Urology Practice Management - June 2015, Vol 4, No 3

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

www.UroPracticeManagement.com

June 2015

Lower Urinary Tract Symptoms and Bladder Cancer

By Rosemary Frei, MSc

Volume 4 • Number 3

Updated NCCN Guideline for Prostate Cancer Allows Early Treatment with Docetaxel

By Wayne Kuznar

T

he updated National Comprehensive Cancer Network (NCCN) guideline allows for the upfront use of docetaxel (Taxotere) in some men with castration-resistant prostate cancer (CRPC). This and other systemic therapies represent the most significant changes in the updated guideline for the treat-

ment of patients with metastatic Andrew J. CRPC, said AnArmstrong, MD, ScM drew J. Armstrong, MD, ScM, Co-Leader, Genitourinary Oncology Research Program, Duke Cancer Institute, Durham, NC, at the 2015 NCCN annual conference.

Continued on page 11

M

Dominique Michaud, ScD

en with lower urinary tract symptoms involving dysfunction in voiding, or voiding and storage, are at higher risk of bladder cancer than men without these forms of urinary dysfunction, according to a study recently published in Urology.1 The voiding dysfunction most strongly associated with bladder cancer risk was frequent urinary hesitancy; authors also observed a stronger Continued on page 24

Programs Raise Awareness of Risks Associated with Testosterone Replacement Therapy

By Chase Doyle

T

wo pilot programs aimed at reducing the utilization of in­ appropriate testosterone replacement therapy, particularly in the treatment of men with age-related hypogonadism, have shown success in

raising awareness of evidence and safety concerns.

Presented at the 2015 annual meeting of the Academy of Managed Care Pharmacy, the study sought to determine the influence of educational efContinued on page 9

ER C l AN a 0 C adic y…1

© 2015 Engage Healthcare Communications, LLC

TE ic R om A t t ST obo tec O R sta PR o Pr

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

Call for Papers

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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.

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In This Issue

PUBLISHING STAFF Senior Vice President/Group Publisher Nicholas Englezos nenglezos@the-lynx-group.com Publisher Cristopher Pires cpires@the-lynx-group.com Vice President, Director of Sales & Marketing Joe Chanley jchanley@the-lynx-group.com Director, Client Services Zach Ceretelle zceretelle@the-lynx-group.com Senior Editorial Director Dalia Buffery dbuffery@the-lynx-group.com Editorial Director Anne M. Cooper acooper@the-lynx-group.com Senior Production Manager Lynn Hamilton The Lynx Group President/CEO Brian Tyburski Chief Operating Officer Pam Rattananont Ferris Vice President of Finance Andrea Kelly Human Resources Jennine Leale Director, Strategy & Program Development John Welz Director, Quality Control Barbara Marino Quality Control Assistant Theresa Salerno Director, Production & Manufacturing Alaina Pede Director, Creative & Design Robyn Jacobs Creative & Design Assistants Lora LaRocca Wayne Williams Content Marketing Director Samantha Weissman Web Content Manager Anthony Trevean Content Digital Manager Allison Musante Digital Programmer Michael Amundsen Jr Digital Media Specialist Charles Easton IV Meeting & Events Planner Linda Mezzacappa Project Managers Deanna Martinez Jeremy Shannon Project Coordinator Rachael Baranoski IT Manager Kashif Javaid Sales Assistant Aadam Mohamed Administrative Assistant Amanda Hedman Office Coordinator Robert Sorensen Engage Healthcare Communications, LLC 1249 South River Road - Ste 202A Cranbury, NJ 08512 phone: 732-992-1880 • fax: 732-992-1881

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

FEATURES Updated NCCN Guideline for Prostate Cancer Allows Early Treatment with Docetaxel.................................................................................. 1

By Wayne Kuznar

Programs Raise Awareness of Risks Associated with Testosterone Replacement Therapy........................................................................................ 1

By Chase Doyle

Lower Urinary Tract Symptoms and Bladder Cancer...................................... 1

By Rosemary Frei, MSc

Popularity of Robotic Radical Prostatectomy Comes with a High Price........................................................................................................ 10

By Rosemary Frei, MSc

Millions in Savings by Using Prolaris Test in All Men with Localized Prostate Cancer................................................................................................. 12

By Alice Goodman

Adherence to Guidelines May Boost Cost of Follow-up Care After Radical Cystectomy................................................................................ 14

By Rosemary Frei, MSc

Continued on page 8

Mission Statement Urology healthcare requires providers to focus attention on financial concerns and strategic decisions that affect the bottom line. To continue to provide the high-quality care urology patients deserve, providers must master the ever-changing business of urology. Urology Practice Management™ offers process solutions for members of the urology care team—medical, surgical, and radiation urologists, as well as executives, administrators, and coders/ billers—to assist them in reimbursement, staffing, electronic health records, REMS, and compliance with state and federal regulations.

Postmaster: Correspondence regarding subscriptions or change of address should be directed to CIRCULATION DIRECTOR, Urology Practice Management™, 1249 South River Road, Cranbury, NJ 08512. Fax: 732-992-1881. Yearly subscription rates: 1 year: $99.00 USD; 2 years: $149.00 USD; 3 years: $199.00 USD. EHC431-3

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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

We’ve Got You Covered Helping Your Patients Financial assistance is available for patients.* Private Insurance $5000/month copay assistance, up to $12,000/year

Medicare/Medicaid Referrals to Independent Copay Foundations†

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New Patients Awaiting Coverage Decision Free XTANDI through XTANDI Quick Start+™ Program

*Subject to eligibility. Void where prohibited by law. Restrictions may apply. † XTANDI Support SolutionsSM has no control over the decisions made by and does not guarantee support by these independent copay foundations.

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1-855-8XTANDI (855-898-2634) 8 AM – 8 PM ET

(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.

076-0472-PM

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 responsibil­ity for any injury and/or damage to persons or property arising out of or related to any use of the material mentioned in this publication.

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

FEATURES... Continued from page 3 Choice of Hospital for Readmissions Influences Mortality Risk in Men with Urologic Cancer............................................................................... 25

By Chase Doyle

Federal Government Outlines Stage 3 of Meaningful Use........................... 26

By Rosemary Frei, MSc

Repeal of Sustainable Growth Rate Met with Relief..................................... 27

By Laura Morgan

Seven Steps to Finding the Right Financial Advisor....................................... 28

By W. Ben Utley, CFP, and Lawrence B. Keller, CFP, CLU, ChFC, RHU, LUTCF

DRUG coding FDA-Approved Medications Used for the Treatment of Prostate Cancer................................................................................................. 31

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

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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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Prostate Cancer

Programs Raise Awareness of Risks... Continued from the cover forts on provider practice patterns and internal practice guidelines, as well as patient interest in evidence-based assessments of their medications, as gauged by website views, survey responses, and e-mail sign-ups. The initial goal of researchers was to coordinate with a regional health system to improve the quality of care and reduce prescription costs; however, based on early findings, a broader outreach program was initiated to develop patient-centered tools.

“Although challenging, partnerships between health systems and health plans may lead to improved quality of care and lowered costs,” reported Kevin L. Chang, PharmD, Clinical Pharmacist Consultant at OmedaRx, Portland, OR. “Based on website visits, it appears that [health plan] members are interested in evidence-based assessments for the therapies they are currently taking.”

Utilization of testosterone replacement therapy has increased significantly over the past several years, Dr Chang noted. From 2010 to 2013, the number of patients in the United States who received a prescription for a testosterone drug rose from 1.3 million annually to 2.3 million annually. Much of this increase, however, has come in men with age-related hypogonadism, a population in whom therapy offers an unclear benefit and poses a potential risk of heart attack or stroke.

“Critical appraisals of the evidence by OmedaRx have concluded that [testosterone replacement therapy] does not provide a clinically meaningful benefit in men with age-related hypogonadism, and there may be a potential cardiovascular risk,” reported Dr Chang.

In a March 2015 Drug Safety Communication, the US Food and Drug Administration (FDA) emphasized this assessment, cautioning against the use of testosterone re-

the current state of the evidence, including a critical appraisal of the evidence that had been previously performed by OmedaRx. The second program, the informational initiative, used Regence Pharmacy claims to identify male, commercially insured members who initiated therapy with any testosterone drug between September 1, 2014, and December 31, 2014. Researchers designed a 1-page informational mailing and website to highlight a lack of evidence for the use of testosterone replacement therapy in men with age-related hypogonadism and provide information on the potential safety concerns to these members.

placement therapy for age-related hypogonadism, and stating that labeling changes will be required to inform patients and providers of possible increased risk of heart attack and stroke.

“Based on these findings, it was hypothesized that a broader, patientfocused, educational initiative would bring value to members currently on therapy.”

—Kevin L. Chang, PharmD

Pilot Programs Before the FDA announcement, the 2 pilot programs were developed with the goal of increasing awareness related to evidence and safety concerns of using testosterone replacement therapy for age-related hypogonadism. The first program, a health system initiative, included commercially insured members with membership attributed to a single health system located in the Pacific Northwest, Dr Chang reported. Members were identified via OmedaRx pharmacy claims.

“Targeted chart reviews were performed to analyze prescribing trends and adherence to institution-specific clinical guidelines,” Dr Chang explained. “Recommendations on specific patient cases were made based on national practice guidelines.”

These potential recommendations included confirming a diagnosis, performing follow-up laboratory monitoring, and following up on symptom improvement. An educational in-­ service was also provided to clinical staff to report findings and describe

Health System Initiative The majority of the charts reviewed was consistent with internal guidelines, according to Dr Chang. Because of recent implementation of a new electronic medical record system, however, historical data on initiation of therapy were not available for all members. Of the 21 charts reviewed in December 2014, recommendations were generated for 7 patients. At the time the study results were presented, health system staff had not yet implemented these recommendations.

“Two patients were noted to have discussed the safety and efficacy with the prescribing physician based on news related to [testosterone replacement therapy] they had read,” noted Dr Chang. “Based on these findings, it was hypothesized that a broader, patient-focused, educational initiative would bring value to members currently on therapy.”

Informational Initiative Of the 311 members who met inclusion criteria to receive the informational mailing, 27% had initiated therapy with a brand drug and 72% had initiated therapy with a generic drug (1% had utilized a Continued on page 30

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Prostate Cancer

Popularity of Robotic Radical Prostatectomy Comes with a High Price

By Rosemary Frei, MSc

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n analysis using the IMS LifeLink Health Plan Claims Database has shown that patients who undergo minimally invasive robotic-assisted radical prostatectomy experience a shorter hospital length of stay and somewhat better postoperative outcomes than patients who undergo open radical prostatectomy, albeit with a higher price tag, according to a study that was published recently in Prostate Cancer and Prostatic Disease.1 Senior author Nilay Shah, PhD, Consultant, Division of Health Care Policy and Research, Mayo Clinic, Rochester, MN, and colleagues from across the United States used the LifeLink database to select privately insured patients with prostate cancer who underwent open radical prostatectomy or minimally invasive radical prostatectomy in the United States between 2003 and 2010.

“The primary outcomes of this study were LOS [length of stay], perioperative complications, 90-day readmission rates, and total hospital reimbursement,” Dr Shah and colleagues wrote.

“We defined perioperative complications similar to previous studies examining the comparative effectiveness of MIRP [minimally invasive robotic-­ assisted radical prostatectomy] versus ORP [open radical prostatectomy].”

The LifeLink database included 8629 patients who underwent open radical prostatectomy in 2003-2010, and 8981 who underwent the minimally invasive radical prostatectomy during the same time period; a total of 4092 surgeons performed these procedures. The rate of minimally invasive radical prostatectomy quickly eclipsed that of open radical prostatectomy, with 1.0% of patients receiving minimally invasive radical prostatectomy

in 2003 and 74% in 2010. The members of the 2 groups had similar average ages—approximately 58 years— and number of comorbidities.

The median length of stay was 1 day for patients in the minimally invasive radical prostatectomy group and 3 days for those in the open radical prostatectomy group (P <.0001).

The rates of wound, vascular, and medical perioperative complications were statistically similar for patients in the 2 groups. There was, however, a significantly lower rate of respiratory complications for patients who underwent minimally invasive radical prostatectomy compared with those undergoing open radical prostatectomy, at 0.7% versus 1.1%, respectively (P = .005). There was also a lower rate of genitourinary complications,

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“The primary outcomes of this study were LOS [length of stay], perioperative complications, 90-day readmission rates, and total hospital reimbursement.”

—Nilay Shah, PhD

June 2015

at 1.2% versus 1.7% (P = .007), respectively. As a result, the rate of overall complications was lower for patients who underwent minimally invasive radical prostatectomy: 2.1% versus 3.0% (P <.001), respectively.

The researchers’ analysis revealed a 24% lower adjusted risk of genitourinary complications (adjusted odds ratio [OR], 0.76; P <.001) for patients undergoing minimally invasive radical prostatectomy and an 18% lower adjusted risk of overall complications (adjusted OR, 0.82; P <.001). The 90-day readmission rates were similar for patients in both groups: 5.2% for patients in the minimally invasive radical prostatectomy group and 5.3% for those in the open radical prostatectomy group (P = .85).

Mean hospital reimbursement was significantly higher for the minimally invasive radical prostatectomy procedure, at $19,292 per procedure compared with $17,347 for the open radical prostatectomy procedure (P <.001). This translates into approximately $126.4 million in additional reimbursement provided to hospitals for performing robotic surgery from 2003 to 2010, the authors calculated.

Dr Shah said that more information is required for a formal cost-­ effectiveness analysis.

“Specifically, we would have to survey patients at different time points after surgeries to be able to calculate QALYs [quality-adjusted life-years]. This data is not yet available, but would be an additional piece of information to further understand the impact of different types of surgeries,” he observed. l Reference

1. Kim SP, Gross CP, Smaldone MC, et al. Perioperative outcomes and hospital reimbursement by type of radical prostatectomy: results from a privately insured patient population. Prost Cancer Prost Dis. 2015;18:13-17.

Prostate Cancer

Updated NCCN Guideline for Prostate... Continued from the cover First-line therapy options in the updated guideline include docetaxel plus prednisone, enzalutamide (Xtandi), and abiraterone (Zytiga) plus prednisone.

“The castration-sensitive guideline allows for the early use of docetaxel in high-volume men who present with metastatic disease,” said Dr Armstrong. “Now, instead of just giving ADT [androgen-deprivation therapy], we have 6 cycles of docetaxel, and that’s associated with about a 17-month improvement in survival.”

The data to which he is referring come from the CHAARTED trial, and have not been published but were presented at the 2014 American Society of Clinical Oncology annual meeting. In that study, the median overall survival (OS) was 13.6 months longer when docetaxel was added to ADT compared with ADT alone; in men with high-volume metastatic disease, the median OS was 17.0 months longer with the addition of docetaxel.

In addition, the guideline now reflects level I evidence (from the PREVAIL trial) for the use of enzalutamide, said Dr Armstrong. In PREVAIL, which was conducted in men with metastatic CRPC before chemotherapy, the median radiographic progression-free survival (PFS) had not yet been reached in enzalutamide recipients compared with 3.9 months in the placebo group.

The rate of radiographic PFS at 12 months was 65% in the enzalutamide

group versus 14% among patients receiving placebo, for an 81% risk reduction with enzalutamide. Furthermore, enzalutamide reduced the risk for death by 29%, and in subsets of

sipuleucel-T relative to placebo, for a 22% reduction in the risk for death.

The newest version of the guideline also addresses the use of abir­ aterone acetate plus prednisone, and

“The castration-sensitive guideline allows for the early use of docetaxel in high-volume men who present with metastatic disease. Now, instead of just giving ADT, we have 6 cycles of docetaxel, and that’s associated with about a 17-month improvement in survival.”

—Andrew J. Armstrong, MD, ScM

men with visceral disease, in whom outcomes are generally worse, enzalutamide delayed PFS. “We also have a little more stratification based on visceral disease” metastases, said Dr Armstrong. “There are some drugs we can’t use in visceral disease. We have multiple lines of therapy now, so there’s a new page that goes over the appropriate options as the disease progresses.”

The recommendations about immunotherapy in the form of sipuleucel-T (Provenge) also find their way into the guideline, courtesy of the IMPACT trial, in which the median OS was extended by 4.1 months with

reflects data from the COU-AA-302 phase 3 registration trial. At the third interim analysis, radiographic PFS was doubled in the abiraterone plus prednisone group compared with the group receiving placebo plus prednisone (16.5 vs 8.3 months), representing a 48% reduction in risk with abir­ aterone. The median OS was also significantly superior with randomization to abiraterone; the median OS was not yet reached in the abiraterone group and was 27.2 months in the placebo group, corresponding to a hazard ratio of 0.57.

Several ongoing phase 3 trials in CRPC have the potential for practice-changing results, said Dr Armstrong, including ipilimumab use in the predocetaxel setting, rilimogene galvacirepvec plus rilimogene glafolivec (PROSTVAC) and granulocyte-macrophage colony-stimulating factor before docetaxel in asymptomatic patients with CRPC, the novel immunomodulator tasquinimod (also in the predocetaxel setting), and novel hormonal therapies such as orteronel. l

Key Points n The updated NCCN guideline calls for the upfront use of docetaxel in men with metastatic CRPC n First-line therapy options for men with CRPC in the guideline now include docetaxel plus prednisone, enzalutamide, and abiraterone plus prednisone n The updated guideline reflects level I evidence for using enzalutamide in metastatic CRPC, which had an 81% risk reduction and a 29% mortality risk reduction versus placebo

June 2015

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Prostate Cancer

Millions in Savings by Using Prolaris Test in All Men with Localized Prostate Cancer

By Alice Goodman

S

ignificant cost-savings in treating patients with prostate cancer could be achieved in the US healthcare system with the use of the cell-cycle progression (CCP) gene-expression assay called Prolaris (from Myriad Genetics Laboratories), according to a poster from E. David Crawford, MD, Professor of Surgery and Radiation Oncology, University of Colorado, Aurora, and colleagues, presented at the 2015 Genitourinary Cancers Symposium.

The use of appropriate treatment in patients with localized prostate cancer based on disease aggressiveness remains a challenge; lack of disease stratification by high- and low-risk disease leads to overtreatment of patients with low-risk prostate cancer and undertreatment of patients with high-risk disease.

Having a strategy that could better differentiate between low- and high-risk localized prostate cancer could improve the use of appropriate treatment, thereby saving costs of eliminating overtreatment.

Prolaris Testing Reduces Costs In a US commercial health plan with 10 million members, the use of Prolaris could reduce the cost per patient tested by $2850 over 10 years, translating to a cost-savings of $16 million, according to an evidence-based economic model with a hypothetical group of patients with localized prostate cancer.

Based on this model, 67% of the savings would occur in the first year of instituting Prolaris testing. A net reduction of $2850 in cost per pa-

In a US commercial health plan with 10 million members, the use of Prolaris could reduce the cost per patient tested by $2850 over 10 years, translating to a cost-savings of $16 million.

—E. David Crawford, MD, and colleagues

tient accrued over 10 years after the initial cost for the assay (approximately $3400).

The model applied assumptions about management and progression based on published clinical data and interviews with board-certified physicians. The study compared reference scenarios and test scenarios.

“Total cost of care was calculated for a reference scenario [current clinical practice] and a test scenario where patient management was altered based on CCP test results,” noted Dr Crawford and colleagues.

Comparisons between the scenarios were made for the following patient management groups—active surveillance, radical prostatectomy only, radiation therapy only, androgen-deprivation therapy only, rad­

Key Points n In a US commercial health plan with 10 million members, the use of Prolaris could reduce the cost per patient tested by $2850 over 10 years n A total of 67% of the savings would occur in the first year of instituting Prolaris testing

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ical prostatectomy and radiation therapy, and radiation therapy and androgen-deprivation therapy.

The costs of the test scenario

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never exceeded the costs in the reference scenarios.

The savings were attributable to 2 key factors, with the majority of the savings attributed to the increased use of active surveillance for low- and intermediate-risk patients, as defined by the American Urological Association.

In these 2 risk-based groups, 15% and 5% of patients, respectively, would have received active surveillance according to current clinical practice. When the test scenario clinical treatment paradigm was applied, these percentages increased to 69% and 27% of active surveillance in these respective groups.

Additional savings came from reduced disease progression rates in high-risk patients with more aggressive disease who moved on to multimodality therapy.

The Prolaris test was added to the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology in October 2014, calling for the use of the test in all men with localized prostate cancer, regardless of the risk category. l

Invitation to Join the UPM Editorial Board The publishers of Urology Practice Management™ (UPM) are inviting qualified urology practice owners and administrators to participate as members of the UPM Editorial Board. As an Editorial Board member, you will play an active role in helping to shape the content of this exciting new publication.

Urology Practice Management is a niche publication focused on process solutions for urology practices. UPM is designed to provide the urology care team—medical, practice administrators, coders, and billers—with the knowledge and skills required to keep abreast of today’s fast-changing business environment, allowing practice professionals more time to concentrate on high-quality patient care. Each issue of UPM will focus on various areas of urology practice, featuring current topics such as:

Urology P ractice Managem ent

• Healthcare technology • Models of care • Staffing • Reimbursement and coding

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MAY 201 3

Take advantage of this unique opportunity to help your peers and enhance your professional reputation by becoming the newest member of the UPM Editorial Board. an affiliate of

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Urologic Cancers

Adherence to Guidelines May Boost Cost of Follow-up Care After Radical Cystectomy

By Rosemary Frei, MSc

A

new analysis suggests that adherence to guidelines for follow-up care in patients who have undergone a radical cystectomy may standardize care but may also increase expenditures compared with the cost of most current approaches, which are more conservative and deviate from existing guidelines. The study, published recently in Urologic Oncology, examined the sources of variation in care and the cost associated with standardizing care to recommended guidelines.1 Until now, standard approaches to follow up with patients in the 2 years after they undergo a radical cystectomy have been poorly defined, noted lead investigator Seth A. Strope, MD, MPH, Assistant Professor of Surgery, Division of Urologic Surgery, Washington University School of Medicine, St. Louis, MO, and colleagues. To evaluate variations in follow-up care, the investigators performed a population-based study using Surveillance, Epidemiology, and End Results (SEER) Medicare data. The cost associated with standardizing care based on current guidelines was also evaluated.

All but 25% of patients with bladder cancer aged between 66 and 90 years undergoing radical cystectomy had less expensive follow-ups than would be incurred using even a low-intensity set of recommendations in the National Comprehensive Cancer Network (NCCN) guidelines. Patients also had less expensive follow-ups than if their physicians had used the European Association of Urology (EAU) guidelines for their postradical cystectomy care. The investigators also found that imaging accounted for most of the cost in both guideline-recommended care and actual clinical practice.

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Seth A. Strope, MD, MPH

Deviating from Recommended Guidelines “Despite the 2 prevailing recommendations for relatively intensive surveillance following extirpative surgery for bladder cancer, our analysis of current practice patterns suggests that providers are conducting a more conservative approach that is, for the most part, less costly than published guidelines,” the investigators wrote.

“Greater compliance with current guidelines would actually increase expenditures for payers and patients.

Additionally, strict adherence to follow-up protocols may restrict patients’ choice, potentially negatively affecting patient’s quality of life.”

However, Dr Strope noted that there is much more work that needs to be done to determine what is truly the best care for patients.

“Current research suggests the survival benefit of follow-up testing after definitive bladder cancer surgery is small,” Dr Strope told Urology Practice Management. “In the absence of strong­ ­er evidence to support intensive follow-up after surgery, more conservative approaches appear indicated.”

Evaluating Variability and Cost The team modeled the variability in expenditures for follow-up care as

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well as how much of the variability could be explained by various factors, such as those specific to the patients or their surgeons. They found that patient-specific factors—primarily nodal status, use of chemotherapy, hospital readmissions, and final disease stage—represented the majority of variation in expenditures. Surgeon-specific factors also accounted for a significant amount of the variability.

In the second part of the study, Dr Strope and colleagues calculated what the patients’ cost of follow-up care would be if the physicians were using NCCN guidelines for high-intensity or low-intensity (ie, conservative) care, or the EAU guidelines, and compared it with the 25th, 50th, and 75th percentiles of cost of care among SEER-database patients.

The guideline-recommended care was more expensive than actual care in every comparison except one: the NCCN conservative follow-up versus the 75th percentile of actual-care cost ($1384 vs $1737). The highest estimated cost was for NCCN-recommended high-intensity follow-up, at $4833. The second-highest was for EAU-recommended follow-up for patients with bladder cancer staged at >2, at $4071. Imaging accounted for the majority of the cost in every category, both actual and estimated.

The team concluded that adherence to published guidelines may boost costs of follow-up care; however, adherence to conservative guidelines would facilitate standardization of care without producing large increases in cost. l

Reference

1. Vemana G, Vetter J, Chen L, et al. Sources of variation in follow-up expenditure after radical cystectomy.

Urol Oncol. 2015 Apr 20 [Epub ahead of print].

In men with mCRPC who progressed on ADT

The story for ZYTIGA® has significantly evolved.

Presenting…

mCRPC = metastatic castration-resistant prostate cancer; ADT = androgen-deprivation therapy.

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.

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.

Please see additional Important Safety Information on the next pages.

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

In men with mCRPC who progressed on ADT, consider ZYTIGA® (abiraterone acetate) first.

Final analysis of the pivotal phase 3 trial.*

Every day tells a story.

IMPORTANT SAFETY INFORMATION 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. *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 OS and radiographic progression-free survival (rPFS). Select exclusion criteria included AST and/or ALT ≥ 2.5X ULN, liver metastases, moderate or severe pain, opiate use for cancer pain, and visceral organ metastases. † At a prespecified final analysis for OS, 65% (354/546) of patients treated with ZYTIGA® + prednisone compared with 71% (387/542) of patients treated with placebo + prednisone had died. ‡Prednisone, as a single agent, is not approved for the treatment of prostate cancer. § rPFS was assessed with the use of sequential imaging studies and was defined by bone scan identification of 2 or more new bone lesions with confirmation (Prostate Cancer Working Group 2 [PCWG2] criteria) and/or modified Response Evaluation Criteria In Solid Tumors (RECIST) criteria for progression of soft tissue lesions. Analysis of rPFS utilized centrally reviewed radiographic assessment of progression.

IIAt the prespecified rPFS analysis, 150 (28%) of patients treated with ZYTIGA® + prednisone and 251 (46%) of patients treated with placebo + prednisone had radiographic progression.

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2015 3/15 028723-150129

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

After a median 4 years (49 months) of follow-up…

ZYTIGA® (abiraterone acetate) + prednisone achieved a median overall survival (OS) of almost 3 years (34.7 months).1† • 4.4 months improvement in median OS—34.7 months with ZYTIGA® + prednisone vs 30.3 months with placebo + prednisone (active compound)‡ Co-primary end point—median OS: hazard ratio (HR)=0.81; 95% CI: 0.70, 0.93; P=0.0033.

Co-primary end point—rPFS: median not reached for ZYTIGA® + prednisone vs a median of 8.28 months for placebo + prednisone; HR=0.425; 95% CI: 0.347, 0.522; P<0.0001.§II

With a median 49 months of follow-up, there were no notable changes in the safety profile of ZYTIGA® + prednisone since the previously reported interim analyses.1 In your patients with mCRPC…

CONSIDER ZYTIGA® FIRST.

Reference: 1. Ryan CJ, Smith MR, Fizazi K, et al; for the COU-AA-302 Investigators. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2015;16(2):152-160.

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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 enzymes CYP2D6 and CYP2C8. 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 a CYP2C8 drug interaction trial in healthy subjects, the AUC of pioglitazone, a CYP2C8 substrate, was increased by 46% when administered with a single dose of ZYTIGA®. Patients should be monitored closely for signs of toxicity related to a CYP2C8 substrate with a narrow therapeutic index if used concomitantly with ZYTIGA®.

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

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 ≥2.5 XULN 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.

Musculoskeletal and Connective Tissue Disorders: myopathy, including rhabdomyolysis.

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 enzymes CYP2D6 and CYP2C8. In

ZYTIGA® (abiraterone acetate) Tablets

ZYTIGA® (abiraterone acetate) Tablets

a CYP2D6 drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively, when 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 a CYP2C8 drug-drug interaction trial in healthy subjects, the AUC of pioglitazone (CYP2C8 substrate) was increased by 46% when pioglitazone was given together with a single dose of 1,000 mg abiraterone acetate.

Therefore, patients should be monitored closely for signs of toxicity related to a CYP2C8 substrate with a narrow therapeutic index if used concomitantly with ZYTIGA [see 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.

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].

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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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Urologic Cancers

Lower Urinary Tract Symptoms and... Continued from the cover link between lower urinary tract symptom severity and noninvasive bladder cancer compared with invasive bladder cancer.

“The different observations with noninvasive and invasive are difficult to interpret,” lead investigator Dominique Michaud, ScD, told Urology Practice Management. “We tried to address the possibility of detection bias—that is, that symptoms result in [more urological testing and in turn] more diagnosis of noninvasive cancers—but it was unclear that it was all detection bias.”

Dr Michaud, Professor of Public Health and Community Medicine, Tufts University School of Medicine, Boston, and colleagues believe that if these findings are confirmed, lower urinary tract symptoms could be used to identify men who may be at higher risk of bladder cancer.

The researchers used data from 30,183 men in the Health Professionals Follow-Up Study—an ongoing study initiated in 1986 to evaluate hypotheses about men’s health—from years 1992, 1994, 1998, and 2000.

They examined the associations between bladder cancer risk and forms of lower urinary tract symptoms in a multivariate analysis that adjusted for age, total fluid intake, intake of fruits and vegetables, intake of bacon, smoking status, pack-years of smoking, and diabetes status.

The results indicated that compared with no lower urinary tract symptoms, voiding dysfunction and mixed voiding–storage dysfunction were significantly associated with el-

evated risk of bladder cancer, with relative risks (RRs) of 1.58 and 1.87, respectively. This result was demonstrated using analysis that ruled out symptoms that may have developed as a result of diagnosed cancer.

“Results suggest that the presence of severe urinary hesitancy might indicate higher volume of postvoid residual urine, which can increase the contact time of potential carcinogens in urine and the bladder urothelium and the risk of bladder cancer.”

—Dominique Michaud, ScD, and colleagues

Results also demonstrated that men who have urinary hesitancy ≥50% of the time have a 2.21-fold elevated risk for bladder cancer compared with men who have no urinary hesitancy. The investigators showed in a separate analysis that men with urinary hesitancy ≥50% of the time also have the highest overall American Urological Association Symptom Index score among all men who experienced any of 7 types of urinary symptoms ≥50% of the time.

No other categories of urinary symptoms were significantly associated with bladder cancer. Furthermore, when the first 2 years of follow-up data were excluded to rule out symptoms occurring in patients who had been diagnosed with bladder cancer,

Key Points n The voiding dysfunction most strongly associated with bladder cancer risk was frequent urinary hesitancy n Voiding dysfunction and mixed voiding–storage dysfunction were significantly associated with elevated risk of bladder cancer n Voiding dysfunction leads to extended contact time between potential carcinogens in the urine and the cells lining the bladder

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there was a significantly elevated risk of noninvasive bladder cancer among men with mixed voiding–storage dysfunction, with an RR of 3.36.

Associations were also significant between moderate lower urinary

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tract symptoms and severe lower urinary tract symptoms and noninvasive cancer, with RRs of 1.87 and 2.62, respectively.

An analysis that excluded the first 4 years of follow-up data uncovered elevated risks for noninvasive bladder cancer in men with mild lower urinary tract symptoms (RR = 2.69), storage dysfunction alone (RR = 2.99), and mixed voiding–storage dysfunction (RR = 6.08). Dr Michaud and colleagues noted that the results fit with the fact that voiding dysfunction leads to extended contact time between potential carcinogens in the urine and the cells lining the bladder.

“Results suggest that the presence of severe urinary hesitancy might indicate higher volume of postvoid residual urine, which can increase the contact time of potential carcinogens in urine and the bladder urothelium and the risk of bladder cancer,” they concluded. l

Reference

1. Zhou J, Kelsey KT, Smith S, et al. Lower urinary tract symptoms and risk of bladder cancer in men: results from the Health Professionals Follow-Up Study.

Urology. 2015 Apr 8 [Epub ahead of print].

Urologic Cancers

Choice of Hospital for Readmissions Influences Mortality Risk in Men with Urologic Cancer

By Chase Doyle

P

atients with urologic cancer who are readmitted after a surgery to a second hospital and not to their original hospital are more likely to have complications than patients readmitted to their original surgical hospital, according to findings presented at the 2015 Genitourinary Cancers Symposium.

“Approximately 1 in 10 patients will require hospital readmission within 90 days of a major urologic cancer surgery,” said lead investigator Jasmir G. Nayak, MD, Department of Urology, University of Washington, Seattle, “and up to 40% of these patients will present to a secondary hospital.”

Although 40% may sound innocuous, the choice of hospital could mean the difference between life and death, according to Dr Nayak’s analysis.

“For patients undergoing surgery in a high-volume center,” he cautioned, “complications managed at secondary hospitals are almost 7 times more likely to be associated with mortality.”

Urologic cancer surgery is often linked with significant morbidity and mortality. Although outcomes vary among hospitals, this may be partly

attributed to differences in failure-­ ing radical prostatectomy, radical to-rescue complications. cystectomy, radical nephrectomy, and partial nephrectomy) with 10% (N = 3113) of readmissions occur“For patients underring within 90 days of surgery. going surgery in a Of the 3113 total readmissions, 1196 patients were diagnosed with a high-volume center, “rescuable” complication. complications managed “Complication rates were based on readmission diagnoses,” said Dr at secondary hospitals Nayak, “and included cardiac, respiare almost 7 times more ratory, bleed, sepsis, venothrombotic event, or renal failure.” likely to be associated Complication rates were the highwith mortality.” est for patients who had undergone —Jasmir G. Nayak, MD radical cystectomy or radical nephrectomy, but these rates differed “Given the regional variation in between those patients admitted to urologic surgery,” said Dr Nayak, primary versus secondary hospitals. “the institution that patients present “For those patients readmitted to to for complication management secondary hospitals following radical may affect outcomes. Specifically, cystectomy, the FTR [failure-to-respresenting to a different hospital cue] rate was 9.1% compared with than where surgery took place may 7.4% for those readmitted to their result in healthcare that is less famil- primary hospital,” said Dr Nayak. iar and thus less prepared to properly Overall, the complications rate identify and manage complications.” was 6.1% for patients readmitted to This retrospective analysis was secondary hospitals compared with based on 1998-2007 and 2009-2013 4.1% for those readmitted to their data from the Washington State original surgical hospital.

Comprehensive Hospital Abstract “Conversely,” Dr Nayak elaboratReporting System. The sample size ed, “when surgery is performed in a consisted of 31,498 surgeries (includ- low-volume center, there is a trend towards a protective benefit of having complications managed at an alternate institution.”

Key Points He noted that the reasons for n Urologic cancer surgery is often linked with significant morbidity these disparities warrant further and mortality investigation. n Patients who are readmitted after a surgery to a hospital that “Understanding the impact that is different than their original hospital are more likely to have site of readmission has on health complications than those readmitted to their original surgical hospital outcomes will inform clinical ben Complication rates were the highest for patients who had haviors around discharge disposiundergone radical cystectomy or radical nephrectomy tion and patient transfers in order to n The complications rate was 6.1% for patients readmitted to ensure optimization of healthcare secondary hospitals compared with 4.1% for those readmitted to value after major cancer surgery,” their original surgical hospital he concluded. l

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Payment Reform

Federal Government Outlines Stage 3 of Meaningful Use

By Rosemary Frei, MSc

C

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riteria for stage 3 of Meaningful Use was announced and published recently, detailing benchmarks that eligible providers and hospitals will have to meet to qualify for certain incentive payments and avoid reimbursement penalties. The proposed ruling by the US Department of Health & Human Services and the Centers for Medicare & Medicaid Services (CMS) outlines a framework that is in some ways more flexible and in others more rigid than stage 1 and stage 2.

“These changes…support our broader efforts to increase simplicity and flexibility in the program while driving interoperability and a focus on patient outcomes in the meaningful use program,” according to a summary of the proposed rule.

As part of stage 3, providers will need to attest to 2 of 3 measures associated with each of the main categories of Meaningful Use: coordi­ nation of care through patient engagement, health information exchange, and public health reporting.

Providers may continue to use 2014 edition electronic health record (EHR) technology through 2017.

There are still exceptions for providers in rural areas or who practice at more than 1 location, as well as for lack of availability of Internet access, newly practicing providers and hospitals, and unforeseen circumstances such as natural disasters.

In addition, the thresholds of most measures have been increased, such as having to use computerized provider order entry (CPOE) systems for >80% of all prescriptions (up from 50% in stage 2), >60% of all laboratory test orders, and >60% of diagnostic imaging orders. Furthermore, stage 3 also requires that >80% of all patients

seen by a provider or discharged from a hospital or emergency department have access to their health information within 24 hours of its availability to the provider.

Compliance with stage 3 requirements will be optional for providers in 2017, but mandatory for all eligible providers starting in 2018 regardless of previous participation in stage 1 or stage 2. CMS also intends stage 3 to be the last stage of Meaningful Use.

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The proposed ruling outlines a framework that is in some ways more flexible and in others more rigid than stage 1 and stage 2.

“The incorporation of the requirements into one stage for all providers is intended to respond to stakeholder input regarding the complexity of the program, the success of certain measures which are part of the meaningful use program to date, and the need to set a long-term, sustainable foundation based on a consolidated set of key advanced use objectives for the Medicare and Medicaid EHR Incentive Programs,” according to the executive summary.

Other key conditions in stage 3, in addition to the raised thresholds described previously, include the following: • Reporting for a full calendar year starting in 2017 for nearly all providers instead of 90 days • Successfully meeting the criteria associated with each of 8 specified

June 2015

program objectives (protect patient health information, electronic prescribing, clinical decision support, CPOE, patient electronic access to their health information, coordination of care through patient engagement, health information exchange, and public health and clinical data registry reporting); in measures with 3 subsets, achieving at least 2 of the 3 • Using secure messages via the electronic messaging function of EHRs to communicate with more than 35% of patients • For more than 40% of new patients and for more than 50% of existing patients being transitioned to other care facilities or providers, creating a summary of the care record in the EHR and sending it electronically to the new providers/facilities.

The executive summary states that the “stage 3 proposed rule would… focus on the advanced use of EHR technology to promote improved patient outcomes and health information exchange.…[It also] would further support efforts to align the EHR Incentive Programs with other CMS quality reporting programs that use certified EHR technology, such as the Hospital Inpatient Quality Reporting (IQR) and Physician Quality Reporting System (PQRS) programs, as well as continue alignment across care settings for providers demonstrating meaningful use.”

CMS has given providers and other stakeholders 2 months to submit comments regarding this rule from the date the rule was published.

Comments and feedback are due by May 29 and can be submitted by visiting www.regulations.gov and referring to file code CMS-3310-P. l

Payment Reform

Repeal of Sustainable Growth Rate Met with Relief

By Laura Morgan

T

he April 14, 2015, repeal of the sustainable growth rate (SGR) formula for physician payments under Medicare is being welcomed by the healthcare community, including the American Society of Clinical Oncology (ASCO). The 392 to 37 vote to pass H.R. 2, called the Medicare Access and Children’s Health Insurance Program Reauthorization Act of 2015, came just in time to avoid the 21% cut in Medicare fees that would have come into effect after the most recent SGR patch expired on March 31, 2015.

Alternative Payment Models Among the provisions of the SGR repeal legislation is a continued emphasis on alternative payment models. Specialists are among those being encouraged to use this approach.

Shortly before the SGR repeal, the US Department of Health & Human Services (HHS) Secretary Sylvia M. Burwell wrote that, “Our target is to have 30% of Medicare payments tied to quality or value through alternative payment models by the end of 2016, and 50% of payments by the end of 2018….We plan to develop and test new payment models for specialty care...” (Burwell SM. N Engl J Med. 2015;372:897-899).

“We think this is a vast improvement over where we’ve been over the last 5 years. And we’re really appreciative of the way Congress worked closely with the physician community over this,” ASCO’s Government Relations Committee Chair, Blase N. Polite, MD, MPH, Assistant Professor of Medicine, University of Chicago, told Urology Practice Management (UPM). “Congress’s intent, we believe, is to allow flexibility—we think there will be 3 or 4 different models for alternative payment models in oncology. You don’t want ev-

Providers who avoid merit-based incentive payment systems by participating in an alternative payment model will receive a 5% bonus an-

erybody to go to the same model; you want HHS to establish the ground rules, and then let innovation come from physicians.”

“You don’t want everybody to go to the same model; you want HHS to establish the ground rules, and then let innovation come from physicians.”

—Blase N. Polite, MD, MPH

Merit-Based Incentive Payment System The new bill also states that healthcare “professionals who receive a significant share of their revenues through an alternative payment model(s)” and meet several criteria will not be subject to the merit-based incentive payment system. Merit-­ based incentive payment systems will come into effect in 2019 and will unify the onerous requirements of the Physician Quality Reporting System, the value-based payment modifier, and the meaningful use of electronic health records. This provides another incentive to move to alternative payment models, said Dr Polite.

“What they [HHS] want you to do is move completely away from feefor-service reimbursement and to value-based reimbursement—they’re asking us to blow up the current system and start doing things differently. And they’re providing a strong incentive to do that in several ways, one of which is to join an alternative payment model and avoid all the requirements associated with merit-­ based incentive payment systems,” Dr Polite told UPM.

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nually from 2019 to 2024. Then, starting in 2026, providers who participate in alternative payment models and meet various criteria will receive an annual 0.75% payment increase, whereas those still participating in other payment systems will only receive increases of 0.25% annually.

Future of the Sustainable Growth Rate The future still remains uncertain, however, noted Robert Steinbrook, MD, Adjunct Professor of General Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, in an article about the SGR repeal (Steinbrook R. JAMA. 2015;313:2025-2026).

“At some point, the cumulative effect of the new payment updates will not keep up with physician costs, unless the volume and cost of services substantially decrease, which is the same underlying issue as with the old payment updates,” Dr Steinbrook pointed out. “The SGR formula lasted 18 years. Within the decade, its replacement is likely to be under scrutiny as well.” l

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Wealth Management

Seven Steps to Finding the Right Financial Advisor

By W. Ben Utley, CFP, and Lawrence B. Keller, CFP, CLU, ChFC, RHU, LUTCF

Credentials and Certifications Finding the right financial advisor to help you build your financial future can be as challenging as choosing the right doctor to care for your health, so it is important to look for several key credentials. Following is a brief summary of some of the most recognizable designations or certifications that you might see among financial service professionals and what it takes to earn them.

Certified Public Accountant (CPA): CPAs provide you with advice on tax matters and help you prepare and

submit your income tax returns to the Internal Revenue Service. To be a CPA, candidates must pass a 14hour computer-based test with 4 sections: auditing and attestation; financial accounting and reporting; regulation; and business environment and concepts. There are also work experience requirements that must be met. Not all accountants are CPAs. CPAs must meet stringent continuing education requirements and are regulated by states as well as their professionâ&#x20AC;&#x2122;s code of ethics.

Personal Financial Specialist (CPA/ PFS): A PFS is a CPA who has demonstrated both knowledge and significant practical experience in the area of personal financial planning. Only CPAs who are members of the American Institute of Certified Public Accountants can earn this designation.

Certified Financial Planner (CFP): The CFP certification is one of the most recognized and prestigious credentials in the financial services industry. CFPs have completed a series of courses in investments, insurance, income taxes, estate, and retirement planning. They have also passed a comprehensive 10-hour certification exam. Additionally, CFPs must have at least 3 years of planning experience and meet stringent continuing education requirements as well as have a bachelorâ&#x20AC;&#x2122;s degree. While an estimated 700,000 people currently call themselves financial planners, only 1 in 10 holds the CFP designation. If you need help with more than 1 issue in your financial life or if you are targeting long-term goals like retirement or college, make sure a CFP is on your list.

Chartered Financial Consultant (ChFC): ChFCs have credentials similar to CFPs. ChFCs have completed a series of courses and exams

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Lawrence B. Keller

s a physician with substantial income (or income potential), you will most likely be contacted by a number of individuals offering various types of financial products and services throughout your career. If you are in the market for an advisor, you will want to know the qualifications and experience level of each one you are considering. Unlike medicine, which has a standardized path that physicians must take to gain the education, training, and experience necessary to obtain board certification, the insurance and financial services industry does not. While advisors must pass certain tests to earn a license in securities or insurance, for the most part, anyone can call himself or herself a financial advisor.

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covering financial, insurance, and estate planning subjects. The ChFC program provides financial planners and others in the financial services industry with in-depth knowledge of the skills needed to perform comprehensive financial planning for their clients.

Chartered Life Underwriter (CLU): CLUs are insurance agents who have completed comprehensive educational courses and demonstrated expertise in different areas of estate and insurance planning. This designation is specifically designed to enhance the knowledge of people employed in the life insurance industry.

CLUs must also have at least 3 years of professional experience.

Chartered Financial Analyst (CFA): CFAs have expertise in investing and portfolio management. They have passed 3 exams based on investment principles, applied financial analysis, and investment management. Each exam is approximately 6 hours in length. Additionally, CFAs must have at least 3 years of expe­ rience in the investment decision-making process. Generally, the CFA designation is recognized as the definitive standard for measuring competence and integrity in the fields of portfolio management and investment analysis.

The Steps Financial planning takes the guesswork out of managing your finances and helps you understand the implications of each financial decision you make. Everyone has different goals, so it is important to have a unique plan that works for you and your financial situation, both now and in the future. The following 7 steps will help you find an advisor who understands and meets your unique goals and needs.

Wealth Management

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Make a Well-Founded List of Prospective Advisors Begin your research by conducting an Internet search using the terms “physician financial advisor” or “physician financial planner.”

Look for signs of expertise such as published articles, a book, or maybe even a blog. A search outside of your community means you increase the odds of finding the best-qualified advice for the price you may pay. A search inside of your state means that the advisors you find are more likely to understand your financial environment, including your state’s tax laws, economy, job market, unique investment opportunities, and other factors that may impact the success of your financial plan. If you are concerned about the advisor’s location, keep in mind that today many financial advisors work with clients by telephone, e-mail, and video conference on a regular basis.

Next, it is important to search a few specific organizations. CFP Board (www.cfp.net) is a nonprofit organization acting in the public interest by fostering professional standards in personal financial planning through its setting and enforcement of the education, examination, experience, ethics, and other requirements for CFP certification.

The National Association of Personal Financial Advisors (www. napfa.org) is the country’s leading professional association of fee-only financial advisors. Finally, the Financial Planning Association (www. plannersearch.org) is the largest membership organization for CFP professionals in the United States and also includes members who support the financial planning process.

To round out your list of prospective advisors, ask your colleagues, your accountant, and your attorney who they recommend. Ask them why they believe this advisor is the best one for you. If their reason sounds valid, add the advisor to your list.

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Select for Quality Every prospective financial advisor on your list should have at least 1 real credential. Beware of generic pseudocredentials like financial advisor, financial consultant, and wealth manager. These titles merely signify that an advisor is in the business and may hold a license. Whereas most licenses require an advisor to pay a fee and pass an exam, these may be easily acquired with a minimal commitment of time and effort.

Conduct an Interview Every advisor on your newly trimmed list warrants a preliminary phone call. This is an interview, and you are the interviewer, not the interviewee, so make sure that you get the answers you need.

First and foremost, ask the candidate how he or she is paid. Planners can be paid in several ways: through fees, commissions, or a combination of both. Your financial planner should clearly state how he or she will be paid for the services to be provided.

Although there is no single method of paying for financial services that is inherently better than another, you will nevertheless want to consider, and discuss with your planner, how the method of compensation could affect the advice you receive or the way you work with the advisor. You and your financial planner should discuss these issues, including any conflicts of interest that may be created by the method of compensation.

Then ask whether the advisor has ever been publicly disciplined for any unlawful or unethical actions in his or her professional career. Several government and professional regulatory organizations, such as the Financial Industry Regulatory Authority, your state insurance and securities departments, and the CFP Board keep rec­ ords on the disciplinary history of financial planners and advisors. If a CFP professional violates any of the CFP Board’s standards, he is subject to disciplinary action up to permanent revocation of certification. Ask which organizations the planner is regulated by and contact these groups to conduct a background check. You can also visit http://brokercheck.finra.org.

Make appointments to visit advisors who remain on your list after this screening round.

Whereas most licenses require an advisor to pay a fee and pass an exam,...certifications usually require a higher level of commitment and dedication.

In contrast, certifications usually require a higher level of commitment and dedication. Formal training, rigorous examination, continuing education, years of experience, and oversight by a board or governing body are part of attaining and keeping a certificate, so certification is an outward indicator of the quality of advice you may receive. Narrow your list by crossing advisors off your list if they do not have at least 1 of the previously listed credentials.

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Do Your Homework Learn more about the advisors who remain on your list. Visit their websites, and search for answers to questions such as the following: • How long have you been in business?

• What type of clients do you work with?

• What services do you provide?

• What is your specialty?

• What is your approach to financial planning?

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Speak with at Least 3 Prospective Advisors Now you are ready to make the biggest mistake that most people Continued on page 30

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Prostate Cancer

Programs Raise Awareness of Risks... Continued from page 9 compounded product). As of March 4, 2015, Dr Chang reported that the informational website had received 58 visits.

“Of the references listed,” Dr Chang noted, “the FDA summary Minutes from the Advisory Committee meeting on [testosterone replacement therapy] was visited the most. However, clicks for all refer-

ences were relatively low.”

Future Research Opportunities The impact of either intervention on pharmacy costs had not yet been fully captured, Dr Chang indicated.

In addition, the informational initiative did not have a control group, so it is unknown how much of a change in pharmacy costs would be attribut-

able to the intervention.

“We will continue to monitor the impact of the health plan–health system partnership and compare results to other health systems that did not receive any outreach,” Dr Chang concluded. “We will also look to explore different ways of presenting evidence-based assessments to broader groups of patients and providers.” l

Seven Steps to Finding the Right... Continued from page 29 make when selecting an advisor: engaging the very first advisor you meet. While this may solve your immediate problem, it may lead to lessthan-stellar results over the long haul. Why? Almost all advisors hold up well during the first interview.

They have been interviewed hundreds of times and are ready to sign you up today. Resist the temptation to sign up for services at the first meeting. Instead, collect information and get a feel for how you and the advisor might work together over the longer haul.

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Consider What You Have Learned Think about your interview with each advisor. Ask yourself these last few questions before making your final decision: • How well did each financial advisor listen to me? The hallmark of a good relationship with your financial advisor will be your ability to communicate your needs. This means that he or she must do an excellent job of listening to you in order to understand how he or she can help.

• How clearly did each financial advisor express himself or herself?

Even if you receive the very best financial advice from your new advisor, you might not follow the advice unless you fully understand it. Consider whether the advisor “speaks your language.”

• What promises did each financial advisor make? Consider how each advisor attempted to win you as a client. The best advisors attempt to set clear, realistic expectations about your work with them during the very first meeting. They know the foundation for a great, longterm advisor–client relationship is their ability to make promises and deliver on them.

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Select a Financial Advisor Who Suits You When you finally decide which advisor to hire, you may realize something that good financial advisors already know: the financial advisor you choose may be a lot like you. People have a natural tendency to trust others who are much like themselves, so the advisor you choose will likely share your inter-

ests, your outlook, and even some of the same financial goals you hold.

Summary No matter which financial advisor you choose, make sure the one thing that you have in common is an uncompromised interest in your financial health. Start your search for a competent financial advisor today and begin enjoying better financial health tomorrow. l W. Ben Utley, CFP, is the lead advisor with Physician Family Financial Advisors, a fee-only financial planning firm helping doctors throughout the United States to save for college and invest for retirement. He can be reached at 541463-0899 or by e-mail to ben@physi cianfamily.com.

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 516-677-6211 or by e-mail to Lkeller@physicianfinancialservices. com with comments or questions.

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Drug Coding Supplied by RJ Health Systems

FDA-Approved Medications Used for the Treatment of Prostate Cancer The following sections will assist healthcare professionals and payers by providing appropriate coding and billing information associated with the treatment of prostate cancer.

The following sections include: • Associated ICD-9-CM codes used for the classification of prostate cancer • Drugs that have been FDA approved in the treatment of prostate cancer • Drugs that are Compendia-listed for off-label use for prostate cancer based on clinical studies that suggest beneficial use in some cases. Please note: If a check mark appears in the FDA column, it will NOT appear in the Compendia off-label use column • Corresponding HCPCS/CPT® codes and code descriptions

Associated ICD-9-CM codes for the treatment of prostate cancer: 185

Malignant neoplasm of prostate Excludes: s eminal vesicles (187.8)

FDA approved for prostate cancer

Compendia off-label uses for prostate cancer

Possible CPT ® administration codes

Generic (brand) name

HCPCS code – code description

abiraterone acetate (Zytiga)

J8999* – Prescription drug, oral, chemotherapeutic, not otherwise specified

√

N/A

abiraterone acetate (Zytiga)

C9399* – Unclassified drugs or ­biologicals (hospital outpatient ­ use ONLY)

√

N/A

Bacillus CalmetteGuerin (Tice BCG)

90585 – Bacillus Calmette-Guerin (BCG) vaccine for tuberculosis, live, for percutaneous use

√

90471

Bacillus CalmetteGuerin (Tice BCG, TheraCys)

90586 – Bacillus Calmette-Guerin (BCG) vaccine for bladder cancer, live, for intravesical use

√

51720

Bacillus CalmetteGuerin (Tice BCG, TheraCys)

J9031 – BCG (intravesical), ­ per installation

√

51720

bevacizumab (Avastin)

J9035 – Injection, bevacizumab, 10 mg

√

96413, 96415

bicalutamide (Casodex)

J8999* – Prescription drug, oral, chemotherapeutic, not otherwise specified

√

N/A

cabazitaxel (Jevtana)

J9043 – Injection, cabazitaxel, 1 mg

√

96413

cisplatin (Platinol-AQ)

J9060 – Injection, cisplatin, powder or solution, per 10 mg

√

96409, 96413, 96415

cyclophosphamide (Cytoxan)

J8530 – Cyclophosphamide, oral, 25 mg

√

N/A

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Drug Coding

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FDA approved for prostate cancer

Compendia off-label uses for prostate cancer

Possible CPT ® administration codes

√

96409, 96413, 96415

Generic (brand) name

HCPCS code – code description

cyclophosphamide (Cytoxan)

J9070 – Cyclophosphamide, 100 mg

degarelix (Firmagon)

J9155 – Injection, degarelix, 1 mg

dexamethasone (Decadron)

J8540 – Dexamethasone, oral, 0.25 mg

docetaxel (Taxotere, Docefrez)

J9171 – Injection, docetaxel, 1 mg

doxorubicin (Adriamycin)

J9000 – Injection, doxorubicin hydrochloride, 10 mg

enzalutamide (Xtandi)

C9399* – Unclassified drugs or biologicals (hospital outpatient use ONLY)

√

N/A

enzalutamide (Xtandi)

J8999* – Prescription drug, oral, chemotherapeutic, not otherwise specified

√

N/A

epirubicin (Ellence)

J9178 – Injection, epirubicin hydrochloride, 2 mg

estradiol valerate (Delestrogen)

J1380 – Injection, estradiol valerate, up to 10 mg

√

96372

estramustine (Emcyt)

J8999* – Prescription drug, oral, chemotherapeutic, not otherwise specified

√

N/A

estrogen (eg, estradiol, conjugated estrogen, esterified estrogen)

J8499* – Prescription drug, oral, nonchemotherapeutic, not otherwise specified

√

N/A

fluorouracil (Adrucil)

J9190 – Injection, fluorouracil, 500 mg

flutamide (Eulexin)

J8999* – Prescription drug, oral, chemotherapeutic, not otherwise specified

√

N/A

flutamide (Eulexin)

S0175 – Flutamide, oral, 125 mg

√

N/A

goserelin acetate (Zoladex)

J9202 – Goserelin acetate implant, per 3.6 mg

√

96372, 96402

histrelin (Vantas)

J9225 – Histrelin implant, 50 mg

√

11981, 11982, 11983

hydrocortisone (Solu-Cortef)

J1720 – Injection, hydrocortisone sodium succinate, up to 100 mg

√

96365, 96366, 96372, 96374

ixabepilone (Ixempra)

J9207 – Injection, ixabepilone, 1 mg

√

96413, 96415

ketoconazole (Nizoral)

J8499* – Prescription drug, oral, nonchemotherapeutic, not otherwise specified

√

N/A

leuprolide acetate (Eligard, Lupron Depot)

J9217 – Leuprolide acetate (for depot suspension), 7.5 mg

urology Practice Management

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June 2015

96402

√ √

96413

√ √

√

√

√

N/A

96409

96409, 96413

96409

96402

Drug Coding

FDA approved for prostate cancer

Compendia off-label uses for prostate cancer

Possible CPT ® administration codes

Generic (brand) name

HCPCS code – code description

leuprolide acetate (Lupron)

J9218 – Leuprolide acetate, per 1 mg

medroxyprogesterone (Depo-Provera)

J1050 – Injection, medroxyprogesterone acetate, 1 mg

√

96402

melphalan (Alkeran)

J8600 – Melphalan, oral, 2 mg

√

N/A

melphalan (Alkeran)

J9245 – Injection, melphalan hydrochloride, 50 mg

√

96409, 96413

methylprednisolone (Medrol)

J7509 – Methylprednisolone, oral, per 4 mg

√

N/A

methylprednisolone (Depo-Medrol)

J1020 – Injection, methylprednisolone acetate, 20 mg

√

11900, 11901, 20600, 20605, 20610, 96372

methylprednisolone (Depo-Medrol)

J1030 – Injection, methylprednisolone acetate, 40 mg

√

11900, 11901, 20600, 20605, 20610, 96372

methylprednisolone (Depo-Medrol)

J1040 – Injection, methylprednisolone acetate, 80 mg

√

11900, 11901, 20600, 20605, 20610, 96372

methylprednisolone (Solu-Medrol)

J2920 – Injection, methylprednisolone sodium succinate, up to 40 mg

√

96365, 96366, 96372, 96374

methylprednisolone (Solu-Medrol)

J2930 – Injection, methylprednisolone sodium succinate, up to 125 mg

√

96365, 96366, 96372, 96374

mitoxantrone (Novantrone)

J9293 – Injection, mitoxantrone hydrochloride, per 5 mg

√

96409, 96413

nilutamide (Nilandron)

J8999* – Prescription drug, oral, chemotherapeutic, not otherwise specified

√

N/A

paclitaxel (Taxol)

J9265 – Injection, paclitaxel, 30 mg

√

96413, 96415

prednisolone (eg, Orapred, Millipred)

J7510 – Prednisolone, oral, per 5 mg

√

N/A

prednisone (Deltasone)

J7506 – Prednisone, oral, per 5 mg

√

N/A

radium Ra dichloride (Xofigo)

A9606 – radium Ra-223 dichloride, therapeutic, per microcurie

√

79101

sipuleucel-T (Provenge) Q2043 – Sipuleucel-T, minimum of 50 million autologous CD54+ cells activated with PAP-GM-CSF, including leukapheresis and all other preparatory procedures, per infusion (code price is per 250 mL)

√

96413, 96415

topotecan (Hycamtin)

96402

√

J9351 – Injection, topotecan, 0.1 mg

trastuzumab (Herceptin) J9355 – Injection, trastuzumab, 10 mg

June 2015

I

√

96413

√

96413, 96415

www.UroPracticeManagement.com

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33

Drug Coding

FDA approved for prostate cancer

Compendia off-label uses for prostate cancer

Possible CPT ® administration codes

Generic (brand) name

HCPCS code – code description

triptorelin (Trelstar Depot, Trelstar LA)

J3315 – Injection, triptorelin pamoate, 3.75 mg

vinBLAStine (Velban)

J9360 – Injection, vinblastine sulfate, 1 mg

√

96409

vinorelbine (Navelbine)

J9390 – Injection, vinorelbine tartrate, per 10 mg

√

96409

96372, 96402

√

*When billing a nonclassified medication using a CMS 1500 claim form, you must include both the HCPCS code in Item 24D and the drug name, strength, and NDC (National Drug Code) in Item 19 or Item 24A (shaded area) in order to ensure appropriate reimbursement.

Please note: Check with payer regarding correct placement of medication information.

References • HCPCS Level II Expert 2015 • Current Procedural Terminology (CPT ®) 2015 • CPT copyright 2015 American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association • ICD-9-CM for Professionals Volumes 1 & 2, 2015 • FDA-approved indication (product Prescribing Information) • Compendia references available upon request • www.ReimbursementCodes.com powered by RJ Health Systems International, LLC, Rocky Hill, Connecticut • CMS (Centers for Medicare & Medicaid Services) CPT ® indicates Current Procedural Terminology ; HCPCS, Healthcare Common Procedure Coding System; PAP-GM-CSF, prostatic acid phosphatase granulocyte-macrophage colony-stimulating factor.

This information was supplied by

30 Cold Spring Road, Rocky Hill, CT 06067 T: (860) 563-1223 F: (860) 563-1650

www.RJHealthSystems.com

34

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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 ≥2.5 XULN 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.

Musculoskeletal and Connective Tissue Disorders: myopathy, including rhabdomyolysis.

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 enzymes CYP2D6 and CYP2C8. In

ZYTIGA® (abiraterone acetate) Tablets

ZYTIGA® (abiraterone acetate) Tablets

a CYP2D6 drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively, when 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 a CYP2C8 drug-drug interaction trial in healthy subjects, the AUC of pioglitazone (CYP2C8 substrate) was increased by 46% when pioglitazone was given together with a single dose of 1,000 mg abiraterone acetate.

Therefore, patients should be monitored closely for signs of toxicity related to a CYP2C8 substrate with a narrow therapeutic index if used concomitantly with ZYTIGA [see 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.

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].

Manufactured by: Patheon Inc. Mississauga, Canada Manufactured for: Janssen Biotech, Inc. Horsham, PA 19044 ©Janssen Biotech, Inc. 2012 Revised: March 2015 030924-150310

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