December 2011 VOL 1, NO 4

ONCOLOGY PRACTICE MANAGEMENT ™

PROCESS IMPROVEMENTS TO ENHANCE PATIENT CARE™

www.OncPracticeManagement.com

DECEMBER 2011

VOLUME 1 • NUMBER 4

From the Editor

10 Steps to MedPAC under Fire for Achieve Proposed SGR Fix “Meaningful Use” Oncologists Face Particular Challenges under This Model Innovation and Change for Community Oncology

By Carla C. Wood, CPC, MS

By Dawn Holcombe, MBA, FACMPE, ACHE

O

n October 6, 2011, the Medicare Payment Advisory Commission (MedPAC) proposed a way that Congress, if it wanted to eliminate the sustainable growth rate (SGR) formula without raising the federal deficit and within the confines of Medicare, could approach an SGR fix. Since that proposal, the opposition has been deafening.

The MedPAC proposal would change the ratio between primary care and specialists for good. The plan is to freeze fees for primary care services for 10 years, while payments for all other services would be reduced by 5.9% for each of the first 3 years, followed by a freeze for the remaining 7 years.

Before the final MedPAC proposal was Continued on page 6

From the publishers of ©2011 Engage Healthcare Communications, LLC

Linda Bosserman, MD, at the 2011 Cancer Center Business Summit.

The pilot, launched on June 1, 2011, was Continued on page 3

ca t l

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hicago, IL—Wilshire Oncology’s patient-centered medical oncology home pilot has transformed care by offering maximum support of patients throughout their treatments, including attention to patients between office visits to minimize side effects and symptoms.

Details of the development and engagement process, the plan to aggressively manage symptoms to reduce cost, and the payment methodology were offered by

N Br T ou A g C ht N om to D W m y PR o i Ph ll t un u h b ys e ity y OV ic S C t In ian uns an he IDE te –P h ce As ra h ine r so R A ct ar A Ce ci C io m c n at n? a t A te io C ... ce ff rs n o E SS ..4 ut ec f 5 i

Continued on page 8

By Wayne Kuznar

PA TIE

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or oncology to move forward, innovation is required. Science, technology, patient care, and communication are all components of this move toward significant improvement. With the advent of government incentives to encourage the uptake of oncologists’ use of technology in a meaningful way, the pressure is on vendors to adapt standards set by the government oversight body, the Office of the National Coordinator (ONC) for Health Information Technology (HIT). This is development, but not necessarily innovation.

True innovation comes when the

Wilshire’s Medical Oncology Home Project: Re-Engineering the Oncology Practice

Cracking the Code

A N N O U N C I N G A N E W J - C O D E F O R X G E V A® A N D P R O L I A® — XGEVA® and Prolia® will have a permanent HCPCS on January 1, 2012 — This new J0897 code will replace miscellaneous codes J3490, J3590, and C9272, which providers have been using to bill for XGEVA ® and Prolia ® to date

HCPCS CODE

DESCRIPTION

EFFECTIVE

J0897

Injection, denosumab, 1 mg

January 1, 2012

www.AmgenAssistOnline.com 1-888-4ASSIST (1-888-427-7478) © 2011 Amgen. All rights reserved. 63513-R1-V1 11/11

Cancer Center Business Summit

Wilshire’s Medical…

Editor-in-Chief Dawn Holcombe, MBA, FACMPE, ACHE President DGH Consulting South Windsor, CT

Editorial Advisory Board Ronald Barkley, MS, JD President Cancer Center Business Development Group Bedford, NH Peggy Barton, RN Practice Manager Toledo Clinic Toledo, OH Risë Marie Cleland President Oplinc, Inc Lawton, OK

Teri U. Guidi, MBA, FAAMA President & CEO Oncology Management Consulting Group Pipersville, PA Ruth Lander, RN, FACMPE Practice Administrator Columbus Oncology & Hematology Associates, Inc Columbus, OH

Bruce A. Cutter, MD President Cutter HealthCare Consulting Spokane, WA

Bonnie J. Miller, RN, BSN, OCN, FAAMA Administrative Director Women’s Cancer Center Fox Chase Cancer Center Philadelphia, PA

Craig Deligdish, MD Medical Director Florida Comprehensive Cancer Network Melbourne, FL

Cindy C. Parman, CPC, CPC-H, RCC CSI Coding Strategies Inc Powder Springs, GA

Patrick A. Grusenmeyer, ScD, FACHE President Christiana Care Health Initiatives Newark, DE

Jeffrey A. Scott, MD Senior Vice President Cardinal Health Dublin, OH Carla C. Wood, CPC, MS President Altos Solutions, Inc Los Altos, CA

Continued from the cover

developed in conjunction with Anthem Blue Cross, CA, which makes it available to some of its members with cancer living in Los Angeles, San Bernardino, and Riverside counties. “We were able to move beyond breast, colon, and lung, to all of our cancer patients being part of this model for payment,” said Dr Bosserman, clinical oncologist and President of the Wilshire Oncology Medical Group.

The medical oncology home pilot offers additional reimbursement for clinicians, symptom management support by nurses, advance care planning, and collaboration with urgent care centers to reduce the number of costly emergency department visits.

Care transformation requires a re-engineering of the practice “from the ground up,” and has resulted in partnerships with payers and providers that have transformed payment methodology to support desired care, said Dr Bosserman. The development process with the health plan took 3 years.

“We’re up 450% in the patients we care for over 3 years. They have never seen such efficiency.”

—Linda Bosserman, MD

“We worked for the past 6 to 10 years to re-engineer every step of our practice…being a group, having group meetings, and agreeing to group standards…having data, feeding back data, continuous improvement, working at every level of the staff to be efficient and fully engage the mission,” she said.

Wilshire has contracts to provide care in 2 counties in California, where 26% of patients are uninsured. “We’re up 450% in the patients we care for over 3 years,” she said.

“They have never seen such efficiency.”

Engaging Payers Engaging payers was an important initial step in the development process to build a medical oncology home.

“We started out with our major payer in California, and we had to build a personal relationship,” she said. “I got on the board of Blue Cross of California—I’m on the physician committee that passes all final decisions for the health plan for the state. Attending quarterly meetings gave me access to decision makers.”

Engagement of medical directors, contracting, actuaries, Continued on page 19

December 2011

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In This Issue

PUBLISHING STAFF

FEATURES

Publisher Nicholas Englezos nick@engagehc.com 732-992-1884

CASE STUDY Practice Changes in Management of Patients Receiving Oral Chemotherapy ..................................13

Associate Publisher Maurice Nogueira maurice@engagehc.com 732-992-1895

By Robert Mancini, PharmD, Dave Wilson, RPh, Colleen Powell, CPhT, and Clementine Mehrens

Director, Client Services Cristopher Pires cris@engagehc.com 732-992-1896

CANCER CENTER BUSINESS SUMMIT First Level III Oncology Medical Home ...................19

Editorial Director Dalia Buffery dalia@engagehc.com 732-992-1889 Editorial Assistant Jennifer Brandt Jennifer@generaladminllc.com 732-992-1536 Production Manager Marie R. S. Borelli Quality Control Director Barbara Marino Business Manager Blanche Marchitto MISSION STATEMENT Oncology healthcare requires providers to focus attention on financial concerns and strategic decisions that affect the bottom line. To continue to provide the highquality care cancer patients deserve, providers must master the ever-changing business of oncology. Oncology Practice Management will offer process solutions for members of the cancer care team— medical, surgical, and radiation oncologists, 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.

VOPM4

Accountable Care Organizations Paying Little Attention to Oncology Services..................................27 DRUG CODING Medications Used for the Treatment of Breast Cancer ..............................................................34 ONCOLOGY NETWORKS Enhancing Oncology Networks..................................42

By Gerard M. Nussbaum and Laura K. Rehfeld

DEPARTMENTS Physician Wealth Management with Lawrence B. Keller, CLU, ChFC, CFP®

Selecting the Best Rider for Your Policy ........................40 Patient and Provider Access brought to you by the Association of Community Cancer Centers

Will the Sunshine Act Affect Physician-Pharmaceutical Interaction?…....................................................................45

By Sydney Abbott, JD

Oncology Practice Management™ is published 4 times a year by Engage Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205A, Monroe Township, NJ 08831. Copyright © 2011 by Engage Healthcare Communications, LLC. All rights reserved. Oncology Practice Management™ is a registered 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. ISSN: applied for.

The ideas and opinions expressed in Oncology 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 Oncology 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.

Postmaster: Correspondence regarding subscriptions or change of address should be directed to CIRCULATION DIRECTOR, Oncology Practice Management™, 241 Forsgate Drive, Suite 205A, Monroe Township, NJ 08831. Fax: 732-992-1881. Yearly subscription rates: 1 year: $99.00 USD; 2 years: $149.00 USD; 3 years: $199.00 USD.

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ONCOLOGY PRACTICE MANAGEMENT

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December 2011

Want integrated care? You need integrated technology.

At McKesson Specialty Health, we combine our in-depth software development experience and oncology practice knowledge to create an integrated technology platform that delivers the solutions you need for an enhanced level of comprehensive, patient-centered care.

Proven, market-leading solutions like our iKnowMed™ EHR and Lynx Mobile® provide practice support while helping you increase your practice productivity, revenue and clinical strength. The result? Even more effective patient care and practice success.

To learn more about McKesson Specialty Health, visit mckessonspecialtyhealth.com/oncology or contact us at: 800.482.6700, Option 4

© 2011 McKesson Specialty Health. All rights reserved.

MedPAC and SGR

MedPAC under Fire‌Continued from the cover revealed, a number of medical organizations, including the American Medical Association, the American College of Cardiology, the American College of Emergency Physicians, the American College of Physicians, the American College of Surgeons, and the American Psychiatric Association, had already urged MedPAC to revise the proposal as it was outlined in an earlier, September draft.

Concerns have ranged from the impracticality of freezing reimbursements to physicians (many of whom operate as small businesses) over 10 years in the face of escalating operating costs, staffing challenges, and technology demands to the needless creation of misaligned interests between primary and specialty doctors, at a time when collaboration and continuity of care is a harbinger of quality and cost-effective care delivery.

Two of the 17 MedPAC commissioners also spoke against the recommendation: both are specialty physicians, expressing concerns about specialty practice viability and the escalating impact from other payers that peg payments to Medicare rates, such as Medicaid.

Oncologists face particular challenges under this MedPAC model: changes in Medicare reimbursement; new edits and service bundling; and changes in base rates of the values for physician work, practice expenses, and geographic indicators have dramatically reduced oncology-related professional fees, in addition to the

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average selling price–related drug reimbursement reductions.

In 2011, few oncologists are covering the costs of treating Medicare patients from direct Medicare reimbursement, and patients are finding it increasingly harder to fund their own copay and coinsurance responsi-

It falls to everyone affected by the MedPAC proposal to productively communicate with Congress and CMS about the impact of focusing solely on funding an SGR fix from within the physician services bucket, and to consider how changes in communication and measurement of quality and care shifting may be better brought into the picture.

bilities, particularly for Medicare Advantage programs. Three years of 5.9% reductions and a 7-year freeze in payments are likely to dramatically change the ability of physicians to provide cancer services to Medicare patients, whether the physician is self-employed or employed by a

ONCOLOGY PRACTICE MANAGEMENT

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December 2011

hospital or by another organization.

Fortunately, oncologists are not alone in expressing concern about this new MedPAC proposal; they can stand with their other physician colleagues from many other specialties.

Congress and the Centers for Medicare & Medicaid Services (CMS) have often not accepted MedPAC recommendations over the years. By engaging in a strong and productive dialogue about the myriad of patient access issues, as well as quality and continuity of care issues that would be created by this MedPAC proposal, the medical community should be able to help those who are in a position to decide to accept or ignore this proposal.

As an alternative, many believe that physicians can be a valued part of the solution to healthcare cost reduction. Traditionally, Medicare Part A (hospital costs) and Part B (physician services) do not communicate or look at related costs of care. Reductions in physician reimbursement quickly lead to increases in more costly care from the nonphysician (usually hospital-based) sector.

It falls to everyone affected by the MedPAC proposal to productively communicate with Congress and CMS about the impact of focusing solely on funding an SGR fix from within the physician services bucket, and to consider how changes in communication and measurement of quality and care shifting may be better brought into the picture. It is not enough to challenge MedPAC for its proposal; it is also necessary to provide suggestions for alternative solutions. l

CANCER DRUG REIMBURSEMENT IS COMPLEX. FINANCIAL BARRIERS EXIST FOR YOUR PATIENTS. IS THE SOLUTION. The OncoADVOCATE Program FOR HEALTH. FOR HELP. FOR YOU. The OncoAdvocate Program is dedicated to helping patients who need financial assistance and support achieve comprehensive access to their oncology drug treatments. In the process, OncoMed relieves your practice of the burden of finding reimbursement solutions and lets you focus on your patient’s health.

Pharmacy / 877.662.6633

Fax / 877.662.6355

Website / OncoMed.net

Innovation

10 Steps…Continued from the cover enhanced technology is fully used and implemented in an oncologist’s office.

A well-run oncology office is a beautiful sight to behold, but one often gets the impression it is a tightrope walk every month. The balance of workload on human resources, finances, and patient health is the primary concern of any oncology practice. And technology, at its best, can help each of these areas significantly.

The Centers for Medicare & Medicaid Services (CMS) Electronic Health Record (EHR) Incentive Program requires HIT be at its best to allow physicians to achieve and successfully attest to “meaningful use,” defined as “ways that can be measured significantly in quality and in quantity.” As overwhelming as achieving meaningful use may seem, however, it can be done.

Implementation and Attestation Northern Hematology Oncology is a community oncology practice in Thornton, CO, that implemented a 2011/2012 ONC-certified EHR system in March 2011 and successfully attested to meaningful use by the end of July, within approximately 120 days. To be clear, this group went from a paper medical chart environment to fully compliant meaningful use workflow in a paperless EHR system in less than 120 days.

Analysis of the successful attestations using this EHR indicates that the innovation was the practice’s adaptability and openness to change throughout the entire team.

Strong physician leadership clearly set expectations for the staff, and also led by example. These doctors, busy with learning a new EHR system, took the time to implement the new technology in a way that set up success for receiving CMS incentives.

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This impressive implementation— and resulting attestation and incentive payments—can be replicated in any oncology practice. The trainers and support staff of the EHR system offer the following 10-step guide to successful meaningful use implementation and attestation.

1

Review all the required meaningful use criteria on the CMS website (www.cms.gov/EHRIncentive Programs/30_Meaningful_Use.asp).

You may choose from Medicare or Medicaid incentive programs.

2

Register each of your eligible providers (physicians) at www.cms. gov/EHRIncentivePrograms/20_Reg istrationandAttestation.asp. It is the

A well-run oncology office is a beautiful sight to behold, but one often gets the impression it is a tightrope walk every month. The balance of workload on human resources, finances, and patient health is the primary concern of any oncology practice.

(http://onc-chpl.force.com/ehrcert).

4

Meet with the entire staff to provide an overview of meaningful use and its requirements for 2011/ 2012, known as Stage 1. Include mention of the eventual penalties if a practice isn’t compliant by 2015.

5

Review criteria for meaningful use and the separate clinical quality measures. Note: the meaningful use criteria are all pass or fail. Each provider must pass each measure for a minimum of 90 days for the first reporting year. Subsequent years require reporting for the entire year. If you fail one meaningful use item within the 90-day reporting period, you receive no prize.

The good news is that clinical quality measures do not require a pass/fail threshold. Each physician is simply responsible for reporting numerators and denominators for each chosen quality measure.

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Evaluate the holes in your practice’s current workflow. If your group currently does not assess patient smoking status, indicate this as a gap. If you do not provide access to a patient portal, put this on the gap list. Do not entertain any aversion to change around these gaps that must be filled. Change can be difficult, but the processes your practice puts in place now for Stage 1 will make the subsequent 2 stages less overwhelming.

7 eligible provider’s responsibility to understand and achieve the incentive requirements.

3

If you are not yet using an EHR system, implement an ONC-certified complete EHR. The ONC provides a list of certified HIT products

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Assign staff members responsibility for workflow changes required for meaningful use. If your practice’s chemotherapy nurses provide patient education, make each nurse responsible for providing patients with a documented patient education experience. If the medical assistants usually enter vitals for the patients they Continued on page 9

American College of Oncology Administrators

Professionals dedicated to providing the best care to oncology patients. Here’s where you belong.

Transform Your Leadership Work Smarter Access Solutions Make Key Contacts Strengthen Your Skills

Annual Oncology Conference Addresses Oncology Management Strategies Chicago, June 20 – 22, 2012 Developed by and for oncology administrators with networking and exhibiting opportunities

Ensure Your Connections. Join Now. www.aameda.org • membership@aameda.org AAMA/ACOA • 701 Lee St., Suite 600 • Des Plaines, IL 60016 • Phone 847-759-8601 • Fax 847-759-8602 ACOA is a national College of the American Academy of Medical Administrators (AAMA)

Innovation

10 Steps…Continued from page 8 escort to the examination rooms, be sure they also include height, weight, and blood pressure in the chart.

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Monitor progress each week. Run a meaningful use report, if your EHR system includes this feature.

Alternatively, create a worksheet to evaluate your progress for each meaningful use measure. Take action to remediate any shortcomings as your providers must pass all measures for a full, consecutive 90 days. Each physician may have a different 90day reporting period if needed.

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Attest. The attestation is quick and easy. This must be done through CMS’s EHR Incentive Program Registration and Attestation System (https://ehrincentives.cms. gov/hitech/login.action). The website is well designed, and it is fairly easy to follow onscreen instructions.

For attestation, you will need your meaningful use report printed and ready to reference, as well as your numerators and denominators for the clinical quality measures.

Sign in and answer all the questions. Each physician will need to

December 2011

complete the attestation, because it requires a statement of attestation and electronic signature. Upon successful attestation, make a note of the attestation number, which is basically a tracking number to allow you to track payment.

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Last, but not least, receive money.

Upon your successful attestation, the celebration of your healthcare innovation should be enjoyed by all.

Share your story, and assist others in their quest to become meaningful. l

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New D eaar M di FFollow-up ll p N Median Data: 55-Y 5-Year YYe Year

In combination with MP* vs MP alone for previously untreated multiple myeloma

VELCADE DELIVERED 13-MONTH OVERALL SURVIVAL ADVANTAGE At 3-Year Median Follow-up, VELCADE® (bortezomib)+MP Provided an OS Advantage Over MP That Was Not Regained With Subsequent Therapies ▼ Of the 69% of MP patients who received subsequent therapies, 50% received VELCADE or a VELCADE-containing regimen1

VELCADE is indicated for the treatment of patients with multiple myeloma.

VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol.

For Patient Assistance Information or Reimbursement Assistance, call 1-866-VELCADE (835-2233), Option 2, or visit VELCADE.com *Melphalan+prednisone. †

VISTA: a randomized, open-label, international phase 3 trial (N=682) evaluating the efficacy and safety of VELCADE in combination with MP vs MP in previously untreated multiple myeloma. The primary endpoint was TTP. Secondary endpoints were CR, ORR, PFS, and OS. At a pre-specified interim analysis (median follow-up 16.3 months), VcMP‡ resulted in significantly superior results for TTP, PFS, OS, and ORR. Further enrollment was halted and patients receiving MP were offered VELCADE in addition.

‡

VELCADE (Vc) in combination with MP.

Reference: 1. Mateos M-V, Richardson PG, Schlag R, et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial. J Clin Oncol. 2010;28(13):2259-2266.

UPDATED VISTA† TRIAL ANALYSIS (60.1-MONTH MEDIAN FOLLOW-UP) 100 90

Median overall survival: survival:

80

556.4 6 .4 vs 443.1 3..1 m months onths

PPatients atients Sur Surviving viving (%)

HR=0.695 (95% CI, 0.57-0.85); P<0.05 P<0.05 <0 < 05 70 60 50 40 30 20

VELC ADE+MP (n=344) VELCADE+MP

10

MP ((n=338) n=338)

0 0

12

24

36

Kaplan-Meier estimate.

48

60

72

Months

IMPORTANT SAFETY INFORMATION VELCADE Warnings and Precautions

Adverse Reactions

▼ Women should avoid becoming pregnant while being treated with VELCADE. Pregnant women should be apprised of the potential harm to the fetus ▼ Peripheral neuropathy, including severe cases, may occur— manage with dose modification or discontinuation. Patients with pre-existing severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment ▼ Hypotension can occur. Caution should be used when treating patients receiving antihypertensives, those with a history of syncope, and those who are dehydrated ▼ Patients with risk factors for, or existing heart disease, should be closely monitored ▼ Acute diffuse infiltrative pulmonary disease has been reported ▼ Nausea, diarrhea, constipation, and vomiting have occurred and may require use of antiemetic and antidiarrheal medications or fluid replacement ▼ Thrombocytopenia or neutropenia can occur; complete blood counts should be regularly monitored throughout treatment ▼ Tumor Lysis Syndrome, Reversible Posterior Leukoencephalopathy Syndrome, and Acute Hepatic Failure have been reported

Most commonly reported adverse reactions (incidence ≥30%) in clinical studies include asthenic conditions, diarrhea, nausea, constipation, peripheral neuropathy, vomiting, pyrexia, thrombocytopenia, psychiatric disorders, anorexia and decreased appetite, neutropenia, neuralgia, leukopenia, and anemia. Other adverse reactions, including serious adverse reactions, have been reported Please see Brief Summary for VELCADE on next page.

Brief Summary INDICATIONS:

ADVERSE EVENT DATA:

VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma.

VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy.

Safety data from phase 2 and 3 studies of single-agent VELCADE 1.3 mg/m2/dose twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously treated multiple myeloma (N=1008, not including the phase 3, VELCADE plus DOXIL® [doxorubicin HCI liposome injection] study) and previously treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma.

CONTRAINDICATIONS: VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol.

WARNINGS AND PRECAUTIONS: VELCADE should be administered under the supervision of a physician experienced in the use of antineoplastic therapy. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory.

However, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. Patients experiencing new or worsening peripheral neuropathy may require change in the dose and schedule of VELCADE. Following dose adjustments, improvement in or resolution of peripheral neuropathy was reported in 51% of patients with ≥Grade 2 peripheral neuropathy in the relapsed multiple myeloma study. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma.

Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 13%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics.

Cardiac Disorders: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have been reported, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart disease should be closely monitored. In the relapsed multiple myeloma study, the incidence of any treatmentemergent cardiac disorder was 15% and 13% in the VELCADE and dexamethasone groups, respectively.

The incidence of heart failure events (acute pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock, pulmonary edema) was similar in the VELCADE and dexamethasone groups, 5% and 4%, respectively. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established.

Pulmonary Disorders: There have been reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome (ARDS) in patients receiving VELCADE. Some of these events have been fatal. In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, a prompt comprehensive diagnostic evaluation should be conducted.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): There have been reports of RPLS in patients receiving VELCADE. RPLS is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances.

Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing RPLS, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing RPLS is not known.

Gastrointestinal Adverse Events: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration.

Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study, the incidence of significant bleeding events (≥Grade 3) was similar on both the VELCADE (4%) and dexamethasone (5%) arms. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. There have been reports of gastrointestinal and intracerebral hemorrhage in association with VELCADE. Transfusions may be considered. The incidence of febrile neutropenia was <1%.

Tumor Lysis Syndrome: Because VELCADE is a cytotoxic agent and can rapidly kill malignant cells, the complications of tumor lysis syndrome may occur. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.

In the integrated analysis, the most commonly reported adverse events were asthenic conditions (including fatigue, malaise, and weakness); (64%), nausea (55%), diarrhea (52%), constipation (41%), peripheral neuropathy NEC (including peripheral sensory neuropathy and peripheral neuropathy aggravated); (39%), thrombocytopenia and appetite decreased (including anorexia); (each 36%), pyrexia (34%), vomiting (33%), anemia (29%), edema (23%), headache, paresthesia and dysesthesia (each 22%), dyspnea (21%), cough and insomnia (each 20%), rash (18%), arthralgia (17%), neutropenia and dizziness (excluding vertigo); (each 17%), pain in limb and abdominal pain (each 15%), bone pain (14%), back pain and hypotension (each 13%), herpes zoster, nasopharyngitis, upper respiratory tract infection, myalgia and pneumonia (each 12%), muscle cramps (11%), and dehydration and anxiety (each 10%). Twenty percent (20%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (5%) and neutropenia (3%). A total of 50% of patients experienced serious adverse events (SAEs) during the studies.

The most commonly reported SAEs included pneumonia (7%), pyrexia (6%), diarrhea (5%), vomiting (4%), and nausea, dehydration, dyspnea and thrombocytopenia (each 3%).

In the phase 3 VELCADE + melphalan and prednisone study, the safety profile of VELCADE in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone. The most commonly reported adverse events in this study (VELCADE+melphalan/ prednisone vs melphalan/prednisone) were thrombocytopenia (52% vs 47%), neutropenia (49% vs 46%), nausea (48% vs 28%), peripheral neuropathy (47% vs 5%), diarrhea (46% vs 17%), anemia (43% vs 55%), constipation (37% vs 16%), neuralgia (36% vs 1%), leukopenia (33% vs 30%), vomiting (33% vs 16%), pyrexia (29% vs 19%), fatigue (29% vs 26%), lymphopenia (24% vs 17%), anorexia (23% vs 10%), asthenia (21% vs 18%), cough (21% vs 13%), insomnia (20% vs 13%), edema peripheral (20% vs 10%), rash (19% vs 7%), back pain (17% vs 18%), pneumonia (16% vs 11%), dizziness (16% vs 11%), dyspnea (15% vs 13%), headache (14% vs 10%), pain in extremity (14% vs 9%), abdominal pain (14% vs 7%), paresthesia (13% vs 4%), herpes zoster (13% vs 4%), bronchitis (13% vs 8%), hypokalemia (13% vs 7%), hypertension (13% vs 7%), abdominal pain upper (12% vs 9%), hypotension (12% vs 3%), dyspepsia (11% vs 7%), nasopharyngitis (11% vs 8%), bone pain (11% vs 10%), arthralgia (11% vs 15%) and pruritus (10% vs 5%).

DRUG INTERACTIONS: Bortezomib is a substrate of cytochrome P450 enzyme 3A4, 2C19 and 1A2. Co-administration of ketoconazole, a strong CYP3A4 inhibitor, increased the exposure of bortezomib by 35% in 12 patients.

Therefore, patients should be closely monitored when given bortezomib in combination with strong CYP3A4 inhibitors (e.g. ketoconazole, ritonavir). Co-administration of omeprazole, a strong inhibitor of CYP2C19, had no effect on the exposure of bortezomib in 17 patients. Co-administration of rifampin, a strong CYP3A4 inducer, is expected to decrease the exposure of bortezomib by at least 45%. Because the drug interaction study (n=6) was not designed to exert the maximum effect of rifampin on bortezomib PK, decreases greater than 45% may occur. Efficacy may be reduced when VELCADE is used in combination with strong CYP3A4 inducers; therefore, concomitant use of strong CYP3A4 inducers is not recommended in patients receiving VELCADE. St. John’s Wort (Hypericum perforatum) may decrease bortezomib exposure unpredictably and should be avoided. Co-administration of dexamethasone, a weak CYP3A4 inducer, had no effect on the exposure of bortezomib in 7 patients. Co-administration of melphalan-prednisone increased the exposure of bortezomib by 17% in 21 patients. However, this increase is unlikely to be clinically relevant.

USE IN SPECIFIC POPULATIONS: Nursing Mothers: It is not known whether bortezomib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VELCADE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use: The safety and effectiveness of VELCADE in children has not been established.

Geriatric Use: No overall differences in safety or effectiveness were observed between patients ≥age 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out.

Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, the drug should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer’s prescribing information.

Patients with Hepatic Impairment: The exposure of VELCADE is increased in patients with moderate and severe hepatic impairment. Starting dose should be reduced in those patients.

Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication.

Please see full Prescribing Information for VELCADE at VELCADE.com.

Hepatic Events: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic events include increases in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible upon discontinuation of VELCADE. There is limited re-challenge information in these patients.

Hepatic Impairment: VELCADE is metabolized by liver enzymes. VELCADE exposure is increased in patients with moderate or severe hepatic impairment. These patients should be treated with VELCADE at reduced starting doses and closely monitored for toxicities.

Use in Pregnancy: Pregnancy Category D. Women of childbearing potential should avoid becoming pregnant while being treated with VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses.

VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners.

Millennium Pharmaceuticals, Inc., Cambridge, MA 02139 Copyright © 2011, Millennium Pharmaceuticals, Inc. All rights reserved.

Printed in USA

V-11-0264

12/11

Case Study

Chemotherapy 2.0

Practice Changes in Management of Patients Receiving Oral Chemotherapy

By Robert Mancini, PharmD, Dave Wilson, RPh, Colleen Powell, CPhT, and Clementine Mehrens, St. Lukes Mountain States Tumor Institute

A

s developments in cancer treatment shift toward oral agents, new processes, procedures, and strategies must be developed to help healthcare providers maintain the same level of interaction with patients. Traditionally, patients are seen by their oncologists and then sent to an infusion center for their intravenous chemotherapy where they interact with nurses and/or pharmacists. These interactions allow for early assessment and intervention of medication-related issues, side effects, and tolerability.

In the shifting paradigm, patients see their oncologist, are given a written prescription, and then sent home. This transfers a bulk of the responsibility onto the patient, with no true indicator of adherence. In addition, the patient has no interaction with other healthcare providers regarding adverse reactions and other medication-related concerns.

One solution is to design and implement a pharmacist-managed oral chemotherapy program, which will ensure that patients can still interact with practitioners between their oncologist visits.

The Process The St. Lukeâ&#x20AC;&#x2122;s Mountain States Tumor Institute created a pharmacist-managed program to help deal with the emerging issues surrounding oral chemotherapy. When a new prescription is written, it is transferred to the oral chemotherapy pharmacist. The pharmacist then evaluates it for accuracy of dosing, as well as indication, drug interactions, and side-effect management. Each

figure the costs and rev-enue potential.

Then, evaluate the salary requirements, estimated number of prescriptions expected, and average costs/ income of each prescription to show the required break-even point. Next, impleRobert Mancini ment a 2- to 3month pilot to verify the assumptions in the initial analysis. Pilot data can then be annualized to justify the long-term program (Figure).

patient is counseled directly by an experienced oncology pharmacist about the drug and the process for filling the prescription.

Next, the script is sent to a closedaccess pharmacy, which can be used solely by staff and patients of the health system. The prescription then is run through insurance and filled.

Once filled, it gets delivered to the patient at the nearest infusion center (or mailed to a select subset of patients with transportation restrictions).

One solution is to design and implement a pharmacist-managed oral chemotherapy program, which will ensure that patients can still interact with practitioners between their oncologist visits.

Barriers to Overcome One of the biggest barriers is overcoming your current processes.

Someone must be able to meet with prescribing oncologists to ensure that prescriptions pass through the oral chemotherapy pharmacist. We use registered nurses who work with each physician to act as gatekeepers to oral chemotherapy prescriptions. In addition, we use standardized order forms, which help remind prescribers that there is something special that needs to happen with these patients.

Another barrier is insurance issues.

A variety of issues may need to be addressed, such as prior authorization forms and requirements to use mail order pharmacies. We had our pharmacy billing specialist analyst set up contracts with third-party payers, which has helped reduce our total population using mail order pharmacies to approximately 10% to 15%.

If issues arise regarding high copay, denial of coverage, or lack of insurance, the cancer centerâ&#x20AC;&#x2122;s financial advocates are brought into the process to help with copay assistance or free drug programs. Finally, after the patient starts the medication, the pharmacist calls the patient on a weekly basis for the first cycle, then monthly 1 week before each refill date.

Justification An institution must be able to justify the staffing requirements of the program. Start by creating a breakeven point analysis, in which you

December 2011

Clinical Impact The program has proved benefiContinued on page 14

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www.OncPracticeManagement.com

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13

Case Study

Practice Changes in Management…Continued from page 13 Figure. Break-Even Point Analysis

Items Addressed

Assumptions/Projections

• Salary expectations (eg, pharmacist, techs) • Overhead expenses (eg, office supplies, shipping costs)

• Salary, $170,000 (pharmacist + technician) • Overhead, $5000

Workload expectations

• Number of patients served • Percentage on oral agents • Percentage of those referred to program • Number of expected refills per patient

• Patients served, 844 • Receiving oral chemo, 25% • Referrals, 50% • Total fills per patient, 4

Prescription parameters

• Average prescription cost • Average mark-up per prescription • Bad debt percentage

• Average prescription cost, $3200 • Average mark-up, $500a • Bad debt percent, 3%

Break-point expectation

• Determine number of scripts required to be filled each year to break even • Include bad debt percentage to determine additional fills required to cover bad debt

• Based on above, need to fill at least 350 prescriptions to break even • Based on 350 scripts, need to fill additional 67 scripts to cover bad debt or a total of 417 scripts annually

Evaluate cost

= 422 fills/year

Results: Required 417 scripts annually is less than the anticipated 422 scripts annually, resulting in a self-sustaining program. Now validate and project after a pilot. a

Mark-up will be determined by institutions purchasing contracts and third-party payer contracts. Value provided is an example only and does not reflect actual mark-up at our institution.

cial to patients, staff, and the health system. Without guidance, patients can have difficulty obtaining their drug, a huge cause of medication nonfulfillment. For example, a patient with pancreatic cancer came to our program stating that a pharmacist at a retail pharmacy told her that “this drug will be about $5000 per month.” Hearing something like this on top of her diagnosis was hugely detrimental. Our financial advocates, however, were able to help this patient find copay assistance.

Furthermore, patients have come to our program asking for help with insurance issues, refill tracking, and monitoring. Many patients have expressed great satisfaction with the processes. One patient made note that when it came to her oral

14

I

chemotherapy, she “knew that it would be taken care of and done right.” In addition, nursing and provider surveys have been overwhelmingly positive regarding the program’s benefits. Sometimes, it only takes one difficult case for a prescriber to realize these benefits and begin to follow the process.

The pharmacists have been able to help manage significant drug interactions as well; to date, there have been interventions on approximately 75 major drug interactions.

Economic Impact The early break-even point analysis proved to be a great underestimate of the potential of this program. Early estimates expected about 500 prescriptions per year, and our

ONCOLOGY PRACTICE MANAGEMENT

I

December 2011

current numbers are nearly triple.

Our pharmacy business analyst showed that our actual revenue generated greatly outweighed costs. This revenue has been able to justify the salary of a pharmacist (1 FTE) and technicians (1.5 FTEs).

The program has been able to acquire more than $1 million of free drug and $200,000 of copay-assistance funds for patients. The program also has been able to reduce write-offs to less than 1% of total drug costs, while making sure nearly every patient has received his or her prescribed medication. By putting the proper controls in place and ensuring proper staffing, institutions can guard against the shifting paradigm of oral chemotherapy leaving them in the lurch. l

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To learn more about our united strength, visit usoncology.com

Effective January 1, 2012

J9179 Injection, eribulin mesylate, 0.1 mg Product coding does not guarantee payor coverage or payment.* For more details visit www.halavenreimbursement.com

Indication Halaven is indicated for the treatment of patients with metastatic breast cancer who have previously received at least two chemotherapeutic regimens for the treatment of metastatic disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting.

Important Safety Information Neutropenia • Monitor complete blood counts prior to each dose, and increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias.

Delay administration and reduce subsequent doses in patients who experience febrile neutropenia or Grade 4 neutropenia lasting longer than 7 days • Severe neutropenia (ANC <500/mm3) lasting more than 1 week occurred in 12% (62/503) of patients.

Patients with elevated liver enzymes >3 × ULN and bilirubin >1.5 × ULN experienced a higher incidence of Grade 4 neutropenia and febrile neutropenia than patients with normal levels • Grade 3 and Grade 4 neutropenia occurred in 28% and 29%, respectively, of patients who received Halaven.

Febrile neutropenia occurred in 5% of patients and two patients (0.4%) died from complications

Peripheral Neuropathy • Patients should be monitored closely for signs of peripheral motor and sensory neuropathy • Grade 3 peripheral neuropathy occurred in 8% of patients, and Grade 4 in 0.4% of patients who received Halaven. Delay administration of Halaven until resolution to Grade 2 or less • Neuropathy lasting more than 1 year occurred in 5% of patients. Twenty-two percent of patients developed a new or worsening neuropathy that had

not recovered within a median follow-up duration

of 269 days (range 25-662 days)

Pregnancy Category D • Halaven is expected to cause fetal harm when administered to a pregnant woman and patients should be advised of these risks

QT Prolongation • In an uncontrolled ECG study in 26 patients, QT prolongation was observed on Day 8, independent of eribulin concentration, with no prolongation on Day 1. ECG monitoring is recommended for patients with congestive heart failure; bradyarrhythmias; concomitant use of drugs that prolong QT interval, including Class Ia and III antiarrhythmics; and electrolyte abnormalities • Correct hypokalemia or hypomagnesemia prior to initiating Halaven and monitor electrolytes periodically during therapy. Avoid in patients with congenital long QT syndrome

Hepatic and Renal Impairment • For patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic and/or moderate (CrCl 3050 mL/min) renal impairment, a reduction in starting dose is recommended

Please see accompanying brief summary of Halaven full Prescribing Information. plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007;357(26):2666References: 1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in 2676. 8. Robert NJ, Dieras V, Glaspy J, et al. RIBBON-1: randomized, double-blind, placebo-controlled, Oncology™: Breast Cancer. Version 2.2011. http:NCCN.org. Published January 5, 2011. Accessed October † phase III trial of chemotherapy with or without bevacizumab (B) for first-line treatment of HER2-negative 18, 2011. 2. Halaven [package insert]. Woodcliff Lake, NJ: Eisai Inc; 2010. 3. Saad ED, Katz A, Buyse M. locally recurrent or metastatic breast cancer (MBC). J Clin Oncol. 2009;27(suppl; abstr 1005). 9. Sparano Overall survival and post-progression survival in advanced breast cancer: a review of recent randomized JA, Vrdoljak E, Rixe O, et al. Randomized phase III trial of ixabepilone plus capecitabine versus capecitabine clinical trials. J Clin Oncol. 2010;28(11):1958-1962. 4. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses Oncol. 2010;28(20):3256-3263. 10. Jones SE, Erban J, Overmoyer B, et al. Randomized phase III study of HER2. N Engl J Med. 2001;344(11):783-792. 5. Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus docetaxel compared with paclitaxel in metastatic breast cancer. J Clin Oncol. 2005;23(24):5542-5551. capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 2006;355(26):2733-2743.

11. Cortes J, O’Shaughnessy J, Loesch D, et al. Eribulin monotherapy versus treatment of physician’s 6. von Minckwitz G, du Bois A, Schmidt M, et al. Trastuzumab beyond progression in human epidermal choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. growth factor receptor 2–positive advanced breast cancer: a German Breast Group 26/Breast International Lancet. 2011;377(9769):914-923.

Group 03-05 study. J Clin Oncol. 2009;27(12):1999-2006. 7. Miller K, Wang M, Gralow J, et al. Paclitaxel *Eisai cannot guarantee payment of any claim. Coding, coverage, and reimbursement may vary significantly by payor, plan, patient, and setting of care. Actual coverage and reimbursement decisions are made by individual payors following the receipt of claims. For additional information, customers should consult with their payors for all relevant coding, reimbursement, and coverage requirements. It is the sole responsibility of the provider to select the proper code and ensure the accuracy of all claims used in seeking reimbursement. All services must be medically appropriate and properly supported in the patient medical record. †Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™) for Breast Cancer V.2.2011. © 2011 National Comprehensive Cancer Network, Inc. All rights reserved.

Accessed October 18, 2011. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES™, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.

HALAVEN ® is a registered trademark used by Eisai Inc. under license from Eisai R&D Management Co., Ltd. © 2011 Eisai Inc. All rights reserved. Printed in USA/December 2011 ERI 81AR2

Scan this code to visit www.halaven.com

A preferred single agent in the NCCN Guidelines™1

DISCOVER

OVERALL SURVIVAL Halaven®: The FIRST and ONLY third-line, single-agent therapy proven to significantly extend overall survival in patients with metastatic breast cancer (MBC) 2-10 The Phase III EMBRACE* trial met its primary endpoint of overall survival (OS) 2,11 • In the primary analysis, conducted when ~50% of events (deaths) had been observed, median OS with Halaven vs Control Arm (Treatment of Physician’s Choice [TPC]) was 13.1 months (95% CI: 11.8, 14.3) vs 10.6 months (95% CI: 9.3, 12.5), HR=0.81 (95% CI: 0.66, 0.99) (P=0.041)† 2,11

UPDATED OVERALL SURVIVAL ANALYSIS (UNPLANNED)†2 Halaven (n=508)

TPC Arm (n=254)

Median OS (months [95% Cl])

13.2 (12.1, 14.4)

10.6 (9.2, 12.0)

Deaths

386

203

1.0 0.9

PROPORTION OF PATIENTS ALIVE

0.8 0.7 0.6

Halaven

0.5

RESULTS CONSISTENT WITH PRIMARY ANALYSIS2

Control Arm

0.4 0.3 0.2 0.1 0.0

0

6

12

18

24

30

36

54 26

11 5

0 0

TIME (MONTHS) Number of patients at risk

508 254

406 178

274 106

142 61

Halaven TPC Arm

Results from an updated, unplanned survival analysis of the Phase III, open-label, multicenter, multinational EMBRACE trial of Halaven vs TPC in patients with MBC (N=762). The primary endpoint was OS. Patients were randomized (2:1) to receive either Halaven 1.4 mg/m2 IV for 2 to 5 minutes on Days 1 and 8 of a 21-day cycle, or any single-agent therapy, selected prior to randomization. At baseline, all patients had received ≥2 prior chemotherapeutic regimens for metastatic disease and demonstrated disease progression within 6 months of their last chemotherapeutic regimen. All patients received prior anthracycline- and taxanebased chemotherapy, unless contraindicated.

Therapies in the TPC Arm consisted of 97% chemotherapy (26% vinorelbine, 18% gemcitabine, 18% capecitabine, 16% taxanes [included paclitaxel, docetaxel, nab-paclitaxel, and ixabepilone], 9% anthracyclines, 10% other chemotherapy), and 3% hormonal therapy.2,11

CI=confidence interval; HR=hazard ratio. *EMBRACE=Eisai Metastatic Breast Cancer Study Assessing Physician’s Choice vs E7389 (Eribulin). †Conducted in the intent-to-treat (ITT) population.

Halaven: Quick administration • 2- to 5-minute intravenous infusion on Days 1 and 8 of a 21-day cycle2

Halaven: Safety profile • Studied in the Phase III EMBRACE trial2

Most Common Adverse Reactions • Most common adverse reactions (≥25%) reported in patients receiving Halaven were neutropenia (82%), anemia (58%), asthenia/fatigue (54%), alopecia (45%), peripheral neuropathy (35%), nausea (35%), and constipation (25%) • The most common serious adverse reactions reported in patients receiving Halaven were febrile neutropenia (4%) and neutropenia (2%) • Peripheral neuropathy (5%) was the most common adverse reaction resulting in discontinuation

HALAVENTM (eribulin mesylate) Injection BRIEF SUMMARY – See package insert for full prescribing information.

2.2 Dose Modification Assess for peripheral neuropathy and obtain complete blood cell counts prior to each dose.

Recommended dose delays • Do not administer HALAVEN on Day 1 or Day 8 for any of the following: – ANC <1,000/mm3 – Platelets <75,000/mm3 – Grade 3 or 4 non-hematological toxicities • The Day 8 dose may be delayed for a maximum of 1 week.

– If toxicities do not resolve or improve to ≤ Grade 2 severity by Day 15, omit the dose.

– If toxicities resolve or improve to ≤ Grade 2 severity by Day 15, administer HALAVEN at a reduced dose and initiate the next cycle no sooner than 2 weeks later.

Recommended dose reductions • If a dose has been delayed for toxicity and toxicities have recovered to Grade 2 severity or less, resume HALAVEN at a reduced dose as set out in Table 1.

• Do not re-escalate HALAVEN dose after it has been reduced.

Table 1 Recommended Dose Reductions Recommended Event Description HALAVEN Dose Permanently reduce the 1.4 mg/m2 HALAVEN dose for any of the following: ANC <500/mm3 for >7 days ANC <1,000 /mm3 with fever or infection Platelets <25,000/mm3 1.1 mg/m2 Platelets <50,000/mm3 requiring transfusion Non-hematologic Grade 3 or 4 toxicities Omission or delay of Day 8 HALAVEN dose in previous cycle for toxicity Occurrence of any event requiring permanent dose reduction while receiving 1.1 mg/m2 0.7 mg/m2 Occurrence of any event requiring permanent dose reduction while receiving 0.7 mg/m2 Discontinue HALAVEN ANC = absolute neutrophil count.

Toxicities graded in accordance with National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0.

5 WARNINGS AND PRECAUTIONS 5.1 Neutropenia Severe neutropenia (ANC <500/mm3) lasting more than one week occurred in 12% (62/503) of patients in Study 1, leading to discontinuation in <1% of patients. Patients with alanine aminotransferase or aspartate aminotransferase >3 × ULN (upper limit of normal) experienced a higher incidence of Grade 4 neutropenia and febrile neutropenia than patients with normal aminotransferase levels. Patients with bilirubin >1.5 × ULN also had a higher incidence of Grade 4 neutropenia and febrile neutropenia.

Monitor complete blood counts prior to each dose; increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias. Delay administration of HALAVEN and reduce subsequent doses in patients who experience febrile neutropenia or Grade 4 neutropenia lasting longer than 7 days. Clinical studies of HALAVEN did not include patients with baseline neutrophil counts below 1,500/mm3.

5.2 Peripheral Neuropathy Grade 3 peripheral neuropathy occurred in 8% (40/503) of patients, and Grade 4 in 0.4% (2/503) of patients in Study 1.

Peripheral neuropathy was the most common toxicity leading to discontinuation of HALAVEN (5% of patients; 24/503).

Neuropathy lasting more than one year occurred in 5% (26/503) of patients. Twenty-two percent (109/503) of patients developed a new or worsening neuropathy that had not recovered within a median follow-up duration of 269 days (range 25-662 days). Monitor patients closely for signs of peripheral motor and sensory neuropathy. Withhold HALAVEN in patients who experience Grade 3 or 4 peripheral neuropathy until resolution to Grade 2 or less.

5.3 Embryo-Fetal Toxicity There are no adequate and well-controlled studies of HALAVEN in pregnant women. HALAVEN is a microtubule inhibitor; therefore, it is expected to cause fetal harm when administered to a pregnant woman. Embryo-fetal toxicity and teratogenicity occurred in rats that received eribulin mesylate at approximately half of the recommended human dose based on body surface area. If this drug is used during pregnancy, or if a patient becomes pregnant while taking this drug, she should be apprised of the potential hazard to the fetus.

5.4 QT Prolongation In an uncontrolled open-label ECG study in 26 patients, QT prolongation was observed on Day 8, independent of eribulin concentration, with no QT prolongation observed on Day 1. ECG monitoring is recommended if therapy is initiated in patients with congestive heart failure, bradyarrhythmias, drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics, and electrolyte abnormalities. Correct hypokalemia or hypomagnesemia prior to initiating HALAVEN and monitor these electrolytes periodically during therapy. Avoid HALAVEN in patients with congenital long QT syndrome.

6 ADVERSE REACTIONS The following adverse reactions are discussed in detail in other sections of the labeling: • Neutropenia • Peripheral neuropathy • QT interval prolongation The most common adverse reactions (≥25%) reported in patients receiving HALAVEN were neutropenia, anemia, asthenia/ fatigue, alopecia, peripheral neuropathy, nausea, and constipation. The most common serious adverse reactions reported in patients receiving HALAVEN were febrile neutropenia (4%) and neutropenia (2%). The most common adverse reaction resulting in discontinuation of HALAVEN was peripheral neuropathy (5%).

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice.

In clinical trials, HALAVEN has been administered to 1,222 patients with multiple tumor types, including 240 patients exposed to HALAVEN for 6 months or longer. The majority of the 1,222 patients were women (82%) with a median age of 58 years (range: 26 to 91 years). The racial and ethnic distribution was Caucasian (83%), Black (5%), Asian (2%), and other (5%).

The adverse reactions described in Table 2 were identified in 750 patients treated in Study 1. In Study 1, patients were randomized (2:1) to receive either HALAVEN (1.4 mg/m2 on Days 1 and 8 of a 21-day cycle) or single agent treatment chosen by their physician (control group). A total of 503 patients received HALAVEN, and 247 patients in the control group received therapy consisting of chemotherapy [total 97% (anthracyclines 10%, capecitabine 18%, gemcitabine 19%, taxanes 15%, vinorelbine 25%, other chemotherapies 10%)] or hormonal therapy (3%). The median duration of exposure was 118 days for patients receiving HALAVEN and 63 days for patients receiving control therapy. Table 2 reports the most common adverse reactions occurring in at least 10% of patients in either group.

Table 2 Adverse Reactions with a Per-Patient Incidence of at Least 10% in Study 1 HALAVEN (n=503) Control Group (n=247) MedDRA ver 10.0 All Grades ≥ Grade 3 All Grades ≥ Grade 3 Blood and Lymphatic System Disordersa Neutropenia 82% 57% 53% 23% Anemia 58% 2% 55% 4% Nervous system disorders b Peripheral neuropathy 35% 8% 16% 2% Headache 19% <1% 12% <1% General disorders and administrative site conditions Asthenia/Fatigue 54% 10% 40% 11% Mucosal inflammation 9% 1% 10% 2% Pyrexia 21% <1% 13% <1% Gastrointestinal disorders Constipation 25% 1% 21% 1% Diarrhea 18% 0 18% 0 Nausea 35% 1% 28% 3% Vomiting 18% 1% 18% 1% Musculoskeletal and connective tissue disorders Arthralgia/Myalgia 22% <1% 12% 1% Back pain 16% 1% 7% 2% Bone pain 12% 2% 9% 2% Pain in extremity 11% 1% 10% 1% Investigations Weight decreased 21% 1% 14% <1% Metabolism and nutrition disorders Anorexia 20% 1% 13% 1%

Table 2 (cont’d) MedDRA ver 10.0

HALAVEN (n=503) All Grades ≥ Grade 3

Control Group (n=247) All Grades ≥ Grade 3

Respiratory, thoracic, and mediastinal disorders Cough 14% 0 9% 0 Dyspnea 16% 4% 13% 4% Skin and subcutaneous tissue disorders Alopecia 45% NAc 10% NAc Infections and Infestations Urinary Tract Infection 10% 1% 5% 0 a Based upon laboratory data. b Includes neuropathy peripheral, neuropathy, peripheral motor neuropathy, polyneuropathy, peripheral sensory neuropathy, and paraesthesia. c Not applicable; (grading system does not specify > Grade 2 for alopecia).

Cytopenias: Grade 3 neutropenia occurred in 28% (143/503) of patients who received HALAVEN in Study 1, and 29% (144/503) of patients experienced Grade 4 neutropenia. Febrile neutropenia occurred in 5% (23/503) of patients; two patients (0.4%) died from complications of febrile neutropenia. Dose reduction due to neutropenia was required in 12% (62/503) of patients and discontinuation was required in <1% of patients. The mean time to nadir was 13 days and the mean time to recovery from severe neutropenia (<500/mm3) was 8 days. Grade 3 or greater thrombocytopenia occurred in 1% (7/503) of patients. G-CSF (granulocyte colony-stimulating factor) or GM-CSF (granulocyte–macrophage colonystimulating factor) was used in 19% of patients who received HALAVEN. Peripheral Neuropathy: In Study 1, 17% of enrolled patients had Grade 1 peripheral neuropathy and 3% of patients had Grade 2 peripheral neuropathy at baseline. Dose reduction due to peripheral neuropathy was required by 3% (14/503) of patients who received HALAVEN. Four percent (20/503) of patients experienced peripheral motor neuropathy of any grade and 2% (8/503) of patients developed Grade 3 peripheral motor neuropathy.

Liver Function Test Abnormalities: Among patients with Grade 0 or 1 ALT levels at baseline, 18% of HALAVEN-treated patients experienced Grade 2 or greater ALT elevation. One HALAVEN-treated patient without documented liver metastases had concomitant Grade 2 elevations in bilirubin and ALT; these abnormalities resolved and did not recur with re-exposure to HALAVEN. Less Common Adverse Reactions: The following additional adverse reactions were reported in ≥5% to <10% of the HALAVEN-treated group: • Eye Disorders: increased lacrimation • Gastrointestinal Disorders: dyspepsia, abdominal pain, stomatitis, dry mouth • General Disorders and Administration Site Conditions: peripheral edema • Infections and Infestations: upper respiratory tract infection • Metabolism and Nutrition Disorders: hypokalemia • Musculoskeletal and Connective Tissue Disorders: muscle spasms, muscular weakness • Nervous System Disorders: dysgeusia, dizziness • Psychiatric Disorders: insomnia, depression • Skin and Subcutaneous Tissue Disorders: rash 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Category D There are no adequate and well-controlled studies with HALAVEN in pregnant women. HALAVEN is a microtubule inhibitor; therefore, it is expected to cause fetal harm when administered to a pregnant woman. Embryo-fetal toxicity and teratogenicity occurred in rats that received eribulin mesylate at approximately half of the recommended human dose based on body surface area. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

In a developmental toxicity study, pregnant rats received intravenous infusion of eribulin mesylate during organogenesis (Gestation Days 8, 10, and 12) at doses approximately 0.04, 0.13, 0.43 and 0.64 times the recommended human dose, based on body surface area (mg/m2). Increased abortion and severe external or soft tissue malformations were observed in offspring at doses 0.64 times the recommended human dose based on body surface area (mg/m2), including the absence of a lower jaw, tongue, stomach and spleen. Increased embryo-fetal death/resorption, reduced fetal weights, and minor skeletal anomalies consistent with developmental delay were also reported at or above doses of 0.43 times the recommended human dose.

Maternal toxicity of eribulin mesylate was reported in rats at or above doses of 0.43 times the recommended human dose (mg/m²), and included enlarged spleen, reduced maternal weight gain and decreased food consumption.

8.3 Nursing Mothers It is not known whether HALAVEN is excreted into human milk. No studies in humans or animals were conducted to determine if HALAVEN is excreted into milk. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in human milk fed infants from HALAVEN, a decision should be made whether to discontinue nursing or to discontinue HALAVEN taking into account the importance of the drug to the mother.

8.4 Pediatric Use The safety and effectiveness of HALAVEN in pediatric patients below the age of 18 years have not been established.

8.6 Hepatic Impairment A study evaluated the PK of eribulin in patients with mild (Child-Pugh A; n=7) and moderate (Child-Pugh B; n=5) hepatic impairment. Compared to patients with normal hepatic function (n=6), eribulin exposure increased 1.8-fold and 2.5-fold in patients with mild and moderate hepatic impairment, respectively. Administration of HALAVEN at a dose of 1.1 mg/m2 to patients with mild hepatic impairment and 0.7 mg/m2 to patients with moderate hepatic impairment resulted in similar exposure to eribulin as a dose of 1.4 mg/m2 to patients with normal hepatic function. A lower starting dose of 1.1 mg/m2 is recommended for patients with mild hepatic impairment (Child-Pugh A) and of 0.7 mg/m2 is recommended for patients with moderate hepatic impairment (Child-Pugh B). HALAVEN was not studied in patients with severe hepatic impairment (Child-Pugh C).

8.7 Renal Impairment No formal PK trials were conducted with HALAVEN in patients with renal impairment. Available data suggests that no dose adjustment is necessary for patients with mild renal impairment (CrCl 50-80 mL/min). However, for patients with moderate renal impairment (CrCl 30-50 mL/min), the geometric mean dose-normalized systemic exposure increased 2-fold compared to patients with normal renal function. A lower starting dose of 1.1 mg/m2 is recommended for patients with moderate renal impairment. The safety of HALAVEN was not studied in patients with severe renal impairment (CrCl <30 mL/min).

10 OVERDOSAGE Overdosage of HALAVEN has been reported at approximately 4 times the recommended dose, which resulted in Grade 3 neutropenia lasting seven days and a Grade 3 hypersensitivity reaction lasting one day.

There is no known antidote for HALAVEN overdose.

12 CLINICAL PHARMACOLOGY 12.2 Pharmacodynamics Cardiac Electrophysiology The effect of HALAVEN on the QTc interval was assessed in an open-label, uncontrolled, multicenter, single-arm dedicated QT trial. A total of 26 patients with solid tumors received 1.4 mg/m2 of HALAVEN on Days 1 and 8 of a 21-day cycle. A delayed QTc prolongation was observed on Day 8, with no prolongation observed on Day 1. The maximum mean QTcF change from baseline (95% upper confidence interval) was 11.4 (19.5) ms.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, mutagenesis, impairment of fertility Carcinogenicity studies have not been conducted with eribulin mesylate.

Eribulin mesylate was not mutagenic in in vitro bacterial reverse mutation assays (Ames test). Eribulin mesylate was positive in mouse lymphoma mutagenesis assays, and was clastogenic in an in vivo rat bone marrow micronucleus assay.

The effects of HALAVEN on human fertility are unknown. Fertility studies have not been conducted with eribulin mesylate in humans or animals. However, nonclinical findings in repeated-dose dog and rat toxicology studies suggest that male fertility may be compromised by treatment with eribulin mesylate. Rats exhibited testicular toxicity (hypocellularity of seminiferous epithelium with hypospermia/aspermia) following dosing with eribulin mesylate at or above 0.43 times the recommended human dose (mg/m2) given once weekly for 3 weeks, or at or above 0.21 times the recommended human dose (mg/m2) given once weekly for 3 out of 5 weeks, repeated for 6 cycles. Testicular toxicity was also observed in dogs given 0.64 times the recommended human dose (mg/m2) weekly for 3 out of 5 weeks, repeated for 6 cycles.

17 PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling • Advise patients to contact their health care provider for a fever of 100.5°F or greater or other signs or symptoms of infection such as chills, cough, or burning or pain on urination.

• Advise women of childbearing potential to avoid pregnancy and to use effective contraception during treatment with HALAVEN. –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– HALAVEN™ is a trademark used by Eisai Inc. under license from Eisai R&D Management Co., Ltd. © 2011 Eisai Inc. All rights reserved. Printed in USA / May 2011 ERI 161

Cancer Center Business Summit

Wilshire’s Medical…Continued from page 3 and pharmacy was also part of the process. Validation of the health plan data and comparators was required.

The key impactable cost drivers in cancer care identified include the costs of therapy, supportive care, symptom management, site of care, and end-of-life care.

Supportive Care The costs of supportive care identified were the management of nausea/vomiting, bone metastases, and white blood cell and red blood cell support. “We decided to focus on nausea and bone medicine support,” she said.

Aggressive management of 7 common symptoms (nausea/vomiting, diarrhea, pain, fever, infection, neutropenic fever, blood clots) in the office or at local urgent care centers was a goal to reduce the number of hospitalizations and keep patients from emergency department visits.

A partnership was therefore begun with local urgent care centers to see patients who experienced these symptoms after hours.

Better oversight of medications, whether oral or intravenous (IV),

was determined to improve medication compliance and adherence, leading to better outcomes.

• Therapies patients are taking and the supportive therapy that accompanies them (whether on or off guidelines) • Potential cost-saving for the regimen chosen compared with a National Comprehensive Cancer Network–allowable regimen • Interval care report (events that required an extended office visit or urgent care visit vs emergency department visit and hospital admission) • End-of-life care report • Nationally validated quality measures (ie, key American Society of Clinical Oncology Quality Oncology Practice Initiative measures, meaningful use, and Medicare Physician Quality Reporting Initiative).

New Payment Methodologies Standard fee-for-service is still part of the payment methodology for which evaluation and management visits are paid, as are infusion codes and reimbursement for IV and oral drugs, using the average sales price plus 6% methodology.

New payment methodologies included the development of new codes for care planning and care management, “so that care planning goes on for every single patient for every type of treatment—adjuvant, neoadjuvant, prevention, maintenance, consolidation, first-line, second-line, and third-line,” said Dr Bosserman. “Everyone who is on active management has a per cycle management fee.”

The entire care plan is paid for in addition to the office visits. Wilshire is committed to delivering 6 reports of transparency: • Number of patients under care and their clinical characteristics

Early Experience The program has led to a 25% increased rate overall in the contract. “We’re not dependent on the drug margin,” said Dr Bosserman.

“We’ll be doing all of the analytics as to what our costs are to deliver, and whether the 25% increase is enough.” l

First Level III Oncology Medical Home Wastes Fewer Resources

By Wayne Kuznar

C

hicago, IL—Offering superior quality of care at lower cost, Consultants in Medical Oncology and Hematology (CMOH) is the first oncology practice in the nation to achieve Level III recognition by the National Committee for Quality Assurance.

“The oncology-patient centered, medical-home model has standardized approaches to care from assess-

ment to patient navigation and disease management,” said John D. Sprandio, MD, oncologist and owner of CMOH. “Four terms to remember in achieving accountable cancer care are patient needs, quality, value, and demonstration of results,” he said at the 2011 Cancer Center Business Summit. “That is what healthcare reform is all about.”

December 2011

Dr Sprandio and his colleagues at CMOH began transforming their practice in 2004 in preparation for a change in payment method that would reimburse the practice based on the quality of care provided.

As the practice was transformed to electronic medical records, customized software was being developed to better suit practice, patient Continued on page 21

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Cancer Center Business Summit

First Level III Oncology…Continued from page 19 needs, and data collection. These customized software applications were also designed to support comprehensive processes of care that were required for the Level III, patient-centered, medical home recognition, Dr Sprandio explained.

Care-Coordinated Model Encourages Clinical Integration The care-coordinated model was developed to “promote a value-based agenda that facilitates physician accountability and encourages clinical integration among like-minded medical oncology practices,” he said.

“It enhances communication and coordination with primary care. In the past 4 months, it has promoted collaboration with payers. It does all this while focusing on patient needs and evidence-based care.”

The primary care team addresses all nononcologic issues. “We take responsibility for the coordination of all oncologic-related services, from the time of diagnosis through the survivorship stage of care or to the time of death,” said Dr Sprandio.

Patient engagement is the focus according to Dr Sprandio, especially the encouragement of patients to be proactive about reporting symptoms, as early treatment of symptoms often results in fewer hospitalizations.

Standardized Care The model promotes collaboration between the caregiving team, adherence to evidence-based guidelines, prevention of complications, and increasing access to care, “all in a standardized way.”

“Everything is standardized…patient assessment, collection of data, documentation, patient navigation….Telephone triage has been a big plus in directing patients away

ment (5.8% overall since 2006) • 5.5% were seen the same day • 4.5% were seen the next day.

“We encourage them to call early.

If they think they might have a problem at 8:00 in the morning, we encourage them to call by 8:15.

Calling us at 4:15 may result in an unnecessary ER evaluation,” said Dr Sprandio.

The impact on emergency department utilization has been significant, Dr Sprandio noted. The number of emergency department visits per chemotherapy-receiving patient has been reduced from 2.6 in 2004 to 0.91 in 2010. The number of hospital admissions per chemotherapyreceiving patient was 0.6 in 2010.

Documentation turnaround time has been reduced from 28 days to less than 1 day.

Patient outcomes have not been affected by the reductions in the number of emergency department visits and hospitalizations, Dr Sprandio observed.

End-of-life care offered by the practice has resulted in an increase in the average hospice length of stay from 26 days in 2009 to 32 days in 2010. The end-of-life discussions have resulted in less use of chemotherapy by the practice, and the number of outpatient chemotherapy visits has declined by 12%.

The oncology medical home model, coupled with a pathways program, has led to: • A 43% reduction in hospitalizations • A 65% reduction in emergency department evaluations • An estimated savings between 6.6% and 12.7% of the total cost of cancer care.

“If you plug in our numbers, it was higher than 13%,” Dr Sprandio said. l

from the ER [emergency room] and more toward self-management,” he said. Potentially avoidable complications have been defined, measured, and reduced in number. “We’re also big proponents of integrated palliative care from the time of diagnosis and allowing physicians to track it.”

“We take responsibility for the coordination of all oncologic-related services, from the time of diagnosis through the survivorship stage of care or to the time of death.”

—John D. Sprandio, MD

Triage Call Service The nurse-triage call service has taken 3900 calls during the past year; of these calls: • 75% of patients’ symptoms were managed at home • 4.3% of patients who went through the phone triage were referred to the emergency depart-

December 2011

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Cancer Center Business Summit

Accountable Care Organizations Paying Little Attention to Oncology Services, Not Seeing the Cost-Savings Cancer Center Business Summit’s Survey Results

By Wayne Kuznar

C

hicago, IL—A survey conducted by the Cancer Center Business Summit of 36 healthcare organizations on accountable care initiatives involved in oncology-specific, nontraditional payment methodology showed a low priority for achieving cost-savings through oncology care services, according to Ronald Barkley, MS, JD, Managing Director, Cancer Center Business Development Group, and the survey’s principal investigator.

Overall, survey responders indicated that the concept of accountable care organizations (ACOs) has focused on chronic diseases, because their costs are more predictable compared with oncology-related costs.

The comments gathered from direct phone interviews of these organizations, conducted during JuneAugust 2011, were identified as either responding to ACO initiatives or participating in nontraditional and innovative payment reimbursement (payment other than fee-for-service format).

The interviews revealed that 10 of the organizations surveyed were ACO proactive, 13 were ACO ex ploratory, 8 took a “wait-and-see” approach, and 2 were ignoring ACOs altogether.

One pattern that emerged from the market profiles of these organizations is that proactive ACO responders tended to vary from somewhat to highly consolidated and highly competitive markets, according to Mr Barkley.

Emerging Patterns Key comments about ACO readiness showed that: The proposed rules were too onerous.

reimbursement for 80% pathways compliance.

Within the ACO responder organizations, there was essentially no variation from traditional payment methods in oncology.

Oncology as a health condition seems to be of lesser priority in the context of ACO planning than is chronic diseases, such as heart disease and chronic obstructive pulmonary disease. The ACO responder organizations tend to agree that

1 2

Uncertainty over Medicare ACO reporting data requirements with respect to cancer (immature data) is too great.

3

Determining the true cost of cancer care is difficult, given the lack of a consistent definition of cancer care.

The survey of 36 healthcare organizations on accountable care initiatives found a low priority for achieving cost-savings through oncology care services.

4

There is a need to “spend a lot of political capital” with physicians to get ready for ACOs.

5

Too much time and effort is spent determining which physicians are fully aligned with the ACO concept.

Of the organizations participating in oncology-specific nontraditional payment methodologies, UnitedHealthcare instituted what it called an episode-of-care payment system, in which a historic drug margin, plus a per-patient administrative fee, is paid for practices complying with selected pathways for select cancer sites (breast, colon, lung, ovarian).

All other services are on a fee-forservice basis. As such, it is not a true episode-of-care payment but rather “locks in” the historic drug margin, said Barkley.

Many state Blue Cross plans and P4 Healthcare have models in which practices are paid premiums on drug

December 2011

these chronic conditions have been cited as better candidates for costsavings, noting that ACO concepts have been developed around primary care, and not as much thought has been given to subspecialty care, which tends to be fragmented.

In general, the sheer volume of chronic disease patients offers more opportunity for cost-savings compared with cancer patients, said Continued on page 28

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Cancer Center Business Summit

Accountable Care…Continued from page 27 ACO responder organizations, and oncology is too complex to tackle in ACO planning, with greater cost variability and unpredictability.

“Cancer is too broad to get disease focus. Whereas hip, knee, and cardiac surgery are more predictable,” replied a health system oncology service executive in the mid-Atlantic region.

Too much money is spent on futile care in the last 6 months of life,

and conversations need to revolve around end-of-life care much earlier than they do now, said executives and medical directors in the ACO responder organizations.

Trends to Watch in 2012 According to Mr Barkley, some trends to watch for include: Expanding beyond pathways to include programs that emphasize

1

cost reductions by reducing redundant hospitalizations and emergency department visits.

2

Oncology practices organizing to be specialist “neighbors” of primary care medical homes.

3

Oncology “bundled” pricing as a new oncologist–hospital alignment strategy. l

Now Is Not the Right Time for Oncology Practices to Jump on the ACO Bandwagon

By Wayne Kuznar

C

hicago, IL—The accountable care organization (ACO) concept is in the early stages of being defined, our oncology practices should keep their options open, “and remain independent while the dust settles,” said Matthew Brow, Vice President of Communication, Government Relations and Public Policy at McKesson Specialty Care Solutions/US Oncology at the Cancer Center Business Summit.

ACOs and the Medicare Shared Savings Program (MSSP) are intended to reduce healthcare spending by realigning incentives for physicians who manage care and better coordinating care across settings.

A sustainable, value-based reimbursement approach for the care of Medicare beneficiaries (instead of a volume-based approach) is the goal of ACOs and the MSSP, according to Mr Brow.

An oncology-led ACO is not permissible under the proposed MSSP rules; under MSSP rules, only pa tients of primary care physicians are

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included in the program; a minimum of 5000 Medicare beneficiaries are required for ACO participation, and oncologist-only practices cannot

A comparison of current to historical costs, adjusted for inflation, does not work in oncology, because expenditure on cancer drugs is expected to increase by more than 10% annually.

meet this minimum. It is permissible under the Medicare Pioneer ACO program, but no one applied in time.

The current ACO model, which

ONCOLOGY PRACTICE MANAGEMENT

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December 2011

revolves around primary care physicians, provides little incentive for oncologists to join. “If the only way for a patient to be assigned to an ACO is through a primary care physician, and patients are only assigned to a primary care physician who provided the plurality of evaluation and management services to a patient, oncologist-managed patients don’t count toward targets or performance,” Mr Brow said. “There is significant pressure to pay for value, and the private side is leading the way in my view.”

The legislative framework for ACOs sets benchmarks for expected Medicare Part A and Part B spending for beneficiaries based on historic cost in the 3 years preceding an ACO contract, adjusted annually for the trend in Medicare cost growth, said Michael L. Blau, Esq, Chair at Venture Health Practices, Foley & Lardner LLP. A comparison of current to historical costs, adjusted for inflation, does not work in oncology, according to

Cancer Center Business Summit

Mr Brow, because expenditure on cancer drugs is expected to increase by more than 10% annually, and “new technology and generics are significant in oncology and mandate concurrent controls and benchmarks versus historical.”

Most practices are opting not to participate, expecting no rate of return on their investment, according to Mr Blau. In addition, several proposed ACO regulations are of concern to oncologists: • A more limited role in ACO governance.

• None of the 65 quality measures are specific to oncology.

• Meeting quality measures is the determinant of shared savings.

Oncology patients carry higher costs and therefore are less likely to

contribute to cost-savings. Furthermore, ACO cost and risks are substantial, and there is no assurance

Mr Brow. “Each ACO must specify its method of allocating and distributing shared savings dollars, and all specialties do not need to be included or treated equally.”

A 3-year lock-in is also required, during which time a practice has to incur downside risk. Before all is settled, oncologists are likely to have additional value-based options with Medicare, so a wait-and-see approach is advised, said Mr Brow.

“Don’t jump in if you’re an oncology practice.”

“The ability to deliver and document high-quality, cost-effective care is vital regardless of whether one joins an ACO,” he said. “Work with an organization that leverages years of investment in technology and physician-driven pathways.” l

“The ability to deliver and document highquality, cost-effective care is vital regardless of whether one joins an ACO.” —Matthew Brow

that oncologists will be allocated a fair share of any savings realized, said

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December 2011

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Announcing: J-code for YERVOYâ&#x201E;˘ (ipilimumab) J9228 Indication YERVOY (ipilimumab) is indicated for the treatment of unresectable or metastatic melanoma.1

J-code for YERVOY2

a

HCPCS Code

Description

Effective

J9228a

Injection, ipilimumab, 1 mg

January 1, 2012

Replaces J9999, J3490, J3590, and C9284.

Product Description

50-mg/10 mL (5 mg/mL), single-use vial of YERVOY

200-mg/40 mL (5 mg/mL), single-use vial of YERVOY

NDC Number 10-digit

0003-2327-11

0003-2328-22

11-digit

00003-2327-11

00003-2328-22

The accurate completion of reimbursement- or coverage-related documentation is the responsibility of the healthcare provider and patient. Bristol-Myers Squibb and its agents make no guarantee regarding reimbursement for any service or item. This coding guidance is not intended to provide specific directions on requesting prior authorization or submitting claims for YERVOY and does not provide a guarantee of receiving prior authorization or reimbursement. Oncology practices need to make coding decisions based on the diagnosis and treatment of each patient and the specific insurer requirements. www.destinationaccess.com 1-800-861-0048 (phone) Monday through Friday, 8:00 1-888-776-2370 (fax)

AM

to 8:00

PM

ET

Important Safety Information WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS YERVOY can result in severe and fatal immune-mediated adverse reactions due to T-cell activation and proliferation. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY. Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy and endocrinopathy and evaluate clinical chemistries including liver function tests (LFTs) and thyroid function tests at baseline and before each dose.

Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions.

Please see Important Safety Information, including Boxed WARNING regarding immune-mediated adverse reactions, continued on adjacent page.

REFERENCES 1. YERVOY (ipilimumab) [package insert]. Princeton, NJ: Bristol-Myers Squibb; March 2011.

2. Alpha-numeric HCPCS. Centers for Medicare & Medicaid Services Web site. http://www.cms.gov/ HCPCSReleaseCodeSetsDownloads/12anweb.zip. Accessed November 1, 2011.

Important Safety Information (cont) Recommended Dose Modifications Withhold dose for moderate immune-mediated adverse reactions until return to baseline, improvement to mild severity, or complete resolution, and patient is receiving <7.5 mg prednisone or equivalent per day.

Permanently discontinue YERVOY™ (ipilimumab) for any of the following: t Persistent moderate adverse reactions or inability to reduce corticosteroid dose to 7.5 mg prednisone or equivalent per day. t Failure to complete full treatment course within 16 weeks from administration of first dose. t Severe or life-threatening adverse reactions.

Immune-mediated Enterocolitis: t In the pivotal Phase 3 study in YERVOY-treated patients, severe, life-threatening or fatal (diarrhea of ≥7 stools above baseline, fever, ileus, peritoneal signs; Grade 3-5) immune-mediated enterocolitis occurred in 34 (7%) and moderate (diarrhea with up to 6 stools above baseline, abdominal pain, mucus or blood in stool; Grade 2) enterocolitis occurred in 28 (5%) patients. t Across all YERVOY-treated patients (n=511), 5 (1%) developed intestinal perforation, 4 (0.8%) died as a result of complications, and 26 (5%) were hospitalized for severe enterocolitis. t Monitor patients for signs and symptoms of enterocolitis (such as diarrhea, abdominal pain, mucus or blood in stool, with or without fever) and of bowel perforation (such as peritoneal signs and ileus).

– In symptomatic patients, rule out infectious etiologies and consider endoscopic evaluation for persistent or severe symptoms.

Immune-mediated Hepatitis: t In the pivotal Phase 3 study in YERVOY-treated patients, severe, life-threatening, or fatal hepatotoxicity (AST or ALT elevations >5X the upper limit of normal (ULN) or total bilirubin elevations >3X the ULN; Grade 3–5) occurred in 8 (2%), with fatal hepatic failure in 0.2% and hospitalization in 0.4%. t 13 (2.5%) additional YERVOY-treated patients experienced moderate hepatotoxicity manifested by LFT abnormalities (AST or ALT elevations >2.5X but ≤5X the ULN or total bilirubin elevation >1.5X but ≤3X the ULN; Grade 2). t Monitor LFTs (hepatic transaminase and bilirubin levels) and assess patients for signs and symptoms of hepatotoxicity before each dose of YERVOY. – In patients with hepatotoxicity, rule out infectious or malignant causes and increase frequency of LFT monitoring until resolution.

Immune-mediated Dermatitis: t In the pivotal Phase 3 study in YERVOY-treated patients, severe, life-threatening or fatal immune-mediated dermatitis (e.g., StevensJohnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; Grade 3–5) occurred in 13 (2.5%) patients.

– 1 (0.2%) patient died as a result of toxic epidermal necrolysis.

– 1 additional patient required hospitalization for severe dermatitis. t There were 63 (12%) YERVOY-treated patients with moderate (Grade 2) dermatitis. t Monitor patients for signs and symptoms of dermatitis such as rash and pruritus. Unless an alternate etiology has been identified, signs or symptoms of dermatitis should be considered immune-mediated.

Immune-mediated Neuropathies: t In the pivotal Phase 3 study in YERVOY-treated patients, 1 case of fatal Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral motor neuropathy were reported. t Across the clinical development program of YERVOY, myasthenia gravis and additional cases of Guillain-Barré syndrome have been reported. t Monitor for symptoms of motor or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, or paresthesia.

Immune-mediated Endocrinopathies: t In the pivotal Phase 3 study in YERVOY-treated patients, severe to life-threatening immune-mediated endocrinopathies (requiring hospitalization, urgent medical intervention, or interfering with activities of daily living; Grade 3-4) occurred in 9 (1.8%).

– All 9 patients had hypopituitarism and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism.

– 6 of the 9 patients were hospitalized for severe endocrinopathies. t Moderate endocrinopathy (requiring hormone replacement or medical intervention; Grade 2) occurred in 12 (2.3%) YERVOYtreated patients and consisted of hypothyroidism, adrenal insufficiency, hypopituitarism, and 1 case each of hyperthyroidism and Cushing’s syndrome. t Median time to onset of moderate to severe immune-mediated endocrinopathy was 11 weeks and ranged up to 19.3 weeks after the initiation of YERVOY. t Monitor patients for clinical signs and symptoms of hypophysitis, adrenal insufficiency (including adrenal crisis), and hyper- or hypothyroidism.

– Patients may present with fatigue, headache, mental status changes, abdominal pain, unusual bowel habits, and hypotension, or nonspecific symptoms which may resemble other causes such as brain metastasis or underlying disease.

– Unless an alternate etiology has been identified, signs or symptoms of endocrinopathies should be considered immune-mediated.

– Monitor thyroid function tests and clinical chemistries at the start of treatment, before each dose, and as clinically indicated based on symptoms.

– In a limited number of patients, hypophysitis was diagnosed by imaging studies through enlargement of the pituitary gland.

Other Immune-mediated Adverse Reactions, Including Ocular Manifestations: t In the pivotal Phase 3 study in YERVOY-treated patients, clinically significant immune-mediated adverse reactions seen in <1% were: nephritis, pneumonitis, meningitis, pericarditis, uveitis, iritis, and hemolytic anemia. t Across the clinical development program for YERVOY, immunemediated adverse reactions also reported with <1% incidence were: myocarditis, angiopathy, temporal arteritis, vasculitis, polymyalgia rheumatica, conjunctivitis, blepharitis, episcleritis, scleritis, leukocytoclastic vasculitis, erythema multiforme, psoriasis, pancreatitis, arthritis, and autoimmune thyroiditis.

Pregnancy & Nursing: t YERVOY is classified as pregnancy category C. There are no adequate and well-controlled studies of YERVOY in pregnant women.

Use YERVOY during pregnancy only if the potential benefit justifies the potential risk to the fetus. t Human IgG1 is known to cross the placental barrier and YERVOY is an IgG1; therefore, YERVOY has the potential to be transmitted from the mother to the developing fetus. t It is not known whether YERVOY is secreted in human milk.

Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from YERVOY, a decision should be made whether to discontinue nursing or to discontinue YERVOY. Common Adverse Reactions: t The most common adverse reactions (≥5%) in patients who received YERVOY at 3 mg/kg were fatigue (41%), diarrhea (32%), pruritus (31%), rash (29%), and colitis (8%).

Please see brief summary of Full Prescribing Information, including Boxed WARNING regarding immune-mediated adverse reactions, on the following spread.

© 2011 Bristol-Myers Squibb 731US11AB18303 YERVOY is a trademark of Bristol-Myers Squibb.

11/11

Printed in USA

YERVOYâ&#x201E;˘ (ipilimumab) Injection, for intravenous infusion Brief Summary of Prescribing Information. For complete prescribing information consult official package insert.

WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS YERVOY (ipilimumab) can result in severe and fatal immune-mediated adverse reactions due to T-cell activation and proliferation. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY. Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions. [See Dosage and Administration (2.2) in Full Prescribing Information] Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate clinical chemistries including liver function tests and thyroid function tests at baseline and before each dose. [See Warnings and Precautions] INDICATIONS AND USAGE YERVOY (ipilimumab) is indicated for the treatment of unresectable or metastatic melanoma.

CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS YERVOY can result in severe and fatal immune-mediated reactions due to T-cell activation and proliferation.

[See Boxed Warning] Immune-mediated Enterocolitis In Study 1, severe, life-threatening, or fatal (diarrhea of 7 or more stools above baseline, fever, ileus, peritoneal signs; Grade 3â&#x20AC;&#x201C;5) immune-mediated enterocolitis occurred in 34 (7%) YERVOY-treated patients, and moderate (diarrhea with up to 6 stools above baseline, abdominal pain, mucus or blood in stool; Grade 2) enterocolitis occurred in 28 (5%) YERVOY-treated patients. Across all YERVOY-treated patients (n=511), 5 (1%) patients developed intestinal perforation, 4 (0.8%) patients died as a result of complications, and 26 (5%) patients were hospitalized for severe enterocolitis.

The median time to onset was 7.4 weeks (range 1.6â&#x20AC;&#x201C;13.4) and 6.3 weeks (range 0.3â&#x20AC;&#x201C;18.9) after the initiation of YERVOY for patients with Grade 3â&#x20AC;&#x201C;5 enterocolitis and with Grade 2 enterocolitis, respectively.

Twenty-nine patients (85%) with Grade 3â&#x20AC;&#x201C;5 enterocolitis were treated with high-dose (â&#x2030;Ľ40 mg prednisone equivalent per day) corticosteroids, with a median dose of 80 mg/day of prednisone or equivalent; the median duration of treatment was 2.3 weeks (ranging up to 13.9 weeks) followed by corticosteroid taper.

Of the 28 patients with moderate enterocolitis, 46% were not treated with systemic corticosteroids, 29% were treated with <40 mg prednisone or equivalent per day for a median duration of 5.1 weeks, and 25% were treated with high-dose corticosteroids for a median duration of 10 days prior to corticosteroid taper. Infliximab was administered to 5 of the 62 patients (8%) with moderate, severe, or life-threatening immune-mediated enterocolitis following inadequate response to corticosteroids.

Of the 34 patients with Grade 3â&#x20AC;&#x201C;5 enterocolitis, 74% experienced complete resolution, 3% experienced improvement to Grade 2 severity, and 24% did not improve. Among the 28 patients with Grade 2 enterocolitis, 79% experienced complete resolution, 11% improved, and 11% did not improve.

Monitor patients for signs and symptoms of enterocolitis (such as diarrhea, abdominal pain, mucus or blood in stool, with or without fever) and of bowel perforation (such as peritoneal signs and ileus). In symptomatic patients, rule out infectious etiologies and consider endoscopic evaluation for persistent or severe symptoms.

Permanently discontinue YERVOY in patients with severe enterocolitis and initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least one month. In clinical trials, rapid corticosteroid tapering resulted in recurrence or worsening symptoms of enterocolitis in some patients.

Withhold YERVOY dosing for moderate enterocolitis; administer anti-diarrheal treatment and, if persistent for more than one week, initiate systemic corticosteroids at a dose of 0.5 mg/kg/day prednisone or equivalent. [See Dosage and Administration (2.2) in Full Prescribing Information] Immune-mediated Hepatitis In Study 1, severe, life-threatening, or fatal hepatotoxicity (AST or ALT elevations of more than 5 times the upper limit of normal or total bilirubin elevations more than 3 times the upper limit of normal; Grade 3â&#x20AC;&#x201C;5) occurred in 8 (2%) YERVOY-treated patients, with fatal hepatic failure in 0.2% and hospitalization in 0.4% of YERVOY-treated patients. An additional 13 (2.5%) patients experienced moderate hepatotoxicity manifested by liver function test abnormalities (AST or ALT elevations of more than 2.5 times but not more than 5 times the upper limit of normal or total bilirubin elevation of more than 1.5 times but not more than 3 times the upper limit of normal; Grade 2). The underlying pathology was not ascertained in all patients but in some instances included immune-mediated hepatitis. There were insufficient numbers of patients with biopsyproven hepatitis to characterize the clinical course of this event.

The median time to onset of moderate, severe, or life-threatening immune-mediated dermatitis was 3.1 weeks and ranged up to 17.3 weeks from the initiation of YERVOY (ipilimumab).

Seven (54%) YERVOY-treated patients with severe dermatitis received high-dose corticosteroids (median dose 60 mg prednisone/day or equivalent) for up to 14.9 weeks followed by corticosteroid taper. Of these 7 patients, 6 had complete resolution; time to resolution ranged up to 15.6 weeks.

Of the 63 patients with moderate dermatitis, 25 (40%) were treated with systemic corticosteroids (median of 60 mg/day of prednisone or equivalent) for a median of 2.1 weeks, 7 (11%) were treated with only topical corticosteroids, and 31 (49%) did not receive systemic or topical corticosteroids. Forty-four (70%) patients with moderate dermatitis were reported to have complete resolution, 7 (11%) improved to mild (Grade 1) severity, and 12 (19%) had no reported improvement.

Monitor patients for signs and symptoms of dermatitis such as rash and pruritus. Unless an alternate etiology has been identified, signs or symptoms of dermatitis should be considered immune-mediated.

Permanently discontinue YERVOY in patients with Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations.

Administer systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. When dermatitis is controlled, corticosteroid tapering should occur over a period of at least 1 month. Withhold YERVOY dosing in patients with moderate to severe signs and symptoms. [See Dosage and Administration (2.2) in Full Prescribing Information] For mild to moderate dermatitis, such as localized rash and pruritus, treat symptomatically. Administer topical or systemic corticosteroids if there is no improvement of symptoms within 1 week.

Immune-mediated Neuropathies In Study 1, one case of fatal Guillain-BarrĂŠ syndrome and one case of severe (Grade 3) peripheral motor neuropathy were reported. Across the clinical development program of YERVOY, myasthenia gravis and additional cases of Guillain-BarrĂŠ syndrome have been reported.

Monitor for symptoms of motor or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, or paresthesia. Permanently discontinue YERVOY in patients with severe neuropathy (interfering with daily activities) such as Guillain-BarrĂŠ-like syndromes. Institute medical intervention as appropriate for management of severe neuropathy. Consider initiation of systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or equivalent for severe neuropathies. Withhold YERVOY dosing in patients with moderate neuropathy (not interfering with daily activities). [See Dosage and Administration (2.2) in Full Prescribing Information] Immune-mediated Endocrinopathies In Study 1, severe to life-threatening immune-mediated endocrinopathies (requiring hospitalization, urgent medical intervention, or interfering with activities of daily living; Grade 3â&#x20AC;&#x201C;4) occurred in 9 (1.8%) YERVOY-treated patients. All 9 patients had hypopituitarism and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism. Six of the 9 patients were hospitalized for severe endocrinopathies. Moderate endocrinopathy (requiring hormone replacement or medical intervention; Grade 2) occurred in 12 (2.3%) patients and consisted of hypothyroidism, adrenal insufficiency, hypopituitarism, and one case each of hyperthyroidism and Cushingâ&#x20AC;&#x2122;s syndrome. The median time to onset of moderate to severe immune-mediated endocrinopathy was 11 weeks and ranged up to 19.3 weeks after the initiation of YERVOY. Of the 21 patients with moderate to life-threatening endocrinopathy, 17 patients required long-term hormone replacement therapy including, most commonly, adrenal hormones (n=10) and thyroid hormones (n=13).

Monitor patients for clinical signs and symptoms of hypophysitis, adrenal insufficiency (including adrenal crisis), and hyper- or hypothyroidism. Patients may present with fatigue, headache, mental status changes, abdominal pain, unusual bowel habits, and hypotension, or nonspecific symptoms which may resemble other causes such as brain metastasis or underlying disease. Unless an alternate etiology has been identified, signs or symptoms of endocrinopathies should be considered immune-mediated.

Monitor thyroid function tests and clinical chemistries at the start of treatment, before each dose, and as clinically indicated based on symptoms. In a limited number of patients, hypophysitis was diagnosed by imaging studies through enlargement of the pituitary gland.

Withhold YERVOY dosing in symptomatic patients. Initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent, and initiate appropriate hormone replacement therapy. [See Dosage and Administration (2.2) in Full Prescribing Information] Other Immune-mediated Adverse Reactions, Including Ocular Manifestations The following clinically significant immune-mediated adverse reactions were seen in less than 1% of YERVOY-treated patients in Study 1: nephritis, pneumonitis, meningitis, pericarditis, uveitis, iritis, and hemolytic anemia.

Across the clinical development program for YERVOY, the following likely immune-mediated adverse reactions were also reported with less than 1% incidence: myocarditis, angiopathy, temporal arteritis, vasculitis, polymyalgia rheumatica, conjunctivitis, blepharitis, episcleritis, scleritis, leukocytoclastic vasculitis, erythema multiforme, psoriasis, pancreatitis, arthritis, and autoimmune thyroiditis.

Permanently discontinue YERVOY for clinically significant or severe immune-mediated adverse reactions.

Initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or equivalent for severe immunemediated adverse reactions.

Monitor liver function tests (hepatic transaminase and bilirubin levels) and assess patients for signs and symptoms of hepatotoxicity before each dose of YERVOY. In patients with hepatotoxicity, rule out infectious or malignant causes and increase frequency of liver function test monitoring until resolution.

Administer corticosteroid eye drops to patients who develop uveitis, iritis, or episcleritis. Permanently discontinue YERVOY for immune-mediated ocular disease that is unresponsive to local immunosuppressive therapy. [See Dosage and Administration (2.2) in Full Prescribing Information]

Permanently discontinue YERVOY in patients with Grade 3â&#x20AC;&#x201C;5 hepatotoxicity and administer systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. When liver function tests show sustained improvement or return to baseline, initiate corticosteroid tapering and continue to taper over 1 month. Across the clinical development program for YERVOY, mycophenolate treatment has been administered in patients who have persistent severe hepatitis despite high-dose corticosteroids. Withhold YERVOY in patients with Grade 2 hepatotoxicity. [See Dosage and Administration (2.2) in Full Prescribing Information]

ADVERSE REACTIONS

Immune-mediated Dermatitis In Study 1, severe, life-threatening, or fatal immune-mediated dermatitis (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; Grade 3â&#x20AC;&#x201C;5) occurred in 13 (2.5%) YERVOY-treated patients. One (0.2%) patient died as a result of toxic epidermal necrolysis and one additional patient required hospitalization for severe dermatitis. There were 63 (12%) patients with moderate (Grade 2) dermatitis.

The following adverse reactions are discussed in greater detail in other sections of the labeling.

t *NNVOF NFEJBUFE FOUFSPDPMJUJT [see Warnings and Precautions].

t *NNVOF NFEJBUFE IFQBUJUJT [see Warnings and Precautions].

t *NNVOF NFEJBUFE EFSNBUJUJT [see Warnings and Precautions].

t *NNVOF NFEJBUFE OFVSPQBUIJFT [see Warnings and Precautions].

t *NNVOF NFEJBUFE FOEPDSJOPQBUIJFT [see Warnings and Precautions].

t 0 UIFS JNNVOF NFEJBUFE BEWFSTF SFBDUJPOT JODMVEJOH PDVMBS NBOJGFTUBUJPOT [see Warnings and Precautions].

Clinical Trials Experience

Immunogenicity

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared with rates in other clinical trials or experience with therapeutics in the same class and may not reflect the rates observed in clinical practice.

In clinical studies, 1.1% of 1024 evaluable patients tested positive for binding antibodies against ipilimumab in an electrochemiluminescent (ECL) based assay. This assay has substantial limitations in detecting anti-ipilimumab antibodies in the presence of ipilimumab. Infusion-related or peri-infusional reactions consistent with hypersensitivity or anaphylaxis were not reported in these 11 patients nor were neutralizing antibodies against ipilimumab detected.

The clinical development program excluded patients with active autoimmune disease or those receiving systemic immunosuppression for organ transplantation. Exposure to YERVOY (ipilimumab) 3 mg/kg for four doses given by intravenous infusion in previously treated patients with unresectable or metastatic melanoma was assessed in a randomized, double-blind clinical study (Study 1). [See Clinical Studies (14) in Full Prescribing Information] One hundred thirty-one patients (median age 57 years, 60% male) received YERVOY as a single agent, 380 patients (median age 56 years, 61% male) received YERVOY with an investigational gp100 peptide vaccine (gp100), and 132 patients (median age 57 years, 54% male) received gp100 peptide vaccine alone. Patients in the study received a median of 4 doses (range 1 to 4 doses). YERVOY was discontinued for adverse reactions in 10% of patients.

The most common adverse reactions (â&#x2030;Ľ5%) in patients who received YERVOY at 3 mg/kg were fatigue, diarrhea, pruritus, rash, and colitis.

Table 1 presents selected adverse reactions from Study 1, which occurred in at least 5% of patients in the YERVOY-containing arms and with at least 5% increased incidence over the control gp100 arm for all-grade events and at least 1% incidence over the control group for Grade 3â&#x20AC;&#x201C;5 events.

Table 1:

Percentage (%) of YERVOY 3 mg/kg n=131

Gastrointestinal Disorders Diarrhea Colitis Skin and Subcutaneous Tissue Disorders Pruritus Rash General Disorders and Administration Site Conditions Fatigue a

DRUG INTERACTIONS No formal drug-drug interaction studies have been conducted with YERVOY (ipilimumab).

USE IN SPECIFIC POPULATIONS Pregnancy

There are no adequate and well-controlled studies of YERVOY in pregnant women. Use YERVOY during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Patientsa

YERVOY 3 mg/kg+gp100 n=380

gp100 n=132

Any Grade

Grade 3â&#x20AC;&#x201C;5

Any Grade

Grade 3â&#x20AC;&#x201C;5

Any Grade

Grade 3â&#x20AC;&#x201C;5

32 8

5 5

37 5

4 3

20 2

1 0

31 29

0 2

21 25

<1 2

11 8

0 0

41

7

34

5

31

3

In a combined study of embryo-fetal and peri-postnatal development, severe toxicities including increased incidences of third-trimester abortion, stillbirth, premature delivery, low birth weight, and infant mortality occurred following intravenous administration of ipilimumab to pregnant cynomolgus monkeys every 21 days from the onset of organogenesis through parturition at doses of 2.6 or 7.2 times the recommended human dose of 3 mg/kg (by AUC). [See Nonclinical Toxicology (13.2) in Full Prescribing Information] In genetically engineered mice in which the gene for CTLA-4 has been deleted (a â&#x20AC;&#x153;knockout mouseâ&#x20AC;?), offspring lacking CTLA-4 were born apparently healthy, but died within 3â&#x20AC;&#x201C;4 weeks due to multi-organ infiltration and damage by lymphocytes.

Human IgG1 is known to cross the placental barrier and ipilimumab is an IgG1; therefore, ipilimumab has the potential to be transmitted from the mother to the developing fetus.

Nursing Mothers

Incidences presented in this table are based on reports of adverse events regardless of causality.

Table 2 presents the per-patient incidence of severe, life-threatening, or fatal immune-mediated adverse reactions from Study 1.

Table 2:

Immunogenicity assay results are highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to YERVOY with the incidences of antibodies to other products may be misleading.

Pregnancy Category C

Selected Adverse Reactions in Study 1

System Organ Class/ Preferred Term

Because trough levels of ipilimumab interfere with the ECL assay results, a subset analysis was performed in the dose cohort with the lowest trough levels. In this analysis, 6.9% of 58 evaluable patients, who were treated with 0.3 mg/kg dose, tested positive for binding antibodies against ipilimumab.

Severe to Fatal Immune-mediated Adverse Reactions in Study 1 Percentage (%) of Patients

Any Immune-mediated Adverse Reaction Enterocolitisa,b Hepatotoxicitya Dermatitisa Neuropathya Endocrinopathy Hypopituitarism Adrenal insufficiency Other Pneumonitis Meningitis Nephritis Eosinophiliac Pericarditisa,c

YERVOY 3 mg/kg n=131

YERVOY 3 mg/kg+gp100 n=380

15 7 1 2 1 4 4 0

12 7 2 3 <1 1 1 1

0 0 1 1 0

<1 <1 0 0 <1

It is not known whether ipilimumab is secreted in human milk. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from YERVOY, a decision should be made whether to discontinue nursing or to discontinue YERVOY, taking into account the importance of YERVOY to the mother.

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

Geriatric Use Of the 511 patients treated with YERVOY at 3 mg/kg, 28% were 65 years and over. No overall differences in safety or efficacy were reported between the elderly patients (65 years and over) and younger patients (less than 65 years).

Renal Impairment No formal studies of YERVOY in patients with renal impairment have been conducted. [See Clinical Pharmacology (12.3) in Full Prescribing Information] Hepatic Impairment No formal studies of YERVOY in patients with hepatic impairment have been conducted. [See Clinical Pharmacology (12.3) in Full Prescribing Information] OVERDOSAGE There is no information on overdosage with YERVOY. PATIENT COUNSELING INFORMATION See MEDICATION GUIDE in Full Prescribing Information. t *OGPSN QBUJFOUT PG UIF QPUFOUJBM SJTL PG JNNVOF NFEJBUFE BEWFSTF SFBDUJPOT t "EWJTF QBUJFOUT UP SFBE UIF :&370: .FEJDBUJPO (VJEF CFGPSF FBDI :&370: JOGVTJPO t "EWJTF XPNFO UIBU :&370: NBZ DBVTF GFUBM IBSN t "EWJTF OVSTJOH NPUIFST OPU UP CSFBTU GFFE XIJMF UBLJOH :&370:

Manufactured by: Bristol-Myers Squibb Company Princeton, NJ 08543 USA

a

Including fatal outcome.

Including intestinal perforation. c Underlying etiology not established. b

Across clinical studies that utilized YERVOY doses ranging from 0.3 to 10 mg/kg, the following adverse reactions were also reported (incidence less than 1% unless otherwise noted): urticaria (2%), large intestinal ulcer, esophagitis, acute respiratory distress syndrome, renal failure, and infusion reaction.

Based on the experience in the entire clinical program for melanoma, the incidence and severity of enterocolitis and hepatitis appear to be dose dependent.

1281558A2

IP-B0001A-03-11

Issued: March 2011

Drug Coding Supplied by: RJ Health Systems

Medications Used for the Treatment of Breast Cancer The following sections will assist healthcare professionals and payers by providing appropriate coding information associated with the management of breast cancer.

Associated ICD-9-CM Codes for Breast Cancer 174 Malignant neoplasm of female breast Includes: breast (female) connective tissue soft parts Paget’s disease of: breast nipple Use additional code to identify estrogen receptor status (V86.0, V86.1) Excludes: skin of the breast (172.5, 173.5) 174.0 Nipple and areola 174.1 Central portion 174.2 Upper-inner quadrant 174.3 Lower-inner quadrant 174.4 Upper-outer quadrant 174.5 Lower-outer quadrant 174.6 Axillary tail 174.8 Other specified sites of female breast Ectopic sites Inner breast Lower breast Malignant neoplasm of contiguous or overlapping sites of breast whose point of origin cannot be determined Midline of breast Outer breast Upper breast 174.9 Breast (female), unspecified

This information includes: • Associated ICD-9-CM codes used for the classification of breast cancer • Drugs that have been FDA-approved in the treatment of breast cancer • Drugs that are Compendia listed for off-label use for breast 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 • Possible CPT® admnistration codes for each medication

175 Malignant neoplasm of male breast Use additional code to identify estrogen receptor status (V86.0, V86.1) Excludes: skin of breast (172.5, 173.5) 175.0 Nipple and areola 175.9 Other and unspecified sites of male breast Ectopic breast tissue, male

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Drug Coding Supplied by: RJ Health Systems

FDA-approved for breast cancer

Compendia listed off-label use for breast cancer

CPT ® administration codes

Generic (brand) name

HCPCS code: code description

anastrozole (Arimidex)

J8999aa: Prescription drug, oral, chemotherapeutic, not otherwise specified

✓

N/A

anastrozole (Arimidex)

S0170: Anastrozole, oral, 1 mg

✓

N/A

Bacillus Calmette-Guerin 90585: Bacillus Calmette-Guerin vaccine (Tice BCG, TheraCys) (BCG) for tuberculosis, live, for percutaneous use

✓

90471

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

✓

51720

Bacillus Calmette-Guerin J9031: BCG (intravesical), per installation (Tice BCG, TheraCys)

✓

51720

bevacizumab (Avastin)

J9035: Injection, bevacizumab, 10 mg

✓

96413, 96415

capecitabine (Xeloda)

J8520: Capecitabine, oral, 150 mg

✓

N/A

capecitabine (Xeloda)

J8521: Capecitabine, oral, 500 mg

✓

N/A

carboplatin (Paraplatin) J9045: Injection, carboplatin, 50 mg

✓

96409, 96413, 96415

cisplatin (Platinol AQ)

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

✓

96409, 96413, 96415

cyclophosphamide (Cytoxan)

J8530: Cyclophosphamide, oral, 25 mg

✓

N/A

cyclophosphamide (Cytoxan)

J9070: Cyclophosphamide, 100 mg

✓

96409, 96413, 96415

dexamethasone (Decadron)

J1100: Injection, dexamethasone sodium phosphate, 1 mg

✓

11900, 11901, 20600, 20605, 20610, 96372, 96374

dexamethasone (Decadron)

J8540: Dexamethasone, oral, 0.25 mg

✓

N/A

docetaxel (Taxotere)

J9171: Injection, docetaxel, 1 mg

✓

96413

doxorubicin HCl (Adriamycin)

J9000: Injection, doxorubicin hydrochloride, 10 mg

✓

96409

doxorubicin HCl liposome (Doxil)

J9001: Injection, doxorubicin hydrochloride, all lipid formulations, 10 mg

epirubicin (Ellence)

J9178: Injection, epirubicin HCl, 2 mg

✓

96409, 96413

eribulin (Halaven)

J9179: Injection, eribulin mesylate, 0.1 mg

✓

96409

estradiol (Estrace)

J8499 : Prescription drug, oral, nonchemotherapeutic, not otherwise specified

✓

N/A

etoposide (Vepesid)

J8560: Etoposide, oral, 50 mg

a

✓

✓

December 2011

I

96413

N/A

www.OncPracticeManagement.com

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Drug Coding Supplied by: RJ Health Systems

Generic (brand) name

HCPCS code: code description

FDA-approved for breast cancer

etoposide (Etopophus, Toposar) exemestane (Aromasin) exemestane (Aromasin) fluorouracil (Adrucil) fluoxymesterone (Androxy)

J9181: Injection, etoposide, 10 mg

J8999a: Prescription drug, oral, chemotherapeutic, not otherwise specified S0156: Exemestane, 25 mg J9190: Injection, fluorouracil, 500 mg J8499a: Prescription drug, oral, nonchemotherapeutic, not otherwise specified fulvestrant (Faslodex) J9395: Injection, fulvestrant, 25 mg gemcitabine (Gemzar) J9201: Injection, gemcitabine hydrochloride, 200 mg goserelin acetate J9202: Goserelin acetate implant, (Zoladex 3.6 mg ONLY) per 3.6 mg hydrocortisone sodium J1720: Injection, hydrocortisone sodium (Solu-Cortef) succinate, up to 100 mg hydroxyurea J8999a: Prescription drug, oral, (Hydrea) chemotherapeutic, not otherwise specified hydroxyurea (Hydrea) S0176: Hydroxyurea, oral, 500 mg ifosfamide (Ifex) J9208: Injection, ifosfamide, 1 g irinotecan (Camptosar) J9206: Injection, irinotecan, 20 mg ixabepilone (Ixempra) J9207: Injection, ixabepilone, 1 mg lapatinib (Tykerb) J8999a: Prescription drug, oral, chemotherapeutic, not otherwise specified letrozole J8999a: Prescription drug, oral, (Femara) chemotherapeutic, not otherwise specified leucovorin calcium J0640: Injection, leucovorin calcium, (Wellcovorin) per 50 mg leuprolide J9217: Leuprolide acetate (Eligard, Lupron Depot) (for depot suspension), 7.5 mg leuprolide (Lupron) J9218: Leuprolide acetate, per 1 mg lomustine J8999a: Prescription drug, oral, (CeeNu) chemotherapeutic, not otherwise specified lomustine (CeeNU) S0178: Lomustine, oral, 10 mg medroxyprogesterone J1051: Injection, medroxyprogesterone (Depo-Provera) acetate, 50 mg megestrol J8999a: Prescription drug, oral, (Megace) chemotherapeutic, not otherwise specified megestrol (Megace) S0179: Megestrol acetate, oral 20 mg melphalan (Alkeran) J8600: Melphalan, oral, 2 mg melphalan (Alkeran) J9245: Injection, melphalan hydrochloride, 50 mg

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Compendia listed off-label use for breast cancer ✓

CPT ® administration codes 96413, 96415

N/A N/A 96409 N/A

✓ ✓ ✓ ✓

✓

96402 96413

✓

96372, 96402

✓

✓

✓

✓ ✓ ✓ ✓

96365, 96366, 96372, 96374 N/A N/A 96413, 96415 96413, 96415 96413, 96415 N/A N/A

✓ ✓

✓

✓

✓ ✓

✓ ✓

96372, 96374, 96409 96402 96402 N/A N/A 96402

✓

N/A

✓ ✓

N/A N/A

✓

96409, 96413

Drug Coding Supplied by: RJ Health Systems

FDA-approved for breast cancer

Compendia listed off-label use for breast cancer

CPT ® administration codes

Generic (brand) name

HCPCS code: code description

methotrexate methotrexate sodium

J8610: Methotrexate, oral, 2.5 mg J9250: Methotrexate sodium, 5 mg

✓

methotrexate sodium

J9260: Methotrexate sodium, 50 mg

✓

methylprednisolone (Depo-Medrol)

J1020: Injection, methylprednisolone acetate, 20 mg

✓

methylprednisolone (Depo-Medrol)

J1030: Injection, methylprednisolone acetate, 40 mg

✓

methylprednisolone (Depo-Medrol)

J1040: Injection, methylprednisolone acetate, 80 mg

✓

methylprednisolone (Solu-Medrol)

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

✓

methylprednisolone (Medrol) mifepristone (Mifeprex) mifepristone (Mifeprex) mitomycin (Mutamycin) mitoxantrone (Novantrone) oxaliplatin (Eloxatin) paclitaxel proteinbound particles (Abraxane) paclitaxel (Taxol) pemetrexed (Alimta) prednisone prednisolone (eg, Orapred, Millipred)

J7509: Methylprednisolone, oral, per 4 mg

✓

N/A 96372, 96374, 96401, 96409, 96450 96372, 96374, 96401, 96409, 96450 11900, 11901, 20600, 20605, 20610, 96372, 96374 11900, 11901, 20600, 20605, 20610, 96372, 96374 11900, 11901, 20600, 20605, 20610, 96372, 96374 11900, 11901, 20600, 20605, 20610, 96372, 96374 N/A

J8499a: Prescription drug, oral, nonchemotherapeutic, not otherwise specified S0190: Mifepristone, oral, 200 mg

✓

N/A

✓

N/A

✓

96409 96409, 96413

✓

J9280: Mitomycin, 5 mg J9293: Injection, mitoxantrone hydrochloride, per 5 mg J9263: Injection, oxaliplatin, 0.5 mg J9264: Injection, paclitaxel protein-bound particles, 1 mg J9265: Injection, paclitaxel, 30 mg

✓

✓

96413, 96415 96413

✓

96413, 96415

✓

J9305: Injection, pemetrexed, 10 mg J7506: Prednisone, oral, per 5 mg J7510: Prednisolone, oral, per 5 mg

✓ ✓ ✓

December 2011

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96409 N/A N/A

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Drug Coding Supplied by: RJ Health Systems

Generic (brand) name

HCPCS code: code description

FDA-approved for breast cancer

tamoxifen (Nolvadex)

J8999a: Prescription drug, oral, chemotherapeutic, not otherwise specified tamoxifen (Nolvadex) S0187: Tamoxifen citrate, oral, 10 mg thiotepa J9340: Injection, thiotepa, 15 mg topotecan (Hycamtin) J8705: Topotecan, oral, 0.25 mg topotecan (Hycamtin) J9350: Injection, pemetrexed, 10 mg toremifene J8999a: Prescription drug, oral, (Fareston) chemotherapeutic, not otherwise specified trastuzumab (Herceptin) J9355: Injection, trastuzumab, 10 mg triptorelin (Trelstar) J3315: Injection, triptorelin pamoate, 3.75 mg vinBLAStine (Velban) J9360: Injection, vinblastine sulfate, 1 mg vinCRIStine J9370: Vincristine sulfate, 1 mg (Vincasar PFS) vinorelbine J9390: Injection, vinorelbine tartrate, (Navelbine) per 10 mg zoledronic acid J3487: Injection, zoledronic acid (Zometa), (Zometa) 1 mg zoledronic acid J3488: Injection, zoledronic acid (Reclast), (Reclast) 1 mg

Compendia listed off-label use for breast cancer

CPT ® administration codes

✓

N/A

✓

N/A 51720, 96409 N/A 96413 N/A

✓ ✓ ✓ ✓

✓

96413, 96415 96372, 96402 96409 96409

✓

96409

✓

96365, 96413

✓

96365, 96374

✓ ✓ ✓

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

a

References • HCPCS Level II Expert 2011 • Current Procedural Terminology (CPT®), 2011 (CPT® copyright 2011. American Medical Association. All rights reserved. CPT® is a registered trademark of the American Medical Association) • ICD-9-CM for Professionals Vol 1, 2, 2011 • FDA-approved indication (from product prescribing information) • Compendia references available upon request • www.ReimbursementCodes.com powered by RJ Health Systems International, LLC., Wethersfield, Connecticut • CMS (Centers for Medicare & Medicaid Services) BCG indicates Bacillus Calmette-Guerin; CPT, Current Procedural Terminology; HCPCS, Healthcare Common Procedure Coding System.

This information was supplied by:

30 Cold Spring Road, Rocky Hill, CT 06067 T: (860) 563-1223 • F: (860) 563-1650 • www.RJHealthSystems.com

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RJ Health Systems The Creators of ReimbursementCodes.com

RJ Health Systems â&#x20AC;&#x201D; the pharmaceutical specialists that healthcare professionals have turned to since 1983 for their drug information.

We work with over 170 Payor organizations that touch approximately 110 million lives.

RJ Health Systems has established and continuously maintains a Library of Drug Intelligence that provides the most comprehensive, trusted, and up-to-date coding and reimbursement information in the industry.

ReimbursementCodes.com incorporates the CMS HCPCS and AMA CPT Drug codes into a system that crosswalks each drug code with the drugâ&#x20AC;&#x2122;s NDC and brand/generic name.

Please visit www.rjhealthsystems.com to learn more about our products and services listed below:

>> >> >> >> >> >> >> >> >>

ReimbursementCodes.com Drug Diagnosis Coding CMAC PartBorPartD.com NDC Conversion Database Min/Max Dosing Advisories Notations Clinical Consulting

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Physician Wealth Management With Lawrence B. Keller, CLU, ChFC, CFP®

Disability Insurance Planning for the Cancer Care Team Selecting the Best Riders for Your Policy

M

y last article described how to begin to determine the amount of individual disability insurance available. This article is focused on what to look for in a policy and help you decide which riders should be part of your policy.

Noncancellable and Guaranteed Renewable If you purchase a policy that is both noncancellable and guaranteed renewable, you are ensured that the premium rates and policy provisions will not be changed. This combination provides the greatest degree of consumer protection.

Definition of Total Disability Whether you are a physician, an executive, a practice or hospital administrator, or working in another capacity, look for a policy that contains a true “own-occupation” definition of total disability. This definition pays benefits if you are disabled and are unable to perform the material and substantial duties of your occupation, even if you are gainfully employed in another occupation.

Residual Disability Rider Although “own-occupation” is the most liberal definition of disability, it is not the end all. What happens if your physician states that you can still work in your occupation but he or she requires that you work fewer days per week or less hours per day? A residual disability rider protects your income by providing ben-

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efits proportionate to your loss of income in the event you are not totally disabled. Generally, to qualify for residual disability benefits, you must experience an income loss of 15% to 20% or more compared with your predisability earnings. In addition, if your loss of earnings were greater than 75% to 80%, then 100% of your monthly disability benefit would be paid.

This rider is also extremely important if you are totally disabled first and then return to your occupation with a limited schedule as you recover, or if you have a continued loss of income, because you were previously disabled, even if you are back to work on a full-time basis.

Finally, it is imperative that you do not purchase a policy that requires that you be totally disabled first to collect benefits under the residual disability rider. Although this is not the case with individual policies, this is very common in group policies offered by medical or other professional associations in which you may be a member.

Cost of Living Adjustment Rider A Cost of Living Adjustment (COLA) rider is designed to help your benefits keep pace with inflation after your disability has lasted for 12 months. This adjustment can be a fixed percentage or tied to the Consumer Price Index. Ideally, you want a COLA that is adjusted annually on a compound interest basis, with no “cap” on the monthly benefit. Although expensive, this rider can provide significant increases to your monthly benefit if you are disabled young. However, if cutting the

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cost of coverage is an issue, this may be the first optional rider to consider excluding from your policy. Alternatively you may use the additional premium associated with this rider to purchase a larger monthly benefit if you are not already contemplating the purchase of the maximum monthly benefit for which you are eligible, based on your income or any other in-force coverage.

Future Increase Option Rider This rider is a must for young professionals. As your income rises, this rider provides you with the ability to increase your disability coverage, without providing evidence of good health. This guarantees that any medical conditions that develop after your original policy’s purchase would be fully covered and not subject to new medical underwriting.

It is important to know when you can increase your coverage, as well as by what increments, on any given option date. Some companies may allow you to use your entire option in one year as long as your then-current income warrants the increase; others, however, may limit the amount that you can purchase.

Catastrophic Disability Benefit Rider If you become catastrophically disabled under the terms of the policy and lose the ability to perform 2 or more activities of daily living without assistance, become cognitively impaired, or become presumptively disabled, you would receive a monthly benefit in addition to the base monthly benefit purchased.

This additional benefit can be as Continued on page 44

Y DA O T 0 R E T $10 S I E G RE SAV

The One Conference You Can’t AFFORD to Miss!

Second Annual Association for Value-Based Cancer Care Conference Strategies for Optimizing Value in Cancer Care Delivery March 29-31, 2012 • JW Marriott • Houston, Texas

REGISTER TODAY at www.regonline.com/avbcc2012 TARGET AUDIENCE This activity was developed for physicians, nurses, pharmacists, and managed care professionals who are involved in the care of patients with cancer.

CONFERENCE GOAL The Association for Value-Based Cancer Care will foster an open dialogue between providers, payers, and/or other members of the oncology team in order for attendees to gain a better understanding of various points of view regarding cost, quality, and access in cancer care.

CONFERENCE CO-CHAIRS Al B. Benson III, MD, FACP Professor of Medicine Associate Director for Clinical Investigations Robert H. Lurie Comprehensive Cancer Center Northwestern University

EDUCATIONAL OBJECTIVES • Discuss the current trends and challenges facing all stakeholders in optimizing value in cancer care delivery • Define the barriers associated with cost, quality, and access as it relates to healthcare reform and what solutions are currently being considered • Compare and contrast the different approaches/tools that providers and payers are utilizing to manage and deliver care collaboratively • Examine the current trends in personalized care and companion diagnostics • Analyze the patient issues around cost, quality, and access to care

Gary Owens, MD President Gary Owens Associates

Burt Zweigenhaft, BS

DESIGNATION OF CREDIT STATEMENTS

President, CEO OncoMed

Physician Accreditation – Joint Sponsor The Medical Learning Institute, Inc. (MLI) designates this live activity for a maximum of 13.5 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Medical Learning Institute, Inc. and the Association for Value-Based Cancer Care, Inc. The Medical Learning Institute, Inc. is accredited by the ACCME to provide continuing medical education for physicians.

Registered Nurse Designation Medical Learning Institute, Inc. (MLI) Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 13.5 contact hours.

Registered Pharmacy Designation Medical Learning Institute, Inc. (MLI) is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. Completion of this activity provides for 13.5 contact hours (1.35 CEUs) of continuing education credit.

This activity is jointly sponsored by Medical Learning Institute, Inc., and the Association for Value-Based Cancer Care

CONFERENCE REGISTRATION

SAVE $100 off full Conference Tuition REGISTER TODAY FOR ONLY $275 at www.regonline.com/avbcc2012 For more information, please visit www.avbcconline.org/2012 or e-mail association@avbcconline.org.

Oncology Networks

Enhancing Oncology Networks Tips for Each Ownership Model

By Gerard M. Nussbaum and Laura K. Rehfeld

A

recent Kurt Salmon survey of best practices among the nation’s leading oncology networks suggests that ownership can have significant influence on a network’s ability to implement best practices, and provides a road map for each ownership type to enhance its level of development.

Keys to Successful Enhancement of Your Oncology Network • Install network-level leadership with representation (clinical and administrative) from member entities • Institute multiyear planning with clearly defined priorities, required investments, and benefits to support ongoing funding and success of major initiatives • In the absence of central, system-level ownership, obtain key site executive sponsorship to help advance network cohesiveness • Write agreements that detail roles and responsibilities, funding commitments, and participation in the network leadership council to cement collaborator and hybrid networks and enhance system networks.

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The study included more than 132 inpatient oncology sites within regional oncology networks across the United States. The participants, who requested confidentiality as a condition for participation, represent some of the largest and most respected oncology centers in the country.

The study found that the most advanced oncology networks are governed through a central oncology network leadership council, have developed highly coordinated centralized systems and resources, and have implemented common clinical care protocol sets across sites and instantaneous access to patient records at any point of care. The ownership model of an oncology network can influence its ability to implement best practices.

System Networks System networks are perhaps best organized to achieve an advanced level of development. Because these networks have a single common owner over all sites, they are better positioned to develop a centralized governing council with clear accountability for goals and direction.

Primary control over the network allows systems to define administrative and physician leadership roles and hire appropriate staff to support network planning and coordination.

The system can mediate the different interests of individual sites and ensure leadership incentives support the network, rather than encourage competition between network participants.

One key benefit of common ownership is that the system can allocate funding to support the oncology network. Within the system networks

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interviewed, most were funded in this way. As part of the system, the oncology network competes for resources with other initiatives, such as other service line development and capital investments. To ensure it receives adequate resources, the oncology network is encouraged to conduct robust planning, define clear priorities, and articulate required investments and benefits.

System networks also have control over all sites of care, operations, and resources, and thus greater ability to mandate care processes, monitor compliance in a highly coordinated fashion, and develop a strong central group of oncology physicians. System networks can adopt common clinical care protocols and processes more rapidly than in other ownership models, a key to improving quality and consistency of care.

Collaborator Networks Collaborator networks are driven by the need to balance various ownership interests, because they are comprised of separate owners who come together to advance oncology care. As such, these networks require stronger central governance models to coordinate collective direction and initiatives.

Within the most advanced of these networks, a dedicated, centralized governing oncology leadership council (OLC) exists to ensure that network goals are achieved. The OLC is responsible for defining administrative and physician leadership roles and hiring appropriate staff to support network planning and coordination.

This is typically an independent function of the OLC, with minimal influence from participating members.

Continued on page 44

VELCADE and Millennium are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners.

Millennium Pharmaceuticals, Inc., Cambridge, MA 02139 Copyright Š 2010, Millennium Pharmaceuticals, Inc. All rights reserved.

Printed in USA

V-10-0196

11/10

Oncology Networks

Enhancing Oncology Networks…Continued from page 42 Collaborator networks require additional effort and attention to balance competition among sites and ensure network strength.

Collaborator networks rely on funding contributions from each site to support network operations. The level of funding can be highly variable among sites and typically is determined by the leadership committee on an annual basis within the provisions of the affiliation agreement. The budget is based on the agreed-upon set of initiatives and resources required to support development and may be limited by the willingness of members to fund major initiatives.

Typically, these networks require more advanced levels of systems (functional staff, information technology [IT]) as is necessary to support the higher complexity of the operations within different hospitals and sites, although actual levels vary greatly.

Collaborator networks are challenged to mandate the adoption of standard treatment protocols and care processes across sites. To address this area, some affiliation agreements define the level of required participa-

tion from each member.

However, because each site still operates within its broader organizational context, adopting common protocols requires complex, timeconsuming processes. These are facilitated by a central guiding body com-

Adding complexity to coordinating clinical care, collaborator networks typically have a greater diversity of IT systems. prised of both network leadership and site clinicians. Adding complexity to coordinating clinical care, collaborator networks typically have a greater diversity of IT systems, because each site has adopted the electronic health record of its organization.

These networks face significant challenge and expense in developing systems (either IT interfaces or staff resources) that can facilitate information flow within the network, and will

Disability Insurance…Continued from page 40 high as $12,000, depending on the specific insurance carrier from which you purchase the policy.

This benefit amount plus the base policy, plus other in-force coverage, if any, generally cannot exceed 100% of your income.

Summary The next, and final, disability insurance article will offer tips on how to compare one company’s policy to another when shopping for coverage. This will help you

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ultimately to choose the company and policy that best meet your individual needs and goals.

Lawrence B. Keller, CLU, ChFC, CFP®, 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 Lkeller @physicianfinancialservices.com for comments or questions.

ONCOLOGY PRACTICE MANAGEMENT

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need to dedicate additional leadership time and network resources to mitigate these barriers.

Hybrid Networks Hybrid networks have wider variability in their governance models, with success driven by a highly developed, central decision-making council. These collaborator networks are a combination of a system network and non-owned or joint venture affiliate sites. Similar to collaborator networks, hybrid networks benefit from strong administrative and physician leadership directed by an OLC. These leaders invest greater effort to balance competition within the network and ensure overall success.

Hybrid networks typically have a “lead system” plus collaborator sites that rely on the lead system to develop and sustain resources while contributing financially to ensure resources are available.

Hybrid networks share the same challenges as collaborator networks when adopting standard treatment protocols and care processes across sites. Both rely on the need to build consensus and protocol adoption over time, and initially achieve agreement on an overarching quality platform as a basis for developing protocols that become more consistent over time. Most hybrid networks also have multiple IT systems, requiring time, staffing resources, technology, and expense to facilitate information flow. l Gerard M. Nussbaum and Laura K. Rehfeld have more than 30 years of experience advising hospital and health system leaders. Kurt Salmon offers strategic planning for clinical programs; developing cutting-edge, operationally efficient facilities; and designing agile information management environments.

Patient and Provider Access Brought to you by the Association of Community Cancer Centers

Will the Sunshine Act Affect Physician–Pharmaceutical Interaction?

By Sydney Abbott, JD

W

e are just now beginning to see some of the lesser known pieces of the 2010 Patient Protection and Affordable Care Act, such as the Federal Physician Sunshine Act (Social Security Act § 1128G), which is designed to illuminate the relationship between physicians and manufacturers. Starting by fall 2012, pharmaceutical and device manufacturers will be required to report payments to physicians and teaching hospitals. These records will be made public from September 30, 2013, onward.

Regulating manufacturers. It is important to note that the Sunshine Act regulates manufacturers; it does not impose any obligations or restrictions on healthcare providers. It requires manufacturers to report the value, nature, purpose, and recipient information for any payment to a physician or teaching hospital. In general, disclosure is required for all meals, gifts, consulting payments, and grants; however, there are a few exceptions.

The Sunshine Act calls for manufacturers to report any individual expense of $10 or more, and if the total of all payments or gifts to a particular healthcare provider exceeds $100 in a given year, then all payments to that provider must be reported, regardless of the value.

Reporting responsibility falls solely to the pharmaceutical or device manufacturer, not the individual provider.

However, providers will have the opportunity to correct inaccurate reports before they are made public.

ACCC members’ interaction with manufacturers. Many members of the Association of Community Cancer Centers (ACCC)

are curious how this new law will impact their interaction with manufacturers. Sales representatives can still visit physicians in their offices, and they may still provide a cup of coffee or small snack to providers at a conference. However, because of

Act delays the public disclosure of clinical trial payments for up to 4 years.

A pharmaceutical or device company may make a grant to the hospital where a physician works to host a continuing medical education program, but that grant would be reported and disclosed to the public if it were made to a teaching hospital or to another entity at the request of a teaching hospital.

Similar laws already on the books in some states. Although the federal Sunshine Act may change healthcare providers’ interactions with drug and device manufacturers, it is certainly not the first law of its kind.

Seven states and the District of Columbia already have laws on the books that impose marketing restrictions and disclosure requirements on manufacturers’ interactions with providers and institutions. The laws vary in scope, but all place reporting responsibility and restrictions on manufacturers. They can be found in California, Connecticut, Massachusetts, Minnesota, Nevada, Vermont, West Virginia, and the District of Columbia. The federal Sunshine Act, like the state laws, arose from a general commitment to transparency in relationships between industry and physicians—shining a light on these interactions.

Further guidance on the Sunshine Act was expected from the Centers for Medicare & Medicaid Services in early October, but as of the writing of this article in November 2011, that final guidance has yet to be released. l

Starting by fall 2012, pharmaceutical and device manufacturers will be required to report payments to physicians and teaching hospitals.

These records will be made public from September 30, 2013, onward. the relatively low spending limit, a drug or device company will have to publicly report taking a physician out to dinner at a restaurant to discuss a new product line. Some healthcare providers have written agreements with pharmaceutical companies to serve on scientific advisory boards.

Reporting reimbursement agreements. Written agreements providing reasonable compensation and reimbursement in connection with bona fide advisory board services are still permissible, but they will be reported and made public. Similarly, payments and reimbursement related to clinical trials are subject to reporting, but a provision in the Sunshine

December 2011

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DOXIL® (doxorubicin HCl liposome injection) for intravenous infusion BRIEF SUMMARY. Please see Full Prescribing Information.

WARNING: INFUSION REACTIONS, MYELOSUPPRESSION, CARDIOTOXICITY, LIVER IMPAIRMENT, ACCIDENTAL SUBSTITUTION 1. The use of DOXIL (doxorubicin HCl liposome injection) may lead to cardiac toxicity. Myocardial damage may lead to congestive heart failure and may occur as the total cumulative dose of doxorubicin HCl approaches 550 mg/m2. In a clinical study in patients with advanced breast cancer, 250 patients received DOXIL at a starting dose of 50 mg/m2 every 4 weeks. At all cumulative anthracycline doses between 450-500 mg/m2 or between 500-550 mg/m2, the risk of cardiac toxicity for patients treated with DOXIL was 11%. Prior use of other anthracyclines or anthracenediones should be included in calculations of total cumulative dosage. Cardiac toxicity may also occur at lower cumulative doses in patients with prior mediastinal irradiation or who are receiving concurrent cyclophosphamide therapy [see Warnings and Precautions]. 2. Acute infusion-related reactions including, but not limited to, flushing, shortness of breath, facial swelling, headache, chills, back pain, tightness in the chest or throat, and/or hypotension have occurred in up to 10% of patients treated with DOXIL. In most patients, these reactions resolve over the course of several hours to a day once the infusion is terminated. In some patients, the reaction has resolved with slowing of the infusion rate. Serious and sometimes life-threatening or fatal allergic/anaphylactoid-like infusion reactions have been reported. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use. DOXIL should be administered at an initial rate of 1 mg/min to minimize the risk of infusion reactions [see Warnings and Precautions]. 3. Severe myelosuppression may occur [see Warnings and Precautions]. 4. Dosage should be reduced in patients with impaired hepatic function [see Full Prescribing Information]. 5. Accidental substitution of DOXIL for doxorubicin HCl has resulted in severe side effects. DOXIL should not be substituted for doxorubicin HCl on a mg per mg basis [see Full Prescribing Information].

INDICATIONS AND USAGE: Ovarian Cancer: DOXIL (doxorubicin HCl liposome injection) is indicated for the treatment of patients with ovarian cancer whose disease has progressed or recurred after platinum-based chemotherapy. AIDS-Related Kaposi’s Sarcoma: DOXIL is indicated for the treatment of AIDS-related Kaposi’s sarcoma in patients after failure of prior systemic chemotherapy or intolerance to such therapy.

Multiple Myeloma: DOXIL in combination with bortezomib is indicated for the treatment of patients with multiple myeloma who have not previously received bortezomib and have received at least one prior therapy.

CONTRAINDICATIONS: DOXIL (doxorubicin HCl liposome injection) is contraindicated in patients who have a history of hypersensitivity reactions to a conventional formulation of doxorubicin HCl or the components of DOXIL [see Warnings and Precautions]. DOXIL is contraindicated in nursing mothers [see Full Prescribing Information].

WARNINGS AND PRECAUTIONS: Cardiac Toxicity: Special attention must be given to the risk of myocardial damage from cumulative doses of doxorubicin HCl. Acute left ventricular failure may occur with doxorubicin, particularly in patients who have received a total cumulative dosage of doxorubicin exceeding the currently recommended limit of 550 mg/m2. Lower (400 mg/m2) doses appear to cause heart failure in patients who have received radiotherapy to the mediastinal area or concomitant therapy with other potentially cardiotoxic agents such as cyclophosphamide. Prior use of other anthracyclines or anthracenodiones should be included in calculations of total cumulative dosage. Congestive heart failure or cardiomyopathy may be encountered after discontinuation of anthracycline therapy. Patients with a history of cardiovascular disease should be administered DOXIL only when the potential benefit of treatment outweighs the risk. Cardiac function should be carefully monitored in patients treated with DOXIL. The most definitive test for anthracycline myocardial injury is endomyocardial biopsy. Other methods, such as echocardiography or multigated radionuclide scans, have been used to monitor cardiac function during anthracycline therapy. Any of these methods should be employed to monitor potential cardiac toxicity in patients treated with DOXIL. If these test results indicate possible cardiac injury associated with DOXIL therapy, the benefit of continued therapy must be carefully weighed against the risk of myocardial injury. In a clinical study in patients with advanced breast cancer, 250 patients received DOXIL at starting dose of 50 mg/m2 every 4 weeks. At all cumulative anthracycline doses between 450-500 mg/m2, or between 500–550 mg/m2, the risk of cardiac toxicity for patients treated with DOXIL was 11%. In this study, cardiotoxicity was defined as a decrease of >20% from baseline if the resting left ventricular ejection fraction (LVEF) remained in the normal range, or a decrease of >10% if the resting LVEF became abnormal (less than the institutional lower limit of normal). The data on left ventricular ejection fraction (LVEF) defined cardiotoxicity and congestive heart failure (CHF) are in the table below.

Table 1: Number of Patients With Advanced Breast Cancer Patients who Developed Cardiotoxicity (LVEF Defined) Cardiotoxicity (With Signs & Symptoms of CHF) Cardiotoxicity (no Signs & Symptoms of CHF) Patients With Signs and Symptoms of CHF Only

DOXIL (n=250) 10 0 10 2

In the randomized multiple myeloma study, the incidence of heart failure events (ventricular dysfunction, cardiac failure, right ventricular failure, congestive cardiac failure, chronic cardiac failure, acute pulmonary edema and pulmonary edema) was similar in the DOXIL+bortezomib group and the bortezomib monotherapy group, 3% in each group. LVEF decrease was defined as an absolute decrease of 15% over baseline or a 5% decrease below the institutional lower limit of normal. Based on this definition, 25 patients in the bortezomib arm (8%) and 42 patients in the DOXIL+bortezomib arm (13%) experienced a reduction in LVEF. Infusion Reactions: Acute infusion-related reactions were reported in 7.1% of patients treated with DOXIL in the randomized ovarian cancer study. These reactions were characterized by one or more of the following symptoms: flushing, shortness of breath, facial swelling, headache, chills, chest pain, back pain, tightness in the chest and throat, fever, tachycardia, pruritus, rash, cyanosis, syncope, bronchospasm, asthma, apnea, and hypotension. In most patients, these reactions resolve over the course of several hours to a day once the infusion is terminated. In some patients, the reaction resolved when the rate of infusion was slowed. In this study, two patients treated with DOXIL (0.8%) discontinued due to infusion-related reactions. In clinical studies, six patients with AIDS-related Kaposi’s sarcoma (0.9%) and 13 (1.7%) solid tumor patients discontinued DOXIL therapy because of infusion-related reactions. Serious and sometimes life-threatening or fatal allergic/anaphylactoid-like infusion reactions have been reported. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use. The majority of infusion-related events occurred during the first infusion.

Similar reactions have not been reported with conventional doxorubicin and they presumably represent a reaction to the DOXIL liposomes or one of its surface components. The initial rate of infusion should be 1 mg/min to help minimize the risk of infusion reactions [see Full Prescribing Information].

Myelosuppression: Because of the potential for bone marrow suppression, careful hematologic monitoring is required during use of DOXIL, including white blood cell, neutrophil, platelet counts, and Hgb/Hct. With the recommended dosage schedule, leukopenia is usually transient. Hematologic toxicity may require dose reduction or delay or suspension of DOXIL therapy. Persistent severe myelosuppression may result in superinfection, neutropenic fever, or hemorrhage. Development of sepsis in the setting of neutropenia has resulted in discontinuation of treatment and, in rare cases, death. DOXIL may potentiate the toxicity of other anticancer therapies. In particular, hematologic toxicity may be more severe when DOXIL is administered in combination with other agents that cause bone marrow suppression. In patients with relapsed ovarian cancer, myelosuppression was generally moderate and reversible. In the three single-arm studies, anemia was the most common hematologic adverse reaction (52.6%), followed by leukopenia (WBC <4,000 mm3; 42.2%), thrombocytopenia (24.2%), and neutropenia (ANC <1,000; 19.0%). In the randomized study, anemia was the most common hematologic adverse reaction (40.2%), followed by leukopenia (WBC <4,000 mm3; 36.8%), neutropenia (ANC <1,000; 35.1%), and thrombocytopenia (13.0%) [see Adverse Reactions]. In patients with relapsed ovarian cancer, 4.6% received G-CSF (or GM-CSF) to support their blood counts [see Full Prescribing Information]. For patients with AIDS-related Kaposi’s sarcoma who often present with baseline myelosuppression due to such factors as their HIV disease or concomitant medications, myelosuppression appears to be the dose-limiting adverse reaction at the recommended dose of 20 mg/m2 [see Adverse Reactions]. Leukopenia is the most common adverse reaction experienced in this population; anemia and thrombocytopenia can also be expected. Sepsis occurred in 5% of patients; for 0.7% of patients the event was considered possibly or probably related to DOXIL. Eleven patients (1.6%) discontinued study because of bone marrow suppression or neutropenia.

Table 10 presents data on myelosuppression in patients with multiple myeloma receiving DOXIL and bortezomib in combination [see Adverse Reactions].

Hand-Foot Syndrome (HFS): In the randomized ovarian cancer study, 50.6% of patients treated with DOXIL at 50 mg/m2 every 4 weeks experienced HFS (developed palmar-plantar skin eruptions characterized by swelling, pain, erythema and, for some patients, desquamation of the skin on the hands and the feet), with 23.8% of the patients reporting HFS Grade 3 or 4 events. Ten subjects (4.2%) discontinued treatment due to HFS or other skin toxicity. HFS toxicity grades are described in Dosage and Administration section [see Full Prescribing Information]. Among 705 patients with AIDS-related Kaposi’s sarcoma treated with DOXIL at 20 mg/m2 every 2 weeks, 24 (3.4%) developed HFS, with 3 (0.9%) discontinuing. In the randomized multiple myeloma study, 19% of patients treated with DOXIL at 30 mg/m2 every three weeks experienced HFS. HFS was generally observed after 2 or 3 cycles of treatment but may occur earlier. In most patients the reaction is mild and resolves in one to two weeks so that prolonged delay of therapy need not occur.

However, dose modification may be required to manage HFS [see Full Prescribing Information]. The reaction can be severe and debilitating in some patients and may require discontinuation of treatment.

Radiation Recall Reaction: Recall reaction has occurred with DOXIL administration after radiotherapy.

Fetal Mortality: Pregnancy Category D: DOXIL can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies in pregnant women. If DOXIL is to be used during pregnancy, or if the patient becomes pregnant during therapy, the patient should be apprised of the potential hazard to the fetus. If pregnancy occurs in the first few months following treatment with DOXIL, the prolonged half-life of the drug must be considered. Women of childbearing potential should be advised to avoid pregnancy during treatment with Doxil. [see Full Prescribing Information].

Toxicity Potentiation: The doxorubicin in DOXIL may potentiate the toxicity of other anticancer therapies.

Exacerbation of cyclophosphamide-induced hemorrhagic cystitis and enhancement of the hepatotoxicity of 6-mercaptopurine have been reported with the conventional formulation of doxorubicin HCl. Radiationinduced toxicity to the myocardium, mucosae, skin, and liver have been reported to be increased by the administration of doxorubicin HCl. Monitoring: Laboratory Tests: Complete blood counts, including platelet counts, should be obtained frequently and at a minimum prior to each dose of DOXIL [see Warnings and Precautions].

ADVERSE REACTIONS: Overall Adverse Reactions Profile: The following adverse reactions are discussed in more detail in other sections of the labeling. • Cardiac Toxicity [see Warnings and Precautions] • Infusion reactions [see Warnings and Precautions] • Myelosuppression [see Warnings and Precautions] • HandFoot syndrome [see Warnings and Precautions] The most common adverse reactions observed with DOXIL are asthenia, fatigue, fever, nausea, stomatitis, vomiting, diarrhea, constipation, anorexia, hand-foot syndrome, rash and neutropenia, thrombocytopenia and anemia. The most common serious adverse reactions observed with DOXIL are described in Section Adverse Reactions in Clinical Trials. The safety data described below reflect exposure to DOXIL in 1310 patients including: 239 patients with ovarian cancer, 753 patients with AIDS-related Kaposi’s sarcoma and 318 patients with multiple myeloma.

Adverse Reactions in Clinical Trials: Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates on other clinical trials and may not reflect the rates observed in clinical practice. The following tables present adverse reactions from clinical trials of DOXIL in ovarian cancer, AIDS-Related Kaposi’s sarcoma, and multiple myeloma.

Patients With Ovarian Cancer: The safety data described below are from 239 patients with ovarian cancer treated with DOXIL (doxorubicin HCl liposome injection) at 50 mg/m2 once every 4 weeks for a minimum of 4 courses in a randomized, multicenter, open-label study. In this study, patients received DOXIL for a median number of 98.0 days (range 1-785 days). The population studied was 27-87 years of age, 91% Caucasian, 6% Black and 3% Hispanic and other. Table 2 presents the hematologic adverse reactions from the randomized study of DOXIL compared to topotecan.

Table 2: Ovarian Cancer Randomized Study Hematology Data Reported in Patients With Ovarian Cancer DOXIL Topotecan Patients Patients (n = 239) (n = 235) Neutropenia 19 (7.9%) 33 (14.0%) 500 - <1000/mm3 10 (4.2%) 146 (62.1%) <500/mm3 Anemia 6.5 - <8 g/dL 13 (5.4%) 59 (25.1%) <6.5 g/dL 1 (0.4%) 10 (4.3%) Thrombocytopenia 3 3 (1.3%) 40 (17.0%) 10,000 - <50,000/mm <10,000/mm3 0 (0.0%) 40 (17.0%) Table 3 presents a comparative profile of the non-hematologic adverse reactions from the randomized study of DOXIL compared to topotecan.

Table 3: Ovarian Cancer Randomized Study Non-Hematologic Adverse Reaction 10% or Greater

Body as a Whole Asthenia Fever Mucous Membrane Disorder Back Pain Infection Headache Digestive Nausea Stomatitis Vomiting Diarrhea Anorexia Dyspepsia Nervous Dizziness Respiratory Pharyngitis Dyspnea Cough increased Skin and Appendages Hand-foot syndrome Rash Alopecia

DOXIL (%) treated (n = 239) All Grades grades 3-4

Topotecan (%) treated (n =235) All Grades grades 3-4

40.2 21.3 14.2

7.1 0.8 3.8

51.5 30.6 3.4

8.1 5.5 0

11.7 11.7 10.5

1.7 2.1 0.8

10.2 6.4 14.9

0.9 0.9 0

46.0 41.4 32.6 20.9 20.1 12.1

5.4 8.3 7.9 2.5 2.5 0.8

63.0 15.3 43.8 34.9 21.7 14.0

8.1 0.4 9.8 4.2 1.3 0

4.2

0

10.2

0

15.9 15.1 9.6

0 4.1 0

17.9 23.4 11.5

0.4 4.3 0

50.6 28.5 19.2

23.8 4.2 N/A

0.9 12.3 52.3

0 0.4 N/A

The following additional adverse reactions (not in table) were observed in patients with ovarian cancer with doses administered every four weeks.

Incidence 1% to 10%: Cardiovascular: vasodilation, tachycardia, deep thrombophlebitis, hypotension, cardiac arrest. Digestive: oral moniliasis, mouth ulceration, esophagitis, dysphagia, rectal bleeding, ileus.

Hemic and Lymphatic: ecchymosis. Metabolic and Nutritional: dehydration, weight loss, hyperbilirubinemia, hypokalemia, hypercalcemia, hyponatremia. Nervous: somnolence, dizziness, depression. Respiratory: rhinitis, pneumonia, sinusitis, epistaxis. Skin and Appendages: pruritus, skin discoloration, vesiculobullous rash, maculopapular rash, exfoliative dermatitis, herpes zoster, dry skin, herpes simplex, fungal dermatitis, furunculosis, acne. Special Senses: conjunctivitis, taste perversion, dry eyes. Urinary: urinary tract infection, hematuria, vaginal moniliasis.

Patients With AIDS-Related Kaposi’s Sarcoma: The safety data below is based on the experience reported in 753 patients with AIDS-related Kaposi’s sarcoma enrolled in four studies. The median age of the population was 38.7 years (range 24-70 years), which was 99% male, 1% female, 88% Caucasian, 6% Hispanic, 4% Black, and 2% Asian/other/unknown. The majority of patients were treated with 20 mg/m2 of DOXIL every two to three weeks. The median time on study was 127 days and ranged from 1 to 811 days. The median cumulative dose was 120 mg/m2 and ranged from 3.3 to 798.6 mg/m2. Twenty-six patients (3.0%) received cumulative doses of greater than 450 mg/m2. Of these 753 patients, 61.2% were considered poor risk for KS tumor burden, 91.5% poor for immune system, and 46.9% for systemic illness; 36.2% were poor risk for all three categories. Patients’ median CD4 count was 21.0 cells/mm3, with 50.8% of patients having less than 50 cells/mm3. The mean absolute neutrophil count at study entry was approximately 3,000 cells/mm3. Patients received a variety of potentially myelotoxic drugs in combination with DOXIL. Of the 693 patients with concomitant medication information, 58.7% were on one or more antiretroviral medications; 34.9% patients were on zidovudine (AZT), 20.8% on didanosine (ddI), 16.5% on zalcitabine (ddC), and 9.5% on stavudine (D4T). A total of 85.1% patients were on PCP prophylaxis, most (54.4%) on sulfamethoxazole/trimethoprim. Eighty-five percent of patients were receiving antifungal medications, primarily fluconazole (75.8%). Seventy-two percent of patients were receiving antivirals, 56.3% acyclovir, 29% ganciclovir, and 16% foscarnet. In addition, 47.8% patients received colonystimulating factors (sargramostim/filgrastim) sometime during their course of treatment. Adverse reactions led to discontinuation of treatment in 5% of patients with AIDS related Kaposi’s sarcoma. Those that did so included bone marrow suppression, cardiac adverse reactions, infusion-related reactions, toxoplasmosis, HFS, pneumonia, cough/dyspnea, fatigue, optic neuritis, progression of a non-KS tumor, allergy to penicillin, and unspecified reasons.

Table 4: Hematology Data Reported in Patients With AIDS-Related Kaposi’s Sarcoma Patients With Total Patients Refractory or Intolerant With AIDS-Related AIDS-Related Kaposi’s Sarcoma Kaposi’s Sarcoma (n = 74) (n = 720) Neutropenia 3 1000/mm 34 (45.9%) 352 (48.9%) 500/mm3 8 (10.8%) 96 (13.3%) Anemia 10 g/dL 43 (58.1%) 399 (55.4%) 8 g/dL 12 (16.2%) 131 (18.2%) Thrombocytopenia 150,000/mm3 45 (60.8%) 439 (60.9%) 25,000/mm3 1 (1.4%) 30 (4.2%) Table 5: Probably and Possibly Drug-Related Non-Hematologic Adverse Reactions Reported in of Patients With AIDS-Related Kaposi’s Sarcoma Adverse Patients With Total Patients Reactions Refractory or Intolerant With AIDS-Related AIDS-Related Kaposi’s Sarcoma Kaposi’s Sarcoma (n = 77) (n = 705) Nausea 14 (18.2%) 119 (16.9%) Asthenia 5 (6.5%) 70 (9.9%) Fever 6 (7.8%) 64 (9.1%) Alopecia 7 (9.1%) 63 (8.9%) Alkaline Phosphatase 1 (1.3%) 55 (7.8%) Increase Vomiting 6 (7.8%) 55 (7.8%) Diarrhea 4 (5.2%) 55 (7.8%) Stomatitis 4 (5.2%) 48 (6.8%) Oral Moniliasis 1 (1.3%) 39 (5.5%)

5%

The following additional (not in table) adverse reactions were observed in patients with AIDS-related Kaposi’s sarcoma. Incidence 1% to 5%: Body as a Whole: headache, back pain, infection, allergic reaction, chills. Cardiovascular: chest pain, hypotension, tachycardia. Cutaneous: herpes simplex, rash, itching. Digestive: mouth ulceration, anorexia, dysphagia. Metabolic and Nutritional: SGPT increase, weight loss, hyperbilirubinemia. Other: dyspnea, pneumonia, dizziness, somnolence. Incidence Less Than 1%: Body As A Whole: sepsis, moniliasis, cryptococcosis. Cardiovascular: thrombophlebitis, cardiomyopathy, palpitation, bundle branch block, congestive heart failure, heart arrest, thrombosis, ventricular arrhythmia. Digestive: hepatitis. Metabolic and Nutritional Disorders: dehydration.

Respiratory: cough increase, pharyngitis. Skin and Appendages: maculopapular rash, herpes zoster.

Special Senses: taste perversion, conjunctivitis.

Patients With Multiple Myeloma: The safety data below are from 318 patients treated with DOXIL (30 mg/m2 as a 1-hr i.v. infusion) administered on day 4 following bortezomib (1.3 mg/m2 i.v. bolus on days 1, 4, 8 and 11) every three weeks, in a randomized, open-label, multicenter study. In this study, patients in the DOXIL + bortezomib combination group were treated for a median number of 138 days (range 21-410 days). The population was 28-85 years of age, 58% male, 42% female, 90% Caucasian, 6% Black, and 4% Asian and other. Table 6 lists adverse reactions reported in 10% or more of patients treated with DOXIL in combination with bortezomib for multiple myeloma.

Table 6: Frequency of treatment emergent adverse reactions reported in 10% patients treated for multiple myeloma with DOXIL in combination with bortezomib, by Severity, Body System, and MedDRA Terminology.

Adverse DOXIL + bortezomib Bortezomib Reaction (n=318) (n=318) Any Grade Grade Any Grade Grade (%) 3 4 (%) 3 4 Blood and lymphatic system disorders Neutropenia 36 22 10 22 11 5 Thrombocytopenia 33 11 13 28 9 8 Anemia 25 7 2 21 8 2 General disorders and administration site conditions Fatigue 36 6 1 28 3 0 Pyrexia 31 1 0 22 1 0 Asthenia 22 6 0 18 4 0 Gastrointestinal disorders Nausea 48 3 0 40 1 0 Diarrhea 46 7 0 39 5 0 Vomiting 32 4 0 22 1 0 Constipation 31 1 0 31 1 0 Abdominal pain Infections and infestations Herpes zoster Herpes simplex Investigations Weight decreased Metabolism and Nutritional disorders

11

1

0

8

1

0

11 10

2 0

0 0

9 6

2 1

0 0

12

0

0

4

0

0

17

3

0

20

4

1

Respiratory, thoracic and mediastinal disorders Cough 18 Skin and subcutaneous tissue disorders Rash** 22

0

0

12

0

0

1

0

18

1

0

Nervous system disorders Neuralgia

*Peripheral neuropathy includes the following adverse reactions: peripheral sensory neuropathy, neuropathy peripheral, polyneuropathy, peripheral motor neuropathy, and neuropathy NOS. **Rash includes the following adverse reactions: rash, rash erythematous, rash macular, rash maculopapular, rash pruritic, exfoliative rash, and rash generalized.

Post Marketing Experience: The following additional adverse reactions have been identified during post approval use of DOXIL. 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. Musculoskeletal and Connective Tissue Disorders: rare cases of muscle spasms. Respiratory, Thoracic and Mediastinal Disorders: rare cases of pulmonary embolism (in some cases fatal). Hematologic disorders: Secondary acute myelogenous leukemia with and without fatal outcome has been reported in patients whose treatment included DOXIL. Skin and subcutaneous tissue disorders: rare cases of erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported.

DRUG INTERACTIONS: No formal drug interaction studies have been conducted with DOXIL. DOXIL may interact with drugs known to interact with the conventional formulation of doxorubicin HCl. USE IN SPECIFIC POPULATIONS: Pediatric Use: The safety and effectiveness of DOXIL in pediatric patients have not been established.

Geriatric Use: Of the patients treated with DOXIL in the randomized ovarian cancer study, 34.7% (n=83) were 65 years of age or older while 7.9% (n=19) were 75 years of age or older. Of the 318 patients treated with DOXIL in combination with bortezomib for multiple myeloma, 37% were 65 years of age or older and 8% were 75 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients.

OVERDOSAGE: Acute overdosage with doxorubicin HCl causes increases in mucositis, leucopenia, and thrombocytopenia. Treatment of acute overdosage consists of treatment of the severely myelosuppressed patient with hospitalization, antibiotics, platelet and granulocyte transfusions, and symptomatic treatment of mucositis.

0016716-5B Manufactured by: Ben Venue Laboratories, Inc. Bedford, OH 44146 Distributed by: Ortho Biotech Products, LP Raritan, NJ 08869-0670

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An ALZA STEALTH® Technology Product

STEALTH® and DOXIL® are registered trademarks of ALZA Corporation.

For your patients receiving or about to start treatment with DOXIL® for recurrent ovarian cancer or relapsed/refractory multiple myeloma…

DOXIL® C.A.R.E.S. Provides Help and Support DOXIL ® C.A.R.E.S. Complements the Efforts of the Healthcare Team With: ◗ Treatment follow-up — Regularly scheduled telephone calls from oncology nurses to review lifestyle tips to help manage potential side effects of DOXIL® therapy such as hand-foot syndrome and stomatitis ◗ Patient education materials Invite your patients to enroll in DOXIL® C.A.R.E.S.: 1-877-CARES-49 (1-877-227-3749) Monday to Friday, 9:30 AM to 10:00 PM (ET). To learn more, visit www.doxil.com.

INDICATIONS ◗ DOXIL® is indicated for the treatment of patients with ovarian cancer whose disease has progressed or recurred after platinum-based chemotherapy ◗ DOXIL® in combination with VELCADE® (bortezomib) is indicated for the treatment of patients with multiple myeloma who have not previously received VELCADE and have received at least one prior therapy

IMPORTANT SAFETY INFORMATION BOXED WARNINGS Cardiotoxicity, infusion reaction, myelosuppression, liver impairment, substitution ◗ The use of DOXIL® may lead to cardiac toxicity. Myocardial damage may lead to congestive heart failure and may occur as the total cumulative dose of doxorubicin HCl approaches 550 mg/m2 — Prior use of other anthracyclines or anthracenediones should be included in calculations of total cumulative dose — Cardiac toxicity may also occur at lower cumulative doses (400 mg/m2) in patients with prior mediastinal irradiation or who are receiving concurrent cyclophosphamide therapy ◗ Acute infusion-related reactions including, but not limited to, flushing, shortness of breath, facial swelling, headache, chills, back pain, tightness in the chest or throat, and/or hypotension have occurred in up to 10% of patients treated with DOXIL®. In most patients, these reactions have resolved within several hours to a day once the infusion is terminated. In some patients, reactions resolved with slowing of the infusion rate — Serious and sometimes life-threatening or fatal allergic/anaphylactoid-like infusion reactions have occurred. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use — The initial rate of infusion should be 1 mg/min to minimize the risk of infusion reactions ◗ Severe myelosuppression may occur ◗ DOXIL® dosage should be reduced in patients with impaired hepatic function ◗ Accidental substitution has resulted in severe side effects. Do not substitute for doxorubicin HCl on a mg per mg basis CONTRAINDICATIONS ◗ Patients with a history of hypersensitivity reactions to a conventional doxorubicin formulation or the components of DOXIL® ◗ Nursing mothers

ADDITIONAL SAFETY INFORMATION ◗ Cardiac function should be carefully monitored — Congestive heart failure or cardiomyopathy may occur after discontinuation of anthracycline therapy — For patients with a history of cardiovascular disease, or if the results of cardiac monitoring indicate possible cardiac injury, the benefit of therapy must be weighed against the risk of myocardial injury — In the randomized multiple myeloma study, 25 patients (8%) in the VELCADE arm and 42 patients (13%) in the DOXIL® plus VELCADE arm experienced left ventricular ejection fraction decrease (defined as absolute decrease 15% over baseline or a 5% decrease below institutional lower limit of normal)

◗ Myelosuppression may occur; frequently monitor complete blood count (including platelet count), at least prior to each dose of DOXIL® — In patients with recurrent ovarian cancer, hematologic toxicity (based on platelet count or absolute neutrophil count) may require dose reduction or delay in administration of DOXIL® — In patients with multiple myeloma, hematologic toxicity (based on platelet count, absolute neutrophil count, hemoglobin level, or neutropenia with fever) may require dose reduction, delay in administration, or suspension of DOXIL® and/or VELCADE — Persistent severe myelosuppression may result in superinfection, neutropenic fever, or hemorrhage — Sepsis occurring during neutropenia has resulted in discontinuation of treatment and in rare cases of death ◗ DOXIL® may potentiate the toxicity of other anticancer therapies, especially hematologic toxicities, when used in combination with other therapies that suppress bone marrow ◗ Hand-foot syndrome (HFS) may occur during therapy with DOXIL® — Based on HFS toxicity grade, dose reduction, delay in administration, or discontinuation of DOXIL® may be required — HFS was generally observed after 2 to 3 cycles of treatment, but may occur earlier • The reaction was mild in most patients, resolving in 1 to 2 weeks • The reaction can be severe and debilitating in some patients, resulting in discontinuation of therapy ◗ DOXIL® is an irritant, not a vesicant; use precautions to avoid extravasation ◗ DOXIL® can cause fetal harm when used during pregnancy ◗ Recall reaction has occurred with DOXIL® administration after radiotherapy ◗ DOXIL® may interact with drugs known to interact with the conventional formulation of doxorubicin HCl ◗ In patients with recurrent ovarian cancer, the most common all-grade adverse reactions (ARs) 20% (DOXIL® vs topotecan, respectively) included: asthenia (40% vs 51%), fever (21% vs 31%), nausea (46% vs 63%), stomatitis (41% vs 15%), vomiting (33% vs 44%), diarrhea (21% vs 35%), anorexia (20% vs 22%), dyspnea (15% vs 23%), HFS (51% vs 1%), and rash (29% vs 12%) — In addition, 19% vs 52.3% reported alopecia (all grades) — Grade 3/4 hematologic ARs reported in 5% (DOXIL® vs topotecan, respectively) were neutropenia (12% vs 76%) and anemia (6% vs 29%) ◗ In patients with multiple myeloma, the most common all-grade ARs 20% (DOXIL® plus VELCADE vs VELCADE, respectively) included: neutropenia (36% vs 22%), thrombocytopenia (33% vs 28%), anemia (25% vs 21%), fatigue (36% vs 28%), pyrexia (31% vs 22%), asthenia (22% vs 18%), nausea (48% vs 40%), diarrhea (46% vs 39%), vomiting (32% vs 22%), constipation (31% vs 31%), mucositis/ stomatitis (20% vs 5%), peripheral neuropathy (42% vs 45%), neuralgia (17% vs 20%), and rash (22% vs 18%) — In addition, 19% vs <1% reported HFS Please see brief summary of Prescribing Information, including Boxed WARNINGS, on adjacent pages.

VELCADE is a registered trademark of Millennium Pharmaceuticals, Inc.

Distributed by: Centocor Ortho Biotech Products, L.P., Horsham, Pennsylvania 19044-3607 © Centocor Ortho Biotech Products, L.P. 2010 9/10 08D10019B