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ONCOLOGY PRACTICE MANAGEMENT ™

PROCESS IMPROVEMENTS TO ENHANCE PATIENT CARE™

www.OncPracticeManagement.com

OCTOBER 2011

VOLUME 1 • NUMBER 3

Federal Audits November 2011: Import of Thanksgiving Pales in Comparison of E/M Services The with “Super” Committee Outcome A Top 10 Survival Guide

By Dawn Holcombe, MBA, FACMPE, ACHE

By Michael Calahan, PA, MBA

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ll eyes are on Washington this fall, as deliberations begin on recommendations from the congressional joint “super” committee. Congress and the president failed to achieve resolution regarding the debt ceiling this summer, and now this newly created 12-person committee will recommend at least $1.5 trillion in additional deficit reduction measures through 2021, by November 23, 2011. If a majority of the com-

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Finding Money for Technology How to Fund EHR, IT, and Medical Equipment Projects By Colleen O’Donnell

meets both short- and long-term goals. Many practices are beginning to qualify for the Health Information Technology for Economic and Clinical Health (HITECH) Act and receive funding. Are you? What are

©2011 Engage Healthcare Communications, LLC

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ince the turn of the century, 2 things have become clear in healthcare. First, change, especially in group practice, is happening at a rate that we have never seen before. Second, we are in the midst of an information technology (IT) evolution. To keep up with these ongoing changes, it has become imperative that group practices incorporate technology while remaining nimble with their capital, both cash and equipment. The question becomes how to fund projects in a way that

gh A Th Com t to ND e m y PR SG u o u an R, nity by O Re d Pro C th VI im Cu m an e A DE bu ts pt- ce ss R rse in M Pa r C oc A C m e y D en iat en di is te ion C c c r t.. a o s o ES ... re un f S

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t is no secret federal auditors promise to assail providers through a variety of strong recoupment initiatives. Evaluation and management (E/M) services are primed for this offensive. No longer able to report consultation codes to the Centers for Medicare & Medicaid Services (CMS), oncologists must improve E/M reporting strategies for routine cognitive services, such as office visits and inpatient hospital visits. This increases the impact of E/M services on practice revenue and elevates these mundane services to “juicy” targets for federal programs such as the Comprehensive Error Rate Testing and Recovery Audit Contractor initiatives. What should oncologists do in the face of this scrutiny? Start by learning which

mittee members endorse a proposal, that proposal is guaranteed to go to a floor vote in both the House and Senate by December 23 without amendment or Senate filibuster. Because these proposals could be passed with any combination of Republican and Democratic votes that add up to a majority, despite pundit warnings that a stalemate could occur, congressional leaders could choose to move for-


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

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In This Issue

PUBLISHING STAFF Publisher Nicholas Englezos nick@engagehc.com 732-992-1884 Associate Publisher Maurice Nogueira maurice@engagehc.com 732-992-1895 Director, Client Services Cristopher Pires cris@engagehc.com 732-992-1896 Editorial Director Dalia Buffery Editor Dawn Lagrosa dawn@greenhillhc.com 732-992-1891 Production Manager Marie R. S. Borelli Quality Control Director Barbara Marino Business Manager Blanche Marchitto

FEATURES MODELS OF CARE Exploring Ways to Translate the Medical Home Model into Oncology................................................................4 REIMBURSEMENT Improving Previsit Processes to Maximize Postvisit Collections ......................................................12 By Sarah W. Rock, MSOD; Debra Gregory

Getting from ICD-9 to ICD-10......................................24 By Richard Vander Burg, RN, BSN

DATA MANAGEMENT Improving Oncology Service Line Management ......21 By Brian Cassel, PhD; Lisa Shickle, MS

CASE STUDY Dana-Farber/New Hampshire Oncology-Hematology ..............................................22

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. VOPM3

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

Disability Insurance Planning ..........................................27 Patient and Provider Access brought to you by the Association of Community Cancer Centers

Hurdles to Appropriate Reimbursement ......................28 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.

October 2011

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Models of Care

Exploring Ways to Translate the Medical Home Model into Oncology

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

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 Bruce A. Cutter, MD President Cutter HealthCare Consulting Spokane, WA Craig Deligdish, MD Medical Director Florida Comprehensive Cancer Network Melbourne, FL Patrick A. Grusenmeyer, ScD, FACHE President Christiana Care Health Initiatives Newark, DE

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Patients, Providers, and Payers Provide Some Answers

Teri U. Guidi, MBA, FAAMA President & CEO Oncology Management Consulting Group Pipersville, PA

By Dawn Lagrosa

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Ruth Lander, RN, FACMPE Practice Administrator Columbus Oncology & Hematology Associates, Inc Columbus, OH Bonnie J. Miller, RN, BSN, OCN, FAAMA Administrative Director Women’s Cancer Center Fox Chase Cancer Center Philadelphia, PA Cindy C. Parman, CPC, CPC-H, RCC CSI Coding Strategies Inc Powder Springs, GA Jeffrey A. Scott, MD Senior Vice President Cardinal Health Dublin, OH Carla C. Wood, CPC, MS President Altos Solutions, Inc Los Altos, CA

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ith today’s focus on the National Committee for Quality Assurance’s Patient-Centered Medical Home (PCMH) as a viable option for healthcare delivery and cost reform, a group of researchers explored how best to translate the concept from the primary care model to oncology care. What they found is that an Oncology Medical Home (OMH) model may revolutionize cancer care and reimbursement (J Clin Oncol. 2011;29[suppl]:Abstract e16641). With their background in identifying breast cancer care coordination challenges, Trosman and colleagues interviewed patients, providers, and payers regarding which characteristics would be most desirable in an OMH for breast cancer care. Four characteristics emerged as important features to include when developing a model for oncology: 1. Each OMH should have a lead physician, in this case, an oncologist or breast surgeon, for the entire episode of cancer care. Survivorship care should be transferred back to the primary care physician, with a corresponding PCMH. 2. A lead physician should facilitate care across the multidisciplinary cancer care team, including surgical, medical, and radiation oncology; radiology; supportive care; and primary care. 3. Each patient’s care and care team should be managed as a project, with key events sequenced and timed in a plan, by a “care project manager.” 4. A unique reimbursement model should be implemented that incentivizes team participation and coordination. Most (89%) patients reported a strong desire for a lead physician, but only one third (33%) noted an interest in the reimbursement reform potential. Providers expressed high interest in all 4 characteristics (73%-85%). Most (88%) payers recognized the potential for a new reimbursement model; however, they disclosed their uncertainty with the specifics of the remaining 3 characteristics. OMH pilots, such as the first recognized OMH Consultants in Medical Oncology and Hematology, are needed to inform specific implementation strategies. As the first OMH, the process took approximately 7 years to implement. However, practice lead physician John D. Sprandio, MD, told Oncology Practice Management that, with that experience behind them, his group has helped streamline the process for others, which he foresees as taking only 1 year for other groups. l

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Finance Staffing

Finding Money…Continued from the cover the best funding options to cover upfront costs? Does your existing technology need to be upgraded? If you have answered yes to any of these questions, this article provides suggestions on how to get started exploring funding options (Sidebar). Reaching out to other practices in your area and specialty to understand what they have done and are doing can be very helpful. What are their experiences and successes? Ask about implementation time and the useful life of the equipment. Try to understand how your peers selected a system and paid for it. You can gather valuable information by joining LinkedIn groups devoted to group practices and electronic health record (EHR) implementation, among other topics. When diving into a project like implementing an EHR system, the costs can be overwhelming. Consulting, software, hardware, implementation, and training are all part of the investment. There are many funding options available, and it is important to understand the benefits of each and how they can work together. It is important to think about funding early, and try to consider what will happen as you navigate your way through the technology path.

Funding Options Bank Financing. Your local bank is most likely familiar with your practice and can provide a traditional loan. This is typically a very easy way to look at financing, and one that you may have already used. A drawback is that some banks require compensating balances, large down payments, and/or limit the amount that might be available on your line of credit.

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Grants. There are many options for grants, including state and local government grants, payers, or local hospitals. Many can be found

by doing research on Foundation center.org. Grants can be time-consuming, and may require you to hire someone to complete all necessary forms and paperwork. Therefore, the process could potentially limit your vendor choices. This is an area in which working with other practices can be helpful. Several organizations can team up to obtain grant funding for their projects. There is value in sharing the responsibilities.

able through organizations such as the Medical Group Management Association, American Medical Group Association, Healthcare Infor mation and Manage ment Systems Soci ety, American Health Information Management Association, as well as the Office for the National Coordinator for Health Information Technology.

It is important to think about funding early, and try to consider what will happen as you navigate your way through the technology path.

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Leasing. Leasing options can provide 100% financing for consulting, software, hardware, and implementation. Leasing is an alternative to your banking relationship that allows you to conserve your cash and working capital. Customized structures like deferred payments and skip payments often are available. It is important to consider the flexibility of a leasing arrangement, specifically for the hardware portion of your technology. Having the ability to upgrade and change hardware when it becomes obsolete, or easily add additional technology when needed, is one of the many benefits of a leasing program. Furthermore, the ability to avoid expensive out-of-warranty maintenance costs is vital. It is important to understand leasing terms and conditions and ask questions about how the program works.

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HITECH Act. This Act provides up to $64,000 per doctor over 5 years. Many practices have been able to prove meaningful use and have already collected their first year payment. This is an exciting opportunity for many practices and worth pursuing. Additional information is avail-

Steps for Evaluating Funding Options

You may decide that using a combination of the available options provides you with the best solution and gives you the most flexibility. l

• Start early, and consider all options. • Ask your peers for help, as they have experience and understand what you are going through and can offer valuable assistance.

Colleen O’Donnell is vice president of the Physician Group Practice division at Insight Financial Services, LLC, a lessor specializing in leasing solutions for technology and medical equipment— www.ifsleasing.com.

• Ask for references.

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Reimbursement

Federal Audits…Continued from the cover audit findings yield valuable opportunities for clinical documentation improvement as well as stronger E/M coding. Here are my “Top 10” audit findings together with survival tips.

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No response to additional documentation requests (ADRs). Most often, physician services are downcoded or denied by auditors because of no response to ADRs.

Survival tips Every provider office should log the receipt, track the processing, and confirm the fulfillment of these medical record (MR) requests to avoid unnecessary repayments.

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Unsigned, illegible, or indeterminate MRs. Unsigned MRs, illegible provider signatures, and/or the inability to differentiate ancillary staff notes from treating provider notes account for a preponderance of audit findings.

Survival tips Change Request 6698 (March 1, 2010) requires legible signatures to certify services; illegible signatures submitted without signature logs/ attestations are adjudged as “indeterminate,” and equated to unsigned documentation. Mixing ancillary staff notes in the body of the clinical note without signature clarification is tantamount to uncertified records. Providers and ancillary staff must each sign/date clinical note contributions, thereby clarifying authorship. Excluding certain hospice notes/orders stamped signatures are not valid.

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Review of systems (ROS) missing or poorly documented. Re cording the history portion of E/M services is the weakest area of provider documentation. Within the history, the most overlooked element

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is the ROS that, when poorly documented, severely limits the level of E/M service legitimately billed. Survival tips Have ancillary staff obtain the ROS; providers should verify and authenticate these data. If obtaining on a separate questionnaire, “bridge” these data to the actual visit notes.

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Poor documentation for E/M code Current Procedural Terminology (CPT) 99211. CPT 99211 is designed for minimal problems requiring “quick” visits carried out by ancillary staff, supervised by the treating provider. Adequately substantiated in the MR documentation, CPT 99211 can be reported for myriad services.

Mixing ancillary staff notes in the body of the clinical note without signature clarification is tantamount to uncertified records.

Survival tips CPT 99211 represents a true E/M service; therefore, the MR documentation must convey both evaluation and management facets. Because a CPT 99211 service is typically furnished by ancillary staff under the provider’s direct supervision, CPT 99211 is reported as “incident to” and the provider must certify the chart notes.

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Misapplication of modifier 25. Modifier 25 is reported with an E/M service when significant, sepa-

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October 2011

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Special Edition

rately identifiable services are rendered by the same physician on the same day of a procedure or other service. Common problem areas include: (a) modifier 25 incorrectly reported with a non-E/M service, for example, CPT 93000 to 93025 for EKG; and (b) modifier 25 reported with an E/M code when the patient presented solely for a prescheduled minor procedure, for example, joint injection. Survival tips Modifier 25 is designed to allow certain E/M services to bypass system edits. Without proper usage, the Medicare carrier may impose claimsdelaying prepayment screens and documentation reviews.

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Time used as the key component for the E/M service. Pro viders can report noontime-based E/M services using time as the key component (instead of the 3 key components of history, physical examination [PE], and medical decision making [MDM]) when counseling and/or coordination of care constitute 50% or greater of the total face-to-face time; however, auditors find no times documented in the MRs.

Survival tips Document 2 strata of times when using this option: (1) total face-toface time for the entire encounter; and (2) total time spent in counseling and/or coordination of care. Content of the counseling/coordination of care must be documented.

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“4x4 rule”: expanded problem focused (EPF) or detailed examination? Confusion surrounds these specific examination levels because the official documentation guidelines (DGs) are ambiguous for both levels by stating they must contain “2 to 7 elements.” This causes pro-


Reimbursement

vider misinterpretation and results in audit findings of “insufficient documentation for detailed exams.” Survival tips Know the “4x4 rule,” which comprises 4 PE elements examined in 4 body areas/organ systems (fully documented). For providers, this rule is a quick method to avoid misinterpretation; for auditors, it allows efficient assessment and exact PE-level differentiation. Providers should check with their Medicare carrier to ascertain the DGs for EPF and detailed PEs.

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Misreporting of CPT 99499 (unlisted E/M service). CMS addresses CPT 99499 in the Medicare Claims Processing Manual 10004 Chapter 12§30, stating “the Carrier has the discretion to value the service” coded with CPT 99499. The carrier is in control, and many carriers maintain that CPT 99499 should be reported only rarely. This is because adjudicators must review documentation and apply individual consideration protocols for correct pricing.

Survival tips Report CPT 99499 in rare circumstances and only per your carriers’ instructions.

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Misapplication of modifier 24. When reporting unrelated E/M services during the global surgical period of a major procedure (90 days) or of a minor procedure (up to 10 days), the MR documentation must support the E/M code appended with modifier 24. MR documentation must detail why the service should be allowed outside the global period. Survival tips This is one of the few E/M areas regularly on the Office of Inspector General Annual Work Plan. Implement steps to prevent inadvertent reporting

of E/M services included in the status post convalescence: careful documentation and ICD-9-CM coding are essential.

your carrier’s preferences. Error 2—PE: Missing or insufficient information. A common PE statement is “no change from prior visit,” but when 3 key components are required, this brief statement is inadequate. “Negative” and “within normal limits” notations are acceptable forms of documentation for unaffected areas/organ systems only. Error 3—MDM: Truncated or disorganized data. MDM information conveys the complexity/risk of the service and therefore must be fully documented. Disorganized MDM data can cause mistakes in copying the requested MRs. Providers should always create a data bridge between the body of the visit text and other supporting visit documents such as an ROS questionnaire. Data bridges are critical when the provider has reviewed old MRs, ordered tests/ studies, carried forward or revised diagnoses and medications, etc. l

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Key components of E/M services not fully documented or missing. For most E/M services, 3 key components govern code selection: (1) history; (2) PE; and (3)

Providers should always create a data bridge between the body of the visit text and other supporting visit documents such as a review-of-systems questionnaire.

MDM. These components must be included in the documentation for new office visits and initial inpatient services. If only 2 key components are required to be documented, for example, CPT 99212 to 99215 or CPT 99231 to 99233, at least 2 components must meet the service’s lowest thresholds.

Michael Calahan, PA, MBA, is the director of physician compliance services at KForce Healthcare, Inc. He works with physicians for coding and revenue cycle management as well as in the facility inpatient/outpatient arenas. He can be contacted at mikiecal@hot mail.com or mcalahan@kforce.com.

Survival tips Error 1—History: Poorly recorded data including chief complaint (CC); history of present illness (HPI); and past medical, family/ social history (PFSH). Contra dictory data among these elements are also a common error, for example, CC states one reason for the visit but the HPI details a different problem. Some carriers require the CC and HPI to be documented by the treating provider only. Terms such as “noncontributory” under the PFSH or ROS may be invalid; know

October 2011

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4QFDJmDQBZNFOUJOTUSVDUJPOTNBZCFPCUBJOFEJOUIF+VMZ0114QSPHSBNJOTUSVDUJPOT BWBJMBCMFBUIUUQXXXDNTHPW)PTQJUBM0VUQBUJFOU114)01145SBOTMJTUBTQ5PQ0G1BHF 

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t.JTDFMMBOFPVTDPEFT+ OPUPUIFSXJTFDMBTTJmFE BOUJOFPQMBTUJDESVHT + VODMBTTJmFECJPMPHJDT  BOE+ VODMBTTJmFEESVHT NBZCFVTFEJOPUIFSTFUUJOHTVOUJMBQFSNBOFOUDPEFIBTCFFOBTTJHOFE 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. Coding for YERVOY is dependent on the insurer and the care setting in which the drug will be administered. Oncology practices need to make coding decisions based on the diagnosis and treatment of each patient and the specific insurer requirements.

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.

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Important Safety Information (cont) Recommended Dose Modifications 8JUIIPMEEPTFGPSNPEFSBUFJNNVOFNFEJBUFEBEWFSTFSFBDUJPOTVOUJM SFUVSOUPCBTFMJOF JNQSPWFNFOUUPNJMETFWFSJUZ PSDPNQMFUFSFTPMVUJPO  BOEQBUJFOUJTSFDFJWJOHNHQSFEOJTPOFPSFRVJWBMFOUQFSEBZ 1FSNBOFOUMZEJTDPOUJOVF:&370:ย™ JQJMJNVNBC GPSBOZPGUIFGPMMPXJOH t1FSTJTUFOUNPEFSBUFBEWFSTFSFBDUJPOTPSJOBCJMJUZUPSFEVDF DPSUJDPTUFSPJEEPTFUPNHQSFEOJTPOFPSFRVJWBMFOUQFSEBZ t'BJMVSFUPDPNQMFUFGVMMUSFBUNFOUDPVSTFXJUIJOXFFLTGSPN BENJOJTUSBUJPOPGmSTUEPTF t4FWFSFPSMJGFUISFBUFOJOHBEWFSTFSFBDUJPOT Immune-mediated Enterocolitis: t*OUIFQJWPUBM1IBTFTUVEZJO:&370:USFBUFEQBUJFOUT TFWFSF  MJGFUISFBUFOJOHPSGBUBM EJBSSIFBPGรถTUPPMTBCPWFCBTFMJOF GFWFS  JMFVT QFSJUPOFBMTJHOT(SBEF JNNVOFNFEJBUFEFOUFSPDPMJUJT PDDVSSFEJO  BOENPEFSBUF EJBSSIFBXJUIVQUPTUPPMT BCPWFCBTFMJOF BCEPNJOBMQBJO NVDVTPSCMPPEJOTUPPM(SBEF  FOUFSPDPMJUJTPDDVSSFEJO  QBUJFOUT t"DSPTTBMM:&370:USFBUFEQBUJFOUT O   EFWFMPQFE JOUFTUJOBMQFSGPSBUJPO   EJFEBTBSFTVMUPGDPNQMJDBUJPOT  BOE  XFSFIPTQJUBMJ[FEGPSTFWFSFFOUFSPDPMJUJT t.POJUPSQBUJFOUTGPSTJHOTBOETZNQUPNTPGFOUFSPDPMJUJT TVDIBT EJBSSIFB BCEPNJOBMQBJO NVDVTPSCMPPEJOTUPPM XJUIPSXJUIPVU GFWFS BOEPGCPXFMQFSGPSBUJPO TVDIBTQFSJUPOFBMTJHOTBOEJMFVT  o*OTZNQUPNBUJDQBUJFOUT SVMFPVUJOGFDUJPVTFUJPMPHJFTBOE DPOTJEFSFOEPTDPQJDFWBMVBUJPOGPSQFSTJTUFOUPSTFWFSFTZNQUPNT Immune-mediated Hepatitis: t*OUIFQJWPUBM1IBTFTUVEZJO:&370:USFBUFEQBUJFOUT TFWFSF  MJGFUISFBUFOJOH PSGBUBMIFQBUPUPYJDJUZ "45PS"-5FMFWBUJPOT9 UIFVQQFSMJNJUPGOPSNBM 6-/ PSUPUBMCJMJSVCJOFMFWBUJPOT9UIF 6-/(SBEF PDDVSSFEJO  XJUIGBUBMIFQBUJDGBJMVSFJO BOEIPTQJUBMJ[BUJPOJO t  BEEJUJPOBM:&370:USFBUFEQBUJFOUTFYQFSJFODFE NPEFSBUFIFQBUPUPYJDJUZNBOJGFTUFECZ-'5BCOPSNBMJUJFT "45PS "-5FMFWBUJPOT9CVUรต9UIF6-/PSUPUBMCJMJSVCJOFMFWBUJPO 9CVUรต9UIF6-/(SBEF  t.POJUPS-'5T IFQBUJDUSBOTBNJOBTFBOECJMJSVCJOMFWFMT BOE BTTFTTQBUJFOUTGPSTJHOTBOETZNQUPNTPGIFQBUPUPYJDJUZCFGPSF FBDIEPTFPG:&370: o*OQBUJFOUTXJUIIFQBUPUPYJDJUZ SVMFPVUJOGFDUJPVTPSNBMJHOBOU DBVTFTBOEJODSFBTFGSFRVFODZPG-'5NPOJUPSJOHVOUJMSFTPMVUJPO Immune-mediated Dermatitis: t*OUIFQJWPUBM1IBTFTUVEZJO:&370:USFBUFEQBUJFOUT TFWFSF  MJGFUISFBUFOJOHPSGBUBMJNNVOFNFEJBUFEEFSNBUJUJT FH 4UFWFOT +PIOTPOTZOESPNF UPYJDFQJEFSNBMOFDSPMZTJT PSSBTIDPNQMJDBUFE CZGVMMUIJDLOFTTEFSNBMVMDFSBUJPO PSOFDSPUJD CVMMPVT PSIFNPSSIBHJD NBOJGFTUBUJPOT(SBEF PDDVSSFEJO  QBUJFOUT o  QBUJFOUEJFEBTBSFTVMUPGUPYJDFQJEFSNBMOFDSPMZTJT oBEEJUJPOBMQBUJFOUSFRVJSFEIPTQJUBMJ[BUJPOGPSTFWFSFEFSNBUJUJT t5IFSFXFSF  :&370:USFBUFEQBUJFOUTXJUINPEFSBUF (SBEF EFSNBUJUJT t.POJUPSQBUJFOUTGPSTJHOTBOETZNQUPNTPGEFSNBUJUJTTVDIBTSBTI BOEQSVSJUVT6OMFTTBOBMUFSOBUFFUJPMPHZIBTCFFOJEFOUJmFE TJHOTPS TZNQUPNTPGEFSNBUJUJTTIPVMECFDPOTJEFSFEJNNVOFNFEJBUFE Immune-mediated Neuropathies: t*OUIFQJWPUBM1IBTFTUVEZJO:&370:USFBUFEQBUJFOUT DBTF PGGBUBM(VJMMBJO#BSSรTZOESPNFBOEDBTFPGTFWFSF (SBEF  QFSJQIFSBMNPUPSOFVSPQBUIZXFSFSFQPSUFE t"DSPTTUIFDMJOJDBMEFWFMPQNFOUQSPHSBNPG:&370: NZBTUIFOJBHSBWJT BOEBEEJUJPOBMDBTFTPG(VJMMBJO#BSSรTZOESPNFIBWFCFFOSFQPSUFE t.POJUPSGPSTZNQUPNTPGNPUPSPSTFOTPSZOFVSPQBUIZTVDIBT VOJMBUFSBMPSCJMBUFSBMXFBLOFTT TFOTPSZBMUFSBUJPOT PSQBSFTUIFTJB

Immune-mediated Endocrinopathies: t*OUIFQJWPUBM1IBTFTUVEZJO:&370:USFBUFEQBUJFOUT TFWFSFUP MJGFUISFBUFOJOHJNNVOFNFEJBUFEFOEPDSJOPQBUIJFT SFRVJSJOH IPTQJUBMJ[BUJPO VSHFOUNFEJDBMJOUFSWFOUJPO PSJOUFSGFSJOHXJUI BDUJWJUJFTPGEBJMZMJWJOH(SBEF PDDVSSFEJO   o"MMQBUJFOUTIBEIZQPQJUVJUBSJTNBOETPNFIBEBEEJUJPOBM DPODPNJUBOUFOEPDSJOPQBUIJFTTVDIBTBESFOBMJOTVGmDJFODZ  IZQPHPOBEJTN BOEIZQPUIZSPJEJTN oPGUIFQBUJFOUTXFSFIPTQJUBMJ[FEGPSTFWFSFFOEPDSJOPQBUIJFT t.PEFSBUFFOEPDSJOPQBUIZ SFRVJSJOHIPSNPOFSFQMBDFNFOUPS NFEJDBMJOUFSWFOUJPO(SBEF PDDVSSFEJO  :&370: USFBUFEQBUJFOUTBOEDPOTJTUFEPGIZQPUIZSPJEJTN BESFOBM JOTVGmDJFODZ IZQPQJUVJUBSJTN BOEDBTFFBDIPGIZQFSUIZSPJEJTN BOE$VTIJOHTTZOESPNF t.FEJBOUJNFUPPOTFUPGNPEFSBUFUPTFWFSFJNNVOFNFEJBUFE FOEPDSJOPQBUIZXBTXFFLTBOESBOHFEVQUPXFFLTBGUFS UIFJOJUJBUJPOPG:&370: t.POJUPSQBUJFOUTGPSDMJOJDBMTJHOTBOETZNQUPNTPGIZQPQIZTJUJT  BESFOBMJOTVGmDJFODZ JODMVEJOHBESFOBMDSJTJT BOEIZQFSPS IZQPUIZSPJEJTN o1BUJFOUTNBZQSFTFOUXJUIGBUJHVF IFBEBDIF NFOUBMTUBUVT DIBOHFT BCEPNJOBMQBJO VOVTVBMCPXFMIBCJUT BOE IZQPUFOTJPO PSOPOTQFDJmDTZNQUPNTXIJDINBZSFTFNCMF PUIFSDBVTFTTVDIBTCSBJONFUBTUBTJTPSVOEFSMZJOHEJTFBTF o6OMFTTBOBMUFSOBUFFUJPMPHZIBTCFFOJEFOUJmFE TJHOTPSTZNQUPNT PGFOEPDSJOPQBUIJFTTIPVMECFDPOTJEFSFEJNNVOFNFEJBUFE o.POJUPSUIZSPJEGVODUJPOUFTUTBOEDMJOJDBMDIFNJTUSJFTBUUIF TUBSUPGUSFBUNFOU CFGPSFFBDIEPTF BOEBTDMJOJDBMMZJOEJDBUFE CBTFEPOTZNQUPNT o*OBMJNJUFEOVNCFSPGQBUJFOUT IZQPQIZTJUJTXBTEJBHOPTFECZ JNBHJOHTUVEJFTUISPVHIFOMBSHFNFOUPGUIFQJUVJUBSZHMBOE Other Immune-mediated Adverse Reactions, Including Ocular Manifestations: t*OUIFQJWPUBM1IBTFTUVEZJO:&370:USFBUFEQBUJFOUT DMJOJDBMMZ TJHOJmDBOUJNNVOFNFEJBUFEBEWFSTFSFBDUJPOTTFFOJOXFSF OFQISJUJT QOFVNPOJUJT NFOJOHJUJT QFSJDBSEJUJT VWFJUJT JSJUJT BOE IFNPMZUJDBOFNJB t"DSPTTUIFDMJOJDBMEFWFMPQNFOUQSPHSBNGPS:&370: JNNVOF NFEJBUFEBEWFSTFSFBDUJPOTBMTPSFQPSUFEXJUIJODJEFODF XFSFNZPDBSEJUJT BOHJPQBUIZ UFNQPSBMBSUFSJUJT WBTDVMJUJT  QPMZNZBMHJBSIFVNBUJDB DPOKVODUJWJUJT CMFQIBSJUJT FQJTDMFSJUJT  TDMFSJUJT MFVLPDZUPDMBTUJDWBTDVMJUJT FSZUIFNBNVMUJGPSNF QTPSJBTJT  QBODSFBUJUJT BSUISJUJT BOEBVUPJNNVOFUIZSPJEJUJT Pregnancy & Nursing: t:&370:JTDMBTTJmFEBTQSFHOBODZDBUFHPSZ$5IFSFBSFOP BEFRVBUFBOEXFMMDPOUSPMMFETUVEJFTPG:&370:JOQSFHOBOUXPNFO 6TF:&370:EVSJOHQSFHOBODZPOMZJGUIFQPUFOUJBMCFOFmUKVTUJmFT UIFQPUFOUJBMSJTLUPUIFGFUVT t)VNBO*H(JTLOPXOUPDSPTTUIFQMBDFOUBMCBSSJFSBOE:&370: JTBO*H(UIFSFGPSF :&370:IBTUIFQPUFOUJBMUPCFUSBOTNJUUFE GSPNUIFNPUIFSUPUIFEFWFMPQJOHGFUVT t*UJTOPULOPXOXIFUIFS:&370:JTTFDSFUFEJOIVNBONJML #FDBVTFNBOZESVHTBSFTFDSFUFEJOIVNBONJMLBOECFDBVTF PGUIFQPUFOUJBMGPSTFSJPVTBEWFSTFSFBDUJPOTJOOVSTJOHJOGBOUT GSPN:&370: BEFDJTJPOTIPVMECFNBEFXIFUIFSUPEJTDPOUJOVF OVSTJOHPSUPEJTDPOUJOVF:&370: Common Adverse Reactions: t5IFNPTUDPNNPOBEWFSTFSFBDUJPOT รถ JOQBUJFOUTXIP SFDFJWFE:&370:BUNHLHXFSFGBUJHVF  EJBSSIFB   QSVSJUVT  SBTI  BOEDPMJUJT  

1MFBTFTFFCSJFGTVNNBSZPGGVMM1SFTDSJCJOH*OGPSNBUJPO JODMVEJOHBoxed WARNING regarding immune-mediated adverse reactions POUIFGPMMPXJOHTQSFBE

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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 *NNVOFNFEJBUFEFOUFSPDPMJUJT[see Warnings and Precautions].



t *NNVOFNFEJBUFEIFQBUJUJT[see Warnings and Precautions].



t *NNVOFNFEJBUFEEFSNBUJUJT[see Warnings and Precautions].



t *NNVOFNFEJBUFEOFVSPQBUIJFT[see Warnings and Precautions].



t *NNVOFNFEJBUFEFOEPDSJOPQBUIJFT[see Warnings and Precautions].



t 0  UIFSJNNVOFNFEJBUFEBEWFSTFSFBDUJPOT JODMVEJOHPDVMBSNBOJGFTUBUJPOT[see Warnings and Precautions].

A


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. n

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:

YERVOY 3 mg/kg n=131

a

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

Table 2 presents the per-patient incidence of severe, life-threatening, or fatal immune-mediated adverse reactions from Study 1. Severe to Fatal Immune-mediated Adverse Reactions in Study 1 Percentage (%) of Patients

e

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

No formal drug-drug interaction studies have been conducted with YERVOY (ipilimumab). USE IN SPECIFIC POPULATIONS Pregnancy

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:

DRUG INTERACTIONS

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.

Percentage (%) of Patientsa

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

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.

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 *OGPSNQBUJFOUTPGUIFQPUFOUJBMSJTLPGJNNVOFNFEJBUFEBEWFSTFSFBDUJPOT t "EWJTFQBUJFOUTUPSFBEUIF:&370:.FEJDBUJPO(VJEFCFGPSFFBDI:&370:JOGVTJPO t "EWJTFXPNFOUIBU:&370:NBZDBVTFGFUBMIBSN t "EWJTFOVSTJOHNPUIFSTOPUUPCSFBTUGFFEXIJMFUBLJOH:&370:

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

Including fatal outcome. Including intestinal perforation. Underlying etiology not established.

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.

d

1281558A2

IP-B0001A-03-11

Issued: March 2011


Reimbursement

Improving Previsit Processes to Maximize Postvisit Collections Liaisons Complete Accurate and Timely Preregistrations By Sarah W. Rock, MSOD; Debra Gregory

gy and hematology practice with 7 primary sites of service in the Kansas City metro area, evaluated its previsit processes to incorporate a complete, accurate, and timely verification of benefits before rendering services.

Identifying the Problems In the winter of 2009, Kansas City Cancer Center practice leadership identified a clear opportunity to Sarah W. Rock, MSOD

A

Debra Gregory

s most of us know, poor previsit processes create havoc on a practice’s ability to post, bill, and collect for services rendered (Petaschnick J. Health Care Collector. 2007;20:1,10-12). A previsit process that is laden with errors, variation, and waste will result in an increase not only in denials and lost revenue, but also in cost associated with catching and correcting errors on the back end. Previsit processes also can be tied directly to patient satisfaction. Perhaps the most obvious is the dissatisfaction that arises when charges are denied as a result of incorrect billing (Lloyd J. Receivables Report. 2011;26: 1,10). Dissatisfaction can be compounded when patients experience anxiety and worry associated with a lack of understanding about their outof-pocket liability before they have received services. Because the financial obligation for oncology patients continues to grow, patients now are seeking alternatives and options, both medically and financially. To decrease the cost of collections and to meet the patient’s expectation to be educated fully about their financial liability, Kansas City Can cer Center, a multispecialty oncolo-

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After a new patient is scheduled at any location, a preregistration liaison contacts the patient within 48 hours to obtain his or her address, phone number, emergency contacts, and insurance information. decrease the number of denied claims. Upon closer examination, they found that 3 of the top 5 denial codes resulted directly from a failure to collect and/or verify the appropriate information at the time of preregistration. These denial codes included: Services Covered by Another Payer, Services Not Covered by This Payer, and Coverage Termed. To evaluate the preregistration process in more detail, the practice assembled a cross-functional team

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and created a standard definition of “complete preregistration”: collecting 100% of the following data elements before the date of service, with 100% accuracy, 100% of the time: • Patient name (first, middle, last) • Address • Date of birth • Gender • Primary and secondary policy and group numbers • Plan addresses • Subscriber demographics (name, date of birth, gender, Social Security number, and employer). Next, the practice measured how well this standard was being met. By counting both missing and inaccurate data, the team calculated a defect rate of 52%. This deficiency was causing work to be duplicated in the form of error correction and time spent locating missing information. In addition, there consistently were defects that made it downstream, which resulted in denials and additional replicated work. At this point, they set out to determine the root causes of the incomplete preregistrations in order to apply the most effective solutions. They identified variation in process between multiple sites of service; excessive touches or hand-offs without clearly defined roles, responsibilities, or accountability; use of inadequate or outdated paper forms resulting in missing, inaccurate, or illegible information; and simple errors in obtaining and recording data elements such as group numbers, insurance plans, dates of birth, subscriber information, and plan numbers. Continued on page 15


We Will

exhaust all possibilities.

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• Prescription status

Monday−Friday, 8:00 AM to 7:00 PM ET

• Free medication program • Celgene products and restricted distribution programs (RevAssist ® or S.T.E.P.S.®)

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Celgene Patient Support®, RevAssist ®, and S.T.E.P.S.® are registered trademarks of Celgene Corporation. ©2010 Celgene Corporation

05/10

CELG10099


Advocacy

November 2011…Continued from the cover ward with the committee’s recommendations. This leaves incredible power in the hands of the joint committee, but also great risk. The $1.5 trillion they have been tasked to cut is a paltry percent of the total debt problem our country faces. It will not make a significant impact in the long run. However, the brunt of either their action or the automatic 2% overall Medicare cuts that will be triggered if they take no action will fall on the providers who care for Medicare patients. At least half of all oncology patients nationwide use Medicare insurance, so the ripple effects for oncologists will be severe. Already rumors are swirling of potential cuts following the first committee meeting. With many possible targets pulled off the table for the committee, one prime target for cuts that remains is physician services for Medicare patients. Oncology services and costs could be affected significantly and adversely for Medicare patients and providers if certain types of cuts happen, either driven by the joint committee or by the automated mandatory universal cuts that would be triggered should the committee not act by November 23.

Impact of Drug Pricing Changes Oncology drugs are billed through the physician services process, so drug reimbursement to physicians who buy drugs out of pocket and seek reimbursement after treatment is vulnerable. Oncology drugs are currently reimbursed by Medicare at average sales price (ASP) plus 6%. The ASP

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is calculated based on prices reported by manufactures when a drug is sold. However, each drug is not sold directly to physicians’ offices, but instead to oncology drug distributors, who collect a margin to cover their operations (usually about 2%). This means that physicians already receive a real net reimbursement of about ASP plus 4%. Oncology practices and hospital centers incur direct drug handling costs between 12% and 27% over the cost to purchase a drug. The margin over ASP is used partially to offset handling and inventory costs, but obviously not fully. To the extent that the joint committee may decide to enact reductions on the ASP plus 6% model, it will put oncologists (who pay the

Oncology services and costs could be affected significantly and adversely for Medicare patients and providers if certain types of cuts happen, either driven by the joint committee or by the automated mandatory universal cuts.

lowest commercially available market rates for oncology drugs as a class of trade) in the position of paying more for drugs for treatment of Medicare patients than they receive in reimbursement. There are some who believe that the consequences of such a policy shift will encourage physicians to stop acquiring drugs on their own

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and either obtain drugs from an external specialty pharmacy or shift the affected Medicare patients to the hospital setting, where they will still have access to the drugs and thus there is no harm nor foul to the Medicare program. This belief is being promulgated actively as part of the discussion of options for the joint committee. The reality is that there are likely to be significant cost increases if such a policy is enacted—the exact opposite of the savings that are intended. There are no specialty pharmacy programs now in place or available as an alternative (such a program was tried and proved to be a complete failure for both providers and specialty pharmacy organizations). Putting aside the question of access for a moment (which itself cannot be ignored due to the much lower capacity in the hospital outpatient setting, which would be overwhelmed by a sudden large shift in Medicare patients from physician treatment sites), the hospital outpatient setting is likely to incur costs for treatment that could run as much as twice the cost of treatment in a physician office setting. Hospital reimbursement structures are quite different from reimbursement structures for physician practices, and involve higher facility and overhead costs not found in the physician office. Because Medicare has not traditionally done a good job of correlating whether or not a policy change in the physician office (Part B) setting has affected hospital setting (Part A) costs, that question probably has not been considered by those contemplating reducing oncology drug reimbursements. The oncology community, however, should bring such discussions to the forefront of the debt reduction debate.


Advocacy

Impact of Making Oncology Practices Financially Vulnerable Should the joint committee propose policy recommendations that make oncology practices too vulnerable financially, the repercussions may be a massive exodus of private oncology practices from the community into employed hospital arrangements. Again, there are those (particularly within the congressional and Medicare infrastructures) who believe this would be a good shift, with improvements in care coordination and oversight. There are, however, significant adverse repercussions from such a shift, which are well recognized by the private insurance industry that closely tracks their inpatient and outpatient costs. Hospital-based care is recognized widely in the private insurance industry as costing more (as described) than care provided in private physician offices. Congress

and Medicare tend to look at costs of healthcare in silos of Part A and Part B, and thus lose sight of how changes in one infrastructure can push Medicare beneficiaries into another higher-cost infrastructure and ultimately increase costs rather than achieve expected reductions. Private health insurance is watching the activities of the joint committee closely. If physicians choose to become hospital employees because of Medicare policies, the private insurance companies also will be affected because physicians would be unlikely to become employed just for their Medicare populations, but for all their patients.

specialty that was already poorly served by the actions of Congress regarding Medicare in 2003 and 2007. Despite the business and reality logic of the situation, there is a high likelihood that, by November, the nation will move much closer to a hospital-employed model for healthcare. Even though the rest of the nation seems to understand that this move is likely to cost significantly more than the current model, Congress and Medicare do not. There are only a few weeks before that date to communicate what such changes may bring, intended or unintended. l

Short Window for Engagement The joint committee will make its recommendations by November 23. If it does not act, automatic acrossthe-board reductions will be triggered. Unfortunately, oncology is a

Dawn Holcombe is President of DGH Consulting, which provides consulting and speaking services to practices, pharma, and payers in strategy development, MD/payer negotiations and relationships, and oncology management and pathways.

Improving Previsit…Continued from page 12 Implementing Solutions To address the flaws in the processes, the practice developed a centralized team of preregistration liaisons (PRLs) to complete accurate and timely preregistrations for all new patients. After a patient is scheduled at any location (most new patient appointments are scheduled by the patient’s referring office), a PRL contacts the patient within 48 hours to obtain his or her address, phone number, emergency contacts, insurance information, and other pertinent demographics. While on the phone, the PRL answers any questions re garding the upcoming visit, such as directions to the clinic or information about the provider or practice. The PRL then contacts the insurance company to verify benefits,

including deductibles, copays, and coinsurance. This information is scanned into the practice manage-

With the development of this new team and processes, the preregistration defect rate ultimately decreased from 52% to 2%, which the practice continues to maintain today. By identifying an opportunity for improvement, defining quality from the customer’s perspective, collecting data, and targeting root causes, practices can make improvements to their previsit processes that will decrease costs, increase revenue, and maintain patient satisfaction. l

Practices can make improvements to their previsit processes that will decrease costs and increase revenue. ment system for access by the site of service. After the treatment has been ordered, the process is picked up by the clinic’s financial counselor, who educates the patient about his or her potential liability and identifies payment assistance if needed.

October 2011

At Kansas City Cancer Center/The University of Kansas Cancer Center, Sarah W. Rock, MSOD, focuses on performance and quality improvement efforts, and Deb Gregory is director of patient financial services.

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Data Management

Data Management

Improving Oncology Service Line Management Using Cancer Analytics to Your Advantage By Brian Cassel, PhD; Lisa Shickle, MS

H

ospital-based cancer centers and service lines face tough competitive pressures from other practices and hospitals competing for market share, reputation, referrals, and managed care contracts. For hospital-based programs, competition also can arise internally, as other service lines and business units compete with oncology for investments and resources at a time when hospital margins are shrinking. To formulate and make the best possible judgments in strategic planning, business development, and revenue cycle management, oncology managers must maximize the power of the data available to them. The problem has been that existing tools were inadequate for the unique challenges of cancer service lines. At Massey Cancer Center of Virginia Commonwealth University we have found that the typical data systems made available to hospital administrators were not adequate for the complexity of the cancer service line. Simple “cube”-based financial tools were not able to capture the many clinics, units, and ancillary services that are used by cancer patients and providers. Many tools were too focused on inpatient care, when in oncology at least 50% of charges were driven by ambulatory chemotherapy, radiation, surgery, and imaging. Standard tools also were unable to deliver diseasefocused output so that each cancer type (eg, breast, colorectal, lung) could be analyzed separately. Nor were they able to capture the entire treatment course from diagnosis, through cancer-directed treatments, and include palliative and end-of-life care.

The Cancer Analytics Solution In response, we created the Massey Data Analysis System that extracts the hospital’s and providers’ claims data, and reconstitutes them in an easy-to-analyze structured query language–based system. Categories of ICD-9-CM codes are stored in reference tables for easy application in any given analysis, for example, giving us the ability to analyze each type of leukemia and lymphoma separately, or to combine them all into a single category of hematopoietic diseases. Each modality of care is categorized into a handful of key types. Automated programs do the bulk of the extraction, categorization, and “predigestion” of data, allowing our analytic resources to be devoted to pro-

Brian Cassel, PhD

Lisa Shickle, MS

ducing useful output for clinical, operational, and financial improvements. The flexibility and power of this system has been invaluable. We have been able to turn one program within our cancer center from an annual loss of $1 million or worse, to a sustained positive net margin. We have developed and implemented strategic plans that are organized around disease-specific centers of excellence. We have combined cancer registry Continued on page 23

Making Analytics Work for You Key Questions and Action Steps

Q:

A:

A:

Q:

Do you have the tools you need to evaluate the costs and revenues of each of your major programs/centers across modalities of care from screening and diagnosis through all forms of treatment? If not, explore options to access and analyze these data in ways that meet your specific needs. Most hospitals have a decision-support department that would be a good first contact.

Q:

Do you have the tools you need to develop and implement disease-focused strategic plans and business development initiatives?

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If not, you need to identify a cancer data analyst who can bring familiarity and expertise regarding cancer and its treatments to assist you in your planning efforts. Do you have the tools you need to answer new questions flexibly as they arise, regarding all aspects of your cancer patients’ use of services? Cancer treatments continually are evolving; and cancer programs adapt to keep pace with scientific developments, regulatory changes, and organizational shifts. Make sure your system can adapt accordingly.

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Case Study

Case Study

Dana-Farber/New Hampshire OncologyHematology Aligning an Academic Cancer Center and a Community Oncology Practice By Dawn Lagrosa

F

rom informal discussions in 2004 to a ribbon cutting in 2008, Dana-Farber Cancer Institute (DFCI) and New Hampshire Oncology-Hematology (NHOH) embarked on an odyssey to provide world-class cancer care in Londonderry, New Hampshire (Sidebar), according to Denis B. Hammond, MD, chief medical oncologist at NHOH, who detailed “why and how” a multisite, single-specialty adult hematology and oncology independent practice affiliated with an academic cancer center at the 2011 annual meeting of the American Society of Clinical Oncology.

Why “We were facing the first serious competition in our history, and we were also facing the same increased economic pressures all of us have been facing in the United States,” said Hammond. To help determine the best collaboration strategy,

NHOH’s leaders posed themselves questions, as stated by Hammond: • Would a closer relationship with another institution support our mission? • Are the values of this other institution consistent with our own? • Have we had successful interactions with this institution in the past? • Is there an alignment of our strategic goals? Their answers aligned well with DFCI. As a Cancer and Leukemia Group B affiliate with a strong commitment to research, NHOH believed that working with DFCI could improve the quality and scope of services it could provide patients, explained Hammond. Next, they needed to pursue building a successful relationship.

How Informal discussion began in 2004, exploring the possibility of a

closer relationship between NHOH and DFCI. In January 2005, according to Hammond, they signed a “memorandum of understanding,” which detailed the affiliation and the lack of a financial relationship. From this, the 2 groups developed programs, which included “opening selective DFCI trials at NHOH, a joint psychosocial research project, genetics clinics at some of our private practices, and a community education program called ‘Let’s Talk’ that featured physicians both from NHOH and DFCI,” he said. Also that year, Elliott Hospital expanded its services from Manchester to Londonderry. This challenge offered an opportunity for shared clinical space and programs at this campus, said Hammond. In December 2006, NHOH signed a “letter of intent” to explore an agreement with DFCI, which would seize this opportunity and set up a shared financial relationship.

Provider Services Agreement Time Line 2004

2005

Begin informal discussions

Sign Memorandum of Understanding detailed the affiliation and that there was NO financial relationship

2006

2007

Sign Letter of Intent Expand clinical services detailed formal plan to at existing sites explore agreement for shared clinical space and programs at Londonderry site; designated shared Elliott Hospital expands financial relationship to Londonderry; builds medical campus Conduct feasibility analysis of various alignment strategies Decide to pursue provider services agreement

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2008 Dana-Farber Cancer Institute signs lease for clinic space at Londonderry Sign long-term provider services agreement at Londonderry Dana-Farber/New Hampshire OncologyHematology provides services at Londonderry


Case Study

To go from intent to agreement, the 2 groups needed to determine what would work best. This feasibility analysis, said Hammond, asked: • Where would the patients come from? • How many patients would we likely see? • What were the reimbursement issues? • What were the regulatory issues? • Could this relationship be structured so as not to alienate referring physicians? • What type of financial relationship would be most profitable for both NHOH and DFCI? • What model of care would work best: an NHOH office with DFCI affiliation (the status quo); a provider services agreement; a joint venture; NHOH as a wholly owned entity of Farber? The entities decided upon a provider services agreement. “NHOH physicians would join the DFCI staff. [NHOH] would provide professional medical and support staff services. The administration of the unit would be carried out by DFCI, with the advisory function of an NHOH physician. There would be joint governance, and there would be a steering committee,” shared Hammond. “The basics of the provider services relationship would be that DFCI would rent the clinical space from Elliott Hospital and equip the unit according to DFCI standards. The staff would perform functions in

staff: a full-time social worker (1 FTE), a nutrition counselor (0.4 FTE), and a chaplain (0.25 FTE). “Patient satisfaction has been high and clinic growth has continued through this present year [June 2011]. Additionally, there is now a fully staffed radiation oncology unit on site, and it is a group through which we have had a long relationship,” he said. To conclude his presentation, Hammond shared how the affiliation has fared in the 2 years since the agreement was signed. Measuring new patients/consults per year, established patients per quarter, and infusions, DF/NHOH analyzed their projected versus actual numbers. For the first year, 2009, projected amounts mirrored the actual, he said; for the second year, 2010, the actuals were significantly lower than what was projected. He offered this analysis of why the projections were off: “The projections were based primarily on the existing demographics of each of the entities involved in the project and did not take into account the subtraction that would happen when the 2 entities joined. In addition, the projections did not account for the increase in competition in the clinic’s catchment area. The projections also did not account for the fact that opening this clinic would alienate some of our referring physicians. And the projections did not account for the fact that some patients just wanted to go downtown for their care.” l

accordance with DFCI policy and procedures. Neither party would take any action that would harm the other. And the clinic would utilize DFCI’s electronic medical record and computerized physician orderentry system.”

“Patient satisfaction has been high and clinic growth has continued through this present year [June 2011].” –Denis B. Hammond, MD

After DFCI signed the lease for clinic space at the Londonderry campus, DFCI and NHOH formalized their alignment by signing a long-term provider services agreement for that location.

Outcomes Now a new entity, Dana-Farber/ New Hampshire Oncology-Hematology (DF/NHOH) has enhanced its services. To date, it has opened genetic, survivorship, and second-opinion clinics; developed joint tumor boards for multiple disease sites; opened DFCI trials in New Hampshire; and begun continuing medical education and community education programs, Hammond extolled. The group also has added

Improving Oncology Service…Continued from page 21 and claims data to analyze utilization patterns and financial outcomes at the patient level by disease type and stage. And we have used this system to develop the financial metrics for our palliative care program. l

Brian Cassel, PhD, and Lisa Shickle, MS, are analysts with Massey Cancer Center of Virginia Commonwealth University, and senior consultants with Data Blueprint, a data management and IT consulting firm that empowers

October 2011

organizations to gain more value from data systems and provides analytic solutions for oncology program decision making. Dr Cassel can be reached at jbcassel@vcu.edu. Ms Shickle can be reached at lmshickle@vcu.edu.

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Reimbursement

Getting from ICD-9 to ICD-10 3 Things Every Practice Manager Should Consider By Richard Vander Burg, RN, BSN

T

he deadline for going live with the International Classification of Diseases (ICD), 10th edition is October 1, 2013, and the Centers for Medicare & Medicaid Services repeatedly has attested this as a firm deadline with no extensions, delays, or grace periods. After the deadline for transition, providers will not be able to use the clinical modification (CM) of the 9th edition, that is, the ICD-9-CM codes. The implication being: If you aren’t live with ICD-10-CM, you won’t get paid. When we hear ICD-10 in the United States, it usually refers to the nation’s latest clinical modification of the ICD, which was developed to support reimbursement coding, called ICD-10-CM. The ICD-10 procedural coding system, designated as PCS, will replace codes in volume 3 of ICD-9-CM in the United States. The Current Procedural Terminology code set will remain unchanged for physician services. So what’s the difference between ICD-9 and ICD-10? The big change has been the increase in the level of detail that will be reported using ICD-10 codes. Within ICD-9, there are about 13,500 valid codes compared with more than 68,000 codes in ICD-10. ICD-9-CM has a maximum of 5 code elements, whereas the new codes have up to 7 alphanumeric digits. The transition from ICD-9 to ICD10 has the potential to impact all areas of how a practice operates. Of particular importance are 3 areas that

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every practice manager should consider in developing a transition plan.

1

Scrutinize vendors. Are they up to speed? Many vendors support revenue cycle management for medical practices. The good ones will be well on their way to completing internal testing of a change to Version 5010 of the Electronic Data Transactions protocol. The deadline for making the transition to this new protocol is well in advance of the deadline for ICD-10 implementation at January 1, 2012. It is important to understand a vendor’s progress toward completing this transition and to develop a joint plan for implementing the change in your practice that allows ample time for addressing challenges that may arise during the rollout.

2

Evaluate your coding solution. Is it the right solution for the future? With the increased complexity of the code structure of ICD-10 compared with ICD-9 and the underlying need for increased knowledge of medical terminology and anatomy, it is important to evaluate if your coding capabilities will meet your re quirements in the ICD-10 world. Considerations about optimizing clinicians’ time with patients and the amount of training required for the entire practice workforce, coupled with the increasing availability of remote coding as a business solution, provide medical practices with many new drivers in selecting a coding solution. Key considerations that can be used in evaluating current versus proposed coding solutions include the amount of time to code a chart, the accuracy of the codes, and cost

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(both the actual cost plus the opportunity cost associated with delayed reimbursement). Even if your current coding solution will be adequate for your expected future needs, a “plan B” should be considered to provide additional coding capability during the period of the transition from ICD-9 to ICD-10.

3

Train everybody. The implications of the transition will impact every facet of a practice. For this reason, everybody needs training. The level of training will range from general awareness training on what is involved in the transition and your practice’s plans for change all the way through detailed coder training on how to apply the new code set. Training everybody to the appropriate level will ensure that this is a practice-wide initiative with all staff equally invested in the success of the ICD-10 implementation. The looming transition to ICD-10 will require changes in how your practice operates. Now is the ideal time to evaluate the current solutions used for revenue cycle management in light of the new business requirements of operating in the ICD-10 environment. Critical consideration should be given to evaluating your vendor’s capability to grow with you and support you, the applicability of your current coding solution for the future, and the need for training across the entire practice. l

Richard Vander Burg, RN, BSN, is senior vice president and director of healthcare services at DOMA Technologies, a software-as-a-service consulting firm.


Wellness-Based Healthcare: Economic Incentives and Benefit Design

Overall Survival Advantage Sustained at 3-Year Median Follow-up In Previously Untreated Multiple Myeloma (MM) VISTA* VISTTA* OVERALL SURVIVAL SURVIV VAL AL (OS) (OS S) ANALYSIS: ANALLY YSIS: VcMP† vs MP (36.7-month median follow-up) MEDIAN OS NOT REACHED FOR VcMP

100 90

% Patients Patients Without Event

80 70 60 50 40 30 20 10

■ VE LCADE+MP (n=344) VELCADE+MP ■ MP (n=338)

HR 0.65 (95% CI, 0.51-0.84); PP=0.00084 =0 =0.00084 =

0 0

3

6

9

12

15

18

21

24

27

30

33

36

39

42

45

48

51

Months Ka Kaplan-Meier plan-Meier estima estimate. te.

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Brief Summary INDICATIONS: 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. 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. 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. 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. 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.

Patients with 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. ADVERSE EVENT DATA:

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. 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:

Co-administration of ketoconazole, a potent CYP3A inhibitor, increased the exposure of bortezomib. Therefore, patients should be closely monitored when given bortezomib in combination with potent CYP3A4 inhibitors (e.g. ketoconazole, ritonavir). Co-administration of melphalan-prednisone increased the exposure of bortezomib. However, this increase is unlikely to be clinically relevant. Co-administration of omeprazole, a potent inhibitor of CYP2C19, had no effect on the exposure of bortezomib. Patients who are concomitantly receiving VELCADE and drugs that are inhibitors or inducers of cytochrome P450 3A4 should be closely monitored for either toxicities or reduced efficacy. 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 www.VELCADE.com

VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners. Millennium Pharmaceuticals, Inc., Cambridge, MA 02139 Copyright © 2011, Millennium Pharmaceuticals, Inc. All rights reserved. Printed in USA

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

Disability Insurance Planning Protecting Your Ability to Earn an Income

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lthough members of the cancer care team will sacrifice their time and energy for the care of their patients, all too often it is done to the detriment of themselves and their families, especially in the areas of personal financial planning. This article focuses on protecting your most valuable asset —your ability to earn an income.

Disability Insurance Disability insurance can be purchased on an individual or group basis. Group insurance usually is provided by an employer or purchased individually from a sponsoring association. Although initially low in cost, group policies have several limitations. They can be canceled (by the association or insurance company), rates increase as you grow older, and premiums are subject to adjustments based on the claims experience of the group. In addition, group and association contracts often contain restrictive definitions of disability as well as less generous contract provisions. First, find out what long-term disability (LTD) benefits, if any, are available or provided to you by your employer. You will need the answers to the following questions: • What percent of your income is covered? Is only your base salary covered or is commission, bonus, and overtime income also included? • What is the maximum monthly benefit? • How long must you be disabled before benefits become payable? • How long are benefits payable? • Are you contributing to the cost of the coverage or is it paid for entirely by your employer?

gender, monthly benefit being purchased, and the optional riders selected. The younger you are when the purchase is made, the lower the cost of the insurance. Therefore, you should purchase a policy as early in your career as possible to lock in lower premium rates. Rates for women are substantially higher and their policies generally cost 50% to 60% more than those for men. Fortunately, many disability insurance carriers offer a “multilife” discount when several employees working for the same hospital or practice purchase individual policies at the same time. Whereas these programs typically produce a savings of 10% to 15% for men, this strategy allows female physicians to save up to 60% on the cost of their disability insurance. Another option is to secure a discount as a result of a professional association in which you are a member or are eligible to join.

• Would benefits paid to you be taxable or income tax–free to you upon receipt? Do you have a choice? • Is the plan mandatory or voluntary? • What is the name of the insurance carrier that underwrites the coverage?

Disability Insurance Limits Insurance companies don’t want you to earn a higher income when you are disabled compared with when you were working. For this reason, most insurance companies will limit the amount of disability insurance available. Ideally, you would like to have 60% of your earned income replaced on an income tax–free basis in the event of your disability. When you have group insurance in place, however, this will limit the amount of individual coverage available to you—even if you were willing to pay for a larger amount of coverage. For this reason, when shopping for an individual disability insurance policy, it is best to provide your agent with a copy of your group LTD plan, the specifics as to how your salary is comprised, your job title, as well as duties. You should also let him or her know if you have any health issues or are taking any prescription medications. They then will go to the marketplace to present you with the options available so you can make a well-informed, educated decision based on your budget and individual needs and goals.

Summary Protecting one’s income in the event of a disability is one of the core elements of financial planning. My next article will describe what features should be included in your policy and how to choose the company and policy to best meet your needs. l Lawrence B. Keller, CLU, ChFC, CFP®, is the founder of Physician Financial Services, a firm specializing in income protection and wealth accumulation strategies for physicians. He can be reached at 516-677-6211 or Lkeller @physicianfinancialservices.com.

The Cost of Disability Insurance Premium rates are based on several factors, including the insured’s age,

October 2011

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

Hurdles to Appropriate Reimbursement The SGR, Prompt-Pay Discounts, and Cuts in Medicare Reimbursement By Sydney Abbott, JD

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his has proven to be a difficult year for reimbursement for community cancer care providers. Although there are many hurdles to appropriate reimbursement, 3 issues are hanging fire in Congress this year. The sustainable growth rate (SGR) formula remains unfixed. Drug manufacturers’ promptpay discount is still calculated in the average sales price (ASP) for physician reimbursement. And most re-

It appears that the committee is looking at provider-side cuts as well—somewhere in the range of a 2% reduction. cently, select members of Congress are considering across-the-board cuts of up to 2% in Medicare reimbursement.

1

The SGR formula. This fundamentally flawed formula links reimbursement rates to increases in the gross domestic product (GDP). Because spending on physician services has grown faster than increases in GDP, the formula has called for cuts in reimbursement each year for most of the past decade. In 2012, the SGR formula calls for nearly a 30% cut to physician reimbursement. Each year, Congress has passed a “doc fix,” pushing those cuts down the road. Once again, a

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similar “fix” is expected by year’s end. However, these continual lastminute “fixes” make future planning and investment difficult for practices that cannot know when, or if, another short-term fix is going to happen. The Association of Community Cancer Centers (ACCC) continues to work with the Centers for Medicare & Medicaid Services (CMS) and Congress to ensure physicians do not see these significant cuts.

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The prompt-pay discount included in the calculation of ASP. ACCC is fighting to remove these customary prompt-pay discounts, which are extended by manufacturers to distributors, from the manufacturers’ calculation of the ASP for Part B drugs and biologicals. These discounts typically are not passed on to the physician purchasing the product. ACCC supports S.733 and HR.905, 2 pieces of companion legislation that would remove the prompt-pay discount from the ASP calculation, aligning Medicare reimbursement methodology with Medicaid methodology. Medicaid methodology excludes these discounts from the calculation of average manufacturers price (AMP), ensuring fair and accurate reimbursement for physicians and clinics. Thanks in part to the hard work of ACCC members, the bills are gaining bipartisan support in both the House and Senate.

3

Congress considering cuts in Medicare reimbursement. Most urgently, Congress recently finalized the members of the bicameral, bipartisan debt reduction “super” committee, which was created by the debt-

ONCOLOGY PRACTICE MANAGEMENT

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October 2011

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Special Edition

ceiling compromise signed into law by President Obama in August. This joint committee has until Thanksgiving to find at least $1.5 trillion in deficit savings over 10 years for an up-or-down vote in both chambers by Christmas 2011. This is of concern to all cancer care providers because Medicare reimbursement is looking at significant cuts. President Obama has been very clear that when he envisions cuts to Medicare, he does not see changes in coverage for beneficiaries, he sees provider-side cuts. It appears that the committee is looking at provider-side cuts as well—somewhere in the range of a 2% reduction. And these cuts will be in addition to projected cuts of almost 30% resulting from the SGR formula. Although these hurdles are significant, ACCC will continue to work until they are overcome. For example, ACCC has worked with congressional offices, held Hill Day events for its members, sponsored congressional briefings on issues affecting its membership, and submitted comments to CMS on the recent Hospital Outpatient Prospective Payment System and Medicare Physician Fee Schedule 2012 proposed rules. ACCC will address these issues in greater detail at ACCC’s 28th National Oncology Conference in Seattle, October 19-22, 2011. For more information visit: www.accccancer.org/meetings/meetingsNO C2011.asp. l

Sydney Abbott, JD, is policy coordinator for the Association of Community Cancer Centers.


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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 1000/mm3 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

TM

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

October 2011, Vol 1, No 3  

Oncology Practice Management Process Improvements to Enhance Patient Care

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