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Dear Colleague: The Oncology Pharmacist features articles written by and for oncology pharmacists and specifically addresses the issues pharmacists and their colleagues face every day in clinical practice. A unique feature of The Oncology Pharmacist is that each issue will an include a continuing education activity accredited by the University of Nebraska Medical Center, Center for Continuing Education. Pharmacists will be able to complete the post-test and obtain credit online at no charge. Other unique features include articles specifically written for pharmacy students and residents as well as articles on practice management and financial and regulatory issues affecting the practice of pharmacy. For your free subscription, please complete and return the FREE Subscription Request card below. Postage is prepaid, so simply fill out the card and drop it in the mail. We look forward to receiving feedback on what you would like to see in future issues of The Oncology Pharmacist. —Susan Goodin, PharmD, FCCP, BCOP Editor-in-Chief
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MEDICAL MINUTES HPV-related cancers of tongue and tonsils respond better to therapy
NEW TECHNOLOGY RFA ablation procedure effective alternative for treating Barrett’s esophagus
page 1
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JUNE 2008 • VOL. 1, NO.2
The
CANCER CENTER PROFILE Multidisciplinary team at Cleveland Clinic Taussig Cancer Center provides patient-centered care
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PHARMACY EDUCATION AND TRAINING
Organizations for the Potential Oncology Practitioner: Which Ones to Join and How Many? Patrick Medina, PharmD, BCOP Oklahoma University College of Pharmacy, Tulsa
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uring the first year of pharmacy school, students often join numerous organizations for several reasons, including social and professional networking, resume building, and increasing knowledge in perceived areas of interest. As a
student’s interests become more focused and career paths are clarified, the number and type of organizations that he or she belongs to will also narrow. Organizations play a vital role in the professional growth of students and residents
and are also integral in maintaining lifelong learning and professional development as a pharmacist. Many organizations are available for professional and educational growth for students and residents
PHARMACY PRACTICE
Prevention and Management of
AMCP:
Oral Mucositis
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New Study Looks at Use of ESAs in Real World Practice
ith the diagnosis of cancer comes the reality of an unforgiving disease process that renders the body’s natural defenses impotent. While this causes great anguish in and of itself, it is often what comes next that proves to be more troublesome. The cancer treatment itself presents formidable challenges to patients—the chemotherapy-induced neutropenia, persistent nausea and vomiting, alopecia,
SAN FRANCISCO—Prescribing practices appear to be changing when it comes to erythropoiesis-stimulating agents (ESAs), according to new data presented at the Academy of Managed Care Pharmacy’s 20th Annual Meeting and Showcase. Researchers found that between 2005 and 2006, there was a decrease in
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MEDICAL MINUTES HPV-related cancers of tongue and tonsils respond better to therapy
NEW TECHNOLOGY RFA ablation procedure effective alternative for treating Barrett’s esophagus
CANCER CENTER PROFILE Multidisciplinary team at Cleveland Clinic Taussig Cancer Center provides patient-centered care
page 1
page 8
page 12
JUNE 2008 • VOL. 1, NO.2
The
www.theoncologypharmacist.com
Oncology
The Official Newspaper of Record for the Hem/Onc Pharmacist
Pharmacist
™
POLICY WATCH
PHARMACY EDUCATION AND TRAINING
White House photo by Evie Draper
Organizations for the Potential Oncology Practitioner: Which Ones to Join and How Many? Patrick Medina, PharmD, BCOP Oklahoma University College of Pharmacy, Tulsa
D
President Bush signs the Genetic Nondiscrimination uring the first year of phar- student’s interests become more and are also integral in maintaining Information Act of 2008 into law.
macy school, students often join numerous organizations for several reasons, including social and professional networking, resume building, and increasing knowledge in perceived areas of interest. As a
focused and career paths are clarified, the number and type of organizations that he or she belongs to will also narrow. Organizations play a vital role in the professional growth of students and residents
lifelong learning and professional development as a pharmacist. Many organizations are available for professional and educational growth for students and residents
PHARMACY PRACTICE
Prevention and Management of
AMCP: New Study Looks at Use of ESAs in Real World Practice
ith the diagnosis of cancer comes the reality of an unforgiving disease process that renders the body’s natural defenses impotent. While this causes great anguish in and of itself, it is often what comes next that proves to be more troublesome. The cancer treatment itself presents formidable challenges to patients—the chemotherapy-induced neutropenia, persistent nausea and vomiting, alopecia,
SAN FRANCISCO—Prescribing practices appear to be changing when it comes to erythropoiesis-stimulating agents (ESAs), according to new data presented at the Academy of Managed Care Pharmacy’s 20th Annual Meeting and Showcase. Researchers found that between 2005 and 2006, there was a decrease in
Continued on page 13
Continued on page 6
W
Complimentary CE Credit
Continued on page 7
SUPPORTIVE CARE
Oral Mucositis
page 5
Cetuximab-induced Hypersensitivity: Case Reports and Discussion of Management
page 16
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RECENT FDA APPROVALS New regimens for HER2-positive breast cancer
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INTERVIEW Christopher Lowe, PharmD, Taussig Cancer Center
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MEDICAL MINUTES
Medical Minutes BY JOHN SCHIESZER
Interactive Electronic Pillbox May Help Older Adults Take Meds as Prescribed John Schieszer is an award-winning national journalist and radio broadcaster of The Medical Minute. He can be reached at medminutes@aol.com.
Older adults using an interactive, multidrug electronic pillbox may be significantly less likely to miss prescribed doses than those not using the box, according to new data presented at the American Geriatrics Society’s 2008 Annual Scientific Meeting. The pillbox beeps when it is time to take each medication and announces the number of pills to take and how to take them. Some research has suggested that more than 10% of older adult hospitalizations are attributable to medication noncompliance. For their study, researchers at the University of Maryland School of Pharmacy monitored the mediation compliance of older adults. All the patients were taking at least four prescription medications, often multiple times per day. The trial was designed to evaluate an integrated system using MedSignals, a four-drug communicating pillbox and to monitor medication intake in a naturalistic setting. In this randomized, crossover study, unprompted, naturalistic pill-
taking patterns were monitored and recorded for 3 weeks. For another 3-week period, pillboxes were set to remind participants when and how to take pills and to provide usage feedback for each of the four medications. The device recorded and time-stamped lid openings and uploaded data on a daily basis to host servers via a telephone line. All subjects were aged 65 years or older; 31% were men, 40% were black, and 22% were Hispanic. When the older adults used the pillbox, they were significantly more likely to take their medications as prescribed than when they did not use the pillbox. Moreover, the difference in compliance rates increased with the number of doses prescribed daily. When using the boxes, older adults were also less likely to miss all doses on a given day. The researchers found that 6% of the patients missed doses when using the box compared with 12% when not using it.
June 2008
Researchers at the University of Michigan have found a series of reduced by more than half of its original size received a full course of markers that indicate which patients are more likely to survive can- chemotherapy and radiation given simultaneously. Patients whose cers of the base of the tongue and tonsils. Most notably, they have tumor did not respond were referred for surgery. found that cancers linked to human papilloBy looking at biopsies taken before treatment, the researchers found mavirus (HPV) are the most responsive to current that 64% of the tumors were positive for high-risk strains of HPV. chemotherapy and radiation treatments, whereas Almost all of the HPV-positive tumors responded to initial chemotumors that express high levels of a certain growth therapy, and 78% of those patients survived with their organs preserved. factor receptor are the least responsive and most Of the HPV-negative study participants, only four of 15 survived. In deadly. addition, the researchers found that patients whose tumor expressed epiThe researchers say identification of these and dermal growth factor receptor (EGFR) had worse outcomes. other markers are a promising step in the direction Overall, the combination of markers was an important indicator, of tailored, individualized treatment for a type of and patients whose tumors expressed high levels of EGFR fared poorcancer that can have a dramatic impact on essen- ly. However, those patients who had high EGFR and were HPV-postial abilities such as swallowing and speaking. itive had some protection. The patients with high EGFR and low “The chemotherapy and radiation therapy we HPV levels fared the worst. Tumors with low expression of a protein use to treat this type of cancer is very aggressive. If called p53, combined with high expression of another protein, we can identify those patients most likely to BCLXL, also had poor outcomes. The authors concluded that these respond, we could reduce the intensity of the ther- markers provide additional targets for potential therapies. apy for those likely to have the best outcomes. At the same time, we hope to idenPreventing Cancer Through Good Oral Health? tify new treatments that specifically target Japanese researchers have found a strong cer-free subjects. They found that people those tumors that we know are not relink between tooth loss and increased risk of with tooth loss were 136% more likely to sponding to current therapies,” said senior three cancers: esophageal, head and neck, develop esophageal cancer; they also had a study author Thomas Carey, PhD, coand lung. The researchers suggest that 68% increased risk of developing head and director of the head and neck oncology preservation of teeth may decrease the risk neck cancer and a 54% greater chance of program at the University of Michigan, of developing these three types of cancer. developing lung cancer. The rate of cancer Ann Arbor. In the May 2008 issue of Cancer increased proportionally to the number of Cancers of the tonsils and the base of the Epidemiology, Biomarkers and Prevention, the teeth a patient had lost. These increased tongue have increased in recent years, in researchers speculate that bacterial infec- risks were seen after researchers took into what Carey calls an “epidemic” of HPVtion and inflammation resulting from poor account a patient’s history of smoking and induced head and neck cancer. This has oral healthcare may be driving the develop- alcohol use. occurred at the same time that declines in ment of these cancers. Periodontal disease Smaller studies have linked tooth loss to smoking rates have lead to a decrease in the is known to increase risk for stroke and different cancers, but this is the largest study incidence of other types of head and neck heart disease. to date and it is also the first study to show cancers. “Tooth loss is a common consequence of a link to lung cancer. The Japanese “The biggest challenge is how best to chronic bacterial infection and may, there- researchers say these findings may be clinitreat patients with tumors that stem from fore, serve as a surrogate for chronic infec- cally significant but more studies are needed. tobacco and alcohol use as opposed to tion and inflammation, which, in turn, may They suggest that widespread inflammatumors linked to HPV. We now know be important to the pathogenesis of cancer,” tion could explain the link between tooth they’re two different cancers,” said study said lead study author Akio Hiraki, PhD, a loss and cancer risk, but point out that coauthor Francis Worden, MD, an assistant researcher at the Aichi Cancer Center, tooth loss in cancer patients may simply professor of internal medicine at the Nagoya, Japan. reflect unhealthy behaviors that contribute University of Michigan. The researchers measured rates of 14 dif- to cancer risk. Furthermore, people who In this study, researchers treated 66 ferent cancers and rates of tooth loss in have lost teeth may not be able to eat a patients with advanced oropharyngeal can5,240 cancer patients in Japan, and com- healthful diet, and diet is also a factor in cer. Study subjects were given an initial pared those rates with 10,480 matched can- cancer development. course of chemotherapy to gauge the tumor’s response. Those whose tumor was G REEN H ILL H EALTH C ARE C OMMUNICATIONS
1
MEDICAL MINUTES
Illustration courtesy of the American Society of Cliniical Oncology.
HPV Linked to Better Survival in Tonsil and Tongue Cancers
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Vol. 1, No. 2
June 2008
Feature Articles
Departments
CONTENTS
1 Medical Minutes
6 Pharmacy Practice Reports from the Academy of Managed Care Pharmacy 20th Annual Meeting and Showcase
12 Cancer Center Profile Cleveland Clinic Taussig Cancer Center
5 8 10
Policy Watch New Technology Recent FDA Approvals
14 Cartoon 21 Meetings
16 Continuing Education Cetuximab-induced hypersensitivity: Case reports and discussion of management
online at Reach us
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EDITORIAL BOARD EDITOR-IN-CHIEF
Susan Goodin PharmD, FCCP, BCOP Cancer Institute of New Jersey New Brunswick, NJ
PUBLISHING STAFF Publisher Philip Pawelko phil@greenhillhc.com Editorial Director Karen Rosenberg karen@greenhillhc.com Managing Editor Lara J. Reiman Senior Production Manager Stephanie Laudien Directors, Client Services John W. Hennessy john@greenhillhc.com Russell Hennessy russell@greenhillhc.com Director of Human Resources Blanche Marchitto blanche@greenhillhc.com Circulation circulation@greenhillhc.com
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Christopher Fausel, PharmD
Christopher J. Lowe, PharmD
Indiana University Cancer Center Indianapolis, IN
Cleveland Clinic Taussig Cancer Center Cleveland, OH
Rebecca S. Finley, PharmD, MS
Robert B. MacArthur, PharmD
Jefferson School of Pharmacy Philadelphia, PA
Columbia University Medical Center New York, NY
David C. Gammon, BSPharm
Emily Mackler, PharmD, BCOP
University of Massachusetts Memorial Hospital Worcester, MA
University of Michigan Ann Arbor, MI
Heidi D. Gunderson, PharmD, BCOP
Patrick Medina, PharmD, BCOP
Mayo Clinic Cancer Center Rochester, MN
University of Oklahoma College of Pharmacy Tulsa, OK
Sandra Horowitz, PharmD, RPh
Laura Boehnke Michaud, PharmD, BCOP, FASHP
The University of Texas MD Anderson Cancer Center Houston, TX
The University of Texas MD Anderson Cancer Center Houston, TX
CONTENTS
David Baribeault, RPh, BCOP
Lew Iacovelli, BS, PharmD, BCOP, CPP
Boston Medical Center Boston, MA
Moses H. Cone Regional Cancer Center Greensboro, NC
Sylvia Bartel, RPh, MPH
Andrea A. Iannucci, PharmD, BCOP
Dana Farber Cancer Institute Boston, MA
University of California Davis Medical Center Sacramento, CA
Marlo Blazer, RPh, PharmD
Cindy Ippoliti, PharmD
Ohio State Comprehensive Cancer Center James Cancer Hospital and Solove Research Institute Columbus, OH
New York Presbyterian Hospital/ Weill Cornell Medical School New York, NY
Debra L. Phillips, PharmD
Bryna Delman Ewachiw, BS, PharmD
Jim Koeller, MS
John M. Valgus, PharmD, BCOP
Johns Hopkins Bayview Medical Center Baltimore, MD
University of Texas at Austin San Antonio, TX
University of North Carolina Chapel Hill, NC
Beth Faiman, RN, MSN, APRN, BC, AOCN
Helen L. Leather, BPharm
Gary C. Yee, PharmD, BCOP
Cleveland Clinic Taussig Cancer Center Cleveland, OH
University of Florida Gainesville, FL
University of Nebraska College of Pharmacy Omaha, NE
2
G REEN H ILL H EALTH C ARE C OMMUNICATIONS
Deborah Moradi, PharmD The Angeles Clinic and Research Institute Los Angeles, CA
LeAnn Best Norris, PharmD, BCPS South Carolina College of Pharmacy Columbia, SC East Carolina University Greenville, NC
June 2008
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Our
vision extends beyond science
…making today’s therapies more accessible and tomorrow’s breakthroughs more achievable Supporting today The Genentech® Access to Care Foundation makes our marketed products available to qualified patients in need* Genentech BioOncology™ Access Solutions™, formerly known as SPOC® (Single Point of Contact) — For patients and their healthcare providers, Genentech BioOncology Access Solutions provides coverage and reimbursement support, patient assistance, and informational resources Investing in tomorrow Genentech BioOncology invests deeply in research and development and is an industry leader in investing a percentage of annual revenues back into R&D Genentech BioOncology funds grant and fellowship programs to support medical education, partner with professional societies, and encourage independent research *The Genentech Access to Care Foundation was established to help qualified patients with unmet medical needs who are uninsured or rendered uninsured by payer denial and who meet specific medical criteria to receive proper medical treatment. The Genentech Access to Care Foundation may be available to help those who are not able to obtain Genentech therapeutics for financial reasons.
www.BioOncology.com
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EDITOR’S LETTER
A Letter from the Editor ith news this week from ASCO of innumerable advances in the treatment of a wide variety of solid tumors and hematologic malignancies coupled with reports of Sen. Kennedy’s successful surgery for brain cancer, it is clear that the outlook for patients with cancer has improved dramatically in recent years. Nonetheless, much remains to be accomplished. With each new advance in therapy come new concerns about side effects, safe handling of hazardous materials, the cost of treatment, and the effect of both the disease and its treatment on quality of life. Clearly then the education of pharmacists and other healthcare professionals is a continuing process. This month, The Oncology Pharmacist is proud to introduce the first in a series of complimentary continuing education articles accredited by the University of Nebraska Medical Center, Center for Continuing Education. The articles in this series are based on outstanding articles in the peer-reviewed literature with commentaries on their potential clinical implications by oncology pharmacists and nurses. The CE article this month addresses the issue of hypersensitivity reactions to cetuximab, a widely used and highly effective monoclonal antibody for treatment of metastatic colorectal cancer and head and neck cancer. Hypersensitivity reactions, although rare, are potentially life-threatening. Findings of a study
W
SUSAN GOODIN, PHARMD, FCCP, BCOP
EDITOR-IN-CHIEF
Coming in the next issue CE article: Calculating the Dosage of Anticancer Drugs in Obese Patients
Reports from ASCO: Advances in Treatment of Colorectal Cancer, Melanoma, Breast Cancer, Kidney Cancer, Hematologic Malignancies
New Approaches to the Treatment of Pediatric Neuroblastoma Managing Opiod-induced Constipation in Patients with Advanced Cancer Improving Patient Adherence to Cancer Therapy
EDITOR’S LETTER
Cancer Center Profile: H. Lee Moffitt Cancer Center & Research Institute
Personal Finances for Pharmacists
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G REEN H ILL H EALTH C ARE C OMMUNICATIONS
recently reported in the New England Journal of Medicine (NEJM) suggest a possible cause for these reactions: preexisting immunoglobulin E (IgE) antibodies were highly predictive of cetuximab-induced anaphylaxis. Interestingly, they found a regional pattern of susceptibility, with patients in certain southeastern states at greatest risk. The CE article in this issue summarizes the key points of the NEJM article and provides case reports and commentaries on the potential application of these important findings in clinical practice. Oral mucositis is another serious complication of cancer therapy that can have a major impact on the patient’s quality of life and ability to tolerate therapy. The article by Frank P. Whyte in this issue provides practical recommendations for prevention and management of this common debilitating side effect. Also in this issue are reports from the recent annual meeting of the Academy of Managed Care Pharmacy on use of erythropoiesisstimulating agents, the recent enactment of the landmark Genetic Information Nondiscrimination Information Act, and an article on what organizations are of value to pharmacy students and residents interested in pursuing a career in oncology pharmacy. We welcome your thoughts on this issue and suggestions on what topics you would like to see covered in future issues. Please send your comments to Karen@greenhillhc.com.
EDITORIAL CORRESPONDENCE should be addressed to EDITORIAL DIRECTOR, The Oncology Pharmacist™, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. E-mail: editorial@greenhillhc.com. YEARLY SUBSCRIPTION RATES: United States and possessions: individuals, $105.00; institutions, $135.00; single issues $17.00. Orders will be billed at individual rate until proof of status is confirmed. Prices are subject to change without notice. Correspondence regarding permission to reprint all or part of any article published in this journal should be addressed to REPRINT PERMISSIONS DEPARTMENT, Green Hill Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. The ideas and opinions expressed in The Oncology Pharmacist™, do not necessarily reflect those of the Editorial Board, the Editorial Director, or the Publisher. Publication of an advertisement or other product mention in The Oncology Pharmacist™, should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturer with questions about the features or limitations of the products mentioned. Neither the Editorial Board nor the Publisher assumes any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this periodical. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosage, the method and duration of administration, or contraindications. It is the responsibility of the treating physician or other healthcare professional, relying on independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Every effort has been made to check generic and trade names, and to verify dosages. The ultimate responsibility, however, lies with the prescribing physician. Please convey any errors to the Editorial Director. ISSN #Applied for in April 2008. The Oncology Pharmacist™, is published 5 times a year by Green Hill Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. Telephone: 732.656.7935. Fax: 732.656.7938. Copyright ©2008 by Green Hill Healthcare Communications LLC. All rights reserved. The Oncology Pharmacist™ logo is a trademark of Green Hill 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.
June 2008
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Genetic Nondiscrimination Information Act Signed into Law On May 21, 2008, President George W. Bush signed H.R. 493, the Genetic Information Nondiscrimination Act (GINA). The first civil rights legislation of this millennium, GINA will protect against discrimination by employers and health insurers based on their genetic information.
eligibility or pricing on genetic information. • Prohibiting employers from using genetic information to deny employment or insurance coverage. • Prohibiting insurers, issuers of Medigap policies, and employers from requesting, requiring, or pur-
chasing results of genetic tests or disclosing personal genetic information. Similar provisions apply to employment agencies and labor organizations. The parts of the law relating to health insurers will take effect by May 2009 and those relating to employers by November 2009. GINA does not apply
to members of the military or to life, disability, or long-term care insurance. According to the National Human Genome Research Institute, the measure “will pave the way for people to take full advantage of the promise of personalized medicine without fear of discrimination.
GINA will protect against discrimination by employers and health insurers based on their genetic information. The measure, which was debated in Congress for 13 years, was passed by a unanimous vote in the Senate and by a 414 to 1 vote in the House. GINA protects against genetic discrimination by: • Prohibiting health insurance plans from basing eligibility or premiums on an individual’s genetic information. • Prohibiting issuers of Medigap policies from basing
POLICY WATCH
Policy Watch
POWER AND PERFORMANCE VIDAZA hits MDS with the strength of transfusion independence.1,2 • 44% of red blood cell (RBC) transfusion-dependent patients achieved RBC transfusion independence.1*
Recognizes NCCN Compendium The Centers for Medicare and Medicaid Services (CMS) has announced that it will recognize the NCCN Drug and Biologics Compendium™ as a mandated reference for establishment of coverage policy and coverage decisions about use of drugs and biologic agents in cancer treatment. At the same time, CMS said it will cease use of the American Medical Association Drug Evaluations (AMA-DE) compendium, which is no longer updated or maintained. The NCCN compendium will be used mainly in determinations about coverage for use of oncology drugs and biologics beyond indications approved by the US Food and Drug Administration. United Healthcare recently announced that it would base its coverage for chemotherapeutic agents on the NCCN compendium.
• Median time to RBC transfusion independence was about 2.5 months.1 • In responding patients,† transfusion independence was durable, lasting a median of 330 days.2
Important Safety Information • VIDAZA is contraindicated in patients with a known hypersensitivity to azacitidine or mannitol and in patients with advanced malignant hepatic tumors. • In clinical studies, the most commonly occurring adverse reactions by SC route were nausea (70.5%), anemia (69.5%), thrombocytopenia (65.5%), vomiting (54.1%), pyrexia (51.8%), leukopenia (48.2%), diarrhea (36.4%), fatigue (35.9%), injection site erythema (35.0%), constipation (33.6%), neutropenia (32.3%), and ecchymosis (30.5%). Other adverse reactions included dizziness (18.6%), chest pain (16.4%), febrile neutropenia (16.4%), myalgia (15.9%), injection site reaction (13.6%), aggravated fatigue (12.7%), and malaise (10.9%). The most common adverse reactions by IV route also included petechiae (45.8%), weakness (35.4%), rigors (35.4%), and hypokalemia (31.3%). • Because treatment with VIDAZA is associated with neutropenia and thrombocytopenia, complete blood counts should be performed as needed to monitor response and toxicity, but at a minimum, prior to each dosing cycle. • Because azacitidine is potentially hepatotoxic in patients with severe preexisting hepatic impairment, caution is needed in patients with liver disease. In addition, azacitidine and its metabolites are substantially excreted by the kidneys and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function. • VIDAZA may cause fetal harm. While receiving treatment with VIDAZA, women of childbearing potential should avoid becoming pregnant, and men should avoid fathering a child. In addition, women treated with VIDAZA should not nurse.
9221 Study Design: A randomized, open-label, phase III study comparing the efficacy and safety of VIDAZA plus supportive care vs supportive care alone. 191 patients (132 male, 59 female, age 31–92) with all 5 subtypes of MDS classified according to the French, American, British (FAB) classification system were studied. VIDAZA was administered to patients subcutaneously at a dose of 75 mg/m2 daily for 7 days every 4 weeks. Dosage adjustments were allowed based on response or adverse events. The primary study endpoint was response rate. Response Criteria: Complete response was defined as <5% blasts in the bone marrow, absence of blasts in the peripheral circulation, and normal CBC (if abnormal at baseline) maintained for at least 4 weeks. Partial response was defined as at least a 50% decrease in bone marrow blasts and improvement of bone marrow dyspoiesis (for RAEB, RAEB-T, and CMMoL only) plus, for all subtypes, at least a 50% restoration in the deficit from normal of baseline white cells, hemoglobin, and platelets (if abnormal at baseline) and no blasts in the peripheral circulation maintained for at least 4 weeks. For CMMoL, if white cells were elevated at baseline, PR also required at least a 75% reduction in the excess count over the upper limit of normal, maintained for at least 4 weeks.
Please see the brief summary of prescribing information on the adjacent page.
*Of the 66 VIDAZA-treated patients who were RBC transfusion dependent at baseline, 29 (44%) achieved RBC transfusion independence.1 CR + PR = 16%. ‡ According to the FAB Classification System.
VIDAZA is a registered trademark of Pharmion Corporation. © 2007 Pharmion Corporation. All rights reserved. 2007288 May 2007 Printed in the USA.
References: 1. Data on file. Pharmion Corporation. 2. VIDAZA full prescribing information.
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VIDAZA is FDA-approved for the treatment of all myelodysplastic syndrome (MDS) subtypes2‡: RA or RARS (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), RAEB, RAEB-T, or CMMoL.
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the ratios of epoetin alfa (EPO) to darbepoetin alfa (DARBE) for patients receiving chemotherapy. The study findings also suggest that there will be even further changes in the coming months and year and annual recalculation may be merited. In the past 2 years, a great deal of attention has been focused on ESAs, in part because of their cost, dosing, and
Brief Summary of Prescribing Information VIDAZA (azacitidine for injection) only For subcutaneous and intravenous use only INDICATIONS AND USAGE VIDAZA is indicated for treatment of patients with the following myelodysplastic syndrome subtypes: refractory anemia or refractory anemia with ringed sideroblasts (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia. CONTRAINDICATIONS VIDAZA is contraindicated in patients with a known hypersensitivity to azacitidine or mannitol. VIDAZA is also contraindicated in patients with advanced malignant hepatic tumors. (See PRECAUTIONS). WARNINGS Pregnancy - Teratogenic Effects: Pregnancy Category D VIDAZA may cause fetal harm when administered to a pregnant woman. Early embryotoxicity studies in mice revealed a 44% frequency of intrauterine embryonal death (increased resorption) after a single IP (intraperitoneal) injection of 6 mg/m (approximately 8% of the recommended human daily dose on a mg/m basis) azacitidine on gestation day 10. Developmental abnormalities in the brain have been detected in mice given azacitidine on or before gestation day 15 at doses of ~3–12 mg/m (approximately 4%–16% the recommended human daily dose on a mg/m basis). In rats, azacitidine was clearly embryotoxic when given IP on gestation days 4–8 (postimplantation) at a dose of 6 mg/m (approximately 8% of the recommended human daily dose on a mg/m basis), although treatment in the preimplantation period (on gestation days 1–3) had no adverse effect on the embryos. Azacitidine caused multiple fetal abnormalities in rats after a single IP dose of 3–12 mg/m (approximately 8% the recommended human daily dose on a mg/m basis) given on gestation day 9, 10, 11 or 12. In this study azacitidine caused fetal death when administered at 3-12 mg/m on gestation days 9 and 10; average live animals per litter was reduced to 9% of control at the highest dose on gestation day 9. Fetal anomalies included: CNS anomalies (exencephaly/ encephalocele), limb anomalies (micromelia, clubfoot, syndactyly, oligodactyly), and others (micrognathia, gastroschisis, edema, and rib abnormalities). There are no adequate and well-controlled studies in pregnant women using VIDAZA. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with VIDAZA. Use in Males Men should be advised to not father a child while receiving treatment with VIDAZA. (See PRECAUTIONS: Carcinogenesis, Mutagenesis, Impairment of Fertility for discussion of premating effects of azacitidine exposure on male fertility and embryonic viability.) PRECAUTIONS General Treatment with VIDAZA is associated with neutropenia and thrombocytopenia. Complete blood counts should be performed as needed to monitor response and toxicity, but at a minimum, prior to each dosing cycle. After administration of the recommended dosage for the first cycle, dosage for subsequent cycles should be reduced or delayed based on nadir counts and hematologic response as described in DOSAGE AND ADMINISTRATION. Safety and effectiveness of VIDAZA in patients with MDS and hepatic or renal impairment have not been studied as these patients were excluded from the clinical trials. Because azacitidine is potentially hepatotoxic in patients with severe preexisting hepatic impairment, caution is needed in patients with liver disease. Patients with extensive tumor burden due to metastatic disease have been rarely reported to experience progressive hepatic coma and death during azacitidine treatment, especially in such patients with baseline albumin <30 g/L. Azacitidine is contraindicated in patients with advanced malignant hepatic tumors (See CONTRAINDICATIONS). Renal abnormalities ranging from elevated serum creatinine to renal failure and death have been reported rarely in patients treated with intravenous azacitidine in combination with other chemotherapeutic agents for nonMDS conditions. In addition, renal tubular acidosis, defined as a fall in serum bicarbonate to <20 mEq/L in association with an alkaline urine and hypokalemia (serum potassium <3 mEq/L) developed in 5 patients with CML treated with azacitidine and etoposide. If unexplained reductions in serum bicarbonate <20 mEq/L or elevations of BUN or serum creatinine occur, the dosage should be reduced or held as described in DOSAGE AND ADMINISTRATION. Patients with renal impairment should be closely monitored for toxicity since azacitidine and its metabolites are primarily excreted by the kidneys (see DOSAGE AND ADMINISTRATION section). Information for Patients Patients should inform their physician about any underlying liver or renal disease. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with VIDAZA. Men should be advised to not father a child while receiving treatment with VIDAZA. Laboratory Tests Complete blood counts should be performed as needed to monitor response and toxicity, but at a minimum, prior to each cycle. Liver chemistries and serum creatinine should be obtained prior to initiation of therapy. Drug Interactions No formal assessments of drug-drug interactions between VIDAZA and other agents have been conducted. (See CLINICAL PHARMACOLOGY.) ®
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safety issues. This past March, a US Food and Drug Administration advisory committee recommended that the use of ESAs be substantially limited in the treatment of anemia in cancer patients. New concerns have been raised because a recent meta-analysis (JAMA. 2008;299:914-924) showed that ESAs may increase the risk of blood clots and death in patients receiving these agents for chemotherapy-induced anemia. Caremark conducted an internal
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Carcinogenesis, Mutagenesis, Impairment of Fertility The potential carcinogenicity of azacitidine was evaluated in mice and rats. Azacitidine induced tumors of the hematopoietic system in female mice at 2.2 mg/kg (6.6 mg/m , approximately 8% the recommended human daily dose on a mg/m basis) administered IP 3 times per week for 52 weeks. An increased incidence of tumors in the lymphoreticular system, lung, mammary gland, and skin was seen in mice treated with azacitidine IP at 2.0 mg/kg (6.0 mg/m , approximately 8% the recommended human daily dose on a mg/m basis) once a week for 50 weeks. A tumorigenicity study in rats dosed twice weekly at 15 or 60 mg/m (approximately 20%–80% the recommended human daily dose on a mg/m basis) revealed an increased incidence of testicular tumors compared with controls. The mutagenic and clastogenic potential of azacitidine was tested in in vitro bacterial systems Salmonella typhimurium strains TA100 and several strains of trpE8, Escherichia coli strains WP14 Pro, WP3103P, WP3104P, and CC103; in in vitro forward gene mutation assay in mouse lymphoma cells and human lymphoblast cells; and in an in vitro micronucleus assay in mouse L5178Y lymphoma cells and Syrian hamster embryo cells. Azacitidine was mutagenic in bacterial and mammalian cell systems. The clastogenic effect of azacitidine was shown by the induction of micronuclei in L5178Y mouse cells and Syrian hamster embryo cells. Administration of azacitidine to male mice at 9.9 mg/m (approximately 9% the recommended human daily dose on a mg/m basis) daily for 3 days prior to mating with untreated female mice resulted in decreased fertility and loss of offspring during subsequent embryonic and postnatal development. Treatment of male rats three times per week for 11 or 16 weeks at doses of 15–30 mg/m (approximately 20%–40%, the recommended human daily dose on a mg/m basis) resulted in decreased weight of the testes and epididymides, and decreased sperm counts accompanied by decreased pregnancy rates and increased loss of embryos in mated females. In a related study, male rats treated for 16 weeks at 24 mg/m resulted in an increase in abnormal embryos in mated females when examined on day 2 of gestation. (See WARNINGS.) Pregnancy Teratogenic Effects: Pregnancy Category D. (See WARNINGS.) Nursing Mothers It is not known whether azacitidine or its metabolites are excreted in human milk. Because of the potential for tumorigenicity shown for azacitidine in animal studies and the potential for serious adverse reactions, women treated with azacitidine should not nurse. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use Of the total number of patients in the 3 clinical studies described in CLINICAL STUDIES, above, 62% were 65 years and older and 21% were 75 years and older. No overall differences in effectiveness were observed between these patients and younger patients. In addition there were no relevant differences in the frequency of adverse events observed in patients 65 years and older compared to younger patients. Azacitidine and its metabolites are known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function (see DOSAGE AND ADMINISTRATION section). ADVERSE REACTIONS Overview Adverse Reactions Described in Other Labeling Sections: neutropenia, thrombocytopenia, elevated serum creatinine, renal failure, renal tubular acidosis, hypokalemia, hepatic coma. Most Commonly Occurring Adverse Reactions (SC or IV Route): nausea, anemia, thrombocytopenia, vomiting, pyrexia, leukopenia, diarrhea, fatigue, injection site erythema, constipation, neutropenia, ecchymosis. The most common adverse reactions by IV route also include petechiae, rigors, weakness and hypokalemia. Adverse Reactions Most Frequently (>2%) Resulting in Clinical Intervention (SC or IV Route): Discontinuation: leukopenia (5.0%), thrombocytopenia (3.6%), neutropenia (2.7%). Dose Held: leukopenia (4.5%), neutropenia (4.5%), febrile neutropenia (2.7%). Dose Reduced: leukopenia (4.5%), neutropenia (4.1%), thrombocytopenia (3.2%). Discussion of Adverse Reactions Information The data described below reflect exposure to VIDAZA in 268 patients, including 116 exposed for 6 cycles (approximately 6 months) or more and 60 exposed for greater than 12 cycles (approximately 1 year). VIDAZA was studied primarily in supportive-care-controlled and uncontrolled trials (n = 150 and n = 118, respectively). The population in the subcutaneous studies (n = 220) was 23 to 92 years old (mean 66.4 years), 68% male, and 94% white, and had MDS or AML. The population in the IV study (n = 48) was 35 to 81 years old (mean 63.1 years), 65% male, and 100% white. Most patients received average daily doses between 50 and 100 mg/m . The following table presents the most common adverse events, whether or not considered drug related by investigators, occurring in at least 5% of patients treated with VIDAZA in the supportive-care-controlled trial and the uncontrolled subcutaneous trial combined. It is important to note that duration of exposure was longer for the VIDAZA-treated group than for the observation group: patients received VIDAZA for a mean of 11.4 months while mean time in the observation arm was 6.1 months. 2
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Table 4: Most Frequently Observed Adverse Events (>5% in All VIDAZA)a Continued
Table 4: Most Frequently Observed Adverse Events (>5% in All VIDAZA)a b
Preferred Term
All VIDAZA (N=220) At least 1 TEAE 219 (99.5) Nausea 155 (70.5) Anemia 153 (69.5) Thrombocytopenia 144 (65.5) Vomiting 119 (54.1) Pyrexia 114 (51.8) Leukopenia 106 (48.2) Diarrhea 80 (36.4) Fatigue 79 (35.9) Injection site erythema 77 (35.0) Constipation 74 (33.6) Neutropenia 71 (32.3) Ecchymosis 67 (30.5) Cough 65 (29.5) Dyspnea 64 (29.1) Weakness 64 (29.1) Rigors 56 (25.5) Petechiae 52 (23.6) Injection site pain 50 (22.7) Arthralgia 49 (22.3) Headache 48 (21.8) Anorexia 45 (20.5) Pain in limb 44 (20.0) Pharyngitis 44 (20.0) Back pain 41 (18.6) Contusion 41 (18.6) Dizziness 41 (18.6) Edema peripheral 41 (18.6) Erythema 37 (16.8) Chest pain 36 (16.4) 36 (16.4) Epistaxis Febrile neutropenia 36 (16.4) Myalgia 35 (15.9) Weight decreased 35 (15.9) Abdominal pain 34 (15.5) Pallor 34 (15.5) Nasopharyngitis 32 (14.5) Pitting edema 32 (14.5) 32 (14.5) Skin lesion Dyspnea exertional 31 (14.1) Injection site bruising 31 (14.1) Rash 31 (14.1) Injection site reaction 30 (13.6) Anxiety 29 (13.2) Appetite decreased 28 (12.7) Fatigue aggravated 28 (12.7) 28 (12.7) Hypokalemia Upper respiratory tract 28 (12.7) infection Pruritus 27(12.3) Abdominal tenderness 26 (11.8) Depression 26 (11.8) Productive cough 25 (11.4) Insomnia 24 (10.9) Malaise 24 (10.9) Pain 24 (10.9) Pneumonia 24 (10.9) Abdominal pain upper 23 (10.5) Crackles lung 23 (10.5) Sweating increased 23 (10.5) Cardiac murmur 22 (10.0) 22 (10.0) Rhinorrhea Gingival bleeding 21 (9.5) Lymphadenopathy 21 (9.5) Herpes simplex 20 (9.1) Hematoma 19 (8.6) Night sweats 19 (8.6) Rales 19 (8.6) Tachycardia 19 (8.6) Wheezing 19 (8.6) Cellulitis 18 (8.2) Dysuria 18 (8.2) Breath sounds 17 (7.7) decreased Lethargy 17 (7.7) Oral mucosal 17 (7.7) petechiae Stomatitis 17 (7.7) Urinary tract infection 17 (7.7) Peripheral swelling 16 (7.3) Dyspepsia 15 (6.8) 15 (6.8) Hemorrhoids Hypotension 15 (6.8) Injection site pruritus 15 (6.8) Transfusion reaction 15 (6.8) Pleural effusion 14 (6.4) Abdominal distension 13 (5.9) Muscle cramps 13 (5.9) Post procedural 13 (5.9) hemorrhage
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Observation (N=92) 89 (96.7) 16 (17.4) 59 (64.1) 42 (45.7) 5 (5.4) 28 (30.4) 27 (29.3) 13 (14.1) 23 (25.0) 0 6 (6.5) 10 (10.9) 14 (15.2) 14 (15.2) 11 (12.0) 19 (20.7) 10 (10.9) 8 (8.7) 0 3 (3.3) 10 (10.9) 6 (6.5) 5 (5.4) 7 (7.6) 7 (7.6) 9 (9.8) 5 (5.4) 10 (10.9) 4 (4.3) 5 (5.4) 9 (9.8) 4 (4.3) 2 (2.2) 10 (10.9) 12 (13.0) 7 (7.6) 3 (3.3) 9 (9.8) 8 (8.7) 15 (16.3) 0 9 (9.8) 0 3 (3.3) 8 (8.7) 4 (4.3) 12 (13.0) 4 (4.3) 11 (12.0) 1 (1.1) 7 (7.6) 4 (4.3) 4 (4.3 1 (1.1) 3 (3.3) 5 (5.4) 3 (3.3) 8 (8.7) 2 (2.2) 8 (8.7) 2 (2.2) 4 (4.3) 3 (3.3) 5 (5.4) 0 3 (3.3) 8 (8.7) 6 (6.5) 2 (2.2) 4 (4.3) 2 (2.2) 1 (1.1) 2 (2.2) 3 (3.3) 0 5 (5.4) 5 (5.4) 4 (4.3) 1 (1.1) 2 (2.2) 0 0 6 (6.5) 4 (4.3) 3 (3.3) 1 (1.1)
Preferred Termb
All VIDAZAc Observationd (N=220) (N=92) At least 1 TEAE 219 (99.5) 89 (96.7) Postnasal drip 13 (5.9) 3 (3.3) Rhonchi 13 (5.9) 2 (2.2) Syncope 13 (5.9) 5 (5.4) Urticaria 13 (5.9) 1 (1.1) Anemia aggravated 12 (5.5) 5 (5.4) Loose stools 12 (5.5) 0 Nasal congestion 12 (5.5) 1 (1.1) Atelectasis 11 (5.0) 2 (2.2) Chest wall pain 11 (5.0) 0 Dry skin 11 (5.0) 1 (1.1) Dysphagia 11 (5.0) 2 (2.2) Dyspnea exacerbated 11 (5.0) 3 (3.3) Hypoesthesia 11 (5.0) 1 (1.1) Injection site 11 (5.0) 0 granuloma Injection site 11 (5.0) 0 pigmentation changes Injection site swelling 11 (5.0) 0 Mouth hemorrhage 11 (5.0) 1 (1.1) Post procedural pain 11 (5.0) 2 (2.2) Sinusitis 11 (5.0) 3 (3.3) Skin nodule 11 (5.0) 1 (1.1) Tongue ulceration 11 (5.0) 2 (2.2) a Mean VIDAZA exposure = 11.4 months. Mean time in observation arm = 6.1 months. b Multiple reports of the same preferred terms for a patient are only counted once within each treatment group. c Includes events from all patients exposed to VIDAZA, including patients after crossing over from observation. d Includes events from observation period only; excludes any events after crossover to VIDAZA. For SC VIDAZA administration, nausea, vomiting, diarrhea, and constipation all tended to increase in incidence with increasing doses of VIDAZA. Nausea, vomiting, injection site erythema, constipation, rigors, petechiae, injection site pain, dizziness, injection site bruising, anxiety, hypokalemia, insomnia, epistaxis, and rales tended to be more pronounced during the first 1-2 cycles of SC VIDAZA treatment compared with later cycles of treatment. There did not appear to be any adverse events that increased in frequency over the course of treatment. There did not appear to be any relevant differences in adverse events by gender. Overall, adverse reactions were qualitatively similar between the IV and SC studies. Adverse reactions that appeared to be specifically associated with the IV route of administration included infusion site reactions (e.g., erythema or pain) and catheter site reactions (e.g., infection, erythema, or hemorrhage). In clinical studies of either SC or IV VIDAZA, the following serious treatment-related adverse events occurring at a rate of <5% (not described in Table 4) were reported: Blood and lymphatic system disorders: agranulocytosis, bone marrow depression, splenomegaly. Cardiac disorders: atrial fibrillation, cardiac failure, cardiac failure congestive, cardiorespiratory arrest, congestive cardiomyopathy. Gastrointestinal disorders: diverticulitis, gastrointestinal hemorrhage, melena, perirectal abscess. General disorders and administration site conditions: catheter site hemorrhage, general physical health deterioration, systemic inflammatory response syndrome. Hepatobiliary disorders: cholecystitis Immune system disorders: anaphylactic shock, hypersensitivity. Infections and infestations: abscess limb, bacterial infection, blastomycosis, injection site infection, Klebsiella sepsis, pharyngitis streptococcal, pneumonia Klebsiella, sepsis, Staphylococcal bacteremia, Staphylococcal infection, toxoplasmosis. Metabolism and nutrition disorders: dehydration. Musculoskeletal and connective tissue disorders: bone pain aggravated, muscle weakness, neck pain. Neoplasms benign, malignant and unspecified: leukemia cutis. Nervous system disorders: convulsions, intracranial hemorrhage. Psychiatric disorders: confusion. Renal and urinary disorders: hematuria, loin pain, renal failure. Respiratory, thoracic and mediastinal disorders: hemoptysis, lung infiltration, pneumonitis, respiratory distress. Skin and subcutaneous tissue disorders: pyoderma gangrenosum, rash pruritic, skin induration. Surgical and medical procedures: cholecystectomy. Vascular disorders: orthostatic hypotension. Manufactured for: Pharmion Corporation Boulder, CO 80301 Manufactured by: Ben Venue Laboratories, Inc. Bedford, OH 44146 Edition Date: 9 January 2007 Brief Summary of Prescribing Information VIDAZA is a registered trademark of Pharmion Corporation. © 2007 Pharmion Corporation. All rights reserved. VIDB010907A January 2007 Printed in USA.
“There are different dose ratios that are cited in the literature today. We wanted to run our own medical claims data to determine what the calculated doses ratio was in our patient population. In addition, given the recent safety concerns with the ESAs, we felt it was important to look at how many patients were actually receiving ESAs and were not receiving chemotherapy,” said study investigator Andrea Straszewski, PharmD, who is specialty pharmacy program manager, CVS Caremark, Northbrook, Ill. Dr Straszewski, who presented the study findings at the meeting, said patients were identified from a medical claims database of approximately 3 million lives. These individuals were in both commercial health plans and employer groups. The selection criteria included a cancer diagnosis, and all the patients had to have had at least two ESAs administered during the analysis year. Patients were excluded if they switched between EPO and DARBE. Patients were also excluded if they received doses outside clinically expected ranges, were receiving renal dialysis, or had myelodysplasia. In addition, patients were excluded if they were taking ribavirin or zidovudine. The researchers found that approximately one sixth of cancer patients using ESAs were not receiving chemotherapy. In addition, they found that cancer patients who were receiving chemotherapy had a higher EPO:DARBE dose ratio than those who were not. The EPO:DARBE ratio for cancer patients receiving chemotherapy decreased from 258 in 2005 to 237 in 2006. However, the EPO:DARBE ratio for cancer patients not receiving chemotherapy did not change significantly: 213 in 2005 to 219 in 2006. The researchers concluded that as drug safety, efficacy, and cost continue to be areas of interest, these types of databases may play an important role in understanding real-world practice. “There are many safety issues regarding the ESAs that are resulting in changes in prescribing practices. It is important for pharmacists to be aware of the changes occurring in this class and to continue to be advocates for patient care,” said Dr Straszewski. —John Schiezer Continued on page 8
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ORGANIZATIONS Continued from cover
interested in oncology pharmacy. Deciding on which of these in one will maintain active memberships requires knowledge of what resources they PATRICK MEDINA, offer. Active memberPharmD, BCOP ship in professional organizations at the national and state level can provide the following benefits: • Increased pharmacy practice skills • Knowledge of professional opportunities • Residency and employment resources • Specific oncology-related professional development • Leadership opportunities Table 1 describes some of the oncology-specific resources available to students and residents from four national organizations. The American Society of Health-System Pharmacists (ASHP) is a 30,000-member national professional association that represents pharmacists who practice in a variety of health-systems pharmacy settings. State affiliates are available in most locations and offer students and residents a smaller atmosphere in which to experience some of the benefits of the larger parent organization. Membership is often offered at a reduced rate for students and residents. ASHP offers numerous resources for students and residents of many subspecialties, including those with an oncology focus. For students, ASHP is the accrediting organization for PGY-1 and PGY-2 residencies and offers information on both the benefits of residency training and steps to successfully obtaining in a PGY-1 position. Information on accredited PGY-2 programs specific for oncology training are available online. ASHP maintains an online residency directory of all accred-
ited PGY-1 and PGY-2 programs that will assist students and residents in navigating this sometimes confusing process. Residents completing their PGY-2 year can search careerPharm.com for potential employment information. ASHP has several networking forums known as “sections,” including a student-specific forum that provides educational and networking opportunities. ASHP also has several educational opportunities and policies specific to oncology pharmacy practice, including policies on the safe handling of hazardous drugs, webbased continuing education programs, and The American Journal of HealthSystems Pharmacy. The American College of Clinical Pharmacy (ACCP) is another national organization that focuses on clinical practice and research. ACCP offers some of the same benefits as ASHP, including an online directory of residencies and fellowships. In addition to residency programs, this directory includes oncology programs accredited by ACCP to provide fellowship training that focuses on developing research skills. Career opportunities and job listings are also available on the web site. For students, ACCP offers several benefits, including numerous leadership and networking opportunities specific to them, as well as a student travel award that provides support to attend the national ACCP meeting. Students and residents may find the Practice and Research Network (PRN) in hematology/oncology a valuable resource. This PRN subsection of ACCP provides members with common practice and research interests in oncology an opportunity to gather for professional interaction, networking, and continuing education. The ACCP’s journal, Pharmacotherapy, which is provided with membership, contains articles pertaining to clinical pharmacy practice and research.
Table 2. Additional Oncology Organizations Organization
Website
American Society of Clinical Oncology
www.asco.org
American Society for Blood and Marrow Transplantation
www.asbmt.org
American Society of Hematology American Association for Cancer Research Multinational Association of Supportive Care in Cancer Oncology Nursing Society
Other national organizations that are not specific to oncology practice but may be useful for students include the American Pharmacists Association (APhA), the Academy of Managed Care Pharmacy (AMCP), and the American Society of Consultant Pharmacists (ASCP). Although oncology practitioners are not the primary membership of these organizations, they do provide educational and professional opportunities for certain students and residents. Until recently, these national organizations with a broad focus were the main organizations available to students and residents with an interest in oncology. The Hematology/Oncology Pharmacy Association (HOPA) was established in 2004 to provide resources specific to hematology/oncology practitioners to assist them in providing “the best possible cancer care.” HOPA provides numerous oncology-specific resources and forums that both students and residents will find valuable in their professional growth. Some specific resources available to members include chemotherapy dose calculators, links to spe-
Table 1. Select Pharmacy-specific Organizations with Oncology Resources Organization
Web site
Discounted student/ resident dues (in US $)
www.hematology.org www.aacr.org www.mascc.org www.ons.org
cific chemotherapy regimens and recommended dose adjustments, oncology continuing education programs and best practices, and an oncology-specific list serv. Job postings are also available to residents searching for oncology-specific employment. Finally, there is an annual meeting focusing on improving patient outcomes and care of cancer patients along with opportunities to network with other oncology professionals. The International Society of Oncology Pharmacy Practitioners (ISOPP) is another organization specific to pharmacy practitioners, which includes an international membership. This organization publishes the Journal of Oncology Pharmacy Practice on a quarterly basis. Although not specific for pharmacy practitioners, and therefore having limited resources pertaining to pharmacy students and residents, other oncologyspecific organizations are useful resources for continued professional growth and provide valuable resources related to oncology patient care. These organizations are listed in Table 2. To obtain the most benefit from these organizations, it is important to join organizations that fit your particular needs and to actively participate in them.
Student/resident and oncology-specific content
American Society of Health-Systems Pharmacists
www.ashp.org
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Residency and job information, continuing education programs, policy statements, student forums, hematology/oncology networking group
American College of Clinical Pharmacy
www.accp.com
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Residency, fellowship and job listings, hematology/oncology Practice and Research Network group
Hematology/Oncology Pharmacy Association
www.hoparx.org
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Specific to the care of cancer patients, job listings (limited residency listings), oncology-specific links to educational and practice resources
International Society of Oncology Pharmacy Practitioners
www.isopp.org
Based on salary
Journal of Oncology Pharmacy Practice, limited other resources for students/ residents
June 2008
PHARMACY EDUCATION AND TRAINING
6/9/08
PHARMACY EDUCATION AND TRAINING
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Did you
Know? Fifty one percent of insured Americans are taking at least one prescription drug for a chronic health condition. The biggest jump was in those 20 to 44 years old, in whom drug use rose 20% from 2001 to 2007. Source: Medco Health Solutions.
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NEW TECHNOLOGY
Endoscopic Procedure for Treating
Barrett’s Esophagus radiofrequency ablation (RFA) procedure is showing promise for the treatment of Barrett’s esophagus, a precancerous condition caused by chronic gastroesophageal reflux disease (GERD). Adenocarcinoma of the esophagus, although rare, is the fastest rising type of cancer in the United States, particularly among white men. The 5-year survival rate is just 17%. Standard management of Barrett’s esophagus is frequent endoscopic surveillance of patients with chronic GERD. In some cases, the condition is treated surgically. Recently
Medicine. Patients were randomly assigned to receive either endoscopic ablation therapy using the HALO ablation system or a sham intervention. Biopsies were taken at regular intervals to detect Barrett’s, dysplasia, and/or cancer. The investigators found that at 12 months, 85% of patients in the RFA group had no detectable dysplasia, and 74% had no signs of Barrett’s esophagus. None of the RFA patients progressed to high-grade dysplasia or esophageal cancer. None of the patients in the control group were free of Barrett’s esophagus and in some, the condition grew worse. “Our interim results are highly At 12 months, 85% of patients in the RFA group promising, demonstrating superiority for ablation therapy for eliminating Barrett’s and dysplahad no dysplasia, and 74% had no signs of sia, as well as reducing the risk for Barrett’s esophagus. disease progression,” Dr Shaheen commented. reported studies suggest that an RFA procedure using the Similarly, in a multicenter registry study of 142 HALO360 and HALO90 Systems (Barrx Medical, Inc, patients with Barrett’s esophagus containing high-grade Sunnyvale, CA) may provide an alternative approach. dysplasia (HGD), Robert A. Ganz, MD, and associates Speaking at Digestive Disease Week 2008 in San Diego, found that 90.2% of patients were free of HGD a mediNicholas Shaheen, MD, MPH, reported interim results of an of 12 months after undergoing endoscopic circumferthe AIM Dysplasia trial, a multicenter study of 127 patients ential ablation with the HALO360 System (Gastrointest with dysplastic Barrett’s esophagus . Dr Shaheen is an asso- Endosc. 2008 Mar 18). The RFA procedure is performed on an outpatient ciate professor of medicine and epidemiology and director of the Center for Esophageal Diseases and Swallowing at the basis under conscious sedation. The HALO360 System University of North Carolina-Chapel Hill School of applies a controlled amount of heat energy to the diseased esophageal tissue, resulting in restoration of a normal esophageal lining in most patients. The HALO90 System is an adjunctive device used to treat small areas of residual disease after the initial treatment. Studies have shown a further increase in response when the two systems are used in a stepwise manner. In the largest study of the two devices used together, 98.4% of patients had complete elimination of Barrett’s tissue 2.5 years after initial therapy. Both systems have been cleared by the US Food and Drug Administration and are commercially available.
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For further information about the HALO ablation systems, contact Barrx Medical at
www.barrx.com AMCP Continued from page 6
NEW TECHNOLOGY
AMCP: Rounding Down Chemotherapy Doses May Be Associated with Significant Cost Savings SAN FRANCISCO—Rounding down chemotherapy doses by the pharmacist in the ambulatory infusion center (AIC) may significantly help reduce drug-acquisition costs and help lower hazardous waste, according to a 8
new study presented at the Academy of Managed Care Pharmacy’s 20th Annual Meeting and Showcase. However, the authors of the study say studies are still needed to evaluate how this practice may affect clinical outcomes and overall waste disposal. “In an effort to conserve the number of bottles we open in a pharmacy, we try to consolidate as much as possible. We found that when doses were rounded down, there were cost savings and decreased waste,” said study investigator Randell Miyahara, PharmD, who is clinical coordinator for pharmacy services at the VA Palo Alto Health Care System, Calif. Dr Miyahara, who presented the
G REEN H ILL H EALTH C ARE C OMMUNICATIONS
study findings at the meeting, said chemotherapeutic agents can cost thousands of dollars per treatment, and there is a great propensity for drug waste. This waste is primarily due to the fact that the quantity of the drug supplied often does not exactly match the dose prescribed by the physician. At several institutions, rounding down chemotherapy doses to the nearest vial size is a common practice. It is believed that this practice can help reduce drug costs, reduce waste, and help further simplify preparation. However, there are no guidelines recommending this practice. “The big picture is that anecdotally we know this is being done at other
pharmacies. We tried to find guidelines on this practice, but we could not find any. So we don’t know if it is an acceptable practice. There are no clinical outcomes studies on this type of practice, but we hope that studies will be done in this area. We think it is reducing waste and saving money, but we need to know more about it. We also need to initiate more dialogue among the pharmacy and oncology communities regarding this practice,” Dr Miyahara told The Oncology Pharmacist. For his study, Dr Miyahara examined what the cost savings are with rounding down chemotherapy doses by a pharmacist in the AIC. The secondary objectives of the study were to determine the average chemotherapy dose reduction at the VA Palo Alto Health Care System and to determine the amount of waste that would have accrued in the absence of dose adjustments.
At several institutions, rounding down chemotherapy doses to the nearest vial size is a common practice. In this retrospective review study, all patients admitted to the AIC for chemotherapy administration from November 1, 2006, to April 30, 2007, were included. All the patients were 18 years of age or older. The study showed that a total of 84 (25%) of 333 collected chemotherapy orders had doses rounded down. The subsequent cost savings for the 6-month study period was estimated to be $6,600 for the VA Palo Alto Health Care System and extrapolated to $13,100 for the average wholesale price. The study also showed the average dose reduction was 2% among all the rounded down orders. The waste avoided was estimated to be 2,330 mg (230 mL) of chemotherapy drugs. In addition, the creation of 40 partial vials was avoided. The study suggested that rounding down doses is an appropriate practice and does help eliminate waste and provide important cost savings. However, Dr Miyahara said this practice needs to be further studied in a prospective fashion with a large number of patients to determine its overall impact on clinical outcomes. “The potential downside is poor patient outcomes due to underdosing. So we don’t want that to happen. We think this 2% is not clinically significant, but we don’t know that yet,” Dr Miyahara explained. —JS Continued on page 10
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PHARMACY PRACTICE
AMCP: HER2 Testing and Treatment Patterns Among Newly Diagnosed Breast Cancer Patients SAN FRANCISCO— A new study by Delaware researchers suggests that human epidermal growth factor receptor type 2 (HER2) testing guidelines are almost always followed and shows little evidence of inappropriate trastuzumab use in HER-underexpressing patients. Their study findings, which were presented at the Academy of Managed Care Pharmacy’s 20th Annual Meeting and Showcase, contradict a prior report suggesting that up to 20% of women who received trastuzumab did not have a HER2 test performed or had HER2 underexpression.
The Tumor Marker Guidelines Panel convened by the American Society of Clinical Oncology since 2001 has recommended the routine testing of HER2 status among all patients with newly diagnosed, recurrent, and metastatic breast cancer. It has been estimated that 18% to 23% of invasive breast carcinomas demonstrate evidence of HER overexpression and may be candidates for treatment with the recombinant humanized anti-HER2 monoclonal antibody trastuzumab.
The big picture is that it did not appear that trastuzumab is being used inappropriately in women with HER2-negative tumors. A recently published interview with a managed care medical director raised concerns about the use of trastuzumab in breast cancer patients. It was suggested that up to 20% of patients with breast cancer may be receiving trastuzumab therapy even though they did not
Recent FDA Approvals • Relistor for Opioid-induced Constipation The US Food and Drug Administration (FDA) has approved methylnaltrexone bromide (Relistor; Wyeth) to relieve constipation stemming from continuous use of opioids by patients with late-stage, advanced illness. Relistor acts by blocking opioid entrance into specific cells, allowing the bowels to function normally. This agent should be injected at intervals, not to exceed once in a 24-hour period. It is not recommended for people with known or possible bowel obstructions. Side effects may include abdominal pain, gas, nausea, dizziness, and diarrhea. • Palifosfamide for Soft-tissue Sarcoma The FDA has granted orphan drug approval for palifosfamide (Ziopharm Oncology) for treatment of soft tissue sarcoma. The intravenous form of palifosfamide is currently being evaluated in phase 2 clinical trials, and the oral form of this agent is expected to enter phase 1 clinical trials in early 2009.
PHARMACY PRACTICE
• New Chemotherapeutic Regimens for
HER2-Positive Early Breast Cancer The FDA has approved two new chemotherapeutic regimens for the adjuvant treatment of HER2-positive early breast cancer based on data from the phase 3 BCIRG 006 trial. The TCH regimen consists of docetaxel (Taxotere) and carboplatin combined with trastuzumab (Herceptin). The AC-TH regimen consists of doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab. TCH and AC-TH both showed a disease-free benefit regardless of the patient’s age, hormone receptor status, or nodal status. Patients treated
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have a documented HER2 test or HER2 overpression. The Delaware researchers decided to evaluate HER2 testing patterns and use of trastuzumab in a community-based observational study of patients with newly diagnosed breast cancer. The researchers reviewed administrative claims data from three health plans and identified women with newly diagnosed breast cancer between June 1, 2005, and June 30, 2006. They reviewed hematology and oncology medical charts, and women with any type of cancer
with these regimens also demonstrated a significant improvement in overall survival. The risk of congestive heart failure was fivefold lower in patients who received TCH than in those who received AC-TH (0.4% vs 1.9%, respectively).
Safety Plans Now Required for 25 Drugs and Biologics In keeping with the recent US Food and Drug Administration Amendments Act of 2007 (FDAAA), manufacturers of certain agents have been asked to submit safety plans to the FDA. These safety plans, called Risk Evaluation and Mitigation Strategy (REMS), are now required for drugs and biologics that may provide important benefit to patients, but which may still pose substantial risks under certain circumstances (eg, agents that may harm a fetus or cause miscarriage if taken during pregnancy). A Federal Register has been issued by the FDA identifying 25 potentially dangerous drugs that were approved before the FDAAA was passed on March 25, 2008. The FDA is advising the public to notify the agency if they believe other agents should be considered to have REMS under this new amendment. Going forward, any new drugs approved by the FDA will be subject to these requirements as well. To view the Federal Register notice, which includes a list of the 25 drugs and biologics required to submit REMS, go to www.fda.gov/OHRMS/DOCKETS/ 98fr/E8-6201.htm.
G REEN H ILL H EALTH C ARE C OMMUNICATIONS
documented in the medical chart prior to June 1, 2005, were excluded. A total of 380 women (mean age, 54 years) treated by 179 different physicians were identified. The researchers found that HER2 testing was performed in 335 (88%) women; 72 (22% ) were HER2-positive, 259 (77%) were HER2-negative, and in four (1%) HER2 status was unknown. Of the 52 women who received trastuzumab treatment , 51 (98%) were HER2 positive. “We saw that HER2 testing was done in almost all the women, which was very good news. So it looks like that is not an issue,” said study investigator John Barron, PharmD, research operations director at HealthCore, Wilmington, Del. “The big picture is that it did not appear that trastuzumab is being used inappropriately in women with HER2negative tumors. There had been some reports in the literature that between 12% and 20% of breast cancer patients were receiving this drug inappropriately. Our findings are reassuring.” Dr Barron and his colleagues found that among the 45 women who did not undergo HER2 testing, 33 (73%) had ductal carcinoma in situ (DCIS) or lobular carcinoma in situ (LCIS). None of the 45 women received trastuzumab. Of the 72 women with HER2- positive tumors, 21 (29%) did not receive trastuzumab. These 21 women tended to be older, received less chemotherapy (43% versus 98%), and had less advanced cancer stages (Stage 0-1: 57% versus 22%) than those who received trastuzumab. Overall, the researchers concluded, use of trastuzumab in newly diagnosed women who were HER2 negative or untested did not appear to be a significant concern. “From a healthcare perspective, the issue is that this agent is very expensive, but it is only effective in specific women. There was a question of whether there should be steps put in place to prevent this problem. However, this study suggests that we don’t need prior authorization programs because there does not appear to be a significant amount of inappropriate use. We don’t need to overburden the process with adding more requirements to ensure appropriate use,” said Dr Barron in an interview with The Oncology Pharmacist. —JS Continued on page 20
online at Reach us
www.theoncologypharmacist.com June 2008
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PEER-SPECTIVES
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CANCER CENTER PROFILE
Cleveland Clinic
Taussig Cancer Center Photo courtesy of Cleveland Clinic
patient-centric focus drives the design and function of the Taussig Cancer Center at the Cleveland Clinic, from electronic medical record keeping, multidisciplinary models of patient care, and extensive support services. As Ohio’s largest cancer center, total visits to the Taussig Cancer Center in 2006 numbered 181,798, and 35,576 treatments were delivered. It is rated by U.S. News & World Report as one of the top 15 cancer centers in the nation. “Our ‘patients first’ philosophy is a very useful focusing tool for everybody at all times…everything flows down from that,” said Derek Raghavan, MD, PhD, director of the Taussig Cancer Center. “In the past 4 years, 50 new faculty members have been recruited, all of whom are engaged in active clinical practice. Everybody from top down sees patients. Everybody who is a leader and running programs is also seeing patients.” The Taussig Cancer Center has set standards in the management of early prostate cancer, as well as kidney and bladder cancer. Cleveland Clinic researchers were involved in a seminal study published this year in the New England Journal of Medicine in which the outcomes, toxicities, and quality of life associated with the various prostate cancer treatments were measured.1 The Bone Marrow Transplant Research Team in the Department of Hematologic Oncology and Blood Disorders boasts a 30-day survival rate of 100% for autologous bone marrow transplantation. The achievement is noteworthy given that 30-day survival rates of
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20% for leukemia transplant patients were not uncommon at most institutions in the past.
CANCER CENTER PROFILE
Extensive research program In 2007, the Leukemia and Lymphoma Society and the Cleveland Clinic Taussig Cancer Center announced a partnership, The Clinical Trial Center for Hematologic Malignancies, to make hematologic cancer clinical trials available to patients in the community. The Taussig Cancer Center was chosen for this collaboration because of its unique structure of 45 oncologists at its main campus and another 20 staff throughout regional hospitals, allowing patients to participate in the center’s clinical trials while remaining with their own team of cancer specialists. “With the volume of patients—about 7,000 new cases of cancer per year—we have a mechanism for defining clinical trials that can be executed within other cities,” said Dr Raghavan. The partnership is expected to accelerate the process of developing cancer drugs since clinical trials will be conducted within a single clinical center. The electronic medical record system facilitates this new paradigm of clinical research by permitting clinicians at regional sites nearly instant access to patients’ records. Patients also have access to their own electronic record on request (sometimes after a review by his/her physician). “Top down, there’s very active patient involvement,” said Dr Raghavan. All cancer departments have extensive research programs. The breast cancer program received federal funding to join two multi-institutional trials in collaboration with Washington University, and the renal cancer program is collaborating with Ohio State University on federally funded clinical trials. The large volume of patients at the Taussig Cancer Center enables groundbreaking work in diagnostics. For example, researchers at Taussig discovered that the level of circulating tumor cells in peripheral blood before treatment was able to predict survival in patients with metastatic breast cancer,2 with the potential to individualize treatment. The same diagnostic assay is being used to predict survival in prostate cancer. A novel blood test to predict thyroid cancer was tested by pathobiologists at the Cleveland Clinic and was found to distinguish accurately between benign and malignant cells. The test detects cancer cells in the bloodstream by amplifying thyroid-stimulating hormone receptor or thyroglobulin messenger ribonucleic acid by reverse transcription polymerase chain reaction. The Taussig Cancer Center is also a major player in clinical trial groups, such as the Southwest Oncology Group and the Radiation Therapy Oncology Group. “We have a very active program of nursing research and we do a lot to edu-
Photo courtesy of Cleveland Clinic
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G REEN H ILL H EALTH C ARE C OMMUNICATIONS
Interview with Taussig Center Pharmacist
Christopher Lowe, PharmD “I would like the Cleveland Clinic to be recognized as one of the leaders in oncology pharmacy in the country,” says Christopher Lowe, PharmD. As an oncology clinical specialist working with the bone marrow transplant team and manager of the outpatient chemotherapy satellite program, as well as through his involvement in a remodeling of the center’s pharmacy, Dr Lowe is hard at work to help the Taussig Cancer Center at the Cleveland Clinic achieve this goal. Dr Lowe came to the Taussig Cancer Center in 2003, taking care of patients at the point of prescribing. He arrived via the University of Pittsburgh, where he received his PharmD in 2000, followed by residency programs at Johns Hopkins Hospital in Baltimore and the Carolinas Medical Center in Charlotte. He manages medications for 15 to 20 inpatients daily while tackling projects to improve the function of the pharmacy. He is currently involved in a complete redesign of the cancer center’s pharmacy that will eventually see it double in size. “The purpose is to improve our capacity and be able to handle the number of patients we’re seeing on a day-to-day basis and also to help it comply with new regulations regarding the compounding of intravenous medications,” he said. “I work with the cancer center administration and the Cleveland Clinic construction office. I never knew that by going to pharmacy school I’d become an architect,” he said. Taking advantage of a system that electronically scans drug orders, Dr Lowe is also working to minimize the time from patient arrival at the clinic to drug dispensing. The electronic system time stamps all steps in the drug delivery process to help identify any problems. “We’re collecting data on every single drug prescribed for every single patient, and we’ll be able to do a much more accurate job of evaluating how long it takes,” he said. “Our number one objective is to get the right drug at the right dose to the right patient. If we can do that as quickly as possible, it dramatically improves the quality of life of the patients who come here to be treated.” The most rewarding aspects of his job at Taussig are watching the oncology clinical pharmacy specialists develop and learn and grow professionally.
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ORAL MUCOSITIS Continued from cover
neuropathies, myalgias, and other related symptoms. Among these, perhaps none is as demoralizing as oral mucositis, a constellation of symptoms affecting the oral mucosa that is induced by chemotherapy and radiation therapy for cancer. Oral mucositis is different from oral lesions with other pathogenic origins, which are generally referred to as stomatitis.1 Inflammation and infection of the oral mucosa lead to a reduced ability to consume food and fluids at a time when nutrition and hydration are critical to the prospect of treatment success. Oral mucositis is also painful and often requires substantial daily doses of opiates. Treatment often requires inpatient admission to the hospital, usually through the emergency department, leading to a significant increase in overall treatment-related expenses. Once admitted, patients are at an increased risk for nosocomial infection, experience a serious disruption of their daily activities, and face the possibility that their treatment protocols will be delayed or even discontinued.
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Epidemiology of oral mucositis Symptoms of oral mucositis may be mild or severe and can vary from vague discomfort to severe pain and an inability to tolerate food and fluids (Table 1). Approximately 400,000 FRANK P. WHYTE, new cases of treatmentRN, OCN induced damage to the oral cavity are reported annually in the United States.2 These include cases of mucositis (stomatitis); xerostomia (dry mouth syndrome); bacterial, viral, and fungal infections; dental caries; disruption of taste; and osteoradionecrosis.2 From 5% to 40% of patients who are treated with standard chemotherapy regimens will develop some form of mucositis.3 In patients receiving more aggressive regimens with agents such as fluorouracil, methotrexate, cyclophosphamide, or cisplatin, the incidence can be much higher and the symptoms much more debilitating.4 Among patients who receive high-dose
Table 1. Grades of Oral Mucositis: NCI Common Toxicity Criteria Grade 1: Erythema (redness) Grade 2: Patchy ulcerations Grade 3: Confluent ulcerations Bleeding with minor trauma
Grade 4: Necrosis, significant spontaneous bleeding Life-threatening
Grade 5: Death related to toxicity Source: Common Terminology Criteria for Adverse Events v3.0. National Cancer Institute; 2006.
chemotherapy in advance of bone marrow transplantation, the incidence can be as high as 75% to 100%.3 Similarly, more than 80% of patients who receive high-dose radiation for head and neck cancers will be affected.3,4 The incidence of oral mucositis will be higher for patients receiving both chemotherapy and radiation.5 The degree and duration of symptoms are related to radiation source, cumulative dose, intensity, and the total volume of irradiated mucosa.6
Pathogenesis of oral mucositis Stephen Sonis, DMD, the preeminent authority on oral mucositis, has suggested a four-stage developmental process for this disorder. According to Sonis and colleagues, there is an initial or vascular stage of development, when exposed cells in the buccal mucosa release free radicals, modified proteins, and proinflammatory cytokines. The net effect of this process is that vascular permeability of mucosal cells is greatly increased, which leads to an increased uptake of cytotoxic drugs into these cells.7,8 This vascular phase then gives way to the epithelial phase, when cell division is retarded and epithelial turnover is reduced, resulting in subsequent epithelial breakdown. Erythema and epithelial atrophy can be expected 4 to 5 days after chemotherapy, and patients may suffer microtrauma of the tissue resulting from speech, swallowing, and chewing.7,8
Table 2. Treatments to Relieve the Symptoms of Oral Mucositis
SUPPORTIVE CARE
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Topical agents Artificial saliva solution (Caphosol)16 “Magic” or “Miracle” mouthwash, includes lidocaine, benzocaine, kaolin, pectin, and chlorhexidine9 Bioadherent oral gel (Gelclair)14 Single agents: benzydamine; morphine9
Systemic agents Patient-controlled analgesia with morphine for stem cell transplant patients Transdermal fentanyl: further study needed9
Antibiotics/antiviral Delivered by appropriate route depending on type of infecting organism: fungal, bacterial, viral
Of particular note, 75% of the population has some degree of periodontal disease, which is a known risk factor. This, coupled with the fact that after chemotherapy many patients will develop acute bacterial super-
Erythema and epithelial atrophy can be expected 4 to 5 days after chemotherapy. Approximately 1 week after treatment, this degenerative process enters the ulcerative or bacteriologic phase, when there is a loss of epithelial cells, exudate formation, and the production of pseudomembranes and ulcers. It is at this time of complete cellular breakdown that cells become colonized by gramnegative organisms and yeast.7,8 The fourth and final phase is the healing phase, which can be expected to last for 12 to 16 days, depending on several factors, including epithelial proliferation rate, hematopoietic recovery, and a reestablishment of normal local microbial flora. Healing will occur as long as there is no persistent infection or mechanical irritation.7,8
Risk factors Several patient-related factors increase the risk of oral mucositis. Individuals at an increased risk for developing oral mucositis include young patients, given their rapid mitotic rate; patients with poor nutritional status and decreased neutrophil counts prior to beginning treatment; and those with preexisting xerostomia. The type of malignancy being treated also plays a role. The risk is particularly high in those with hematologic cancers because of the prolonged and intense myelosuppression associated with these malignancies. Increased epidermal growth factor receptors, poor oral hygiene, ill-fitting dental prostheses, and use of medications with anticholinergic effects, such as tricyclic antidepressants, all predispose patients to developing oral mucositis.6
infections, suggests that clinical vigilance for signs and symptoms of oral mucositis in patients undergoing medical or radiation therapy is well justified.5
Prevention and treatment None of the available treatments is completely successful at preventing oral mucositis.9 A thorough dental evaluation to detect problem areas should be conducted on every patient before beginning treatment.6 Patients should also be encouraged to use a soft toothbrush with fluoridated toothpaste, and toothbrushes should be replaced monthly. If financial hardship is an issue, advise patients to run their existing toothbrush through the dishwasher monthly instead.5 A balanced and nutritious diet is also essential for maintaining oral health.9 Although oral mucositis cannot be totally prevented, there are a number of interventions that health professionals can undertake to reduce the risk and to treat it if it develops. Clinical studies evaluating the benefit of cryotherapy, which refers to the near-constant use of ice chips during the at-risk period in the days immediately following the administration of chemotherapy, has shown some benefit. It is thought that the vasoconstriction caused by the cold temperature reduces uptake of cytotoxic materials at a time when mucosal cells would be otherwise at an increased risk, secondary to permeability changes as described in the Sonis paradigm.9-11 Continued on page 15
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®
CAPHOSOL – Proven Efficacy Against Oral Mucositis Confirmed in a randomized, placebo-controlled trial1 Days of Mucositis > Grade 1
Reduction in duration of mucositis • Caphosol 3.7 days vs control (fluoride rinse) 7.2 days
40% of CAPHOSOL-treated patients
had no mucositis (vs 19% control) *
Don’t Wait – Start cancer therapy...start CAPHOSOL
• 4 doses per day from the onset of the cancer treatment • Use for the duration of the treatment or as instructed by physician For a Cytogen Representative or Reimbursement Assistance, Please Call 800-833-3533. For more information visit www.Caphosol.com. Important Safety Information Avoid eating or drinking at least 15 minutes after use. Patients restricted to a low sodium diet should consult their physician before use. Federal law restricts this device to sale by or on the order of a physician or dentist. KEEP OUT OF REACH OF CHILDREN. * Mucositis ≤ Grade 1. Reference 1. Papas AS, Clark RE, Martuscelli G, O’Loughlin KT, Johansen E, Miller KB. A prospective, randomized trial for the prevention of mucositis in patients undergoing hematopoietic stem cell transplantation. Bone Marrow Transplantation. 2003;31:705-712. Caphosol is used in conjunction with standard oral care.
Start Cancer Therapy...Start Caphosol
CAPHOSOL® is a registered trademark of Cytogen Corporation. © 2007 Cytogen Corporation
All rights reserved.
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There have also been numerous studies evaluating the benefit of certain mouthwash preparations. Amifostine, which is associated with certain tolerability issues,9,12 palifermin,13 and Gelclair bioadherent oral gel,14 have all shown similar limited benefit, as have fluoride tray treatments, when given before chemotherapy administration. A study published in 2003 by Papas and associates showed significant decreases in the incidence, frequency, and severity of oral mucositis with the use of a supersaturated calcium phosphate oral rinse, commercially available as Caphosol.15,16 Caphosol was originally designed to restore the normal ionic and pH balance of the oral cavity. In their study, Papas and associates discovered that when the rinse was used in conjunction with four fluoride tray treatments, it reduced total days of mucositis, peak level of mucositis, and days requiring treatment with morphine for the discomfort associated with mucositis. Forty percent of patients treated with Caphosol had no mucositis compared with 19% of the controls treated with fluoride rinse alone. Compared with controls, those in the Caphosol group had 49% fewer days of mucositis and a 67% lower peak median level of mucositis. Caphosol was particularly beneficial in patients who were intensely myelosuppressed before hematopoietic stem cell transplantation and in those with xerostomia.16 In addition to recommending commercially available products, healthcare professionals can do much in their daily practices
CARTOON
“Jerry, the Hermans take the same pharmaceuticals we do !” June 2008
to assist their chemotherapy and radiation therapy patients with oral mucositis. • As much as possible, patients should be positioned sitting up at a 90-degree angle with their heads tilted slightly forward. • Frequent use of ice chips in the days immediately following treatment is recommended. • Patients should be encouraged to eat small, frequent meals. Food and drinks should be warm, not hot, to avoid scalding mucosal tissues. Patients should select soft foods and avoid crunchy foods. • If poor appetite is an issue or if oral mucositis has decreased a patient’s desire to eat, suggest baby food or highprotein milkshakes as an alternative. Commercially available products, such as Ensure or Boost, may also help to provide adequate caloric intake. • Alcohol and tobacco should also be avoided, as should spicy and acidic foods. • Patients should be instructed not to talk while they have food in their mouth. • Patients should rinse their mouth thoroughly before and after meals.3,6,9
Conclusions In recent decades, oral mucositis has been recognized as a significant disorder that can have a serious impact on cancer treatment. Severe discomfort can lead to reduced intake of food and fluids, depression, and potentially nonadherence during a critical period in initial and subsequent treatment cycles. Oral mucositis can also lead to long-term destruction of the teeth and bony structures of the oral cavity. New research has led to the development of products that are yielding positive results. Healthcare professionals should be aware of the potentially catastrophic results of severe mucositis and should promote within their practices interventions and products that can prevent or control this disorder. References 1. Dose AM. The symptom experience of mucositis, stomatitis, and xerostomia. Semin Oncol Nurs. 1995;11:248-255. 2. Naidu MU, Ramana GV, Rani PU, et al. Chemotherapy-induced and/or radiation therapyinduced oral mucositis—complicating the treatment of cancer. Neoplasia. 2004;6:423-431. 3. Peterson DE. New strategies for management of oral mucositis in cancer patients. J Support Oncol. 2006;4(2 suppl 1):9-13. 4. Silverman S Jr. Diagnosis and management of oral mucositis. J Support Oncol. 2007;5(2 suppl 1):13-21. 5. Wilkes JD. Prevention and treatment of oral mucositis following cancer chemotherapy. Semin Oncol. 1998; 25:538-551. 6. Berger AM, Kilroy TJ. Oral complications. In: DeVita VT, Hellman S, Rosenberg SA, eds. Cancer: Principles & Practice of Oncology. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins;2001: 2714-2725. 7. Sonis ST. Mucositis as a biological process: a new hypothesis for the development of chemotherapyinduced stomatotoxicity. Oral Oncol. 1998;34:39-43. 8. Sonis ST, Elting LS, Keefe D, et al. Perspectives on cancer therapy-induced mucosal injury: pathogenesis, measurement, epidemiology, and consequences for patients. Cancer. 2004;100(9 suppl):1995-2025. 9. Rubenstein EB, Peterson DE, Schubert M, et al. Clinical practice guidelines for the prevention and treatment of cancer therapy-induced oral and gastrointestinal mucositis. Cancer. 2004;100(9 suppl):2026-2046. 10. Rocke LK. A randomized clinical trial of two different durations of oral cryotherapy for prevention of 5-fluorouracil-related stomatitis. Cancer. 1993;72:2234-2238.
Oral Mucositis:
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Facts and Concerns • Chemotherapy damage to mucosal tissues is reversible. • Radiation damage to mucosal tissues is permanent. • Mucosal infection should be of primary concern. • Mucositis will have a great impact on quality of life. • Tooth enamel is not connected to the rest of the body except through saliva. • Humans need saliva to keep food from sticking to the side of the mouth. • Decreased saliva can lead to an inability to speak. • Saliva flow is decreased at night, often causing patients to awake. • Oral infection is a significant cause of death in immunocompromised patients. • The normal flora of the oral cavity is changed with neutropenia. • The mouth and tongue must be kept as clean as possible to prevent infection and improve function. • Irradiated patients may need to use a saliva substitute for the remainder of their lives. • The pseudomembranes of mucositis can become infected. • The microenvironment of the oral mucosa can be stabilized with electrolyte solutions. • Prevention is the goal but may be difficult to achieve. • Targeted therapies increase the risk of mucositis. • Healthcare professionals must be aware of mucositis risk and educate patients about the importance of early intervention.
11. Mahood DJ, Dose AM, Loprinzi CL, et al. Inhibition of fluorouracil-induced stomatitis by oral cryotherapy. J Clin Oncol. 1991;9:449-452. 12. Köstler WJ, Hejna M, Wenzel C, et al. Oral mucositis complicating chemotherapy and/or radiotherapy: options for prevention and treatment. CA Cancer J Clin. 2001;51:290-315. 13. Spielberger R, Stiff P, Bensinger W, et al. Palifermin for oral mucositis after intensive therapy for hematologic cancers. N Engl J Med. 2004;351:2590-2598. 14. Gelclair (bioadherent oral gel) [package insert]. Cedar Knolls, NJ: EKR Therapeutics, Inc; 2006. 15. Caphosol [package insert]. Princeton, NJ: Cytogen Corporation; 2007. 16. Papas AS, Clark RE, Martuscelli G, et al. A prospective, randomized trial for the prevention of mucositis in patients undergoing hematopoietic stem cell transplantation. Bone Marrow Transpl. 2003;31:705-712.
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Complimentary
Continuing Education CIK 9788 • RELEASE DATE: June 18, 2008 • EXPIRATION DATE: June 18, 2009
Cetuximab-induced Hypersensitivity: Case Reports and Discussion of Management BY EMILY CHAN, MD, PhD,1 AND CHRISTINE H. CHUNG, MD2 1 Division of Hematology/Oncology, Department of Medicine and 2Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee
HOW TO RECEIVE CREDIT To receive continuing education credit, learners must: • Read the article in its entirety. • Take the CE self-assessment test and complete the evaluation at: www.unmc.edu/ coned • The learner must answer at least 70% of the questions on the post-test correctly. • The estimated time to complete this activity is 1 hour. Your continuing education certificate can be printed by following the directions online after successful completion of the post-test and evaluation. TARGET AUDIENCE Registered pharmacists and other interested healthcare professionals, especially those caring for cancer patients. COST This program is complimentary for all learners.
etuximab is a chimeric antibody against the epidermal growth factor receptor. According to the cetuximab package insert, the incidence of severe hypersensitivity reactions is 3%.1,2 Higher incidence rates have been reported, however, in the southeast region of the United States, including North Carolina, Arkansas, Missouri, Virginia, and Tennessee, with reaction rates up to 22% in recent studies.3,4 Signs and symptoms of hypersensitivity reactions include fever, rash, flushing, bronchospasm, urticaria, edema/ angioedema, hypotension, and anaphylaxis (Table 1). Presented here are two cases that illustrate the characteristics and management of a severe hypersensitivity reaction.
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Case 1 SS, a 52-year-old man, initially underwent resection of a stage III colon cancer. He received adjuvant chemotherapy with 5-fluorouracil (5-FU) and leucovorin. Approximately 4 years later, he developed recurrence with metastatic disease in the mediastinum and abdomen. He was treated with 5-FU, leucovorin, oxaliplatin, and bevacizumab, but had to discontinue treatment because of toxicity. Subsequently, he was treated with capecitabine, irinotecan, and bevacizumab, but again developed progressive disease. He then enrolled in a phase 2 clinical trial for metastatic colorectal cancer with the combination of cetuximab and celecoxib. He was premedicated with dexamethasone 20 mg intravenously (IV) and diphenhydramine 50 mg IV. Approximately 20 minutes into his initial cetuximab infusion, the patient experienced pruritus and facial flushing. He then developed chest tightness FACULTY/PLANNER DISCLOSURES It is the policy of the University of Nebraska Medical Center, Center for Continuing Education that all planners and faculty participating in continuing education activities provided by the University of Nebraska Medical Center, Center for Continuing Education are to disclose to the audience any real or apparent conflicts of interest with providers of commercial products and/or devices relating to the topics of this educational activity and also disclose discussion of labeled/unapproved uses of drugs or devices discussed in their presentation. The planners and faculty have been advised that this activity must be free from commercial bias and based upon all the available scientifically rigorous data from research that
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DISCLAIMERS The opinions or views expressed in this continuing education activity are those of the faculty and do not necessarily reflect the opinions or recommendations of the University of Nebraska Medical Center (UNMC), Center for Continuing Education. While the University of Nebraska Medical Center, Center for Continuing Education is an ACPE accredited organization, this does not imply endorsement by the UNMC or ACPE of any commercial products affiliated with this activity. LEARNING OBJECTIVES After completing this activity, the reader should be better able to: • Explain the hypothesis about the link between immunoglobulin E antibodies and cetuximab-induced hypersensitivity reactions • Recognize the signs/symptoms of a hypersensitivity reaction • Describe an appropriate premedication regimen for a patient who is being treated with cetuximab • Summarize appropriate management of cetuximab-induced hypersensitivity reactions
and felt as though he was wheezing although his lungs were clear on examination. Cetuximab was stopped when the symptoms developed. Supplemental oxygen was started, and the patient was given an additional 25 mg of IV diphenhydramine as well as methylprednisolone 125 mg IV, and albuterol nebulizer treatment. His symptoms improved, but because of his grade 3 hypersensitivity reaction, he was removed from the study and was not rechallenged with cetuximab.
Case 2 DB, a 54-year-old man with stage IV oropharyngeal squamous cell carcinoma. He was treated with induction chemotherapy followed by concurrent chemoradiation therapy using carboplatin and paclitaxel. Approximately 6 months after completing the primary treatment, he had disease recurrence with lung metastasis and was treated on a phase 2 clinical trial regimen containing docetaxel and bortezomib; however, his disease progressed after 6 weeks. He was given cetuximab as a palliative measure. His premedication regimen was diphenhydramine 50 mg IV and dexamethasone 12 mg IV. Within 5 minutes of starting the infusion, he became unarousable and apneic. Blood pressure was not measurable because of severe hypotension. The infusion was immediately stopped. He was given epinephrine 1:1000 intramuscularly and hydrocortisone 100 mg IV. He was transferred to the emergency department and admitted to the intensive care unit for close monitoring. Because of his grade 4 hypersensitivity reaction, he was not rechallenged with cetuximab after his recovery.
conforms to accepted standards of experimental design, data collection, and analysis. The following authors, reviewers, and planning committee members listed below have stated they have no significant or substantial relationship with providers of commercial products and/or devices discussed in this activity and/or with any commercial supporter of this activity: Lois Colburn Brenda Ram, CMP Karen Rosenberg Lara J. Reiman Cass Hammond, RN, MSN, CRNP Audrea H. Szabatura, PharmD, BCOP Gary C. Yee, PharmD, FCCP, BCOP
G REEN H ILL H EALTH C ARE C OMMUNICATIONS
The following authors and/or planners have stated that they have the following financial relationship(s): Emily Chan, MD, PhD, states that she is on the advisory boards of Bristol-Myers Squibb and Amgen and receives honoraria for her services. She receives research funds from Amgen. Christine H. Chung, MD, states that she is on the advisory boards of Bristol-Myers Squibb and receives honoraria for her services. Taline Khoukaz, RN, ACNP-C, states that she is on the speakers bureau of sanofi-aventis and BristolMyers Squibb.ImClone and is a consultant to BristolMyers Squibb.ImClone. There was no pharmaceutical support for this activity.
PLANNING COMMITTEE Lois Colburn Executive Director Center for Continuing Education University of Nebraska Medical Center 986800 Nebraska Medical Center Omaha, NE 68198-6800 Brenda Ram, CMP Coordinator Center for Continuing Education University of Nebraska Medical Center 986800 Nebraska Medical Center Omaha, NE 68198-6800 Karen Rosenberg Editorial Director Green Hill HealthCare Communications, LLC 241 Forsgate Drive Monroe Twp, NJ 08831 Lara J. Reiman Managing Editor Green Hill HealthCare Communications, LLC 241 Forsgate Drive Monroe Twp, NJ 08831 Cass Hammond, RN, MSN, CRNP Avid Education Partners 18071 Crampton Lane Sharpsburg, MD 21782 REVIEWER Gary C. Yee, PharmD, FCCP, BCOP Professor Department of Pharmacy Practice University of Nebraska Medical Center 986405 Nebraska Medical Center Omaha, NE 68198-6045
ACCREDITATION The University of Nebraska Medical Center, Center for Continuing Education is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. The ACPE provider number is 447-000-08-067-H04-P. To receive the 1 contact hour of continuing education credit, pharmacists should complete the activity requirements and evaluation at the conclusion of the activity. Approval is valid from the initial release date of June 18, 2008. The expiration date is June 18, 2009. A statement of credit will be available for printing online upon completion of the post-test with a score of 70% or better and the evaluation instrument.
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Continuing Education CIK 9788 • RELEASE DATE: June 18, 2008 • EXPIRATION DATE: June 18, 2009 Table 1. National Cancer Institute Common Toxicity Criteria for Allergic Reaction/hypersensitivity Grade 1 2
Description Transient flushing or rash; drug fever <38oC (<100.4oF) Rash; flushing; urticaria; dyspnea, drug fever ≥38oC (≥100.4oF)
3
Symptomatic bronchospasm, with or without urticaria; parenteral medication(s) indicated; allergy-related edema/ angioedema; hypotension
4
Anaphylaxis
5
Death
can be made against a sugar molecule, while it is well known that IgE antibodies can be made against a protein epitope. • The results of this study also have potential implications for patients receiving other monoclonal antibodies or immunotherapies for other conditions, including inflammatory bowel disease, rheumatoid arthritis, and asthma.
What we do not know: • The exact reasons why individuals in certain areas of the United States to produce the IgE antibodies that react with cetuximab. For example, are the specific IgE antibodies the result of differences in regional exposures to ticks or other parasites or to infectious organisms that express alpha-1,3-galactosyltransferase? • The implications of our findings in screening the patients before the use of cetuximab as well as other monoclonal antibodies for other diseases.
Clinical management of hypersensitivity reactions The majority of hypersensitivity reactions to cetuximab occur during the first infusion. Therefore, these patients should be watched closely during the first infusion and observed for an hour after the infusion. In addition, there should be a stocked crash cart readily available. Prompt recognition and immediate medical attention is key to management. Given the high rate of grade 3-4 hypersensitivity reaction seen at the authors’ institution in Tennessee, premedication with oral dexamethasone 20 mg the night before and the morning of treatment in addition to diphenhydramine before treatment was incorporated into a clinical trial; we have seen, however, that the infusion reactions can still occur even with this premedication. The cetuximab infusion should be discontinued immediately after the recognition of a hypersensitivity reaction, and supportive medications should be given. Supportive medications include epicontinued on page 18
Reprinted with permission from Reference 2.
C O M M E N TA R Y Retrospective study findings We learned from a retrospective study4 that severe hypersensitivity reactions to cetuximab tend to occur within minutes of initial exposure to the drug, which suggests the presence of preexisting immunoglobulin (Ig) E antibodies against the drug, such as in the cases described above. We examined this hypothesis by analyzing serum samples from 538 individuals for IgE antibodies against cetuximab, including 76 samples from cetuximab-treated cancer patients. Of the 76 cetuximab-treated patients, 25 developed hypersensitivity reactions, and 17 of these individuals demonstrated a positive reaction for IgE antibodies to the drug. Of the 51 patients who did not have a hypersensitivity reaction, only one had these antibodies before the start of cetuximab therapy. Both patients described in the case studies tested positive for the IgE in the pretreatment sera. Using a new immunoassay, we also found that the IgE associated with cetuximab-induced hypersensitivity is specific for the oligosaccharide, galactose-alpha-1,3-galactose, which is located on the Fab portion of the cetuximab heavy chain and attached to cetuximab during the manufacturing process by an enzyme, alpha-1,3-galactosyltransferase, present in the cell line. Clinical implications Our recent study, along with information from published studies, case reports, and our own anecdotal observations, has significantly improved our understanding about the relationship between cetuximab and severe hypersensitivity reactions. What we now know: • Severe hypersensitivity reactions to cetuximab have a marked regional pattern in the United States, with more clustered cases in North Carolina, Arkansas, Missouri, Virginia, and Tennessee. • Galactose-alpha-1,3-galactose is attached to cetuximab because cetuximab is produced in the cell line SP2/0, which expresses alpha-1,3-galactosyltransferase, an enzyme that adds oligosaccharide to cetuximab. Most of the other monoclonal antibodies in clinical use are produced in a Chinese hamster ovary cell line that does not express the enzyme. • Our study is the first to show that IgE antibodies June 2008
Cetuximab-induced Hypersensitivity: A pharmacist’s perspective BY AUDREA H. SZABATURA, PHARMD, BCOP Department of Pharmacy, University of Massachusetts Memorial Medical Center, Levine Cancer Center, Worcester
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mmune-mediated hypersensitivity reactions complicate up to 10% of therapeutic drug courses.1 Cetuximab specifically has been noted to cause severe hypersensitivity reactions in 3% of patients.2 A recent article by Chung and colleagues reveals new information regarding underlying mechanisms of infusion reactions.3 The investigators’ findings suggest a potential way to tailor drug therapy according to individual needs, especially in cases where an alternative agent exists. With this information, patients at risk for hypersensitivity reactions may be screened in advance, potentially preventing life-threatening adverse reactions. Furthermore, the investigators’ results have implications for research and development of monoclonal antibodies in the future. If we can knock out the gene for alpha-1,3-galactosyltransferase in a strain of pigs, which is one of the major barriers to organ transplantation, perhaps this can be accomplished as we go forth in drug development.4 It is interesting that the investigators reveal that many patients (68%) in their study who experienced hypersensitivity reactions to cetuximab, already had immunoglobin E (IgE) antibodies against cetuximab before the initiation of therapy. These antibodies were specific for the sugar molecule galactose-alpha-1,3-galactose, which is found on the Fab portion of the cetuximab heavy chain. Furthermore, there have been correlations between the incidence of cetuximab-related infusion reactions and certain areas of the United States, such as North Carolina and Tennessee.5 Chung and colleagues note that natural exposure to galactose-alpha1,3-galactose seems to stimulate production of
IgE antibodies and suggest that tick bites are the most likely cause.2 It is interesting, however, that a report by the Centers for Disease Control and Prevention shows that the geographical area with the highest incidence of Lyme disease cases, and therefore exposure to ticks and potential production of IgE antibodies, is the northeast.6 This seems contrary to Chung’s results, in which only 0.6% of patients in the Boston area had IgE antibodies against cetuximab. Chung and colleagues provide new information concerning the mechanism of hypersensitivity reactions; however, many questions remain, especially regarding the production of IgE antibodies. Also yet to be determined is how the findings by Chung and colleagues might change policies or protocols regarding hypersensitivity reactions at large institutions, and, of even greater concern, in the oncologist office setting, where access to personnel or resources may be more limited. References 1. Riedl MA, Casillas AM. Adverse drug reactions: types and treatment options. Am Fam Physician. 2003;68:1781-1790. 2. Erbitux [package insert]. New York, NY: ImClone Systems, Inc, and Princeton, NJ: Bristol-Myers Squibb Company; 2007. 3. Chung CH, Mirakhur B, Chan E, et al. Cetuximab-induced anaphylaxis and IgE specific for galactose-alpha-1,3-galactose. N Engl J Med. 2008;358:1109-1117. 4. Liu QP, Yuan H, Bennett EP, et al. Identification of a GH110 subfamily of alpha-1,3-galactosidases: novel enzymes for removal of the alpha-3Gal xenotransplantation antigen. J Biol Chem. 2008;283:8545-8554. 5. O’Neil BH, Allen R, Spigel DR, et al. High incidence of cetuximab-related infusion reactions in Tennessee and North Carolina and the association with atopic history. J Clin Oncol. 2007;25:3644-3648. 6. Centers for Disease Control and Prevention Division of Vectorborne Infectious Diseases. Reported Lyme disease cases by state, 1993-2006. http://www.cdc.gov/ncidod/dvbid/Lyme/ ld_rptdLymeCasesbyState.htm. Accessed May 16, 2008.
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Continuing Education CIK 9788 • RELEASE DATE: June 18, 2008 • EXPIRATION DATE: June 18, 2009 continued from page 17
Table 2. Suggested Management of Anaphylaxis Drug Epinephrine*
Dosage For mild-to-moderate anaphylaxis 0.3 to 0.5 mg IM (1:1000), repeated every 15-20 minutes if no clinical improvement For mild-to-moderate anaphylaxis 0.1 mg IV (1:10000) infused slowly over 5 minutes. Infusion rate of 1-4 mcg/min may prevent the need for frequent epinephrine injections Close patient monitoring is necessary because fatal epinephrine overdose has been reported
instead of cetuximab, minimize unnecessary use of premedications and monitoring, and select candidates appropriate for desensitization to cetuximab as a clinical trial. Further studies are ongoing to resolve these issues for safe administration of cetuximab. Corresponding author: Christine H. Chung, MD, Division of Hematology/Oncology, Department of Medicine and Cancer Biology, Vanderbilt University School of Medicine, 2220 Pierce Ave, 777 Preston Research Building, Nashville, TN 37232-6307, USA. E-mail: Christine.Chung@Vanderbilt.edu Acknowledgement: Supported by grant from the Vanderbilt University GI SPORE (P50-CA-95103); and by the Damon Runyon Clinical Investigator Award (CL28-05) and National Institutes of Health R01-DE017982 to Dr Chung.
1. Erbitux [package insert]. New York, NY: ImClone Systems, Inc, and Princeton, NJ: Bristol-Myers Squibb Company; 2007. 2. Cancer Therapy Evaluation Program. Common Terminology Criteria for Adverse Events, Version 3.0. http://ctep.cancer.gov/forms/CTCAEv3.pdf. Accessed May 16, 2008. 3. O’Neil BH, Allen R, Spigel DR, et al. High incidence of cetuximab-related infusion reactions in Tennessee and North Carolina and the association with atopic history. J Clin Oncol. 2007;25:3644-3668. 4. Chung CH, Mirakhur B, Chan E, et al. Cetuximab-induced anaphylaxis and IgE specific for galactose-alpha-1,3-galactose. N Engl J Med. 2008;358:1109-1117. 5. 2005 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Part 10.6: Anaphylaxis. Circulation. 2005;112:IV-143-IV-145.
C O M M E N TA R Y
Cetuximab-induced Hypersensitivity: A nurse’s perspective
Administer at high flow rates
BY TALINE KHOUKAZ, MSN, ACNP-C University of Southern California, Norris Cancer Center and Hospital, Los Angeles
Isotonic crystalloid
Rapid infusion of 1-2 L if hypotension is present
etuximab is a chimeric murine-human immunoglobulin G1 monoclonal antibody, which is indicated for the treatment of colorectal cancer and squamous cell carcinoma of the head and neck. Although the drug does not have significant side effects other than the development of an acne-like rash, 3% of cetuximab-treated patients can expect to develop a severe hypersensitivity reaction. Ninety percent of the reactions are associated with the first infusion of cetuximab, despite the use of prophylactic antihistamines. It has been observed that most severe hypersensitivity reactions have an unusual geographic distribution, primarily concentrated in the southeast region of the United States. Dr Chung and her colleagues recently reported their finding of an immunoglobulin E (IgE) antibody against cetuximab, which was present in pretreatment blood samples of 68% of patients who had a hypersensitivity reaction to the drug, but only 2% of those did not have a reaction.1 Using a newly developed assay, the researchers analyzed sera from patients with severe hypersensitivity reactions to cetuximab. They noted that hypersensitivity reactions were associated with IgE antibodies specific for sugar glactose-alpha1,3 galactose, which is present on the Fab portion of the cetuximab heavy chain. The researchers are trying to determine what causes a high proportion of the population in certain parts of the United States to produce these particular IgE antibodies that react with cetuximab. Another question remains: Are there any potential implications of these findings for nurses administering cetuximab or other monoclonal antibodies, and if so, what are they? A complete record of the patient’s prior history to allergies is imperative. The risk of an allergic or anaphylactic reaction is greater in those
Antihistamines
Diphenhydramine 25-50 mg slowly via IV or IM
H2 blockers
Cimetidine 300 mg IV Ranidtidine 50 mg IV Famotidine 20 mg IV
Inhaled betaAlbuterol nebulizer treatment adrenergic agents Corticosteroids
Methylprednisolone 30-125 mg IV Hydrocortisone 100 mg IV Dexamethasone 20 mg IV
*Patients taking β-blockers can develop a paradoxical reaction to epinephrine. Inhaled ipratropium or glucagon may be useful in treatment of bronchospasm in these patients. IM indicates intramuscular; IV, intravenous. Adapted with permission from Reference 5.
nephrine, steroids, IV antihistamines, bronchodilators, H2 blockers, and oxygen (Table 2).5 In the case of a severe (grade 3 to 4) reaction, as in the cases reported above, patients should not be rechallenged.1 In the case of a mild-to-moderate (grade 1 to 2) reaction, patients can be rechallenged at a slower infusion rate (decreasing the rate by half) once the symptoms have completely abated.1 At present, there is no US Food and Drug Administration–approved test for the existence of this antibody nor are there prospective data showing that screening for this antibody is useful. It may eventually be possible to prescreen patients using the ImmunoCAP assay that was used in our study4 before cetuximab treatment. The patients residing in high-risk areas would be the probable target population. If we can identify the patients at risk of severe reaction, we can use alternative therapies 18
www.unmc.edu/coned
References
Oxygen
(eg, normal saline)
To receive complimentary CE credit, log onto
C
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with multiple allergies. Furthermore, it is essential to be able to differentiate between an allergic reaction and a common side effect, such as nausea and vomiting. Before administering cetuximab, it is important to review the relevant protocols of the institution in case an infusion reaction occurs. The crash cart and supportive medications should be available and up to date, including sufficient amounts of epinephrine, diphenhydramine, bronchodilators, intravenous fluids, and oxygen. Because the majority of hypersensitivity reactions to cetuximab occur during the first infusion, these patients should be monitored closely. Vital signs should be checked before, during, after, and one hour after the infusion is administered. All patients should be premedicated with dexamethasone and diphenhydramine or any antihistamine before cetuximab infusion. At the first sign of an infusion reaction, the infusion should be stopped and supportive medication should be administered. For mild-to-moderate (grade 1 to 2) reactions, treatment can continue using a reduced rate (reducing the rate by half) once the symptoms have resolved. For severe (grade 3 to 4) reactions, patients should not be rechallenged, and cetuximab should be discontinued. There is no US Food and Drug Administration–approved test to screen for the presence of the IgE antibodies against cetuximab. Increased awareness of the potential adverse reactions, particularly when treating patients who live in known high-risk areas, can lead to management that is more effective and will minimize the frequency and severity of treatment-related adverse events. References 1. Chung CH, Mirakhur B, Chan E, et al. Cetuximab-induced anaphylaxis and IgE specific for galactose-alpha-1,3-galactose. N Engl J Med. 2008;358:1109-1117.
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Oncology Nurse
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CONSIDERATIONS IN MULTIPLE MYELOMA A Newsletter Series for Cancer Care Professionals Center of Excellence Media, along with Editor-in-Chief Sagar Lonial, MD, of Emory University, will proudly offer the multidisciplinary cancer team at your center a series of newsletters focusing on the challenges in treating patients with multiple myeloma.
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About Multidisciplinary Cancer Care Multidisciplinary Cancer Care newsletters provide a forum for sharing expert interdisciplinary treatment perspectives on patient care with the ultimate goal of promoting ongoing professional education to physicians, nurses, and pharmacists in the hematology/oncology community. Target Audience This educational publication is designed for physicians, nurses, and pharmacists who wish to enhance their knowledge concerning the management of patients with multiple myeloma and renal dysfunction.
Learning Objectives At the completion of this educational activity, you should be able to • Describe the prevalence of renal insufficiency among patients with multiple myeloma (MM) • Recognize the special challenges in pharmacologic treatment of the many patients with MM who also have renal insufficiency, especially those requiring dialysis • Discuss the results of studies showing treatments that are active and safe in MM patients with renal impairment, including those with advanced renal failure requiring dialysis
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Pharmacists CME Consultants is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. This activity has been designated for 1 contact hour (0.100 CEU). In order to receive credit, all participants must complete an evaluation, request for credit form, and a posttest. Statements of Credit will be mailed to participants within six weeks. ACPE #309-999-08-012-H01-P Initial Release Date: 05/07/08. Planned Expiration Date: 05/07/09. Nurses CME Consultants is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation. CME Consultants designates this program for 1 contact hour. Participants should claim only those contact hours actually spent in the educational activity. In order to receive credit for this program, each participant must complete the evaluation form, posttest, and certificate request form. Certificates will be mailed to program participants in approximately four to six weeks after receipt of the completed evaluation form, posttest, and certificate request form.
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CANCER CENTER PROFILE
TAUSSIG Continued from page 12
cate our nurses,” said Dr Raghavan. The entire nursing team in the hematologic and medical oncology outpatient treatment facility is certified in the administration of chemotherapy.
Therapeutic discoveries The renal cancer program has been successful at refining therapies. Taussig Cancer Center investigators have found that sorefanib is associated with a doubling of the average progression-free survival in patients with advanced renal cell carcinoma. Investigators in the renal cancer program led an international group that conducted studies on a tyrosine kinase inhibitor (sunitinib malate) for the treatment of kidney cancer, which received priority review and was approved in less than 6 months. The agent is indicated for the treatment of patients with renal cell cancer (and gastrointestinal stromal tumors who have disease progression despite treatment with imatinib mesylate or who are unable to tolerate imatinib). In patients with metastatic kidney cancer whose tumors progressed following cytokine-based therapy, sunitinib was associated with an overall response rate of 26% to 37%. Taussig researchers in hematologic oncology contributed to the discovery that AMG-531, a thrombopoiesis-stimulating protein, can stimulate platelet production in patients with immune thrombocytopenic purpura. Another clinical trial in which Taussig Cancer Center researchers participated led to the approval of dasatinib for use in adults with chronic-phase, accelerated-phase, or myeloid or lymphoid blast–phase chronic myeloid leukemia. In lung cancer research, bevacizumab, which is approved for the treatment of advanced colon cancer, is being explored for early cancer.
AMCP Continued from page 10
AMCP: Specialty Pharmacy Clinical Services Drive Appropriate Use of ESAs
CANCER CENTER PROFILE
SAN FRANCISCO—In collaboration with health plans, personalized clinical services provided by a specialty pharmacy may help drive the appropriate use of erythropoiesis-stimulating agents (ESAs) through communication with physicians to reduce the risk of adverse events. In addition, this approach may provide a significant cost savings, according to researchers in Massachusetts. New guidelines by the US Food and Drug Administration for the use of ESAs indicate an increased risk of serious life-threatening adverse events when given to maintain hemoglobin levels greater than 12 g/dL. Injectable medications, which include darbepoetin alfa, epoetin alfa, and epoetin alfa, are frequently prescribed by specialty pharmacies. The Massachusetts researchers wanted to assess the impact of a specialty 20
Extensive support services Patients and families have access to a wide variety of support services to help them cope with cancer and its treatment. The Scott Hamilton CARES Initiative is one of the features that sets the Taussig Cancer Center apart from others, Dr Raghavan believes. It was developed by the ice skater Scott Hamilton, who was treated there for testicular cancer and has since helped to
Photo courtesy of Cleveland Clinic
raise more than $10 million in funds for CARES through various philanthropic functions. CARES is focused on cancer education, research, and support. As part of CARES, a program called the 4th Angel Mentoring Program was developed in which former cancer patients are matched with new patients with the same type of cancer. The 4th Angel mentor is a cancer survivor trained in peer counseling and one-on-one outreach and support.
pharmacy clinical intervention program on appropriate use of ESAs and the cost savings associated with pharmacist recommendations. Working with physicians, a process was put in place by the specialty pharmacy clinical team to obtain the necessary patient information and make appropriate recommendations for patients receiving ESA therapy for anemia. Over a 60-day period, all patients from two regional health plans who were receiving ESAs through one specialty pharmacy were identified from the dispensing database. For each patient identified, the physician’s office was contacted by the clinical team via phone or fax to obtain pertinent patient information. This information included diagnosis, laboratory dates, serum hemoglobin levels, and target hemoglobin levels. After collecting the data, recommendations for dose reductions, medication discontinuation, or updating of laboratory work were made by the specialty pharmacy clinical team. “We found physicians were very cooperative about sending over the data on the blood work, and we evaluated it. For those we found to be outside of the guidelines, we asked the physician to reevaluate the patient and to either discontinue or lower the dose. We found
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Patients undergoing chemotherapy participate in customized classes led by oncology nurses to lessen anxiety and prepare them for the treatment process.
Multidisciplinary approach Multidisciplinary management is a pillar of cancer management at the Taussig Cancer Center. Patients are typically managed by a team of staff physicians, nurses, residents, and pharmacists to provide a level of expertise that may not be available at smaller institutions. “A patient with breast cancer will have the opportunity of involvement by a surgeon, radiation therapist oncologist, diagnostic radiologist, mammographer, and medical oncologist from the beginning,” said Dr Raghavan. “Someone with node-positive disease would see everybody.” He continued, “One of our models, because we’re so multidisciplinary, is that we have a lot of neoadjuvant studies. The idea is that we’ll give either chemotherapy, a novel agent, or a differentiating agent to a patient who is due to have a mastectomy or prostatectomy or bladder cancer removal, and it would be part of a standard of care. If a patient has a high-risk tumor, we might give chemotherapy and try to shrink the cancer, and at the same time we’ll look at the molecular biology—what has happened to that tumor after it has had that particular agent. This is obviously done only in the context of a clinical trial, with informed consent.” A recent study assessed a nano-engineered taxol derivative and the molecular correlates of its success and failure, he said. Other novel chemotherapy studies have been performed in patients with breast cancer. References 1. Sanda MG, Dunn RL, Michalski J, et al. Quality of life and satisfaction with outcome among prostate-cancer survivors. N Engl J Med. 2008;358:1250-1261. 2. Cristofanilli M, Budd GT, Ellis MJ, et al. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med. 2004;351:781-791.
80% were willing to do so,” said lead study investigator David Baker, RPh, MBA, who is director of clinical services at SpecialtyScripts Pharmacy Services, Fall River, Mass. Mr Baker, who presented the study findings at the Academy of Managed Care Pharmacy’s 20th Annual Meeting and Showcase, said a total of 64 patients receiving ESAs were evaluated. The pharmacy team found that 14 (22%) of the 64 patients had recent serum hemoglobin levels of 12.0 g/dL or greater. Recommendations to discontinue or lower the ESA dose were accepted for 11 (79%) of the 14 patients and rejected for three (21%) patients. The researchers determined that the total quarterly medication cost savings to the two health plan providers totaled $47,461.62 as a result of the interventions. In addition, the 11 patients whose doses were lowered or stopped saved a total of $465 in copayments throughout the quarter. Overall, the researchers found that medication cost savings to payors are significant and can be precisely calculated as part of the anemia intervention process. They said that drug cost savings are measurable as a result of immediate drug discontinuation or dose reduction.
“The biggest message is that as a specialty pharmacy we are able to manage ESA therapy, and we have a clinical team in place that can have an impact on driving appropriate use of these agents. This, in turn, can reduce the number of adverse events. It is something that hasn’t been utilized enough in the past. We can help reduce inappropriate use of these medications and help lower overall costs,” said Mr Barker in an interview with The Oncology Pharmacist. “Other pharmacies, especially specialty pharmacies, can duplicate this process, and so there could be a greater impact if this were done on a larger scale.” —JS
Did you
Know? Professional attendance at healthcare meetings increased an average of 13.8% in the past 5 years. Source: www.hcca.org
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Meetings JULY 2008
SAN FRANCISCO, CA 7th International Conference on Head and Neck Cancer The American Head and Neck Society www.ahns.info
24 – 26 CANCUN, MEXICO 3rd Interamerican Breast Cancer Conference www.imedex.com/calendars/onc ology.asp
AUGUST 2008
3 – 8 VAIL, CO
Methods in Clinical Cancer Research Joint ASCO/AACR Workshop www.aacr.org
14 – 16 WASHINGTON, DC American Society of HealthSystem Pharmacists 2008 Residency Preceptors Conference www.ashp.org
27 – 31
GENEVA, SWITZERLAND International Union against Cancer (UICC) World Cancer Congress www.uicc-congress08.org
June 2008
5 – 7 WASHINGTON, DC 2008 Breast Cancer Symposium www.astro.org
RITUXAN® (Rituximab) Brief summary—Please consult full prescribing information. WARNING: FATAL INFUSION REACTIONS, TUMOR LYSIS SYNDROME (TLS), SEVERE MUCOCUTANEOUS REACTIONS, and PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML) Infusion Reactions: Rituxan administration can result in serious, including fatal infusion reactions. Deaths within 24 hours of Rituxan infusion have occurred. Approximately 80% of fatal infusion reactions occurred in association with the first infusion. Carefully monitor patients during infusions. Discontinue Rituxan infusion and provide medical treatment for Grade 3 or 4 infusion reactions [see Warnings and Precautions, Adverse Reactions]. Tumor Lysis Syndrome (TLS): Acute renal failure requiring dialysis with instances of fatal outcome can occur in the setting of TLS following treatment of non-Hodgkin’s lymphoma (NHL) patients with Rituxan [see Warnings and Precautions, Adverse Reactions]. Severe Mucocutaneous Reactions: Severe, including fatal, mucocutaneous reactions can occur in patients receiving Rituxan [see Warnings and Precautions, Adverse Reactions]. Progressive Multifocal Leukoencephalopathy (PML): JC virus infection resulting in PML and death can occur in patients receiving Rituxan [see Warnings and Precautions, Adverse Reactions].
INDICATIONS AND USAGE Non-Hodgkin’s Lymphoma (NHL) Rituxan® (rituximab) is indicated for the treatment of patients with: Relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL as a single agent; Previously untreated follicular, CD20-positive, B-cell NHL in combination with CVP chemotherapy; Non-progressing (including stable disease), low-grade, CD20positive B-cell NHL, as a single agent, after first-line CVP chemotherapy; Previously untreated diffuse large B-cell, CD20-positive NHL in combination with CHOP or other anthracycline-based chemotherapy regimens. WARNINGS AND PRECAUTIONS Infusion Reactions Rituxan can cause severe, including fatal, infusion reactions. Severe reactions typically occurred during the first infusion with time to onset of 30–120 minutes. Rituxan-induced infusion reactions and sequelae include urticaria, hypotension, angioedema, hypoxia, bronchospasm, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, cardiogenic shock, or anaphylactoid events. Premedicate patients with an antihistamine and acetaminophen prior to dosing. Institute medical management (e.g., glucocorticoids, epinephrine, bronchodilators, or oxygen) for infusion reactions as needed. Depending on the severity of the infusion reaction and the required interventions, consider resumption of the infusion at a minimum 50% reduction in rate after symptoms have resolved. Closely monitor the following patients: those with preexisting cardiac or pulmonary conditions, those who experienced prior cardiopulmonary adverse reactions, and those with high numbers of circulating malignant cells (>25,000/mm3). [See Boxed Warning, Warnings and Precautions, Adverse Reactions.] Tumor Lysis Syndrome (TLS) Rapid reduction in tumor volume followed by acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia, can occur within 12–24 hours after the first infusion. Fatal TLS cases have occurred after administration of Rituxan. A high number of circulating malignant cells (*25,000/mm3) or high tumor burden confers a greater risk of TLS after rituximab. Consider prophylaxis for TLS in patients at high risk. Correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including dialysis as indicated. [See Boxed Warning.] Severe Mucocutaneous Reactions Mucocutaneous reactions, some with fatal outcome, can occur in patients treated with Rituxan. These reactions include paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis. The onset of these reactions has varied from 1–13 weeks following Rituxan exposure. Discontinue Rituxan in patients who experience a severe mucocutaneous reaction. The safety of readministration of Rituxan to patients with severe mucocutaneous reactions has not been determined. [See Boxed Warning, Adverse Reactions.] Progressive Multifocal Leukoencephalopathy (PML) JC virus infection resulting in PML and death can occur in Rituxan-treated patients with hematologic malignancies or with autoimmune diseases for which Rituxan has not been approved. The majority of patients with hematologic malignancies diagnosed with PML received Rituxan in combination with chemotherapy or as part of a hematopoietic stem cell transplant. The patients with autoimmune diseases had prior or concurrent immunosuppressive therapy and were diagnosed with PML within 12 months of their last infusion of Rituxan. Consider the diagnosis of PML in any patient presenting with new-onset neurologic manifestations. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture. Discontinue Rituxan and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML. [See Boxed Warning, Adverse Reactions.] Hepatitis B Virus (HBV) Reactivation Hepatitis B Virus (HBV) reactivation with fulminant hepatitis, hepatic failure, and death can occur in patients with hematologic malignancies treated with Rituxan. The median time to the diagnosis of hepatitis was approximately 4 months after the initiation of Rituxan and approximately one month after the last dose. Screen patients at high risk of HBV infection before initiation of Rituxan. Closely monitor carriers of hepatitis B for clinical and laboratory signs of active HBV infection for several months following Rituxan therapy. Discontinue Rituxan and any concomitant chemotherapy in patients who develop viral hepatitis, and institute appropriate treatment including antiviral therapy. Insufficient data exist regarding the safety of resuming Rituxan in patients who develop hepatitis subsequent to HBV reactivation. [See Adverse Reactions.] Other Viral Infections The following additional serious viral infections, either new, reactivated, or exacerbated, have been identified in clinical studies or postmarketing reports. The majority of patients received Rituxan in combination with chemotherapy or as part of a hematopoietic stem cell transplant. These viral infections included cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West Nile virus, and hepatitis C. In some cases, the viral infections occurred as late as one year following discontinuation of Rituxan and have resulted in death. [See Adverse Reactions.] Cardiovascular Discontinue infusions for serious or lifethreatening cardiac arrhythmias. Perform cardiac monitoring during and after all infusions of Rituxan for patients who develop clinically significant arrhythmias or who have a history of arrhythmia or angina. [See Adverse Reactions.] Renal Severe, including fatal, renal toxicity can occur after Rituxan administration in patients with hematologic malignancies. Renal toxicity has occurred in patients with high numbers of circulating malignant cells (>25,000/mm3) or high tumor burden who experience tumor lysis syndrome and in patients with NHL administered concomitant cisplatin therapy during clinical trials. The combination of cisplatin and Rituxan is not an approved treatment regimen. Use extreme caution if this non-approved combination is used in clinical trials and monitor closely for signs of renal failure. Consider discontinuation of Rituxan for patients with a rising serum creatinine or oliguria. Bowel Obstruction and Perforation Abdominal pain, bowel obstruction and perforation, in some cases leading to death, can occur in patients receiving Rituxan in combination with chemotherapy. In postmarketing reports, the mean time to documented gastrointestinal
MEETINGS
American Association of Colleges of Pharmacy 2008 Annual Meeting www.aacp.org
17 – 20 SAN FRANCISCO, CA 19 – 20 MIAMI, FL 25th National Oncology Economics Conference www.accc-cancer.org
9th Annual Perspectives in Colorectal Cancer www.imedex.com
perforation was 6 (range 1–77) days in patients with NHL. Perform a thorough diagnostic evaluation and institute appropriate treatment for complaints of abdominal pain, especially early in the course of Rituxan therapy. [See Adverse Reactions.] Immunization The safety of immunization with live viral vaccines following Rituxan therapy has not been studied and vaccination with live virus vaccines is not recommended. For NHL patients, the benefits of primary or booster vaccinations should be weighted against the risks of delay in initiation of Rituxan therapy. Laboratory Monitoring Because Rituxan binds to all CD20positive B lymphocytes (malignant and non-malignant), obtain complete blood counts (CBC) and platelet counts at regular intervals during Rituxan therapy and more frequently in patients who develop cytopenias [see Adverse Reactions]. The duration of cytopenias caused by Rituxan can extend months beyond the treatment period. ADVERSE REACTIONS The most common adverse reactions of Rituxan (incidence *25%) observed in patients with NHL are infusion reactions, fever, chills, infection, asthenia, and lymphopenia. The most important serious adverse reactions of Rituxan are infusion reactions, tumor lysis syndrome, mucocutaneous toxicities, hepatitis B reactivation with fulminant hepatitis, PML, other viral infections, cardiac arrhythmias, renal toxicity, and bowel obstruction and perforation. Clinical Trials Experience Non-Hodgkin’s Lymphoma 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. The data described below reflect exposure to Rituxan in 1606 patients, with exposures ranging from a single infusion up to 6–8 months. Rituxan was studied in both single-agent and active-controlled trials (n = 356 and n = 1250). These data were obtained in adults with low-grade, follicular, or DLBCL NHL. Most patients received Rituxan as an infusion of 375 mg/m2 per infusion, given as a single agent weekly for up to 8 doses, in combination with chemotherapy for up to 8 doses, or following chemotherapy for up to 16 doses. Infusion Reactions In the majority of patients with NHL, infusion reactions consisting of fever, chills/rigors, nausea, pruritus, angioedema, hypotension, headache, bronchospasm, urticaria, rash, vomiting, myalgia, dizziness, or hypertension occurred during the first Rituxan infusion. Infusion reactions typically occurred within 30 to 120 minutes of beginning the first infusion and resolved with slowing or interruption of the Rituxan infusion and with supportive care (diphenhydramine, acetaminophen, and intravenous saline). The incidence of infusion reactions was highest during the first infusion (77%) and decreased with each subsequent infusion. [See Boxed Warning, Warnings and Precautions.] Infections Serious infections (NCI CTCAE Grade 3 or 4), including sepsis, occurred in less than 5% of patients with NHL in the single-arm studies. The overall incidence of infections was 31% (bacterial 19%, viral 10%, unknown 6%, and fungal 1%). [See Warnings and Precautions.] In randomized, controlled studies where Rituxan was administered following chemotherapy for the treatment of follicular or low-grade NHL, the rate of infection was higher among patients who received Rituxan. In diffuse large B-cell lymphoma patients, viral infections occurred more frequently in those who received Rituxan. Cytopenias and hypogammaglobulinemia In patients with NHL receiving rituximab monotherapy, NCI-CTC Grade 3 and 4 cytopenias were reported in 48% of patients. These included lymphopenia (40%), neutropenia (6%), leukopenia (4%), anemia (3%), and thrombocytopenia (2%). The median duration of lymphopenia was 14 days (range, 1–588 days) and of neutropenia was 13 days (range, 2–116 days). A single occurrence of transient aplastic anemia (pure red cell aplasia) and two occurrences of hemolytic anemia following Rituxan therapy occurred during the single-arm studies. In studies of monotherapy, Rituxan-induced B-cell depletion occurred in 70% to 80% of patients with NHL. Decreased IgM and IgG serum levels occurred in 14% of these patients. Single-Agent Rituxan Adverse reactions in Table 1 occurred in 356 patients with relapsed or refractory, lowgrade or follicular, CD20-positive, B-cell NHL treated in single-arm studies of Rituxan administered as a single agent. Most patients received Rituxan 375 mg/m2 weekly for 4 doses. Table 1 Incidence of Adverse Events in *5% of Patients with Relapsed or Refractory, LowGrade or Follicular NHL, Receiving Single-agent Rituxan (N = 356)a,b
and 4 adverse reactions and serious adverse reactions. In Study 7, a review of cardiac toxicity determined that supraventricular arrhythmias or tachycardia accounted for most of the difference in cardiac disorders (4.5% for R-CHOP vs. 1.0% for CHOP). The following Grade 3 or 4 adverse reactions occurred more frequently among patients in the R-CHOP arm compared with those in the CHOP arm: thrombocytopenia (9% vs. 7%) and lung disorder (6% vs. 3%). Other Grade 3 or 4 adverse reactions occurring more frequently among patients receiving RCHOP were viral infection (Study 7), neutropenia (Studies 7 and 8), and anemia (Study 8). Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The observed incidence of antibody (including neutralizing antibody) positivity in an assay is 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 the incidence of antibodies to Rituxan with the incidence of antibodies to other products may be misleading. Using an ELISA assay, antihuman anti-chimeric antibody (HACA) was detected in 4 of 356 (1.1%) patients with low-grade or follicular NHL receiving single-agent Rituxan. Three of the four patients had an objective clinical response. The clinical relevance of HACA formation in rituximab treated patients is unclear. Postmarketing Experience The following adverse reactions have been identified during postapproval use of Rituxan in hematologic malignancies. 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. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to Rituxan. Hematologic: prolonged pancytopenia, marrow hypoplasia, and late-onset neutropenia, hyperviscosity syndrome in Waldenstrom’s macroglobulinemia. Cardiac: fatal cardiac failure. Immune/Autoimmune Events: uveitis, optic neuritis, systemic vasculitis, pleuritis, lupus-like syndrome, serum sickness, polyarticular arthritis, and vasculitis with rash. Infection: viral infections, including progressive multifocal leukoencephalopathy (PML), increase in fatal infections in HIV-associated lymphoma, and a reported increased incidence of Grade 3 and 4 infections in patients with previously treated lymphoma without known HIV infection. Neoplasia: disease progression of Kaposi’s sarcoma. Skin: severe mucocutaneous reactions. Gastrointestinal: bowel obstruction and perforation. Pulmonary: fatal bronchiolitis obliterans and pneumonitis (including interstitial pneumonitis). DRUG INTERACTIONS Formal drug interaction studies have not been performed with Rituxan. USE IN SPECIFIC POPULATIONS Pregnancy Category C: There are no adequate and well-controlled studies of rituximab in pregnant women. NonHodgkin’s lymphoma and severe rheumatoid arthritis are serious conditions that require treatment. Rituximab should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Rituximab is a genetically engineered IgG molecule, and IgG crosses the human placenta. Reproduction studies in cynomolgus monkeys at maternal exposures similar to human therapeutic exposures showed no evidence of teratogenic effects. However, B-cell lymphoid tissue was reduced in the offspring of treated dams. The B-cell counts returned to normal levels, and immunologic function was restored within 6 months of birth. Other than target B lymphocytes, rituximab is not known to bind to any normal human tissues in an ex vivo assay. However, it is not known if binding occurs to unique embryonic or fetal tissue receptors in vivo. Nursing Mothers It is not known whether Rituxan is secreted into human milk. However, Rituxan is secreted in the milk of lactating cynomolgus monkeys, and IgG is excreted in human milk. Published data suggest that antibodies in breast milk do not enter the neonatal and infant circulations in substantial amounts. The unknown risks to the infant from gastrointestinal or limited systemic exposure to Rituxan should be weighed against the known benefits of breastfeeding. Pediatric Use The safety and effectiveness of Rituxan in pediatric patients have not been established. Geriatric Use Diffuse Large B-Cell NHL Among patients with DLBCL evaluated in three randomized, active-controlled trials, 927 patients received Rituxan in combination with chemotherapy. Of these, 396 (43%) were age 65 or greater and 123 (13%) were age 75 or greater. No overall differences in effectiveness were observed between these patients and younger patients. Cardiac adverse reactions, mostly supraventricular arrhythmias, occurred more All Grades (%) Grade 3 and 4 (%) All Grades (%) Grade 3 and 4 (%) frequently among elderly patients. Serious pulmonary adverse reactions were also Respiratory System 38 4 Any Adverse Events 99 57 more common among the elderly, including pneumonia and pneumonitis. Low86 10 Increased Cough 13 1 Body as a Whole Fever 53 1 Rhinitis 12 1 Grade or Follicular Non-Hodgkin’s Lymphoma Clinical studies of Rituxan in Chills 33 3 Bronchospasm 8 1 low-grade or follicular, CD20-positive, B-cell NHL did not include sufficient Infection 31 4 Dyspnea 7 1 Asthenia 26 1 Sinusitis 6 0 numbers of patients aged 65 and over to determine whether they respond Headache 19 1 Metabolic and Nutritional Abdominal Pain 14 1 Disorders 38 3 differently from younger subjects. OVERDOSAGE There has been no experience Pain 12 1 Angioedema 11 1 with overdosage in human clinical trials. Single doses of up to 500 mg/m2 have Back Pain 10 1 Hyperglycemia 9 1 Throat Irritation 9 0 Peripheral Edema 8 0 been given in dose-escalation clinical trials. NONCLINICAL TOXICOLOGY Flushing 5 0 LDH Increase 7 0 Heme and Lymphatic System 67 48 Digestive System 37 2 Carcinogenesis, Mutagenesis, Impairment of Fertility No long term animal Lymphopenia 48 40 Nausea 23 1 Leukopenia 14 4 Diarrhea 10 1 studies have been performed to establish the carcinogenic or mutagenic potential Neutropenia 14 6 Vomiting 10 1 of Rituxan or to determine potential effects on fertility in males or females. Thrombocytopenia 12 2 Nervous System 32 1 Anemia 8 3 Dizziness 10 1 PATIENT COUNSELING INFORMATION Patients should be provided the Rituxan Skin and Appendages 44 2 Anxiety 5 1 Night Sweats 15 1 Musculoskeletal System 26 3 Medication Guide and provided an opportunity to read prior to each treatment Rash 15 1 Myalgia 10 1 session. Because caution should be exercised in administering Rituxan to patients Pruritus 14 1 Arthralgia 10 1 Urticaria 8 1 Cardiovascular System 25 3 with active infections, it is important that the patient’s overall health be assessed Hypotension 10 1 Hypertension 6 1 at each visit and any questions resulting from the patient’s reading of the Medication Guide be discussed. Rituxan is detectable in serum for up to six a b Adverse reactions observed up to 12 months following Rituxan. Adverse reactions graded for severity by months following completion of therapy. Individuals of childbearing potential NCI-CTC criteria. In these single-arm Rituxan studies, bronchiolitis obliterans occurred during and should use effective contraception during treatment and for 12 months after up to 6 months after Rituxan infusion. Rituxan in Combination With Rituxan therapy. Chemotherapy Adverse reactions information below is based on 1250 patients who received Rituxan in combination with chemotherapy or following chemotherapy. Rituxan in Combination With Chemotherapy for Low-Grade NHL In Study 4, patients in the R-CVP arm experienced a higher incidence of Revised 1/2008 (4835504) infusional toxicity and neutropenia compared to patients in the CVP arm. The Jointly Marketed by: following adverse reactions occurred more frequently (*5%) in patients receiving Biogen Idec Inc. 5200 Research Place San Diego, CA 92122 R-CVP compared to CVP alone: rash (17% vs. 5%), cough (15% vs. 6%), flushing Genentech USA, Inc. 1 DNA Way South San Francisco, CA 94080-4990 (14% vs. 3%), rigors (10% vs. 2%), pruritus (10% vs. 1%), neutropenia (8% vs. 3%), and chest tightness (7% vs. 1%). In Study 5, the following adverse reactions were reported more frequently (*5%) in patients receiving Rituxan following CVP compared to patients who received no further therapy: fatigue (39% vs. 14%), anemia (35% vs. 20%), peripheral sensory neuropathy (30% vs. 18%), infections (19% vs. 9%), pulmonary toxicity (18% vs. 10%), hepato-biliary toxicity (17% vs. ©2008 Biogen Idec Inc. and Genentech, Inc. 7140916 March 2008 7%), rash and/or pruritus (17% vs. 5%), arthralgia (12% vs. 3%), and weight gain (11% vs. 4%). Neutropenia was the only Grade 3 or 4 adverse reaction that occurred more frequently (*2%) in the Rituxan arm compared with those who received no further therapy (4% vs. 1%). Rituxan in Combination With Chemotherapy for DLBCL In Studies 6 and 7, the following adverse reactions, regardless of severity, were reported more frequently (*5%) in patients age *60 years receiving R-CHOP as compared to CHOP alone: pyrexia (56% vs. 46%), lung disorder (31% vs. 24%), cardiac disorder (29% vs. 21%), and chills (13% vs. 4%). Detailed safety data collection in these studies was primarily limited to Grade 3
G REEN H ILL H EALTH C ARE C OMMUNICATIONS
MEETINGS
19 – 23 CHICAGO, IL
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For previously untreated diffuse large B-cell, CD20-positive NHL in combination with CHOP or other anthracycline-based chemotherapy regimens
When planning a treatment course for DLBCL
Take the essential path toward improved survival RITUXAN+CHOP is proven to prolong survival in DLBCL
47% INCREASE
in 7-year OS in GELA* trial 1,2
• At 7 years, 8 cycles of RITUXAN+ CHOP increased overall survival (OS) from 36% to 53% compared with CHOP alone1 • At 5 years, 8 cycles of RITUXAN+ CHOP increased OS from 46% to 58% compared with CHOP alone5
BOXED WARNINGS and Additional Important Safety Information The most important serious adverse reactions of RITUXAN are fatal infusion reactions, tumor lysis syndrome (TLS), severe mucocutaneous reactions, progressive multifocal leukoencephalopathy (PML), hepatitis B reactivation with fulminant hepatitis, other viral infections, cardiovascular events, renal toxicity, and bowel obstruction and perforation. The most common adverse reactions of RITUXAN (incidence ≥25%) observed in patients with NHL are infusion reactions, fever, chills, infection, asthenia, and lymphopenia.5 RITUXAN in Combination with CHOP Chemotherapy for DLBCL: The following adverse reactions, regardless of severity, were reported more frequently (≥5%) in patients age ≥60 years receiving R-CHOP as compared to CHOP alone: pyrexia (56% vs 46%), lung disorder (31% vs 24%), cardiac disorder (29% vs 21%), and chills (13% vs 4%). In the GELA LNH 98-5 study, a review of cardiac toxicity determined that supraventricular arrhythmias or tachycardia accounted for most of the difference in cardiac disorders (4.5% for R-CHOP vs 1.0% for CHOP).5 The following Grade 3 or 4 adverse reactions occurred more frequently among patients in the R-CHOP arm compared with those in the CHOP arm: thrombocytopenia (9% vs 7%) and lung disorder (6% vs 3%). Other Grade 3 or 4 adverse reactions reported more frequently among patients receiving R-CHOP were viral infection (GELA LNH 98-5 study), neutropenia (GELA LNH 98-5 and MInT studies), and anemia (MInT study).5
Please see brief summary of prescribing information on adjacent page. Attention Healthcare Provider: Provide Medication Guide to patient prior to RITUXAN infusion. *GELA (Groupe d’Etude des Lymphomes de l’Adulte) LNH 98-5 trial: A Phase III trial of 399 previously untreated elderly (age ≥60 years) DLBCL patients.3,4 †CHOP: Cyclophosphamide, doxorubicin, vincristine, and prednisone. References: 1. Coiffier B, Feugier P, Mounier N, et al. Long-term results of the GELA study comparing R-CHOP and CHOP chemotherapy in older patients with diffuse large B-cell lymphoma show good survival in poor-risk patients. J Clin Oncol. 2007;25(suppl 18S):443s. Abstract 8009. 2. Coiffier B, Feugier P, Mounier N, et al. Long-term results of the GELA study comparing R-CHOP and CHOP chemotherapy in older patients with diffuse large B-cell lymphoma show good survival in poor-risk patients. Paper presented at: 43rd American Society of Clinical Oncology Annual Meeting; June 1-5, 2007; Chicago, Ill. Abstract 8009. 3. Coiffier B, Lepage E, Brière J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002;346:235-242. 4. Data on file, Genentech, Inc. 5. RITUXAN® (Rituximab) full prescribing information, Genentech, Inc., 2008.
PROVE N. POWE R FU L.
©2008 Genentech, Inc., and Biogen Idec Inc. All rights reserved. 3 Printed in USA on Recycled Paper 8974801 April 2008