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PHARMACY EDUCATION AND TRAINING Jefferson School of Pharmacy builds on first year successes
Re f gi Se or M st Ixabepilone provides new option ult con Y ip l d ou er for metastatic breast cancer a e n ww My nu r To By Timothy Tyler, PharmD, FCSHP w. elomaal Con Fre day page 26 co new side e ex sle rati CE m tter ons www.theoncologypharmacist.com .co ser in m ies CLINICAL PHARMACY REVIEW
An interview with Rebecca S. Finley, PharmD, MS
page 14 SEPTEMBER/OCTOBER 2009 • VOL. 2, NO. 6
er d a Le and e h T ews in N eeting e M erag Cov Hopa 5th annual conference
New HOPA President Seeks to Set Standards An Interview with Philip E. Johnson, MS, RPh, FASHP
hilip E. Johnson, MS, RPh, FASHP, became the sixth president of the Hematology/ Oncology Pharmacy Association (HOPA) at the annual meeting in Miami, Florida. Johnson is director of pharmacy at H. Lee Moffitt Cancer Center in Tampa, Florida. In this interview, he spoke about what
led to his own interest in oncology, the growth of the oncology pharmacy specialty, and what he hopes to accomplish in his term in office.
How did you get involved in oncology pharmacy, and what led you to your involvement in HOPA?
Continued on page 6
Continued on page 10
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COMPLIMENTARY CE CREDIT
Newly Approved Pralatrexate Evoked a Complete or Partial Response in 27% of Patients
o you’re ready to start designing your oncology clinic. Have you given very much thought to what you will need? In this installment, I will discuss some of the common decisions that have to be made in selecting equipment for an ambulatory clinic.
Illinois Cancer Center, Peoria
Continued on page 7
n September 25, 2009, pralatrexate (Folotyn, Allos Therapeutics) was granted accelerated approval by the US Food and Drug Administration (FDA) for treatment of relapsed or refractory peripheral T-cell lymphoma (PTCL) and should already be available for patients. Final results released in February from the largestever prospectively designed single-agent phase 2 trial in
By Michele Woods, PharmD, BCOP
MIAMI—Although the use of complementary alternative medicine (CAM) has increased significantly for patients with cancer, this information is often not shared with their pharmacists, according to a survey-based analysis presented at the 5th annual meeting of the Hematology/ Oncology Pharmacy Association. “We realized that the use of alternative medicines has gotten more and more prevalent in cancer patients over the past decade,” said Trang Tran, PharmD, pharmacy practice resident at the
recent fDa approvalS
Challenges of Oncology Pharmacy Practice in the Community Setting. Part 2
When I graduated from college 40 years ago, oncology was not a well-developed field. My mentor, Dr Herb Carlin, offered a new program at the University of Illinois in which he introduced some of the concepts of clinical pharmacy, such as working as part of a multidiscipli-
CAM Use Increases, Information Often Not Shared with Pharmacists
Prediction and Promise: KRAS and Colorectal Cancer
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TOPSept_Oct09_v4 10/5/09 11:52 AM Page 1
I SUSAN GOODIN, PHARMD, FCCP, BCOP
PATRICK MEDINA, PHARMD, BCOP
n an interview with The Oncology Pharmacist, Philip E. Johnson, MS, RPh, FASAP, incoming president of the Hematology/Oncology Pharmacy Association (HOPA), speaks of how both oncology and clinical pharmacy have evolved over the span of his career. Not only has there been tremendous growth in the options available for treatment of cancer, but also the role of oncology pharmacists has expanded to include direct patient care, clinical research, practice management, and patient advocacy. To keep up with the increasing complexity of the field, HOPA plans to enhance its educational offerings and to develop oncologybased standards for education and technology. Proving the value of pharmacy is a major challenge, he said, and HOPA will also work
with other professional organizations to address legislative and regulatory issues affecting oncology practice. To keep up with the demand for pharacists, new schools of pharmacy have opened recently or are being planned. Last year, we spoke with Rebecca S. Finley, PharmD, MS, founding dean of the Jefferson School of Pharmacy, as they prepared to welcome their first class. Now we follow up with her on how that class is progressing and what is planned for the future. One thing she noted was the diversity of the students now enrolled in pharmacy school and the need to adapt class scheduling and educational materials to meet their needs. Many new graduates work in community cancer centers and find that in addition to
their clinical knowledge and skills, they need to learn about practical matters such as clinic design. In the second part of her series on the challenges of oncology pharmacy practice in the community setting, Michele Woods, PharmD, BCOP, makes suggestions about engineering controls for the clean room, use of automated dispensing systems, and other everyday considerations. As the debate about the future of healthcare continues, healthcare professionals and the organizations that represent us will need to make our views known on matters such as reimbursement for cancer drugs and potential implementation of evaluation and mitigation systems for opioids and other drugs widely used in oncology that will have a major impact on our practices and our patients. ●
News Notes News Updates of Relevance to Everyday Oncology Practice ■ Azacitidine Upgraded to NCCN Category 1 The National Comprehensive Cancer Network (NCCN) has upgraded azacitidine (Vidaza, Celgene) to a Category 1 recommendation for the treatment of patients with intermediate-2 and highrisk myelodysplastic syndromes. The recommendation was based on the recently reported findings of a large international randomized phase 3 clinical trial, in which azacitidine demonstrated a near doubling of overall survival rates at 2 years compared with conventional care regimens (best supportive care, low-dose ARA-C, standard chemotherapy). In the
study, median overall survival in the azacitidine group (n = 179) was 24.5 months; in the conventional care regimens arm (n = 179), it was 15 months (P = .0001) (Celgene Corporation). ■ GAO Confirms Unequal Access to Medicaid for Breast Cancer Treatment A new report from the Government Accountability Office (GAO) highlights the disparity in access to screening for and treatment of breast cancer. Lack of funding is responsible for more than half of eligible lowincome, uninsured women not receiving recommended breast cancer screening. In addition, restrictions to
EDITORIAL CORRESPONDENCE should be addressed to EDITORIAL DIRECTOR, The Oncology Pharmacist®, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. E-mail: email@example.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 #1944-9607. The Oncology Pharmacist® is published 7 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 ©2009 by Green Hill Healthcare Communications LLC. All rights reserved. The Oncology Pharmacist® logo is a registered 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.
Medicaid coverage for breast and cervical cancer screening in more than a dozen states effectively eliminate all but a small fraction of low-income women from benefiting from screening programs. The Komen Advocacy Alliance worked with Senators Max Baucus (D-MT), Barbara Mikulski (DMD), and Debbie Stabenow (D-MI) to request the study. The report identified that 16 states plus the District of Columbia limit access to Medicaid coverage, that 60% of eligible women do not receive breast cancer screening from any provider, and that few statewide options for treatment are available to lowincome, uninsured women who are not eligible for Medicaid under the Treatment Act (Susan G. Komen for the Cure). ■ FDA Issues Final Rules for Expanded Access to Investigational Drugs The US Food and Drug Administration (FDA) has amended two regulations regarding investigational new drugs. One final rule expands access to these agents for treating patients. It clarifies the existing regulations and adds new types of expanded access: • Individual patients, including in emergencies • Intermediate-size patient populations • Larger populations under treatment protocol or treatment investigational new drug application. Another rule amends the regulation on charging patients for investigational drugs by: • Clarifying the circumstances under which charging for an investigational drug in a clinical trial is appropriate • Setting forth criteria for charging for an investigational drug for the different types of expanded access for treatment described above • Clarifying what costs can be recovered. In a press release, American Society of Clinical Oncology President Douglas W. Blayney, MD, stated that the new rules “strike a balance between meeting the immediate needs of seriously ill cancer patients, while safeguarding the clinical trials system so it can develop to treat cancer patients in the future.” ●
G REEN H ILL H EALTHCARE C OMMUNICATIONS
A Letter from the Editors
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Vol. 2, No. 6
September/October 2009 Departments
Feature Articles 7
Conference News: HOPA
Pharmacist-managed zoledronic acid dose adjustments decrease process time by half hour per order Cisplatin-based chemotherapy may increase incidence of thromboembolic events Long-term romiplostim treatment appears safe, effective for on-site and home administration
Continuing Education Prediction and promise: KRAS and colorectal cancer
Editorial Director Karen Rosenberg firstname.lastname@example.org
Letter to the Editors
Associate Editor Dawn Lagrosa
Healthcare reform, and how we treat the elderly
Pharmacy Careers and Education Pharmacy school provides a well-rounded education
Clinical Pharmacy Review Ixabepilone: a new treatment for metastatic breast cancer
PUBLISHING STAFF Publisher Philip Pawelko email@example.com
Oncology Drug Codes
Production Manager Lynn Hamilton Director, Client Services John W. Hennessy firstname.lastname@example.org Business Manager Blanche Marchitto email@example.com Executive Administrator Andrea Boylston
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Steven L. D’Amato, RPh, BCOP
Jim Koeller, MS
Maine Center for Cancer Medicine Scarborough, ME
University of Texas at Austin San Antonio, TX
Bryna Delman Ewachiw, BS, PharmD
Helen L. Leather, BPharm
Johns Hopkins Bayview Medical Center Baltimore, MD
University of Florida Gainesville, FL
Anjana Elefante, PharmD, BSc, BScPhm, RPh
Christopher J. Lowe, PharmD
Roswell Park Cancer Institute Buffalo, NY
Novant Health Winston-Salem, NC
Beth Faiman, RN, MSN, APRN, BC, AOCN
Helen McFarland, PharmD, BCOP
Susan Goodin, PharmD, FCCP, BCOP
Cleveland Clinic Taussig Cancer Center Cleveland, OH
Union Memorial Hospital Baltimore, MD
Cancer Institute of New Jersey New Brunswick, NJ
Christopher Fausel, PharmD
Emily Mackler, PharmD, BCOP
Indiana University Simon Cancer Center Indianapolis, IN
University of Michigan Health System & College of Pharmacy Ann Arbor, MI
Patrick Medina, PharmD, BCOP
Rebecca S. Finley, PharmD, MS
Laura Boehnke Michaud, PharmD, BCOP, FASHP
Jefferson School of Pharmacy Philadelphia, PA
The University of Texas MD Anderson Cancer Center Houston, TX
David C. Gammon, BSPharm
Deborah Moradi, PharmD
University of Massachusetts Memorial Hospital Worcester, MA
The Angeles Clinic and Research Institute Los Angeles, CA
Heidi D. Gunderson, PharmD, BCOP
LeAnn Best Norris, PharmD, BCPS, BCOP
Mayo Clinic Cancer Center Rochester, MN
South Carolina College of Pharmacy Columbia, SC
Sandra Horowitz, PharmD, RPh
Debra L. Phillips, PharmD
The University of Texas MD Anderson Cancer Center Houston, TX
East Carolina University Greenville, NC
Lew Iacovelli, BS, PharmD, BCOP, CPP
Steve Stricker, PharmD, MS
Oklahoma University College of Pharmacy Tulsa, OK
John F. Aforismo, BSC Pharm, RPh, FASCP RJ Health Systems International, LLC Wethersfield, CT
David Baribeault, RPh, BCOP Boston Medical Center Boston, MA
Sylvia Bartel, RPh, MPH
Moses H. Cone Health System Greensboro, NC
Samford University McWhorter School of Pharmacy Birmingham, AL
Andrea A. Iannucci, PharmD, BCOP
Timothy G. Tyler, PharmD, FCSHP
University of California Davis Medical Center Sacramento, CA
Desert Regional Medical Center Palm Springs, CA
Cindy Ippoliti, PharmD
John M. Valgus, PharmD, BCOP
James Cancer Hospital & Solove Research Institute Columbus, OH
New York Presbyterian Hospital/Weill Cornell Medical School New York, NY
University of North Carolina Hospitals and Clinics Chapel Hill, NC
Betty M. Chan, PharmD, BCOP
Dwight Kloth, PharmD, FCCP, BCOP
Gary C. Yee, PharmD, FCCP, BCOP
USC/Norris Cancer Hospital Los Angeles, CA
Fox Chase Cancer Center Philadelphia, PA
University of Nebraska College of Pharmacy Omaha, NE
Dana-Farber Cancer Institute Boston, MA
Deborah Blamble, PharmD, BCOP The University of Texas MD Anderson Cancer Center Houston, TX
Marlo Blazer, RPh, PharmD
G REEN H ILL H EALTHCARE C OMMUNICATIONS
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A deeper exploration — uncovering new opportunities in oncology
At Genentech BioOncology, we’re leading the fight against cancer with innovative science. We believe that great science and the right people can lead to significant advances in cancer treatment. Dedicated scientists — Our researchers are dedicated to defining the molecular basis of cancer and developing groundbreaking treatments. Gold standard clinical development — We identify biomarkers and develop companion diagnostics wherever possible, with the goal of matching each patient with the most appropriate therapy. A commitment to patients — We actively pursue ways to ensure patient access to therapeutics through a variety of patient support programs so healthcare providers can remain focused on patient care. Our goal is to fundamentally change the way cancer is treated — not just with incremental advances, but with new standards of care.
© 2009 Genentech USA, Inc. All rights reserved. 9708400 Printed in USA.
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LETTER TO THE EDITORS
Letter to the Editors Healthcare Reform and How We Treat the Elderly To the Editors:
t wasn’t supposed to happen this way. The 1000page House of Representatives healthcare reform bill, America’s Affordable Health Choices Act, was supposed to follow the new congressional passage sequence: distribute it to all the usual suspects, read it on the cab ride to the hotel, and immediately sign it into law. So when congressional members on both sides of the aisle started boring into the draft of the bill and came back with concern over language that only suggested a troubling threat to seniors, political veterans were caught off guard. Since then, with protests ringing across the country at town hall meetings and every other conceivable venue, it has become clear that Americans want a healthcare system bent on healing. The immediate concern was over the now infamous end-of-life counseling provision, Section 1233, which would have authorized Medicare to pay for a consultation between a patient and doctor or nurse about how much or little medical care is desired in the event of incapacitation, informing patients about the benefits of hospice and palliative care. At first blush, there was nothing alarming here. Providers and payers have been wrestling to draw the line between aggressive care for the terminally ill, and the pointless, wasteful use of costly drugs that do little to improve or extend life in terminally ill patients. But there is an existing context for this language and the net effect of other provisions in the House bill that are intended to ration care, which would lead to the same result: an early and cost-effective death, all in the name of efficient healthcare resource allocation. (Note that there is all the difference in the world between a medically driven consultation with one’s doctor and an agenda-driven consultation designed a priori to discourage care.) Concern arose immediately over end-of-life counseling and rationing for the elderly, with fears that it signaled the start of limiting access to healthcare for our sickest, usually oldest, patients. Fueling this fear is the fact that a quarter of Medicare funds go to patients in the last year of their lives. Because policy must be drafted with an eye to clarity, the public wanted assurances that the government was not simply implementing a cost-saving measure designed to convince seniors to opt out of appropriate treatment when they are terminally ill. Evaluating the language within the context of political policy, the concern is that the bill is an incremental move toward replacing a progressive healthcare system with a regressive one, with the elderly as its first victims. The ensuing debate has helped to bring a central issue out in the forefront: will seniors receive the care they need? It is important that we decide whether we are committed to a progressive healthcare system—one that aggressively pursues disease prevention, intervention, and innovation—or to a Brave New World of limited healthcare resources, concluding that the best years of healthcare are behind us. If the latter, then we must become adept at rationing care for the elderly, ultimately endorsing euthanasia, assisted suicide, and rationed care as practical remedies. Society must choose sides—it cannot finesse both ends of the spectrum, because the war on disease takes all the resolve of a true all-out war. As healthcare reform takes shape, we must take stock of how we treat our elderly, a fun-
damental measure of the decency of our society. And as we look at new initiatives for dealing with end-of-life care, we must ask if the United States will follow the lead of Great Britain and provide coverage based on quality-adjusted life-years, calculating coverage eligibility based on the cost of intervention measured against one’s age. By encouraging hospice-oriented care for the elderly and the rationing of care, is government embracing a regressive healthcare system? Is government’s healthcare vision one of reduced access to care for the elderly and infirm, coupled with reduced development of new life-saving drugs because payer coverage strategies are skewed against coverage of branded medications, the profits of which are needed for innovation? If this is the picture, would the affluent consent to the terms that a regressive healthcare system proffers to the public at large? Would the wealthy accept a government mandate that says it is your turn to die? Be it death counseling or rationing, the end goal is the same: death is good for the bottom line. It has not escaped notice of policymakers that the major epidemiologic factor facing American healthcare is the aging of the baby boomers. The real crisis facing America’s healthcare system is what will happen 10 years from now when baby boomers begin contracting geriatric disease states and consuming vast healthcare resources, if nothing is done to improve current efficiencies to healthcare. But it is the nature of a free people to reorder their circumstances to overcome challenges to their survival. In the face of the graying of America, some policymakers would have us encourage the elderly and infirm to die quickly and “will their estates” to the young. This is classical pessimism reincarnated 21st-century style under the guise of “death-with-dignity” allocation of resources. It is an easy guess that lawmakers and the wealthy endorsing this process for the public at large would exempt themselves from it. It is also an easy guess that most lawmakers do not want this to happen. If that is the case, it is imperative to insert language into the final healthcare bill that ensures the elderly have an “even playing field,” where healthcare eligibility is not driven by age or productivity. Visit the National Museum of the Marine Corps and you see testimony to patriots who faced down seemingly invincible armies by an unshakable resolve to win. Their approach was simple: the enemy was out to annihilate America, and surrender was not an option. As politicians set out to assist the healthcare system, it is imperative that they adopt the same strategy. Disease is not something to run from, but to address head on. Ultimate solutions for solving the entire picture do not constitute reform, just utopianism. In a recent appearance on Charlie Rose, Mayo Clinic CEO and president Denis Cortese advised we undertake healthcare reform one chunk at a time, not all at once. He also faulted the bill for its emphasis on cost-containment instead of balancing this with quality; combine them and you have value, not just cost-savings, he warned. The ultimate abdication from quality of care is the restriction of access to care for the oldest and sickest, the facilitation of death via dehydration, starvation, avoidance of cardiac resuscitation or ventilator use, or simply rationing care. The concern over the afore-
G REEN H ILL H EALTHCARE C OMMUNICATIONS
mentioned consultations in the healthcare reform bill stems from apprehension over realpolitik, where cost trumps quality and politics trumps cost. Is the bill the first stage of a strategy to entice seniors to sign boilerplate forms amounting to “do not resuscitate”? If so, it is placing American healthcare on the slippery slope to icy utilitarianism. If not, then the language must clearly forbid it. The American spirit of can-do that the Marines showed at Belleau Wood and Iwo Jima in World War II is the proper approach to American healthcare system reform. But first, government must stop trying to dominate the triangle of sectors (clinical, business, regulatory) and instead support the clinical and business systems. Periodically, each of these three sectors regards itself as the one with the answers and seeks hegemony over the system, when it is balance of power that is needed. Enlightened government is measured not by its power over citizens, but its protection of their liberty. Government healthcare policy must avoid domination of the healthcare process and policies that encourage—and eventually mandate—terminally ill patients to die quickly and inexpensively. The language of the healthcare bill must be crafted to pursue healing, not dying. It must keep the emerging American healthcare system true to our positive core values: life, liberty, and pursuit of happiness—not quality-adjusted life-years. To be progressive and effective, the American healthcare system must embrace prevention, intervention, and innovation, conspicuous by its absence is any fourth point called do not resuscitate. Instead of planning for an ultimate retreat from healthcare for seniors, policymakers should embrace strategies that encourage development of new drugs and devices that save lives and money spent when illness drives patients into nursing homes and hospitals. A society not committed to taking care of its elderly is essentially indecent and on its way out. We are better than that. We can and will take care of the sickest—not with foolhardy, reckless usage of costly medications that do little to prolong or improve life, but with new treatments and medications, and equally resourceful payer utilization processes that deliver quality on the high road of medicine. We must continue to define our healthcare system as one befitting a free people, a system supportive of progress and the health of its citizens, a system confident in the ability of science and physicians to find the cures needed to sustain our healthcare system. The best is yet to come if we remain positive and avoid surrendering up our sickest out of fear that we do not yet have all the resources to treat them. As we codify our healthcare system, let us retain its noblest elements and reward our oldest citizens with the resolve to heal, not abandon them in their last years. l BY ROBERT EMMETT HENRY
Editor-in-Chief American Health & Drug Benefits
Send comments on this and other topics to Karen@greenhillhc.com. All comments will be posted on our website www.theoncologypharmacist.com.
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STRONG. FROM THE START.
FOR A SUCCESSFUL CINV PREVENTION STRATEGY FROM THE FIRST CYCLE yWhen patients experience acute chemotherapyeir induced nausea and vomiting (CINV) during their first cycle of chemotherapy, they may have an increased risk of CINV on subsequent days and in subsequent cycles.1-3 ALOXI®: A single IV dose lasts up to 5 days after MEC4,5* The only IV 5-HT3 antiemetic specifically approved for prevention of both acute and delayed CINV associated with MEC6*
mens6† Can be used with multiple-day chemotherapy regimens * Moderately emetogenic chemotherapy. † Based on sNDA approval in August 2007, the restriction on repeated dosing of ALOXI (palonosetron HCl) injection within a 7-day interval was removed.
Indication ALOXI® (palonosetron HCl) injection 0.25 mg is indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy, and acute nausea and vomiting associated with initial and repeat courses of highly emetogenic chemotherapy. Important Safety Information • ALOXI is contraindicated in patients known to have hypersensitivity to the drug or any of its components • Most commonly reported adverse reactions in chemotherapy-induced nausea and vomiting include headache (9%) and constipation (5%) Please see the following brief summary of prescribing information. REFERENCES: 1. The Italian Group for Antiemetic Research. Dexamethasone alone or in combination with ondansetron for the prevention of delayed nausea and vomiting induced by chemotherapy. N Engl J Med. 2000;342:1554-1559. 2. Hickok JT, Roscoe JA, Morrow GR, et al. 5-hydroxytryptamine-receptor antagonists versus prochlorperazine for control of delayed nausea caused by doxorubicin: a URCC CCOP randomised controlled trial. Lancet Oncol. 2005;6:765-772. Epub September 13, 2005. 3. Cohen L, de Moor CA, Eisenburg P, Ming EE, Hu H. Chemotherapy-induced nausea and vomiting: incidence and impact on patient quality of life at community oncology settings. Support Care Cancer. 2007;15:497-503. Epub November 14, 2006. 4. Gralla R, Lichinitser M, Van der Vegt S, et al. Palonosetron improves prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy: results of a double-blind randomized phase III trial comparing single doses of palonosetron with ondansetron. Ann Oncol. 2003;14:1570-1577. 5. Eisenberg P, Figueroa-Vadillo J, Zamora R, et al. Improved prevention of moderately emetogenic chemotherapy-induced nausea and vomiting with palonosetron, a pharmacologically novel 5-HT3 receptor antagonist: results of a phase III, single-dose trial versus dolasetron. Cancer. 2003;98:2473-2482. 6. ALOXI® (palonosetron HCl) injection full prescribing information.
ALOXI® is a registered trademark of Helsinn Healthcare SA, Switzerland, used under license. Distributed and marketed by Eisai Inc. © 2009 Eisai Inc. All rights reserved. Printed in USA. AL448-A 08/09
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New HOPA President Continued from cover nary team with physicians, and I became intrigued with direct patient care. Also, when I was in college I lost a couple of family members to cancer, so I had developed an interest in cancer even though the therapies available then were not very effective. As oncology and clinical pharALOXI® (palonosetron HCl) injection BRIEF SUMMARY OF PRESCRIBING INFORMATION INDICATIONS AND USAGE Chemotherapy-Induced Nausea and Vomiting ALOXI is indicated for: • Moderately emetogenic cancer chemotherapy – prevention of acute and delayed nausea and vomiting associated with initial and repeat courses • Highly emetogenic cancer chemotherapy – prevention of acute nausea and vomiting associated with initial and repeat courses DOSAGE AND ADMINISTRATION Recommended Dosing Chemotherapy-Induced Nausea and Vomiting Dosage for Adults - a single 0.25 mg I.V. dose administered over 30 seconds. Dosing should occur approximately 30 minutes before the start of chemotherapy. Instructions for I.V. Administration ALOXI is supplied ready for intravenous injection. ALOXI should not be mixed with other drugs. Flush the infusion line with normal saline before and after administration of ALOXI. Parenteral drug products should be inspected visually for particulate matter and discoloration before administration, whenever solution and container permit. CONTRAINDICATIONS ALOXI is contraindicated in patients known to have hypersensitivity to the drug or any of its components. [see Adverse Reactions (6) in full prescribing information ] WARNINGS AND PRECAUTIONS Hypersensitivity Hypersensitivity reactions may occur in patients who have exhibited hypersensitivity to other 5-HT 3 receptor antagonists. ADVERSE REACTIONS 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 reported in practice. In clinical trials for the prevention of nausea and vomiting induced by moderately or highly emetogenic chemotherapy, 1374 adult patients received palonosetron. Adverse reactions were similar in frequency and severity with ALOXI and ondansetron or dolasetron. Following is a listing of all adverse reactions reported by ≥ 2% of patients in these trials (Table 1). Table 1: Adverse Reactions from ChemotherapyInduced Nausea and Vomiting Studies ≥ 2% in any Treatment Group ALOXI Ondansetron Dolasetron Event 0.25 mg 32 mg I.V. 100 mg I.V. (N=410) (N=633) (N=194) Headache 60 (9%) 34 (8%) 32 (16%) Constipation 29 (5%) 8 (2%) 12 (6%) Diarrhea 8 (1%) 7 (2%) 4 (2%) Dizziness 8 (1%) 9 (2%) 4 (2%) Fatigue 3 (< 1%) 4 (1%) 4 (2%) Abdominal Pain 1 (< 1%) 2 (< 1%) 3 (2%) Insomnia 1 (< 1%) 3 (1%) 3 (2%) In other studies, 2 subjects experienced severe constipation following a single palonosetron dose of approximately 0.75 mg, three times the recommended dose. One patient received a 10 mcg/kg oral dose in a postoperative nausea and vomiting study and one healthy subject received a 0.75 mg I.V. dose in a pharmacokinetic study. In clinical trials, the following infrequently reported adverse reactions, assessed by investigators as treatment-related or causality unknown, occurred following administration of ALOXI to adult patients receiving concomitant cancer chemotherapy: Cardiovascular: 1%: non-sustained tachycardia, bradycardia, hypotension, < 1%: hypertension, myocardial ischemia, extrasystoles, sinus tachycardia, sinus arrhythmia, supraventricular extrasystoles and QT prolongation. In many cases, the relationship to ALOXI was unclear. Dermatological: < 1%: allergic dermatitis, rash. Hearing and Vision: < 1%: motion sickness, tinnitus, eye irritation and amblyopia. Gastrointestinal System: 1%: diarrhea, < 1%: dyspepsia, abdominal pain, dry mouth, hiccups and flatulence.
macy practice developed, I grew along with them. HOPA evolved out of the Making a Difference in Oncology conference that started 14 years ago here at Moffitt. So I was involved with HOPA from the very beginning. Becoming president is indeed quite General: 1%: weakness, < 1%: fatigue, fever, hot flash, flu-like syndrome. Liver: < 1%: transient, asymptomatic increases in AST and/or ALT and bilirubin. These changes occurred predominantly in patients receiving highly emetogenic chemotherapy. Metabolic: 1%: hyperkalemia, < 1%: electrolyte fluctuations, hyperglycemia, metabolic acidosis, glycosuria, appetite decrease, anorexia. Musculoskeletal: < 1%: arthralgia. Nervous System: 1%: dizziness, < 1%: somnolence, insomnia, hypersomnia, paresthesia. Psychiatric: 1%: anxiety, < 1%: euphoric mood. Urinary System: < 1%: urinary retention. Vascular: < 1%: vein discoloration, vein distention. Postmarketing Experience The following adverse reactions have been identified during postapproval use of ALOXI. 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. Very rare cases (<1/10,000) of hypersensitivity reactions and injection site reactions (burning, induration, discomfort and pain) were reported from postmarketing experience of ALOXI 0.25 mg in the prevention of chemotherapy-induced nausea and vomiting. DRUG INTERACTIONS Palonosetron is eliminated from the body through both renal excretion and metabolic pathways with the latter mediated via multiple CYP enzymes. Further in vitro studies indicated that palonosetron is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1 and CYP3A4/5 (CYP2C19 was not investigated) nor does it induce the activity of CYP1A2, CYP2D6, or CYP3A4/5. Therefore, the potential for clinically significant drug interactions with palonosetron appears to be low. Coadministration of 0.25 mg I.V. palonosetron and 20 mg I.V. dexamethasone in healthy subjects revealed no pharmacokinetic drug-interactions between palonosetron and dexamethasone. In an interaction study in healthy subjects where palonosetron 0.25 mg (I.V. bolus) was administered on day 1 and oral aprepitant for 3 days (125 mg/80 mg/80 mg), the pharmacokinetics of palonosetron were not significantly altered (AUC: no change, Cmax: 15% increase). A study in healthy volunteers involving single-dose I.V. palonosetron (0.75 mg) and steady state oral metoclopramide (10 mg four times daily) demonstrated no significant pharmacokinetic interaction. In controlled clinical trials, ALOXI injection has been safely administered with corticosteroids, analgesics, antiemetics/antinauseants, antispasmodics and anticholinergic agents. Palonosetron did not inhibit the antitumor activity of the five chemotherapeutic agents tested (cisplatin, cyclophosphamide, cytarabine, doxorubicin and mitomycin C) in murine tumor models. USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects: Category B Teratology studies have been performed in rats at oral doses up to 60 mg/kg/day (1894 times the recommended human intravenous dose based on body surface area) and rabbits at oral doses up to 60 mg/ kg/day (3789 times the recommended human intravenous dose based on body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to palonosetron. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, palonosetron should be used during pregnancy only if clearly needed. Labor and Delivery Palonosetron has not been administered to patients undergoing labor and delivery, so its effects on the mother or child are unknown. Nursing Mothers It is not known whether palonosetron is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants and the potential for tumorigenicity shown for palonosetron in the rat carcinogenicity study, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
G REEN H ILL H EALTHCARE C OMMUNICATIONS
an honor and, for me, it’s the same pride you feel watching your child grow up and become successful.
Over the course of your career have you seen a trend toward more students going in for specialty training? Pediatric Use Safety and effectiveness in patients below the age of 18 years have not been established. Geriatric Use Population pharmacokinetics analysis did not reveal any differences in palonosetron pharmacokinetics between cancer patients ≥ 65 years of age and younger patients (18 to 64 years). Of the 1374 adult cancer patients in clinical studies of palonosetron, 316 (23%) were ≥ 65 years old, while 71 (5%) were ≥ 75 years old. No overall differences in safety or effectiveness were observed between these subjects and the younger subjects, but greater sensitivity in some older individuals cannot be ruled out. No dose adjustment or special monitoring are required for geriatric patients. Of the 1520 adult patients in ALOXI PONV clinical studies, 73 (5%) were ≥65 years old. No overall differences in safety were observed between older and younger subjects in these studies, though the possibility of heightened sensitivity in some older individuals cannot be excluded. No differences in efficacy were observed in geriatric patients for the CINV indication and none are expected for geriatric PONV patients. However, ALOXI efficacy in geriatric patients has not been adequately evaluated. Renal Impairment Mild to moderate renal impairment does not significantly affect palonosetron pharmacokinetic parameters. Total systemic exposure increased by approximately 28% in severe renal impairment relative to healthy subjects. Dosage adjustment is not necessary in patients with any degree of renal impairment. Hepatic Impairment Hepatic impairment does not significantly affect total body clearance of palonosetron compared to the healthy subjects. Dosage adjustment is not necessary in patients with any degree of hepatic impairment. Race Intravenous palonosetron pharmacokinetics was characterized in twenty-four healthy Japanese subjects over the dose range of 3 – 90 mcg/kg. Total body clearance was 25% higher in Japanese subjects compared to Whites, however, no dose adjustment is required. The pharmacokinetics of palonosetron in Blacks has not been adequately characterized. OVERDOSAGE There is no known antidote to ALOXI. Overdose should be managed with supportive care. Fifty adult cancer patients were administered palonosetron at a dose of 90 mcg/kg (equivalent to 6 mg fixed dose) as part of a dose ranging study. This is approximately 25 times the recommended dose of 0.25 mg. This dose group had a similar incidence of adverse events compared to the other dose groups and no dose response effects were observed. Dialysis studies have not been performed, however, due to the large volume of distribution, dialysis is unlikely to be an effective treatment for palonosetron overdose. A single intravenous dose of palonosetron at 30 mg/kg (947 and 474 times the human dose for rats and mice, respectively, based on body surface area) was lethal to rats and mice. The major signs of toxicity were convulsions, gasping, pallor, cyanosis and collapse. PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling (17.2) in full prescribing information Instructions for Patients • Patients should be advised to report to their physician all of their medical conditions, any pain, redness, or swelling in and around the infusion site [see Adverse Reactions (6) in full prescribing information]. • Patients should be instructed to read the patient insert. Rx Only Mfd by OSO Biopharmaceuticals, LLC, Albuquerque, NM, USA or Pierre Fabre, Médicament Production, Idron, Aquitaine, France and Helsinn Birex Pharmaceuticals, Dublin, Ireland.
ALOXI® is a registered trademark of Helsinn Healthcare SA, Switzerland, used under license. Distributed and marketed by Eisai Inc., Woodcliff Lake, NJ 07677. © 2009 Eisai Inc. All rights reserved. Printed in USA. AL449 08/09
There definitely has been an increase in the number of students, and also seasoned practitioners, going on for specialty training. I think one reason is that the technology, especially in oncology, is becoming so complex that you really have to specialize. Some large institutions such as Moffitt subspecialize in specific types of cancer and areas of supportive care. Not only is the technology more complex, but also the pharmacist’s role has evolved to include more than just the drug therapy. As the patient’s advocate for safe and effective care, we become involved in research, and in the financial and business aspect of care. Assisting patients with the financial burden of cancer care has become an important part of ensuring access to appropriate therapy.
What are your goals for your year as president of HOPA? My predecessors have built a strong organizational structure that provides outstanding education opportunities in a variety of venues. The next logical step in our strategic plan is to develop oncology-focused standards that we can promote as an organization. There will be standards for clinical practice, such as standards related to chemotherapy safety and drug dosing. We will develop and promote oncology-related standards for academia and course work for both pharmacists and technicians. Standards are also needed for computer systems and other kinds of technology that will facilitate the complexity and personalized therapies required by cancer patients. HOPA will continue to expand our membership (currently at 1400) and to foster more collaboration with other professional organizations so that we can mutually support practice standards and develop a consensus position on regulatory issues that affect pharmacy and oncology. Of course, we also want to enhance our current educational offerings and expand into new venues. HOPA University is a good example of that, as is our commitment to promoting “best practices.” We are excited about starting something new this year called “boot camp,” which covers the basics of oncology for pharmacists who aren’t formally trained in oncology or who aren’t fulltime oncology practitioners but need to improve their oncology skills. Another strategic goal is to initiate some practice-based research. We are establishing a research and education foundation that should be in place this year, and will provide a platform for developing research by HOPA members. My personal goal is to tackle what I think is our biggest national issue— Continued on page 8
Conference News The 5th Annual Conference of the Hematology/Oncology Pharmacy Association was held at the Doral Marriott in Miami, Florida, June 17-20. A total of 728 participants, including pharmacists and industry representatives, participated in workshops, symposia, poster sessions, and other events.
CAM Use Increases Continued from cover University of California San Diego for frequently used CAM. (UCSD) Medical Center during her The investigators enrolled 210 poster presentation. Because CAM use patients (mean age, 57.6 years; 54.8% is not usually assessed during the med- male) who received active cancer ication reconciliation treatment at the UCSD process, “we decided to Moores Cancer Center from do this study to look at June 2008 to March 2009. the usage pattern of A patient medication assess[CAM] in our patient ment survey consisting of 14 population.” questions on demographics and Primarily, Tran and her CAM use was given to each parteam sought to assess the ticipant, either at the outpatient current use of CAM in pharmacy consultation window, patients at their cancer Trang Tran, PharmD in the outpatient clinic, or in center. Secondarily, they the infusion center. compared the characteristics of Results showed that 76.7% of patients who chose to use CAM patients took at least one form of with those who did not, evaluated CAM. Although more than 65% the usage patterns and reasons for reported talking to their oncologist using CAM, examined the processes about their CAM use, only 35% used by patients to gather informa- reported discussing it with their tion about CAM, and developed a pharmacists. database of drug interaction studies On average, each patient used two
CAM products, the most common being multivitamins (used by 48%), calcium (24%), vitamin B (15%), fish oil (13%), vitamin C (13%), and folic acid (13%). Among those, only vitamin C and folic acid have drug– drug interactions with certain chemotherapy medications. When examining patient characteristics, the investigators found that female patients tended to use CAMs more than male patients (83% vs 61%), and use by older patients was greater than by younger ones. The most common sources of information consulted for CAM included healthcare providers, family members, and friends. “Based on my interviews with the patients, I found that they do a lot of research on this subject,” Tran said. “They consult with their oncologist, they read magazines and books, and
they ask loved ones. But as pharmacists, we know the most about this information, and we should be the main resource for our patients.” The most common reasons for using CAM included beneficial for anticancer effects, general health, and recommended by their physician. Although 45.7% of the patients considered CAM products a type of medication, 67.2% believed CAM to be safe, and 58.1% believed it to be effective. “After this study, we realized that as pharmacists, we now have to be more proactive to find out about CAM use in our patients,” Tran said. “Often patients don’t even think about mentioning their CAM use. So we should definitely go ahead and ask them, especially if they’re female or older.” —Deborah Brauser
Pharmacist-managed Zoledronic Acid Dose Adjustments Decrease Process Time by Half Hour per Order MIAMI—Cancer center pharmacists should assume the responsibility of adjusting zoledronic acid doses in accordance with US Food and Drug Administration (FDA) guidelines, according to a poster presentation at the 5th annual meeting of the Hematology/ Oncology Pharmacy Association. Amal K. Arnaout, PharmD, BOC specialist and senior pharmacist at the Dana-Farber Cancer Institute (DFCI) in Boston, Massachusetts, presented the results. “Zoledronic acid has become an integral part of a patient’s cancer treatment and supportive care,” she said. “Its use has expanded tremendously here, especially since the new literature talks about using it in the adjuvant setting and in breast cancer.” This increased use necessitated the development of a program at DFCI to improve efficiency in the ambulatory setting. An important consideration was the FDA’s recommended doseadjustment parameters for zoledronic
acid that take into consideration a patient’s renal function status at the time of administration. For this analysis, the first 200 patients were selected randomly from an extensive report on zoledronic acid dispensing from July 1, 2007, to January 31, 2008, at DFCI. Of these, Arnaout and her team assessed 193 patients (118 female; median age, 53 years; 579 total doses dispensed) as to demographics, disease, drug administration, dosage, and dose adjustment. Order entry and pharmacy interventions were also reviewed. Results showed that in 96% of the zoledronic acid doses administered, proper laboratory workups were ordered in accordance with FDA requirements, and the proper dose level was dispensed. In addition, of all dose adjustments made, 76% were in response to a pharmacist-initiated request after finding changes in renal function. This process involved the pharmacist contacting the physician to write a new order, fol-
lowed by the pharmacist reentering the in accordance with FDA guidelines. order, a nurse activating the order, and The new algorithm involves the then the pharmacy dispensing pharmacist verifying dose it. Altogether, it resulted in and interval of a zoledelays of more than 30 minutes dronic acid order, checkin dose administration. ing the renal function “So what is supposed to be a tests, and calculating the 15-minute stay in the chair creatinine clearance in became a 45-minute stay in the accordance with FDA chair,” explained Arnaout. “In guidelines. When dose addition to the inconvenience adjustments are deemed to the patient, we do charge for Amal K. Arnaout, necessary, they are now the chair time. That drives PharmD, BOC specialist made by the pharmacist, costs—and the patient’s temwho then enters a new per—up. And it takes a lot of the phar- order to be cosigned by the provider. macist’s time.” “This is a win-win-win situation,” She continued, “Our analysis showed Arnaout concluded. “It’s a win for that pharmacy-driven dose adjustments the doctors, for the nurses, and for could minimize unnecessary delays the pharmacists. There’s no reason to while preserving patient safety and waste our time. It’s also a big win for convenience.” the patients.” This study resulted in the approval by the DFCI Pharmacy and Thera—DB peutics committee for a pharmacymanaged dose-adjustment algorithm HOPA Conference News continued on page 16 G REEN H ILL H EALTHCARE C OMMUNICATIONS
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New HOPA President PHARMACY PRACTICE
Continued from page 6 patient compliance. It is important that patients take responsibility for their own healthcare by leading a healthy lifestyle, practicing early detection and prevention of disease, and also complying with therapy once they have been diagnosed and treatment has been prescribed. I would like to conduct research on how we can better educate patients and incentivize them to be more compliant with their therapy.
dence-based guidelines, which have been proven to benefit clinical outcomes, we will be reimbursed. HOPA supports the proposed national mandate to develop a national healthcare database that connects all patients. This will help individual patient care and
Has HOPA taken a stand in the current debate about healthcare reform? Healthcare reform, whatever shape it finally takes, must address patient access, and that means such issues as insurance coverage for preexisting conditions and catastrophic costs. Another part of healthcare reform is support for the national cancer research network. So far, there is a commitment to support the National Cancer Institute funding and other cancer research funding. A major issue for pharmacy is to regain support for specialty residency programs. In the past, PGY2 residencies were allowed as a Medicare deductible expense. Another important issue is to support pharmacist direct involvement in patient care by ensuring that we are reimbursed for our services under Medication Therapy Management provisions. Perhaps the biggest issue is the level of reimbursement for cancer care in general, and drugs in particular. Medicare, for example, reimburses in the outpatient setting at average sales price plus a very small percentage for overhead. That does not cover the true cost of overhead and certainly does not cover the additional costs that have been imposed on us by new federal regulations. For example, converting operations to preparing sterile solutions using USP <797> standards has probably increased the cost and decreased the efficiency of preparation by 20%. The US Food and Drug Administration is beginning to require risk evaluation and mitigation systems (REMS) for drugs they consider to be a high risk for toxicity. All of these programs require the registration of a physician to prescribe the drug, getting informed consent from the patient, and many of them require working through a specialty pharmacy. Right now, REMS are required for a few specialty drugs, but they could be instituted for all the opioids or any drug with a black box warning, which includes most cancer drugs. That will add a lot of extra work and cost and, in my opinion, will place barriers to patients receiving appropriate therapy. Also related to reimbursement, we want assurance that if we follow evi-
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research, but to be successful the informatics vendors must be held accountable for providing the necessary technology and infrastructure. In other words, if we are going to have electronic prescribing and electronic medical records, the technology has to address the complexity and
variety of oncology practice. It is clear that the national healthcare system that we have now is not sustainable because of cost. In my opinion, healthcare reform is good because it is going to bring the stakeholders together and force us to collaborate.
(cetuximab): FOR PATIENTS WITH HEAD AND NECK C ANCER*
ERBITUX + RT: 26% reduction in Risk of Death from SCCHN1,2
Important Safety Information Including Boxed WARNINGS Infusion Reactions I Grade 3/4 infusion reactions occurred in approximately 3% of patients receiving ERBITUX® (cetuximab) in clinical trials, with fatal outcome reported in less than 1 in 1000 — Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of ERBITUX, included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest — Immediately interrupt and permanently discontinue ERBITUX infusions for serious infusion reactions I Most (90%) of the severe infusion reactions were associated with the first infusion of ERBITUX despite premedication with antihistamines — Caution must be exercised with every ERBITUX infusion, as there were patients who experienced their first severe infusion reaction during later infusions — Monitor patients for 1 hour following ERBITUX infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Longer observation periods may be required in patients who require treatment for infusion reactions Cardiopulmonary Arrest I Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients with squamous cell carcinoma of the head and neck treated with radiation therapy and ERBITUX, as compared to none of 212 patients treated with radiation therapy alone. Fatal events occurred within 1 to 43 days after the last ERBITUX treatment — Carefully consider the use of ERBITUX in combination with radiation therapy in head and neck cancer patients with a history of coronary artery disease, congestive heart failure or arrhythmias in light of these risks — Closely monitor serum electrolytes including serum magnesium, potassium, and calcium during and after ERBITUX therapy Pulmonary Toxicity I Interstitial lung disease (ILD), which was fatal in one case, occurred in 4 of 1570 (<0.5%) patients receiving ERBITUX in clinical trials. Interrupt ERBITUX for acute onset or worsening of pulmonary symptoms. Permanently discontinue ERBITUX where ILD is confirmed Dermatologic Toxicities I In clinical studies of ERBITUX, dermatologic toxicities, including acneform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (eg, S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis, cheilitis), and hypertrichosis, occurred in patients receiving ERBITUX therapy. Acneform rash occurred in 76-88% of 1373 patients receiving ERBITUX in clinical trials. Severe acneform rash occurred in 1-17% of patients — Acneform rash usually developed within the first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days — Monitor patients receiving ERBITUX for dermatologic toxicities and infectious sequelae — Sun exposure may exacerbate these effects ERBITUX Plus Radiation Therapy and Cisplatin I The safety of ERBITUX in combination with radiation therapy and cisplatin has not been established — Death and serious cardiotoxicity were observed in a single-arm trial with ERBITUX, radiation therapy, and cisplatin (100 mg/m2) in patients with locally advanced squamous cell carcinoma of the head and neck — Two of 21 patients died, one as a result of pneumonia and one of an unknown cause — Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events
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What are some of the greatest challenges facing oncology pharmacy today? With healthcare reform being focused on costs, one of the things we have to do is to prove the value of pharmacy. A lot of physicians will say they couldn’t prac-
tice without pharmacists, but how do you actually put a dollar value on it? A lot of what we do involves preventing mistakes or managing toxicities of drugs to make sure that something bad doesn’t happen. It is very important not to make mis-
takes and to avoid toxicities, but it’s also very difficult to measure these things. To stay strong in the business model that is emerging, we are going to have to start proving what our value is—how we support physicians and other colleagues, how we ensure that the patients get safe
ERBITUX + RT (%) (n = 208)
and effective therapy, and how we make sure that all the decision makers in healthcare, including patients and payers, are informed and their decisions are based on solid evidence. l —Karen Rosenberg
RT Alone (%) (n = 212)
No. (%) of Patients ERBITUX + RT (n = 211)
RT Alone (n = 213)
Delivery of planned RT dose Adequate delivery per protocol Inadequate delivery per protocol
184 (87.2) 27 (12.8)
26 (12.2) I
† No difference in radiation dose delivered between the 2 treatment groups in a randomized trial comparing ERBITUX + RT versus RT alone in patients with locally or regionally advanced SCCHN.2
The incidences of grades 3/4 xerostomia, mucositis/stomatitis, and radiation dermatitis were more frequent in the ERBITUX plus RT arm
*INDICATIONS I ERBITUX® (cetuximab), in combination with radiation therapy, is indicated for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck IERBITUX, as a single agent, is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck for whom prior platinum-based therapy has failed SCCHN = squamous cell carcinoma of the head and neck; RT = radiation therapy.
Electrolyte Depletion I Hypomagnesemia occurred in 55% (199/365) of patients receiving ERBITUX® (cetuximab) and was severe (NCI CTC grades 3 & 4) in 6-17%. The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of ERBITUX therapy — Monitor patients periodically for hypomagnesemia, hypocalcemia and hypokalemia, during, and for at least 8 weeks following the completion of, ERBITUX therapy — Replete electrolytes as necessary Late Radiation Toxicities I The overall incidence of late radiation toxicities (any grade) was higher with ERBITUX in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65%/56%), larynx (52%/36%), subcutaneous tissue (49%/45%), mucous membranes (48%/39%), esophagus (44%/35%), and skin (42%/33%) in the ERBITUX and radiation versus radiation alone arms, respectively — The incidence of grade 3 or 4 late radiation toxicities were similar between the radiation therapy alone and the ERBITUX plus radiation therapy arms Pregnancy I In women of childbearing potential, appropriate contraceptive measures must be used during treatment with ERBITUX and for 6 months following the last dose of ERBITUX. ERBITUX may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. ERBITUX should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus Adverse Events I The most serious adverse reactions associated with ERBITUX across all studies were infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus I The most common adverse reactions associated with ERBITUX (incidence ≥25%) are cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection I The most frequent adverse events seen in patients with carcinomas of the head and neck receiving ERBITUX in combination with radiation therapy (n=208) versus radiation alone (n=212) (incidence ≥50%) were acneform rash (87%/10%), radiation dermatitis (86%/90%), weight loss (84%/72%), and asthenia (56%/49%). The most common grade 3/4 adverse events for ERBITUX in combination with radiation therapy (≥10%) included: radiation dermatitis (23%), acneform rash (17%), and weight loss (11%) For more information, please visit www.ERBITUX.com or call 1-888-ERBITUX (372-4889). References: 1. ERBITUX® (cetuximab) Package Insert. ImClone LLC, New York, NY 10014 and Bristol-Myers Squibb, Princeton, NJ 08543; July 2009. 2. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006;354:567-578. 3. Data on file, Bristol-Myers Squibb, ERBI 001.
Please see brief summary of Full Prescribing Information including Boxed WARNINGS regarding infusion reactions and cardiopulmonary arrest on adjacent page.
© 2009, ImClone LLC, New York, New York 10014, U.S.A. and Bristol-Myers Squibb, Princeton, New Jersey 08543, U.S.A. All rights reserved. ERBITUX is a registered trademark of ImClone LLC.
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New HOPA President
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Challenges of Oncology PHARMACY PRACTICE
Continued from cover I will also identify some things that are unique to oncology clinics and describe some of the problems and solutions I have encountered in remodeling our satellite clinics. I hope this will get your planning process started on the right foot.
In the past 5 years, I have participated in eight satellite clinic remodels (four of which occurred after we got approval for USP <797> compliance) as well as the redesign of our central facility. We currently have five of the 15 satellite clinics in various stages of the remodeling
process. All of this requires a certain amount of juggling of contact information and other details. Many of our sites are in hospitals or hospital-owned medical buildings, while others are in freestanding buildings that we either lease or own. Learning and managing different
ERBITUX® (cetuximab) Solution for intravenous infusion Brief Summary of Prescribing Information. For complete prescribing information consult official package insert. WARNING: SERIOUS INFUSION REACTIONS and CARDIOPULMONARY ARREST Infusion Reactions: Serious infusion reactions occurred with the administration of Erbitux in approximately 3% of patients in clinical trials, with fatal outcome reported in less than 1 in 1000. [See Warnings and Precautions and Adverse Reactions.] Immediately interrupt and permanently discontinue Erbitux infusion for serious infusion reactions. [See Warnings and Precautions and Dosage and Administration (2.4) in Full Prescribing Information.] Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 2% of 208 patients with squamous cell carcinoma of the head and neck treated with radiation therapy and Erbitux. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux. [See Warnings and Precautions.] INDICATIONS AND USAGE Squamous Cell Carcinoma of the Head and Neck (SCCHN) Erbitux® (cetuximab) is indicated in combination with radiation therapy for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck. [See Clinical Studies (14.1) in Full Prescribing Information.] Erbitux, as a single agent, is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck for whom prior platinum-based therapy has failed. [See Clinical Studies (14.1) in Full Prescribing Information.] Colorectal Cancer Erbitux, as a single agent, is indicated for the treatment of epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer after failure of both irinotecan- and oxaliplatin-based regimens. Erbitux, as a single agent, is also indicated for the treatment of EGFR-expressing metastatic colorectal cancer in patients who are intolerant to irinotecan-based regimens. [See Clinical Studies (14.2) in Full Prescribing Information and Warnings and Precautions.] Erbitux, in combination with irinotecan, is indicated for the treatment of EGFR-expressing metastatic colorectal carcinoma in patients who are refractory to irinotecan-based chemotherapy. The effectiveness of Erbitux in combination with irinotecan is based on objective response rates. Currently, no data are available that demonstrate an improvement in disease-related symptoms or increased survival with Erbitux in combination with irinotecan for the treatment of EGFR-expressing, metastatic colorectal carcinoma. [See Clinical Studies (14.2) in Full Prescribing Information and Warnings and Precautions.] Retrospective subset analyses of metastatic or advanced colorectal cancer trials have not shown a treatment benefit for Erbitux in patients whose tumors had KRAS mutations in codon 12 or 13. Use of Erbitux is not recommended for the treatment of colorectal cancer with these mutations [see Clinical Studies (14.2) and Clinical Pharmacology (12.1) in Full Prescribing Information]. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Infusion Reactions Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of Erbitux, included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest. Severe (NCI CTC Grades 3 and 4) infusion reactions occurred in 2–5% of 1373 patients in clinical trials, with fatal outcome in 1 patient. Approximately 90% of severe infusion reactions occurred with the first infusion despite premedication with antihistamines. Monitor patients for 1 hour following Erbitux infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Monitor longer to confirm resolution of the event in patients requiring treatment for infusion reactions. Immediately and permanently discontinue Erbitux in patients with serious infusion reactions. [See Boxed Warning and Dosage and Administration (2.4) in Full Prescribing Information.] Cardiopulmonary Arrest Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients treated with radiation therapy and Erbitux as compared to none of 212 patients treated with radiation therapy alone in a randomized, controlled trial in patients with SCCHN. Three patients with prior history of coronary artery disease died at home, with myocardial infarction as the presumed cause of death. One of these patients had arrhythmia and one had congestive heart failure. Death occurred 27, 32, and 43 days after the last dose of Erbitux. One patient with no prior history of coronary artery disease died one day after the last dose of Erbitux. Carefully consider use of Erbitux in combination with radiation therapy in head and neck cancer patients with a history of coronary artery disease, congestive heart failure, or arrhythmias in light of these risks. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux. [See Boxed Warning and Warnings and Precautions.] Pulmonary Toxicity Interstitial lung disease (ILD), including 1 fatality, occurred in 4 of 1570 (<0.5%) patients receiving Erbitux in clinical trials. Interrupt Erbitux for acute onset or worsening of pulmonary symptoms. Permanently discontinue Erbitux for confirmed ILD. Dermatologic Toxicity Dermatologic toxicities, including acneform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (for example S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis, cheilitis), and hypertrichosis occurred in patients receiving Erbitux therapy. Acneform rash occurred in 76–88% of 1373 patients receiving Erbitux in clinical trials. Severe acneform rash occurred in 1–17% of patients. Acneform rash usually developed within the first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days. Monitor patients receiving Erbitux for dermatologic toxicities and infectious sequelae. Instruct patients to limit sun exposure during Erbitux therapy. [See Dose Modifications (2.4) in Full Prescribing Information.] Use of Erbitux in Combination With Radiation and Cisplatin The safety of Erbitux in combination with radiation therapy and cisplatin has not been established. Death and serious cardiotoxicity were observed in a single-arm trial with Erbitux, radiation therapy, and cisplatin (100 mg/m2) in patients with locally advanced SCCHN. Two of 21 patients died, one as a result of pneumonia and one of an unknown cause. Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events. Hypomagnesemia and Electrolyte Abnormalities In patients evaluated during clinical trials, hypomagnesemia occurred in 55% of patients (199/365) receiving Erbitux and was severe (NCI CTC Grades 3 and 4) in 6–17%. The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of Erbitux. Periodically monitor patients for hypomagnesemia, hypocalcemia, and hypokalemia, during and for at least 8 weeks following the completion of Erbitux. Replete electrolytes as necessary.
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site policies and rules is part of the process, as well as determining whose approval is needed at that site. Some of the most common decisions that involve pharmacists prior to opening a clinic site include: • choice of engineering controls for
Epidermal Growth Factor Receptor (EGFR) Expression and Response Because expression of EGFR has been detected in nearly all SCCHN tumor specimens, patients enrolled in the head and neck cancer clinical studies were not required to have immunohistochemical evidence of EGFR tumor expression prior to study entry. Patients enrolled in the colorectal cancer clinical studies were required to have immunohistochemical evidence of EGFR tumor expression. Primary tumor or tumor from a metastatic site was tested with the DakoCytomation EGFR pharmDx™ test kit. Specimens were scored based on the percentage of cells expressing EGFR and intensity (barely/faint, weak-to-moderate, and strong). Response rate did not correlate with either the percentage of positive cells or the intensity of EGFR expression. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Infusion reactions [See Boxed Warning and Warnings and Precautions.] • Cardiopulmonary arrest [See Boxed Warning and Warnings and Precautions.] • Pulmonary toxicity [See Warnings and Precautions.] • Dermatologic toxicity [See Warnings and Precautions.] • Hypomagnesemia and Electrolyte Abnormalities [See Warnings and Precautions.] The most common adverse reactions with Erbitux (cetuximab) (incidence ≥25%) are cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection. The most serious adverse reactions with Erbitux are infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus. Across all studies, Erbitux was discontinued in 3–10% of patients because of adverse reactions. Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data below reflect exposure to Erbitux in 1373 patients with colorectal cancer or SCCHN in randomized Phase 3 (Studies 1 and 3) or Phase 2 (Studies 2 and 4) trials treated at the recommended dose and schedule for a median of 7 to 14 weeks. [See Clinical Studies (14) in Full Prescribing Information.] Infusion reactions: Infusion reactions, which included pyrexia, chills, rigors, dyspnea, bronchospasm, angioedema, urticaria, hypertension, and hypotension occurred in 15–21% of patients across studies. Grades 3 and 4 infusion reactions occurred in 2–5% of patients; infusion reactions were fatal in 1 patient. Infections: The incidence of infection was variable across studies, ranging from 13–35%. Sepsis occurred in 1–4% of patients. Renal: Renal failure occurred in 1% of patients with colorectal cancer. Squamous Cell Carcinoma of the Head and Neck Table 1 contains selected adverse events in 420 patients receiving radiation therapy either alone or with Erbitux for locally or regionally advanced SCCHN in Study 1. Erbitux was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Patients received a median of 8 infusions (range 1–11). Table 1:
Incidence of Selected Adverse Events (≥10%) in Patients with Locoregionally Advanced SCCHN Erbitux plus Radiation Radiation Therapy Alone (n=208) (n=212) Body System Grades Grades Grades Grades Preferred Term 1–4 3 and 4 1–4 3 and 4 % of Patients Body as a Whole Asthenia 56 4 49 5 29 1 13 1 Fever1 Headache 19 <1 8 <1 15 3 2 0 Infusion Reaction2 Infection 13 1 9 1 16 0 5 0 Chills1 Digestive Nausea 49 2 37 2 Emesis 29 2 23 4 Diarrhea 19 2 13 1 Dyspepsia 14 0 9 1 Metabolic/Nutritional Weight Loss 84 11 72 7 Dehydration 25 6 19 8 3 43 2 21 1 Alanine Transaminase, high Aspartate Transaminase, high3 38 1 24 1 33 <1 24 0 Alkaline Phosphatase, high3 Respiratory Pharyngitis 26 3 19 4 Skin/Appendages 87 17 10 1 Acneform Rash4 Radiation Dermatitis 86 23 90 18 Application Site Reaction 18 0 12 1 Pruritus 16 0 4 0 1 2
Includes cases also reported as infusion reaction. Infusion reaction is defined as any event described at any time during the clinical study as “allergic reaction” or “anaphylactoid reaction”, or any event occurring on the first day of dosing described as “allergic reaction”, “anaphylactoid reaction”, “fever”, “chills”, “chills and fever”, or “dyspnea”. Based on laboratory measurements, not on reported adverse events, the number of subjects with tested samples varied from 205–206 for Erbitux plus Radiation arm; 209–210 for Radiation alone. Acneform rash is defined as any event described as “acne”, “rash”, “maculopapular rash”, “pustular rash”, “dry skin”, or “exfoliative dermatitis”.
The incidence and severity of mucositis, stomatitis, and xerostomia were similar in both arms of the study. Late Radiation Toxicity The overall incidence of late radiation toxicities (any grade) was higher in Erbitux in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65% versus 56%), larynx (52% versus 36%), subcutaneous tissue (49% versus 45%), mucous membrane (48% versus 39%), esophagus (44% versus 35%), skin (42% versus 33%). The incidence of Grade 3 or 4 late radiation toxicities was similar between the radiation therapy alone and the Erbitux plus radiation treatment groups.
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the clean room • whether and how to use an automated dispensing system • how the integrity of refrigerated drugs will be ensured • how patients will receive continuous infusion medication.
The decision to use an electronic medical record or preprinted chemotherapy sheets is also often made before opening or altering a clinic site, but this decision is usually made by practice administration, with pharmacy playing an active role in implementation.
Colorectal Cancer Table 2 contains selected adverse events in 562 patients receiving best supportive care (BSC) alone or with Erbitux (cetuximab) monotherapy for metastatic colorectal cancer in Study 3. Erbitux was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Table 2:
Incidence of Selected Adverse Events Occurring in ≥10% of Patients with Advanced Colorectal Carcinoma1 Treated with Erbitux Monotherapy
Body System Preferred Term Dermatology Rash/Desquamation Dry Skin Pruritus Other-Dermatology Nail Changes Body as a Whole Fatigue Fever Infusion Reactions3 Rigors, Chills Pain Abdominal Pain Pain-Other Headache Bone Pain Pulmonary Dyspnea Cough Gastrointestinal Constipation Diarrhea Vomiting Stomatitis Other-Gastrointestinal Mouth Dryness Infection Infection without neutropenia Neurology Insomnia Confusion Anxiety Depression
Erbitux plus BSC (n=288) Any Grades Grades2 3 and 4 % of Patients
BSC alone (n=274) Any Grades Grades 3 and 4
89 49 40 27 21
12 0 2 1 0
16 11 8 6 4
<1 0 0 1 0
89 30 20 13
33 1 5 <1
59 51 33 15
14 16 4 3
52 34 11 7
16 7 0 2
46 39 37 25 23 11
4 2 6 1 10 0
38 20 29 10 18 4
5 2 6 <1 8 0
30 15 14 13
1 6 2 1
15 9 8 6
1 2 1 <1
Adverse reactions occurring more frequently in Erbitux-treated patients compared with controls. Adverse events were graded using the NCI CTC, V 2.0. 3 Infusion reaction is defined as any event (chills, rigors, dyspnea, tachycardia, bronchospasm, chest tightness, swelling, urticaria, hypotension, flushing, rash, hypertension, nausea, angioedema, pain, pruritus, sweating, tremors, shaking, cough, visual disturbances, or other) recorded by the investigator as infusionrelated. BSC = best supportive care 2
The most frequently reported adverse events in 354 patients treated with Erbitux plus irinotecan in clinical trials were acneform rash (88%), asthenia/malaise (73%), diarrhea (72%), and nausea (55%). The most common Grades 3–4 adverse events included diarrhea (22%), leukopenia (17%), asthenia/malaise (16%), and acneform rash (14%). Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. Immunogenic responses to cetuximab were assessed using either a double antigen radiometric assay or an ELISA assay. Due to limitations in assay performance and sampling timing, the incidence of antibody development in patients receiving Erbitux has not been adequately determined. Non-neutralizing anti-cetuximab antibodies were detected in 5% (49 of 1001) of evaluable patients without apparent effect on the safety or antitumor activity of Erbitux. The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Erbitux with the incidence of antibodies to other products may be misleading. DRUG INTERACTIONS A drug interaction study was performed in which Erbitux was administered in combination with irinotecan. There was no evidence of any pharmacokinetic interactions between Erbitux and irinotecan.
Engineering controls for the clean room While I will not attempt a full discussion of USP <797> in this article, selection of engineering controls is an important decision that nearly always involves the pharmacist. You will cer-
USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of Erbitux (cetuximab) in pregnant women. Based on animal models, EGFR has been implicated in the control of prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, Erbitux may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Erbitux should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnant cynomolgus monkeys were treated weekly with 0.4 to 4 times the recommended human dose of cetuximab (based on body surface area) during the period of organogenesis (gestation day [GD] 20–48). Cetuximab was detected in the amniotic fluid and in the serum of embryos from treated dams at GD 49. No fetal malformations or other teratogenic effects occurred in offspring. However, significant increases in embryolethality and abortions occurred at doses of approximately 1.6 to 4 times the recommended human dose of cetuximab (based on total body surface area). Nursing Mothers It is not known whether Erbitux is secreted in human milk. IgG antibodies, such as Erbitux, can be excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Erbitux, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, based on the mean half-life of cetuximab [see Clinical Pharmacology (12.3) in Full Prescribing Information], nursing should not be resumed earlier than 60 days following the last dose of Erbitux. Pediatric Use The safety and effectiveness of Erbitux in pediatric patients have not been established. The pharmacokinetics of cetuximab have not been studied in pediatric populations. Geriatric Use Of the 1062 patients who received Erbitux with irinotecan or Erbitux monotherapy in five studies of advanced colorectal cancer, 363 patients were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients. Clinical studies of Erbitux conducted in patients with head and neck cancer did not include sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. Of the 208 patients with head and neck cancer who received Erbitux with radiation therapy, 45 patients were 65 years of age or older. OVERDOSAGE The maximum single dose of Erbitux administered is 1000 mg/m2 in one patient. No adverse events were reported for this patient. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been performed to test cetuximab for carcinogenic potential, and no mutagenic or clastogenic potential of cetuximab was observed in the Salmonella-Escherichia coli (Ames) assay or in the in vivo rat micronucleus test. Menstrual cyclicity was impaired in female cynomolgus monkeys receiving weekly doses of 0.4 to 4 times the human dose of cetuximab (based on total body surface area). Cetuximab-treated animals exhibited increased incidences of irregular or absent cycles, as compared to control animals. These effects were initially noted beginning week 25 of cetuximab treatment and continued through the 6-week recovery period. In this same study, there were no effects of cetuximab treatment on measured male fertility parameters (ie, serum testosterone levels and analysis of sperm counts, viability, and motility) as compared to control male monkeys. It is not known if cetuximab can impair fertility in humans. Animal Pharmacology and/or Toxicology In cynomolgus monkeys, cetuximab, when administered at doses of approximately 0.4 to 4 times the weekly human exposure (based on total body surface area), resulted in dermatologic findings, including inflammation at the injection site and desquamation of the external integument. At the highest dose level, the epithelial mucosa of the nasal passage, esophagus, and tongue were similarly affected, and degenerative changes in the renal tubular epithelium occurred. Deaths due to sepsis were observed in 50% (5/10) of the animals at the highest dose level beginning after approximately 13 weeks of treatment. PATIENT COUNSELING INFORMATION Advise patients: • To report signs and symptoms of infusion reactions such as fever, chills, or breathing problems. • Of the potential risks of using Erbitux during pregnancy or nursing and of the need to use adequate contraception in both males and females during and for 6 months following the last dose of Erbitux therapy. • That nursing is not recommended during, and for 2 months following the last dose of Erbitux therapy. • To limit sun exposure (use sunscreen, wear hats) while receiving and for 2 months following the last dose of Erbitux. Erbitux® is a registered trademark of ImClone Systems Incorporated. Manufactured by ImClone Systems Incorporated, Branchburg, NJ 08876 Distributed and Marketed by Bristol-Myers Squibb Company, Princeton, NJ 08543
Copyright ©2009 by ImClone Systems Incorporated and Bristol-Myers Squibb Company. All rights reserved. 1236886A5 ER-B0001A-07-09
Rev July 2009
tainly have to decide where you will mix your chemotherapy. Many clinics are purchasing barrier isolators to avoid full USP <797> remodels. We considered this an option for our sites. Although some types of isolators are recommended by the guideline and do provide an alternative, they are expensive, difficult to clean, and awkward to use. Worst of all, when used properly, barrier isolators add too many minutes to turnaround time. We felt that this was a deal breaker, because operators, especially nurses, would have too much incentive to skip necessary steps when using the isolators in the clinic. The biological safety cabinets that are appropriate for use in chemotherapy admixture are Class II type A or type B. Type B hoods can be vented 100%, whereas type A hoods can only be vented 70% with 30% being recirculated through a high-efficiency particulate air (HEPA) filter. If you have to use a partial venting method, an air gap (or “thimble”) may be needed. It is better to be capable of 100% exhaust, but only type A hoods are available as 2-footwide models. You may have to consider the space you have available and make a compromise. Space issues are a big problem in private clinics. Many private clinics are set in regular office buildings or store spaces, and the space allocated to intravenous (IV) preparation is often limited. We’ve had to cut inches off the legs of stands we have bought for hoods because the stands are designed for hospital ceilings. If your ceilings are low, you may be better off having a sturdy cabinet built to hold your new hood. Technically, hazardous drugs will need to be mixed separately from nonhazardous drugs. I know of very few private clinics that actually have a plan for this, but a newly built clinic should consider the necessity. A laminar flow hood is all that is necessary for nonhazardous drugs. We use an old (decontaminated) biological safety cabinet that is not currently being used for hazardous drugs. In practice, a site can also decontaminate the biological safety cabinet between uses, but this is very labor intensive. Using different hoods for cytotoxics and biologic agents is controversial and more likely to occur in a hospital, where resources are available for such a policy.
Use of automated dispensing systems Another decision that may require pharmacist input is the use of automated dispensing systems. If you can automate dispensing at your site, you should, and here is why. You may not get to choose what type of automated dispensContinued on page 12
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Challenges of Oncology
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Challenges of Oncology PHARMACY PRACTICE
Continued from page 11 Commonly used chemotherapy regimens can be built as kits, including the infusion charge codes, charges for bags, and any other ancillary charges that have to be entered manually and are often missed. When the kit is “pulled,” the codes get charged automatically with the drugs. • How will temperature deviations Reporting functions are another benbe handled? efit of automated dispensing systems. • What constitutes an emergency? Because each transaction is recorded A reasonable response time? and associated with a password, accountability is improved. Reports can • Who will be available to make be generated for drug utilization and adjustments or “rescue” drugs? total inventory for any given time, item • Will your clinic area be accessiauditing to track discrepancies, patient ble after hours or on weekends? treatment history, pharmacy drug cost for budgeting, and expiration date or lot number tracking. With custom reports, ing system you use, because this is the potential exists for much more. almost always determined by your Many wholesalers will work with you to wholesaler. Once you have chosen an create the reports you need on a oneautomated dispensing system, it must be time or even recurring basis. implemented. A mistake that hospitals Practices that perform research can often make with automation, is to use take advantage of automated dispensing only minimal features—the automated in another way. A wholesaler can set up a dispensing system becomes little more separate cabinet for provided research than a locked cabinet, and drugs, meeting the National hospital pharmacy staff Cancer Institute requirement ends up working for the for separate, locked condicabinet, instead of having tions, and improving accountthe cabinet work for them. ability for provided drugs. Used properly, automated Naming provided drugs by dispensing facilitates invenstudy, National Safety Council tory control, billing, reports, number, etc, will reduce the and research. chance of mistaking them Automated dispensing is for commercial agents, and an excellent system of each transaction will be reinventory control, with or Michele Woods, PharmD, corded. You can compare BCOP without ordering capability. reports from the automated If you have an exclusive arrangement dispensing system with written logs, with your wholesaler, you can set up and electronic records could potentialautomatic ordering. We set maximum ly replace written logs. and minimum par levels for each item at each of our clinic sites, and our whole- Maintaining the integrity of saler polls our machines via data or refrigerated drugs Automated or not, drug storage will phone line daily at a set time, creating an order. No one has to “walk the shelves” have to include a plan for maintaining to create a manual order. This allows us the integrity of refrigerated drugs. The to keep a very low inventory in stock, a most important aspect of refrigeration is very cost-effective system of just-in-time avoiding accumulation of ice in refrigerordering, even though we have a very ators. Ice causes the temperature range large, complicated practice. Even with- to be inconsistent; puddles of water out ordering capability, inventory con- from melting ice can saturate packagtrol allows you to identify and correct ing, and large ice blocks may even block discrepancies early. We inventory every the door seal. If possible, buy frost-free drug in every machine in our system to refrigerators. If your refrigerator does the milligram every day. This policy has have a freezer compartment, you must a multitude of advantages when dealing maintain a strict defrosting schedule. Full-size refrigerators are much more with expensive chemotherapy agents. Automated dispensing facilitates reliable and last longer than bar-size or any billing system. Charges can be sub- dorm-size refrigerators. There are several options for monitormitted directly from most automated dispensing systems. If you submit your ing refrigerator temperatures and assurcharges from another system (like your ing drug quality and several factors to electronic medical record), you can use consider in choosing which to use your automated dispensing system for (Table). The standard system includes a auditing, to minimize missed charges. thermometer with manual log entry, but Another way automated dispensing as you may have observed in your own can facilitate billing is the use of kits. practice, this is a woefully inadequate
Table. Considerations in Implementing a Plan to Maintain Integrity of Refrigerated Drugs
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Used properly, automated dispensing facilitates inventory control, billing, reports, and research. method for temperature monitoring. Our practice is not open every day. Some of our sites are open only once a week. Even sites that are open Monday through Friday could have a power failure on Friday evening and return to normal on Sunday afternoon and be perfectly fine by the time the thermometer is checked on Monday morning. Other options include digital range thermometers, data-collecting thermometers, and 24hour continuous monitoring systems with notification capability. Digital range thermometers are the cheapest option. They allow you to set a maximum and minimum temperature range. The display shows the current temperature, and most models show any alarms or extreme temperatures reached since the last time the thermometer was set. Digital range thermometers are very simple to use, but have no reporting capability. They do not tell how long the temperature was out of range or when. Data-collection thermometers provide much more useful information about the actual temperatures over time. They are also much more expensive. These devices usually consist of a graphing thermometer attached to the refrigerator. The graphs can then be collected and filed. Data-collection thermometers are most suitable for situations in which documentation of temperature monitoring is required (eg, research). The downside of data collection is that response to out-ofrange temperatures is limited to when the temperature graph is being read. This is less useful for sites that are not open every day, because someone must be on site to collect and read the graph. The most useful and relevant form of refrigerator monitoring for oncology clinics are the 24-hour continuous monitoring systems. Although these are definitely the most expensive methods, notification capability more than makes up for the cost. All the other systems only make you aware that a temperature deviation has occurred in the past. Notification capability gives you a chance to save the drug, and thus prevent waste. An electronic monitoring system will likely consist of a probe, usually set in a vial of glass beads, wires, and a box. The box may connect to a telephone system or your computer. There are a number of these systems on the market, and it is worth shopping around. If you are not sure how much it is worth to you, add up the cost of the inventory that is in your refrigerator at any given time. When you choose to purchase a 24hour monitoring system, you will need to
write a policy. Implementing such a system is no small project. The policy should include how temperature deviations will be handled, what constitutes an emergency, and what constitutes a reasonable response time. You must decide who will be available to make temperature adjustments or “rescue” drugs and how your clinic will be accessed after hours and on weekends. The bigger your practice is, the more complicated your policy is likely to be. It is much better to decide this beforehand than while the alarm is going off.
Other considerations Whether or not to prime tubing has become a hot topic on the oncology Listservs, although I am not sure why. Priming tubing with neutral fluid before adding chemotherapy is the standard published by both the American Society of Health-System Pharmacists and the Oncology Nursing Society. It is also standard practice in most outpatient clinics. Hospital pharmacies have been slow adopters of this practice. If you are new to outpatient oncology practice, this may be new information, but it is well worth reviewing. Your nurses will expect it. You will need IV poles and tubing in your pharmacy to allow for priming. You may need to find out if they prefer primary or secondary tubing and when to use pump tubing or filtered tubing. This may be a whole new education for you, as it was for me. In the era of leucovorin calcium, fluorouracil, and oxaliplatin (FOLFOX), home infusion pumps are another consideration for full-service pharmacy departments, even in private practice clinics. Whether you own or lease your pumps, you will need systems for paperwork, tracking, and cleaning and charging them. Outsourcing is also an option, but there are delays associated with outsourcing that are seldom acceptable in the outpatient environment. In addition to all of these equipment issues, there are a couple of other things that are helpful around the clinic. Cabinets and countertops should be adequate for the work that needs to be done and should be relative to the size of the items to be stored. Surfaces should be limited in the actual clean room. Bins can be used to limit cardboard in the clean areas, and these are available in an infinite number of shapes and sizes. Your technician is the best person to organize these areas. Don’t forget chairs and stools in the work areas: Nurses often stand to mix, but technicians do not. l September/October 2009
Newly Approved Pralatrexate Continued from cover patients with relapsed or refractory PTCL demonstrated that 29 (27%) of 109 evaluable patients achieved a complete or partial response to the novel targeted antifolate agent pralatrexate, with a response duration of 287 days (9.4 months), meeting both study end points. The most common side effects in the clinical trial were mucous membrane inflammation, nausea, fatigue, and lowered levels of platelets. T-cell lymphomas are a group of uncommon, biologically diverse hematologic malignancies comprising about 10% to 15% of all non-Hodgkin’s lymphomas in North America.1 Historically, PTCL patients have had a very poor outcome with conventional chemotherapy. Conventional chemotherapy treatments in PTCL patients have not been effective, and there were no pharmaceutical agents approved for use in the treatment of either first-line or relapsed or refractory PTCL. Overall 5-year survival is only about 25% after first-line therapy, and most patients relapse or become refractory after their initial combination chemotherapy.
or Refractory Peripheral T-cell Lymph oma] trial, told The Oncology Pharmacist. “This study has shown us that it may now be possible to extend this benefit well over 9 months. I consider this to be spectacular, especially given the treatment-resistant nature of the disease in this study population. This drug could change the natural history of this PTCL, and hopefully put us on a path to cure more and more of these T-cell lymphoma patients every year.” Furthermore, he said, several patients who did not respond to chemotherapy but responded to pralatrexate became eligible for definitive and potentially curable bone marrow transplants. “If this holds up, it could be another significant benefit of pralatrexate.” For many patients in PROPEL, pralatrexate effectively did what conventional therapy could not—achieve a remission of the patient’s lymphoma. “For some patients, this now means they may become eligible for autologous or allogeneic hematopoietic transplantation,” O’Connor explained. “Per-
“This drug could change the natural history of this PTCL, and hopefully put us on a path to cure more and more of these T-cell lymphoma patients every year.” Pralatrexate, designed to look like the natural B vitamin folic acid, inhibits DNA synthesis in tumor cells. The drug is designed to selectively accumulate in tumor cells, after which it induces apoptosis in the cancer cells. Pralatrexate is a novel folate analog designed to have high affinity for the reduced folate carrier, exhibiting improved internalization and efficacy over other aminopterin derivatives; it successfully disrupts DNA synthesis in tumor cells. In the trial, the most common grade 3/4 adverse events were thrombocytopenia, which was observed in 32% of patients; mucosal inflammation in 21%; neutropenia in 20%; and anemia in 17%.
Pralatrexate could change the natural history of PTCL “Until now, these patients could only expect to survive for weeks to a few months,” according to Owen A. O’Connor, MD, PhD, director of the Lymphoid Development and Malignancy Program, chief of the Lymphoma Service at the Herbert Irving Comprehensive Cancer Center at New York-Presbyterian Hospital/Columbia University Medical Center, and principal investigator and international study chair of the PROPEL [Pralatrexate in patients with Relapsed
forming a bone marrow transplant on patients in remission now opens the door for curative therapy; and for those with relapsed disease, pralatrexate allows patients to be bridged to a transplant, which has been definitive and curative in several patients.” When asked how he managed to assemble such a relatively large patient population for the PTCL study when it is a relatively rare cancer with 7100 cases annually, O’Connor said it was an international collaborative effort: “I tapped friends from around the world who have experience in this rare T-cell disease. I went to major international referral centers in different parts of the world; in this case, I went to friends in Italy, France, England, Canada. We brought everyone together for the benefit of the patients we are trying to help. Everyone was enthusiastic about being involved; it was a real team effort.”
PROPEL took all comers PROPEL took all enrollees, even those whose prognosis was exceedingly grim. O’Connor, who sees patients at New York-Presbyterian Hospital/ Columbia University Medical Center, stressed that the PROPEL trial is of par-
ticular significance because this study group was not limited in the number of prior chemotherapy treatments they could have received. Eligibility criteria included the requirement that the patient had recovered from the toxic effects of prior therapy. Patients treated with monoclonal antibody therapy were enrolled regardless of the timeframe of treatment if they had progression of disease (ClinicalTrials.gov Identifier: NCT00 364923). O’Connor said every enrollee, regardless of his or her history, had a reasonable chance of achieving remission: “Our patient population had no limit on the number of prior chemotherapy treatments; most of them were refractory to their prior line of chemotherapy, and, when you look at our response rate, the median number of prior therapies was three with a range of one to 12— that’s a very high number.” He noted that he and his colleagues intentionally selected patients who had had poor outcomes with conventional chemotherapy: “The fact that there was no limit of prior chemotherapy is very unusual in registration-directed clinical trials. Most studies state, ‘No more than two prior lines of treatment,’ so many trials don’t want patients that have already failed twice. And if you go back to our patient population, those patients who never responded to chemotherapy, the median number was three; one of four patients never responded to any chemotherapy program; 20 of those responded to pralatrexate. That shows you that pralatrexate works in a way that is unique and distinctly different from our conventional chemotherapy.” O’Connor continued: “If you look at the patients who were refractory to their prior line of chemotherapy, 53% of patients on PROPEL did not respond to the chemotherapy regimen immediately prior to receiving pralatrexate, whereas 25% of patients on PROPEL never responded to any chemotherapy regimen. One other piece of information is the duration of response—9.5 months is the median duration of response. I consider this to be an exciting feature of this trial; most new drugs in this disease are looking for overall response rates of 20% with a duration response of 2 to 3 months.”
Combination regimens being studied Allos Therapeutics has agreed to undertake additional clinical studies to further verify and describe the clinical benefit of pralatrexate in patients with T-cell lymphoma. O’Connor said that it was the encouraging data from PROPEL that provided substantial evidence for expanding the current promising results into new disease-management strategies
with a variety of combined biologic drug therapies. “In this study, pralatrexate was given alone. Now we’re working on combining it with a number of other drugs; right now it almost doesn’t matter what drug you combine it with, because most of the ones we have tested have shown mathematical synergy when combined with pralatrexate. We’re doing a phase 1/2 study to figure out how to best combine pralatrexate and gemcitabine [ClinicalTrials.gov Identifier: NCT00481871], and we will soon begin a study with pralatrexate and bortezomib in a phase 1 trial.” He said: “We need to find new ways to get patients into remission, and, to do that, we need to look at unique drugs. If we’re at 27% by itself with pralatrexate, and if we combine it with bortezomib or gemcitabine, or the histone deacetylase inhibitors, we can possibly get up to 70%; each of these classes of drugs alone produces response rates of about 20% to 30% in patients with T-cell lymphoma, so conceivably, we could have 30% increases to 60%, which increases to a 90% response.” He summed it up, “At that point, we would be changing the natural history of a challenging disease.” l
Reference 1. Molina AM, Horwitz SM. Rare T-cell lymphomas. In: Rare Hematological Malignancies. New York, NY: Springer; 2008:331-347.
Recent FDA Approvals • MammoSite ML to Help Prevent Recurrences of Breast Cancer The FDA has approved a new version of the MammoSite system, the MammoSite ML (Hologic). MammoSite devices deliver radiation seeds to prevent recurrences of breast cancer. According to the company, the new version allows physicians to better target specific areas of tissue than the original version, allows therapists to treat patients who are not otherwise good candidates for radiation seeding, and is usable in more typical cases. • Zevalin for First-line Treatment of Follicular Non-Hodgkin’s Lymphoma The FDA has approved an expanded label for Zevalin (Spectrum Pharmaceuticals) as part of first-line treatment of follicular non-Hodgkin’s lymphoma. The label extends the agent’s use to patients with previously untreated follicular nonHodgkin’s lymphoma who achieve a partial or complete response to first-line chemotherapy. This approval was based on data from the FIT Study presented at the 2008 annual meeting of the American Society of Hematology.
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RECENT FDA APPROVALS
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PHARMACY CAREERS AND EDUCATION
Pharmacy Careers and Education Pharmacy School Provides a Well-rounded Education An Interview with Rebecca S. Finley, PharmD, MS Jefferson School of Pharmacy, Philadelphia
ast year, the Jefferson School of Pharmacy welcomed its first class of students. As the school enters its second year, founding dean Rebecca S. Finley, PharmD, MS, reflects on the first year and discusses her hopes for the future.
ing the material the way they should. We also brought in additional speakers on topics that students were interested in. We tried to identify things that will be helpful to the students within their professional lives as well as in their academic careers at Jefferson, such as opportunities to get them together with Tell us about your first year. students from other programs. It’s been a great experience. From We had a lot of diversity for our first our standpoint, it went very smoothly. class of 73 students. When they arrived We were very impressed with our first last fall, they ranged in age from 20 to class—a very mature, hard44 years. We had several working group of individuals. people starting a second With any new program, when career; we had several you are building from scratch nurses and a couple of you get lots of good ideas durengineers; we had some ing the building process. We with 4-year degrees and tried to stay as flexible as possome with only 2 years of sible and, as good ideas came prepharmacy courses. We up, we tried to implement had people who were them. Academically, the first married with families and class did quite well, probably Rebecca S. Finley, people who were just 2 better than we hoped for a PharmD, MS years out of high school. first class. No major issues So we tried to figure out came up. We learned from our experi- how to schedule classes and lab coursence and keep moving forward. In es, to identify what would be the most addition to getting ready for the sec- student-centered organization of classond class, we are busy building the es, as well as how to organize classes to coursework for the second year. create bigger blocks of study time durIt will be nice to have two classes of ing the day, because many students had students on campus. The first class was in to go to work and go home to families a very difficult position, because they did in the evening. Wherever we could do not have upperclassmen to talk to and those kinds of things, we did. We tried find out the lay of the land. The new to listen to the students and figure out class will have the first class to go to for how we could individualize things and advice about courses, professors, and what types of helpful information we standards. The first class has also been could offer online. very involved with identifying extracurYou said that some students came ricular activities for the new class. We have been very successful in from other professions, such as recruiting an outstanding faculty. We engineering and nursing. Why have been able to bring in a diverse are they going into pharmacy at group of people with different back- this point in their lives? It is a different reason for each pergrounds and research interests, as well as some who have a lot of teaching son. Both of our nurses were still active experience. Already this year, two of in nursing. One of them said that she our faculty members are officers in always wanted to be a pharmacist but national pharmacy organizations, and a somehow got committed to nursing by third person is running for office in a family. Now 20 years later with her chilnational pharmacy organization, so I’m dren grown, she could make her own decision. The other nurse had a lot of extremely proud of that. exposure to pharmacy in his nursing What were some of the good practice. He has a keen interest in pharideas you got from students? macy and just decided to make a career For specific courses, we learned what change. The engineers that we had in tools might be most valuable to students the first class had worked as engineers beyond PowerPoint slides or handout for a few years and were not happy with materials. They recommended addi- what they were doing. tional reading materials that might be helpful. Also, for some courses, we pro- Do you have an idea of how many vided online self-assessment quizzes so of your graduates will go on to students can figure out if they are learn- work in retail pharmacy as
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opposed to going into specialized fields like oncology? I don’t know the most recent numbers, but nationwide, approximately 50% of graduates go directly into community pharmacy, whether in chain drugstores or stores like Target and WalMart or independent pharmacies. Of the other 50%, about 25% to 30% go on to postdoctoral training, most into a residency program, a few into fellowships, and a few into graduate school. For those who go into residency and fellowships, there are many different specialty areas and career opportunities available. Oncology is one of the boardcertified specialty areas in pharmacy, along with nuclear pharmacy, pharmacotherapy, nutritional support, and psychiatric pharmacy. This past June, the Board of Pharmacy Specialties approved ambulatory care as a new official specialty within pharmacy practice. So probably beginning in 2011, there will be a examination for pharmacists to get specialty certification in ambulatory care. A handful of graduates from pharmacy school who get a doctorate of pharmacy degree go directly on to a PhD degree with the intent of becoming laboratory researchers. Then, there are a small proportion of graduates nationwide—probably less than 5%— who go directly into the pharmaceutical or other related industries. Are there opportunities for students who are interested in oncology or other specialized areas to gain experience in those fields during their school years? Absolutely. Thirty percent of the curriculum in any pharmacy school is experiential education, where the students work side by side with a pharmacist preceptor. This means that 30% of their credit hours are experiential, and, as part of that experience, they are given the opportunity to do some inhospital pharmacy and some incommunity pharmacy practice. A number of rotations are set aside so the students can pick different specialty areas. For example, they can go into oncology for a month, or critical care or nutritional support or compounding pharmacy to test the areas and see if they meet their interests. We try to expose them to as many different aspects of pharmacy as possible. We want them to make the decision that is best for them. And for the 30% of students who go on to residency programs, they are exposed to even more
specialty areas during their first year of residency so they can decide on a more focused, specialized area for their second year of residency.
Are there any courses at the undergraduate level that deal with practice management and business issues such as insurance, reimbursement, and coding? Every pharmacy school has some sort of management course or coursework within the curriculum; that is part of the accreditation standards. Most pharmacy schools offer some additional electives in business management, reimbursement programs, or human resources management. Nationwide, many schools offer the opportunity for joint degrees, such as a PharmD/MBA, and those joint degree programs are becoming more popular. Our medical school at Jefferson partners with Widener University, also in Philadelphia, and offers a joint MD/ MBA. At some point, I’m sure we will be entering into a partnership like that. At the Philadelphia School of Pharmacy, students can take their foundation courses for their MBA while still a PharmD student. Because many pharmacists also have either business or managerial responsibility and almost every pharmacist is a supervisor, students need to learn those skills. Almost every pharmacist from the day he or she gets a license is at least supervising pharmacy technicians and pharmacy students, making these skills very important. I think a lot of pharmacy students don’t realize how important that part of their training is. The chain stores are a good example; for promising young pharmacists starting within the chain pharmacies, they offer management development certification programs. Many pharmacists don’t see themselves as a store manager, a director of pharmacy in a hospital, or a manager or an executive in a chain pharmacy. But after they get out of school, they realize that these are very viable career ladders and they get very interested. They realize that they probably could have taken added coursework that would have helped them. So, we are trying to strengthen this aspect within our curriculum. We all have to think of the financial implications of everything we do. l —Karen Rosenberg September/October 2009
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Cisplatin-based Chemotherapy May Increase Incidence of Thromboembolic Events MIAMI—Patients treated with cis- orial Sloan-Kettering Cancer Center, platin-based chemotherapy in an outpa- New York. “We decided to look at how tient setting at a cancer center had an much it played a part in contributing to increased incidence rate of thromboem- TEEs at our cancer center.” bolic events (TEEs), according to a retroUsing their pharmacy information spective study presented at the 5th annu- system, the investigators identified al meeting of the Hematology/Oncology 1142 patients who received at least one Pharmacy Association. dose of cisplatin-based chemotherapy Cancer patients have a fourfold in the outpatient setting between increased risk of a venous thromboem- January 1, 2008, and February 28, bolism (VTE) compared with 2009. Of the 249 patients retnoncancer patients and a sixrospectively reviewed to date, fold increased risk of a VTE 200 (median age, 61 years; when treated with chemother51.5% female) met the incluapy. Although cisplatin has sion criteria of at least 18 years been reported to significantly of age, received at least 4 increase risk of venous and weeks of follow-up after last arterial TEEs, there are curdose of cisplatin, and did not rently no specific recommenreceive any erythropoietindations regarding the use of stimulating agents from 6 Russell A. Moore, prophylactics in treating cis- PharmD weeks before to 4 weeks after platin-based chemotherapy. cisplatin. “With cisplatin being such an old TEE occurrence was based on results agent, we didn’t think of it really as one from angiography, magnetic resonance of those agents that we needed to worry imaging or computed tomography about causing clots,” said lead investi- (CT) of the head, CT of the chest gator Russell A. Moore, PharmD, and/or lower extremities, venous Doponcology pharmacy resident at Mem- pler ultrasound, or ventilation/perfu-
sion scan, along with patient electronic medical record information. Results showed that 41 (20.5%) of the 200 patients had a TEE within 4 weeks of their last cisplatin administration. A total of 37 (90.2%) of those experienced their TEE within 90 days, and 35 (85%) had deep-vein thrombosis and/or pulmonary embolism. “Strikingly, most of the clots occurred early,” reported Moore, “and most occurred within the first three doses.” TEE incidence was highest in patients with pancreatic, gastric, or esophageal cancers; metastatic disease; and those on bevacizumab-, docetaxel-, or gemcitabine-containing cisplatin regimens. “We found that the incidence of a TEE was 20.5% in the 200 patients receiving cisplatin,” said Moore. “That incidence is significantly higher than what has been reported in the literature, which has been 17.6% and reportedly mostly found in lung cancer patients. So this is the highest we’ve seen so far.” He added that the highest incidence
overall was in patients with pancreatic cancer, 10 (35.7%) of 28 of whom had a TEE. “Gastric cancer at 26% and esophageal cancer at 21.4% were also high,” said Moore. The lung cancer patients had a 17% incidence of TEEs, which does match the literature.” When asked about the number one takeaway, Moore said, “I think it’s just to be vigilant and be wary of the fact that TEEs can happen, especially with pancreatic cancer.” Further, “Think about cisplatin as something that can cause clots as opposed to just being an old agent that no one needs to worry about. Monitor and be aware of symptoms such as shortness of breath or leg swelling. If that happens and the patient is receiving cisplatin, you should probably check for clots,” he advised. The investigators are hoping to use this information as the basis of a future prospective study looking at anticoagulation and prophylaxis in patients receiving cisplatin. —DB
Long-term Romiplostim Treatment Appears Safe, Effective for On-site and Home Administration MIAMI—Romiplostim remains safe and effective after 4 years of use, and offers the same benefits in home administration (HA), for patients with chronic thrombocytopenic purpura (ITP), according to three posters from a multinational open-label extension study presented at the 5th annual meeting of the Hematology/Oncology Pharmacy Association. “Adult chronic ITP has an incidence of 5.8 to 6.6 per 100,000 people per year in the United States,” reported Shane D. Scott, PharmD, BCPS, BCOP, associate director of clinical development of IV therapy and nutrition at Baxter Healthcare Corp- Shane D. Scott, oration, Deerfield, Illinois, PharmD, BCPS, during his presentation of BCOP the posters. For these patients, persistently low platelet counts are associated with a risk of fatal bleeding, and that risk increases with age. Romiplostim is an Fc-peptide fusion protein (peptibody) that increases and sustains platelet counts in a manner similar to thrombopoietin. It previously has shown to be effective and well tolerated in patients with ITP for up to 3 years. In this study, investigators reviewed safety and efficacy results from a 4-year
update of an open-label romiplostim trial. They included findings from study-site and/or home-administered injections in 223 patients (mean age, 50 years; 62% female; 99 splenectomized). All patients had completed a previous romiplostim study with no significant changes in their medical history. Efficacy end points included long-term platelet response, incidence and severity of bleeding over time, and reduction or discontinuation of concurrent therapy for ITP. The study drug was administered subcutaneously once per week, starting at 1µg/kg and adjusted as needed to maintain platelet counts between 50 × 109/L and 200 × 109/L. As of July 2008, 215 of these patients had received romiplostim for a median of 72 weeks, and baseline platelet counts (median [Q1, Q3]) were 24 (12, 43) × 109/L. Results at the end of the study showed that platelet counts were increased and sustained in most of the patients. Counts ≥50 × 109/L and double baseline were achieved by 30% of patients after the first dose and 74% of patients overall. Among those receiving concurrent medications for ITP at baseline, 74% (25/34) discontinued or reduced their dose by >25%, and rescue medication use decreased over time. In addition,
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bleeding of moderate or greater severity declined from 14% of the patients during weeks 1 to 24 to 10%, 7%, and 5% during subsequent 24-week periods. Adverse events, reported in 86% of the patients, were generally mild-tomoderate in severity, the most common being headache (34%), contusion (32%), and fatigue (31%). In addition, thrombotic events were reported in 3% of the patients, and bone marrow reticulin was increased or present in 4%. Of the four deaths, none were considered treatment-related. The proportion of those experiencing adverse events did not increase with study duration: 82% were reported during weeks 1 to 23, 85% during weeks 24 to 47, and <75% during all subsequent 24-week periods. For the HA evaluation, 135 (61%) of the 223 patients originally enrolled (median age, 53 years; 62% female) initiated self-injection after receiving romiplostim for a median of 9 weeks previously. Training was given for selfinjection or injection by a home caregiver, and evaluations were made every 4 weeks at the study center. “While some of these patients felt comfortable giving themselves an injection, others weren’t,” said Scott. “If they wanted to participate but didn’t want to self-inject or have a caregiver to help
them, it made it more difficult. That’s one reason that we offered training.” Results from this part of the study showed that the median average weekly doses were comparable 8 weeks before and 8 weeks after initiating HA (4µg/kg vs 5µg/kg, respectively). Plus, mean (±standard deviation) platelet counts increased with the romiplostim treatment and stabilized after HA initiation, from 89 (±104) × 109/L 8 weeks before to 128 (±109) × 109/L 8 weeks after. Similar numbers of patients reported adverse events in the 8 weeks before HA at 56% versus 58% afterward. Serious adverse events occurred in three patients before and seven after HA. One treatment-related serious adverse event and no deaths occurred. “Home administration of romiplostim, including self-injection or caregiver injection, was maintained in most patients without apparent changes in platelet response or safety profiles, suggesting it is a convenient, effective, and well-tolerated treatment for ITP patients,” Scott reported. He concluded that overall, “Our results show that romiplostim can be given safely over an extended time period. Now we’d like to know what happens at the 10-year mark.” —DB
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at www.thEonCologypharmaCist.Com Program #CIK10257 • RELEASE DATE: October 15, 2009 • EXPIRATION DATE: October 14, 2010 EDITORIAL BOARD Betty M. Chan, PharmD, BCOP Assistant Professor of Clinical Pharmacy University of Southern California Clinical Pharmacist USC/Norris Comprehensive Cancer Center 1441 Eastlake Avenue Los Angeles, CA 90033 Christos S. Karapetis, MD Director of Clinical Research Department of Medical Oncology Flinders Medical Centre Flinders Drive Bedford Park SA 5042 Adelaide, Australia Sandra E. Kurtin, RN, MS, AOCN, ANP-C Clinical Assistant Professor of Medicine and Nursing University of Arizona Hematology/Oncology Nurse Practitioner Arizona Cancer Center 3838 N. Campbell Avenue Tucson, AZ 85719 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 Dawn Lagrosa Associate Editor Green Hill Healthcare Communications, LLC 241 Forsgate Drive Monroe Twp, NJ 08831 Karen Rosenberg Editorial Director Green Hill Healthcare Communications, LLC 241 Forsgate Drive Monroe Twp, NJ 08831
Prediction and Promise: KRAS and Colorectal Cancer BY CHRISTOS S. KARAPETIS, MD Department of Medical Oncology, Flinders Medical Centre, Bedford Park, Adelaide, Australia 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 test: 1. Log on to www.theoncologypharmacist.com. 2. Click on “CE Credits.” 3. Click on “Click Here To complete the post-test and obtain a CE certificate online.” 4. Click on “CE Credits.” 5. Enter program # CIK10257 • 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.
ACPE of any commercial products affiliated with this activity.
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.
TARGET AUDIENCE Registered pharmacists and other interested healthcare professionals, especially those caring for cancer patients
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
ancer remains a major cause of death and disability in the developed world. As we enter the new millennium, the promise of improved cancer biology knowledge leading to new cancer treatments is being realized. We want to be able to offer these breakthrough treatments to patients who will benefit from them. Moreover, we would like to avoid initiating therapy in patients who have little chance of responding, and hence eliminate the toxicity of ineffective therapy and enable other treatment approaches to be pursued. Up until recently, however, there were no such predictors of response and benefit to guide our management approach to advanced colorectal cancer. Chemotherapy drugs with or without bevacizumab were tried and changed when treatment failure was observed. The results of the CO.17 trial have helped to change the treatment paradigm for metastatic colorectal cancer when using monoclonal antibodies that target the epidermal growth factor receptor (EGFR).1
Why did we look at KRAS? Study CO.17 was initiated by the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) in collaboration with the Australasian Gastro-Intestinal Trials Group (AGITG). This multicenFACULTY/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 conforms to accepted standards of experimental design, data collection, and analysis.
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LEARNING OBJECTIVES After completing this activity, the reader should be better able to: • Explain the rationale for studying the effect of KRAS mutations in patients with metastatic colorectal cancer • Discuss how KRAS mutations affect response to epidermal growth factor receptor (EGFR) inhibitor therapy in patients with metastatic colorectal cancer • Describe common toxicities associated with use of anti-EGFR monoclonal antibodies and measures that can be taken to prevent and manage them • Explain how use of biomarkers such as KRAS mutations to select therapy can lead to more cost-effective treatment of patients with cancer
COST This program is complimentary for all learners.
ter, prospective, open-label, randomized, phase 3 trial compared cetuximab plus best supportive care (BSC) with BSC alone in patients with pretreated metastatic colorectal carcinoma.2 All the patients had received previous chemotherapy, and the treating physician considered that further chemotherapy would not help the patient. The only remaining standard therapy for patients entering this study, as recommended by the investigator, was BSC. Patients in the cetuximab arm received the agent as a once-per-week intravenous infusion. The trial demonstrated that cetuximab when used as a single agent improves overall survival and prolongs progression-free survival in patients with colorectal cancer after failure of chemotherapy, but the majority of patients did not respond to cetuximab in this setting, more than 50% of patients showing disease progression at the time of the first disease-response assessment.2 Cetuximab is a monoclonal antibody that binds to the EGFR with high affinity and inhibits the subsequent activation of downstream signaling pathways.3 Kirsten rat sarcoma (KRAS), a small protein downstream of EGFR, is an essential component of the EGFR signaling cascade and may represent a bottleneck in the pathway.4 Mutations in the KRAS gene can lead to constitutive activation of the pathway, and this
The 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 • Sandra E. Kurtin, RN, MS, AOCN, ANP-C • Dawn Lagrosa • Brenda Ram, CMP • Karen Rosenberg The following authors have stated that he/she has the following financial relationships: • Betty M. Chan, PharmD, BCOP, has received research/ grant support from Merck & Co.
• Christos S. Karapetis, MD, is on the advisory board for Merck Serono. ACCREDITATION AND CONTACT HOURS STATEMENT 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 0447-0000-078-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 October 15, 2009. The expiration date is October 14, 2010. 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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at www.thEonCologypharmaCist.Com Program #CIK10257 • RELEASE DATE: October 15, 2009 • EXPIRATION DATE: October 14, 2010
The results: KRAS does matter We observed a significant difference in survival times, but only for one of the KRAS groups. Overall survival was almost doubled for patients treated with cetuximab if the tumor did not have a KRAS mutation (ie, the KRAS wildtype subgroup). In the KRAS wild-type subgroup, median survival was 9.5 months in those receiving cetuximab and 4.8 months with BSC alone (Figure). Similarly, progression-free survival was also prolonged with cetuximab therapy in patients with KRAS wild-type tumors (3.7 months vs 1.9 months). In contrast, the survival time was not prolonged with cetuximab treatment in patients whose tumors had KRAS mutations. For those patients, median survival was the same in the cetuximab-treated and BSC arms, 4.5 and 4.6 months, respectively. Progression-free survival was also the same in the two arms for patients with KRASmutant tumors. KRAS mutation status was found to be correlated with overall survival, progression-free survival, and radiologic response. Quality-of-life analysis also demonstrated that patients
Figure. Kaplan-Meier Curves for Overall Survival According to Treatment A. Mutated KRAS 100
Overall Survival (%)
Examination of tumor tissue is crucial For the current study, colorectal cancer tumor samples were collected from 394 patients involved in the CO.17 trial, representing 69% of all the patients in that trial. Mutation analysis for the KRAS gene was performed by direct gene sequencing to examine the tumor DNA in detail and look specifically at the DNA that codes for the KRAS gene. We effectively divided the tumor samples into two groups, those that exhibited KRAS mutations and those that did not. KRAS genes without mutations are called “wild type.” We found that 42% of the tumor samples examined exhibited mutations of the KRAS gene, and this frequency is in keeping with previously published reports. We then set out to see whether KRAS mutation status was associated with differences in patient outcome.
with KRAS wild-type tumors derived the greatest benefit. Overall, the benefit obtained with cetuximab in the setting of advanced colorectal cancer previously treated with chemotherapy was isolated to patients with tumors that do not exhibit KRAS gene mutations. No benefit was observed from using cetuximab in patients whose tumors had KRAS mutations. This correlation of KRAS mutation status and treatment effect has also been observed in other published retrospective series.10-13
80 60 40
Best supportive care alone
Cetuximab plus best supportive care
P = .89
Is KRAS also a prognostic factor? The presence of a KRAS mutation may predispose to more aggressive biological behavior of the cancer, but the prognostic significance of KRAS mutations has varied in reported series.7-9,14,15 In our study, we were able to examine the survival of patients who did not receive any cancer treatment, because these patients were in the BSC arm. In this way, we could examine the impact of KRAS on survival without having to consider a possible effect of treatment. We did not observe that the presence of a KRAS mutation predicts for a more aggressive cancer and a poorer prognosis. We found no difference in the survival of patients according to KRAS mutation status in the BSC group. Median survival was 4.6 months in patients with KRAS-mutant tumors on BSC and 4.8 months in those with KRAS wild-type tumors on BSC, with 1-year survival of 19.6% and 20.1%, respectively. This analysis provides the best assessment of the influence of KRAS mutation status on survival without the effect of another variable such as treatment with cetuximab.
Months after Randomization No. at Risk Cetuximab plus best supportive care Best supportive care alone
B. Wild-type KRAS 100
Overall Survival (%)
may render inhibitors of components of the cascade upstream of KRAS ineffective. KRAS mutations, therefore, may predict for lack of efficacy of inhibitors that target the EGFR.5 KRAS gene mutations occur early in the stages of carcinogenesis, as the colorectal adenoma progresses to develop into a carcinoma.6 KRAS mutations are found in 30% to 50% of colorectal cancers.7-10
Cetuximab plus best supportive care
60 40 20
Best supportive care alone
P <.001 0 0
Months after Randomization No. at Risk Cetuximab plus best supportive care Best supportive care alone
Reprinted with permission from Reference 1.
Where to now? Although KRAS mutations may represent a common genetic aberration involved in cancer development, other gene mutations can also lead to unrestricted cancer cell growth. Some of these are already being examined, including loss of PTEN activity,16 gene expression of the EGFR ligands amphiregulin and epiregulin,17 and PI3KCA mutations.18 Over the past decade, there has been a paradigm shift in the way we manage patients with advanced colorectal cancer. Multiagent chemotherapy and multiple lines of therapy are now part of optimal treatment strategies. Anti angiogenic therapy has contributed further to improving the outcome of such patients, particularly in progression-free
survival, with an associated prolongation of overall survival. The benefit of antiangiogenic therapy has been observed when bevacizumab is used as part of either first- or second-line therapy. EGFR-directed therapy, particularly using cetuximab and panitumumab, has also prolonged survival and progressionfree survival, but this prolongation is restricted to patients with KRAS wildtype tumors. In the future, cost-benefit analysis may become a major factor in deciding on wider availability of these agents. Cetuximab is a relatively expensive pharmacologic therapy. The cost-effectiveness of this treatment approach improves when the treatment can be delivered to those patients with a higher
chance of benefiting. The major challenge is the identification of appropriate predictors of response to these drugs. Low response rates, short survival times, and relatively expensive new drugs have provided an understandable impetus to discover predictors of benefit from therapy. Avoiding therapy in patients who have little chance of responding can help to eliminate toxicity of ineffective therapy and allow other treatment approaches to be pursued. The results of the CO.17 study have identified a biomarker that can effectively exclude a significant proportion of patients with colorectal cancer, approximately 40% with tumors that have Continued on page 20
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KRAS mutations, from a therapy that has very little prospect of providing a benefit. An accurate and reliable biomarker that allows selection of a subpopulation of patients with advanced colorectal cancer who will benefit from new therapies represents a significant advance in the clinical management of this disease. KRAS has now been proved to
be such a biomarker and should be routinely examined and used to select patients for treatment with EGFR-directed monoclonal antibodies such as cetuximab and panitumumab. The ideal predictive biomarker is one that identifies all of those patients who will benefit from therapy before initiation of treatment, and excludes the
patients who will not respond. Although KRAS has a significant predictive effect, it is not perfect. In our study, some patients with KRAS wild-type tumors did not respond to cetuximab and had rapid cancer progression. Other prognostic and predictive variables that can be reliably and easily measured need to be identified. l
Commentary KRAS and Colorectal Cancer: A Pharmacist’s Perspective BY BETTY M. CHAN, PHARMD, BCOP University of Southern California/Norris Comprehensive Cancer Center, Los Angeles
ecent advances with chemotherapeutic agents (ie, oxaliplatin, irinotecan) and targeted biologic agents (ie, anti–epidermal growth factor receptors [EGFRs] cetuximab, panitumumab; anti– vascular endothelial growth factor bevacizumab) have greatly expanded our treatment options for patients with colorectal cancer. Recent findings on use of Kirsten rat sarcoma (KRAS) mutational status to predict response to anti-EGFR monoclonal antibodies further demonstrated our need to streamline patient selection to those likely to derive the greatest benefit (ie, those with KRAS wild-type tumors only) from treatment so as to minimize treatment toxicities and provide cost-effective treatment. In the article by Karapetis, the author reported that results from the CO.17 trial have helped change the treatment paradigm for metastatic colorectal cancer. In the study, overall survival and progression-free survival were significantly improved in patients with KRAS wild-type tumors who received treatment with cetuximab compared with best supportive care.1 In addition to the findings reported by Karapetis and colleagues, several other recent publications have reported greater improvement in response rates, progression-free survival, and overall survival when an anti-EGFR monoclonal antibody (ie, cetuximab or panitumumab) is used as monotherapy or in combination with chemotherapy agents in patients with advanced colorectal cancer who have KRAS wild-type tumors.2-6 Although treatment with an anti-EGFR monoclonal antibody (cetuximab or panitumumab) is much better tolerated by patients compared with chemotherapy, most patients receiving treatment do experience toxicities.7,8 As with other monoclonal antibodies, infusion-related symptoms include fever, chills, urticaria, flushing, fatigue, headache, bronchospasm, dyspnea, angioedema, and hypotension. Incidence rates are higher in patients receiving cetuximab, a chimeric monoclonal antibody, than in those receiving panitumumab, a fully humanized IgG2 monoclonal antibody. Premedication is needed in patients before treatment with cetuximab because the incidence of infusion reactions is higher with the first infusion (40%-50% reported) than with subsequent infusions (<1%). Close monitoring for all infusions is recommended, however, to minimize infusion reactions and to pro-
vide supportive care if infusion reactions develop.7,8 Skin toxicity, although often considered a surrogate marker for clinical activity, is, nevertheless, another common toxicity associated with anti-EGFR monoclonal antibodies. Commonly observed skin toxicities include acneiform skin rash with papulopustular eruption on the face and upper trunk, dry skin with pustular eruptions, and pruritus. Management includes educating patients to avoid sun exposure, which may exacerbate skin reactions, and to apply a paraaminobenzoic acid-free sunscreen with a sun-protection factor of 15 or higher before sun exposure. Dosage adjustment may be necessary, depending on the severity of skin toxicity. Topical antibiotics with clindamycin or its derivatives (ie, clindamycin phosphate 1% gel for isolated lesions and clindamycin phosphate 1% lotion for scattered lesions) can be used for mild skin toxicity. For moderate-to-severe skin toxicity, systemic oral antibiotics (ie, minocycline or doxycycline 100 mg orally twice a day for 10-14 days) can be used. For dry skin, applying emollient twice a day may provide relief of symptoms. Pruritus can be managed with diphenhydramine or hydroxyzine 25 mg to 50 mg orally every 6 hours as needed.9-12 Electrolyte abnormalities such as hypomagnesemia and hypocalcemia have also been reported. Hypomagnesemia has been observed as early as 3 weeks into treatment with cetuximab.13,14 Close monitoring of magnesium and calcium levels before treatment is recommended, providing electrolytes supplementation as needed. Pulmonary toxicity including interstitial lung disease, although rare (<1%), has been reported with anti-EGFR monoclonal antibodies. Patients with acute-onset or worsening pulmonary symptoms (eg, increased cough, dyspnea, and pulmonary infiltrates) must be carefully monitored, and holding or discontinuing treatment may be necessary in patients with pulmonary toxicities.7,8 Generalized malaise and asthenia have been observed (with cetuximab more than panitumumab).7,8 Paronychial inflammation and swelling of lateral nail folds of fingers and toes has also been reported in patients receiving treatment for a prolonged period of time. Management options include topical antibiotics or topical corticosteroids.11,12 Although toxicities associated with anti-EGFR
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monoclonal antibody therapy are generally mild and manageable, frequent assessment and close monitoring are still required to minimize toxicities and patient discomfort. Nurses and pharmacists can assist with the assessment and monitoring of these toxicities, and develop management guidelines in their institution for the treatment of skin toxicities and the management of hypomagnesemia.
References 1. Karapetis CS, Khambata-Ford S, Jonker DJ, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008;359:1757-1765. 2. Lièvre A, Bachet J-B, Boige V, et al. KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol. 2008;26:374-379. 3. Van Cutsem E, Lang I, D’haens G, et al. KRAS status and efficacy in the first-line treatment of patients with metastatic colorectal cancer (mCRC) treated with FOLFIRI with or without cetuximab: the CRYSTAL experience. J Clin Oncol. 2008; 26(15S):Abstract 2. 4. Amado RG, Wolf M, Peeters M, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastastic colorectal cancer. J Clin Oncol. 2008;26:1626-1634. 5. Khambata-Ford S, Garrett CR, Meropol NJ. Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. J Clin Oncol. 2007;25:3230-3237. 6. Bokemeyer C, Bondarenko I, Hartmann T, et al. KRAS status and efficacy of first-line treatment of patients with metastatic colorectal cancer (mCRC) with FOLFOX with or without cetuximab: the OPUS experience. J Clin Oncol. 2008; 26(15S):Abstract 4000. 7. Erbitux (cetuximab) [package insert]. Branchburg, NJ: ImClone Systems Inc/Princeton, NJ: Bristol-Meyers Squibb Co; 2008. 8. Vectibix (panitumumab) [package insert]. Thousand Oaks, CA: Amgen Inc; 2008. 9. Busam KJ, Capodieci P, Motzer R, et al. Cutaneous side-effects in cancer patients treated with the antiepidermal growth factor receptor antibody C225. Br J Dermatol. 2001;144:1169-1176. 10. Scope A, Agero AL, Dusza SW, et al. Randomized double-blind trial of prophylactic oral minocycline and topical tazarotene for cetuximab-associated acne-like eruption. J Clin Oncol. 2007; 25:5390-5396. 11. Hu JC, Sadeghi P, Pinter-Brown LC, et al. Cutaneous side effects of epidermal growth factor receptor inhibitors: clinical presentation, pathogenesis, and management. J Am Acad Dermatol. 2007;56:317-326. 12. Lynch TJ Jr, Kim ES, Eaby B, et al. Epidermal growth factor receptor inhibitor-associated cutaneous toxicities: an evolving paradigm in clinical management. Oncologist. 2007;12:610-621. 13. Fakih MG, Wilding G, Lombardo J. Cetuximab-induced hypomagnesemia in patients with colorectal cancer. Clin Colorectal Cancer. 2006;6:152-156. 14. Schrag D, Chung YK, Flombaum C, Saltz L. Cetuximab therapy and symptomatic hypomagnesemia. J Natl Cancer Inst. 2005; 97:1221-1224.
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at www.thEonCologypharmaCist.Com Program #CIK10257 • RELEASE DATE: October 15, 2009 • EXPIRATION DATE: October 14, 2010 References 1. Karapetis CS, Khambata-Ford S, Jonker DJ, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008;359:1757-1765. 2. Jonker DJ, O’Callaghan CJ, Karapetis CS, et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med. 2007;357:2040-2048. 3. Baselga J, Norton L, Masui H, et al. Antitumor effects of doxorubicin in combination with anti-epidermal growth factor receptor monoclonal antibodies. J Natl Cancer Inst. 1993;85:1327-1333. 4. Baselga J. The EGFR as a target for anticancer therapy—focus on cetuximab. Eur J Cancer. 2001;37(suppl 4):S16-S22. 5. Benvenuti S, Sartore-Bianchi A, Di Nicolantonio F, et al. Oncogenic activation of the RAS/RAF signalling pathway impairs the response of metastatic colorectal cancers to anti-epidermal growth factor receptor antibody therapies. Cancer Res. 2007; 67:2643-2648. 6. Vogelstein B, Fearon ER, Hamilton SR, et al. Genetic alterations during colorectal-tumor development. N Engl J Med. 1988; 319:525-532. 7. Andreyev HJ, Norman AR, Cunningham D, et al. Kirsten ras muta-
tions in patients with colorectal cancer: the multicenter “RASCAL” study. J Natl Cancer Inst. 1998;90:675-684. 8. Esteller M, Gonzalez S, Risques RA, et al. K-ras and p16 aberrations confer poor prognosis in human colorectal cancer. J Clin Oncol. 2001;19:299-304. 9. Bazan V, Agnese V, Corsale S, et al. Specific TP53 and/or Ki-ras mutations as independent predictors of clinical outcome in sporadic colorectal adenocarcinomas: results of a 5-year Gruppo Oncologico dell’Italia Meridionale (GOIM) prospective study. Ann Oncol. 2005;16(suppl 4):iv50-iv55. 10. Amado RG, Wolf M, Peeters M, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 2008;26:1626-1634. 11. Fransén K, Klintenäs M, Osterström A, et al. Mutation analysis of the BRAF, ARAF and RAF-1 genes in human colorectal adenocarcinomas. Carcinogenesis. 2004;25:527-533. 12. De Roock W, Piessevaux H, De Schutter J, et al. KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab. Ann Oncol. 2008;19:508-515.
13. Di Fiore F, Blanchard F, Charbonnier F, et al. Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by cetuximab plus chemotherapy. Br J Cancer. 2007;96:1166-1169. 14. Andreyev HJ, Ross PJ, Cunningham D, Clarke PA. Antisense treatment directed against mutated Ki-ras in human colorectal adenocarcinoma. Gut. 2001;48:230-237. 15. Bleeker WA, Hayes VM, Karrenbeld A, et al. Impact of KRAS and TP53 mutations on survival in patients with left- and right-sided Dukes’ C colon cancer. Am J Gastroenterol. 2000;95:2953-2957. 16. Frattini M, Saletti P, Romagnani E, et al. PTEN loss of expression predicts cetuximab efficacy in metastatic colorectal cancer patients. Br J Cancer. 2007;97:1139-1145. 17. Khambata-Ford S, Garrett CR, Meropol NJ, et al. Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. J Clin Oncol. 2007;25:3230-3237. 18. Sartore-Bianchi A, Martini M, Molinari F, et al. PIK3CA mutations in colorectal cancer are associated with clinical resistance to EGFR-targeted monoclonal antibodies. Cancer Res. 2009;69: 1851-1857.
CommEntary KRAS and Colorectal Cancer: A Nurse’s Perspective BY SANDRA E. KURTIN, RN, MS, AOCN, ANP-C Arizona Cancer Center and University of Arizona, Tucson
he search for the silver bullet in cancer treatment has long been the elusive coup de grâce. We envision a time when treatments are selected based on clearly defined targets with little or no collateral damage. With the advent of molecular profiling and advanced tissue analysis, which can identify key components of signaling pathways, we are moving toward this future. Signaling pathways are present in both normal and abnormal cellular function and provide attractive targets for manipulation of abnormal pathways. Inhibition of the epidermal growth factor receptor (EGFR) and its downstream pathways using targeted monoclonal antibodies has provided a unique treatment strategy in patients with colorectal cancer. EGFR upregulation is present in 25% to 80% of colorectal cancers, making it an attractive target.1 Blocking EGFR pathways may interrupt the pathologic effects of EGFR overexpression, including cell cycle progression, apoptosis, angiogenesis, tumor cell motility, and metastasis.2 Recently, the role of the Ras/Raf/mitogen-activated protein kinase pathway has elucidated the critical role of the Ras oncogene in colorectal tumorigenesis and response to EGFR-inhibiting agents.3 KRAS, an intracellular signal transducer, is the gene that codes for the Ras signaling pathway. Mutations in KRAS are present in approximately 40% of colorectal tumors, with a high concordance (90%) between primary and metastatic sites at the time of diagnosis.4 KRAS mutations are thought to alter protein activity, leading to unregulated cellular proliferation and malignant transformation.5 KRAS mutations in codon 12 and 13 have been extensively analyzed in phase 2 and 3 clinical trials using EGFR inhibitors either as monotherapy or in combination with other agents.3,6-8 In all studies, patients with KRAS mutations did not derive benefit from treatment with EGFR-inhibiting monoclonal antibodies (cetuximab
and panitumumab). Despite the retrospective and subset-analysis techniques used in the majority of these studies, the strength of the data has been largely undisputed by clinicians. As a result of these studies, the American Society of Clinical Oncology (ASCO) issued a Provisional Clinical Opinion7: “Based on systematic reviews of the relevant literature, all patients with metastatic colorectal carcinoma who are candidates for antiEGFR antibody therapy should have their tumor tested for KRAS mutations in a [Clinical Laboratory Improvement Amendments] CLIA-accredited laboratory, according to ASCO. If KRAS mutation in codon 12 or 13 is detected, then patients with metastatic colorectal carcinoma should not receive anti-EGFR antibody therapy as a part of their treatment.” Importantly, the group did offer qualifications that KRAS mutational status has not been validated as a prognostic factor in the analyzed studies. [Editor’s note: On July 17, 2009, the US Food and Drug Administration approved class labeling changes to cetuximab and panitumumab, noting that these agents are not recommended for treatment of colorectal cancer with KRAS mutations in codons 12 and 13.] These findings have changed the treatment paradigm for colorectal cancer, mandating comprehensive and accurate tissue testing at the time of diagnosis for all newly diagnosed colorectal cancers, testing of existing tissue blocks for those who have recurrent or progressive disease when testing has not already been done, and effectively eliminating a treatment option for a large number of patients with metastatic disease who test positive for the KRAS mutation. The mandate for clinicians and researchers is clear: We must work diligently to enroll patients in clinical trials that may provide new treatment options for this disease. Proactive and aggressive management of disease and treatment-related toxicities is essential to optimal clinical outcomes and necessary to avoid the
elimination of future treatment options because of residual toxicities or secondary organ damage. This applies to effective management of EGFR inhibitor– associated toxicities for those patients who are fortunate enough to have KRAS wild-type tumors. Strategies for evaluation of treatment response and grading of toxicities will need to be refined to avoid premature discontinuation of therapies. Analysis of the sequencing of the seven commonly used US Food and Drug Administration–approved agents for this disease may be required to achieve optimal outcomes with the limited treatment options for metastatic colorectal cancer. Personalized medicine through molecularly driven treatment selection is definitely a double-edged sword.
1. Cunningham D, Humbelet Y, Sienna S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in Irinotecanrefractory metastatic colorectal cancer. N Engl J Med. 2004;351:337-345. 2. Probeska I, Harlozinska A, Bojarowski T. Expression of the tyrosine kinase activity growth factor receptors (EGFR, ERB B2, ERB B3) in colorectal adenocarcinomas and adenomas. Tumour Biol. 2000;21:105-115. 3. Karapetis C, Khambata-Ford S, Jonker D, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008;359:1757-1765. 4. Santini D, Loupakis F, Vincenzi B, et al. High concordance of KRAS status between primary colorectal tumors and related metastatic sites: implications for clinical practice. Oncologist. 2008;13:1270-1275. 5. McDermott U, Longley DB, Johnston PG. Molecular and biochemical markers in colorectal cancer. Ann Oncol. 2002;13 (suppl 4):235-245. 6. Lièvre A, Bachet JB, Boige V, et al. KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol. 2008;26:374-379. 7. Allegra C, Jessup JM, Somerfield M. American Society of Clinical Oncology Provisional Clinical Opinion: testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy. J Clin Oncol. 2009; 27:2091-2096. 8. Jimeno A, Messersmith W, Hirsch F, et al. KRAS mutations and sensitivity to epidermal growth factor receptor inhibitors in colorectal cancer: practical application of patient selection. J Clin Oncol. 2009;27:1130-1136.
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ONCOLGY DRUG CODES
Oncology Drug Codes Medications Used for the Treatment of Breast Cancer The following sections include: • Associated ICD-9-CM codes used for the classification of breast cancer • Drugs that have been FDA-approved in breast cancer. Please note: if a check mark appears in the FDA column it will NOT appear in the Compendia section even if a drug is included in the NCCN (National Comprehensive Cancer Network) Drugs & Biologics Compendium • Drugs included in the NCCN Drugs & Biologics Compendium for off-label use in breast cancer. NCCN is recognized by the Centers for Medicare & Medicaid Services (CMS) as a referencing source • Corresponding HCPCS/CPT codes and code descriptions • Current Code Price (AWP-based pricing) • Most recent ASP plus 6% (Medicare allowable) • Possible CPT Administration Codes for each medication.
Associated ICD-9-CM Codes Used for Breast Cancer 174
Malignant neoplasm of female breast Use additional code to identify estrogen-receptor status (V86.0, V86.1) Includes: breast (female) connective tissue soft parts Paget’s disease of: breast nipple Excludes: skin of breast (172.5, 173.5) 174.0 Nipple and areola 174.1 Central portion 174.2 Upper inner quadrant 174.3 Lower inner quadrant 174.4 Upper outer quadrant 174.5 Lower outer quadrant 174.6 Axillary tail 174.8 Other specified sites of female breast Ectopic sites Inner breast Lower breast Malignant neoplasm of contiguous or overlapping sites of breast whose point of origin cannot be determined Midline of breast Outer breast Upper breast 174.9 Breast (female), unspecified
175 Malignant neoplasm of male breast Use additional code to identify estrogen-receptor status (V86.0, V86.1) Excludes: skin of breast (172.5, 173.5) 175.0 Nipple and areola 175.9 Other and unspecified sites of male breast Ectopic breast tissue, male
FDAapproved for breast cancer
NCCN Drugs & Biologics Compendium off-label use for breast cancer
Current code price (AWP-based pricing), effective 10/1/09
Medicare allowable (ASP + 6%), effective 10/1/09-12/31/09
CPT administration codes
Generic (brand) name
HCPCS code: code description
J8999a: prescription drug, oral, chemotherapeutic, not otherwise specified S0170: anastrozole, oral, 1 mg
NDC level pricing $13.04
bevacizumab (Avastin) capecitabine (Xeloda) capecitabine (Xeloda) carboplatin (Paraplatin)
J9035: injection, bevacizumab, 10 mg J8520: capecitabine, oral, 150 mg J8521: capecitabine, oral, 500 mg J9045: injection, carboplatin, 50 mg
NDC level pricing S0170: not payable by Medicare $57.48
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96409, 96413, 96415
Generic (brand) name
HCPCS code: code description
cisplatin (Platinol AQ) cisplatin (Platinol AQ) cyclophosphamide oral (Cytoxan) cyclophosphamide injection (Cytoxan) cyclophosphamide injection (Cytoxan) cyclophosphamide injection (Cytoxan) docetaxel (Taxotere) doxorubicin HCl (Adriamycin) doxorubicin HCl liposome (Doxil)
J9060: cisplatin, powder or solution, per 10 mg J9062: cisplatin, 50 mg J8530: cyclophosphamide, oral, 25 mg J9090: cyclophosphamide, 500 mg J9091: cyclophosphamide, 1.0 g J9092: cyclophosphamide, 2.0 g J9170: injection, docetaxel, 20 mg J9000: injection, doxorubicin HCl, 10 mg J9001: injection, doxorubicin HCl, all lipid formulations, 10 mg J9178: injection, epirubicin HCl, 2 mg J8499a: prescription drug, oral, nonchemotherapeutic, not otherwise specified J8560: etoposide, oral, 50 mg J8999a: prescription drug, oral, chemotherapeutic, not otherwise specified S0156: exemestane, 25 mg
epirubicin (Ellence) estradiol (Estrace) etoposide (Vepesid) exemestane (Aromasin) exemestane (Aromasin) fluorouracil (Adrucil) fluoxymesterone (Androxy)
FDAapproved for breast cancer
J9190: injection, fluorouracil, 500 mg J8499a: prescription drug, oral, nonchemotherapeutic, not otherwise specified fulvestrant J9395: injection, (Faslodex) fulvestrant, 25 mg gemcitabine J9201: injection, (Gemzar) gemcitabine HCl, 200 mg goserelin acetate J9202: goserelin acetate implant, (Zoladex 3.6 mg ONLY) per 3.6 mg ixabepilone J9207: injection, (Ixempra) ixabepilone, 1 mg lapatinib ditosylate J8999a: prescription drug, (Tykerb) oral, chemotherapeutic, not otherwise specified letrozole J8999a: prescription drug, (Femara) oral, chemotherapeutic, not otherwise specified leuprolide (Eligard, J9217: leuprolide acetate Lupron Depot) (for depot suspension), 7.5 mg leuprolide J9218: leuprolide acetate, (Lupron) per 1 mg megestrol J8999a: prescription drug, (Megace) oral, chemotherapeutic, not otherwise specified
NCCN Drugs & Biologics Compendium off-label use for breast cancer
Current code price (AWP-based pricing), effective 10/1/09
Medicare allowable (ASP + 6%), effective 10/1/09-12/31/09
CPT administration codes
96409, 96413, 96415
96409, 96413, 96415
96409, 96413, 96415
96409, 96413, 96415
96409, 96413, 96415
NDC level pricing $47.64
NDC level pricing $0.46
NDC level pricing $12.38
NDC level pricing S0156: not payable by Medicare $1.52
96409, 96413 N/A
NDC level pricing $96.33
NDC level pricing $82.18
NDC level pricing NDC level pricing $352.56
NDC level pricing NDC level pricing $214.57
NDC level pricing
NDC level pricing
ONCOLGY DRUG CODES
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ONCOLGY DRUG CODES
FDAapproved for breast cancer
NCCN Drugs & Biologics Compendium off-label use for breast cancer
Current code price (AWP-based pricing), effective 10/1/09
Medicare allowable (ASP + 6%), effective 10/1/09-12/31/09
CPT administration codes
Generic (brand) name
HCPCS code: code description
S0179: megestrol acetate, oral, 20 mg
J8610: methotrexate, oral, 2.5 mg J9250: methotrexate sodium, 5 mg J9260: methotrexate sodium, 50 mg J9264: injection, paclitaxel protein-bound particles, 1 mg J9265: injection, paclitaxel, 30 mg J7506: prednisone, oral, per 5 mg J8999a: prescription drug, oral, chemotherapeutic, not otherwise specified S0187: tamoxifen citrate, oral, 10 mg
S0179: not payable by Medicare $0.12
96372, 96374, 96401, 96409, 96450 96372, 96374, 96401, 96409, 96450 96413
NDC level pricing $138.00
NDC level pricing S0187: not payable by Medicare NDC level pricing $99.57
NDC level pricing $74.49
NDC level pricing $64.73
methotrexate sodium methotrexate sodium paclitaxel (Abraxane) paclitaxel (Taxol) prednisone tamoxifen (Nolvadex) tamoxifen (Nolvadex) testolactone (Teslac) thiotepa (Thiotepa) toremifene citrate (Fareston) trastuzumab (Herceptin) vinBLAStine vinorelbine (Navelbine)
J8999a: prescription drug, oral, chemotherapeutic, not otherwise specified J9340: injection, thiotepa, 15 mg J8999a: prescription drug, oral, chemotherapeutic, not otherwise specified J9355: injection, trastuzumab, 10 mg J9360: injection, vinblastine sulfate, 1 mg J9390: injection, vinorelbine tartrate, per 10 mg
NDC level pricing $1.89
51720, 96409 N/A
billing a nonclassified medication using a CMS 1500 claim form you must include both the HCPCS code (ie, J8999 for tamoxifen) in Column 24D and the drug name, strength, and National Drug Code (NDC) in Box 19 in order to ensure appropriate reimbursement. References • HCPCS Level II Expert, 2009 • CPT 2009; 2008 • ICD-9-CM for Professionals Volumes 1 & 2; 2009 • The Drug Reimbursement Coding and Pricing Guide, Vol 6, No 4; RJ Health Systems International LLC; 4th Quarter 2009 • FDA-approved indication (from products’ prescribing information) • NCCN • National Cancer Institute • www.ReimbursementCodes.com powered by RJ Health Systems International, LLC, Wethersfield, Connecticut • CMSMedicare allowable 4th Quarter 2009 (effective dates 10/1/09-12/31/09). Prices listed herein are effective as of October 1, 2009. ASP indicates average sales price; AWP, average wholesale price; CMS, Centers for Medicare & Medicaid Services; CPT, Current Procedural Terminology; FDA, US Food and Drug Administration; G-CSF, granulocyte-colony stimulating factor; GM-CSF, granulocyte macrophage-colony stimulating factor; HCPCS, Healthcare Common Procedure Coding System; NCCN, National Comprehensive Cancer Network.
This information was supplied by:
MORE ONCOLOGY DRUG CODES ONLINE Chemotherapy-induced anemia Chemotherapy-induced nausea and vomitting Chemotherapy-induced neutropenia
PO BOX 290616, Wethersfield, CT 06109 T: (860) 563-1223 • F: (860) 563-1650 • www.RJHealthSystems.com
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www.theoncologypharmacist.com September/October 2009
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Presents The Second Annual 2009 Curriculum for
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, are pleased to offer your multidisciplinary cancer team with this series of newsletters focusing on the challenges in treating patients with multiple myeloma.
SAGAR LONIAL, MD Associate Professor of Hematology and Oncology Emory University
# Earn Continuing Education Credits # Eight part newsletter series
CLINICAL TOPICS: • Retreatment Settings • Maintenance Therapy • Do CRs Correlate with Clinical Benefit?
• Perspectives on Relevant Endpoints of Clinical Trials • Stem Cell Mobilization • Cytogenic Testing in the MM Patient
• To Transplant or Not to Transplant…That is the Question • Sequencing Strategies in MM: Treatment with Case Studies
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• Continuing Education credits available to physicians, pharmacists, and nurses
PARTICIPATE TODAY at www.COEXM.com Stem Cell Mobilization Statement of Need The purpose of this activity is to enhance knowledge concerning the treatment of patients with multiple myeloma (MM). Target Audience This activity was developed for physicians, nurses, and pharmacists. Learning Objectives At the completion of this activity participants should be able to: • Explain how various agents and combination regimens used in induction regimens for multiple myeloma (MM) may affect stem cell mobilization • Describe the safety and efficacy of standard agents used for stem cell mobilization in patients with MM • Interpret data from clinical trials evaluating novel approaches to stem cell mobilization as reported at the 2008 ASH meeting Physician Accreditation This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Global Education Group (Global) and Medical Learning Institute, Inc. (MLI). Global is accredited by the ACCME to provide continuing medical education for physicians.
Physician Credit Designation Global Education Group designates this educational activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity. Registered Nurse Designation Medical Learning Institute, Inc. Provider approved by the California Board of Registered Nursing, Provider 15106, for 1.0 contact hour. Registered Pharmacy Designation MLI is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. Completion of this activity provides for 1.0 contact hour (0.1 CEU) of continuing education credit. The universal program number for this activity is 468-999-09-027-H01-P. Agenda: 1 hour Articles/Commentaries: 45 minutes Evaluation/Posttest: 15 minutes Date of original release: August 31, 2009 Valid for CME credit through: August 31, 2010
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Clinical Pharmacy Review Ixabepilone: A New Treatment for Metastatic Breast Cancer BY timothy tyler, pharmd, fcshp COMPREHENSIVE CANCER CENTER, DESERT REGIONAL MEDICAL CENTER, PALM SPRINGS, CALIFORNIA
axanes are currently among the most active agents available to treat metastatic breast cancer (MBC), achieving typical response rates between 60% and 65% when combined with an anthracycline in the first-line setting.1-5 A proportion of patients will have inherent resistance to taxanes, however, and all patients will eventually progress after treatment.6 The epothilones, a novel class of antineoplastic agents, have a lower susceptibility to multiple mechanisms of drug resistance.7-9 Ixabepilone, a semisynthetic analog of the natural product epothilone B, has a chemical structure (a macrolide antibiotic 15-membered ring) and a tubulin-binding mode that are distinct from those of the taxanes. Like the taxanes, ixabepilone stabilizes
microtubular structures, resulting in mitotic arrest and apoptosis, but ixabepilone is more potent than paclitaxel in inducing in vitro tubulin polymerization,7,10 and it shows a low susceptibility to tumor mechanisms of resistance in vitro and in vivo, demonstrating antitumor activity in tumor cells with intrinsic or acquired taxane resistance.7-9,11 Ixabepilone’s activity in chemoresistant cells is one reason that this drug is so intriguing. Tumors frequently express higher levels of multidrug-resistant proteins, such as P-glycoprotein and multidrug-resistant protein 1. These transport proteins pump the chemotherapeutic agent out of the cell, inhibiting the drug’s cytotoxic ability. A large number of cytotoxic agents are highly susceptible to this resistance
mechanism, including anthracyclines, taxanes, vinca alkaloids, and topoisomerase-1 inhibitors. In contrast, epothilones such as ixabepilone have low susceptibility for the proteins responsible for this multidrug-resistant phenotype.7-9 Furthermore, overexpression of class III tubulin does not affect the activity of ixabepilone.11,12 The strong preclinical data supporting the use of ixabepilone have been confirmed clinically in patients with MBC.13-18 Ixabepilone, as a single agent or in combination with the oral fluoropyrimidine capecitabine, has demonstrated clinical efficacy across the spectrum of advanced breast cancer, including patients with disease that has progressed after anthracycline and/or taxane treatment. In taxane-resistant
Table 1. Dosing Schedules, DLTs, and MTD of Ixabepilone in Phase 1 Dose-finding Studies in Patients with a Range of Advanced Tumors Dosing schedule 2
1.5 mg/m to 14 mg/m daily, by 1-hour infusion for 5 consecutive days
Grade 4 neutropenia at 8 mg/m
6 mg/m2 by 1-hour infusion for 5 consecutive days
1 mg/m2 to 30 mg/m2 by 30-minute infusion each week on a continuous 21-day cycle
Grade 3 fatigue at 30 mg/m2
25 mg/m2 by 30-minute infusion each week on a continuous 21-day cycle
15 mg/m2 to 25 mg/m2 by 60-minute infusion each week for 3 weeks followed by a 1-week break in treatment
No DLTs observed; however, cumulative neurotoxicity was reported with 25 mg/m2
20 mg/m2 by 60-minute infusion each week for 3 weeks followed by a 1-week break
7.4 mg/m2 to 59.2 mg/m2 by 3-hour infusion every 3 weeks
Grade 4 neutropenia, febrile neutropenia, grade 3 fatigue at 50 mg/m2
40 mg/m2 by 3-hour infusion every 3 weeks
7.4 mg/m2 to 59.2 mg/m2 by 3-hour infusion every 3 weeks
Grade 4 neutropenia, neutropenic sepsis at 50 mg/m2
40 mg/m2 by 3-hour infusion every 3 weeks
7.4 mg/m2 to 65 mg/m2 by 1- or 3-hour infusion every 3 weeks
1-hour infusion: febrile neutropenia, neutropenia, myalgia/arthralgia, fatigue, nausea, vomiting, stomatitis/pharyngitis, sensory neuropathy at doses >50 mg/m2
50 mg/m2 by 1-hour infusion every 3 weeksa
3-hour infusion: anorexia, diarrhea, mucositis, depressed level of consciousness, infection with neutropenia, stomatitis/pharyngitis, myalgia at 40-mg/m2 or 50-mg/m2 doses DLTs indicates dose-limiting toxicities; MTD, maximum tolerated dose. aWhen this schedule was used as the starting dose in phase 2 trials, the dose was amended to 40 mg/m2 over 3 hours on the basis of early safety results. Sources: References 21-25.
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patients, ixabepilone has achieved response rates of 12% (single agent) and 35% (with capecitabine), median time to progression ranging from 2 to 6 months.13-18 Furthermore, in a phase 3 trial (n = 752) the addition of ixabepilone to capecitabine significantly prolonged progression-free survival (PFS) compared with capecitabine alone in patients with anthracycline- and taxane-resistant MBC (5.8 months vs 4.2 months; P <.0001).13 Ixabepilone has also demonstrated antitumor activity in patients with triple-negative breast tumors17—those not characterized by estrogen, progesterone, or overexpressed human epidermal growth factor receptor type 2 (HER2) receptors. Because endocrine therapies and anti-HER2 manipulations are ineffective in this subgroup, historically these patients have been difficult to treat successfully. Before the approval of ixabepilone, capecitabine was the only US Food and Drug Administration–approved agent for MBC after failure of anthracycline and taxane therapy. Clinical data supporting the use of ixabepilone have led to its approval in combination with capecitabine for the treatment of patients with locally advanced or MBC that is resistant to treatment with an anthracycline and a taxane, or for those whose cancer is taxane-resistant, and for whom further anthracycline therapy is contraindicated. Ixabepilone is also approved as monotherapy for the treatment of locally advanced or MBC in patients whose tumors are resistant or refractory to anthracyclines, taxanes, and capecitabine.19 This article provides dosage and administration guidelines for ixabepilone in patients with advanced breast cancer, and it highlights specific considerations for using this drug, including adverse events, special patient groups that require dosage adjustment, and circumstances in which the drug is contraindicated.
Ixabepilone dosing The recommended dosage of ixabepilone is 40 mg/m2 administered intravenously (IV) over 3 hours every 3 weeks.19 For patients with a body surface area (BSA) exceeding 2.2 m2, dose-capping at a BSA of 2.2 m2 is recommended.
When used in combination with capecitabine, the dose of ixabepilone is the same as it is in monotherapy (40 mg/m2), administered IV on day 1 of a 21-day cycle, with capecitabine 2000 mg/m2 administered orally as two divided doses on days 1 through 14 of the 21-day cycle.13 The capecitabine dosage is based on recommendations from the capecitabine prescribing information20; however, clinicians should rely on their own experience to
determine whether the dose is appropriate in individual situations.
Dose-finding studies The optimal dosing schedule of single-agent ixabepilone was derived from several phase 1 studies in patients with a range of tumor types (Table 1).21-25 These studies established a dose of 6 mg/m2 daily for 5 continuous days every 21 days.15 Phase 2 testing also established a dose of 50 mg/m2 by 1-hour
Table 2. Common Hematologic and Nonhematologic Adverse Events Occurring with Ixabepilone Treatment in Patients with Metastatic Breast Cancer
infusion every 3 weeks in MBC.14,18 Based on these phase 2 results, the manufacturer’s recommended dose was changed to 40 mg/m2 by 3-hour infusion every 3 weeks to minimize neurotoxicity, myelosuppression, and mucositis.19 Pharmacokinetic properties The elimination half-life of ixabepilone 40 mg/m2 after a 3-hour infusion in patients with advanced cancer is 52 hours, and the mean volume of distri-
bution is 1844 L.26 Pharmacokinetic analyses indicate that no plasma accumulation occurs when ixabepilone is administered on a 3-weekly schedule. No active metabolites of ixabepilone have been identified. Compared with values when administered separately, coadministration of ixabepilone with capecitabine results in a decreased maximum plasma concentration and Continued on page 28
Table 3. Ixabepilone Dose-adjustment Guidelines Adverse event Nonhematologic
Nonhematologic events occurring in ≥20% of patients • Peripheral sensory neuropathy • Vomiting
Grade 2 neuropathy (moderate) lasting ≥7 days
Decrease dose by 20%
Decrease dose by 20%
Grade 3 neuropathy (severe) lasting <7 days
• Musculoskeletal pain
Grade 3 neuropathy (severe) lasting ≥7 days or disabling neuropathy
Any grade 3 toxicity (severe) other than neuropathy
Decrease dose by 20%
Transient grade 3 myalgia/arthralgia or fatigue
No change in dose
• Abdominal pain
Grade 3 palmar-plantar erythrodysesthesia syndrome
No change in dose
• Nail disorder
Any grade 4 toxicity (disabling)
• Nausea Additional reactions in combination treatment: • Palmar-plantar erythrodysesthesia syndrome • Anorexia
• Constipation Hematologic abnormalities occurring in >40% of patients • Neutropenia • Leukopenia • Anemia • Thrombocytopenia
Hematologic Neutrophil <500 cells/mm3 for ≥7 days
Decrease dose by 20%
Decrease dose by 20% 3
Platelets <25,000/mm or platelets <50,000/mm3 with bleeding
Decrease dose by 20%
Source: Reference 19.
Commentary Ixabepilone: A Physician’s Perspective BY DENISE A. YARDLEY, MD Sarah Cannon Research Institute, Nashville, Tennessee
nvestments made in breast cancer research over the past 35 years have translated into significant advances in treatment. Ixabepilone is a novel microtubulin-stabilizing agent with documented clinical efficacy in advanced breast cancer. Its safety profile has been well characterized, and dose modifications have been shown to be effective managing commonly encountered toxicities. Its differential binding to β-tubulin may explain its activity in tumors generally refractory to taxanes as well as its activity in tumors that develop resistance to them. In fact, ixabepilone’s low susceptibility to resistance mechanisms, such as overexpression of the P-glycoprotein or multidrug resistance that frequently compromise the activity of the taxanes as well as other chemotherapeutic agents, has resulted in great excitement and enthusiasm regarding ixabepilone’s role in breast cancer. Generally well tolerated, ixabepilone’s most limiting toxicities are neutropenia and cumulative neu-
ropathy. The majority of the adverse events are mild to moderate, manageable, and do not result in notable dose reductions or discontinuation of therapy. In fact, in previously untreated breast cancer patients treated with four cycles of neoadjuvant ixabepilone, only a 3% incidence of grade 3/4 peripheral neuropathy and only a 1% incidence of sensory neuropathy were reported.1 Ixabepilone activity in this earlier disease setting was also remarkable with an 18% rate of pathologic complete response (pCR) for all patients and a 26% pCR rate in triple-negative patients. This level of demonstrated single-agent activity in the neoadjuvant setting is largely unmatched by other agents. Evidence of ixabepilone’s retained activity against tumor cells that overexpress the class III β-tubulin isotype, a critical determinant of primary taxane resistance, is of increasing importance. In view of the fact that up to 60% of triple-negative breast cancers demonstrate overexpression of β-tubulin III, ixabepilone’s role in this poor-prognosis breast cancer sub-
type has generated great interest. In further support of this, retrospective subset analyses of this poorprognosis breast cancer subtype treated with ixabepilone in other trials have confirmed ixabepilone’s remarkable activity in these patients. As a result of these findings, the Sarah Cannon Research Institute has designed and launched an ongoing national trial known as the TITAN trial (Trial of Ixabepilone vs Taxol in Adjuvant Triple Negative Breast Cancer) in early-stage, triple-negative breast cancer. This study will not only explore ixabepilone’s role in the adjuvant setting but also the role of β-tubulin III expression in treatment outcomes. The identification of this novel new class of chemotherapy agents promises to improve outcomes for patients with breast cancer.
Reference 1. Baselga J, Zambetti M, Llombart-Cussac A, et al. Phase II genomics study of ixabepilone as neoadjuvant treatment for breast cancer. J Clin Oncol. 2009;27:526-534.
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Ixabepilone: A New Treatment Continued from page 27 and nonhematologic toxicities have resolved or improved to grade 1 (mild).
Table 4. Ixabepilone Dose-adjustment Guidelines for Patients with Hepatic Impairment
Ixabepilone dose, mg/m2
AST and ALT ≤2.5 x ULN
≤1 x ULN
AST and ALT ≤10 x ULN
≤1.5 x ULN
AST and ALT ≤10 x ULN
>1.5 x ULN to ≤3 x ULN
ALT indicates alanine aminotransferase; AST, aspartate aminotransferase; ULN, upper limit of normal. Source: Reference 19.
area-under-the-curve (AUC) for both ixabepilone (by 19% and 6%, respectively) and capecitabine (by 27% and 5%, respectively).26 These reductions are considered minor and are unlikely to alter the safety profile or efficacy of either drug.26
Other formulations in development An oral formulation of ixabepilone has been developed and is currently undergoing phase 1 evaluation, either as a daily dose given on 5 consecutive days every 21 days (Clinical Trial No. NCT00422097) or as three doses, each separated by 6 hours every 21 days (Clinical Trial No. NCT00632424). Final results from these studies are expected in 2009 and 2010, respectively.
As with paclitaxel, polyoxyethylated castor oil (Cremophor EL) is used in the current ixabepilone formulation to improve its solubility, although the amount of Cremophor EL in a 40-mg/m2 dose of ixabepilone is less than that found in a 175-mg/m2 dose of paclitaxel.26 Because the alcohol in Cremophor EL has the potential to induce hypersensitivity reactions, the safety and tolerability of a Cremophor EL–free ixabepilone formulation (infused over 24 hours) is being evaluated in a phase 1 trial in patients with solid malignancies (Clinical Trial No. NCT00162136). The study’s final data-collection date for primary outcome measures was July 2008.
Recommended dose adjustments Adverse events Table 2 summarizes common nonhematologic and hematologic adverse reactions, occurring in ≥20% and >40% of patients treated with ixabepilone, respectively. Dose reduction and delay are the most effective tools in managing ixabepilone toxicity. If toxicities are present, treatment should be delayed to allow recovery.19 Recommended dose adjustments are summarized in Table 3 and should be based on nonhematologic toxicity or blood counts from the preceding cycle. Patients should not begin a new cycle of treatment unless their neutrophil count is ≥1500 cells/mm3, platelet count is ≥100,000 cells/mm3,
Peripheral sensory neuropathy Peripheral sensory neuropathy is a common reason for ixabepilone dose reduction and/or delay, and is the most frequent drug-related cause of treatment discontinuation (approximately 10% of patients). In clinical trials, peripheral neuropathy has primarily been mild to moderate in severity and occurs early in treatment, with approximately 75% of new-onset or worsening neuropathy reported during the first three to four treatment cycles.13-18 With appropriate dose modifications and discontinuations, peripheral neuropathy is mostly reversible within an acceptable timeframe (median time required for resolution to baseline or grade 1 was 6 weeks with combination therapy and 4.6 weeks with monotherapy). It is important to note that all the patients in both the monotherapy and capecitabine combination trials with ixabepilone were heavily pretreated, and a number of the patients had baseline neuropathy from prior therapy. It is not yet clear what the incidence and severity of neuropathy with ixabepilone will be in patients who are not as heavily pretreat-
Commentary Ixabepilone: A Nurse’s Perspective BY CYNTHIA FRANKEL, RN, OCN Memorial Cancer Institute, Hollywood, Florida
s we progress in the treatment of both earlyand late-stage breast cancers, we continue our vigilance to identify niche phenotypes and apply specific, individualized strategies that prove to be effective and well-tolerated. We have made great strides in the treatment of metastatic, endocrinesensitive breast cancer by strategically positioning various treatment options, including aromatase inhibitors, antiestrogens, and estrogen downregulators, before moving into cytotoxic regimens. We have advanced the treatment of human epidermal growth factor receptor type 2 (HER2)-positive disease, from the metastatic to the adjuvant setting with expansive improvements in disease-free and overall survival, to the point where accruing to metastatic HER2-positive trials has become increasingly difficult. Metastatic trials using combinations of trastuzumab and lapatinib are providing increasingly long-term visceral control as we continue to seek the same control in the central nervous system. The first large-scale adjuvant trials in triple-negative breast cancer are under way, in hopes of identifying a potent and effective combination that will yield the same successes we have seen in other settings. The review by Tyler exemplifies the challenges inherent in finding an effective therapy in the
advanced-disease setting, when most patients diagnosed with early-stage breast cancer, in particular triple-negative disease, have already been exposed to at least an anthracycline and a taxane. The art is in controlling advanced disease with the most effective and least toxic therapy to maintain long-term control and quality of life—when feasible, using single agents in an effort to extend time and fight resistance while managing toxicity. With its novel mechanism of action, specifically its decreased susceptibility to drug resistance, as well as unique properties that differentiate it from the first generation of taxanes, ixabepilone lends itself to this setting and is strategically applicable as both a single agent and in combination with capecitabine. The success of the therapy will depend on the selection of the correct patients, with careful proactive surveillance whether using ixabepilone as a single agent or in combination with capecitabine. Nursing interventions include, at the onset of each cycle, monitoring the patient’s hemagram and, when used in combination with capecitabine, assuring that neutrophil levels are ≥1500 cells/mm3 and biochemical profiles of aspartate aminotransferase or alanine aminotranferase are <2.5 times the upper limit of normal (ULN) or bilirubin <1 × ULN.1 When used as a single agent, the dose of ixabepi-
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lone should be reduced to 20 mg/m2 at treatment onset for patients with moderate hepatic impairment, with subsequent dosing based on liver enzymes.2 As with many new drugs, concomitant medications must be frequently assessed, and any strong CYP3A4 inhibitors must be identified and avoided.2 Adequate premedication must be used to avoid hypersensitivity reactions.2 Neurotoxicity must be monitored throughout the course of treatment, and appropriate drug reductions or delays must be made as required to prevent neuropathy.2 Cardiac history must be part of the initial assessment because arrhythmias have been observed in patients receiving combination therapy.2 New treatment options for advanced breast cancer allow for a wider selection of non–cross-resistant therapies. Careful evaluation and attentive monitoring to avoid toxicity will serve the patient well. Patients with metastatic breast cancer have new treatment options that can contribute to successful management of their disease and maintain their quality of life.
References 1. Bristol-Myers Squibb Research and Development. Ixabepilone (BMS-247550). Bristol-Myers Squibb Investigator Brochure 2007. 2. Ixempra Kit (ixabepilone) [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2007.
ed with other agents that also cause peripheral neuropathy. In terms of management, a 20% reduction in dose is recommended for patients with grade 2 neuropathy lasting â‰Ľ1 week, or for any grade 3 neuropathy. Treatment should be discontinued in patients with grade 3 neuropathy lasting >1 week, or with any report of disabling neuropathy (Table 3). Because diabetes mellitus is associated with neuropathy, patients with diabetes receiving ixabepilone therapy may be at increased risk for severe neuropathy and should be managed aggressively. Myelosuppression Myelosuppression with ixabepilone is dose-dependent and primarily manifests as neutropenia. In clinical trials, grade 4 neutropenia (<500 cells/mm3) has been reported in 36% of patients given ixabepilone/capecitabine combination therapy and in 23% of patients given ixabepilone monotherapy.13,17 Patients experiencing severe neutropenia or thrombocytopenia should have their dose reduced (Table 3), and ixabepilone should not be administered to patients with a neutrophil count <1500 cells/mm3. Hypersensitivity In clinical studies, hypersensitivity occurred in 1% (9/1323) of ixabepilonetreated patients19; therefore, patients with a history of severe hypersensitivity to agents containing Cremophor EL or its derivatives (ie, polyoxyethylated castor oil) should not be treated with ixabepilone. All patients should be premedicated with an H1 and an H2 antagonist approximately 1 hour before ixabepilone infusion and observed for hypersensitivity reactions (eg, flushing, rash, dyspnea, and bronchospasm). In contrast to taxane therapy, however, corticosteroid premedication is not mandatory in all patients; those who experience a hypersensitivity reaction in one cycle of ixabepilone should be premedicated in subsequent cycles with a corticosteroid, in addition to the H1 and H2 antagonists, and a longer infusion time should be considered. If severe hypersensitivity reactions occur, ixabepilone infusion should be stopped and aggressive supportive treatment (eg, epinephrine, corticosteroids, and/or diphenhydramine) initiated. Cardiac events The frequency of cardiac adverse reactions was higher when ixabepilone was administered in combination with capecitabine compared with capecitabine alone.19 Caution should be exercised when administering ixabepilone in patients with a history of cardiac disease, and treatment discontinuation should be considered in patients who develop cardiac ischemia or impaired cardiac function.
by the liver through the CYP3A4 system, nia-related death. Monotherapy in so patients with existing hepatic impair- patients with AST or ALN >10 Ă— ULN ment should receive a modified dose or bilirubin >3 Ă— ULN is not recom(Table 4).19 These patients are at greater mended. Furthermore, because limited risk of toxicity as a result of their data are available for patients with AST increased exposure to ixabepilone during or ALT >5 Ă— ULN, caution should be treatment (increased 22%, 30%, and used when treating these patients. The pharmacokinetic properties of 81% in patients with mild, moderate, and severe hepatic impairment, respective- ixabepilone do not appear to be affectly).26 Ixabepilone/capecitabine combina- ed by age, gender, or mild renal impairtion therapy is contraindicated in ment.26 However, data are not availpatients with aspartate aminotransferase able in patients <18 years old or those (AST) or alanine aminotranferase (ALT) with moderate or severe renal impair>2.5 times the upper limit of normal ment. In addition, no adequate studies (ULN) or bilirubin >1 Ă— ULN, because of have addressed how ixabepilone be in pregnant women, so women increased risk of toxicity and neutropehaves
should be advised of a potential fetal risk associated with treatment. Although there appear to be no pharmacokinetic differences according to ethnicity,26 subgroup analysis of the ixabepilone/capecitabine phase 3 study suggests that addition of ixabepilone to capecitabine may reduce PFS in African-American patients.13 However, patient numbers were too low to have statistical validity and, until further data are collected and analyzed, no definitive conclusions can be made regarding the effect of ethnicity or race on ixabepilone efficacy. Continued on page 30
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Special patient populations Ixabepilone is extensively metabolized
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Ixabepilone: A New Treatment Continued from page 29 Table 5. Concomitant Therapy to Be Avoided with Ixabepilone, If Possiblea Drug class CYP3A4 inducers
Strong CYP3A4 inhibitors
Common examples • Carbamazepine • Dexamethasone • Phenobarbital • Phenytoin • Rifampin • St. John’s wort • Amprenavir • Atazanavir • Clarithromycin • Delavirdine • Grapefruit juice • Indinavir • Itraconazole • Ketoconazole • Nefazodone • Nelfinavir • Ritonavir • Saquinavir • Telithromycin • Voriconazole
If not possible, a 50% dose reduction of ixabepilone is warranted. A 1-week washout period of the strong inhibitor is all that is required to return to full dosing at 40 mg/m2.
Source: Reference 19.
Drug interactions Because CYP3A4 and CYP3A5 are the main enzymes responsible for the oxidative metabolism of ixabepilone, concomitant use of agents that either induce or inhibit CYP3A4 should be avoided if possible19,27 (Table 5). If concomitant strong CYP3A4 inhibitor use is unavoidable, a 50% dose reduction (20 mg/m2) administered at the same 3-week intervals is predicted to adjust the ixabepilone AUC to the range observed without inhibitors. If the inhibitor is discontinued, a washout period of approximately 1 week should be allowed before adjusting to the indicated dose of ixabepilone. Contraindications Patients with a known severe hypersensitivity to Cremophor EL (National Cancer Institute Common Toxicity Criteria grade 3 or 4), a neutrophil count <1500 cells/mm3, or platelet count <100,000 cells/mm3 should not receive ixabepilone. As previously mentioned, patients with an AST or ALT >2.5 × ULN or bilirubin >1 × ULN must not be treated with ixabepilone in combination with capecitabine.19
Considerations for administration of ixabepilone in clinical practice Ixabepilone for IV administration is supplied in a two-vial system consisting of a sterile, lyophilized white powder in 30
single-use 15-mg and 45-mg vials; and a diluent, provided as a 50/50 vol/vol solution of purified polyoxyethylated castor oil (purified Cremophor EL) and dehydrated alcohol. The vials should be refrigerated for storage and brought to room temperature for approximately 30 minutes before constitution. The reconstituted ixabepilone is 2 mg/mL and may be stored at room temperature and room light for a maximum of 1 hour (but not in the syringe, because of concerns about leaching plastic from a di[2-ethylhexy]phthalate [DEHP]-containing syringe). Before administration, the solution should be further diluted with lactated Ringer’s injection (LRI), USP (or equivalent LRI with a pH range of 6.07.5) to a final ixabepilone concentration ranging from 0.2 mg/mL to 0.6 mg/mL. DEHP-free infusion containers and administration sets must be used. The appropriate volume of constituted solution should be transferred to an IV bag containing the appropriate volume of LRI to achieve the final desired concentration. For the vast majority of patients (without dose reductions), the typical ixabepilone dose will be within the appropriate concentration after being added to 250 mL of LRI. The main reason for using LRI, a solution more suited to the surgery suite than the chemotherapy arena, is the relative pH needed for stability of ixabepilone.
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Although LRI is currently the only approved diluent, other alternatives (such as normal saline) are currently being investigated. After final dilution with LRI, the solution is stable at room temperature and light for 6 hours (including the infusion time, which means only 3 hours before hanging the medication). The ixabepilone infusion should be administered through an appropriate in-line filter with a 0.2-mm to 1.2-mm microporous membrane. As mentioned, to minimize the risk of Cremophor EL hypersensitivity, all patients must be premedicated with a H1 or H2 antagonist 1 hour before infusion of ixabepilone. Additional premedication with corticosteroids is required only in patients who experience a hypersensitivity reaction with ixabepilone. This practice is unlike the standard corticosteroid premedication associated with taxane administration, because the ixabepilone solution contains less Cremophor EL than paclitaxel solution when administered at the 3-weekly schedule. Cremophor EL also contains alcohol and has been shown to impair cognitive function; therefore, any patient who has undergone rapid infusion of products containing Cremophor EL should not drive a vehicle or operate heavy machinery immediately after treatment.
Conclusion Ixabepilone represents a novel treatment for heavily pretreated patients with MBC. Understanding how to administer this drug effectively and safely should ensure that ixabepilone is successfully integrated into the clinical management of patients with MBC whose disease has become resistant to other treatments. Acknowledgment Editorial and writing support was provided by Gardiner-Caldwell US, funded by Bristol-Myers Squibb. l References 1. Jassem J, Pienkowski T, Pluzanska A, et al; for the Central & Eastern Europe and Israel Paclitaxel Breast Cancer Study Group. Doxorubicin and paclitaxel versus fluorouracil, doxorubicin, and cyclophosphamide as first-line therapy for women with metastatic breast cancer: final results of a randomized phase III multicenter trial. J Clin Oncol. 2001;19:1707-1715. 2. Biganzoli L, Cufer T, Bruning P, et al. Doxorubicin and paclitaxel versus doxorubicin and cyclophosphamide as first-line chemotherapy in metastatic breast cancer: The European Organization for Research and Treatment of Cancer 10961 Multicenter Phase III Trial. J Clin Oncol. 2002;20:3114-3121. 3. Nabholtz JM, Falkson C, Campos D, et al; for the TAX 306 Study Group. Docetaxel and doxorubicin compared with doxorubicin and cyclophosphamide as first-line chemotherapy for metastatic breast cancer: results of a randomized, multicenter, phase III trial. J Clin Oncol. 2003;21:968-975. 4. Bonneterre J, Dieras V, Tubiana-Hulin M, et al. Phase II multicentre randomised study of docetaxel plus epirubicin vs 5-fluorouracil plus epirubicin and cyclophosphamide in metastatic breast cancer. Br J Cancer. 2004;91:1466-1471.
5. Bontenbal M, Creemers GJ, Braun HJ, et al. Phase II to III study comparing doxorubicin and docetaxel with fluorouracil, doxorubicin, and cyclophosphamide as first-line chemotherapy in patients with metastatic breast cancer: results of a Dutch Community Setting Trial for the Clinical Trial Group of the Comprehensive Cancer Centre. J Clin Oncol. 2005;23:7081-7088. 6. Chien AJ, Moasser MM. Cellular mechanisms of resistance to anthracyclines and taxanes in cancer: intrinsic and acquired. Semin Oncol. 2008;35(2 suppl 2):S1-S14. 7. Lee FY, Borzilleri R, Fairchild CR, et al. BMS247550: a novel epothilone analog with a mode of action similar to paclitaxel but possessing superior antitumor efficacy. Clin Cancer Res. 2001;7:1429-1437. 8. Coley HM. Mechanisms and strategies to overcome chemotherapy resistance in metastatic breast cancer. Cancer Treat Rev. 2008;34:378-390. 9. Goodin S, Kane MP, Rubin EH. Epothilones: mechanism of action and biologic activity. J Clin Oncol. 2004;22:2015-2025. 10. Lee FY, Borzilleri R, Fairchild CR, et al. Preclinical discovery of ixabepilone, a highly active antineoplastic agent. Cancer Chemother Pharmacol. 2008;63:157-166. 11. Lee FY, Smykla R, Johnston K, et al. Preclinical efficacy spectrum and pharmacokinetics of ixabepilone. Cancer Chemother Pharmacol. 2009; 63:201-212. 12. Jordan M, Miller H, Ni L, et al. The Pat-21 breast cancer model derived from a patient with primary Taxol resistance recapitulates the phenotype of its origin, has altered beta-tubulin expression and is sensitive to ixabepilone [abstract]. Proc Am Assoc Cancer Res. 2006;47:LB-280a. 13. Thomas ES, Gomez HL, Li RK, et al. Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment. J Clin Oncol. 2007;25:5210-5217. 14. Roche H, Yelle L, Cognetti F, et al. Phase II clinical trial of ixabepilone (BMS-247550), an epothilone B analog, as first-line therapy in patients with metastatic breast cancer previously treated with anthracycline chemotherapy. J Clin Oncol. 2007;25:3415-3420. 15. Denduluri N, Low JA, Lee JJ, et al. Phase II trial of ixabepilone, an epothilone B analog, in patients with metastatic breast cancer previously untreated with taxanes. J Clin Oncol. 2007; 25:3421-3427. 16. Low JA, Wedam SB, Lee JJ, et al. Phase II clinical trial of ixabepilone (BMS-247550), an epothilone B analog, in metastatic and locally advanced breast cancer. J Clin Oncol. 2005;23:2726-2734. 17. Perez EA, Lerzo G, Pivot X, et al. Efficacy and safety of ixabepilone (BMS-247550) in a phase II study of patients with advanced breast cancer resistant to an anthracycline, a taxane, and capecitabine. J Clin Oncol. 2007;25:3407-3414. 18. Thomas E, Tabernero J, Fornier M, et al. Phase II clinical trial of ixabepilone (BMS-247550), an epothilone B analog, in patients with taxaneresistant metastatic breast cancer. J Clin Oncol. 2007;25:3399-3406. 19. Ixempra Kit (ixabepilone) [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2007. 20. Xeloda (capecitabine) [package insert]. Nutley, NJ: Roche Laboratories; 2006. 21. Abraham J, Agrawal M, Bakke S, et al. Phase I trial and pharmacokinetic study of BMS-247550, an epothilone B analog, administered intravenously on a daily schedule for five days. J Clin Oncol. 2003;21:1866-1873. 22. Awada A, Piccart MJ, Jones SF, et al. Phase I dose escalation study of weekly ixabepilone, an epothilone analog, in patients with advanced solid tumors who have failed standard therapy. Cancer Chemother Pharmacol. 2009;63:417-425. 23. Mani S, McDaid H, Hamilton A, et al. Phase I clinical and pharmacokinetic study of BMS247550, a novel derivative of epothilone B, in solid tumors. Clin Cancer Res. 2004;10:1289-1298. 24. Gadgeel SM, Wozniak A, Boinpally RR, et al. Phase I clinical trial of BMS-247550, a derivative of epothilone B, using accelerated titration 2B design. Clin Cancer Res. 2005;11:6233-6239. 25. Aghajanian C, Burris HA 3rd, Jones S, et al. Phase I study of the novel epothilone analog ixabepilone (BMS-247550) in patients with advanced solid tumors and lymphomas. J Clin Oncol. 2007;25:1082-1088. 26. Bristol-Myers Squibb Research and Development. Ixabepilone (BMS-247550). BristolMyers Squibb Investigator Brochure 2007. 27. Goel S, Cohen M, Comezoglu SN, et al. The effect of ketoconazole on the pharmacokinetics and pharmacodynamics of ixabepilone: a first in class epothilone B analogue in late-phase clinical development. Clin Cancer Res. 2008;14: 2701-2709.
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Medical Minutes MEDICAL MINUTES
BY john schieszer
Wine May Provide Some Radioprotective Effects for Breast Cancer Patients Drinking wine while undergoing radiation treatment for breast carcinoma may reduce the incidence of skin toxicity in breast cancer patients, according to Italian researchers. They say this latest finding is promising news given the high cost and potential serious side effects associated with radioprotective agents, such as amifostine. Preventing radiation therapy–induced side effects is an important part of a patient’s cancer treatment management. Several medications are available to help protect healthy organs from the effects of radiation, but they are often expensive, have side effects themselves, and can provide protection to tumor cells as well as healthy cells. Researchers at Catholic University in Campobasso, Italy, and at the National Research Council’s BioMatLab in Rome, Italy, conducted a study to determine whether the natural antioxidants in wine would help protect against acute skin toxicity in patients undergoing radiation therapy after conservative surgery for breast cancer. The study consisted of 348 patients divided into three groups based on the
dose/fractionation scheme used. The researchers found that patients consuming wine had a lower incidence of grade 2 or higher acute toxicity than those who did not consume wine. The researchers found that the daily amount of alcohol intake influenced the incidence of skin toxicity, with an incidence of 38.4% in patients who consumed no wine, 31.8% in patients drinking just a half of a glass of wine per day, and 13.6% in patients drinking one glass of wine per day. A multivariate analysis by the researchers found that wine consumption, planning target volume, and radiotherapy protocol were all “significantly correlated” with acute toxicity. “If wine can prevent radiotherapy-induced toxicity without affecting antitumor efficacy, as we observed, it also has the potential to enhance the therapeutic benefit in cancer patients without increasing their risk of serious adverse effects,” said study author Vincenzo Valentini, MD, a radiation oncologist at Catholic University, Rome, Italy. “The possibility that particular dietary practices or interventions can reduce radiation-induced toxicity is very intriguing.”
MRI Combined with Oxygen May Help Determine Optimal Cancer Therapy Approach A simple magnetic resonance imaging (MRI) test involving the inhalation of oxygen might help clinicians determine the best treatment plan for some cancer patients. It is well known that the amount of oxygen present in a tumor can be a predictor of how well a patient will respond to treatment. Tumors with little
oxygen tend to grow stronger and resist both radiotherapy and chemotherapy. Until now, the only way to gauge the oxygen level in a tumor and thus determine which treatment might be more effective was to insert a needle directly into the cancerous tumor. Now, it appears there may be a simpler and less invasive technique. The newer technique is called
The Truth about Green Tea Consumption and Cancer
venting cell growth and thus having the potential to prevent cancer. The review found that green tea had limited benefits for liver cancer, but found conflicting evidence for other gastrointestinal cancers, such as cancer of the esophagus, colon, and pancreas. One study found a decreased risk of prostate cancer for men who consumed higher quantities of green tea or its extracts. However, the review did not find any benefit for preventing death from gastric cancer. Interestingly, the review showed that green tea might even increase the risk of urinary bladder cancer. Despite conflicting findings, there was “limited moderate-tostrong evidence” of a benefit for lung, pancreatic, and colorectal cancers. None of the studies that simply observed a group of people over time found a benefit for breast cancer prevention. However, both of the case-control studies, which compared people without the condition with people with it, found a positive association between green tea consumption and a decreased risk of breast cancer. The review has been published in The Cochrane Library, which is a publication of The Cochrane Collaboration, an international organization that evaluates medical research (Boehm K, et al. 2009;Jul 8(3):CD005004).
G REEN H ILL H EALTHCARE C OMMUNICATIONS
Many Americans are turning to green tea as a form of cancer prevention, and countless numbers of cancer patients are consuming green tea in the battle against their disease. Yet, a new review of studies examining the effects of green tea on cancer prevention has yielded conflicting results. Researchers looked at 51 medium-to-highquality studies that included more than 1.6 million participants. The studies focused on the relationship between green tea consumption and a variety of cancers, including breast, lung, digestive tract, urologic, gynecologic, and oral cancers. The comprehensive review analyzed studies conducted from 1985 through 2008. “Despite the large number of included studies, the jury still seems to be out on the question of whether green tea can in fact prevent the development of various cancer types,” said lead review author Katja Boehm, PhD, a member of the Unconventional and Complementary Methods in Oncology Study Group, Nuremburg, Germany. Three types of tea (black, green, and oolong) come from the plant Camellia sinensis, and all contain polyphenols. Catechins, a subgroup of the polyphenols, are powerful antioxidants. Some researchers believe the polyphenols in green tea are unique, pre-
BOLD (blood oxygen level dependent) MRI. “The patient simply inhales pure oxygen, which then circulates through the bloodstream, including to the tumors,” said investigator Ralph Mason, MD, professor of radiology at the University of Texas Southwestern Medical Center, Dallas. “Using MRI, we can then go in and estimate how much oxygen a particular tumor is taking up, providing us some insight into how the tumor is behaving and what sort of treatment might be effective.” He said the most important finding that has recently come to light is that BOLD MRI appears to perform as well as the standard yet more invasive procedure, FREDOM (fluorocarbon relaxometry using echo planar imaging for dynamic oxygen mapping) MRI. Mason said BOLD MRI has been used extensively in studying brain function, but the procedure has only recently begun to be used to assess blood oxygenation and vascular function in tumors. Currently, researchers at the University of Texas Southwestern are testing BOLD MRI in patients with cervical, prostate, and head and neck cancers. They have proposed using it in lung cancer patients as well. Previous studies have shown that these specific tumor types are more likely to have little oxygen. Before this approach can be adopted on a widespread basis, researchers need to answer some key questions. Mason said he and his colleagues are now trying to determine how much oxygen must be inhaled by a patient to be effective. The next step is to expand studies in patients and prove the relevance to more tumor types. “The BOLD technique appears to indicate accurately John Schieszer is an the oxygen levels in tumors,” award-winning national said Mason. “Because BOLD journalist and radio is immediately applicable to broadcaster of The patients, this holds promise as Medical Minute. a new method of predicting He can be reached at response to therapy.” firstname.lastname@example.org.
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Meetings 10-14 NEW YORK, NY The Chemotherapy Foundation Symposium XXVII
13-14 HOUSTON, TX
13th Annual Symptom Control, Palliative and Hospice Care Conference www.mdanderson.org
15-19 BOSTON, MA Molecular Targets and Cancer Therapeutics www.aacr.org
5-8 NEW ORLEANS, LA 51st American Society of Hematology Annual Meeting and Exposition www.hematology.org
6-10 LAS VEGAS, NV American Society of Health-System Pharmacists Midyear Clinical Meeting www.ashp.org
22-24 ORLANDO, FL
13-16 SAN DIEGO, CA
5-7 SAN FRANCISCO, CA
2010 Gastrointestinal Cancers Symposium www.asco.org
Scripps Cancer Center’s 30th Annual Conference: Clinical Hematology and Oncology www.scripps.org
Genitourinary Cancers Symposium www.asco.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. 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. Most cases of PML were diagnosed within 12 months of their last infusion of Rituxan. Consider the diagnosis of PML in any patient presenting with new-onset neurologic manifestations. 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 life-threatening 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 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
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 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 R-CHOP 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. Postmarketing data indicate that B-cell lymphocytopenia generally lasting less than six months can occur in infants exposed to rituximab in-utero. Rituximab was detected postnatally in the serum of infants exposed in-utero. Non-Hodgkin’s lymphoma is a serious condition that requires treatment. Rituximab should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. 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. 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 oral ingestion of 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, activecontrolled 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 All Grades (%) Grade 3 and 4 (%) All Grades (%) Grade 3 and 4 (%) greater. No overall differences in effectiveness were observed between these Respiratory System 38 4 Any Adverse Events 99 57 patients and younger patients. Cardiac adverse reactions, mostly supraventricular Increased Cough 13 1 Body as a Whole 86 10 Rhinitis 12 1 Fever 53 1 arrhythmias, occurred more frequently among elderly patients. Serious pulmonary Bronchospasm 8 1 Chills 33 3 adverse reactions were also more common among the elderly, including Dyspnea 7 1 Infection 31 4 Sinusitis 6 0 Asthenia 26 1 pneumonia and pneumonitis. Low-Grade or Follicular Non-Hodgkin’s Metabolic and Nutritional Headache 19 1 Lymphoma Clinical studies of Rituxan in low-grade or follicular, CD20-positive, Abdominal Pain 14 1 Disorders 38 3 Pain 12 1 Angioedema 11 1 B-cell NHL did not include sufficient numbers of patients aged 65 and over to Back Pain 10 1 Hyperglycemia 9 1 Throat Irritation 9 0 Peripheral Edema 8 0 determine whether they respond differently from younger subjects. Flushing 5 0 LDH Increase 7 0 OVERDOSAGE There has been no experience with overdosage in human clinical Heme and Lymphatic System 67 Digestive System 48 37 2 Lymphopenia 48 40 Nausea 23 1 trials. Single doses of up to 500 mg/m2 have been given in dose-escalation Leukopenia 14 4 Diarrhea 10 1 Neutropenia 14 6 Vomiting 10 1 clinical trials. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Thrombocytopenia 12 2 Nervous System 32 1 Impairment of Fertility No long term animal studies have been performed to Anemia 8 3 Dizziness 10 1 Skin and Appendages Anxiety 5 1 44 2 establish the carcinogenic or mutagenic potential of Rituxan or to determine Musculoskeletal System Night Sweats 15 1 26 3 Rash 15 1 Myalgia 10 1 potential effects on fertility in males or females. PATIENT COUNSELING Pruritus 14 1 Arthralgia 10 1 INFORMATION Patients should be provided the Rituxan Medication Guide and Urticaria 8 1 Cardiovascular System 25 3 Hypotension 10 1 provided an opportunity to read prior to each treatment session. Because caution Hypertension 6 1 should be exercised in administering Rituxan to patients with active infections, it is a Adverse reactions observed up to 12 months following Rituxan. bAdverse reactions graded for severity by important that the patient’s overall health be assessed at each visit and any NCI-CTC criteria. questions resulting from the patient’s reading of the Medication Guide be In these single-arm Rituxan studies, bronchiolitis obliterans occurred during and discussed. Rituxan is detectable in serum for up to six months following up to 6 months after Rituxan infusion. Rituxan in Combination With completion of therapy. Individuals of childbearing potential should use effective Chemotherapy Adverse reactions information below is based on 1250 patients contraception during treatment and for 12 months after Rituxan therapy. 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 infusional toxicity and neutropenia compared to patients in the CVP arm. The following adverse reactions occurred more frequently (≥5%) in patients receiving R-CVP compared to CVP alone: rash (17% vs. 5%), cough (15% vs. 6%), flushing (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 Revised 9/2008 (4835505) were reported more frequently (≥5%) in patients receiving Rituxan following CVP Jointly Marketed by: compared to patients who received no further therapy: fatigue (39% vs. 14%), Biogen Idec Inc. 5200 Research Place San Diego, CA 92122 anemia (35% vs. 20%), peripheral sensory neuropathy (30% vs. 18%), infections Genentech USA, Inc. 1 DNA Way South San Francisco, CA 94080-4990 (19% vs. 9%), pulmonary toxicity (18% vs. 10%), hepato-biliary toxicity (17% vs. 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 ©2008 Biogen Idec Inc. and Genentech, Inc. 7140917 October 2008
G REEN H ILL H EALTHCARE C OMMUNICATIONS
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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
Cumulative Cumulative Proportion Proportion Surviving Surviving
RITUXAN+CHOP is proven to prolong survival in DLBCL
in 7-year OS in GELA* trial 1,2
0.8 0.6 0.4 R-CHOP (n=202) CHOP† (n=197) p =0.0004
0.2 0 0 Years
• 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