ONCOLOGY PRACTICE MANAGEMENT ™
PROCESS IMPROVEMENTS TO ENHANCE PATIENT CARE™
From the Editor
An Emerging Breed of Super Administrator By Dawn Holcombe, MBA, FACMPE, ACHE
VOLUME 2• NUMBER 1
From Independent Medical Practice to Hospital Employment: A Physician’s Perspective By Bonnie K. Ciresi, CPA, Mountjoy Chilton Medley, LLP, Louisville, KY
n March 1, 2010, Consultants in Blood Disorders and Cancer (CBC), PSC, in Louisville, KY, sold all its assets to Baptist Medical Associates, a division of Baptist East Hospital, and the physicians became employees of the hospital. The events leading up to this decision culminated over several years and are not
unique to this particular oncology/hematology practice. However, the outlook for this medical practice almost 2 years later may be unique. Michael D. Kommor, MD, current President of CBC, shared his insights and experiences with me as his practice made this transition from an independent practice to hospital employment. Continued on page 28
By Wayne Kuznar
From the publishers of ©2012 Engage Healthcare Communications, LLC
The Section 340B Drug Pricing Program is a federally mandated program that is intended to provide financial relief to facilities that provide care for medically underserved persons. In 1990, the Medicaid Continued on page 8
... .4 8
Chicago, IL—Participation in the 340B Drug Pricing Program can result in considerable savings on prescription drugs. Therefore, it is necessary that potential covered entities understand the requirements for 340B eligibility, the enrollment process, and the criteria that define the patient of a covered entity. C. Frederick Geilfus II, JD, partner at Foley and Lardner, LLP, provided an overview of the 340B Drug Pricing Program during the 2011 Cancer Center Business Summit.
N Br T ou A g C ht N om to D m yo PR un u O b O En AC ity C y nc ou O a th VID ol gh F nc e A ER og t in e s y o E al R r C soc Te n u e ia AC am tic le nte tio C : rs n ?… e th of ES S . e
Continued on page 3
Understanding the 340B Drug Pricing Program Requirements
he scope of oncology practice management is undergoing seismic changes. Groups that formerly focused on the survival of their patients, now have to wonder about their own operational survival, but under what evolving model? Administrators are being asked to oversee the operation of the practice, as well as scores of reporting measures and new contractual relationships, and perhaps even new institutional relationships. The practice administrators’ “to do” list looks dramatically different from the way it did just 4 years ago. How does one stay prepared? No matter what the practice size, the challenges are rapid and
Cracking the Code
A N N O U N C I N G A N E W J - C O D E F O R X G E V A® A N D P R O L I A® — XGEVA® and Prolia® will have a permanent HCPCS on January 1, 2012 — This new J0897 code will replace miscellaneous codes J3490, J3590, and C9272, which providers have been using to bill for XGEVA ® and Prolia ® to date
Injection, denosumab, 1 mg
January 1, 2012
www.AmgenAssistOnline.com 1-888-4ASSIST (1-888-427-7478) © 2011 Amgen. All rights reserved. 63513-R1-V1 11/11
From the Editor
An Emerging Breed of Super…Continued from the cover unrelenting. The topics remain consistent with medical practice administration elements, but for 2012 and beyond, the magnitude of demands and sophistication of management that is needed to deal with those elements will challenge even the most experienced administrator. If you are not faced with the following issues yet, you are likely soon to be:
Ownership In cities and towns across the country, private oncology practices and hospital cancer centers echo the same refrain, “what will we look like next year?” Some of the variables that will shape those answers include: • Drugs: source more than price (Will practices continue to acquire drugs from their source of choice, or will buy and bill continue? Will a delivered model evolve?) • Site of service: will care be delivered in a physician office, hos-
Data analytics New analytics will be needed to prove the value of your care to others, and to validate internal quality and efficiency measures
Regulations Federal and state regulations will continue to become more onerous. Miss one, and there will usually be an auditor waiting to catch you, with increasingly severe penalties. Practice administrators who delegate responsibility for regulatory oversight and compliance are ultimately still responsible
Contracting No longer limited to rates and fee schedules, payer contracting could soon become a complex process of episode of care bundling, performance measures and payments, and coordination with other oncology management tools external to your practice. Contracting or negotiations with other entities, such as hospitals seeking affiliations or ownership, will only increase in 2012
Staffing Creative staffing, beyond the traditional oncology model, will be a staple for 2012 and beyond. Oncology pharmacists are emerging as a complement to the shrinking pool of oncology physicians. Will you be collaborating with or employing oncology pharmacists?
Finance Watching the bottom line is now the bottom line for any healthcare model—practice or hospital. Not only understanding
Continued on page 6
Editorial Advisory Board
Editor-in-Chief Dawn Holcombe, MBA, FACMPE, ACHE President DGH Consulting South Windsor, CT
Bruce A. Cutter, MD President Cutter HealthCare Consulting Spokane, WA
Ronald Barkley, MS, JD President Cancer Center Business Development Group Bedford, NH
Craig Deligdish, MD Medical Director Florida Comprehensive Cancer Network Melbourne, FL
Peggy Barton, RN Practice Manager Toledo Clinic, OH
Patrick A. Grusenmeyer, ScD, FACHE President Christiana Care Health Initiatives Newark, DE
Risë Marie Cleland President Oplinc, Inc Lawton, OK
the internal finances of your group, but also looking outside to oversee how treatment decisions can affect the total cancer spend, is becoming critical for your position in the medical community
pital, freestanding center, or through home infusion?
Teri U. Guidi, MBA, FAAMA President & CEO Oncology Management Consulting Group Pipersville, PA Ruth Lander, RN, FACMPE Practice Administrator Columbus Oncology & Hematology Associates, Inc Columbus, OH 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
In This Issue
PUBLISHING STAFF Publisher Nicholas Englezos email@example.com 732-992-1884 Associate Publisher Maurice Nogueira firstname.lastname@example.org 732-992-1895 Director, Client Services Cristopher Pires email@example.com 732-992-1896 Editorial Director Dalia Buffery firstname.lastname@example.org 732-992-1889 Editorial Assistant Jennifer Brandt email@example.com 732-992-1536 Production Manager Marie R. S. Borelli Sales Assistant Zach Ceretelle Quality Control Director Barbara Marino Business Manager Blanche Marchitto
MISSION STATEMENT Oncology healthcare requires providers to focus attention on financial concerns and strategic decisions that affect the bottom line. To continue to provide the highquality care cancer patients deserve, providers must master the ever-changing business of oncology. Oncology Practice Management will offer process solutions for members of the cancer care team— medical, surgical, and radiation oncologists, as well as executives, administrators, and coders/billers—to assist them in reimbursement, staffing, electronic health records, REMS, and compliance with state and federal regulations.
FEATURES CANCER CENTER BUSINESS SUMMIT Ultimate Goal in Selling a Practice Is to Research a Collaborative Agreement ......................................13 Oncology Practice Trends: Operating Margins Will Continue to Decline, Alternatives to Fee-for-Services Gain Traction ....................................14 An Array of Compensation Models to Align Oncologists’ and Hospitals’ Interests ......................................................16 Know the Federal Laws that Apply to Buying and Selling Oncology Practices..................................20 SUVIVORSHIP Seasons of Survival: Redefining the Paradigm for Cancer Survivorship for 2011..............................................31 By Kenneth Miller, MD; Irit Ben-Aharon MD, PhD; Lindsay Haines, BA
DRUG CODING Medications Used for Supportive Care in Cancer Treatment ..............................................................40 DEPARTMENTS Legal Update Maintaining Your Records: In What Form and for How Long? ..........................................................................28 By Jennifer Kirschenbaum, Esq
Physician Wealth Management With Lawrence B. Keller, CLU, ChFC, CFP®
Disability Insurance Planning for the Cancer Care Team ................................................................................46 Patient and Provider Access Brought to you by the Association of Community Cancer Centers
ACO Final Rule: Enough to Entice the Oncology Team? ........................................................................................48 By Sydney Abbott, JD
Oncology Practice Management™, ISSN 2164-4403(print), is published 4 times a year by Engage Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205A, Monroe Township, NJ 08831. Copyright © 2012 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. 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.
ONCOLOGY PRACTICE MANAGEMENT
I February 2012
with dedicated Amgen Reimbursement Counselors There is A place you can go for user-friendly online tools and reimbursement forms… …where your coverage questions can be Answered …where online Access to forms is simple …where you can talk to A single Amgen Reimbursement Counselor for all your reimbursement activity
www.AmgenAssistOnline.com 1-888-4ASSIST (1-888-427-7478)
For insurance verification…prior authorization…patient assistance program information…billing and claims processing support…and appeals support. Amgen Assist ® and Amgen Inc. do not guarantee success in obtaining reimbursement. Third party payment for medical products and services is affected by numerous factors, not all of which can be anticipated or resolved by our Amgen Assist® staff. ©Amgen. All rights reserved. MC48319-B-1 08/11
Making Access easier.
From the Editor
An Emerging Breed of Super…Continued from page 3 Staying (or Becoming) a “Super Administrator” Each administrator of an oncology practice today has already developed his or her own unique strengths. There is no one “right” profile for an administrator, and it may not matter what your background is. It is clear that successful administrators for future oncology practices will share new universal strengths:
Perspective The ability to listen to the needs and interests of other key players along the healthcare continuum and to adjust your message in terms of their needs and interests
Technology acumen Our billing systems and electronic medical records are not equipped out of the box to answer the quality and utilization questions we now need answered, at least not without constant modification. It will be essential not only to understand the technology in the practice, but also to look beyond the traditional functions and direct the strategic adaptations that will produce the data you need for operations and quality management
Vision Vision not just for the details but also for the bigger picture for your practice and beyond the walls of the practice. Practices have traditionally focused very well on processes to treat individuals. They will now be required to integrate processes not just for the patients who are individuals, but also to streamline population and disease groupings of large numbers of patients. Practices will be required to improve communications and infor-
mation sharing bridges between their operations and other aspects of healthcare (eg, primary care and other specialty physicians, patient navigators, case managers, pharmacy managers, hospitals and possibly other sites of care, hospices, and home infusion). Whether the integration is virtual or driven by an acquisition or merger, practice administrators will need to lead their groups through this new territory
Creativity There is great impetus for new leadership for quality and effectiveness in healthcare. We are in a period of transition, where many solutions are tried and we may hit obstacles as they evolve. Practice administrators who stay informed during the transition, and contribute to the body of knowledge, and lead their groups through what could be a myriad of new opportunities will be well positioned to be the leaders in demand for the future, whatever shape it takes
Business common sense Oncology is a specialty that draws compassionate individuals, whether they provide clinical support or business support to cancer patients and those who serve them. The old adage “there is no mission without a margin” is very true. The practice administrator is now asked to help the physician serve several perspectives of financial responsibility: what is affordable and appropriate for the patient, the practice, the health plan, the employer, and society.
Leveraging Professional Resources So, how does a practice administrator stay equipped to lead his/her
ONCOLOGY PRACTICE MANAGEMENT
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group into the future? It will only happen through information, communication, and education. The need to stay connected and informed is growing stronger. You can leverage and manage the information flow by subscribing to specific news lists and discussion groups. HealthLeaders, the American Society of Clinical Oncology (ASCO), the Association of Community Cancer Centers (ACCC), Community Oncology Alliance (COA), and Oncology Business Review all offer good summaries and overviews. The professional networking website LinkedIn offers a wealth of interesting discussion groups from each of these organizations, as well as topicdriven groups. You may also choose to subscribe to the discussion boards hosted by your own state association groups, or groups such as ASCO, ACCC, COA, and ACOA (American College of Oncology Administrators). Conferences and webinars remain one of the primary opportunities to network outside of your own market and learn about trends and innovations, even opportunities and threats. State associations for oncologists and administrators offer strong networking and update opportunities. Publications such as Oncology Practice Management, Value-Based Cancer Care, and others bring the outside world to your door or computer. Human nature is to hunker down when the weather gets fierce. The storms of change swirling around oncology practice administrators today demand a strong leader, one who will stand tall in that wind and set a new course for the group. It will not be easy, but it will happen. l
or appeal claims for callers, nor can it guarantee that you will be successful
VELCADE and Millennium are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners.
in obtaining reimbursement
Millennium Pharmaceuticals, Inc., Cambridge, MA 02139
*The VELCADE Reimbursement Assistance Program does not file claims
Copyright ÂŠ 2010, Millennium Pharmaceuticals, Inc. All rights reserved. Printed in USA
Cancer Center Business Summit
Understanding the 340B…Continued from the cover Rebate Program was created, in which drug manufacturers had to pay a rebate to Medicaid based in part on the manufacturer’s best price. Soon after, the 340B Drug Pricing Program was enacted into law. It established a maximum price similar to the Medicaid price in the rebate program. Under the 340B program, manufacturers that participate in Medicaid must make outpatient drugs available to covered entities as defined by the program. “In contrast to Medicaid, which is a rebate paid after the fact, here you have up-front discounts, and the manufacturers are precluded from selling the covered outpatient drugs to a covered entity for a price greater than a statutory ceiling price,” said Mr Geilfus.
Price Limits The maximum price that can be charged is based on the Medicaid rebate formula, but the discount is built into the manufacturer’s or the wholesaler’s selling price rather than being paid as a postpurchase rebate. For branded drugs, the 340B ceiling price is the lower of the manufacturer’s best price, or 15.1% off the drug’s average manufacturer price (AMP). Brand-name manufacturers must provide an additional discount on a covered outpatient drug if the price has increased faster than the rate of inflation. For generic and overthe-counter drugs, the 340B ceiling price is 11% off the AMP. “These are ceiling prices, and covered entities are free to negotiate prices that are lower than the 340B ceiling price,” said Mr Geilfus. The cost-savings are estimated to be 20% to 50% on prices otherwise achievable if 340B pricing is used. “You have the right to negotiate reduced prices, and the government has established a prime vendor program. A prime vendor involved can help you navigate it and help you
negotiate pricing with the drug manufacturer,” he pointed out. “The fact that you get your drug prices cheaper does not necessarily mean that that is all profit,” he said. A recent survey by the General Accounting Office showed that 60% of covered entities had received revenue that exceeded the drug-related costs.
“You have up-front discounts, and the manufacturers are precluded from selling the covered outpatient drugs to a covered entity for a price greater than a statutory ceiling price.” —C. Frederick Geilfus II, JD
Utilizing the Savings “One factor you’ll want to consider when you approach this is your reimbursement level, and how is that going to be affected when you get in the program,” Mr Geilfus warned. The 340B program does not specify how the savings are to be utilized. “You can use them to serve more patients, expand your formulary, expand available services, subsidize prescriptions, or you can use it in any other way,” he said. “The one caveat is that for a lot of the grant-funded covered entities, you may be required to use that surplus consistent with how the grant was provided.” Participation Criteria Eligibility for participation in the
ONCOLOGY PRACTICE MANAGEMENT
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340B program is strictly limited to the specific categories of entities specified in the statute. Before the Patient Protection and Affordable Care Act (ACA), typical entities eligible to receive 340B pricing were federally qualified health centers, Ryan White HIV/AIDS clinics, black lung clinics, Title X Family Planning clinics, state-operated AIDS drug assistance programs, disproportionate-share hospitals, and certain children’s hospitals. Newly eligible entities under the ACA are free-standing cancer hospitals, critical access hospitals, rural referral centers (with a disproportionate share >8%), sole community hospitals (with a disproportionate share >8%), and certain children’s hospitals. To be eligible for 340B drug pricing, free-standing cancer hospitals must meet the Centers for Medicare & Medicaid Services criteria for exclusion from the Medicare Prospective Payment System, and they must have a disproportionateshare adjustment of more than 11.75%. They must also be a government-owned, government-operated, or nonprofit hospital with a contract to provide services to low-income individuals. To avoid double discount, the hospital cannot acquire drugs under a group purchasing organization contract.
Filing an Application Hospitals are required to file an application to participate; they must notify the Office of Pharmacy Administration (OPA) of their intent to participate. The application needs to be filed the month before the quarter in which participation is intended. Once the OPA receives and processes the registration information, the covered entity is eligible to purchase pharmaceuticals at 340B pricing at the start of the next calendar quarter.
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Understanding the 340B…Continued from page 8 “One of the key compliance issues you need to worry about is that you can sell only to patients of covered entities; drugs cannot be diverted to patients of noncovered entities,” Mr Geilfus stated. Although the term “patient” is not defined, the US Health Resources and Services Administration has issued guidelines regarding the definition of a patient. According to these guidelines, to be considered a patient, the covered entity must maintain records of the individual’s healthcare, the responsibility for care must be with the covered entity, and the individual must receive healthcare services from the covered entity that are consistent with services for which grant fund-
ing or federally qualified health center look-alike status has been provided (disproportionate-share hospitals
“patients” if the only service they receive from the covered entity is the dispensing of drugs for self-adminis-
“You have the right to negotiate reduced prices, and the government has established a prime vendor program, [which] can help you navigate it and help you negotiate pricing with the drug manufacturer.” —C. Frederick Geilfus II, JD
are exempt from this requirement). Individuals are not considered
tration or administration in a home setting. l
N D New 55-YYYear di FFollow-up ll p Yeeaar M Median Data: 5-Year
In combination with MP* vs MP alone for previously untreated multiple myeloma
VELCADE DELIVERED 13-MONTH OVERALL SURVIVAL ADVANTAGE At 3-Year Median Follow-up, VELCADE® (bortezomib)+MP Provided an OS Advantage Over MP That Was Not Regained With Subsequent Therapies ▼ Of the 69% of MP patients who received subsequent therapies, 50% received VELCADE or a VELCADE-containing regimen1
VELCADE is indicated for the treatment of patients with multiple myeloma. VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. For Patient Assistance Information or Reimbursement Assistance, call 1-866-VELCADE (835-2233), Option 2, or visit VELCADE.com *Melphalan+prednisone. †
VISTA: a randomized, open-label, international phase 3 trial (N=682) evaluating the efficacy and safety of VELCADE in combination with MP vs MP in previously untreated multiple myeloma. The primary endpoint was TTP. Secondary endpoints were CR, ORR, PFS, and OS. At a pre-specified interim analysis (median follow-up 16.3 months), VcMP‡ resulted in significantly superior results for TTP, PFS, OS, and ORR. Further enrollment was halted and patients receiving MP were offered VELCADE in addition.
VELCADE (Vc) in combination with MP.
Reference: 1. Mateos M-V, Richardson PG, Schlag R, et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial. J Clin Oncol. 2010;28(13):2259-2266.
UPDATED VISTA† TRIAL ANALYSIS (60.1-MONTH MEDIAN FOLLOW-UP) 100 90
Median overall survival: survival:
556.4 6 .4 vs 443.1 3.11 m months onths
PPatients atients Sur Surviving viving (%)
HR=0.695 (95% CI, 0.57-0.85); P<0.05 P<0.05 <0 < 05 70 60 50 40 30 20
VELC ADE+MP (n=344) VELCADE+MP
MP ((n=338) n=338)
IMPORTANT SAFETY INFORMATION VELCADE Warnings and Precautions
▼ Women should avoid becoming pregnant while being treated with VELCADE. Pregnant women should be apprised of the potential harm to the fetus ▼ Peripheral neuropathy, including severe cases, may occur— manage with dose modification or discontinuation. Patients with pre-existing severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment ▼ Hypotension can occur. Caution should be used when treating patients receiving antihypertensives, those with a history of syncope, and those who are dehydrated ▼ Patients with risk factors for, or existing heart disease, should be closely monitored ▼ Acute diffuse infiltrative pulmonary disease has been reported ▼ Nausea, diarrhea, constipation, and vomiting have occurred and may require use of antiemetic and antidiarrheal medications or fluid replacement ▼ Thrombocytopenia or neutropenia can occur; complete blood counts should be regularly monitored throughout treatment ▼ Tumor Lysis Syndrome, Reversible Posterior Leukoencephalopathy Syndrome, and Acute Hepatic Failure have been reported
Most commonly reported adverse reactions (incidence ≥30%) in clinical studies include asthenic conditions, diarrhea, nausea, constipation, peripheral neuropathy, vomiting, pyrexia, thrombocytopenia, psychiatric disorders, anorexia and decreased appetite, neutropenia, neuralgia, leukopenia, and anemia. Other adverse reactions, including serious adverse reactions, have been reported Please see Brief Summary for VELCADE on next page.
Brief Summary INDICATIONS:
ADVERSE EVENT DATA:
VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma. VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy.
Safety data from phase 2 and 3 studies of single-agent VELCADE 1.3 mg/m2/dose twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously treated multiple myeloma (N=1008, not including the phase 3, VELCADE plus DOXIL® [doxorubicin HCI liposome injection] study) and previously treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma.
CONTRAINDICATIONS: VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. WARNINGS AND PRECAUTIONS: VELCADE should be administered under the supervision of a physician experienced in the use of antineoplastic therapy. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory. However, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. Patients experiencing new or worsening peripheral neuropathy may require change in the dose and schedule of VELCADE. Following dose adjustments, improvement in or resolution of peripheral neuropathy was reported in 51% of patients with ≥Grade 2 peripheral neuropathy in the relapsed multiple myeloma study. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma. Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 13%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics. Cardiac Disorders: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have been reported, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart disease should be closely monitored. In the relapsed multiple myeloma study, the incidence of any treatmentemergent cardiac disorder was 15% and 13% in the VELCADE and dexamethasone groups, respectively. The incidence of heart failure events (acute pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock, pulmonary edema) was similar in the VELCADE and dexamethasone groups, 5% and 4%, respectively. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established. Pulmonary Disorders: There have been reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome (ARDS) in patients receiving VELCADE. Some of these events have been fatal. In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, a prompt comprehensive diagnostic evaluation should be conducted. Reversible Posterior Leukoencephalopathy Syndrome (RPLS): There have been reports of RPLS in patients receiving VELCADE. RPLS is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing RPLS, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing RPLS is not known. Gastrointestinal Adverse Events: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration. Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study, the incidence of significant bleeding events (≥Grade 3) was similar on both the VELCADE (4%) and dexamethasone (5%) arms. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. There have been reports of gastrointestinal and intracerebral hemorrhage in association with VELCADE. Transfusions may be considered. The incidence of febrile neutropenia was <1%. Tumor Lysis Syndrome: Because VELCADE is a cytotoxic agent and can rapidly kill malignant cells, the complications of tumor lysis syndrome may occur. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.
In the integrated analysis, the most commonly reported adverse events were asthenic conditions (including fatigue, malaise, and weakness); (64%), nausea (55%), diarrhea (52%), constipation (41%), peripheral neuropathy NEC (including peripheral sensory neuropathy and peripheral neuropathy aggravated); (39%), thrombocytopenia and appetite decreased (including anorexia); (each 36%), pyrexia (34%), vomiting (33%), anemia (29%), edema (23%), headache, paresthesia and dysesthesia (each 22%), dyspnea (21%), cough and insomnia (each 20%), rash (18%), arthralgia (17%), neutropenia and dizziness (excluding vertigo); (each 17%), pain in limb and abdominal pain (each 15%), bone pain (14%), back pain and hypotension (each 13%), herpes zoster, nasopharyngitis, upper respiratory tract infection, myalgia and pneumonia (each 12%), muscle cramps (11%), and dehydration and anxiety (each 10%). Twenty percent (20%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (5%) and neutropenia (3%). A total of 50% of patients experienced serious adverse events (SAEs) during the studies. The most commonly reported SAEs included pneumonia (7%), pyrexia (6%), diarrhea (5%), vomiting (4%), and nausea, dehydration, dyspnea and thrombocytopenia (each 3%). In the phase 3 VELCADE + melphalan and prednisone study, the safety profile of VELCADE in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone. The most commonly reported adverse events in this study (VELCADE+melphalan/ prednisone vs melphalan/prednisone) were thrombocytopenia (52% vs 47%), neutropenia (49% vs 46%), nausea (48% vs 28%), peripheral neuropathy (47% vs 5%), diarrhea (46% vs 17%), anemia (43% vs 55%), constipation (37% vs 16%), neuralgia (36% vs 1%), leukopenia (33% vs 30%), vomiting (33% vs 16%), pyrexia (29% vs 19%), fatigue (29% vs 26%), lymphopenia (24% vs 17%), anorexia (23% vs 10%), asthenia (21% vs 18%), cough (21% vs 13%), insomnia (20% vs 13%), edema peripheral (20% vs 10%), rash (19% vs 7%), back pain (17% vs 18%), pneumonia (16% vs 11%), dizziness (16% vs 11%), dyspnea (15% vs 13%), headache (14% vs 10%), pain in extremity (14% vs 9%), abdominal pain (14% vs 7%), paresthesia (13% vs 4%), herpes zoster (13% vs 4%), bronchitis (13% vs 8%), hypokalemia (13% vs 7%), hypertension (13% vs 7%), abdominal pain upper (12% vs 9%), hypotension (12% vs 3%), dyspepsia (11% vs 7%), nasopharyngitis (11% vs 8%), bone pain (11% vs 10%), arthralgia (11% vs 15%) and pruritus (10% vs 5%). DRUG INTERACTIONS: Bortezomib is a substrate of cytochrome P450 enzyme 3A4, 2C19 and 1A2. Co-administration of ketoconazole, a strong CYP3A4 inhibitor, increased the exposure of bortezomib by 35% in 12 patients. Therefore, patients should be closely monitored when given bortezomib in combination with strong CYP3A4 inhibitors (e.g. ketoconazole, ritonavir). Co-administration of omeprazole, a strong inhibitor of CYP2C19, had no effect on the exposure of bortezomib in 17 patients. Co-administration of rifampin, a strong CYP3A4 inducer, is expected to decrease the exposure of bortezomib by at least 45%. Because the drug interaction study (n=6) was not designed to exert the maximum effect of rifampin on bortezomib PK, decreases greater than 45% may occur. Efficacy may be reduced when VELCADE is used in combination with strong CYP3A4 inducers; therefore, concomitant use of strong CYP3A4 inducers is not recommended in patients receiving VELCADE. St. John’s Wort (Hypericum perforatum) may decrease bortezomib exposure unpredictably and should be avoided. Co-administration of dexamethasone, a weak CYP3A4 inducer, had no effect on the exposure of bortezomib in 7 patients. Co-administration of melphalan-prednisone increased the exposure of bortezomib by 17% in 21 patients. However, this increase is unlikely to be clinically relevant. USE IN SPECIFIC POPULATIONS: Nursing Mothers: It is not known whether bortezomib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VELCADE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: The safety and effectiveness of VELCADE in children has not been established. Geriatric Use: No overall differences in safety or effectiveness were observed between patients ≥age 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out. Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, the drug should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer’s prescribing information. Patients with Hepatic Impairment: The exposure of VELCADE is increased in patients with moderate and severe hepatic impairment. Starting dose should be reduced in those patients. Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication.
Please see full Prescribing Information for VELCADE at VELCADE.com.
Hepatic Events: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic events include increases in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible upon discontinuation of VELCADE. There is limited re-challenge information in these patients. Hepatic Impairment: VELCADE is metabolized by liver enzymes. VELCADE exposure is increased in patients with moderate or severe hepatic impairment. These patients should be treated with VELCADE at reduced starting doses and closely monitored for toxicities. Use in Pregnancy: Pregnancy Category D. Women of childbearing potential should avoid becoming pregnant while being treated with VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses.
VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners. Millennium Pharmaceuticals, Inc., Cambridge, MA 02139 Copyright © 2011, Millennium Pharmaceuticals, Inc. All rights reserved. Printed in USA
Cancer Center Business Summit
Ultimate Goal in Selling a Practice Is to Reach a Collaborative Agreement By Wayne Kuznar
Chicago, IL—“Practice acquisitions have many nuts and bolts components beyond regulatory issues, including the type of purchase (asset or stock purchase) and physician compensation structure,” said Alan H. Einhorn, of Foley and Lardner, LLP, Boston, at the Cancer Center Business Summit. Acquisitions can be either a stock or an asset deal. “In a stock deal, you’re buying stock and all the liabilities, you’re buying the entity. In an asset deal, you are not buying the entity. The practice entity is left behind, but you’re buying specific assets and liabilities,” Mr Einhorn said. Most buyers prefer to purchase assets to limit their liability exposure and because it is easier to be selective with the assets. Because the buyer generally has a greater exposure to liability in a stock deal, the purchaser may want to create a special escrow for indemnification. “Sellers obviously like to limit escrows and indemnification; that is part of the negotiating process,” Mr Einhorn noted. In asset purchases, clinical and nonclinical staff typically become employees and/or leased employees of the hospital or health system clinic that purchased the assets. Physician employees are compensated at fair market value in Stark Law–compliant employment arrangements. Physicians can also remain employed by the physician practice and enter into a long-term professional services agreement for fair market value compensation. This
arrangement will also require contracts that define the duration of the agreement. Termination rights and the basis for termination are also important factors. Termination provisions may relate to material changes in payment methodologies as global payments and bundling enter the market, potentially changing the terms for fair market value.
address with the buyer, is whether there will be any antidilution protection,” Mr Einhorn explained. “In other words, will you be protected in case your practice erodes somewhat, particularly in Stark? And what happens if the buyer brings on new physicians that may also erode your ability to generate RVUs?” What role the physician will play in governance is another question. “This is a factor for both the hospital and the physician,” he said. “Will physicians have a meaningful say in the service line or how the market practice will operate postclosing? Will they have a role in determining the strategic plan or in determining the budget?” Other considerations in the transaction are: • Will there be a comanagement agreement associated with the transaction? • Will the seller have a right of first opportunity at the hospital once it sets up a new site, and will the seller have the opportunity to participate? • Will there be a noncompete agreement, and if so, what will it cover (ie, which services, the geography, the duration, will there be a basis for terminating the noncompete agreement)? • Will there be an unwind? If an unwind does occur, it generally means that the professional services agreement terminates. The right to purchase your assets back at fair market value can also be part of that unwind. l
“If the compensation is on an RVU or productivity basis, one of the things you’ll want to consider as a physician, and you’ll have to address with the buyer, is whether there will be any antidilution protection.” —Alan H. Einhorn
The basis for physician compensation—fixed fee, relative value unit (RVU); fixed fee plus productivity— will also need to be negotiated. “If the compensation is on an RVU or productivity basis, one of the things you’ll want to consider as a physician, and you’ll have to
Cancer Center Business Summit
Oncology Practice Trends: Operating Margins Will Continue to Decline, Alternatives to Fee-for-Service Gain Traction By Wayne Kuznar
Chicago, IL—Community oncology practices can expect a continuing decrease in operating margins, a slowing of the gains in business and clinical operating efficiencies, and rising labor costs. In addition, chemotherapy drug margins will shrink. As a result, current business models of oncology practices may be difficult to maintain, said Thomas R. Barr, MBA, General Manager at Oncology Metrics, speaking at the Cancer Center Business Summit in Chicago. Mr Barr reported oncology practice trends based on a period of more than 6 years (from 2005 to 2010), reflecting data in surveys of approximately 1400 oncology practices across the country. In providing a historical perspective of practice revenue and operating costs, Mr Barr described a stable period of operating margins between 1991 and 2003. During this time, several trends became apparent: • Infusions migrated out of the hospital and into the office • The number of specialty distributors of drugs increased • Antiemetics and growth factors began to define supportive care • Drug spending per hematologist/ oncologist steadily increased • Reimbursement from Medicare was governed by average wholesale price (AWP) • The total revenue and total operating costs steadily diverged, leading to “free cash” accumulation. “The period also saw an increase in oncology aggregators (eg, OnCare, Texas Oncology, Physician Reliance Network) that wanted to aggregate
oncologists into larger groups,” said Mr Barr. Then came the Medicare Modernization Act of 2004-2006, which changed the reimbursement methodology for chemotherapy drugs, replacing AWP with average sales price as an index for payment. “That
Community oncology practices will have to prepare for the future. The margins on drugs and diagnostics will continue to fall, and diagnostics and ancillary services will take on greater importance. —Thomas R. Barr, MBA
launched a period of instability,” said Mr Barr. “We saw that our top line revenue continued to rise during the initial years of the Medicare Modernization Act, and we saw that our drug spending really spiked upward.” The “squeeze” came in 2007, according to Mr Barr, when the curves for total medical revenues and total operating costs started to converge. “For the very first time, we saw the drug spend for medical
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I February 2012
oncologists go down, and they went down sharply,” he said. “This was a time when we had increased payer information requirements.” The squeeze is driven by demographics, as Medicare has assumed the role as essential payer, Mr Barr suggests. The number of Medicare enrollees, which was 34 million in 2000, is expected to explode over the next 20 years, reaching 68 million by 2030. These demographic changes have resulted in a huge spending increase—from $408.3 billion in 2006 to an expected $862.5 billion in 2016.
Future Trends in Oncology Practice Mr Barr listed several trends that are most likely to continue: The squeeze will persist for oncology practices. Total medical revenue will decline “because we’re not getting paid as well as we have in the past for the services that we provide,” he said. “Drug revenue will continue to increase but not as fast as the money spent to buy those drugs.” The result is a narrowing drug margin, which has already fallen from 22% in 2005 to 9% in 2010.
The pace of efficiency improvement falters. Much of the improvement in efficiency in the past was a result of inventory reduction. “We used to have a lot of drugs on the shelf, now we don’t have many drugs on the shelf,” said Mr Barr. An acceleration in collections also contributed to an improved efficiency, but the resulting increase in Continued on page 18
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Cancer Center Business Summit
An Array of Compensation Models to Align Oncologists’ and Hospitals’ Interests By Wayne Kuznar
Chicago, IL—Comanagement arrangements between hospitals and physicians must be structured properly to avoid violation of federal healthcare statutes and regulations. The basic principles of comanagement agreements were covered during a session on compensation models to align hospital and oncologist interests delivered at the 2011 Cancer Center Business Summit. A comanagement agreement differs from hospital employment of a physician in that in a comanagement agreement both entities usually have shared involvement in daily operations of a service line. This definition can vary and will depend on a review of appropriateness by legal counsel, according to Terri U. Guidi, MBA, FAAMA, President and CEO, Oncology Management Consulting Group, and editorial advisory board member of Oncology Practice Management. The hospital usually pays physicians a fixed-base rate plus a performance-based bonus, but the performance cannot be tied to volume of business, charges, or revenue, said Ms Guidi. Base compensation covers the management of the service line, such as oversight of operations, leadership, and development and implementation of strategy. Performance incentives reward the leadership of the service line to specified targets or goals that may be based on the overall growth of the program or improvements in operational efficiencies (ie, staffing cost per new patient encounter to encourage physicians to staff more efficiently), budget performance, and quality indicators (ie, creating quality pro-
grams or meeting quality targets). “A lot of issues pertain to those who are thinking long-term. You
“A lot of issues pertain to those who are thinking long-term. You have a target to improve operational efficiency by x percent. Each year you need to reestablish those targets. How much more can you improve something before it becomes a meaningless measure?” —Terri U. Guidi, MBA, FAAMA
have a target to improve operational efficiency by x percent. Each year you need to reestablish those tar-
ONCOLOGY PRACTICE MANAGEMENT
I February 2012
gets,” she said. “How much more can you improve something before it becomes a meaningless measure?” Targets must be measurable and reproducible, with an established baseline. “If you don’t get reports that measure operational efficiency, don’t put it in there as a measure or you can spend months just trying to figure it out,” said Ms Guidi. The payment for a medical directorship may be a stipend or another arrangement but there must be a means of justifying the payment through defined duties or time and effort expended. The duties must not duplicate other arrangements. “Using incentives for a medical directorship are extremely rare, and it is very difficult,” she said. Compensation parameters for clinical research oversight are similar to those for a medical directorship. The bottom line is to “compensate physicians for what they’re actually doing at a reasonable value and you should be fine,” said Ms Guidi.
Service Line Staffing If a practice is going to provide staff to the hospital, a key consideration is whether the hospital is going to manage all or some of the service line or whether it will be outsourced to a capable entity. Oncology practices usually have the experienced staff to operate outpatient oncology services, said Ronald Barkley, MS, JD, Managing Director, Cancer Center Business Development Group, and editorial advisory board member of Oncology Practice Management. Examples of programs for which the practice would assume responsibility are billing and collections, Continued on page 18
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EDUCATIONAL OBJECTIVES • Discuss the current trends and challenges facing all stakeholders in optimizing value in cancer care delivery • Define the barriers associated with cost, quality, and access as it relates to healthcare reform and what solutions are currently being considered • Compare and contrast the different approaches/tools that providers and payers are utilizing to manage and deliver care collaboratively • Examine the current trends in personalized care and companion diagnostics • Analyze the patient issues around cost, quality, and access to care
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Cancer Center Business Summit
An Array of Compensation…Continued from page 16 implementing and managing pathways programs, implementing and managing quality oncology practice initiative (QOPI) programs, and implementing and managing an oncology medical home. For service line billing and collections, a typical compensation of staff members ranges from 4% to 6% of collections. “It’s probably one of the most difficult management services to implement at the hospital because you have a tremendous amount of issues around information technology and identifying best classes of services so that it fits in with the hospital’s level of admission,” Mr Barkley said. “When it can be accomplished, the lion’s share of the billing collection responsibility lies with the practice billing personnel that are familiar with the codes.” Rather than have the staff change employers (from the practice to the hospital), the staff can be leased. In such cases, it is typical for compensation to be structured as payroll plus a 5% to 10% management premium.
Two approaches to managing clinical pathways programs are the for-
“It’s probably one of the most difficult management services to implement at the hospital because you have a tremendous amount of issues around information technology and identifying best classes of services so that it fits in with the hospital’s level of admission.” —Ronald Barkley, MS, JD
mation of practice disease committees to refine guidelines (such as
those from the National Comprehensive Cancer Network) and the purchase of turn-key pathway programs from providers as a “plug-in” to hospital services, said Mr Barkley. The most common approach to compensating physicians for developing and managing pathways programs with a hospital service line is in the $40,000 range annually. The QOPI has been established by the American Society of Clinical Oncology and has 89 oncology-specific measures that can also serve as a plug-in for the hospital service line. Such a program can be established by different hospitals. Compensation for managing such a program is typically about $100,000 annually. The oncology medical home is a developing model that is designed to aggressively manage symptoms, with resulting reductions in emergency department visits, hospitalizations, and drug costs. Health plans are actively experimenting with oncology medical home payment methodologies with enhanced payment to participating providers. l
Oncology Practice Trends: Operating Margins Will Continue to Decline…Continued from page 14 cash flow was probably a one-time event. Bad debt also decreased as unfunded care in the community practice setting declined, but this trend “can’t be taken a whole lot further.”
Service delivery per hematologist/oncologist has peaked and that stability in the number of visits per hematologist/oncologist has already occurred.
Labor costs will increase faster than revenue as the number of full-time employees increases, which is not being driven by service demand. “Staff will be added to deal with things that don’t generate revenue,” he said. As change occurs, community oncology practices will have to prepare for the future, according to Mr Barr. The margins on drugs and diagnostics will continue to fall, and
ONCOLOGY PRACTICE MANAGEMENT
I February 2012
diagnostics and ancillary services will take on greater importance. “As we look to the future, we don’t see fee-for-service dying: it may be a small and lingering death that will take a while,” he said. “Private payer programs are out there, and they may have some traction in some markets, but Medicare will be the game changer, although the rescue could take years.” l
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Cancer Center Business Summit
Know the Federal Laws that Apply to Buying and Selling Oncology Practices By Wayne Kuznar
Chicago, IL—Financial relationships between hospitals and physicians after acquisition of practices must comply with the federal antikickback statute and physician selfreferral laws (Stark Law). Legal and regulatory considerations in practice acquisitions were offered by Alan H. Einhorn, of counsel with Foley and Lardner, LLP, Boston, at the 2011 Cancer Center Business Summit. Awareness of antikickback statutes and safe harbors is a must. Antikickback statutes prohibit the knowing and willful payment to induce one party to refer to another for items and services covered by a federal healthcare program. Penalties can be up to $25,000 for each violation. Safe harbors can provide immunity for certain practice acquisition arrangements, Mr Einhorn said, but most practice acquisitions are not safe-harbored. In the case of hospitals acquiring practices, safe harbors are sales completed within 3 years, where a seller is not in a position to refer after the sale completion and there are diligent and good faith efforts by the purchaser to recruit a successor within 1 year to take over the practice. Failure to satisfy a safe harbor does not mean that the statute is violated. If a safe harbor is not met, the question is whether the purchase price is a disguised kickback from the buyer (overpayment) or the seller (underpayment) to induce referrals after the sale. “Valuation is key,” said Mr Einhorn. “To help negate any inference of improper intent, the parties should obtain an independent fair market value appraisal.” Fair market value is defined as the
value in arm’s-length transactions consistent with the general market value. This value is the price that an asset would bring as the result of bona fide bargaining between wellinformed buyers and sellers who are not otherwise in a position to gener-
“Valuation is key. To help negate any inference of improper intent, the parties should obtain an independent fair market value appraisal.” —Alan H. Einhorn
ate business for the other party at the time of the acquisition or service agreement. The 3 approaches to valuing physician practices are market, cost, and income, according to James R. Hills, CPA/ABV, Partner at Health-
ONCOLOGY PRACTICE MANAGEMENT
I February 2012
Care Appraisers, in Chicago. All 3 are valid, Mr Hills said, but a market approach is generally of little value because of the lack of comparability and reliable data. A cost approach restates the entity’s balance sheet, specifically the identified intangible assets, such as the workforce in place. An income approach discounts (or capitalizes) expected future cash flows to the buyer. The Office of the Inspector General (OIG) views with suspicion payments for intangibles that reflect past or future referrals or are affected by the expectation of a certain volume of business. In a letter concerning the application of Medicare and Medicaid antikickback statute 42 U.S.C. 1320a-7b(b), the OIG noted that specific items that could raise a question as to whether a payment reflects the value of a referral stream includes payment for: 1. Goodwill 2. Value of ongoing business unit 3. Covenants not to compete 4. Exclusive dealing agreements 5. Patient lists or patient records.
The Stark Law The Stark Law prohibits a physician from making referrals for Medicare-reimbursable designated health services to an entity with which he or she (or an immediate family member) has a financial relationship, unless an exception applies. Penalties for Stark violations can be payment denial or recoupment by Medicare and Medicaid, as well as civil monetary penalties of up to $15,000 per the prohibited service or billing. Financial relationships include both ownership/investment interests and compensation relationships.
Cancer Center Business Summit
Know the Federal Laws…Continued from page 20 If a physician has a financial relationship with a designated health services entity, he or she cannot refer to it for Medicare-covered designated health services, and the entity cannot bill for the referred services, unless an exception applies. “Acquisitions of physician practices create a financial relationship that will prohibit referrals to the hospital buyer, unless a Stark exception applies,” Mr Einhorn said. One requirement for an isolated transaction exception is that aggregate payments be fixed in advance and the amount of remuneration is consistent with fair market value of the transaction, similar to the valuation issues under the antikickback
statute. Furthermore, “remuneration can’t take into account volume,” Mr Einhorn said.
postclosing adjustments can occur for 6 months after the acquisition. Any associated transactions, such
“Acquisitions of physician practices create a financial relationship that will prohibit referrals to the hospital buyer, unless a Stark exception applies.” —Alan H. Einhorn
Remuneration must be commercially reasonable and absent of any referrals. Only Stark-excepted transactions and commercially reasonable
as employment, consultations, or lease agreements, must also meet a Stark exception. “All rely heavily on fair market value,” Mr Einhorn added. l
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Indication ZOMETA (zoledronic acid) 4 mg/5 mL Injection is indicated for the treatment of patients with multiple myeloma and documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer should have progressed after treatment with at least one hormonal therapy.
Important Safety Information ZOMETA is contraindicated in patients with hypersensitivity to zoledronic acid or any components of ZOMETA. Hypersensitivity reactions, including rare cases of urticaria and angioedema, and very rare cases of anaphylactic reaction/shock, have been reported. Patients being treated with ZOMETA should not be treated with Reclast® (zoledronic acid) as they contain the same active ingredient. In patients with impaired renal function, the risk of adverse reactions (especially renal adverse reactions) may be greater. ZOMETA treatment is not recommended in patients with bone metastases with severe renal impairment. Preexisting renal insufficiency and multiple cycles of ZOMETA and other bisphosphonates are risk factors for subsequent renal deterioration with ZOMETA. Do not use doses greater than 4 mg. ZOMETA should be administered by IV infusion over no less than 15 minutes. Monitor serum creatinine before each dose. Osteonecrosis of the jaw (ONJ) has been reported predominantly in cancer patients treated with intravenous bisphosphonates, including ZOMETA. Many of these patients were also receiving chemotherapy and corticosteroids, which may be risk factors for ONJ. Postmarketing experience and the literature suggest a greater frequency of reports of ONJ based on tumor type (advanced breast cancer, multiple myeloma) and dental status (dental extraction, periodontal disease, local trauma, including poorly fitting dentures). Many reports of ONJ involved patients with signs of local infection, including osteomyelitis. Cancer patients should maintain good oral hygiene and should have a dental examination with preventive dentistry prior to treatment with bisphosphonates. While on treatment, these patients should avoid invasive dental procedures, if possible, as recovery may be prolonged. For patients who develop ONJ while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of ONJ. A causal relationship between bisphosphonate use and ONJ has not been established. Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment. ZOMETA should not be used during pregnancy. Women of childbearing potential should be advised to avoid becoming pregnant. If the patient becomes pregnant or plans to breast-feed while taking this drug, the patient should be apprised of the potential harm to the fetus or baby. In postmarketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates including ZOMETA. Discontinue use if severe symptoms develop, and a subset of patients had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate. There have been reports of bronchoconstriction in aspirin sensitive patients receiving bisphosphonates. The most common adverse events (≥15%) in bone metastases clinical trials, regardless of causality, with ZOMETA 4 mg (n=1031) were as follows: bone pain (55%), nausea (46%), fatigue (39%), anemia (33%), pyrexia (32%), vomiting (32%), constipation (31%), dyspnea (27%), diarrhea (24%), weakness (24%), myalgia (23%), anorexia (22%), cough (22%), arthralgia (21%), lowerlimb edema (21%), malignant neoplasm aggravated (20%), headache (19%), dizziness (excluding vertigo) (18%), insomnia (16%), decreased weight (16%), back pain (15%), and paresthesia (15%). Patients should also be made aware of the potential for abdominal pain. Ocular adverse events may occur with bisphosphonates, including ZOMETA. Cases of uveitis, scleritis, episcleritis, conjunctivitis, iritis, and orbital inflammation including orbital edema have been reported during postmarketing use. In some cases, symptoms resolved with topical steroids. Caution is advised when bisphosphonates, including ZOMETA, are administered with aminoglycosides, loop diuretics, and potentially nephrotoxic drugs. Patients should be administered an oral calcium supplement of 500 mg and a multiple vitamin containing 400 IU of vitamin D daily. Please see the brief summary of full Prescribing Information on the following pages.
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Zometa® (zoledronic acid) Injection Concentrate for Intravenous Infusion Initial U.S. Approval: 2001
Cancer patients should maintain good oral hygiene and should have a dental examination with preventive dentistry prior to treatment with bisphosphonates.
BRIEF SUMMARY: Please see package insert for full prescribing information.
While on treatment, these patients should avoid invasive dental procedures if possible. For patients who develop ONJ while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of ONJ. Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment [see Adverse Reactions (6.2)].
1 INDICATIONS AND USAGE 1.1 Hypercalcemia of Malignancy Zometa is indicated for the treatment of hypercalcemia of malignancy defined as an albumin-corrected calcium (cCa) of >12 mg/dL [3.0 mmol/L] using the formula: cCa in mg/dL=Ca in mg/dL + 0.8 (4.0 g/dL - patient albumin (g/dL)). 1.2 Multiple Myeloma and Bone Metastases of Solid Tumors Zometa is indicated for the treatment of patients with multiple myeloma and patients with documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer should have progressed after treatment with at least one hormonal therapy. 1.3 Important Limitation of Use The safety and efficacy of Zometa in the treatment of hypercalcemia associated with hyperparathyroidism or with other nontumor-related conditions has not been established. 4 CONTRAINDICATIONS 4.1 Hypersensitivity to Zoledronic Acid or Any Components of Zometa Hypersensitivity reactions including rare cases of urticaria and angioedema, and very rare cases of anaphylactic reaction/shock have been reported [see Adverse Reactions (6.2)]. 5 WARNINGS AND PRECAUTIONS 5.1 Drugs with Same Active Ingredient Zometa contains the same active ingredient as found in Reclast® (zoledronic acid). Patients being treated with Zometa should not be treated with Reclast. 5.2 Hydration and Electrolyte Monitoring Patients with hypercalcemia of malignancy must be adequately rehydrated prior to administration of Zometa. Loop diuretics should not be used until the patient is adequately rehydrated and should be used with caution in combination with Zometa in order to avoid hypocalcemia. Zometa should be used with caution with other nephrotoxic drugs. Standard hypercalcemia-related metabolic parameters, such as serum levels of calcium, phosphate, and magnesium, as well as serum creatinine, should be carefully monitored following initiation of therapy with Zometa. If hypocalcemia, hypophosphatemia, or hypomagnesemia occur, short-term supplemental therapy may be necessary. 5.3 Renal Impairment Zometa is excreted intact primarily via the kidney, and the risk of adverse reactions, in particular renal adverse reactions, may be greater in patients with impaired renal function. Safety and pharmacokinetic data are limited in patients with severe renal impairment and the risk of renal deterioration is increased [see Adverse Reactions (6.1)]. Preexisting renal insufficiency and multiple cycles of Zometa and other bisphosphonates are risk factors for subsequent renal deterioration with Zometa. Factors predisposing to renal deterioration, such as dehydration or the use of other nephrotoxic drugs, should be identified and managed, if possible. Zometa treatment in patients with hypercalcemia of malignancy with severe renal impairment should be considered only after evaluating the risks and benefits of treatment. In the clinical studies, patients with serum creatinine >400 µmol/L or >4.5 mg/dL were excluded. Zometa treatment is not recommended in patients with bone metastases with severe renal impairment. In the clinical studies, patients with serum creatinine >265 µmol/L or >3.0 mg/dL were excluded and there were only 8 of 564 patients treated with Zometa 4 mg by 15-minute infusion with a baseline creatinine >2 mg/dL. Limited pharmacokinetic data exists in patients with creatinine clearance <30 mL/min [see Clinical Pharmacology (12.3) in the full prescribing information]. 5.4 Osteonecrosis of the Jaw Osteonecrosis of the jaw (ONJ) has been reported predominantly in cancer patients treated with intravenous bisphosphonates, including Zometa. Many of these patients were also receiving chemotherapy and corticosteroids which may be risk factors for ONJ. Postmarketing experience and the literature suggest a greater frequency of reports of ONJ based on tumor type (advanced breast cancer, multiple myeloma), and dental status (dental extraction, periodontal disease, local trauma including poorly fitting dentures). Many reports of ONJ involved patients with signs of local infection including osteomyelitis.
5.5 Pregnancy Zometa should not be used during pregnancy. Zometa may cause fetal harm when administered to a pregnant woman. In reproductive studies in the pregnant rat, subcutaneous doses equivalent to 2.4 or 4.8 times the human systemic exposure (an IV dose if 4 mg based on an AUC comparison) resulted in pre- and postimplantation losses, decreases in viable fetuses and fetal skeletal, visceral, and external malformations. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use In Specific Populations (8.1)]. 5.6 Musculoskeletal Pain In postmarketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates. This category of drugs includes Zometa. The time to onset of symptoms varied from one day to several months after starting the drug. Discontinue use if severe symptoms develop. Most patients had relief of symptoms after stopping. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate [see Adverse Reactions (6.2)]. 5.7 Patients with Asthma While not observed in clinical trials with Zometa, there have been reports of bronchoconstriction in aspirin sensitive patients receiving bisphosphonates. 5.8 Hepatic Impairment Only limited clinical data are available for use of Zometa to treat hypercalcemia of malignancy in patients with hepatic insufficiency, and these data are not adequate to provide guidance on dosage selection or how to safely use Zometa in these patients. 6 ADVERSE REACTIONS 6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Hypercalcemia of Malignancy The safety of Zometa was studied in 185 patients with hypercalcemia of malignancy (HCM) who received either Zometa 4 mg given as a 5-minute intravenous infusion (n=86) or pamidronate 90 mg given as a 2-hour intravenous infusion (n=103). The population was aged 33-84 years, 60% male and 81% Caucasian, with breast, lung, head and neck, and renal cancer as the most common forms of malignancy. NOTE: pamidronate 90 mg was given as a 2-hour intravenous infusion. The relative safety of pamidronate 90 mg given as a 2-hour intravenous infusion compared to the same dose given as a 24-hour intravenous infusion has not been adequately studied in controlled clinical trials. Renal Toxicity Administration of Zometa 4 mg given as a 5-minute intravenous infusion has been shown to result in an increased risk of renal toxicity, as measured by increases in serum creatinine, which can progress to renal failure. The incidence of renal toxicity and renal failure has been shown to be reduced when Zometa 4 mg is given as a 15-minute intravenous infusion. Zometa should be administered by intravenous infusion over no less than 15 minutes [see Warnings And Precautions (5) and Dosage And Administration (2) in the full prescribing information]. The most frequently observed adverse events were fever, nausea, constipation, anemia, and dyspnea (see Table 3). Table 3 provides adverse events that were reported by 10% or more of the 189 patients treated with Zometa 4 mg or Pamidronate 90 mg from the two HCM trials. Adverse events are listed regardless of presumed causality to study drug.
Table 3: Percentage of Patients with Adverse Events ≥10% Reported in Hypercalcemia of Malignancy Clinical Trials by Body System
Patients Studied Total No. of Patients Studied Total No. of Patients with any AE Body as a Whole Fever Progression of Cancer Cardiovascular Hypotension Digestive Nausea Constipation Diarrhea Abdominal Pain Vomiting Anorexia Hemic and Lymphatic System Anemia Infections Moniliasis Laboratory Abnormalities Hypophosphatemia Hypokalemia Hypomagnesemia Musculoskeletal Skeletal Pain Nervous Insomnia Anxiety Confusion Agitation Respiratory Dyspnea Coughing Urogenital Urinary Tract Infection
Zometa 4 mg n (%)
Pamidronate 90 mg n (%)
86 (100) 81 (94)
103 (100) 95 (92)
Grade 4 Laboratory Parameter
Serum Creatinine1 Hypocalcemia2 Hypophosphatemia3 Hypomagnesemia4
Zometa 4 mg
Pamidronate 90 mg
0/86 0/86 1/70 0/71
— — (1%) —
1/100 0/100 4/81 1/84
(1%) — (5%) (1%)
3 (>3x Upper Limit of Normal); Grade 4 (>6x Upper Limit of Normal) 3 (<7 mg/dL); Grade 4 (<6 mg/dL) 3Grade 3 (<2 mg/dL); Grade 4 (<1 mg/dL) 4Grade 3 (<0.8 mEq/L); Grade 4 (<0.5 mEq/L) 2Grade
25 23 15 14 12 8
(29) (27) (17) (16) (14) (9)
28 13 17 13 17 14
(27) (13) (17) (13) (17) (14)
11 10 9
(13) (12) (11)
2 16 5
(2) (16) (5)
13 12 11 11
(15) (14) (13) (13)
10 8 13 8
(10) (8) (13) (8)
Multiple Myeloma and Bone Metastases of Solid Tumors The safety analysis includes patients treated in the core and extension phases of the trials. The analysis includes the 2,042 patients treated with Zometa 4 mg, pamidronate 90 mg, or placebo in the three controlled multicenter bone metastases trials, including 969 patients completing the efficacy phase of the trial, and 619 patients that continued in the safety extension phase. Only 347 patients completed the extension phases and were followed for 2 years (or 21 months for the other solid tumor patients). The median duration of exposure for safety analysis for Zometa 4 mg (core plus extension phases) was 12.8 months for breast cancer and multiple myeloma, 10.8 months for prostate cancer, and 4.0 months for other solid tumors.
Table 6 describes adverse events that were reported by ≥10% of patients. Adverse events are listed regardless of presumed causality to study drug.
The following adverse events from the two controlled multicenter HCM trials (n=189) were reported by a greater percentage of patients treated with Zometa 4 mg than with pamidronate 90 mg and occurred with a frequency of greater than or equal to 5% but less than 10%. Adverse events are listed regardless of presumed causality to study drug: Asthenia, chest pain, leg edema, mucositis, dysphagia, granulocytopenia, thrombocytopenia, pancytopenia, nonspecific infection, hypocalcemia, dehydration, arthralgias, headache and somnolence. Rare cases of rash, pruritus, and chest pain have been reported following treatment with Zometa. Acute Phase Reaction-like Events Symptoms consistent with acute phase reaction (APR) can occur with intravenous bisphosphonate use. Fever has been the most commonly associated symptom, occurring in 44% of patients treated with Zometa 4 mg and 33% of patients treated with Pamidronate 90 mg. Occasionally, patients experience a flu-like syndrome consisting of fever, chills, flushing, bone pain and/or arthralgias, and myalgias. Mineral and Electrolyte Abnormalities Electrolyte abnormalities, most commonly hypocalcemia, hypophosphatemia and hypomagnesemia, can occur with bisphosphonate use. Grade 3 and Grade 4 laboratory abnormalities for serum creatinine, serum calcium, serum phosphorus, and serum magnesium observed in two clinical trials of Zometa in patients with HCM are shown in Table 4 and 5. Table 4: Grade 3 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Two Clinical Trials in Patients with HCM Grade 3 Laboratory Parameter
Serum Creatinine1 Hypocalcemia2 Hypophosphatemia3 Hypomagnesemia4
Table 5: Grade 4 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Two Clinical Trials in Patients with HCM
Zometa 4 mg
Pamidronate 90 mg
2/86 1/86 36/70 0/71
(2%) (1%) (51%) —
3/100 2/100 27/81 0/84
(3%) (2%) (33%) —
Injection Site Reactions Local reactions at the infusion site, such as redness or swelling, were observed infrequently. In most cases, no specific treatment is required and the symptoms subside after 24-48 hours. Ocular Adverse Events Ocular inflammation such as uveitis and scleritis can occur with bisphosphonate use, including Zometa. No cases of iritis, scleritis or uveitis were reported during these clinical trials. However, cases have been seen in postmarketing use [see Adverse Reactions (6.2)].
Table 6: Percentage of Patients with Adverse Events ≥10% Reported in Three Bone Metastases Clinical Trials by Body System Zometa 4 mg n (%) Patients Studied Total No. of Patients 1031 (100) Total No. of Patients with any AE 1015 (98) Blood and Lymphatic Anemia 344 (33) Neutropenia 124 (12) Thrombocytopenia 102 (10) Gastrointestinal Nausea 476 (46) Vomiting 333 (32) Constipation 320 (31) Diarrhea 249 (24) Abdominal Pain 143 (14) Dyspepsia 105 (10) Stomatitis 86 (8) Sore Throat 82 (8) General Disorders and Administration Site Fatigue 398 (39) Pyrexia 328 (32) Weakness 252 (24) Edema Lower Limb 215 (21) Rigors 112 (11) Infections Urinary Tract Infection 124 (12) Upper Respiratory Tract Infection 101 (10) Metabolism Anorexia 231 (22) Weight Decreased 164 (16) Dehydration 145 (14) Appetite Decreased 130 (13)
Pamidronate 90 mg n (%)
556 (100) 548 (99)
455 (100) 445 (98)
175 (32) 83 (15) 53 (10)
128 (28) 35 (8) 20 (4)
266 183 162 162 81 74 65 61
(48) (33) (29) (29) (15) (13) (12) (11)
171 122 174 83 48 31 14 17
(38) (27) (38) (18) (11) (7) (3) (4)
240 172 108 126 62
(43) (31) (19) (23) (11)
130 89 114 84 28
(29) (20) (25) (19) (6)
50 (9) 82 (15)
81 (15) 50 (9) 60 (11) 48 (9)
105 (23) 61 (13) 59 (13) 45 (10) (continued)
Table 6: Percentage of Patients with Adverse Events ≥10% Reported in Three Bone Metastases Clinical Trials by Body System Zometa 4 mg n (%) Musculoskeletal Bone Pain Myalgia Arthralgia Back Pain Pain in Limb Neoplasms Malignant Neoplasm Aggravated Nervous Headache Dizziness (excluding vertigo) Insomnia Paresthesia Hypoesthesia Psychiatric Depression Anxiety Confusion Respiratory Dyspnea Cough Skin Alopecia Dermatitis
569 239 216 156 143
Pamidronate 90 mg n (%)
(55) (23) (21) (15) (14)
205 (20) 191 180 166 149 127
(19) (18) (16) (15) (12)
146 (14) 112 (11) 74 (7)
316 143 131 106 84
(57) (26) (24) (19) (15)
97 (17) 149 91 111 85 65
(27) (16) (20) (15) (12)
95 (17) 73 (13) 39 (7)
Placebo n (%) 284 74 73 40 52
(62) (16) (16) (9) (11)
89 (20) 50 58 73 35 43
(11) (13) (16) (8) (10)
49 (11) 37 (8) 47 (10)
282 (27) 224 (22)
155 (28) 129 (23)
125 (12) 114 (11)
80 (14) 74 (13)
107 (24) 65 (14) 36 38
Table 7: Grade 3 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Three Clinical Trials in Patients with Bone Metastases Grade 3
Serum Creatinine1* Hypocalcemia2 Hypophosphatemia3 Hypermagnesemia4 Hypomagnesemia5
Zometa 4 mg n/N (%)
Pamidronate 90 mg n/N (%)
7/529 (1%) 4/268 (2%) 4/241 (2%) 6/973 (<1%) 4/536 (<1%) 0/415 — 115/973 (12%) 38/537 (7%) 14/415 (3%) 19/971 (2%) 2/535 (<1%) 8/415 (2%) 1/971 (<1%) 0/535 — 1/415 (<1%)
1Grade 3 (>3x Upper Limit of Normal); Grade 4 (>6x Upper Limit of Normal) *Serum creatinine data for all patients randomized after the 15-minute infusion amendment 2Grade 3 (<7 mg/dL); Grade 4 (<6 mg/dL) 3Grade 3 (<2 mg/dL); Grade 4 (<1 mg/dL) 4Grade 3 (>3 mEq/L); Grade 4 (>8 mEq/L) 5Grade 3 (<0.9 mEq/L); Grade 4 (<0.7 mEq/L)
Table 8: Grade 4 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Three Clinical Trials in Patients with Bone Metastases Grade 4 Laboratory Parameter
Serum Creatinine1* Hypocalcemia2 Hypophosphatemia3 Hypermagnesemia4 Hypomagnesemia5
Zometa 4 mg n/N (%) 2/529 7/973 5/973 0/971 2/971
Renal Toxicity In the bone metastases trials, renal deterioration was defined as an increase of 0.5 mg/dL for patients with normal baseline creatinine (<1.4 mg/dL) or an increase of 1.0 mg/dL for patients with an abnormal baseline creatinine (≥1.4 mg/dL). The following are data on the incidence of renal deterioration in patients receiving Zometa 4 mg over 15 minutes in these trials (see Table 9). Table 9: Percentage of Patients with Treatment Emergent Renal Function Deterioration by Baseline Serum Creatinine* Patient Population/Baseline Creatinine Multiple Myeloma and Breast Cancer
Zometa 4 mg Pamidronate 90 mg n/N
Normal Abnormal Total Solid Tumors
(<1%) (<1%) (<1%) — (<1%)
Pamidronate 90 mg n/N (%) 1/268 (<1%) 3/536 (<1%) 0/537 — 0/535 — 1/535 (<1%)
0/241 — 2/415 (<1%) 1/415 (<1%) 2/415 (<1%) 0/415 —
1Grade 3 (>3x Upper Limit of Normal); Grade 4 (>6x Upper Limit of Normal) *Serum creatinine data for all patients randomized after the 15-minute infusion amendment 2Grade 3 (<7 mg/dL); Grade 4 (<6 mg/dL) 3Grade 3 (<2 mg/dL); Grade 4 (<1 mg/dL) 4Grade 3 (>3 mEq/L); Grade 4 (>8 mEq/L) 5Grade 3 (<0.9 mEq/L); Grade 4 (<0.7 mEq/L)
Among the less frequently occurring adverse events (<15% of patients), rigors, hypokalemia, influenza-like illness, and hypocalcemia showed a trend for more events with bisphosphonate administration (Zometa 4 mg and pamidronate groups) compared to the placebo group.
Normal Abnormal Total Prostate Cancer
Zometa 4 mg (%)
17/154 (11%) 1/11 (9%) 18/165 (11%) Zometa 4 mg n/N
Normal Abnormal Total
27/246 (11%) 2/26 (8%) 29/272 (11%) n/N
Grade 3 and Grade 4 laboratory abnormalities for serum creatinine, serum calcium, serum phosphorus, and serum magnesium observed in three clinical trials of Zometa in patients with bone metastases are shown in Tables 7 and 8.
Less common adverse events reported more often with Zometa 4 mg than pamidronate included decreased weight, which was reported in 16% of patients in the Zometa 4 mg group compared with 9% in the pamidronate group. Decreased appetite was reported in slightly more patients in the Zometa 4 mg group (13%) compared with the pamidronate (9%) and placebo (10%) groups, but the clinical significance of these small differences is not clear.
12/82 (15%) 4/10 (40%) 16/92 (17%)
23/246 2/22 25/268
(9%) (9%) (9%)
10/143 1/20 11/163
(7%) (5%) (7%)
8/68 (12%) 2/10 (20%) 10/78 (13%)
*Table includes only patients who were randomized to the trial after a protocol amendment that lengthened the infusion duration of Zometa to 15 minutes. The risk of deterioration in renal function appeared to be related to time on study, whether patients were receiving Zometa (4 mg over 15 minutes), placebo, or pamidronate. In the trials and in postmarketing experience, renal deterioration, progression to renal failure and dialysis have occurred in patients with normal and abnormal baseline renal function, including patients treated with 4 mg infused over a 15-minute period. There have been instances of this occurring after the initial Zometa dose. 6.2 Postmarketing Experience The following adverse reactions have been reported during postapproval use of Zometa. Because these reports are from a population of uncertain size and are subject to confounding factors, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Osteonecrosis of the Jaw Cases of osteonecrosis (primarily involving the jaws) have been reported predominantly in cancer patients treated with intravenous bisphosphonates including Zometa. Many of these patients were also receiving chemotherapy and corticosteroids which may be a risk factor for ONJ. Data suggests a greater frequency of reports of ONJ in certain cancers, such as advanced breast cancer and multiple myeloma. The majority of the reported cases are in cancer patients following invasive dental procedures, such as tooth extraction. It is therefore prudent to avoid invasive dental procedures as recovery may be prolonged [see Warnings And Precautions (5)]. Musculoskeletal Pain Severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported with bisphosphonate use [see Warnings And Precautions (5)]. Ocular Adverse Events Cases of uveitis, scleritis, episcleritis, conjunctivitis, iritis, and orbital inflammation including orbital edema have been reported during postmarketing use. In some cases, symptoms resolved with topical steroids. Hypersensitivity Reactions There have been rare reports of allergic reaction with intravenous zoledronic acid including angioedema, and bronchoconstriction. Very rare cases of anaphylactic reaction/shock have also been reported. Additional adverse reactions reported in postmarketing use include: CNS: taste disturbance, hyperesthesia, tremor; Special Senses: blurred vision; Gastrointestinal: dry mouth; Skin: increased sweating; Musculoskeletal: muscle cramps; Cardiovascular: hypertension, bradycardia, hypotension (associated with syncope or circulatory collapse primarily in patients with underlying risk factors); Respiratory: bronchoconstriction; Renal: hematuria, proteinuria; General Disorders and Administration Site: weight increase, influenza-like illness (pyrexia, asthenia, fatigue or malaise)
persisting for greater than 30 days; Laboratory Abnormalities: hyperkalemia, hypernatremia. 7 DRUG INTERACTIONS In-vitro studies indicate that zoledronic acid is approximately 22% bound to plasma proteins. In-vitro studies also indicate that zoledronic acid does not inhibit microsomal CYP450 enzymes. In-vivo studies showed that zoledronic acid is not metabolized, and is excreted into the urine as the intact drug. 7.1 Aminoglycosides Caution is advised when bisphosphonates are administered with aminoglycosides, since these agents may have an additive effect to lower serum calcium level for prolonged periods. This effect has not been reported in Zometa clinical trials. 7.2 Loop Diuretics Caution should also be exercised when Zometa is used in combination with loop diuretics due to an increased risk of hypocalcemia. 7.3 Nephrotoxic Drugs Caution is indicated when Zometa is used with other potentially nephrotoxic drugs. 7.4 Thalidomide No dose adjustment for Zometa 4 mg is needed when co-administered with thalidomide. In a pharmacokinetic study of 24 patients with multiple myeloma, Zometa 4 mg given as a 15 minute infusion was administered either alone or with thalidomide (100 mg once daily on days 1-14 and 200 mg once daily on days 15-28). Co-administration of thalidomide with Zometa did not significantly change the pharmacokinetics of zoledronic acid or creatinine clearance. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Zometa should not be used during pregnancy. There are no studies in pregnant women using Zometa. If the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant [see Warnings And Precautions (5.4)]. Pregnancy Category D Bisphosphonates are incorporated into the bone matrix, from where they are gradually released over periods of weeks to years. The extent of bisphosphonate incorporation into adult bone, and hence, the amount available for release back into the systemic circulation, is directly related to the total dose and duration of bisphosphonate use. Although there are no data on fetal risk in humans, bisphosphonates do cause fetal harm in animals, and animal data suggest that uptake of bisphosphonates into fetal bone is greater than into maternal bone. Therefore, there is a theoretical risk of fetal harm (e.g., skeletal and other abnormalities) if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on this risk has not been established. In female rats given subcutaneous doses of zoledronic acid of 0.01, 0.03, or 0.1 mg/kg/day beginning 15 days before mating and continuing through gestation, the number of stillbirths was increased and survival of neonates was decreased in the mid- and high-dose groups (≥0.2 times the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison). Adverse maternal effects were observed in all dose groups (with a systemic exposure of ≥0.07 times the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison) and included dystocia and periparturient mortality in pregnant rats allowed to deliver. Maternal mortality may have been related to druginduced inhibition of skeletal calcium mobilization, resulting in periparturient hypocalcemia. This appears to be a bisphosphonate-class effect. In pregnant rats given a subcutaneous dose of zoledronic acid of 0.1, 0.2, or 0.4 mg/kg/day during gestation, adverse fetal effects were observed in the mid- and high-dose groups (with systemic exposures of 2.4 and 4.8 times, respectively, the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison). These adverse effects included increases in pre- and postimplantation losses, decreases in viable fetuses, and fetal skeletal, visceral, and external malformations. Fetal skeletal effects observed in the high-dose group included unossified or incompletely ossified bones, thickened, curved or shortened bones, wavy ribs, and shortened jaw. Other adverse fetal effects observed in the high-dose group included reduced lens, rudimentary cerebellum, reduction or absence of liver lobes, reduction of lung lobes, vessel dilation, cleft palate, and edema. Skeletal variations were also observed in the low-dose group (with systemic exposure of 1.2 times the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison). Signs of maternal toxicity were observed in the high-dose group and included reduced body weights and food consumption, indicating that maximal exposure levels were achieved in this study. In pregnant rabbits given subcutaneous doses of zoledronic acid of 0.01, 0.03, or 0.1 mg/kg/day during gestation (≤0.5 times the human intravenous dose of 4 mg, based on a comparison of relative body surface areas), no adverse fetal effects were observed. Maternal mortality and abortion occurred in all treatment groups (at doses ≥0.05 times the human
intravenous dose of 4 mg, based on a comparison of relative body surface areas). Adverse maternal effects were associated with, and may have been caused by, drug-induced hypocalcemia. 8.3 Nursing Mothers It is not known whether Zometa is excreted in human milk. Because many drugs are excreted in human milk, and because Zometa binds to bone long term, Zometa should not be administered to a nursing woman. 8.4 Pediatric Use Zometa is not indicated for use in children. The safety and effectiveness of zoledronic acid was studied in a one-year active-controlled trial of 152 pediatric subjects (74 receiving zoledronic acid). The enrolled population was subjects with severe osteogenesis imperfecta, aged 1-17 years, 55% male, 84% Caucasian, with a mean lumbar spine BMD of 0.431 gm/cm2, which is 2.7 standard deviations below the mean for age-matched controls (BMD Z-score of -2.7). At one year, increases in BMD were observed in the zoledronic acid treatment group. However, changes in BMD in individual patients with severe osteogenesis imperfecta did not necessarily correlate with the risk for fracture or the incidence or severity of chronic bone pain. The adverse events observed with Zometa use in children did not raise any new safety findings beyond those previously seen in adults treated for hypercalcemia of malignancy or bone metastases. However, adverse reactions seen more commonly in pediatric patients included pyrexia (61%), arthralgia (26%), hypocalcemia (22%) and headache (22%). These reactions, excluding arthralgia, occurred most frequently within 3 days after the first infusion and became less common with repeat dosing. Because of long-term retention in bone, Zometa should only be used in children if the potential benefit outweighs the potential risk. Plasma zoledronic acid concentration data was obtained from 10 patients with severe osteogenesis imperfecta (4 in the age group of 3-8 years and 6 in the age group of 9-17 years) infused with 0.05 mg/kg dose over 30 min. Mean Cmax and AUC(0-last) was 167 ng/mL and 220 ng.h/mL, respectively. The plasma concentration time profile of zoledronic acid in pediatric patients represent a multi-exponential decline, as observed in adult cancer patients at an approximately equivalent mg/kg dose. 8.5 Geriatric Use Clinical studies of Zometa in hypercalcemia of malignancy included 34 patients who were 65 years of age or older. No significant differences in response rate or adverse reactions were seen in geriatric patients receiving Zometa as compared to younger patients. Controlled clinical studies of Zometa in the treatment of multiple myeloma and bone metastases of solid tumors in patients over age 65 revealed similar efficacy and safety in older and younger patients. Because decreased renal function occurs more commonly in the elderly, special care should be taken to monitor renal function. 10 OVERDOSAGE Clinical experience with acute overdosage of Zometa is limited. Two patients received Zometa 32 mg over 5 minutes in clinical trials. Neither patient experienced any clinical or laboratory toxicity. Overdosage may cause clinically significant hypocalcemia, hypophosphatemia, and hypomagnesemia. Clinically relevant reductions in serum levels of calcium, phosphorus, and magnesium should be corrected by intravenous administration of calcium gluconate, potassium or sodium phosphate, and magnesium sulfate, respectively. In an open-label study of zoledronic acid 4 mg in breast cancer patients, a female patient received a single 48-mg dose of zoledronic acid in error. Two days after the overdose, the patient experienced a single episode of hyperthermia (38°C), which resolved after treatment. All other evaluations were normal, and the patient was discharged seven days after the overdose. A patient with non-Hodgkin’s lymphoma received zoledronic acid 4 mg daily on four successive days for a total dose of 16 mg. The patient developed paresthesia and abnormal liver function tests with increased GGT (nearly 100U/L, each value unknown). The outcome of this case is not known. In controlled clinical trials, administration of Zometa 4 mg as an intravenous infusion over 5 minutes has been shown to increase the risk of renal toxicity compared to the same dose administered as a 15-minute intravenous infusion. In controlled clinical trials, Zometa 8 mg has been shown to be associated with an increased risk of renal toxicity compared to Zometa 4 mg, even when given as a 15-minute intravenous infusion, and was not associated with added benefit in patients with hypercalcemia of malignancy [see Dosage And Administration (2.4) in the full prescribing information]. 16 STORAGE Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Manufactured by Novartis Pharma Stein AG Stein, Switzerland for Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 T2011-01 ©Novartis
Maintaining Your Records: In What Form and for How Long? By Jennifer Kirschenbaum, Esq
or those asking whether managed care will still be around in 5 or 10 years, or whether certain treatments for stage IV cancer will be relevant at the end of that timeframe, uncertainty clouds any potential answer. In contrast, the fact remains that regardless of the payer or the treatment, you will be required to document the care provided by your practice. In addition, you will most likely be required to maintain your documentation. Whether the form of your documentation and/or the maintenance requirements will be the same as today remains unclear, we do have some insight into what the future may hold.
CMS Leading the Way The Centers for Medicare & Medicaid Services (CMS) is widely accepted as the industry trendsetter when it comes not only to reimbursement rates but also to documentation requirements related to reimbursement. As such, CMS began taking steps to encourage the switch to electronic health records (otherwise known as EHR) with its “carrots and stick” incentives. Practices that have switched to EHR that meet the established CMS standard (otherwise known as qualified for “meaningful use”) by the end of 2012 will be rewarded with an incentive payment of up to $44,000. Furthermore, practices that fail to implement the EHR requirement by 2015 are scheduled to incur a reimbursement deduction of 1% in 2015, followed by an additional 1% deduction for each year that practice fails to comply, with a maximum potential deduction of 5%.
If you are wondering why CMS is so eager for practices to adopt EHR, one answer is that once a practice has accepted EHR, CMS will be better positioned to survey each practice for inefficiency and waste, which is readily apparent on an even cursory review of CMS’s recovery audit contractor (RAC) program. Briefly, under the RAC program, CMS is authorized to contract with third parties to audit healthcare providers to identify
One question our practice is often asked in relation to transitioning is, “Am I required to maintain my original paper records, or may I discard them once I’ve transitioned to EHR?”
fraud, abuse, and waste in the Medicare program. Many of these RAC audits are based on data mining. For example, RAC auditors may audit based solely on uncovering a pattern of a practice’s use of a certain high-paying CPT code. Because the RAC program contractors are paid on contingency based on recovery, the process is rarely fair, and providers should not engage in an audit without proper
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legal representation, to ensure that their rights are being protected.
Documentation Form For any practice that has not yet made the switch to EHR, keep in mind that doing so is no small task. Selecting the right EHR system is a monumental process. To make such election, we recommend basing your decision on recommendations from similarly situated practices or oncology-specific professional associations as opposed to making such election solely based on cost. Choosing the wrong EHR system may likely cost you much more on the back end than the right one would cost you on the front end. Once you have made your selection, the transition to EHR is its own project. An often overlooked element in the transition to EHR is the additional policy and procedure requirements mandated by government authorities. For instance, the Office for Civil Rights enforces the federal HITECH Act requirement that all practices utilizing EHR are required to have a security policy detailing the protections that have been put in place to safeguard electronic data. Ensuring that a practice is in compliance with applicable regulatory requirements is only one of the many steps toward adopting a proper EHR, and is an example that highlights the need to work with the right professionals who could provide knowledgeable healthcare counsel throughout the process. One question our practice is often asked in relation to transitioning is, “Am I required to maintain my original paper records, or may I discard Continued on page 30
ts and Providers with the Reimburse n e i t a P ment g Proc Helpin ess 1-888-587-3263 www.TevaCORE.com
Our C RE commitment CORE Hotline Offers Assistance Related to: Benefit verification and coverage determination Precertifications / prior authorization support Coverage guidelines and claim requirements of payers Personalized support through the claims and appeals process Templates for letters of medical necessity Cephalon Oncology Patient Assistance Program
To enroll in CORE Phone 1-888-587-3263 Monday through Friday, 9 AM to 8 PM (ET), fax 1-866-676-4073, or visit www.TevaCORE.com
Supporting Teva Oncology Products Reimbursement Assistance and Support through CORE - the Comprehensive Oncology Reimbursement Expertise Program
CephalonCares® Foundation offers a Patient Assistance Program to provide FDA-approved products free of charge for patients who qualify. Teva Oncology also partners with patient advocacy organizations, such as the Leukemia & Lymphoma Society, and others that have programs designed to help patients access the treatment they need.
© Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved, ONC-2139, Printed in USA
Maintaining Your Records…Continued from page 28 them once I’ve transitioned to EHR?” The answer is that although there are no federal regulations that require practices to maintain original records once an EHR system has been implemented, states are authorized to enact stricter requirements, and they often do so (New York, for example, currently does not require that original documents be maintained). Regardless of whether your jurisdiction requires maintenance of original records, maintaining original records may prove useful. For example, a medical practice represented by our firm was recently investigated for allegedly providing “phantom” treatments. We were able to successfully defend that allegation and forego paying or having to negotiate a hefty recoupment demand by producing the originally dated patient sign-in sheets, as well as patient signatures in their individual charts that were dated with the treatment date, both of which happened to be maintained by our client. In this matter, our client’s diligence in her record keeping aided our defense in staving off a massive potential repayment, as well as a potential fraud allegation. Should you decide to destroy original records, be advised that under the Health Insurance Portability and Accountability Act of 1996 (HIPAA) Privacy and Security Rules you are required to safeguard “protected health information” and to ensure that confidential patient information is not disclosed to any unauthorized parties: HIPAA and other regulations authorize severe penalties should a breach result. As such, be sure that all paper records are destroyed properly.
Documentation Maintenance Another question our practice is frequently asked is, “How long am I required to maintain my records for?” The answer is that recordretention requirements are confusing, mainly because varying regulations exist on multiple levels on this topic. Federal regulations require that Medicare fee-for-service physician providers retain medical records for 6 years from the date of creation.1 But under the Federal False Claims Act, the government may request records for up to 10 years after treatment.2 To make matters even more confusing, states are also authorized under HIPAA to enact their own more-stringent record-keeping requirements. New York, for example, requires the retention of all patient records for a minimum of 6 years, but also requires that obstetrics records and records of minor patients are retained for a minimum of 6 years, or until 1 year after the minor patient reaches the age of 18 years, whichever is longer.3 So, which record-keeping requirements are you required to abide by? Regretfully, the answer is—any and all legitimate requirements that apply to your practice. This, however, provides us the opportunity to highlight a major benefit (and liability) of switching to EHR: once an electronic record is created, it will likely exist in some form on some server to be discoverable at any time after that. And, electronic maintenance of any such record will likely be remarkably more affordable than physical storage options. It is, therefore, unclear whether record maintenance requirements will change
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along with technology. Requiring records to be maintained for the lifetime of a patient and beyond may not be viewed as unreasonable once that record is electronic.
Conclusion Creating and maintaining proper documentation in compliance with applicable form, substance, and maintenance requirements is a challenge for any practice, regardless of its size, as is staying abreast of required policies and procedures. The best way to protect your practice with the many likely changes ahead is to continue to educate yourself and to avail yourself to the right resources. l References 1. 64 Fed. Reg. 59994. 2. 31 U.S.C. §§ 3729–3733. 3. NY Education Law §6530(32).
This article is for education and discussion purposes only and does not constitute legal advice.
Jennifer Kirschenbaum, Esq, manages Kirschenbaum & Kirschenbaum’s healthcare department, which specializes in representing healthcare practitioners in regulatory compliance, audit defense, licensure, and transactional matters. She can be reached at 516-747-6700 x302 or by e-mail at Jennifer@kirschen baumesq.com. For updates on changes in documentation requirements, and general healthcare updates visit www.ny healthcareattorneys.com. Anish Mashettiwar, Esq, and Erica Youngerman, Esq, associates in Kirschenbaum & Kirschenbaum, PC’s healthcare department, assisted in the preparation of this article.
Seasons of Survival Redefining the Paradigm for Cancer Survivorship for 2011 By Kenneth Miller, MD, Adult Survivorship Clinic, Lance Armstrong Foundation, Dana-Farber Cancer Institute, Boston, Massachusetts Irit Ben-Aharon, MD, PhD, Institute of Oncology, Davidoff Center, Rabin Medical Center, Beilinson Campus, Petah-Tiqva, Israel Lindsay Haines, BA, Research Associate, Dana-Farber Cancer Institute, Boston, Massachusetts
ore than 25 years ago, Dr Fitzhugh Mullan described the seasons of survival in a narrative of his personal experience of being diagnosed and treated for cancer and facing the other side of the stethoscope in the New England Journal of Medicine in 1985.1 His description of cancer survivorship included an individual’s experience across the cancer continuum, from initial diagnosis through the remainder of life. “It was desperate days of nausea and depression. It was the elation at the birth of a daughter in the midst of treatment. It was the anxiety of my monthly chest xrays.…It was survival, an absolutely predictable but ill-defined condition that all cancer patients pass through as they struggle with their illness.”1 “Seasons of Survival” was also one of the first articles to describe the natural history of cancer survivorship. That paradigm included 3 phases (Figure 1).1 During the past 3 decades, however, seminal advances in cancer detection and treatment have evolved. Improved understanding of cancer biology and molecular profiling of patients’ tumors has led to more targeted therapy. The 5-year survival rate of adult cancer patients is growing steadily and currently is estimated at 64%.2 And the number of cancer survivors grows constantly, increasing from 3 million in 1971 to an estimated 11.7 million in 2007 (Figure 2).3 By 2020, it is estimated that there will be 20 million cancer survivors in the United States.
Figure 1. The 3 Seasons of Survival Described by Mullen in 1985
Source: Reference 1.
Figure 2. Estimated Cancer Survivors in the United States
Source: Reference 3.
Improvements in long-term survival rates vary significantly among cancer types. Survival rates of patients with chronic myelogenous leukemia (CML) have improved dramatically because of highly effective treatment, leading to a growing number of survivors living in remission. Survival rates have improved
somewhat less in breast cancer and even less in lung cancer (Figure 3).4 In total, however, the number of cancer survivors who live beyond 5 years also has increased (Figure 4).4
A New Paradigm In light of the growing number of Continued on page 32
Seasons of Survival…Continued from page 31 Figure 3A. Mortality Rates for Chronic Myelogenous Leukemia
cantly in the past 25 years; although new drugs, dose intensity, and dose density have added new toxicities. Supportive care has been improved greatly, however.
Transition The title of the Institute of Medicine’s 2005 report, From Cancer Patient to Cancer Survivor: Lost in Transition, aptly describes what for many is a difficult transition back to “normal” or a “new normal.”5
Source: Reference 4.
Figure 3B. Mortality Rates for Breast Cancer
Extended Cancer Survivorship Mullan described extended survivorship as a period of watchful waiting and uncertainty about the future. Traditionally this was considered to be the 5-year period of observation after a cancer diagnosis. Now it is clear that the risk may drop off substantially before 5 years or may continue almost indefinitely. Chronic Survivorship A growing number of cancer survivors are living with cancer as a chronic disease. Patients with CML or gastrointestinal stromal tumors exemplify chronic cancer survivorship. Chronic survivorship also collectively refers to patients with metastatic disease who live with cancer for an extended time because of the introduction of newer agents and protocols.
Source: Reference 4.
cancer survivors and the practical issues of healthcare delivery, we propose a revision in the seasons of survival paradigm (Figure 5). The survivorship trajectory for individual cancer survivors is quite variable, and the transitions may occur at different intervals. In addition, as some survivors develop secondary malig-
nancies, they essentially reenter acute survivorship. End of life also is encompassed within the cancer survivorship experience.
Acute Survivorship Many emotional aspects of the acute period of cancer diagnosis and treatment have not changed signifi-
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Permanent Survivorship Mullan characterized this season as a time when cancer survivors experience less fear and an increasing sense of permanency. This is a heterogeneous group, however: some are “cancer free and free of cancer,” whereas others are “cancer free but not free of cancer”—either physically or emotionally. Some cancer survivors reenter the acute phase of survivorship when diagnosed with a second cancer or a secondary cancer
related to previous therapy. Cancer Free and Free of Cancer. Cancer survivors may be cured either surgically or by local or systemic therapy and live for many decades. Many do not experience late or long-term medical or emotional effects of the experience and cancer feels like a distant part of their past medical history. Cancer Free But Not Free of Cancer. Aziz and Rowland distinguished the term “late effects” as a group of unrecognized toxicities that are absent or subclinical at the end of therapy and become manifest later with the unmasking of potential injury due to any of the following factors: developmental processes; the failure of compensatory mechanisms with the passage of time; or organ senescence.6 In contrast, the term “long-term effects” refers to any side effects or complications of treatment that begin during treatment and continue after treatment has ceased.6 Some researchers classify cognitive problems, fatigue, lymphedema, and peripheral neuropathy as long-term effects; others classify them as late effects.7-10 Second Cancers and Secondary Cancers. The number of patients who develop second cancers is increasing, estimated at 16% of the cancer incidents reported to the National Cancer Institute-Surveillance, Epidemiology and End Results program in 2004.11 Second cancers can reflect the late effect of therapy (ie, radiation, chemotherapy, hormonal therapy), the results of habitual behavior (eg, smoking, alcohol), host factors (ie, cancer syndromes), environmental determinants, and synergism between the risk factors.12
Figure 3C. Mortality Rates for Lung Cancer
Figure 4. Length of Survival for All Cancer Survivors, 2007
Source: Reference 4.
Figure 5. The New Paradigm of “Seasons of Survival”
End of Life End of life is part of cancer survivorship, either during acute survivorship if the cancer progresses despite treatment, after a survivor is Continued on page 34
Seasons of Survival…Continued from page 33 living with cancer as a chronic survivor, after relapse from extended survivorship, or after some period as a permanent survivor. Although a great deal is known about end-of-life care for patients who have been treated actively for cancer, less is known about how the dying experience may be different or special for permanent cancer survivors and their caregivers after having faced the possibility of dying years or decades before.
Implications for Practice More than 25 years have passed since Mullan’s landmark article. The chance of living beyond acute cancer survivorship has increased, as has the total number of permanent survivors. Recent data suggest quantitative and qualitative shifts in the composition of the prevalent population of cancer survivors. The revised paradigm for the seasons of survival presented here differs from the model proposed by Mullan, by recognizing the significant period of transition after the completion of treatment; the heterogeneity of permanent, long-term cancer survivors; and the growing group of patients in chronic survivorship who are living with cancer. Comprehension of the seasons of survival along with the
individuality of survivors and their diversity of needs may enhance our ability to provide needs-based care for cancer survivors. Care of cancer survivors includes attention to all seasons of survival.13,14 Surveillance for recurrence is important, as are treatment of cancer-related adverse events and other comorbidities, surveillance to detect second and secondary cancers, and education to optimize health and enhance quality of life. Potentially, reducing comorbidities may reduce the risk and severity of late or longterm effects on a survivor’s health.15 Cancer survivorship programs can impact cancer survivors during 1 or more of the seasons of survival. Although it may be difficult to try to serve all cancer survivors in each and every season of survivorship, because their needs for surveillance for disease recurrence differ, health education, health behavior improvement, and secondary prevention can benefit any cancer survivor. Survivorship programs have an opportunity to tailor the types of services they offer to cancer survivors during the different seasons of survival based on the perceived and expressed needs of their medical community and, more important, their patients. l
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References 1. Mullan F. Seasons of survival: reflections of a physician with cancer. N Engl J Med. 1985;313:270-273. 2. Oeffinger KC, McCabe MS. Models for delivering survivorship care. J Clin Oncol. 2006;24:5117-5124. 3. Altekruse SF, Kosary CL, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2007, National Cancer Institute. Bethesda, MD, http://seer.cancer. gov/csr/1975_2007/, based on November 2009 SEER data submission, posted to the SEER website, 2010. 4. SEER Cancer Statistics Review, 1975-2007, National Cancer Institute. Bethesda, MD, http://seer. cancer.gov/csr/1975_2007/, based on November 2009 SEER data submission, posted to the SEER website, 2010. 5. Hewitt M, Greenfield S, Stovall E, eds. From Cancer Patient to Cancer Survivor: Lost in Transition. Washington, DC: The National Academies Press; 2005. 6. Aziz NM, Rowland JH. Trends and advances in cancer survivorship research: challenge and opportunity. Semin Radiat Oncol. 2003;13:248-266. 7. Loescher LJ, Welch-McCaffrey D, Leigh SA, et al. Surviving adult cancers. Part 1: physiologic effects. Ann Intern Med. 1989;111:411-432. 8. Welch-McCaffrey D, Hoffman B, Leigh SA, et al. Surviving adult cancers. Part 2: psychosocial implications. Ann Intern Med. 1989;111:517-524. 9. Herold AH, Roetzheim RG. Cancer survivors. Prim Care. 1992;19:779-791. 10. Marina N. Long-term survivors of childhood cancer. The medical consequences of cure. Pediatr Clin North Am. 1997;44:1021-1042. 11. Ries LAG, Melbert D, Krapcho M, et al; eds. SEER Cancer Statistics Review, 1975-2004, National Cancer Institute. Bethesda, MD, http://seer.cancer. gov/csr/1975_2004/, based on November 2006 SEER data submission, posted to the SEER website, 2007. 12. Travis LB, Rabkin CS, Brown LM, et al. Cancer survivorship—genetic susceptibility and second primary cancers: research strategies and recommendations. J Natl Cancer Inst. 2006;98:15-25. 13. Given LS, Black B, Lowry G, et al. Collaborating to conquer cancer: a comprehensive approach to cancer control. Cancer Causes Control. 2005;16(suppl 1):3-14. 14. Pollack LA, Greer GE, Rowland JH, et al. Cancer survivorship: a new challenge in comprehensive cancer control. Cancer Causes Control. 2005;16(suppl 1):51-59. 15. Aziz NM. Cancer survivorship research: state of knowledge, challenges and opportunities. Acta Oncol. 2007;46:417-432.
Announcing: J-code for YERVOYâ„˘ (ipilimumab) J9228 Indication
Replaces J9999, J99 999,, J3490,, J3590,, and C9284.
50-mg/10 mL (5 mg/mL), single-use vial of YER VOY YERVOY
200-mg/40 mL (5 mg/mL), single-use vial of YER VOY YERVOY
NDC Number 10-digit
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 uarantee e 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 YER VOY and does not provide a guarantee of receiving prior authorization or YERVOY reimbursement. Oncology practices need to make coding decisions based on the diagnosis and treatment of each patient and the specific insurer requirements. www.destinationaccess.com 1-800-861-0048 (phone) Monday through Friday, 8:00 1-888-776-2370 (fax)
Important Safety Information WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS
Important Safety Information (cont) Recommended Dose Modifications t
Immune-mediated Hepatitis: t
Immune-mediated Enterocolitis: t
t Immune-mediated Dermatitis: t
t t t
Important Safety Information (cont) t
Immune-mediated Neuropathies: t t t t
Other Immune-mediated Adverse Reactions, Including Ocular Manifestations: t
t t Immune-mediated Endocrinopathies: t t
Pregnancy & Nursing: t
Common Adverse Reactions: t
YERVOYâ„˘ (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€“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€“13.4) and 6.3 weeks (range 0.3â€“18.9) after the initiation of YERVOY for patients with Grade 3â€“5 enterocolitis and with Grade 2 enterocolitis, respectively. Twenty-nine patients (85%) with Grade 3â€“5 enterocolitis were treated with high-dose (â‰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€“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€“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€“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€™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€“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]
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€“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.
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t *NNVOFNFEJBUFEEFSNBUJUJT[see Warnings and Precautions].
t *NNVOFNFEJBUFEOFVSPQBUIJFT[see Warnings and Precautions].
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t 0 UIFSJNNVOFNFEJBUFEBEWFSTFSFBDUJPOT JODMVEJOHPDVMBSNBOJGFTUBUJPOT[see Warnings and Precautions].
Clinical Trials Experience
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‰Ľ5%) in patients who received YERVOY at 3 mg/kg were fatigue, diarrhea, pruritus, rash, and colitis. Table 1 presents selected adverse reactions from Study 1, which occurred in at least 5% of patients in the YERVOY-containing arms and with at least 5% increased incidence over the control gp100 arm for all-grade events and at least 1% incidence over the control group for Grade 3â€“5 events. Table 1:
Percentage (%) of YERVOY 3 mg/kg n=131
Gastrointestinal Disorders Diarrhea Colitis Skin and Subcutaneous Tissue Disorders Pruritus Rash General Disorders and Administration Site Conditions Fatigue a
DRUG INTERACTIONS No formal drug-drug interaction studies have been conducted with YERVOY (ipilimumab). USE IN SPECIFIC POPULATIONS Pregnancy
There are no adequate and well-controlled studies of YERVOY in pregnant women. Use YERVOY during pregnancy only if the potential benefit justifies the potential risk to the fetus.
YERVOY 3 mg/kg+gp100 n=380
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€œknockout mouseâ€?), offspring lacking CTLA-4 were born apparently healthy, but died within 3â€“4 weeks due to multi-organ infiltration and damage by lymphocytes. Human IgG1 is known to cross the placental barrier and ipilimumab is an IgG1; therefore, ipilimumab has the potential to be transmitted from the mother to the developing fetus. Nursing Mothers
Incidences presented in this table are based on reports of adverse events regardless of causality.
Table 2 presents the per-patient incidence of severe, life-threatening, or fatal immune-mediated adverse reactions from Study 1. Table 2:
Immunogenicity assay results are highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to YERVOY with the incidences of antibodies to other products may be misleading.
Pregnancy Category C
Selected Adverse Reactions in Study 1
System Organ Class/ Preferred Term
Because trough levels of ipilimumab interfere with the ECL assay results, a subset analysis was performed in the dose cohort with the lowest trough levels. In this analysis, 6.9% of 58 evaluable patients, who were treated with 0.3 mg/kg dose, tested positive for binding antibodies against ipilimumab.
Severe to Fatal Immune-mediated Adverse Reactions in Study 1 Percentage (%) of Patients
Any Immune-mediated Adverse Reaction Enterocolitisa,b Hepatotoxicitya Dermatitisa Neuropathya Endocrinopathy Hypopituitarism Adrenal insufficiency Other Pneumonitis Meningitis Nephritis Eosinophiliac Pericarditisa,c
YERVOY 3 mg/kg n=131
YERVOY 3 mg/kg+gp100 n=380
15 7 1 2 1 4 4 0
12 7 2 3 <1 1 1 1
0 0 1 1 0
<1 <1 0 0 <1
It is not known whether ipilimumab is secreted in human milk. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from YERVOY, a decision should be made whether to discontinue nursing or to discontinue YERVOY, taking into account the importance of YERVOY to the mother. Pediatric Use Safety and effectiveness of YERVOY have not been established in pediatric patients. Geriatric Use Of the 511 patients treated with YERVOY at 3 mg/kg, 28% were 65 years and over. No overall differences in safety or efficacy were reported between the elderly patients (65 years and over) and younger patients (less than 65 years). Renal Impairment No formal studies of YERVOY in patients with renal impairment have been conducted. [See Clinical Pharmacology (12.3) in Full Prescribing Information] Hepatic Impairment No formal studies of YERVOY in patients with hepatic impairment have been conducted. [See Clinical Pharmacology (12.3) in Full Prescribing Information] OVERDOSAGE There is no information on overdosage with YERVOY. PATIENT COUNSELING INFORMATION See MEDICATION GUIDE in Full Prescribing Information. t *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. c Underlying etiology not established. b
Across clinical studies that utilized YERVOY doses ranging from 0.3 to 10 mg/kg, the following adverse reactions were also reported (incidence less than 1% unless otherwise noted): urticaria (2%), large intestinal ulcer, esophagitis, acute respiratory distress syndrome, renal failure, and infusion reaction. Based on the experience in the entire clinical program for melanoma, the incidence and severity of enterocolitis and hepatitis appear to be dose dependent.
Issued: March 2011
Drug Coding Supplied by RJ Health Systems
FDA-Approved Medications Used for Supportive Care in Cancer Treatment The following sections will assist healthcare professionals and payers by providing appropriate coding and billing information associated with supportive care for the management of patients with cancer. The following sections include: • Associated ICD-9-CM codes used for the classification of supportive care in cancer • Drugs that have been FDA-approved for supportive care in cancer • Corresponding HCPCS/CPT® codes and code descriptions • Corresponding HCPCS/CPT® codes and code descriptions Please note: The following list does not include drugs that may be listed in the Compendia for off-label uses for Supportive Care in Cancer Treatment
Associated ICD-9-CM Codes for Supportive Care in Cancer 787.0 Nausea and vomiting Emesis Excludes: hematemesis NOS (578.0) vomiting bilious, following gastrointestinal surgery (564.3) cyclical (536.2) >associated with migraine (346.2)< psychogenic (306.4) excessive, in pregnancy (643.0-643.9) habit (536.2) of newborn (779.3) psychogenic NOS (307.54) 787.01 Nausea and vomiting 787.02 Nausea alone 787.03 Vomiting alone 280 Iron deficiency anemias Includes: anemia: asiderotic hypochromic-microcytic sideropenic Excludes: familial microcytic anemia (282.49) 280.0 Secondary to blood loss (chronic) Normocytic anemia due to blood loss Excludes: acute posthemorrhagic anemia (285.1) 284.8 Other specified aplastic anemias 284.89 Other specified aplastic anemias Aplastic anemia (due to): chronic systemic disease drugs infection radiation toxic (paralytic) Use additional E code to identify cause 285 Other and unspecified anemias 285.1 Acute posthemorrhagic anemia Anemia due to acute blood loss
ONCOLOGY PRACTICE MANAGEMENT
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Drug Coding Supplied by RJ Health Systems
Excludes: anemia due to chronic blood loss (280.0) blood-loss anemia NOS (280.0) 285.21 Anemia in chronic kidney disease Anemia in end-stage renal disease Erythropoietin-resistant anemia (EPO-resistant anemia) 285.3 Antineoplastic chemotherapy-induced anemia Anemia due to antineoplastic chemotherapy Excludes: anemia due to drug NEC-code to type of anemia anemia in neoplastic disease (285.22) aplastic anemia due to antineoplastic chemotherapy (284.89) 288.0 Neutropenia Decreased absolute neutrophil count [ANC] Use additional code for any associated: fever >(780.61)< mucositis (478.11, 528.00-528.09, 538, 616.81) Excludes: neutropenic splenomegaly (289.53) transitory neonatal neutropenia (776.7) 288.00 Neutropenia, unspecified 288.01 Congenital neutropenia Congenital agranulocytosis Infantile genetic agranulocytosis Kostmannâ€™s syndrome 288.02 Cyclic neutropenia Cyclic hematopoiesis Periodic neutropenia 288.03 Drug-induced neutropenia Use additional E code to identify drug 288.04 Neutropenia due to infection 288.09 Other neutropenia Agranulocytosis Neutropenia: immune toxic 288.5 Decreased white blood cell count Excludes: neutropenia (288.01-288.09) 288.50 Leukocytopenia, unspecified Decreased leukocytes, unspecified Decreased white blood cell count, unspecified Leukopenia NOS 288.59 Other decreased white blood cell count Basophilic leukopenia Eosinophilic leukopenia Monocytopenia Plasmacytopenia
Drug Coding Supplied by RJ Health Systems
Associated ICD-9-CM Codes for Supportive Care in Cancer continued E930.7 Antineoplastic antibiotics Actinomycins, such as: Bleomycin Cactinomycin Dactinomycin Daunorubicin Mitomycin Excludes: other antineoplastic drugs (E933.1) E933.1 Antineoplastic and immunosuppressive drugs Azathioprine Busulfan Chlorambucil Cyclophosphamide Cytarabine Fluorouracil Mechlorethamine HCl Mercaptopurine Triethylenethiophosphamide (thio-TEPA) Excludes: antineoplastic antibiotics (E930.7)
Generic (brand) name
HCPCS code: code description
CPT 速 administration codes
aprepitant (Emend) darbepoetin alfa (Aranesp) darbepoetin alfa (Aranesp) dronabinol (Marinol) dronabinol (Marinol)
J8501: Aprepitant, oral, 5 mg J0881: Injection, darbepoetin alfa, 1 mcg (non-ESRD use)
N/A 96372, 96374
J0882: Injection, darbepoetin alfa, 1 mcg (for ESRD on dialysis)
J8597a: Antiemetic drug, oral, not otherwise specified Q0167: Dronabinol, 2.5 mg oral, FDA-approved prescription antiemetic, for use as a complete therapeutic substitute for an IV antiemetic at time of chemotherapy treatment, not to exceed a 48-hour dosage regimen Q0168: Dronabinol, 5 mg oral, FDA-approved prescription antiemetic, for use as a complete therapeutic substitute for an IV antiemetic at time of chemotherapy treatment, not to exceed a 48-hour dosage regimen J0885: Injection, epoetin alfa (for non-ESRD use), 1000 units
J0886: Injection, epoetin alfa, 1000 units (for ESRD on dialysis) (renal dialysis facilities and hospitals must use code Q4081 effective 1/1/07) Q4081: Injection, epoetin alfa, 100 units (for ESRD on dialysis) (for renal dialysis facilities and hospital use) J1440: Injection, filgrastim (G-CSF), 300 mcg
dronabinol (Marinol) epoetin alfa (Procrit, Epogen) epoetin alfa (Procrit, Epogen) epoetin alfa (Procrit, Epogen) filgrastim (Neupogen)
ONCOLOGY PRACTICE MANAGEMENT
I February 2012
96372, 96374 96365, 96366, 96369, 96370, 96372, 96374
Drug Coding Supplied by RJ Health Systems
Generic (brand) name
HCPCS code: code description
CPT ® administration codes
J1441: Injection, filgrastim (G-CSF), 480 mcg
96365, 96366, 96369, 96370, 96372, 96374
J1453: Injection, fosaprepitant, 1 mg
J1626: Injection, granisetron hydrochloride, 100 mcg
Q0166: Granisetron hydrochloride, 1 mg oral, FDA-approved prescription antiemetic, for use as a complete therapeutic substitute for an IV antiemetic at time of chemotherapy treatment, not to exceed a 24-hour dosage regimen
S0091: Granisetron hydrochloride, 1 mg (for circumstances falling under the Medicare statute, use Q0166)
metoclopramide (Reglan) J2765: Injection, metoclopramide HCl, up to 10 mg
J8650: Nabilone, oral, 1 mg
J2405: Injection, ondansetron hydrochloride, per 1 mg
Q0162: Ondansetron 1 mg, oral, FDA-approved prescription antiemetic, for use as a complete therapeutic substitute for an IV antiemetic at the time of chemotherapy treatment, not to exceed a 48-hour dosage regimen - see also S0119
S0119: Ondansetron, oral, 4 mg (for circumstances falling under the Medicare statute, use HCPCS code Q0162)
J2469: Injection, palonosetron HCl, 25 mcg
pegfilgrastim (Neulasta) J2505: Injection, pegfilgrastim, 6 mg
sargramostim (Leukine) J2820: Injection, sargramostim (GM-CSF), 50 mcg
96365, 96366, 96372
When billing a non-classified medication using a CMS 1500 claim form you must include both the HCPCS code in Column 24D and the drug name, strength, and NDC (National Drug Code) in Box 19 in order to ensure appropriate reimbursement. a
References HCPCS Level II Expert 2012 • Current Procedural Terminology (CPT®) 2012 • CPT® copyright 2012 American Medical Association. All rights reserved. CPT® is a registered trademark of the American Medical Association • ICD-9-CM for Professionals Vol 1, 2, 2012 • FDA-approved indication (product prescribing information) • www.ReimbursementCodes.com powered by RJ Health Systems International, LLC, Rocky Hill, Connecticut • CMS (Centers for Medicare & Medicaid Services).
This information was supplied by:
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RJ Health Systems â€” the pharmaceutical specialists that healthcare professionals have turned to since 1983 for their drug information. We work with over 170 Payor organizations that touch approximately 110 million lives. RJ Health Systems has established and continuously maintains a Library of Drug Intelligence that provides the most comprehensive, trusted, and up-to-date coding and reimbursement information in the industry. ReimbursementCodes.com incorporates the CMS HCPCS and AMA CPT Drug codes into a system that crosswalks each drug code with the drugâ€™s NDC and brand/generic name. Please visit www.rjhealthsystems.com to learn more about our products and services listed below:
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Partnering with Hospitals
From Independent Medical Practice…Continued from the cover Three years ago, the physicians at CBC were beginning to face financial and market challenges that would not only affect long-term patient care but also compensation and the overall viability of the practice. Revenue reductions were the result of different reasons, beginning with the reduced reimbursement for available generic drugs. The use of oral generics enhances the ability of patients to directly purchase and administer many medications that were previously administered in the office, and the widespread reduction in insurance reimbursements significantly contributed to the monetary decline. In addition, the recent implementation of electronic medical records required a substantial capital investment.
The Options The group began to explore options that might reduce its financial risks, as well as offer the providers a more stable income and increase the level of patient care. The options considered included: • Consolidation with other practices • A joint venture with a hospital • Selling the practice to a hospital and becoming hospital employees. After careful study and weighing all the options, an agreement was entered with Baptist Hospital East to purchase the practice, with each individual provider entering into a separate employment contract with the hospital. The hospital presented a “captured practice model,” in which the medical practice would be acquired by the hospital, but the hospital would not manage the practice. Through the cooperative management of Baptist Hospital East, the transition was nearly seamless: there were no interruptions of any kind in
addition of facility fees that are being billed by the hospital. Also, the doctors are busier now than before, because there are more meetings and committee memberships, along with more regulatory requirements under the hospital system. The physicians are also expected to cover more locations than they had in the past. However, being a formal part of the hospital network, the physicians now talk to more primary care physicians to consult with them on patient care, and the unbillable time they spend in these meetings and consultations is being funded by the hospital, as part of their patient care initiative.
patient care. The group was allowed to continue to practice their most important operating systems.
The Benefits of Partnership The hospital management took on the responsibility of employee benefits and management, and subsequently increased the value of these benefits, contributing to higher employee morale. The assumption of these clerical and administrative tasks also affords the members more time for patient care. Of course, one of the most popular benefits is an increased compensation level for the individual members. The partnership with Baptist Hospital East has afforded the practice many more opportunities to improve care and facilities. An upgraded pharmacy and laboratory were made available, encompassing all the latest protocols, a feat that most likely would have been beyond the reach of the private practice. The hospital’s ability to procure the best possible pricing for drugs and for supplies further enhances the elements of financial success. More important, patient care has been substantially improved by using the hospital “forum” concept. This process affords doctors of different specialties—thoracic, radiation, pathology, and oncology—the time to collaborate on individual patient care. Meeting weekly, this previously unbillable time is now not only compensated by the hospital but is a requirement of the institution. The ability to share expertise and compare and explore the effects of various types of care adds a dimension of care heretofore unavailable.
Expert Advice Dr Kommor offers the following advice for any practices pursuing a similar relationship: Compare the practice model of your group and the new partner to make certain they align
Weigh the quality-of-care issues that may affect overall patient well-being and treatment
Consider how location changes and additions may challenge individual lifestyles
Although compensation is a major consideration, secondary benefits can outweigh the cost of change
Evaluate how the arrangement will affect your current patient flow and referral network
Consider an early and enthusiastic commitment to this process that could yield the additional benefit of helping to shape the oncology vision for the hospital. l
Disadvantages Some of the downsides have been complaints by patients about the
Physician Wealth Management With Lawrence B. Keller, CLU, ChFC, CFP®
Disability Insurance Planning for the Cancer Care Team
his final article in our disability insurance series provides tips on how to compare one company’s policy to another company’s policy when shopping for disability insurance coverage. This will help you ultimately choose the right policy to best meet your individual needs and goals.
Occupational Classification and Pricing Proper classification of occupations is of primary importance in establishing the premium rate that you will be charged by the insurance company. In general, the higher the occupational classification assigned to your profession or medical specialty, the lower your premium rate will be. It is also important to note that different insurance companies may assign a different occupational class to the same occupation and, as a result, the premium rate may vary greatly from one company to another. It is therefore important to “shop” for the coverage that you will be purchasing, or to employ the services of an insurance agent or financial planner that specializes in this type of coverage and represents several companies. For example, one company recently created a new occupational classification (6M) for oncologists among a few other medical specialties. As a result of this upgrade (from class 5S), rates for oncologists were reduced by approximately 27%. Another carrier assigns a more favorable occupational classification (5M compared with 4M) to radiolo-
gists who have been practicing for more than 5 years—not including residency or fellowship—either at the time of their initial purchase or once the 5-year time horizon has been met.
This seemingly small difference can either cause them to pay substantially more for their coverage or allow them to pay substantially less for the same coverage.
Therefore, when applying to that carrier, it is vital that radiation oncologists accurately note their medical specialty on the application for coverage. If they list their occupation as “radiation oncologist,” they would not qualify for the 5M occupational classification available to radiologists. However, if they list their occupation as a “therapeutic radiologist,” they would potentially qualify for the 5M occupational classification. This seemingly small difference can either cause them to pay substantially more for their coverage or allow them to pay substantially less for the same coverage.
How Do Policies Compare? Other than cost, the following policy provisions may help you decide which disability insurance policy or policies to ultimately purchase.
ONCOLOGY PRACTICE MANAGEMENT
I February 2012
Foreign Residence and Travel Some carriers allow an insured to travel or reside in countries outside of the United States, the District of Columbia, or Canada, but the majority of carriers will limit payments of these claims to a lifetime maximum of 12 months. Therefore, if you may consider working outside of the United States in the future or would choose to leave the United States in the event that you became disabled, you should make sure that any disability insurance policy you purchase does not contain a limitation for this type of claim. Mental and Nervous Conditions Some carriers will cover claims for mental and nervous conditions in the same fashion as other disabilities, but the majority of companies limit these claims to a lifetime maximum of 24 months if the primary cause of disability is solely a psychiatric or substance abuse disorder or diagnosis, including, but not limited to, posttraumatic stress syndrome, anxiety, depression, and/or alcohol abuse/ addiction. Although many insured persons will opt to purchase disability coverage with the least amount of restrictions, some willingly accept a policy with this limitation to take advantage of the cost-savings associated with it. Recovery Benefits A recovery benefit continues to pay benefits (in the same fashion as the Residual Rider) if you return to work on a full-time basis, with no loss of time or duties, but you continue to suffer a loss of income. Continued on page 49
“Managing patients with myeloma means staying current.”
Ira Klein, MD, MBA, FACP Chief of Staff to the Chief Medical Officer Aetna Hartford, CT
Value-Based Care in Myeloma !&%0!,- !2 &/-%0! %(.!,0%!1( *!,-*! .%0!- ,!& .! .) )-. +/ &%.3 ( !-- %--/!*! % & -! .%)(- "), -! &%(% % (0 ( ! *, .% ! (/,-!- ( *$ ,' %-.- 1%&& &-) ") /- )( .$! /(%+/! $ &&!(#!%( .$! ' ( #!'!(. )" '/&.%*&! '3!&)'
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Patient and Provider Access Brought to you by the Association of Community Cancer Centers
ACO Final Rule: Enough to Entice the Oncology Team? By Sydney Abbott, JD, Policy Coordinator, Association of Community Cancer Centers
he result of the November 17, 2011, hyperpartisan Congress is policymaking stuck firmly in division and gridlock. Many healthcare issues remain in contention, including key components of the Patient Protection and Affordable Care Act (ACA). Whereas some legislators have tried to mitigate—or even eliminate—the ACA, their efforts have been unsuccessful within the 2 chambers of Congress. The US Supreme Court has agreed to rule on the constitutionality of the individual mandate in 2012, and we will have a better idea of the muscle of the ACA once its final decision is reached. Until then, implementations of various aspects of the ACA are moving forward, such as insurance reforms and the establishment of accountable care organizations (ACOs). The Centers for Medicare & Medicaid Services (CMS) recently released its final rule on ACOs to mixed reviews. CMS appears to have read the 1300 public comments carefully, because it made considerable improvements to the final rule. Although the final rule is a dramatic improvement to the proposed rule, provider groups such as the Association of Community Cancer Centers (ACCC) are still unsure whether the rule goes far enough to entice specialists to join an ACO. CMS’s final rule addresses several obstacles that individual practices and cancer programs faced in forming or joining ACOs. CMS had proposed 2 entrances into risk-sharing
during the first 3-year cycle of the ACO. However, both entrance models created an important costrelated barrier to enter an ACO, by assuming a 2-sided risk for every participant during the first cycle. Despite significant start-up costs, in the proposed rule oncologists and other specialists could be required to make payments back to CMS for not meeting set benchmarks. It is fortunate that CMS listened to what
Probably the most significant change from the proposal to the final rule is the shift from retrospective to prospective assignment of beneficiaries.
ACCC and other groups said in the comments and altered the final rule to include a truly 1-sided model for risk-sharing in the first 3 years. A 2sided model is still available, but we do not expect that many ACOs will elect to undertake a greater risk, even if there is a potential for greater rewards. CMS also surprised us by reducing the number of reportable quality measures from 65 down to 33. This is a welcome change. The greater the number of quality measures to report, the higher the barrier to entering an ACO, because greater preparation is required of each ACO participant. Instead of requiring all
ONCOLOGY PRACTICE MANAGEMENT
I February 2012
65 quality measures at the outset, 33 will be reported initially, with the remainding 32 to be phased in over 3 years. CMS’s final ACO rule also reduced the electronic health record meaningful user requirement. CMS will allow ACOs to build up to the proposed 50% meaningful user requirement over the first 3 years of the program. Probably the most significant change from the proposal to the final rule is the shift from retrospective to prospective assignment of beneficiaries. In its comments to CMS, the ACCC noted the difficulty that retrospective assignment would bring by prohibiting providers from planning for their responsibilities. Retrospective assignment would allow CMS to notify an ACO as to which patients that ACO was responsible for after the closing of the ACO cycle. Providers, therefore, would be left in the dark about which patients counted toward meeting cost and quality thresholds that are required to achieve shared savings under an ACO. In the final rule, CMS changed assignment to a more prospective model. Now, CMS will notify participating providers on a quarterly basis as to which patients are likely under their responsibility. This will allow providers greater planning and will help them to take a more active role in the quality improvement and cost-containment goals of the ACO. The ACCC believes that all these changes in the final ACO rule will help reduce barriers to entry into an ACO. Still, it remains unclear if the changes are enticing enough to Continued on page 49
Patient and Provider Access
ACO Final Rule…Continued from page 48 encourage oncology providers to participate. ACO-related expenses remain very high. CMS expects startup costs to range from $29 million to $157 million, but many provider groups anticipate even higher initial costs, with annual operating costs expected to be at least $60 million. ACCC’s members are also concerned about where they fit into the equation—ACOs remain primary care practitioner–centered. The ACCC commented on the possibility of an oncology-centered ACO, but CMS did not address that option in its final rulemaking. Oncology patients are typically much more expensive to care for than a patient without a cancer diagnosis, and it remains unclear how those patients will affect an ACO’s bottom line in meeting quality and cost thresholds. The question remains unanswered whether ACOs will chill research. Oncology relies heavily on the knowledge gleaned from clinical tri-
als, but research is extremely expensive, and the quality thresholds set for ACOs could be too costly or too burdensome. Finally, many oncology practices and cancer programs are already run-
There are certainly many considerations for oncology providers to weigh in when making the decision to participate or pass on the ACOs. The final CMS rule did make significant improvements from its pro-
The ACCC commented on the possibility of an oncology-centered ACO, but CMS did not address that option in its final rulemaking. Oncology patients are typically much more expensive to care for than a patient without a cancer diagnosis, and it remains unclear how those patients will affect an ACO’s bottom line. ning high-quality, low-cost facilities, and the additional improvements required to earn shared savings may be difficult for them to achieve.
posal, but is it enough to entice the oncology team? The answer is just one more unknown in the world of ACOs. l
Physician Wealth Management With Lawrence B. Keller, CLU, ChFC, CFP®
Disability Insurance Planning…Continued from page 46 If there is a demonstrable relationship between your current loss of income and your previous disability, some companies will continue to potentially pay benefits until you reach either age 65 years or 67, for as long as the required loss of income is met. Other companies, however, may limit recovery benefit payments to a maximum of 6, 12, 24, or 36 months—even if you continue to suffer a loss of income.
Conclusion The disability insurance marketplace has changed dramatically over the past few years. Although monthly benefits have increased, new riders have been introduced and discounts are, for the most part, easily available. It is important for you to take the time to understand what you are purchasing, and to make sure that the policy meets your individual needs and goals. l
Lawrence B. Keller, CLU, ChFC, CFP®, is the founder of Physician Financial Services, a New York–based firm specializing in income protection and wealth accumulation strategies for physicians. He can be reached at 516677-6211 or by e-mail to Lkeller@ physicianfinancialservices.com with comments or questions.
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
15.9 15.1 9.6
0 4.1 0
17.9 23.4 11.5
0.4 4.3 0
50.6 28.5 19.2
23.8 4.2 N/A
0.9 12.3 52.3
0 0.4 N/A
The following additional adverse reactions (not in table) were observed in patients with ovarian cancer with doses administered every four weeks. Incidence 1% to 10%: Cardiovascular: vasodilation, tachycardia, deep thrombophlebitis, hypotension, cardiac arrest. Digestive: oral moniliasis, mouth ulceration, esophagitis, dysphagia, rectal bleeding, ileus. Hemic and Lymphatic: ecchymosis. Metabolic and Nutritional: dehydration, weight loss, hyperbilirubinemia, hypokalemia, hypercalcemia, hyponatremia. Nervous: somnolence, dizziness, depression. Respiratory: rhinitis, pneumonia, sinusitis, epistaxis. Skin and Appendages: pruritus, skin discoloration, vesiculobullous rash, maculopapular rash, exfoliative dermatitis, herpes zoster, dry skin, herpes simplex, fungal dermatitis, furunculosis, acne. Special Senses: conjunctivitis, taste perversion, dry eyes. Urinary: urinary tract infection, hematuria, vaginal moniliasis. Patients With AIDS-Related Kaposi’s Sarcoma: The safety data below is based on the experience reported in 753 patients with AIDS-related Kaposi’s sarcoma enrolled in four studies. The median age of the population was 38.7 years (range 24-70 years), which was 99% male, 1% female, 88% Caucasian, 6% Hispanic, 4% Black, and 2% Asian/other/unknown. The majority of patients were treated with 20 mg/m2 of DOXIL every two to three weeks. The median time on study was 127 days and ranged from 1 to 811 days. The median cumulative dose was 120 mg/m2 and ranged from 3.3 to 798.6 mg/m2. Twenty-six patients (3.0%) received cumulative doses of greater than 450 mg/m2. Of these 753 patients, 61.2% were considered poor risk for KS tumor burden, 91.5% poor for immune system, and 46.9% for systemic illness; 36.2% were poor risk for all three categories. Patients’ median CD4 count was 21.0 cells/mm3, with 50.8% of patients having less than 50 cells/mm3. The mean absolute neutrophil count at study entry was approximately 3,000 cells/mm3. Patients received a variety of potentially myelotoxic drugs in combination with DOXIL. Of the 693 patients with concomitant medication information, 58.7% were on one or more antiretroviral medications; 34.9% patients were on zidovudine (AZT), 20.8% on didanosine (ddI), 16.5% on zalcitabine (ddC), and 9.5% on stavudine (D4T). A total of 85.1% patients were on PCP prophylaxis, most (54.4%) on sulfamethoxazole/trimethoprim. Eighty-five percent of patients were receiving antifungal medications, primarily fluconazole (75.8%). Seventy-two percent of patients were receiving antivirals, 56.3% acyclovir, 29% ganciclovir, and 16% foscarnet. In addition, 47.8% patients received colonystimulating factors (sargramostim/filgrastim) sometime during their course of treatment. Adverse reactions led to discontinuation of treatment in 5% of patients with AIDS related Kaposi’s sarcoma. Those that did so included bone marrow suppression, cardiac adverse reactions, infusion-related reactions, toxoplasmosis, HFS, pneumonia, cough/dyspnea, fatigue, optic neuritis, progression of a non-KS tumor, allergy to penicillin, and unspecified reasons. Table 4: Hematology Data Reported in Patients With AIDS-Related Kaposi’s Sarcoma Patients With Total Patients Refractory or Intolerant With AIDS-Related AIDS-Related Kaposi’s Sarcoma Kaposi’s Sarcoma (n = 74) (n = 720) Neutropenia 3 1000/mm 34 (45.9%) 352 (48.9%) 500/mm3 8 (10.8%) 96 (13.3%) Anemia 10 g/dL 43 (58.1%) 399 (55.4%) 8 g/dL 12 (16.2%) 131 (18.2%) Thrombocytopenia 150,000/mm3 45 (60.8%) 439 (60.9%) 25,000/mm3 1 (1.4%) 30 (4.2%) Table 5: Probably and Possibly Drug-Related Non-Hematologic Adverse Reactions Reported in of Patients With AIDS-Related Kaposi’s Sarcoma Adverse Patients With Total Patients Reactions Refractory or Intolerant With AIDS-Related AIDS-Related Kaposi’s Sarcoma Kaposi’s Sarcoma (n = 77) (n = 705) Nausea 14 (18.2%) 119 (16.9%) Asthenia 5 (6.5%) 70 (9.9%) Fever 6 (7.8%) 64 (9.1%) Alopecia 7 (9.1%) 63 (8.9%) Alkaline Phosphatase 1 (1.3%) 55 (7.8%) Increase Vomiting 6 (7.8%) 55 (7.8%) Diarrhea 4 (5.2%) 55 (7.8%) Stomatitis 4 (5.2%) 48 (6.8%) Oral Moniliasis 1 (1.3%) 39 (5.5%)
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
Respiratory, thoracic and mediastinal disorders Cough 18 Skin and subcutaneous tissue disorders Rash** 22
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
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
Published on Feb 27, 2012