. Treatment discontinuation due to liver enzyme increases occurred in 1% of patients taking ZYTIGA. No deaths clearly related to ZYTIGA were reported due to hepatotoxicity events.

Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA, every two weeks for the first three months of treatment and monthly thereafter. In patients with baseline moderate hepatic impairment receiving a reduced ZYTIGA dose of 250 mg, measure ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every two weeks for the following two months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop.

Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the ULN, or the bilirubin rises above three times the ULN, interrupt ZYTIGA treatment and closely monitor liver function.

Re-treatment with ZYTIGA at a reduced dose level may take place only after return of liver function tests to the patient’s baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN [see Dosage and Administration (2.2) in full Prescribing Information].

The safety of ZYTIGA re-treatment of patients who develop AST or ALT greater than or equal to 20X ULN and/or bilirubin greater than or equal to 10X ULN is unknown.

Increased ZYTIGA Exposures with Food: ZYTIGA must be taken on an empty stomach. No food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state. The safety of these increased exposures when multiple doses of abiraterone acetate are taken with food has not been assessed [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

ZYTIGA® (abiraterone acetate) Tablets ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: • Hypertension, Hypokalemia, and Fluid Retention due to Mineralocorticoid Excess [see Warnings and Precautions].

• Adrenocortical Insufficiency [see Warnings and Precautions].

• Hepatotoxicity [see Warnings and Precautions].

• Increased ZYTIGA Exposures with Food [see Warnings and Precautions].

Clinical Trial 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.

Two randomized placebo-controlled, multicenter clinical trials enrolled patients who had metastatic castration-resistant prostate cancer who were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy. In both Study 1 and Study 2 ZYTIGA was administered at a dose of 1,000 mg daily in combination with prednisone 5 mg twice daily in the active treatment arms. Placebo plus prednisone 5 mg twice daily was given to control patients.

The most common adverse drug reactions (≥10%) reported in the two randomized clinical trials that occurred more commonly (>2%) in the abiraterone acetate arm were fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion.

The most common laboratory abnormalities (>20%) reported in the two randomized clinical trials that occurred more commonly (≥2%) in the abiraterone acetate arm were anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT and hypokalemia.

Study 1: Metastatic CRPC Following Chemotherapy: Study 1 enrolled 1195 patients with metastatic CRPC who had received prior docetaxel chemotherapy. Patients were not eligible if AST and/or ALT ≥2.5X ULN in the absence of liver metastases. Patients with liver metastases were excluded if AST and/or ALT >5X ULN. Table 1 shows adverse reactions on the ZYTIGA arm in Study 1 that occurred with a ≥2% absolute increase in frequency compared to placebo or were events of special interest. The median duration of treatment with ZYTIGA was 8 months.

Table 1: Adverse Reactions due to ZYTIGA in Study 1 ZYTIGA with Placebo with Prednisone (N=791) Prednisone (N=394) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % Musculoskeletal and connective tissue disorders Joint swelling/ discomfort2 29.5 4.2 23.4 4.1 Muscle discomfort3 26.2 3.0 23.1 2.3 General disorders Edema4 26.7 1.9 18.3 0.8 Vascular disorders Hot flush 19.0 0.3 16.8 0.3 Hypertension 8.5 1.3 6.9 0.3 Gastrointestinal disorders Diarrhea 17.6 0.6 13.5 1.3 Dyspepsia 6.1 0 3.3 0 Infections and infestations Urinary tract infection 11.5 2.1 7.1 0.5 Upper respiratory tract infection 5.4 0 2.5 0 Respiratory, thoracic and mediastinal disorders Cough 10.6 0 7.6 0 Renal and urinary disorders Urinary frequency 7.2 0.3 5.1 0.3 Nocturia 6.2 0 4.1 0 Injury, poisoning and procedural complications Fractures5 5.9 1.4 2.3 0 Cardiac disorders Arrhythmia6 7.2 1.1 4.6 1.0 Chest pain or chest discomfort7 3.8 0.5 2.8 0 Cardiac failure8 2.3 1.9 1.0 0.3

ZYTIGA® (abiraterone acetate) Tablets

ZYTIGA® (abiraterone acetate) Tablets

1 Adverse events graded according to CTCAE version 3.0 2 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness 3 Includes terms Muscle spasms, Musculoskeletal pain, Myalgia,

Table 3: Adverse Reactions in ≥5% of Patients on the ZYTIGA Arm in Study 2 (continued) ZYTIGA with Placebo with Prednisone (N=542) Prednisone (N=540) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % Renal and urinary disorders Hematuria 10.3 1.3 5.6 0.6 Skin and subcutaneous tissue disorders Rash 8.1 0.0 3.7 0.0 1 Adverse events graded according to CTCAE version 3.0 2 Includes terms Edema peripheral, Pitting edema, and Generalized edema 3 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness

Musculoskeletal discomfort, and Musculoskeletal stiffness terms Edema, Edema peripheral, Pitting edema, and Generalized edema 5 Includes all fractures with the exception of pathological fracture 6 Includes terms Arrhythmia, Tachycardia, Atrial fibrillation, Supraventricular tachycardia, Atrial tachycardia, Ventricular tachycardia, Atrial flutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Bradyarrhythmia 7 Includes terms Angina pectoris, Chest pain, and Angina unstable.

Myocardial infarction or ischemia occurred more commonly in the placebo arm than in the ZYTIGA arm (1.3% vs. 1.1% respectively).

8 Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased 4 Includes

Table 2 shows laboratory abnormalities of interest from Study 1. Grade 3-4 low serum phosphorus (7%) and low potassium (5%) occurred at a greater than or equal to 5% rate in the ZYTIGA arm.

Table 2: Laboratory Abnormalities of Interest in Study 1 Abiraterone (N=791) Placebo (N=394) Laboratory All Grades Grade 3-4 All Grades Grade 3-4 Abnormality (%) (%) (%) (%) Hypertriglyceridemia 62.5 0.4 53.0 0 High AST 30.6 2.1 36.3 1.5 Hypokalemia 28.3 5.3 19.8 1.0 Hypophosphatemia 23.8 7.2 15.7 5.8 High ALT 11.1 1.4 10.4 0.8 High Total Bilirubin 6.6 0.1 4.6 0 Study 2: Metastatic CRPC Prior to Chemotherapy: Study 2 enrolled 1088 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy. Patients were ineligible if AST and/or ALT ≥2.5X ULN and patients were excluded if they had liver metastases.

Table 3 shows adverse reactions on the ZYTIGA arm in Study 2 that occurred with a ≥2% absolute increase in frequency compared to placebo.

The median duration of treatment with ZYTIGA was 13.8 months.

Table 3: Adverse Reactions in ≥5% of Patients on the ZYTIGA Arm in Study 2 ZYTIGA with Placebo with Prednisone (N=542) Prednisone (N=540) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % General disorders Fatigue 39.1 2.2 34.3 1.7 Edema2 25.1 0.4 20.7 1.1 Pyrexia 8.7 0.6 5.9 0.2 Musculoskeletal and connective tissue disorders Joint swelling/ discomfort3 30.3 2.0 25.2 2.0 Groin pain 6.6 0.4 4.1 0.7 Gastrointestinal disorders Constipation 23.1 0.4 19.1 0.6 Diarrhea 21.6 0.9 17.8 0.9 Dyspepsia 11.1 0.0 5.0 0.2 Vascular disorders Hot flush 22.3 0.2 18.1 0.0 Hypertension 21.6 3.9 13.1 3.0 Respiratory, thoracic and mediastinal disorders Cough 17.3 0.0 13.5 0.2 Dyspnea 11.8 2.4 9.6 0.9 Psychiatric disorders Insomnia 13.5 0.2 11.3 0.0 Injury, poisoning and procedural complications Contusion 13.3 0.0 9.1 0.0 Falls 5.9 0.0 3.3 0.0 Infections and infestations Upper respiratory tract infection 12.7 0.0 8.0 0.0 Nasopharyngitis 10.7 0.0 8.1 0.0

Table 4 shows laboratory abnormalities that occurred in greater than 15% of patients, and more frequently (>5%) in the ZYTIGA arm compared to placebo in Study 2. Grade 3-4 lymphopenia (9%), hyperglycemia (7%) and high alanine aminotransferase (6%) occurred at a greater than 5% rate in the ZYTIGA arm.

Table 4: Laboratory Abnormalities in >15% of Patients in the ZYTIGA Arm of Study 2 Abiraterone (N=542) Placebo (N=540) Laboratory Grade 1-4 Grade 3-4 Grade 1-4 Grade 3-4 Abnormality % % % % Hematology Lymphopenia 38.2 8.7 31.7 7.4 Chemistry 1 Hyperglycemia 56.6 6.5 50.9 5.2 High ALT 41.9 6.1 29.1 0.7 High AST 37.3 3.1 28.7 1.1 Hypernatremia 32.8 0.4 25.0 0.2 Hypokalemia 17.2 2.8 10.2 1.7 1Based on non-fasting blood draws Cardiovascular Adverse Reactions: In the combined data for studies 1 and 2, cardiac failure occurred more commonly in patients treated with ZYTIGA compared to patients on the placebo arm (2.1% versus 0.7%).

Grade 3-4 cardiac failure occurred in 1.6% of patients taking ZYTIGA and led to 5 treatment discontinuations and 2 deaths. Grade 3-4 cardiac failure occurred in 0.2% of patients taking placebo. There were no treatment discontinuations and one death due to cardiac failure in the placebo group.

In Study 1 and 2, the majority of arrhythmias were grade 1 or 2. There was one death associated with arrhythmia and one patient with sudden death in the ZYTIGA arms and no deaths in the placebo arms. There were 7 (0.5%) deaths due to cardiorespiratory arrest in the ZYTIGA arms and 3 (0.3%) deaths in the placebo arms. Myocardial ischemia or myocardial infarction led to death in 3 patients in the placebo arms and 2 deaths in the ZYTIGA arms.

Post Marketing Experience The following additional adverse reactions have been identified during post approval use of ZYTIGA. 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.

Respiratory, Thoracic and Mediastinal Disorders: non-infectious pneumonitis.

DRUG INTERACTIONS Drugs that Inhibit or Induce CYP3A4 Enzymes: Based on in vitro data, ZYTIGA is a substrate of CYP3A4.

In a dedicated drug interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%. Avoid concomitant strong CYP3A4 inducers during ZYTIGA treatment. If a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA dosing frequency [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) in full Prescribing Information].

In a dedicated drug interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone [see Clinical Pharmacology (12.3) in full Prescribing Information].

Effects of Abiraterone on Drug Metabolizing Enzymes: ZYTIGA is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. In a CYP2D6 drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively, when

ZYTIGA® (abiraterone acetate) Tablets

ZYTIGA® (abiraterone acetate) Tablets

dextromethorphan was given with abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily. Avoid co-administration of abiraterone acetate with substrates of CYP2D6 with a narrow therapeutic index (e.g., thioridazine).

If alternative treatments cannot be used, exercise caution and consider a dose reduction of the concomitant CYP2D6 substrate drug [see Clinical Pharmacology (12.3) in full Prescribing Information].

In vitro, ZYTIGA inhibits CYP2C8. There are no clinical data on the use of ZYTIGA with drugs that are substrates of CYP2C8. However, patients should be monitored closely for signs of toxicity related to the CYP2C8 substrate if used concomitantly with abiraterone acetate.

Patients with Renal Impairment: In a dedicated renal impairment trial, the mean PK parameters were comparable between healthy subjects with normal renal function (N=8) and those with end stage renal disease (ESRD) on hemodialysis (N=8) after a single oral 1,000 mg dose of ZYTIGA. No dosage adjustment is necessary for patients with renal impairment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

OVERDOSAGE Human experience of overdose with ZYTIGA is limited.

There is no specific antidote. In the event of an overdose, stop ZYTIGA, undertake general supportive measures, including monitoring for arrhythmias and cardiac failure and assess liver function.

Storage and Handling: Store at 20°C to 25°C (68°F to 77°F); excursions permitted in the range from 15°C to 30°C (59°F to 86°F) [see USP controlled room temperature].

Based on its mechanism of action, ZYTIGA may harm a developing fetus.

Therefore, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves [see Use in Specific Populations].

PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information) • Patients should be informed that ZYTIGA and prednisone are used together and that they should not interrupt or stop either of these medications without consulting their physician.

• Patients receiving GnRH agonists should be informed that they need to maintain this treatment during the course of treatment with ZYTIGA and prednisone.

• Patients should be informed that ZYTIGA must not be taken with food and that no food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. They should be informed that the tablets should be swallowed whole with water without crushing or chewing. Patients should be informed that taking ZYTIGA with food causes increased exposure and this may result in adverse reactions.

• Patients should be informed that ZYTIGA is taken once daily and prednisone is taken twice daily according to their physician’s instructions.

• Patients should be informed that in the event of a missed daily dose of ZYTIGA or prednisone, they should take their normal dose the following day. If more than one daily dose is skipped, patients should be told to inform their physician.

• Patients should be apprised of the common side effects associated with ZYTIGA, including peripheral edema, hypokalemia, hypertension, elevated liver function tests, and urinary tract infection. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION. • Patients should be advised that their liver function will be monitored using blood tests.

• Patients should be informed that ZYTIGA may harm a developing fetus; thus, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves. Patients should also be informed that it is not known whether abiraterone or its metabolites are present in semen and they should use a condom if having sex with a pregnant woman. The patient should use a condom and another effective method of birth control if he is having sex with a woman of child-bearing potential. These measures are required during and for one week after treatment with ZYTIGA.

USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category X [see Contraindications].: ZYTIGA can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. While there are no adequate and well-controlled studies with ZYTIGA in pregnant women and ZYTIGA is not indicated for use in women, it is important to know that maternal use of a CYP17 inhibitor could affect development of the fetus. Abiraterone acetate caused developmental toxicity in pregnant rats at exposures that were lower than in patients receiving the recommended dose. ZYTIGA is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with ZYTIGA. In an embryo-fetal developmental toxicity study in rats, abiraterone acetate caused developmental toxicity when administered at oral doses of 10, 30 or 100 mg/kg/day throughout the period of organogenesis (gestational days 6-17). Findings included embryo-fetal lethality (increased post implantation loss and resorptions and decreased number of live fetuses), fetal developmental delay (skeletal effects) and urogenital effects (bilateral ureter dilation) at doses ≥10 mg/kg/day, decreased fetal ano-genital distance at ≥30 mg/kg/day, and decreased fetal body weight at 100 mg/kg/day. Doses ≥10 mg/kg/day caused maternal toxicity. The doses tested in rats resulted in systemic exposures (AUC) approximately 0.03, 0.1 and 0.3 times, respectively, the AUC in patients.

Nursing Mothers: ZYTIGA is not indicated for use in women. It is not known if abiraterone acetate 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 ZYTIGA, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother.

Pediatric Use: Safety and effectiveness of ZYTIGA in pediatric patients have not been established.

Geriatric Use: Of the total number of patients receiving ZYTIGA in phase 3 trials, 73% of patients were 65 years and over and 30% were 75 years and over. No overall differences in safety or effectiveness were observed between these elderly patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Patients with Hepatic Impairment: The pharmacokinetics of abiraterone were examined in subjects with baseline mild (n=8) or moderate (n=8) hepatic impairment (Child-Pugh Class A and B, respectively) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone after a single oral 1,000 mg dose of ZYTIGA increased by approximately 1.1-fold and 3.6-fold in subjects with mild and moderate baseline hepatic impairment, respectively compared to subjects with normal hepatic function.

In another trial, the pharmacokinetics of abiraterone were examined in subjects with baseline severe (n=8) hepatic impairment (Child-Pugh Class C) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone increased by approximately 7-fold and the fraction of free drug increased 2-fold in subjects with severe baseline hepatic impairment compared to subjects with normal hepatic function.

No dosage adjustment is necessary for patients with baseline mild hepatic impairment. In patients with baseline moderate hepatic impairment (ChildPugh Class B), reduce the recommended dose of ZYTIGA to 250 mg once daily. Do not use ZYTIGA in patients with baseline severe hepatic impairment (Child-Pugh Class C). If elevations in ALT or AST >5X ULN or total bilirubin >3X ULN occur in patients with baseline moderate hepatic impairment, discontinue ZYTIGA treatment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

For patients who develop hepatotoxicity during treatment, interruption of treatment and dosage adjustment may be required [see Dosage and Administration (2.2) in full Prescribing Information, Warnings and Precautions, and Clinical Pharmacology (12.3)] in full Prescribing Information.

f d e fi i l p ® m i s A G I T Y Z o t s s e c c A Manufactured by: Patheon Inc. Mississauga, Canada

Manufactured for: Janssen Biotech, Inc. Horsham, PA 19044 © Janssen Biotech, Inc. 2012 Revised: May 2014 015924-140528

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Before prescribing ZYTIGA® (abiraterone acetate), please see the accompanying full Prescribing Information including DOSAGE and ADMINISTRATION, WARNINGS and PRECAUTIONS. Navigator™ is a registered trademark of Engage Healthcare Communications, LLC, an affiliate of The Lynx Group. No part of these materials 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.

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Genitourinary Cancers Symposium

AR-V7 Predicts Chemotherapy Sensitivity in Metastatic Prostate Cancer

By Phoebe Starr

E

xperts are hopeful that the field of prostate cancer will soon be catching up to breast cancer and some other tumor types with regard to genomic markers.

A study featured at the 2015 Genitourinary Cancers Symposium suggests that the androgen receptor (AR) abnormality known as “AR-V7” will turn out to be a predictive marker to help in treatment selection for patients with metastatic castration-resistant prostate cancer (CRPC).

The study showed that the presence of AR-V7 in circulating tumor cells was predictive of sensitivity to chemotherapy with the taxanes docetaxel (Taxotere) and cabazitaxel (Jevtana) in men with metastatic CRPC. A previous study by the same team of researchers showed that patients whose circulating tumor cells harbored AR-V7 had primary resistance to AR-directed therapy with enzalutamide (Xtandi) and abiraterone (Zytiga); the study was published late last year (Antonarakis ES, et al. N Engl J Med. 2014;371:1028-1038).

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testing may be extremely valuable in guiding treatment decisions for men with hormone-resistant disease in the near future.”

Dr Antonarakis noted that the findings related to AR-V7 need to be validated in a prospective multicenter trial.

“AR-V7 testing may be extremely valuable in guiding treatment decisions for men with hormone-resistant disease in the near future….Taxanes may be more efficacious than AR-directed therapy in AR-V7–positive men.”

—Emmanuel S. Antonarakis, MBBCh

No commercial test for AR-V7 is currently available. These researchers and other investigators are working on developing a CLIA (Clinical Laboratory Improvement Amendments)-approved test for AR-V7, Dr Antonarakis said.

“Taxanes may be more efficacious than AR-directed therapy in AR-V7– positive men,” Dr Antonarakis stated.

“We need to prospectively validate this marker for therapy selection. The utility of the test will be greater in positive patients, if confirmed, whereas the utility in AR-V7–negative patients is not so great.”

In Search of Biomarkers Taken together, the studies suggest that patients who are AR-V7– positive should be offered chemotherapy with one of the taxanes instead of enzalutamide or abiraterone, whereas patients who are AR-V7–negative can be offered either type of therapy safely.

Lead investigator Emmanuel S. Antonarakis, MBBCh, Assistant Professor of Oncology, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, said, “We urgently need markers that predict which therapies are going to be effective, and which will not, in individual patients with prostate cancer. AR-V7

Study Details The present study included 37 men with metastatic CRPC who were initiating chemotherapy with docetaxel or enzalutamide; 17 of 37

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(46%) patients were found to be AR-V7–positive. In general, at least 33% of patients with CRPC are AR-V7–positive.

The primary end point of the study was the associations between AR-V7 status and prostate-specific antigen (PSA) response rates; a ≥50% reduc-

April 2015

tion in PSA from baseline was considered to be a positive PSA response to therapy. Other end points were progression-free survival (PFS) as measured by PSA levels and by clinical or radiographic progression.

PSA responses were achieved in 41% of AR-V7–positive and 65% of AR-V7–negative patients. The median PSA-based PFS rates were comparable between these 2 groups—4.5 months versus 6.2 months, respectively; the median PFS was also comparable: 5.1 months versus 6.9 months, respectively.

When the investigators incorporated data from their previous study of 62 men who received abiraterone or enzalutamide, clinical outcomes were superior in AR-V7–positive men who received taxanes versus abiraterone or enzalutamide, where-

Genitourinary Cancers Symposium

History of Testicular Cancer Increases Risk... Continued from the cover cancer sometime in the future.

This case-control study included approximately 180,000 men from the Surveillance, Epidemiology, and End Results registry, of whom 32,435 men had a history of testicular cancer and 147,044 had a history of melanoma. Melanoma was selected as a control cancer, because it has no known link to prostate cancer.

First Evidence for a New Biologic Link By age 80 years, 12.6% of men with a history of testicular cancer developed prostate cancer compared with only 2.8% of those with no such history, an almost 10% increase in risk. The incidence of intermediate- or high-risk prostate cancer was 5.8% in those with a history of testicular cancer versus 1.1% in those with no such history.

Overall, a history of testicular cancer was associated with a 4.7-fold increased risk for prostate cancer and a 5.2-fold increased risk for intermediate- or high-risk disease.

“This study should alert men with a history of testicular cancer to be more proactive about discussing

Maryland School of Medicine, and Director of Urologic Robotic Surgery, University of Maryland Marlene and Stewart Greenebaum Cancer Center, Baltimore.

After controlling for other risk factors for prostate cancer, including age, race, and previous radiotherapy, there was still an increased risk for prostate cancer and intermediate- and high-risk prostate cancer in men with a history of testicular cancer. However, the absolute risk for developing intermediate- or high-risk cancer was relatively low, Dr Siddiqui pointed out—approximately 5.8%.

“Ninety-five percent of men who have had testicular cancer will not develop aggressive prostate cancer,” he said. Nevertheless, the results should encourage close follow-up of men who have had testicular cancer, he noted.

“This study is suggestive, and we need further validation studies to establish this association with certainty,” Dr Siddiqui said. He emphasized his hopes that these findings will prompt further research on the biologic link between these 2 diseases. l

“This study should alert men with a history of testicular cancer to be more proactive about discussing screening for prostate cancer risk with their doctors.”

—Mohummad Minhaj Siddiqui, MD

screening for prostate cancer risk with their doctors,” said senior study investigator Mohummad Minhaj Siddiqui, MD, of the University of

AR-V7 Predicts Chemotherapy... Continued from page 24 as outcomes were not significantly different for AR-V7–negative men who received either type of therapy.

A striking difference in PSA response was observed between the 2 types of therapy in AR-V7–positive men; 41% of patients showed positive response with the taxanes versus 0% (P <.001) with enzalutamide or abiraterone.

The median PSA-based PFS and the median PFS were significantly

longer in AR-V7–positive men who received taxanes (P = .001 and P = .003, respectively).

“The AR-V7 biomarker is better at separating patients requiring AR-directed therapy versus chemotherapy. If a patient is AR-V7–positive, he has a greater chance of progression on enzalutamide or abiraterone compared with taxanes.

In fact, he has a 79% lower chance of progression on a taxane and a 4.8-fold

greater increase in risk of progression on enzalutamide or abiraterone,” Dr Antonarakis commented. “In ARV7–negative patients, there is no difference in PFS between taxanes or AR-directed therapy.”

According to these results, the presence of AR-V7 in circulating tumor cells is not associated with primary resistance to the taxanes; it is, however, associated with primary resistance to AR-directed therapy. l

Urology Practice Management is available online at: www.UroPracticeManagement.com

April 2015

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FOR UROLOGISTS, PRACTICE MANAGERS, FINANCIAL COUNSELORS, AND REIMBURSEMENT SPECIALISTS™

Call for Papers

Do you have a practice management story to share

?

In your background as a urology practice manager, it’s likely there’s one business experience—and maybe more—that practice managers across the nation would want to read about.

High-interest topics include: the solution you found to a practice management challenge, reimbursement, your experience with EMR, Medicare audits, a memorable encounter that shaped the way you now run your business and/or practice medicine, or how you successfully integrated ancillary products and services into your practice as a revenue generator.

Send us your ideas!

Submit a 600- to 1500-word original article to Urology Practice Management that your fellow practice managers will want to read.

Submit to: info@the-lynx-group.com UPM_73114

?

Genitourinary Cancers Symposium

Caution: Active Surveillance Ill Advised in Men with Intermediate-Risk Prostate Cancer

By Phoebe Starr

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ctive surveillance is sometimes used as management strategy in patients with intermediate-risk prostate cancer, especially in older, sicker men with short life expectancy. A new study validates the use of active surveillance for men with low-risk prostate cancer but provides sobering data regarding this type of management for those with intermediate-risk prostate cancer. The study results were presented at the 2015 Genitourinary Cancers Symposium.

Surveillance Can Increase Mortality The study findings showed that intermediate-risk patients had almost a 4-fold higher risk for dying from prostate cancer compared with patients with low-risk prostate cancer when managed by active surveillance.

“This is the first study to analyze long-term outcomes of intermediate-risk patients managed by active surveillance. This study validates active surveillance for low-risk patients with prostate cancer. We were surprised by the greater risk of prostate cancer death in the intermediate-risk patients assigned to active surveillance,” stated senior investigator, D. Andrew Loblaw, MD, MSc, of the Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.

Lead investigator Hima Bindu Musunuru, MD, of the Sunnybrook Health Sciences Centre, said, “Extreme caution should be exercised if active surveillance were to be implemented for intermediate-risk patients.”

Dr Loblaw said that further study is needed to define favorable versus unfavorable intermediate-risk patients.

“We think there may be a subgroup of intermediate-risk patients out there

ate-risk group, and 98.2% and 96.3%, respectively, for the low-risk patients (P = .006).

Just under 66% of the intermediate-risk patients were aged >70 years. In the study, active surveillance was offered to men with shorter life expectancy and comorbidities, which is in line with the current National Comprehensive Cancer Network guidelines.

The risk for dying from any cause

who may be safely managed by active surveillance,” he stated.

Study Details The prospective study included 945 patients with prostate cancer who were managed with active surveillance between 1995 and 2013 at Sunnybrook Health Sciences Centre; 237 (23.9%) patients had intermediate-risk disease and a median follow-up of 6.9 years, and 708 pa-

“This study validates active surveillance for low-risk patients with prostate cancer. We were surprised by the greater risk of prostate cancer death.”

—D. Andrew Loblaw, MD, MSc

tients had low-risk prostate cancer and a median follow-up of 6.4 years.

The median treatment-free interval for intermediate-risk patients was 12.3 years.

Patients with progressive disease, as reflected by a prostate-specific antigen doubling time of <3 years, were offered radiation or surgery; 86 patients with intermediate-risk prostate cancer received treatment.

For patients with intermediate-risk prostate cancer, the 10- and 15-year overall survival rates were 68.4% and 50.3%, respectively, versus 83.6% and 68.8%, respectively, for low-risk patients (P <.001).

The 10- and 15-year cancer-specific survival was 95.5% and 88.5%, respectively, for the intermedi-

April 2015

was twice as high for intermediate-risk patients compared with lowrisk patients. Moreover, the risk for prostate cancer–specific death at 15 years was 3.75 times higher for intermediate-risk patients compared with low-risk patients at the same time point (11.5% vs 3.7%, respectively).

Future Research The field of molecular and biological markers for intermediate-risk prostate cancer is an active area of investigation, according to Dr Loblaw and American Society of Clinical Oncology Expert and 2015 Genitourinary Cancers Symposium News Planning Committee team member Charles Ryan, MD, of the University of California, San Francisco. l

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Clinical Trial Tracker

Trials Under Way for Patients with Benign Prostatic Hyperplasia

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he following clinical trials are currently recruiting patients with benign prostatic hyperplasia for inclusion in several investigations. Each trial description includes the NLM Identifier to use as a reference with ClinicalTrials.gov.

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Placebo-Controlled Study of Talaporfin Sodium This phase 2, double-blind, placebo-controlled study investigates the safety and efficacy of talaporfin sodium that are activated by an intraurethrally placed drug-activating device. Patients who have symptoms of benign prostatic hyperplasia and who are aged ≥45 years, weigh ≤200 kg, have had lower urinary tract symptoms for ≥6 months, and have been stabilized for ≥6 months on 5-alpha reductase inhibitors or ≥3 months with other drugs may enroll if other criteria are met. Patients who have withdrawn from their regularly prescribed medication will require a washout period. Patients are randomized in a 2:2:1:1 ratio to receive a single treatment of talaporfin sodium or saline placebo activated at either a higher or lower dose of light.

The primary outcome is the International Prostate Symptom Score at 12 weeks, measured as the score change from baseline. Secondary outcome measures include the Modified International Prostate Symptom Score, Patient and Clinical Global Impressions of Improvement, and quality of life. The maximum urinary flow rate, postvoid residual volume, 3-day frequency/volume data, and serum prostate-specific antigen levels are also collected. This study is expected to enroll 192 patients in Anchorage, AK, and Pompano Beach, FL. For more information, contact

Maggie Wilson or Sally Rooney at info@contact-clinical-­trials.com. The NLM Identifier is NCT02326454.

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Postmarketing Study Using Prolieve The objective of this phase 4, open-label, single-group assignment study is to collect safety and effectiveness data for 5 years in patients who are treated with Prolieve, a transurethral microwave therapy device. This data will provide information on long-term treatment effects and time to retreatment. Patients aged ≥18 years with a peak urine flow rate of <12 mL/sec on voided volume of >125 mL and an American Urological Association (AUA) Symptom Score of ≥9 many enroll if other criteria are met. All patients will receive Prolieve throughout the study.

The primary outcome is the time to retreatment estimated over 5 years. The secondary outcome is the change from baseline in AUA total score at 5 years, based on the number of patients who worsened, had no change (1%-29%), or had ≥30% improvement. A responder analysis will also be conducted on the peak flow rate of each category. This trial is expected to enroll 250 patients at locations throughout the United States. For more information, contact Perry Weiner, DO, FACOS, at 215-503-3300. The NLM Identifier is NCT02021032.

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Prostate Artery Embolization versus TURP This phase 3, randomized, open-label, parallel-assignment study evaluates symptom improvement in patients who receive prostatic artery embolization (PAE) using Embosphere Microspheres versus conventional transurethral resection of the

prostate (TURP). Patients aged 50 to 79 years with lower urinary tract symptoms secondary to benign pro­ static hyperplasia for ≥6 months before study treatment, who are refractory to medical treatment or for whom medication is contraindicated, and who have a baseline International Prostate Symptom Score of >13 and a prostate size of 50 to 90 g may enroll if other criteria are met.

Patients are randomized to receive either PAE or TURP. The primary outcome measure is International Prostate Symptom Score improvement at 12 months postprocedure. Secondary outcome measures include the duration of hospitalization postprocedure, duration of postprocedure catheterization, adverse events, and safety.

Other measured outcomes include the change from baseline in peak urine flow rate, erectile function, mean prostate volume, postvoid residual urinary volume, detrusor muscle pressure, and prostate-specific antigen. This study is expected to enroll 186 patients at sites throughout the United States. For more information, contact Melodie Domurad, PhD, at 781-681-7900 or best@ merit.com. The NLM Identifier is NCT01789840.

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Prostate Artery Embolization Patients The objective of this phase 2, open-label, single-group assignment study is to evaluate the safety and efficacy of PAE for the treatment of benign prostatic hyperplasia in patients who have a prostate size >90 g as measured by transrectal ultrasound (TRUS), and who experience lower urinary tract symptoms. Patients aged 50 to 85 years who have an International Prostate Symptom Score Continued on page 30

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Oncology Providers Practice and Personalized Medicine Trends

Barbara L. McAneny, MD Chair, Board of Trustees American Medical Association

Sanjiv S. Agarwala, MD Professor of Medicine Temple University School of Medicine Chief, Medical Oncology & Hematology St. Luke’s Cancer Center

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MAY 5, 2015

7:00 am – 8:00 am

Meet the Experts Breakfast

8:00 am – 8:15 am

Introduction and Opening Remarks Barbara L. McAneny, MD, American Medical Association Sanjiv S. Agarwala, MD, Temple University School of Medicine

8:15 am – 9:15 am

Session 1 - Win-Win-Win Approaches to Oncology Care: How Providers, Patients, and Payers Can All Benefit from Improving the Way We Pay for Cancer Treatment Harold Miller, Center for Healthcare Quality and Payment Reform

1:15 pm – 2:00 pm

Session 6 - Keynote Session Value-Based Cancer Care: How Do We Get There in the ’Omics Era? Gary Palmer, MD, JD, MBA, MPH, Nanthealth

2:00 pm – 2:45 pm

Session 7 - Can We Afford Personalized Medicine?

Michael Kolodziej, MD, Aetna

2:45 pm – 3:30 pm

Session 8 - The Precision Medicine Initiative: Deliverables from Those on the Front Lines of Personalizing Care Harold Varmus, MD, National Cancer Institute (Invited)

3:30 pm – 4:15 pm

Session 9 - Adapting Regulation to Meet the Needs of the Exponential Growth of the Molecular Testing Era Victoria Pratt, MD (Invited)

4:15 pm – 5:00 pm

Session 10 - Role of Pathologist in the Age of Personalized Medicine Pranil Chandra, DO, PathGroup (Invited)

5:00 pm – 5:45 pm

Session 11 - The Role of Immunotherapy in Personalizing Treatment James Allison, PhD, MD Anderson Cancer Center (Invited)

9:15 am – 10:00 am

Session 2 - Pitfalls or Challenges of New Payment Models Bruce Pyenson, Milliman

10:00 am – 10:15 am

Break

10:15 am – 11:00 am

Session 3 - Oncology Medical Home – A Patient-Centric System for Delivering Quality Cancer Care Barbara L. McAneny, MD, American Medical Association

11:00 am – 11:45 am

Session 4 - FDA on Testing and Personalized Medicine Speaker TBD

11:45 am – 12:15 pm

Session 5 - Revamping Research Raju Kucherlapati, PhD, Harvard Medical School

5:45 pm – 6:00 pm

Poster Award Q & A

12:15 pm – 1:15 pm

Networking Lunch in Exhibit Hall or Sponsored Lunch Presentation

6:00 pm – 6:15 pm

Closing Remarks

6:15 pm – 8:15 pm

Reception in Exhibit Hall

*Agenda subject to change.

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Trials Under Way for Patients... Continued from page 28 of ≥13, a peak urine flow rate of <12 mL/sec, who refuse surgical treatment, and who are refractory to or contraindicated for medical treatment may enroll if other criteria are met. All patients will receive PAE with Embosphere Microspheres within 4 weeks of the TRUS. The primary outcome measure is the improvement of disease symptoms as assessed by the International Prostate Symptom Score at 12 months postembolization. Safety will be evaluated throughout the initial 12 months of the study by assessing adverse events and findings on physical examination. Follow-up visits will be conducted at 1, 3, 6, and 12 months after PAE. Repeat TRUS and urodynamic tests are conducted at 6- and 12-month follow-up visits.

This trial is expected to enroll 30 patients at Tampa General Hospital, FL. For more information, contact Haydy Rojas, RN, at 813-844-5012 or hrojas@tgh.org. The NLM Identifier is NCT02167009.

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Prostate Embolization for Benign Prostatic Hyperplasia The purpose of this phase 1/2, open-label, prospective, single-­ group observational study is to determine the safety of PAE for patients with benign prostatic hyperplasia. Patients aged 50 to 90 years with symptomatic disease for ≥6

months with a prostate enlargement of 50 to 100 cc, and who have symptoms and urinary flow rates that meet entrance criteria may enroll if other conditions are met. All patients will receive embolization with Embosphere Microspheres sized at 300 to 500 μm.

Primary outcomes measure the evidence of bladder or rectal ischemic injury 1 week after PAE, and detection of bladder or rectal ischemic injury at 3, 6, and 12 months postprocedure; both are assessed via cystoscopy. Patients who experience an adverse event will be scored using Society of Interventional Radiology definitions. Secondary outcomes include improvement in International Prostate Symptom Score, International Index of Erectile Function, and uroflowmetry postembolization at 3, 6, and 12 months, and then annually for 5 years posttreatment.

Measurements of the prostate volume, serum prostate-specific antigen, procedure time and radiation parameters, and the percentage of prostate tissue that is devascularized are also collected. This study is expected to enroll 30 patients at MedStar Georgetown University Hospital in Washington, DC. For more information, contact Angela White at 202444-6825 or amwd@gunet.george town.edu. The NLM Identifier is NCT01924988.

ANNUAL CONFERENCE

M AY 3-6, 2015 Omni Shoreham Hotel Washington, DC

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OnaBoNT-A (Botox) versus Oral Tamsulosin This phase 2, double-blind, placebo-controlled study compares the treatment effects of onaBoNT-A 200 U versus oral tamsulosin 0.4 mg in veterans who are diagnosed with moderate-to-severe lower urinary tract symptoms associated with benign prostatic hyperplasia. This investigation will assess whether onaBoNT-A shows potential for treating this condition. Males aged ≥50 years with voided volume >125 mL and a maximum urinary flow rate of <15 mL/sec may enroll if other criteria are met. Patients will be randomized to an onaBoNT-A 1-time injection with placebo oral capsules, or a normal saline 1-time injection into the prostate and tamsulosin 0.4-mg oral capsules. There will be 5 clinic visits and 2 telephone follow-ups throughout the study.

The primary outcome is the AUA Symptom Score measured for a time frame of 3 months. This trial is expected to enroll 74 patients at the Michael E. DeBakey VA Medical Center in Houston, TX. For more information, contact Sebrina A. Tello at 713-791-1414 (extension 25326) or sebrina.tello@va.gov, or Christopher P. Smith, MD, at 713791-1414 or christopherp.smith@ va.gov. The NLM Identifier is NCT01589263. l

Patient and Provider Access

Bringing the Oncology Care Model into Focus

By Leah Ralph, Manager, Provider Economics and Public Policy, Association of Community Cancer Centers

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n February 12, the US Department of Health & Human Services announced its much-anticipated Oncology Care Model, developed by the Centers for Medicare & Medicaid (CMS) Innovation Center as part of the broader effort to lower healthcare costs and tie reimbursement to quality and value. The Association of Community Cancer Centers has been conducting an in-depth analysis, and the model generally looks similar to the discussion draft made available in August last year; although the model contains many positive elements, many questions still remain.

At its core, the Oncology Care Model looks similar to a patient-­ centered oncology medical home or accountable care organization, with a target expenditure and shared savings component that encompasses the total cost of patient care during a particular period of treatment. The model is a voluntary, 5-year program slated to begin in spring 2016. Physician group practices, hospital-based practices (except for prospective payment system–exempt hospitals), and solo practitioners who furnish cancer chemotherapy are eligible to participate.

Payments will be based on a 6-month episode of chemotherapy treatment that is triggered by the administration of a preset list of chemotherapy drugs, and will take into account all Part A and Part B, and some Part D expenditures for that patient during the episode. In addition to a fee-for-service payment, providers will receive a care coordination payment to improve quality of care ($160 per patient, per month during the episode) and, to incentivize lower costs, a perfor-

quirements, including effective use of electronic health records, providing 24-hour access to practitioners who can consult the patient’s medical record in real time, developing comprehensive patient care plans, offering patient navigation services, and targeting continuous quality improvement.

Although we were pleased to see much of the Association of Community Cancer Centers’ feedback incorporated into the final version of this model—and we appreciated the opportunity to provide meaningful input before the model was finalized—our dialogue with CMS is ongoing. Our members continue to have questions about the benchmarking methodology, specifics on

mance-based payment that will be based on the difference between a risk-adjusted target price and actual expenditures during the episode.

The payment arrangement is 1-sided risk, with the option of converting to a 2-sided risk in the third year.

At its core, the Oncology Care Model looks similar to a patient-centered oncology medical home or accountable care organization, with a target expenditure and shared savings component that encompasses the total cost of patient care during a particular period of treatment.

Importantly, the care model is a multipayer model in which commercial payers and state Medicaid agencies are encouraged to participate. Aligning financial incentives by engaging multiple payers will leverage the opportunity to transform oncology care across a broader population. During its process of selecting practices to participate, CMS will favor those that participate with other payers in addition to Medicare. Practices will also have to meet certain quality metrics and undergo practice transformation re-

April 2015

the quality metrics and practice transformation requirements, eligibility to participate in the model, and more. We continue to work with CMS to secure answers to these questions.

If your practice is interested in participating, or considering participation, we encourage you to submit a nonbinding letter of intent to CMS by the deadline of May 7, 2015. We anticipate that CMS will continue to provide additional guidance until the final application deadline of June 18, 2015. l

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Wealth Management

Why You Need Disability Insurance: A Doctor’s Story

By Stuart E. Lowenkron, MD, Associate, Physician Financial Services

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embers of the medical profession sacrifice their time and energy without reservation for the care of patients. All too often, however, it is done to the detriment of themselves and their families—especially in the areas of personal financial planning. Many physicians opine the cost of the various insurance policies we purchase, whether life insurance, homeowners insurance, or disability insurance.

We forget, as I almost did, that we need these policies to protect our most valuable asset: our ability to earn an income.

Early Career In the early 1990s I was completing my fellowship. The future seemed bright, and it was time to take the first steps toward short-term and long-term planning for my family. At that early stage of my career, I thought there would be plenty of time to take care of these things. Since I was still relatively young and in good health, I wanted to concentrate on the present, and the future would take care of itself. At the urging of my personal and financial advisors, however, I purchased life insurance and disabil­ ity insurance, and began putting money into tax-deferred accounts for

the future. Unbeknownst to me, taking these steps, or more specifically, purchasing my disability insurance policy, would be among the most important and smartest decisions I would ever make.

Purchasing my disability insurance policy would be among the most important and smartest decisions I would ever make.

Upon completion of my residency and fellowship training, I uprooted my young family to a small Southern town, where I had been recruited to set up shop as a specialist. Within 3 years, I had a thriving practice and started to build a comfortable lifestyle for myself and my family. Two years later, though, it was gone: my home, my family as a result of divorce, my practice, my money, and my friends.

The primary reason was my health. I had begun to suffer from major depression, a disease that would follow me and impact the rest of my life.

Depression: Facts and Figures n Depression affects nearly 1 in 10 adults each year, and women are more likely to experience the disorder than men n Biochemistry, genetic, personality, and environmental factors can all play roles in a person’s depression n For a diagnosis of depression, symptoms must last for ≥2 weeks n Depression is one of the most treatable mental disorders, with 80% to 90% of people with depression eventually responding well to treatment.

Source: American Psychiatric Association.

The Impact of Depression For me, depression has manifested in a number of ways, including profound sadness and severe fatigue, often with an inability to get out of bed.

Difficulty concentrating would result in mental paralysis, often impairing my ability to perform even the simplest of tasks. Taking care of patients always seemed to be the easy part of my job, but dealing with my depression and taking care of myself was a different story. I have been battling this disease a good part of my life, have been in and out of treatment and taking medication since I was in my 20s, and it has been an exhausting mental and physical endeavor.

The most significant of all the problems at the onset of the disease and at points throughout my medical career was an inability to work, with subsequent loss of income and the inability to support and care for myself and my family. In my third year of private practice, my health deteriorated significantly. I finally reached a point where I became overwhelmed and “paralyzed”; I was unable to work, and eventually I had to give up my practice. All of a sudden I had no income and an overwhelming number of problems, and I was barely able to function due to serious depression.

The Silver Lining Despite these problems, I had 2 things going for me that essentially saved me. First, when I bought my disability and life insurance policies, I began a relationship with the agent who sold them to me that has lasted more than 20 years. He did not just sell me a policy and disappear. He kept in touch with me to see how things were going and whether there was anything else he could help me Continued on page 34

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Government and Employer Trends

Jayson Slotnik, JD, MPH Partner Health Policy Strategies, Inc

F. Randy Vogenberg, PhD, RPh Principal Institute for Integrated Healthcare (IIH)

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*

MAY 6, 2015

7:00 am – 8:00 am

Meet the Experts Breakfast

8:00 am – 8:15 am

Introduction and Opening Remarks Jayson Slotnik, JD, MPH, Health Policy Strategies, Inc F. Randy Vogenberg, PhD, RPh, Institute for Integrated Healthcare

8:15 am – 9:00 am

Session 1 - Oncology Bundled Payments Speaker TBD

9:00 am – 9:45 am

Session 2 - Media Coverage Oncology Panel Speaker TBD

9:45 am – 10:00 am

Break

10:00 am – 10:45 am

Session 3 - Actuary View and Future Market Landscape Speaker TBD

10:45 am – 11:30 am

Session 4 - Coverage Parameter Trends in Health Benefits Impacting Oncology Speaker TBD

11:30 am – 12:15 pm

12:15 pm – 1:15 pm

Networking Lunch in Exhibit Hall or Sponsored Lunch Presentation

1:15 pm – 2:00 pm

Session 6 - Private Health Exchanges Laurel Pickering, Northeast Business Group on Health

2:00 pm – 2:45 pm

Session 7 - Onsite and Retail Clinic Services Expansion Larry Boress, Midwest Business Group on Health

2:45 pm – 3:30 pm

Session 8 - Group Health Benefits 2016 and Beyond Brian Klepper, PhD, National Business Coalition on Health

3:30 pm – 4:15 pm

Session 9 - Panel Discussion: Patient Engagement Patrick McKercher, PhD, Patient Assistance Network Foundation

4:15 pm – 4:30 pm

Closing Remarks

*Agenda subject to change.

Session 5 - Keynote Session – 21st-Century Cures Speaker TBD

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Wealth Management

Why You Need Disability Insurance... Continued from page 32 with; he ultimately became a loyal friend. In fact, it was he who reminded me about the second thing I had going for me: the disability insurance policy that I had not wanted to purchase several years before.

The insurance policies that I complained about having to purchase, believing I was probably never going to need them, became of utmost importance. Like most physicians who deal with disabled patients, I found it hard to believe that I had become one of them. The monthly income from my disability insurance policy saved my life.

After a few years, I felt I was ready to return to work. I would need to

return to employment as a new employee of either a hospital or some-

The insurance policies that I complained about having to purchase became of utmost importance. one’s private practice. How would I make it work financially? I was residing in an area with a higher cost of living; I had remarried and was granted custody of my children. I

also needed to purchase a home. It appeared that if I wanted to continue to live where I was, I was going to have to work for a lot less money than I had been earning previously.

With income from my disability insurance policy, I able to do this once again. It contained a rider that would pay benefits, proportionate to my loss of income, even though I was still working in my original field (see related article on this page). Although I believed I was no longer sick, my income was. With a little lifestyle adjustment, the salary I would earn plus the supplemental income I received from my disability policy allowed me to take a job at a

Disability Insurance: Deciphering the COLA Rider

By Lawrence B. Keller, CFP®, CLU®, ChFC®, RHU®, LUTCF

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f you are unable to work due to a sickness or injury, disability insurance can help you meet your expenses and maintain your standard of living. One of the options available when purchasing an individual disability insurance policy is the cost of living adjustment (COLA) rider.

What Is the COLA Rider?

The COLA rider is designed to help your disability insurance benefit keep pace with inflation. These riders generally adjust your policy’s monthly benefit on an annual basis, based on a fixed percentage or tied to the consumer price index after you have been disabled for 12 months. These adjustments apply to total and residual disabilities and can be based on a simple or compound basis. Although expensive, this rider can provide signifi-

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cant increases to your monthly benefit if you are disabled early in your career.

Is the COLA Rider Worth Purchasing?

My general rule is that the younger you are and the fewer assets you have accumulated, the more impor­tant the COLA rider is and the more it should be part of your policy. However, if you are not opting for the maximum

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amount of coverage that you qualify for based upon your earned income, you should consider removing the COLA rider and using the dollars you would have allocated to the COLA rider to purchase a larger monthly benefit. Remember, the COLA rider will not increase your monthly benefit until you have been disabled for 12 months. Therefore, if you are not disabled for a long-term period, and have been paying premiums for a COLA rider, you may not realize much of an economic benefit from the rider.

Do the Math Assume that you are a 35-yearold male hematologist–oncologist in New York earning $290,000 per year. You were planning to purchase $10,000 per month of individual coverage from an established

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hospital, followed by a move back into private practice. Both paid well below what I needed, but I was able to support my family until my salary increased to something more in line with my cost of living.

A New Beginning Unfortunately, after working fulltime for 6 more years, I once again became too sick to work and had to claim total disability. After about a year and a half, and much discussion with family, friends, and medical professionals, I made a life-changing decision: I changed professions. Although I would always be a doctor, my medical condition would no longer allow me to actively practice clinical medicine, and I changed course to some-

insurance company (you qualified for $13,000 per month, but wanted to reduce your premium outlay), payable after 90 days of disability to age 65 years with an enhanced residual disability rider and a 3% compound COLA rider. The monthly premium would be $267, including a 10% association discount. If you removed the COLA rider, the monthly premium would be reduced to $203; this is a savings of $64, or approximately 24% of the cost of the policy.

If you took that premium savings, how much additional monthly benefit would that allow you to purchase? A policy for $13,000 per month, payable after 90 days to age 65 years would have a monthly premium of $262, including a 10% association discount. This is almost identical to the premium for the $10,000 monthly benefit with the COLA rider included.

In this scenario, does it make sense to forgo the COLA rider?

What is the break-even period?

That is easy to calculate. If you

thing that would provide a more favorable work environment.

I now devote my time and energy, using my experience, to make sure physicians and other healthcare professionals have the same type of income protection in place. Life has taught me a valuable lesson. Unfortunately, in the medical profession, we are too busy or do not realize that taking steps early in our career can help us avoid mistakes that can be financially devastating. Thankfully, my disability insurance policy contained a valuable “own occupation” definition of total disability that allows me to continue to receive monthly income until age 65 years, regardless of my ability to work in another profession. In addition, my benefits also in-

crease annually due to the cost of living rider that I purchased.

I am now, once again, able to provide for my family while working in a profession more conducive to my medical issues. Without my disability policy, which I did not want to buy and cursed every time I paid a premium, I do not know how my family and I would have survived. I am so glad I never had to find out. l Stuart E. Lowenkron, MD, is an associate of Physician Financial Services, a New York–based firm specializing in income protection and wealth accumulation strategies for physicians. He can be reached at (800) 481-6447 or by e-mail to Slowenkronmd@physicianfinancial services.com with comments or questions.

took $10,000 monthly and invested it at a 3% compound rate of return, in 10 years (1 year of disability plus 9 years of investing at 3%), the $10,000 would grow to $13,048.

By the same token, if you purchased a policy with a $10,000 monthly benefit and a 3% compound COLA rider, the maximum potential benefit for total disability (assuming a total disability began on the effective date of the policy and continued until the age of 65 years) would be $5.70 million. If you purchased a policy with a $13,000 monthly benefit and no COLA rider, the maximum potential benefit for the same disability would be $4.64 million.

Ideally, should you decide to purchase the COLA rider, I would suggest one that is compounded, and the higher the maximum is the better, taking overall policy premiums into consideration.

While the example above utilized the sample company’s 3% compound COLA rider, a similar anal-

April 2015

ysis can easily be done for most insurance companies.

Summary The COLA rider is designed to help your disability insurance benefits keep pace with inflation. Generally, the younger you are and the fewer assets you have accumulated, the more important the COLA rider is and the more it should be part of your policy. However, if you are not opting for the maximum amount of coverage that you qualify for based upon your earned income, you should consider removing the COLA rider and using the dollars you would have allocated to the COLA rider to purchase a larger monthly benefit. l Lawrence B. Keller, CFP®, CLU®, ChFC®, RHU®, LUTCF, is the founder of Physician Financial Services, a New York–based firm specializing in income protection and wealth accumulation strategies for physicians. He can be reached at 800-481-6447 or by e-mail to Lkeller@physician financialservices.com.

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ZYTIGA® (abiraterone acetate) Tablets Brief Summary of Prescribing Information.

INDICATIONS AND USAGE ZYTIGA is a CYP17 inhibitor indicated in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer.

CONTRAINDICATIONS Pregnancy: ZYTIGA can cause fetal harm when administered to a pregnant woman. ZYTIGA is not indicated for use in women. ZYTIGA is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss [see Use in Specific Populations].

WARNINGS AND PRECAUTIONS Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess: ZYTIGA may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see Clinical Pharmacology (12.1) in full Prescribing Information].

In the two randomized clinical trials, grade 3 to 4 hypertension occurred in 2% of patients, grade 3 to 4 hypokalemia in 4% of patients, and grade 3 to 4 edema in 1% of patients treated with ZYTIGA [see Adverse Reactions].

Co-administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in the incidence and severity of these adverse reactions. Use caution when treating patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia or fluid retention, e.g., those with heart failure, recent myocardial infarction or ventricular arrhythmia. Use ZYTIGA with caution in patients with a history of cardiovascular disease. The safety of ZYTIGA in patients with left ventricular ejection fraction <50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in Study 2) was not established because these patients were excluded from these randomized clinical trials [see Clinical Studies (14) in full Prescribing Information]. Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment with ZYTIGA. Adrenocortical Insufficiency: Adrenal insufficiency occurred in the two randomized clinical studies in 0.5% of patients taking ZYTIGA and in 0.2% of patients taking placebo. Adrenocortical insufficiency was reported in patients receiving ZYTIGA in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations [see Warnings and Precautions].

Hepatotoxicity: In the two randomized clinical trials, grade 3 or 4 ALT or AST increases (at least 5X ULN) were reported in 4% of patients who received ZYTIGA, typically during the first 3 months after starting treatment. Patients whose baseline ALT or AST were elevated were more likely to experience liver test elevation than those beginning with normal values. Treatment discontinuation due to liver enzyme increases occurred in 1% of patients taking ZYTIGA. No deaths clearly related to ZYTIGA were reported due to hepatotoxicity events.

Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA, every two weeks for the first three months of treatment and monthly thereafter. In patients with baseline moderate hepatic impairment receiving a reduced ZYTIGA dose of 250 mg, measure ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every two weeks for the following two months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop.

Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the ULN, or the bilirubin rises above three times the ULN, interrupt ZYTIGA treatment and closely monitor liver function.

Re-treatment with ZYTIGA at a reduced dose level may take place only after return of liver function tests to the patient’s baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN [see Dosage and Administration (2.2) in full Prescribing Information].

The safety of ZYTIGA re-treatment of patients who develop AST or ALT greater than or equal to 20X ULN and/or bilirubin greater than or equal to 10X ULN is unknown.

Increased ZYTIGA Exposures with Food: ZYTIGA must be taken on an empty stomach. No food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state. The safety of these increased exposures when multiple doses of abiraterone acetate are taken with food has not been assessed [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

ZYTIGA® (abiraterone acetate) Tablets ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: • Hypertension, Hypokalemia, and Fluid Retention due to Mineralocorticoid Excess [see Warnings and Precautions].

• Adrenocortical Insufficiency [see Warnings and Precautions].

• Hepatotoxicity [see Warnings and Precautions].

• Increased ZYTIGA Exposures with Food [see Warnings and Precautions].

Clinical Trial 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.

Two randomized placebo-controlled, multicenter clinical trials enrolled patients who had metastatic castration-resistant prostate cancer who were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy. In both Study 1 and Study 2 ZYTIGA was administered at a dose of 1,000 mg daily in combination with prednisone 5 mg twice daily in the active treatment arms. Placebo plus prednisone 5 mg twice daily was given to control patients.

The most common adverse drug reactions (≥10%) reported in the two randomized clinical trials that occurred more commonly (>2%) in the abiraterone acetate arm were fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion.

The most common laboratory abnormalities (>20%) reported in the two randomized clinical trials that occurred more commonly (≥2%) in the abiraterone acetate arm were anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT and hypokalemia.

Study 1: Metastatic CRPC Following Chemotherapy: Study 1 enrolled 1195 patients with metastatic CRPC who had received prior docetaxel chemotherapy. Patients were not eligible if AST and/or ALT ≥2.5X ULN in the absence of liver metastases. Patients with liver metastases were excluded if AST and/or ALT >5X ULN. Table 1 shows adverse reactions on the ZYTIGA arm in Study 1 that occurred with a ≥2% absolute increase in frequency compared to placebo or were events of special interest. The median duration of treatment with ZYTIGA was 8 months.

Table 1: Adverse Reactions due to ZYTIGA in Study 1 ZYTIGA with Placebo with Prednisone (N=791) Prednisone (N=394) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % Musculoskeletal and connective tissue disorders Joint swelling/ discomfort2 29.5 4.2 23.4 4.1 Muscle discomfort3 26.2 3.0 23.1 2.3 General disorders Edema4 26.7 1.9 18.3 0.8 Vascular disorders Hot flush 19.0 0.3 16.8 0.3 Hypertension 8.5 1.3 6.9 0.3 Gastrointestinal disorders Diarrhea 17.6 0.6 13.5 1.3 Dyspepsia 6.1 0 3.3 0 Infections and infestations Urinary tract infection 11.5 2.1 7.1 0.5 Upper respiratory tract infection 5.4 0 2.5 0 Respiratory, thoracic and mediastinal disorders Cough 10.6 0 7.6 0 Renal and urinary disorders Urinary frequency 7.2 0.3 5.1 0.3 Nocturia 6.2 0 4.1 0 Injury, poisoning and procedural complications Fractures5 5.9 1.4 2.3 0 Cardiac disorders Arrhythmia6 7.2 1.1 4.6 1.0 Chest pain or chest discomfort7 3.8 0.5 2.8 0 Cardiac failure8 2.3 1.9 1.0 0.3

ZYTIGA® (abiraterone acetate) Tablets

ZYTIGA® (abiraterone acetate) Tablets

1 Adverse events graded according to CTCAE version 3.0 2 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness 3 Includes terms Muscle spasms, Musculoskeletal pain, Myalgia,

Table 3: Adverse Reactions in ≥5% of Patients on the ZYTIGA Arm in Study 2 (continued) ZYTIGA with Placebo with Prednisone (N=542) Prednisone (N=540) 1 System/Organ Class All Grades Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % Renal and urinary disorders Hematuria 10.3 1.3 5.6 0.6 Skin and subcutaneous tissue disorders Rash 8.1 0.0 3.7 0.0 1 Adverse events graded according to CTCAE version 3.0 2 Includes terms Edema peripheral, Pitting edema, and Generalized edema 3 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness

Musculoskeletal discomfort, and Musculoskeletal stiffness terms Edema, Edema peripheral, Pitting edema, and Generalized edema 5 Includes all fractures with the exception of pathological fracture 6 Includes terms Arrhythmia, Tachycardia, Atrial fibrillation, Supraventricular tachycardia, Atrial tachycardia, Ventricular tachycardia, Atrial flutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Bradyarrhythmia 7 Includes terms Angina pectoris, Chest pain, and Angina unstable.

Myocardial infarction or ischemia occurred more commonly in the placebo arm than in the ZYTIGA arm (1.3% vs. 1.1% respectively).

8 Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased 4 Includes

Table 2 shows laboratory abnormalities of interest from Study 1. Grade 3-4 low serum phosphorus (7%) and low potassium (5%) occurred at a greater than or equal to 5% rate in the ZYTIGA arm.

Table 2: Laboratory Abnormalities of Interest in Study 1 Abiraterone (N=791) Placebo (N=394) Laboratory All Grades Grade 3-4 All Grades Grade 3-4 Abnormality (%) (%) (%) (%) Hypertriglyceridemia 62.5 0.4 53.0 0 High AST 30.6 2.1 36.3 1.5 Hypokalemia 28.3 5.3 19.8 1.0 Hypophosphatemia 23.8 7.2 15.7 5.8 High ALT 11.1 1.4 10.4 0.8 High Total Bilirubin 6.6 0.1 4.6 0 Study 2: Metastatic CRPC Prior to Chemotherapy: Study 2 enrolled 1088 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy. Patients were ineligible if AST and/or ALT ≥2.5X ULN and patients were excluded if they had liver metastases.

Table 3 shows adverse reactions on the ZYTIGA arm in Study 2 that occurred with a ≥2% absolute increase in frequency compared to placebo.

The median duration of treatment with ZYTIGA was 13.8 months.

Table 3: Adverse Reactions in ≥5% of Patients on the ZYTIGA Arm in Study 2 ZYTIGA with Placebo with Prednisone (N=542) Prednisone (N=540) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % General disorders Fatigue 39.1 2.2 34.3 1.7 Edema2 25.1 0.4 20.7 1.1 Pyrexia 8.7 0.6 5.9 0.2 Musculoskeletal and connective tissue disorders Joint swelling/ discomfort3 30.3 2.0 25.2 2.0 Groin pain 6.6 0.4 4.1 0.7 Gastrointestinal disorders Constipation 23.1 0.4 19.1 0.6 Diarrhea 21.6 0.9 17.8 0.9 Dyspepsia 11.1 0.0 5.0 0.2 Vascular disorders Hot flush 22.3 0.2 18.1 0.0 Hypertension 21.6 3.9 13.1 3.0 Respiratory, thoracic and mediastinal disorders Cough 17.3 0.0 13.5 0.2 Dyspnea 11.8 2.4 9.6 0.9 Psychiatric disorders Insomnia 13.5 0.2 11.3 0.0 Injury, poisoning and procedural complications Contusion 13.3 0.0 9.1 0.0 Falls 5.9 0.0 3.3 0.0 Infections and infestations Upper respiratory tract infection 12.7 0.0 8.0 0.0 Nasopharyngitis 10.7 0.0 8.1 0.0

Table 4 shows laboratory abnormalities that occurred in greater than 15% of patients, and more frequently (>5%) in the ZYTIGA arm compared to placebo in Study 2. Grade 3-4 lymphopenia (9%), hyperglycemia (7%) and high alanine aminotransferase (6%) occurred at a greater than 5% rate in the ZYTIGA arm.

Table 4: Laboratory Abnormalities in >15% of Patients in the ZYTIGA Arm of Study 2 Abiraterone (N=542) Placebo (N=540) Laboratory Grade 1-4 Grade 3-4 Grade 1-4 Grade 3-4 Abnormality % % % % Hematology Lymphopenia 38.2 8.7 31.7 7.4 Chemistry Hyperglycemia1 56.6 6.5 50.9 5.2 High ALT 41.9 6.1 29.1 0.7 High AST 37.3 3.1 28.7 1.1 Hypernatremia 32.8 0.4 25.0 0.2 Hypokalemia 17.2 2.8 10.2 1.7 1Based on non-fasting blood draws Cardiovascular Adverse Reactions: In the combined data for studies 1 and 2, cardiac failure occurred more commonly in patients treated with ZYTIGA compared to patients on the placebo arm (2.1% versus 0.7%).

Grade 3-4 cardiac failure occurred in 1.6% of patients taking ZYTIGA and led to 5 treatment discontinuations and 2 deaths. Grade 3-4 cardiac failure occurred in 0.2% of patients taking placebo. There were no treatment discontinuations and one death due to cardiac failure in the placebo group.

In Study 1 and 2, the majority of arrhythmias were grade 1 or 2. There was one death associated with arrhythmia and one patient with sudden death in the ZYTIGA arms and no deaths in the placebo arms. There were 7 (0.5%) deaths due to cardiorespiratory arrest in the ZYTIGA arms and 3 (0.3%) deaths in the placebo arms. Myocardial ischemia or myocardial infarction led to death in 3 patients in the placebo arms and 2 deaths in the ZYTIGA arms.

Post Marketing Experience The following additional adverse reactions have been identified during post approval use of ZYTIGA. 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.

Respiratory, Thoracic and Mediastinal Disorders: non-infectious pneumonitis.

DRUG INTERACTIONS Drugs that Inhibit or Induce CYP3A4 Enzymes: Based on in vitro data, ZYTIGA is a substrate of CYP3A4.

In a dedicated drug interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%. Avoid concomitant strong CYP3A4 inducers during ZYTIGA treatment. If a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA dosing frequency [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) in full Prescribing Information].

In a dedicated drug interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone [see Clinical Pharmacology (12.3) in full Prescribing Information].

Effects of Abiraterone on Drug Metabolizing Enzymes: ZYTIGA is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. In a CYP2D6 drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively, when

ZYTIGA® (abiraterone acetate) Tablets

ZYTIGA® (abiraterone acetate) Tablets

dextromethorphan was given with abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily. Avoid co-administration of abiraterone acetate with substrates of CYP2D6 with a narrow therapeutic index (e.g., thioridazine).

If alternative treatments cannot be used, exercise caution and consider a dose reduction of the concomitant CYP2D6 substrate drug [see Clinical Pharmacology (12.3) in full Prescribing Information].

In vitro, ZYTIGA inhibits CYP2C8. There are no clinical data on the use of ZYTIGA with drugs that are substrates of CYP2C8. However, patients should be monitored closely for signs of toxicity related to the CYP2C8 substrate if used concomitantly with abiraterone acetate.

Patients with Renal Impairment: In a dedicated renal impairment trial, the mean PK parameters were comparable between healthy subjects with normal renal function (N=8) and those with end stage renal disease (ESRD) on hemodialysis (N=8) after a single oral 1,000 mg dose of ZYTIGA. No dosage adjustment is necessary for patients with renal impairment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

OVERDOSAGE Human experience of overdose with ZYTIGA is limited.

There is no specific antidote. In the event of an overdose, stop ZYTIGA, undertake general supportive measures, including monitoring for arrhythmias and cardiac failure and assess liver function.

Storage and Handling: Store at 20°C to 25°C (68°F to 77°F); excursions permitted in the range from 15°C to 30°C (59°F to 86°F) [see USP controlled room temperature].

Based on its mechanism of action, ZYTIGA may harm a developing fetus.

Therefore, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves [see Use in Specific Populations].

PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information) • Patients should be informed that ZYTIGA and prednisone are used together and that they should not interrupt or stop either of these medications without consulting their physician.

• Patients receiving GnRH agonists should be informed that they need to maintain this treatment during the course of treatment with ZYTIGA and prednisone.

• Patients should be informed that ZYTIGA must not be taken with food and that no food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. They should be informed that the tablets should be swallowed whole with water without crushing or chewing. Patients should be informed that taking ZYTIGA with food causes increased exposure and this may result in adverse reactions.

• Patients should be informed that ZYTIGA is taken once daily and prednisone is taken twice daily according to their physician’s instructions.

• Patients should be informed that in the event of a missed daily dose of ZYTIGA or prednisone, they should take their normal dose the following day. If more than one daily dose is skipped, patients should be told to inform their physician.

• Patients should be apprised of the common side effects associated with ZYTIGA, including peripheral edema, hypokalemia, hypertension, elevated liver function tests, and urinary tract infection. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION. • Patients should be advised that their liver function will be monitored using blood tests.

• Patients should be informed that ZYTIGA may harm a developing fetus; thus, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves. Patients should also be informed that it is not known whether abiraterone or its metabolites are present in semen and they should use a condom if having sex with a pregnant woman. The patient should use a condom and another effective method of birth control if he is having sex with a woman of child-bearing potential. These measures are required during and for one week after treatment with ZYTIGA.

USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category X [see Contraindications].: ZYTIGA can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. While there are no adequate and well-controlled studies with ZYTIGA in pregnant women and ZYTIGA is not indicated for use in women, it is important to know that maternal use of a CYP17 inhibitor could affect development of the fetus. Abiraterone acetate caused developmental toxicity in pregnant rats at exposures that were lower than in patients receiving the recommended dose. ZYTIGA is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with ZYTIGA. In an embryo-fetal developmental toxicity study in rats, abiraterone acetate caused developmental toxicity when administered at oral doses of 10, 30 or 100 mg/kg/day throughout the period of organogenesis (gestational days 6-17). Findings included embryo-fetal lethality (increased post implantation loss and resorptions and decreased number of live fetuses), fetal developmental delay (skeletal effects) and urogenital effects (bilateral ureter dilation) at doses ≥10 mg/kg/day, decreased fetal ano-genital distance at ≥30 mg/kg/day, and decreased fetal body weight at 100 mg/kg/day. Doses ≥10 mg/kg/day caused maternal toxicity. The doses tested in rats resulted in systemic exposures (AUC) approximately 0.03, 0.1 and 0.3 times, respectively, the AUC in patients.

Nursing Mothers: ZYTIGA is not indicated for use in women. It is not known if abiraterone acetate 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 ZYTIGA, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother.

Pediatric Use: Safety and effectiveness of ZYTIGA in pediatric patients have not been established.

Geriatric Use: Of the total number of patients receiving ZYTIGA in phase 3 trials, 73% of patients were 65 years and over and 30% were 75 years and over. No overall differences in safety or effectiveness were observed between these elderly patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Patients with Hepatic Impairment: The pharmacokinetics of abiraterone were examined in subjects with baseline mild (n=8) or moderate (n=8) hepatic impairment (Child-Pugh Class A and B, respectively) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone after a single oral 1,000 mg dose of ZYTIGA increased by approximately 1.1-fold and 3.6-fold in subjects with mild and moderate baseline hepatic impairment, respectively compared to subjects with normal hepatic function.

In another trial, the pharmacokinetics of abiraterone were examined in subjects with baseline severe (n=8) hepatic impairment (Child-Pugh Class C) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone increased by approximately 7-fold and the fraction of free drug increased 2-fold in subjects with severe baseline hepatic impairment compared to subjects with normal hepatic function.

No dosage adjustment is necessary for patients with baseline mild hepatic impairment. In patients with baseline moderate hepatic impairment (ChildPugh Class B), reduce the recommended dose of ZYTIGA to 250 mg once daily. Do not use ZYTIGA in patients with baseline severe hepatic impairment (Child-Pugh Class C). If elevations in ALT or AST >5X ULN or total bilirubin >3X ULN occur in patients with baseline moderate hepatic impairment, discontinue ZYTIGA treatment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

For patients who develop hepatotoxicity during treatment, interruption of treatment and dosage adjustment may be required [see Dosage and Administration (2.2) in full Prescribing Information, Warnings and Precautions, and Clinical Pharmacology (12.3)] in full Prescribing Information.

Manufactured by: Patheon Inc. Mississauga, Canada Manufactured for: Janssen Biotech, Inc. Horsham, PA 19044 © Janssen Biotech, Inc. 2012 Revised: May 2014 015924-140528

INDICATION and IMPORTANT SAFETY INFORMATION about ZYTIGA® (abiraterone acetate) INDICATION ZYTIGA® (abiraterone acetate) in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC).

IMPORTANT SAFETY INFORMATION

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Contraindications ZYTIGA® (abiraterone acetate) is not indicated for use in women. ZYTIGA® can cause fetal harm (Pregnancy Category X) when administered to a pregnant woman and is contraindicated in women who are or may become pregnant.

Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess Use with caution in patients with a history of cardiovascular disease or with medical conditions that might be compromised by increases in blood pressure, hypokalemia, or fluid retention. ZYTIGA® may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition. Safety has not been established in patients with LVEF <50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in Study 2) because these patients were excluded from these randomized clinical trials. Control hypertension and correct hypokalemia before and during treatment. Monitor blood pressure, serum potassium, and symptoms of fluid retention at least monthly.

Adrenocortical Insufficiency (AI) AI was reported in patients receiving ZYTIGA® in combination with prednisone, after an interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of AI if prednisone is stopped or withdrawn, if prednisone dose is reduced, or if the patient experiences unusual stress. Symptoms and signs of AI may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA®. Perform appropriate tests, if indicated, to confirm AI. Increased dosages of corticosteroids may be used before, during, and after stressful situations.

Hepatotoxicity Monitor liver function and modify, withhold, or discontinue ZYTIGA® dosing as recommended (see Prescribing Information for more information). Measure serum transaminases [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] and bilirubin levels prior to starting treatment with ZYTIGA®, every two weeks for the first three months of treatment, and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the upper limit of normal (ULN) or the bilirubin rises above three times the ULN, interrupt ZYTIGA® treatment and closely monitor liver function.

Increased ZYTIGA® Exposures with Food ZYTIGA® must be taken on an empty stomach. No food should be eaten for at least two hours before the dose of ZYTIGA® is taken and for at least one hour after the dose of ZYTIGA® is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10- fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state.

Adverse Reactions The most common adverse reactions (≥10%) are fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion.

The most common laboratory abnormalities (>20%) are anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT and hypokalemia.

Drug Interactions Based on in vitro data, ZYTIGA® is a substrate of CYP3A4. In a drug interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%. Avoid concomitant strong CYP3A4 inducers during ZYTIGA® treatment. If a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA® dosing frequency only during the co-administration period [see Dosage and Administration (2.3)]. In a dedicated drug interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone.

ZYTIGA® is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. Avoid co-administration with CYP2D6 substrates with a narrow therapeutic index. If alternative treatments cannot be used, exercise caution and consider a dose reduction of the CYP2D6 substrate drug. In vitro, ZYTIGA® inhibits CYP2C8. There are no clinical data on the use of ZYTIGA® with drugs that are substrates of CYP2C8. Patients should be monitored closely for signs of toxicity related to the CYP2C8 substrate if used concomitantly with abiraterone acetate.

Use in Specific Populations Do not use ZYTIGA® in patients with baseline severe hepatic impairment (Child-Pugh Class C).

Please see Brief Summary of Prescribing Information on adjacent pages. © Janssen Biotech, Inc. 2014

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Our goal is to help make access to ZYTIGA®(abiraterone acetate) easy.

Support for you: 4-6

Support for your patients:

Rapid investigation and assessment of patient eligibility and coverage • Prior authorization support • Information on cost support options, including updates on independent foundation funding status • Electronic enrollment through an online portal • Identification of a Specialty Pharmacy Provider (SPP) • Access to medication order information • A personally-assigned Site Coordinator Business Hours

• Explanation of benefits from a personally-assigned Care Coordinator • Referral to cost support options, including the ZytigaOne® Instant Savings Program for eligible patients • Upon request, follow-up status calls to those referred for cost support • Coordination with SPP for processing and delivery of medication • Educational materials and personalized prescription reminders, if requested

Take advantage of ZytigaOne® Support today.

1-855-ZYTIGA-1 (998-4421) Monday–Friday, 8:00 AM–8:00 PM ET

ACCESS TO ZYTIGA® SIMPLIFIED FOR YOU AND YOUR PATIENTS More information at ZYTIGAHCP.com

Please see Important Safety Information on back, and Brief Summary of Prescribing Information on adjacent pages.

Patient insurance benefit investigation is provided as a service by The Lash Group, Inc., under contract for Janssen Biotech, Inc. In this regard, The Lash Group, lnc., 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. This reimbursement support service has no independent value to providers apart from the product and is included within the cost of the product.

Importantly, insurance verification is the ultimate responsibility of the provider. Third-party reimbursement is affected by many factors. This document is presented for informational purposes only and is not intended to provide reimbursement or legal advice and does not promise or guarantee coverage, levels of reimbursement, payment or charge. Similarly, all CPT and HCPCS codes are supplied for informational purposes only and represent no promise or guarantee that these codes will be appropriate or that reimbursement will be made. It is not intended to increase or maximize reimbursement by any payer. Laws, regulations and policies concerning reimbursement are complex and are updated frequently. While we have made an effort to be current as of the issue date of this document the information may not be as current or comprehensive when you view it. We strongly recommend you consult with your counsel, payer organization, or reimbursement specialist for any reimbursement or billing questions. While The Lash Group, Inc., attempts to provide correct information, they and Janssen Biotech, Inc., make no representations or warranties, expressed or implied, as to the accuracy of the information. In no event shall The Lash Group, Inc., Janssen Biotech, Inc., or its employees or agents be liable for any damages resulting from or relating to the services. All providers and other users of this information agree that they accept responsibility for the use of this service. © Janssen Biotech, Inc. 2014 11/14 006076-141015