Journal of Hematology Oncology Pharmacy by The Oncology Pharmacist

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SEPTEMBER 2011

JOURNAL OF

VOL 1 I NO 3

HEMATOLOGY ONCOLOGY ™ PHARMACY THE PEER-REVIEWED FORUM FOR ONCOLOGY PHARMACY PRACTICE

EDITORIAL Brother, Can You Spare Some Chemotherapy? No End in Sight for Drug Shortages

Timothy G. Tyler, PharmD, FCSHP ORIGINAL RESEARCH Ifosfamide Neurotoxicity in Pediatric Patients: A Multi-Institutional Case Series Report

Amy Lee, MD; David W. Henry, MS, BCOP, FASHP; John Szechung Ng, PharmD; Kerry Parsons, PharmD, BCOP; Betsy Bickert Poon, PharmD, FCCP; Jeff Schwartz, MD; Tara Smith, PharmD; Chatchawin Assanasen, MD Carboplatin Dosing in Overweight and Obese Patients: A Single-Center Experience

Ginah Nightingale, PharmD, BCOP; James A. Trovato, PharmD, MBA, BCOP, FASHP; Myounghee Lee, PhD, PharmD; Jennifer Thompson, PharmD, BCOP COMMENTARY Dosing Chemotherapy in Obese Patients: No Clear Answers, Yet

Scott Soefje, PharmD, BCOP

From the Literature Concise Reviews from the Literature Relevant to Hematology Oncology Pharmacy

Robert J. Ignoffo, PharmD, FASHP, FCSHP

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EDITORIAL BOARD

CO-EDITORS-IN-CHIEF Patrick J. Medina, PharmD, BCOP Associate Professor Department of Pharmacy University of Oklahoma College of Pharmacy Oklahoma City, OK

Val R. Adams, PharmD, BCOP, FCCP Associate Professor, Pharmacy Program Director, PGY2 Specialty Residency Hematology/Oncology University of Kentucky College of Pharmacy Lexington, KY

SECTION EDITORS CLINICAL CONTROVERSIES

ORIGINAL RESEARCH

Christopher Fausel, PharmD, BCPS, BCOP Clinical Director Oncology Pharmacy Services Indiana University Simon Cancer Center Indianapolis, IN

Gary C. Yee, PharmD, FCCP, BCOP Professor, Department of Pharmacy Practice College of Pharmacy, University of Nebraska Medical Center, Omaha, NE

REVIEW ARTICLES R. Donald Harvey, PharmD, FCCP, BCPS, BCOP Assistant Professor, Hematology/Medical Oncology Department of Hematology/Medical Oncology Director, Phase 1 Unit Winship Cancer Institute Emory University, Atlanta, GA

PRACTICAL ISSUES IN PHARMACY MANAGEMENT Timothy G. Tyler, PharmD, FCSHP Director of Pharmacy Comprehensive Cancer Center Desert Regional Medical Center Palm Springs, CA

FROM THE LITERATURE Robert J. Ignoffo, PharmD, FASHP, FCSHP Professor of Pharmacy, College of Pharmacy, Touro Universityâ&#x20AC;&#x201C;California Mare Island Vallejo, CA

EDITORS-AT-LARGE Sandra Cueller, PharmD, BCOP Director Oncology Specialty Residency University of Illinois at Chicago Medical Center Chicago, IL

Steve Stricker, PharmD, MS, BCOP Assistant Professor of Pharmacy Practice Samford University McWhorter School of Pharmacy Birmingham, AL

Sachin Shah, PharmD, BCOP Associate Professor Texas Tech University Health Sciences Center Dallas, TX

John M. Valgus, PharmD, BCOP Hematology/Oncology Senior Clinical Pharmacy Specialist University of North Carolina Hospitals and Clinics Chapel Hill, NC

Scott Soefje, PharmD, BCOP Associate Director, Oncology Pharmacy Smilow Cancer Hospital at Yale New Haven Yale New Haven Hospital New Haven, CT

Vol 1, No 3

September 2011

Daisy Yang, PharmD, BCOP Clinical Pharmacy Specialist University of Texas M. D. Anderson Cancer Center Houston, TX

www.AHDBonline.com

American Health & Drug Benefits

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SEPTEMBER 2011

VOLUME 1, NUMBER 3 PUBLISHING STAFF Senior Vice President, Sales & Marketing Philip Pawelko phil@greenhillhc.com Publisher John W. Hennessy john@greenhillhc.com 732.992.1886 TM

THE PEER-REVIEWED FORUM FOR ONCOLOGY PHARMACY PRACTICE

TABLE OF CONTENTS

Associate Editors Brett Kaplan Lara J. Lorton

EDITORIAL

Brother, Can You Spare Some Chemotherapy? No End in Sight for Drug Shortages Timothy G. Tyler, PharmD, FCSHP

ORIGINAL RESEARCH

Ifosfamide Neurotoxicity in Pediatric Patients: A Multi-Institutional Case Series Report Amy Lee, MD; David W. Henry, MS, BCOP, FASHP; John Szechung Ng, PharmD; Kerry Parsons, PharmD, BCOP; Betsy Bickert Poon, PharmD, FCCP; Jeff Schwartz, MD; Tara Smith, PharmD; Chatchawin Assanasen, MD Carboplatin Dosing in Overweight and Obese Patients: A Single-Center Experience Ginah Nightingale, PharmD, BCOP; James A. Trovato, PharmD, MBA, BCOP, FASHP; Myounghee Lee, PhD, PharmD; Jennifer Thompson, PharmD, BCOP

COMMENTARY

Dosing Chemotherapy in Obese Patients: No Clear Answers, Yet Scott Soefje, PharmD, BCOP

FROM THE LITERATURE

Editorial Director Dalia Buffery dalia@greenhillhc.com 732.992.1889

Concise Reviews from the Literature Relevant to Hematology Oncology Pharmacy Robert J. Ignoffo, PharmD, FASHP, FCSHP

Editorial Assistant Jennifer Brandt 732.992.1536 Directors, Client Services Joe Chanley joe@greenhillhc.com 732.992.1524 Jack Iannaccone jack@greenhillhc.com 732.992.1537 Production Manager Stephanie Laudien Quality Control Director Barbara Marino Business Manager Blanche Marchitto blanche@greenhillhc.com Editorial Contact: Telephone: 732.992.1536 Fax: 732.656.7938 E-mail: JHOP@greenhillhc.com

MISSION STATEMENT The Journal of Hematology Oncology Pharm acy is an independent, peer-reviewed journal founded in 2011 to provide hematology and oncology pharmacy practitioners and other healthcare professionals with highquality peer-reviewed information relevant to hematologic and oncologic conditions to help them optimize drug therapy for patients.

Journal of Hematology Oncology Pharmacy™, ISSN applied for (print); ISSN applied for (online), is published 4 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 ©2011 by Green Hill Healthcare Communications LLC. All rights reserved. Journal of Hematology Oncology Pharmacy™ logo is a trademark of Green Hill Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the Publisher. Printed in the United States of America. EDITORIAL CORRESPONDENCE should be addressed to EDITORIAL DIRECTOR, Journal of Hematology Oncology Pharmacy™, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. E-mail: JHOP@greenhillhc.com. YEARLY SUBSCRIPTION RATES: United States and possessions: individuals, $105.00; institutions, $135.00; single issues, $17.00. Orders will be billed at individual rate until proof of status is confirmed. Prices are subject to change without notice. Correspondence regarding permission to reprint all or part of any article published in this journal should be addressed to REPRINT PERMISSIONS DEPARTMENT, Green Hill Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. The ideas and opinions expressed in Journal of Hematology Oncology Pharmacy™ do not necessarily reflect those of the Editorial Board, the Editorial Director, or the Publisher. Publication of an advertisement or other product mention in Journal of Hematology Oncology Pharmacy™ 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.

Journal of Hematology Oncology Pharmacy

www.JHOPonline.com

September 2011

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CALL FOR PAPERS The Journal of Hematology Oncology Pharmacy is the nation’s first peer-reviewed clinical journal for oncology pharmacists. As pharmacy practice and research become integral to improving both the clinical care of cancer patients as well as expanding the research literature in contemporary oncology pharmacy, new avenues are necessary to ensure this information gets disseminated to the profession. The recently launched Journal of Hematology Oncology Pharmacy provides a new avenue for the publication of peer-reviewed, high-quality pharmacy reviews and original research to help oncology pharmacy practitioners and other hematology oncology professionals optimize drug therapy for patients with cancer. Readers are invited to submit articles addressing new research, clinical, and practice management issues in oncology pharmacy. All articles will undergo a blind peer-review process, and acceptance is based on that review.

ORIGINAL RESEARCH

REVIEW ARTICLES

• Clinical • Basic science • Translational • Practice-based • Case reports • Case series

• New drug classes • Disease states • Basic science • Pharmacology • Pathways and the drugs targeting them

CLINICAL CONTROVERSIES

PRACTICAL ISSUES IN PHARMACY MANAGEMENT

• Point and counterpoint • Roundtable discussions • “How I treat”

• Logistics • Economics • Practice-influencing issues

COMMENTARIES

LETTERS TO THE EDITOR

Manuscripts should follow the Author Guidelines on pages 29-30 and available at www.JHOPonline.com. For more information, call 732-992-1536.

Journal of Hematology Oncology Pharmacy

www.JHOPonline.com

September 2011

Vol 1, No 3

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EDITORIAL

Brother, Can You Spare Some Chemotherapy? No End in Sight for Drug Shortages Timothy G. Tyler, PharmD, FCSHP, Section Editor Director of Pharmacy Services, Comprehensive Cancer Center Desert Regional Medical Center, Palm Springs, CA

t was on the front page of my newspaper. It is in the data services I subscribe to for the American Society of Health-System Pharmacists and the American Society of Clinical Oncology. It is the feature of a new survey from the Hematology Oncology Pharmacy Association and is the lead-in for the Pharmacists’ Newsletter. It is on the nightly news, and it was explored in depth in the last issue of the Journal of Hematology Oncology Pharmacy (JHOP). What exactly is this “it,” you may wonder. The drug shortage, of course. For pharmacists involved in any way with drug procurement, this shortage has been a source of extreme consternation, fear, apprehension, and frustration. Even the general population is becoming alarmed by drugs that are no longer readily available. We have an advanced civilization, but we apparently cannot figure out how to reliably provide some of the cheaper drugs that have significant impact on patient care. Or at least that seems to be the message that is promulgated today. During a 30-minute newspaper interview on this issue at the end of August, I had to redirect the interviewer on 3 separate occasions to avoid inaccurate and sensational tendencies in the story. I reiterated 3 times that this was a national issue not unique to my center, and all the regional centers around us had the exact same (and in some cases worse) scenario. Nevertheless, what appeared on the front page of the published article was that my hospital was unable to treat patients with cancer, because of my inability to get drugs. Ironically, the day the story appeared in print, I received shipments of the main 2 drugs (liposomal doxorubicin and paclitaxel) that had caused us serious problems. I have read stories about drug mark-ups in the gray market, and about the concern with the safety of the current drug supply. Michael R. Cohen, RPh, MS, president of the Institute for Safe Medication Practices (www.ismp.org), has just presented a teleconference on this subject. MSNBC posted a story on the drug shortage online in late August, and the more than 600 reader com-

Vol 1, No 3

September 2011

ments were vitriolic, bashing everyone from the current and past federal administrations to the evils of capitalism, and complaining that hospitals and doctors are “sticking it” to patients. Having now been involved as a Section Editor of JHOP and the author of the article on this topic that ran in the June 2011 issue of the journal, I believe I have some credibility in this regard. As such, the vast majority of the comments in the media were off base. The drug shortage problems are complex and multifactorial; no single issue can be blamed alone. The Center for Drug Evaluation and Research is planning a public workshop titled “Approach to Addressing Drug Shortage” for September 26, 2011, but to date, the only expedient solutions appear to be focused on giving more authority to the government. Knowing that a problem is forthcoming may allow professionals to have better communication and planning, but giving more control to those in government who cannot balance a single budget (eg, the US Postal Service Office, Medicare, Social Security) makes me uneasy at best.

For pharmacists involved in any way with drug procurement, this shortage has been a source of extreme consternation, fear, apprehension, and frustration. Even the general population is becoming alarmed by drugs that are no longer readily available. In addition, some colleagues in the pharmaceutical industry are worried that confidential marketing plans and strategies would be required to be divulged to federal agencies. Finally, although the US Food and Drug Administration (FDA) is not the primary culprit, it is certainly playing a role in this crisis with the increased regulatory scrutiny. Furthermore, the FDA has admitted that it only has 4 employees who are dedicated to working with generic approvals.

www.JHOPonline.com

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EDITORIAL

The pharmaceutical companies also have some burden to bear, but in a capitalistic system such as ours, the problem arises from taking a product that has little profit and removing whatever remains of that profit incentive, by imposing new rules and increased regulatory compliance. Add to the mix the unstable world in which many of these drugs are sourced and manufactured, and the situation gets even worse. Many generic manufacturers can no longer afford to compete if the drugs are manufactured in the United States, with labor costs being more affordable elsewhere. The other concern is not controlled by manufacturers, but by payers. The federal government—via Medicare and Medicaid reimbursement—is the single largest payer in the world today. Remember that the average sales price (ASP) system is only a few years old, and all drug manufacturers must submit (or suffer egregious fines) the prices for all the drugs they sell to the

Journal of Hematology Oncology Pharmacy

United States, and the US government then publishes the ASP for each drug based on these drug prices. That has a devastating effect on contracting and negotiating a drug price. The effect on profits has been curtailed by companies succumbing to pressure and conforming to a mean, even with a minimal profit for a time, but eventually looking for a better use of the company’s resources. Many times that means exiting existing markets, which results in the current drug shortage that is plaguing our system today. Solutions are neither easy nor obvious, but we can hope that the coming summit will provide more than just giving the federal government even more power. In the meantime—brother, can you spare some paclitaxel? ■ Author Disclosure Statement Dr Tyler is on the Speaker’s Bureau of Bristol-Myers Squibb and Eisai Pharmaceuticals.

www.JHOPonline.com

September 2011

Vol 1, No 3

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Help stop CINV before it starts, with a regimen including EMEND, a 5-HT3 antagonist, and a corticosteroid

Have you included EMEND from Cycle 1?

These highly and moderately emetogenic chemotherapy regimens increase the risk of CINV. Breast Cancer1,2 AC (doxorubicin + cyclophosphamide) TAC (docetaxel + doxorubicin + cyclophosphamide) TC (docetaxel + cyclophosphamide) CMF (cyclophosphamide + methotrexate + fluorouracil) TCH (docetaxel + carboplatin + trastuzumab)

Lymphoma1,5 ABVD (doxorubicin + bleomycin + vinblastine + dacarbazine) CHOP (cyclophosphamide + doxorubicin + vincristine + prednisone) ± rituximab CVP (cyclophosphamide + vincristine + prednisone)

Lung Cancer1,3 Carbo-Tax (carboplatin + paclitaxel) Cisplatin + vinorelbine Cisplatin + gemcitabine Cisplatin + pemetrexed

Colorectal Cancer1,6,7 FOLFOX (oxaliplatin + leucovorin + 5-fluorouracil) FOLFIRI (irinotecan + leucovorin + 5-fluorouracil) CapeOX (capecitabine + oxaliplatin) Irinotecan Cisplatin-based regimens

Head and Neck Cancer1,4 Cisplatin-based regimens Carboplatin-based regimens

Ovarian Cancer1,8 Carbo-Tax (carboplatin + paclitaxel) IP cis (intraperitoneal cisplatin) Cisplatin

EMEND, in combination with other antiemetic agents, is indicated in adults for prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy, including high-dose cisplatin; and for prevention of nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy. EMEND has not been studied for treatment of established nausea and vomiting. Chronic continuous administration of EMEND is not recommended.

Selected Important Safety Information EM EN D should b e used with caution in patient s re ceiving concomitant medications, including chemotherapy a g e nt s , t hat are pr imar il y m et a b o lize d t hro ugh C Y P3A 4 . I nhib i t i o n of C Y P3A 4 by EM EN D co ul d re sul t in e l e vate d plasma concentrations of these concomitant medications. Conversely, when EMEND is used concomitantly with another CY P3A 4 inhibitor, aprepitant plasma concentrations could be elevated. When EMEND is used concomitantly with medications that induce CYP3A4 activity, aprepitant plasma concentrations could be reduced, and this may result in decreased efficacy of aprepitant. Chemotherapy agents that are known to be metabolized by CYP3A4 include docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide, imatinib, vinorelbine, vinblastine, and vincristine. In clinical studies, EMEND 125 mg / 80 mg was administered commonly with etoposide, vinorelbine, or paclitaxel. The doses of these agents were not adjusted to account for potential drug interactions. In separate pharmacokinetic studies, EMEND 125 mg / 8 0 mg did not influence the pharmacokinetic s of docetaxel or vinorelbine. Because a small number of patients in clinical studies received the CYP3A4 substrates vinblastine, vincristine, or ifosfamide, particular caution and careful monitoring are advised in patients receiving these agents or other chemotherapy agents metabolized primarily by CYP3A4 that were not studied. The efficacy of hormonal contraceptives may be reduced during coadministration with EMEND and for 28 days after the last

dose of EMEND. Alternative or backup methods of contraception should be used during treatment with EMEND and for 1 month after the last dose of EMEND. Coadministration of EMEND with warfarin (a CYP2C9 substrate) may result in a clinically significant decrease in international normalized ratio (INR) of prothrombin time. In patients on chronic warfarin therapy, the INR should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of EMEND with each chemotherapy cycle. Chronic continuous use of EMEND for prevention of nausea and vomiting is not recommended because it has not been studied and because the drug interaction profile may change during chronic continuous use. In clinical trials of EMEND, the most common adverse events reported at a frequency greater than with standard therapy, and at an incidence greater than 10%, in patients receiving highly emetogenic chemotherapy were asthenia /fatigue (17.8% EMEND vs 11.8% standard therapy), nausea (12.7% vs 11.8%), hiccups (10.8% vs 5.6%), diarrhea (10.3% vs 7.5%), and anorexia (10.1% vs 9.5%). In clinical trials of EMEND, the most common adverse events reported at a frequency greater than with standard therapy in patients receiving moderately emetogenic chemotherapy were alopecia (12.4% EMEN D vs 11.9% standard therapy) , dyspepsia (5.8% vs 3.8%), nausea (5.8% vs 5.1%), neutropenia ( 5. 8 % v s 5.6%) , as thenia ( 4.7% v s 4.6%) , and s tomatitis (3.1% vs 2.7%). In clinical trials, EMEND increased the AUC of dexamethasone, a CYP3A4 substrate, by approximately 2.2-fold; therefore, the dexamethasone dose administered in the regimen with EMEND should be reduced by approximately 50% to achieve exposures of dexamethasone similar to those obtained without EMEND. See PRECAUTIONS, Drug Interactions, in the Prescribing Information for EMEND for additional information on dosage adjustment for methylprednisolone when coadministered with EMEND. Please read the Brief Summary of the Prescribing Information for EMEND on the following pages.

References : 1. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: antiemesis—V.1.2011. www.nccn.org/professionals/physician_gls/ f_guidelines.asp. Accessed January 5, 2011. 2. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: breast cancer—V.2.2011. www.nccn.org/ professionals/physician_gls/f_guidelines.asp. Accessed January 5, 2011. 3. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: non-small cell lung cancer—V.2.2011. www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed January 5, 2011. 4. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: head and neck cancers—V.2.2010. www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed January 5, 2011. 5. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: Hodgkin lymphoma—V.2.2010. www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed January 5, 2011. 6. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: colon cancer—V.2.2011. www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed January 5, 2011. 7. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: rectal cancer—V.2.2011. www.nccn.org/professionals/ physician_gls/f_guidelines.asp. Accessed January 5, 2011. 8. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: ovarian cancer—V.2.2011. www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed January 5, 2011. CINV=chemotherapy-induced nausea and vomiting.

An antiemetic regimen including

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Brief Summary of the Prescribing Information for

INDICATIONS AND USAGE Prevention of Chemotherapy-Induced Nausea and Vomiting (CINV): EMEND, in combination with other antiemetic agents, is indicated for prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy (HEC), including high-dose cisplatin; and CAPSULES for prevention of nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC). Prevention of Postoperative Nausea and Vomiting (PONV): EMEND is indicated for prevention of postoperative nausea and vomiting. Limitations of Use: EMEND has not been studied for treatment of established nausea and vomiting. Chronic continuous administration is not recommended. CONTRAINDICATIONS EMEND is contraindicated in patients who are hypersensitive to any component of the product. EMEND is a dose-dependent inhibitor of cytochrome P450 isoenzyme 3A4 (CYP3A4). EMEND should not be used concurrently with pimozide, terfenadine, astemizole, or cisapride. Inhibition of CYP3A4 by aprepitant could result in elevated plasma concentrations of these drugs, potentially causing serious or life-threatening reactions [see Drug Interactions]. WARNINGS AND PRECAUTIONS CYP3A4 Interactions: EMEND, a dose-dependent inhibitor of CYP3A4, should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4. Moderate inhibition of CYP3A4 by aprepitant, 125-mg/80-mg regimen, could result in elevated plasma concentrations of these concomitant medications. Weak inhibition of CYP3A4 by a single 40-mg dose of aprepitant is not expected to alter the plasma concentrations of concomitant medications that are primarily metabolized through CYP3A4 to a clinically significant degree. When aprepitant is used concomitantly with another CYP3A4 inhibitor, aprepitant plasma concentrations could be elevated. When EMEND is used concomitantly with medications that induce CYP3A4 activity, aprepitant plasma concentrations could be reduced and this may result in decreased efficacy of EMEND [see Drug Interactions]. Chemotherapy agents that are known to be metabolized by CYP3A4 include docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide, imatinib, vinorelbine, vinblastine, and vincristine. In clinical studies, EMEND (125-mg/80-mg regimen) was administered commonly with etoposide, vinorelbine, or paclitaxel. The doses of these agents were not adjusted to account for potential drug interactions. In separate pharmacokinetic studies no clinically significant change in docetaxel or vinorelbine pharmacokinetics was observed when EMEND (125-mg/80-mg regimen) was coadministered. Due to the small number of patients in clinical studies who received the CYP3A4 substrates vinblastine, vincristine, or ifosfamide, particular caution and careful monitoring are advised in patients receiving these agents or other chemotherapy agents metabolized primarily by CYP3A4 that were not studied [see Drug Interactions]. Coadministration With Warfarin (a CYP2C9 substrate): Coadministration of EMEND with warfarin may result in a clinically significant decrease in international normalized ratio (INR) of prothrombin time. In patients on chronic warfarin therapy, the INR should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of the 3-day regimen of EMEND with each chemotherapy cycle, or following administration of a single 40-mg dose of EMEND for prevention of postoperative nausea and vomiting [see Drug Interactions]. Coadministration With Hormonal Contraceptives: Upon coadministration with EMEND, the efficacy of hormonal contraceptives during and for 28 days following the last dose of EMEND may be reduced. Alternative or backup methods of contraception should be used during treatment with EMEND and for 1 month following the last dose of EMEND [see Drug Interactions]. Patients With Severe Hepatic Impairment: There are no clinical or pharmacokinetic data in patients with severe hepatic impairment (Child-Pugh score >9). Therefore, caution should be exercised when EMEND is administered in these patients. Chronic Continuous Use: Chronic continuous use of EMEND for prevention of nausea and vomiting is not recommended because it has not been studied and because the drug interaction profile may change during chronic continuous use. ADVERSE REACTIONS The overall safety of aprepitant was evaluated in approximately 5300 individuals. 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 clinical practice. Clinical Trials Experience: Chemotherapy-Induced Nausea and Vomiting: Highly Emetogenic Chemotherapy: In 2 well-controlled clinical trials in patients receiving highly emetogenic cancer chemotherapy, 544 patients were treated with aprepitant during Cycle 1 of chemotherapy and 413 of these patients continued into the Multiple-Cycle extension for up to 6 cycles of chemotherapy. EMEND was given in combination with ondansetron and dexamethasone. In Cycle 1, clinical adverse experiences were reported in approximately 69% of patients treated with the aprepitant regimen compared with approximately 68% of patients treated with standard therapy. Following are the percentage of patients receiving highly emetogenic chemotherapy in Cycle 1 with clinical adverse experiences reported at an incidence of ≥3% for the aprepitant regimen (n=544) and standard therapy (n=550), respectively: Body as a whole/Site unspecified: asthenia/fatigue: 17.8, 11.8; dizziness: 6.6, 4.4; dehydration: 5.9, 5.1; abdominal pain: 4.6, 3.3; fever: 2.9, 3.5; mucous membrane disorder: 2.6, 3.1 Digestive system: nausea: 12.7, 11.8; constipation: 10.3, 12.2; diarrhea: 10.3, 7.5; vomiting: 7.5, 7.6; heartburn: 5.3, 4.9; gastritis: 4.2, 3.1; epigastric discomfort: 4.0, 3.1 Eyes, ears, nose, and throat: tinnitus: 3.7, 3.8 Hemic and lymphatic system: neutropenia: 3.1, 2.9 Metabolism and nutrition: anorexia: 10.1, 9.5 Nervous system: headache: 8.5, 8.7; insomnia: 2.9, 3.1 Respiratory system: hiccups: 10.8, 5.6 In addition, isolated cases of serious adverse experiences, regardless of causality, of bradycardia, disorientation, and perforating duodenal ulcer were reported in highly emetogenic CINV clinical studies. Moderately Emetogenic Chemotherapy: During Cycle 1 of 2 moderately emetogenic chemotherapy studies, 868 patients were treated with the aprepitant regimen and 686 of these patients continued into extensions for up to 4 cycles of chemotherapy. In the combined analysis of Cycle 1 data for these 2 studies, adverse experiences were reported in approximately 69% of patients treated with the aprepitant regimen compared with approximately 72% of patients treated with standard therapy. In the combined analysis of Cycle 1 data for these 2 studies, the adverse-experience profile in both moderately emetogenic chemotherapy studies was generally comparable to the highly emetogenic chemotherapy studies. Following are the percentage of patients receiving moderately emetogenic chemotherapy in Cycle 1 with clinical adverse experiences reported at an incidence of ≥3% for the aprepitant regimen (n=868) and standard therapy (n=846), respectively: Blood and lymphatic system disorders: neutropenia: 5.8, 5.6 Metabolism and nutrition disorders: anorexia: 6.2, 7.2 Psychiatric disorders: insomnia: 2.6, 3.7 Nervous system disorders: headache: 13.2, 14.3; dizziness: 2.8, 3.4 Gastrointestinal disorders: constipation: 10.3, 15.5; diarrhea: 7.6, 8.7; dyspepsia: 5.8, 3.8; nausea: 5.8, 5.1; stomatitis: 3.1, 2.7 Skin and subcutaneous tissue disorders: alopecia: 12.4, 11.9

EMEND® (aprepitant) capsules General disorders and general administration site conditions: fatigue: 15.4, 15.6; asthenia: 4.7, 4.6 In a combined analysis of these 2 studies, isolated cases of serious adverse experiences were similar in the 2 treatment groups. Highly and Moderately Emetogenic Chemotherapy: The following additional clinical adverse experiences (incidence >0.5% and greater than standard therapy), regardless of causality, were reported in patients treated with the aprepitant regimen in either HEC or MEC studies: Infections and infestations: candidiasis, herpes simplex, lower respiratory infection, oral candidiasis, pharyngitis, septic shock, upper respiratory infection, urinary tract infection Neoplasms benign, malignant, and unspecified (including cysts and polyps): malignant neoplasm, non–small-cell lung carcinoma Blood and lymphatic system disorders: anemia, febrile neutropenia, thrombocytopenia Metabolism and nutrition disorders: appetite decreased, diabetes mellitus, hypokalemia Psychiatric disorders: anxiety disorder, confusion, depression Nervous system: peripheral neuropathy, sensory neuropathy, taste disturbance, tremor Eye disorders: conjunctivitis Cardiac disorders: myocardial infarction, palpitations, tachycardia Vascular disorders: deep venous thrombosis, flushing, hot flush, hypertension, hypotension Respiratory, thoracic, and mediastinal disorders: cough, dyspnea, nasal secretion, pharyngolaryngeal pain, pneumonitis, pulmonary embolism, respiratory insufficiency, vocal disturbance Gastrointestinal disorders: abdominal pain upper, acid reflux, deglutition disorder, dry mouth, dysgeusia, dysphagia, eructation, flatulence, obstipation, salivation increased Skin and subcutaneous tissue disorders: acne, diaphoresis, pruritus, rash Musculoskeletal and connective tissue disorders: arthralgia, back pain, muscular weakness, musculoskeletal pain, myalgia Renal and urinary disorders: dysuria, renal insufficiency Reproductive system and breast disorders: pelvic pain General disorders and administrative site conditions: edema, malaise, pain, rigors Investigations: weight loss Stevens-Johnson syndrome was reported as a serious adverse experience in a patient receiving aprepitant with cancer chemotherapy in another CINV study. Laboratory Adverse Experiences: Following are the percentage of patients receiving highly emetogenic chemotherapy in Cycle 1 with laboratory adverse experiences reported at an incidence of ≥3% for the aprepitant regimen (n=544) and standard therapy (n=550), respectively: Proteinuria: 6.8, 5.3 ALT increased: 6.0, 4.3 Blood urea nitrogen increased: 4.7, 3.5 Serum creatinine increased: 3.7, 4.3 AST increased: 3.0, 1.3 The following additional laboratory adverse experiences (incidence >0.5% and greater than standard therapy), regardless of causality, were reported in patients treated with the aprepitant regimen: alkaline phosphatase increased, hyperglycemia, hyponatremia, leukocytes increased, erythrocyturia, leukocyturia. The adverse-experience profiles in the Multiple-Cycle extensions of HEC and MEC studies for up to 6 cycles of chemotherapy were generally similar to that observed in Cycle 1. Postoperative Nausea and Vomiting: In well-controlled clinical studies in patients receiving general anesthesia, 564 patients were administered 40-mg aprepitant orally and 538 patients were administered 4-mg ondansetron IV. Clinical adverse experiences were reported in approximately 60% of patients treated with 40-mg aprepitant compared with approximately 64% of patients treated with 4-mg ondansetron IV. Following are the percentage of patients receiving general anesthesia with clinical adverse experiences reported at an incidence of ≥3% in the combined studies for aprepitant 40 mg (n=564) and ondansetron (n=538), respectively: Infections and infestations: urinary tract infection: 2.3, 3.2 Blood and lymphatic system disorders: anemia: 3.0, 4.3 Psychiatric disorders: insomnia: 2.1, 3.3 Nervous system disorders: headache: 5.0, 6.5 Cardiac disorders: bradycardia: 4.4, 3.9 Vascular disorders: hypotension: 5.7, 4.6; hypertension: 2.1, 3.2 Gastrointestinal disorders: nausea: 8.5, 8.6; constipation: 8.5, 7.6; flatulence: 4.1, 5.8; vomiting 2.5, 3.9 Skin and subcutaneous tissue disorders: pruritus: 7.6, 8.4 General disorders and general administration site conditions: pyrexia: 5.9, 10.6 The following additional clinical adverse experiences (incidence >0.5% and greater than ondansetron), regardless of causality, were reported in patients treated with aprepitant: Infections and infestations: postoperative infection Metabolism and nutrition disorders: hypokalemia, hypovolemia Nervous system disorders: dizziness, hypoesthesia, syncope Vascular disorders: hematoma Respiratory, thoracic, and mediastinal disorders: dyspnea, hypoxia, respiratory depression Gastrointestinal disorders: abdominal pain, abdominal pain upper, dry mouth, dyspepsia Skin and subcutaneous tissue disorders: urticaria General disorders and administrative site conditions: hypothermia, pain Investigations: blood pressure decreased Injury, poisoning, and procedural complications: operative hemorrhage, wound dehiscence Other adverse experiences (incidence ≤0.5%) reported in patients treated with aprepitant 40 mg for postoperative nausea and vomiting included: Nervous system disorders: dysarthria, sensory disturbance Eye disorders: miosis, visual acuity reduced Respiratory, thoracic, and mediastinal disorders: wheezing Gastrointestinal disorders: bowel sounds abnormal, stomach discomfort There were no serious adverse drug-related experiences reported in the postoperative nausea and vomiting clinical studies in patients taking 40-mg aprepitant. Laboratory Adverse Experiences: One laboratory adverse experience, hemoglobin decreased (40-mg aprepitant 3.8%, ondansetron 4.2%), was reported at an incidence ≥3% in a patient receiving general anesthesia. The following additional laboratory adverse experiences (incidence >0.5% and greater than ondansetron), regardless of causality, were reported in patients treated with aprepitant 40 mg: blood albumin decreased, blood bilirubin increased, blood glucose increased, blood potassium decreased, glucose urine present. The adverse experience of increased ALT occurred with similar incidence in patients treated with aprepitant 40 mg (1.1%) as in patients treated with ondansetron 4 mg (1.0%). Other Studies: In addition, 2 serious adverse experiences were reported in postoperative nausea and vomiting (PONV) clinical studies in patients taking a higher dose of aprepitant: 1 case of constipation, and 1 case of subileus.

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EMEND® (aprepitant) capsules Angioedema and urticaria were reported as serious adverse experiences in a patient receiving aprepitant in a non-CINV/non-PONV study. Postmarketing Experience: The following adverse reactions have been identified during postmarketing use of aprepitant. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to the drug. Skin and subcutaneous tissue disorders: pruritus, rash, urticaria Immune system disorders: hypersensitivity reactions including anaphylactic reactions DRUG INTERACTIONS Aprepitant is a substrate, a weak-to-moderate (dose-dependent) inhibitor, and an inducer of CYP3A4. Aprepitant is also an inducer of CYP2C9. Effect of Aprepitant on the Pharmacokinetics of Other Agents: CYP3A4 substrates: Weak inhibition of CYP3A4 by a single 40-mg dose of aprepitant is not expected to alter the plasma concentrations of concomitant medications that are primarily metabolized through CYP3A4 to a clinically significant degree. However, higher aprepitant doses or repeated dosing at any aprepitant dose may have a clinically significant effect. As a moderate inhibitor of CYP3A4 at a dose of 125 mg/80 mg, aprepitant can increase plasma concentrations of concomitantly administered oral medications that are metabolized through CYP3A4 [see Contraindications]. The use of fosaprepitant may increase CYP3A4 substrate plasma concentrations to a lesser degree than the use of oral aprepitant (125 mg). 5-HT3 antagonists: In clinical drug interaction studies, aprepitant did not have clinically important effects on the pharmacokinetics of ondansetron, granisetron, or hydrodolasetron (the active metabolite of dolasetron). Corticosteroids: Dexamethasone: EMEND, when given as a regimen of 125 mg with dexamethasone coadministered orally as 20 mg on Day 1, and EMEND when given as 80 mg/day with dexamethasone coadministered orally as 8 mg on Days 2 through 5, increased the AUC of dexamethasone, a CYP3A4 substrate, by 2.2-fold on Days 1 and 5. The oral dexamethasone doses should be reduced by approximately 50% when coadministered with EMEND (125-mg/80-mg regimen), to achieve exposures of dexamethasone similar to those obtained when it is given without EMEND. The daily dose of dexamethasone administered in clinical chemotherapy-induced nausea and vomiting studies with EMEND reflects an approximate 50% reduction of the dose of dexamethasone. A single dose of EMEND (40 mg) when coadministered with a single oral dose of dexamethasone 20 mg, increased the AUC of dexamethasone by 1.45-fold. Therefore, no dose adjustment is recommended. Methylprednisolone: EMEND, when given as a regimen of 125 mg on Day 1 and 80 mg/day on Days 2 and 3, increased the AUC of methylprednisolone, a CYP3A4 substrate, by 1.34-fold on Day 1 and by 2.5-fold on Day 3, when methylprednisolone was coadministered intravenously as 125 mg on Day 1 and orally as 40 mg on Days 2 and 3. The IV methylprednisolone dose should be reduced by approximately 25% and the oral methylprednisolone dose should be reduced by approximately 50% when coadministered with EMEND (125-mg/80-mg regimen) to achieve exposures of methylprednisolone similar to those obtained when it is given without EMEND. Although the concomitant administration of methylprednisolone with the single 40-mg dose of aprepitant has not been studied, a single 40-mg dose of EMEND produces a weak inhibition of CYP3A4 (based on midazolam interaction study) and it is not expected to alter the plasma concentrations of methylprednisolone to a clinically significant degree. Therefore, no dose adjustment is recommended. Chemotherapeutic agents: [see Warnings and Precautions] Docetaxel: In a pharmacokinetic study, EMEND (125-mg/80-mg regimen) did not influence the pharmacokinetics of docetaxel. Vinorelbine: In a pharmacokinetic study, EMEND (125-mg/80-mg regimen) did not influence the pharmacokinetics of vinorelbine to a clinically significant degree. CYP2C9 substrates (warfarin, tolbutamide): Aprepitant has been shown to induce the metabolism of S(–) warfarin and tolbutamide, which are metabolized through CYP2C9. Coadministration of EMEND with these drugs or other drugs that are known to be metabolized by CYP2C9, such as phenytoin, may result in lower plasma concentrations of these drugs. Warfarin: A single 125-mg dose of EMEND was administered on Day 1 and 80 mg/day on Days 2 and 3 to healthy subjects who were stabilized on chronic warfarin therapy. Although there was no effect of EMEND on the plasma AUC of R(+) or S(–) warfarin determined on Day 3, there was a 34% decrease in S(–) warfarin (a CYP2C9 substrate) trough concentration accompanied by a 14% decrease in the prothrombin time (reported as international normalized ratio or INR) 5 days after completion of dosing with EMEND. In patients on chronic warfarin therapy, the prothrombin time (INR) should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of the 3-day regimen of EMEND with each chemotherapy cycle, or following administration of a single 40-mg dose of EMEND for prevention of postoperative nausea and vomiting. Tolbutamide: EMEND, when given as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, decreased the AUC of tolbutamide (a CYP2C9 substrate) by 23% on Day 4, 28% on Day 8, and 15% on Day 15, when a single dose of tolbutamide 500 mg was administered orally prior to the administration of the 3-day regimen of EMEND and on Days 4, 8, and 15. EMEND, when given as a 40-mg single oral dose on Day 1, decreased the AUC of tolbutamide (a CYP2C9 substrate) by 8% on Day 2, 16% on Day 4, 15% on Day 8, and 10% on Day 15, when a single dose of tolbutamide 500 mg was administered orally prior to the administration of EMEND 40 mg and on Days 2, 4, 8, and 15. This effect was not considered clinically important. Oral contraceptives: Aprepitant, when given once daily for 14 days as a 100-mg capsule with an oral contraceptive containing 35 mcg of ethinyl estradiol and 1 mg of norethindrone, decreased the AUC of ethinyl estradiol by 43%, and decreased the AUC of norethindrone by 8%. In another study, a daily dose of an oral contraceptive containing ethinyl estradiol and norethindrone was administered on Days 1 through 21, and EMEND was given as a 3-day regimen of 125 mg on Day 8 and 80 mg/day on Days 9 and 10 with ondansetron 32 mg IV on Day 8 and oral dexamethasone given as 12 mg on Day 8 and 8 mg/day on Days 9, 10, and 11. In the study, the AUC of ethinyl estradiol decreased by 19% on Day 10 and there was as much as a 64% decrease in ethinyl estradiol trough concentrations during Days 9 through 21. While there was no effect of EMEND on the AUC of norethindrone on Day 10, there was as much as a 60% decrease in norethindrone trough concentrations during Days 9 through 21. In another study, a daily dose of an oral contraceptive containing ethinyl estradiol and norgestimate (which is converted to norelgestromin) was administered on Days 1 through 21, and EMEND 40 mg was given on Day 8. In the study, the AUC of ethinyl estradiol decreased by 4% and 29% on Day 8 and Day 12, respectively, while the AUC of norelgestromin increased by 18% on Day 8 and decreased by 10% on Day 12. In addition, the trough concentrations of ethinyl estradiol and norelgestromin on Days 8 through 21 were generally lower following coadministration of the oral contraceptive with EMEND 40 mg on Day 8 compared to the trough levels following administration of the oral contraceptive alone. The coadministration of EMEND may reduce the efficacy of hormonal contraceptives (these can include birth control pills, skin patches, implants, and certain IUDs) during and for 28 days after administration of the last dose of EMEND. Alternative or backup methods of contraception should be used during treatment with EMEND and for 1 month following the last dose of EMEND. Midazolam: EMEND increased the AUC of midazolam, a sensitive CYP3A4 substrate, by 2.3-fold on Day 1 and 3.3-fold on Day 5, when a single oral dose of midazolam 2 mg was coadministered on Day 1 and Day 5 of a regimen of EMEND 125 mg on Day 1 and 80 mg/day on Days 2 through 5. The potential effects of increased plasma concentrations of midazolam or other benzodiazepines metabolized via CYP3A4 (alprazolam, triazolam) should be considered when coadministering these agents with EMEND (125 mg/80 mg). A single dose of EMEND (40 mg) increased the AUC of midazolam by 1.2-fold on Day 1, when a single oral dose of midazolam 2 mg was coadministered on Day 1 with EMEND 40 mg; this effect was not considered clinically important. In another study with intravenous administration of midazolam, EMEND was given as 125 mg on Day 1 and 80 mg/ day on Days 2 and 3, and midazolam 2 mg IV was given prior to the administration of the 3-day regimen of EMEND and on Days 4, 8, and 15. EMEND increased the AUC of midazolam by 25% on Day 4 and decreased the AUC of midazolam by 19% on Day 8 relative to the dosing of EMEND on Days 1 through 3. These effects were not considered clinically important. The AUC of midazolam on Day 15 was similar to that observed at baseline. An additional study was completed with intravenous administration of midazolam and EMEND. Intravenous midazolam 2 mg was given 1 hour after oral administration of a single dose of EMEND 125 mg. The plasma AUC of midazolam was increased by 1.5-fold. Depending on clinical situations (eg, elderly patients) and degree of

monitoring available, dosage adjustment for intravenous midazolam may be necessary when it is coadministered with EMEND for the chemotherapy-induced nausea and vomiting indication (125 mg on Day 1 followed by 80 mg on Days 2 and 3). Effect of Other Agents on the Pharmacokinetics of Aprepitant: Aprepitant is a substrate for CYP3A4; therefore, coadministration of EMEND with drugs that inhibit CYP3A4 activity may result in increased plasma concentrations of aprepitant. Consequently, concomitant administration of EMEND with strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir) should be approached with caution. Because moderate CYP3A4 inhibitors (eg, diltiazem) result in a 2-fold increase in plasma concentrations of aprepitant, concomitant administration should also be approached with caution. Aprepitant is a substrate for CYP3A4; therefore, coadministration of EMEND with drugs that strongly induce CYP3A4 activity (eg, rifampin, carbamazepine, phenytoin) may result in reduced plasma concentrations of aprepitant that may result in decreased efficacy of EMEND. Ketoconazole: When a single 125-mg dose of EMEND was administered on Day 5 of a 10-day regimen of 400 mg/ day of ketoconazole, a strong CYP3A4 inhibitor, the AUC of aprepitant increased approximately 5-fold and the mean terminal half-life of aprepitant increased approximately 3-fold. Concomitant administration of EMEND with strong CYP3A4 inhibitors should be approached cautiously. Rifampin: When a single 375-mg dose of EMEND was administered on Day 9 of a 14-day regimen of 600 mg/ day of rifampin, a strong CYP3A4 inducer, the AUC of aprepitant decreased approximately 11-fold and the mean terminal half-life decreased approximately 3-fold. Coadministration of EMEND with drugs that induce CYP3A4 activity may result in reduced plasma concentrations and decreased efficacy of EMEND. Additional Interactions: EMEND is unlikely to interact with drugs that are substrates for the P-glycoprotein transporter, as demonstrated by the lack of interaction of EMEND with digoxin in a clinical drug interaction study. Diltiazem: In patients with mild to moderate hypertension, administration of aprepitant once daily, as a tablet formulation comparable to 230 mg of the capsule formulation, with diltiazem 120 mg 3 times daily for 5 days, resulted in a 2-fold increase of aprepitant AUC and a simultaneous 1.7-fold increase of diltiazem AUC. These pharmacokinetic effects did not result in clinically meaningful changes in ECG, heart rate, or blood pressure beyond those changes induced by diltiazem alone. Paroxetine: Coadministration of once-daily doses of aprepitant, as a tablet formulation comparable to 85 mg or 170 mg of the capsule formulation, with paroxetine 20 mg once daily, resulted in a decrease in AUC by approximately 25% and Cmax by approximately 20% of both aprepitant and paroxetine. USE IN SPECIFIC POPULATIONS Pregnancy: Teratogenic effects: Pregnancy Category B: Reproduction studies have been performed in rats at oral doses up to 1000 mg/kg twice daily (plasma AUC 0–24hr of 31.3 mcg•hr/mL, about 1.6 times the human exposure at the recommended dose) and in rabbits at oral doses up to 25 mg/kg/day (plasma AUC 0–24hr of 26.9 mcg•hr/mL, about 1.4 times the human exposure at the recommended dose) and have revealed no evidence of impaired fertility or harm to the fetus due to aprepitant. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nursing Mothers: Aprepitant is excreted in the milk of rats. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for possible serious adverse reactions in nursing infants from aprepitant and because of the potential for tumorigenicity shown for aprepitant in rodent carcinogenicity studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: Safety and effectiveness of EMEND in pediatric patients have not been established. Geriatric Use: In 2 well-controlled chemotherapy-induced nausea and vomiting clinical studies, of the total number of patients (N=544) treated with EMEND, 31% were 65 and over, while 5% were 75 and over. In well-controlled postoperative nausea and vomiting clinical studies, of the total number of patients (N=1120) treated with EMEND, 7% were 65 and over, while 2% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. Dosage adjustment in the elderly is not necessary. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies were conducted in SpragueDawley rats and in CD-1 mice for 2 years. In the rat carcinogenicity studies, animals were treated with oral doses ranging from 0.05 to 1000 mg/kg twice daily. The highest dose produced a systemic exposure to aprepitant (plasma AUC 0–24hr ) of 0.7 to 1.6 times the human exposure (AUC 0–24hr =19.6 mcg•hr/mL) at the recommended dose of 125 mg/day. Treatment with aprepitant at doses of 5 to 1000 mg/kg twice daily caused an increase in the incidences of thyroid follicular cell adenomas and carcinomas in male rats. In female rats, it produced hepatocellular adenomas at 5 to 1000 mg/kg twice daily and hepatocellular carcinomas and thyroid follicular cell adenomas at 125 to 1000 mg/kg twice daily. In the mouse carcinogenicity studies, the animals were treated with oral doses ranging from 2.5 to 2000 mg/kg/day. The highest dose produced a systemic exposure of about 2.8 to 3.6 times the human exposure at the recommended dose. Treatment with aprepitant produced skin fibrosarcomas at 125 and 500 mg/ kg/day doses in male mice. Aprepitant was not genotoxic in the Ames test, the human lymphoblastoid cell (TK6) mutagenesis test, the rat hepatocyte DNA strand break test, the Chinese hamster ovary (CHO) cell chromosome aberration test, and the mouse micronucleus test. Aprepitant did not affect the fertility or general reproductive performance of male or female rats at doses up to the maximum feasible dose of 1000 mg/kg twice daily (providing exposure in male rats lower than the exposure at the recommended human dose and exposure in female rats at about 1.6 times the human exposure). PATIENT COUNSELING INFORMATION [See FDA-Approved Patient Labeling.] Instructions: Physicians should instruct their patients to read the patient package insert before starting therapy with EMEND and to reread it each time the prescription is renewed. Patients should be instructed to take EMEND only as prescribed. For prevention of chemotherapy-induced nausea and vomiting (CINV), patients should be advised to take their first dose (125 mg) of EMEND 1 hour prior to chemotherapy treatment. For prevention of postoperative nausea and vomiting (PONV), patients should receive their medication (40-mg capsule of EMEND) within 3 hours prior to induction of anesthesia. Allergic reactions, which may be serious, and may include hives, rash, and itching, and cause difficulty in breathing or swallowing, have been reported in general use with EMEND. Physicians should instruct their patients to stop taking EMEND and call their doctor right away if they experience an allergic reaction. EMEND may interact with some drugs including chemotherapy; therefore, patients should be advised to report to their doctor the use of any other prescription or nonprescription medication or herbal products. Patients on chronic warfarin therapy should be instructed to have their clotting status closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of the 3-day regimen of EMEND 125 mg/80 mg with each chemotherapy cycle, or following administration of a single 40-mg dose of EMEND for prevention of postoperative nausea and vomiting. Administration of EMEND may reduce the efficacy of hormonal contraceptives. Patients should be advised to use alternative or backup methods of contraception during treatment with EMEND and for 1 month following the last dose of EMEND. For detailed information, please read the Prescribing Information. Rx only

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ORIGINAL RESEARCH

J Hematol Oncol Pharm. 2011;1(3):12-17 www.JHOPonline.com Disclosures are at end of text

Background: Ifosfamide is a frequently used nitrogen mustard chemotherapeutic alkylating agent that is available commercially in either an aqueous or powder formulation. Documented toxicities related to ifosfamide include a unique neurotoxicity that has been associated with hypoalbuminemia, previous or concurrent administration of other neurotoxic agents, and renal dysfunction. Although data regarding ifosfamide neurotoxicity are available in adult medical oncology literature, studies regarding pediatric neurotoxicity are limited. Objective: To review the clinical and pharmacologic characteristics of ifosfamide-induced neurotoxicity associated with the use of aqueous ifosfamide in pediatric patients. Methods: Retrospective chart review was used to identify cases of ifosfamide-induced encephalopathy at 5 pediatric oncology centers. Results: This multi-institutional case series evaluates 13 pediatric cases of ifosfamide-induced encephalopathy. The patients exhibited confusion, lethargy, aphasia, incontinence, and auditory hallucinations. Less than half of the patients had hypoalbuminemia, and none had renal dysfunction at the onset of neurotoxicity that was associated with ifosfamide administration. Three patients had previous exposure to cisplatin. New anecdotal evidence presented in this study suggests that the aqueous formulation of ifosfamide may be associated with higher incidence of neurotoxicity than the powder formulation. A total of 5 patients were rechallenged with the powder formulation, without recurrence of neurotoxicity. Conclusion: Our observation lends credence to the clinical opinion that the aqueous formulation of ifosfamide may be a risk factor for neurotoxicity.

fosfamide is a chemotherapeutic agent frequently used in the treatment of sarcomas and hematologic malignancies. Ifosfamide is associated with unique neurotoxicity that may include confusion, seizures, hallucinations, incontinence, and cranial nerve abnormalities. Currently, ifosfamide is available commercially as either a lyophilized powder or a liquid formulation. Since the release of aqueous ifosfamide in 2002, several institutions have transitioned to utilizing this formulation as a costsaving measure, but ifosfamide dosing strategies have

essentially remained the same. Previous pharmacologic studies have not identified any distinct differences in metabolism between these 2 formulations.1 The mechanisms related to ifosfamide-induced neurotoxicity remain unclear; however, reports suggest an association with accumulation of neurotoxic metabolites such as chloroacetaldehyde (CAA), concurrent use of aprepitant, cisplatin exposure, reduced thiamine bioavailability, hypoalbuminemia, low hemoglobin level, low total bilirubin level, and renal dysfunction.2-6

Dr Lee is a Pediatric Resident, Florida State University, Sacred Heart Women and Children’s Hospital, Pensacola; Mr Henry is Associate Professor, Pharmacy Practice, University of Kansas Medical Center, Kansas City; Dr Ng is Pediatric Clinical Pharmacist, Department of Pharmacy, Wolfson Children’s Hospital, and College of Pharmacy, University of Florida, Jacksonville; Dr Parsons is Pediatric Oncology Pharmacist, Children’s Hospital of Alabama, Birmingham; Dr Poon is Hematology/Oncology Clinical Pharmacist, Florida Hospital for Children, Orlando; Dr Schwartz is Chief, Pediatric Hematology/Oncology, Nemours Children’s Clinic, Pensacola, FL; Dr Smith is Clinical Pharmacy Manager, Pediatrics, Sacred Heart Women and Children’s Hospital, Pensacola, FL; and Dr Assanasen is Assistant Professor, Pediatric Hematology-Oncology, University of Texas Health Science Center at San Antonio, CHRISTUS Santa Rosa Children’s Hospital.

Journal of Hematology Oncology Pharmacy

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September 2011

Vol 1, No 3

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Ifosfamide Neurotoxicity in Pediatric Patients

Methods This retrospective chart review of patients diagnosed with ifosfamide-induced neurotoxicity was conducted at 5 pediatric oncology centers—Children’s Hospital of Alabama, Birmingham; Wolfson Children’s Hospital, Jacksonville, FL; Sacred Heart Children’s Hospital, Pensacola, FL; Florida Hospital, Orlando; and University of Kansas Hospital, Kansas City. Pertinent data reviewed for this study included patient age, diagnosis, treatment regimen, ifosfamide dose and formulation, description of neurotoxicity symptoms, concurrent use of aprepitant, cisplatin exposure, serum albumin levels, serum creatinine, and the use of methylene blue, an electron acceptor. Results We reviewed 13 cases of ifosfamide-induced neurotoxicity in children and teens aged 4 to 19 years who were diagnosed between 2002 and 2010 (Table). The predominant diagnosis was sarcoma (N = 11), although 2 other patients received ifosfamide as therapy for pre–B-cell acute lymphocytic leukemia (ALL) and primitive neuro ectodermal tumor. All patients initially received the aqueous formulation of ifosfamide. Daily dosages of ifosfamide ranged from 1.8 g/m2 per dose to 3.5 g/m2 per dose. Only 1 patient received concurrent therapy with aprepitant. All patients exhibited multiple symptoms of neurotoxicity: confusion (N = 7), lethargy (N = 5), aphasia (N = 4), and incontinence (N = 4). One patient experienced auditory hallucinations. Data were analyzed for possible organic predisposing factors for neurotoxicity. Of the 13 patients, 9 received intravenous methylene blue as treatment, and all patients experienced abatement of symptoms within 5 days. After the resolution of neurotoxicity, 5 patients who had previously received the aqueous compound received subsequent dosing with the powder formulation of ifosfamide, without further recurrence of neuropsychiatric symptoms. Discussion Incidence of Ifosfamide-Induced Neurotoxicity Approximately 10% to 40% of pediatric and adult patients who receive ifosfamide experience encephalopathy.2-4,6 Although widely reported in adult medical oncology literature, this phenomenon is less frequent in the pediatric population.7 Ifosfamide neuro toxicity in the pediatric patient varies in presentation but most often consists of confusion, hallucinations, and incontinence.8 Predisposing Factors Risk factors for ifosfamide neurotoxicity, such as

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September 2011

hypoalbuminemia, renal dysfunction, concurrent use of aprepitant, and a history of cisplatin exposure, were identified in our patient population (Table). Other less reported risk factors, such as low hemoglobin and low total bilirubin levels, were not evaluated in our study. Currently, the greatest risk factor for neurotoxicity is hypoalbuminemia, predominantly a serum albumin level <3.3 g/dL.2,3 Recent reports show that prophylaxis with an albumin infusion has no apparent effect on the development of ifosfamide-related neurotoxicity, suggesting that hepatic dysfunction rather than albumin depletion may account for such a predisposition.

Currently, the greatest risk factor for neurotoxicity is hypoalbuminemia, predominantly a serum albumin level <3.3 g/dL. Recent reports show that prophylaxis with an albumin infusion has no apparent effect on the development of ifosfamide-related neurotoxicity. Of the often implicated risk factors, hypoalbuminemia was the most frequently identified risk factor in our study. A total of 7 patients had hypoalbuminemia with albumin levels of ≤3.3 g/dL at the time of ifosfamide administration. In addition, 3 of the 5 patients who were rechallenged with the powder remained hypoalbuminemic but did not experience recurrent symptoms of neurotoxicity when the powder formulation was used. Renal dysfunction was not identified as a risk factor in our patient population, because only 1 patient experienced elevated creatinine level (1.3 mg/dL) throughout the course of therapy. Only 1 patient had concurrent use of aprepitant, suggesting that this is also difficult to identify as a predisposing factor in the pediatric population. Although 3 patients had a history of previous cisplatin exposure, they had normal renal function at the time of ifosfamide administration. Of these patients, 2 did not experience encephalopathy when rechallenged with a powder formulation. Therefore, in our population it is difficult to determine if cisplatin exposure is related to ifosfamide neurotoxicity, particularly in the setting of normal renal function.

Mechanism of Neurotoxicity The metabolism of ifosfamide by the hepatic cytochrome (CY) P450 system results in inactive metabolites, toxic metabolites, and the active form of the drug, isophosphoramide, a nitrogen mustard. Neurotoxic effects are thought to be associated with disruption of the mitochondrial respiratory chain and the

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No/No

Rhabdomyosarcoma 1.8 g/m2 ⳯ 5 days

No/No

3 g/m2 ⳯ 3 days

No/Yes

No/No

2.8 g/m2 ⳯ 5 days

Osteosarcoma

Clear-cell sarcoma right medial thigh

Metastatic desmoplastic round cell tumor

1.8 g/m2 ⳯ 5 days

No/No

1.8 g/m2 ⳯ 5 days

Pre–B-cell ALL

No/No

Clear-cell sarcoma 3 g/m2 ⳯ 3 days of kidney with central nervous system relapse

Diagnosis

Sex

Age, yr

Ifosfamide dose (liquid)

Concurrent use of aprepitant?/ History of cisplatin exposure?

Alternating agitation and lethargy, unable to ambulate, disorientation Confusion, asthenia, presyncope

Lethargy, confusion, incontinence

Ataxia, vertigo, lethargy

Ifosfamide symptoms

Aphasia, confusion, aggression

Disorientation, aphasia, new tremor, emotional lability

Table Characteristics of Pediatric Patients with Ifosfamide Neurotoxicity

2.7

3.7

3.8

3.2

2.1

3.5

0.8

0.71

0.5

0.8

0.3

0.7

Head CT and MRI negative EEG indicative of encephalopathy Powder formulation used on later date and no neurotoxicity

Yes ⳯ 2

MRI and LP negative Returned to baseline on hospital day 4 Rechallenged 2 months later with same regimen without recurrent symptoms

Symptoms resolved after 24 hrs of treatment Finished proton beam therapy, transferred back to referral center Not rechallenged

Yes ⳯ 4

Head CT negative Dose 3 held Returned to baseline status and discharged on hospital day 5 Not rechallenged

Head MRI negative Symptoms experienced after dose 4 Powder formulation used for dose 5 without recurrent symptoms

Head CT negative Neurotoxicity occurred on last cycle of chemotherapy Did not rechallenge

Comments

Yes ⳯ 1

Yes ⳯ 2

Serum Serum albumin, creatinine, Methylene g/dL blue mg/L

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l No/No

No/No

Alveolar 1.8 g/m2 ⳯ 5 days rhabdomyosarcoma 3.5 g/m2 ⳯ 5 days

Disorientation, confusion

Amnesia, confusion

Aphasia, lethargy, confusion

Disorientation, confusion

Aphasia, lethargy, facial twitch and myoclonic jerks

Agitation, aphasia, incontinence

Incontinence, tremor, auditory hallucinations

Ifosfamide symptoms

3.5

4.1

3.6

3.2

3.1

2.9

0.7

0.8

1.3

0.5

0.6

Head CT negative Returned to baseline on hospital day 4 Not rechallenged Last course of chemotherapy before expiration Course shortened because of symptoms Returned to baseline within 4 days Rechallenged with dose reduction without recurrent symptoms

Yes ⳯ 1

Yes ⳯ 8

Ifosfamide discontinued Switched to nonifosfamidecontaining regimen Returned to baseline within 48 hrs Ifosfamide discontinued Not rechallenged

Yes ⳯ 8

Last 2 doses ifosfamide held Returned to baseline within 5 days Rechallenged with dose reduction without recurrent symptoms

Completed course with frequent dosing methylene blue Not rechallenged

Yes ⳯ 8

Powder formulation used on subsequent admission, no neurotoxicity

Comments

Yes ⳯ 6

Serum Serum albumin, creatinine, Methylene g/dL blue mg/L

ALL indicates acute lymphocytic leukemia; CT, computed tomography; EEG, electroencephalogram; LP, lumbar puncture; MRI, magnetic resonance imaging; PNET, primitive neuroectodermal tumor.

Spinal osteosarcoma

No/No

Undifferentiated 2.8 g/m2 ⳯ 5 days sarcoma

No/No

3 g/m2 ⳯ 2 days

3.5 g/m2 ⳯ 5 days

No/Yes

3 g/m2 ⳯ 3 days

Osteosarcoma

Yes/Yes

2.8 g/m ⳯ 5 days

Ifosfamide dose (liquid)

Concurrent use of aprepitant?/ History of cisplatin exposure?

Osteosarcoma

Metastatic PNET

Diagnosis

Sex

Age, yr

Table (Continued)

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Ifosfamide Neurotoxicity in Pediatric Patients

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ORIGINAL RESEARCH

Figure Mechanism of Ifosfamide-Induced Neurotoxicity Ifosfamide

Extrahepatic MAO activity

CAA

Methylene blue

Other metabolites

NADH CAA catabolism

Chloroethylamineinduced inhibition of mitochondrial respiratory chain

Neurotoxicity

Methylene blue

Competitive inhibition of thiamine pyrophosphate and/or thiamine triphosphate

Isophosphoramide mustard (active)

Thiamine

CAA indicates chloroacetaldehyde; MAO, monoamine oxidase; NADH, nicotinamide adenine dinucleotide hydride.

accumulation of nicotinamide adenine dinucleotide hydride, which prevents dehydrogenation of the neurotoxic metabolite CAA.9,10 Therefore, factors that may account for predisposition to neurotoxicity include markers of hepatic function, such as albumin, or concurrent administration of substances that affect the CYP450 enzymes, including aprepitant.

The treatment of ifosfamide-induced neurotoxicity is focused on the reduction of excess electrons and restoration of the mitochondrial respiratory chain, resulting in increased metabolism of CAA. Recent reports show that prophylaxis with an albumin infusion has no apparent effect on the development of ifosfamide-related neurotoxicity, further suggesting that hepatic dysfunction rather than albumin depletion may account for this predisposition.11 The treatment of ifosfamide-induced neurotoxicity is focused on the reduction of excess electrons and restoration of the mito-

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chondrial respiratory chain, resulting in increased metabolism of CAA (Figure). Methylene blue has traditionally been used to accomplish this.9,10,12 Methylene blue may also reduce the formation of CAA by blocking activity of monoamine oxidases. Although not as well described, intravenous thiamine administration has been reported in the literature as an intervention for ifosfamide-induced neurotoxicity. The proposed mechanism of action has been postulated to be related to ifosfamide-induced thiamine dysfunction or reduced thiamine availability.13-15 Alternatively, attempts have been made to prevent neurotoxicity by modifying the ifosfamide molecule, altering metabolism so that CAA production is hindered.16

Patient Characteristics Characteristics of rechallenged patients are also shown in the Table. For several years, anecdotal observations suggesting a higher incidence of encephalopathy with the aqueous formulation of ifosfamide have been discussed among oncologists and oncologic pharmacists. In this case series, we report 5 cases in which patients who developed encephalopathy with an aqueous ifos-

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Ifosfamide Neurotoxicity in Pediatric Patients

famide formulation did not experience recurrence of such symptoms when rechallenged with the powder formulation. A 19-year-old male with undifferentiated sarcoma and an 11-year-old female with osteosarcoma experienced neurotoxicity with the liquid formulation and later during therapy received the powder formulation without adverse effects. Neither had hypoalbuminemia or renal dysfunction when encephalopathy occurred. The 11-year-old female did have a history of cisplatin exposure. Both patients had normal serum albumin levels at the time of infusion with powder formulation. Two additional patients, a 14-year-old female with rhabdomyosarcoma and a 15-year-old female with osteosarcoma, both of whom had also had hypoalbuminemia, developed encephalopathy with the liquid formulation. Both patients were rechallenged at a later date with the powder formulation, which did not result in any adverse effect. The patients remained hypoalbuminemic at the time of infusion with the powder formulation (serum albumin levels, 3.3 g/dL and 3.1 g/dL, respectively). It is interesting to note that the 15-year-old female who was rechallenged had 3 known risk factors for ifosfamide-associated neurotoxicity—hypoalbuminemia, previous cisplatin exposure, and concurrent use of aprepitant. However, she did not experience recurrent encephalopathy with the powder formulation. A 7-year-old male with pre–B-cell ALL experienced lethargy, confusion, and incontinence after 4 doses of the liquid formulation of ifosfamide. He was persistently hypoalbuminemic throughout his hospital course and had no history of cisplatin exposure or renal dysfunction. He was not administered methylene blue. Rather, the patient’s next dose of ifosfamide was held, and his symptoms resolved within 24 hours. He was then administered the fifth dose of ifosfamide, using the powder formulation, and did not experience neurotoxicity.

Conclusion Ifosfamide-induced neurotoxicity has been frequently reported in the literature. Our case series raises some interesting questions regarding this phenomenon. Serum albumin has been reported as a risk factor, and this was identified in patients in this pediatric case series. However, low serum albumin levels were not consistently associated with neurotoxicity. Other risk factors, such as renal dysfunction or previous cisplatin exposure, could

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not be identified in our small population. In addition, the lack of neurotoxicity in patients rechallenged with the powder formulation of ifosfamide suggests a possible increased incidence of ifosfamide neurotoxicity with the liquid formulation of the drug. The current aqueous formulation of ifosfamide could be a contributing factor to neurotoxicity, and further studies are warranted to evaluate this trend. Investigation utilizing high-performance light chromatography or nuclear magnetic resonance spectroscopy to analyze possible differences in toxic metabolite formation between formulations may be helpful. ■

Author Disclosure Statement Dr Parsons is on the Speaker’s Bureau of Sigma Tau Pharmaceuticals. Drs Lee, Ng, Poon, Schwartz, Smith, and Assanasen, and Mr Henry have reported no actual or potential conflicts of interest. References 1. Gilard V, Martino R, Malet-Martino M, Niemeyer U. Stability of commercial formulations and aqueous solutions of ifosfamide: a reply. Drug Metab Dispos. 1997;25:927-931. 2. David KA, Picus J. Evaluating risk factors for the development of ifosfamide encephalopathy. Am J Clin Oncol. 2005;28:277-280. 3. Sweiss KI, Beri R, Shord SS. Encephalopathy after high-dose ifosfamide: a retrospective cohort study and review of the literature. Drug Saf. 2008;31:989-996. 4. Howell JE, Szabatura AH, Hatfield Seung A, Nesbit SA. Characterization of the occurrence of ifosfamide-induced neurotoxicity with concomitant aprepitant. J Oncol Pharm Pract. 2008;14:157-162. 5. Lee A, Assanasen C. Ifosfamide-induced neuropsychiatric toxicity in pediatrics. Pediatr Blood Cancer. 2010;54:857. 6. Tajino T, Kikuchi S, Yamada H, et al. Ifosfamide encephalopathy associated with chemotherapy for musculoskeletal sarcomas: incidence, severity, and risk factors. J Orthop Sci. 2010;15:104-111. 7. Dufour C, Grill J, Sabouraud P, et al. Ifosfamide induced encephalopathy: 15 observations. Arch Pediatr. 2006;13:140-145. 8. Di Cataldo A, Astuto M, Rizzo G, et al. Neurotoxicity during ifosfamide treatment in children. Med Sci Monit. 2009;15:CS22-CS25. 9. Pelgrims J, De Vos F, Van den Brande J, et al. Methylene blue in the treatment and prevention of ifosfamide-induced encephalopathy: report of 12 cases and a review of the literature. Br J Cancer. 2000;82:291-294. 10. Alici-Evcimen Y, Breitbart WS. Ifosfamide neuropsychiatric toxicity in patients with cancer. Psychooncology. 2007;16:956-960. 11. Kettle JK, Grauer D, Folker TL, et al. Effectiveness of exogenous albumin administration for the prevention of ifosfamide-induced encephalopathy. Pharmacotherapy. 2010;30:812-817. 12. Küpfer A, Aeschlimann C, Wermuth B, Cerny T. Prophylaxis and reversal of ifosfamide encephalopathy with methylene blue. Lancet. 1994;343:763-764. 13. Buesa JM, Garcia-Teijido P, Losa R, Fra J. Treatment of ifosfamide encephalopathy with intravenous thiamin. Clin Cancer Res. 2003;9:4636-4637. 14. Hamadani M, Awan F. Role of thiamine in managing ifosfamide-induced encephalopathy. J Oncol Pharm Pract. 2006;12:237-239. 15. Lombardi G, Zustovich F, Nicoletto MO, et al. Important role of thiamine in preventing ifosfamide-induced encephalopathy. J Oncol Pharm Practice. 2010;16:135-136. 16. Storme T, Deroussent A, Mercier L, et al. New ifosfamide analogs designed for lower associated neurotoxicity and nephrotoxicity with modified alkylating kinetics leading to enhanced in vitro anticancer activity. J Pharmacol Exp Ther. 2009;328:598-609.

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Carboplatin Dosing in Overweight and Obese Patients: A Single-Center Experience Ginah Nightingale, PharmD, BCOP; James A. Trovato, PharmD, MBA, BCOP, FASHP; Myounghee Lee, PhD, PharmD; Jennifer Thompson, PharmD, BCOP

J Hematol Oncol Pharm. 2011;1(3):18-24 www.JHOPonline.com Disclosures are at end of text

Background: Serum creatinine–based formulas are used to estimate glomerular filtration rate when calculating carboplatin dosage with the Calvert formula. In overweight and obese patients, body weight applied to serum creatinine–based formulas may overestimate glomerular filtration rate. Overestimation may result in divergent carboplatin dosages that correlate with dose-limiting thrombocytopenia, treatment delays, and dose reductions. Objective: The primary objective of this study was to evaluate physician prescribing practices with the Calvert formula in overweight and obese patients. The secondary objective was to identify presence of grade 3 or 4 thrombocytopenia, per the National Cancer Institute Common Toxicity Criteria for Adverse Events, treatment delays, and dose reductions. Method: A retrospective analysis was conducted using data from a total of 20 patients who received carboplatin therapy. Adults who received at least 1 dose of carboplatin with documentation of desired area under the concentration-time curve were included. Patients were excluded if baseline laboratory values were not available. We identified the serum creatinine–based formula utilized, the body weight descriptor applied to the glomerular filtration rate formula, and whether a maximal/capped creatinine clearance rate was determined. Results: A total of 50 patients were screened for eligibility, and 20 were included in the final analysis. Prescribers utilized the Cockcroft-Gault formula to estimate glomerular filtration rate in 100% of the participants (N = 20). Actual body weight was applied in 95% (N = 19) of the patients. Twenty-five percent of the patients (N = 5) experienced grade 3 or 4 thrombocytopenia, 10% (N = 2) experienced a carboplatin treatment delay, and 10% (N = 2) had a documented carboplatin dose reduction secondary to toxicity. Conclusion: The use of actual body weight in the Cockcroft-Gault equation to estimate glomerular filtration rate in the Calvert formula was associated with a high percentage of adverse clinical events. Increased awareness is needed in the oncology community to highlight unique considerations and confirm quality assurance when estimating renal clearance in the Calvert formula in overweight and obese patients. Prospective studies are needed to substantiate these preliminary clinical data.

arboplatin has been approved by the US Food and Drug Administration for the treatment of ovarian cancer and has been used off-label for the treatment of many solid tumors, including lung, head and neck, endometrial, breast, and cervical cancers.1 As a nonclassical alkylating agent, carboplatin acts by covalently binding to DNA, thereby interfering with the cross-

linking and synthesis of DNA and cell replication. Carboplatin is excreted almost exclusively by the kidneys. Approximately 65% to 70% of the total platinum dose is eliminated as intact carboplatin in the urine during the first 12 to 16 hours after administration.1 Carboplatin dosage relies on glomerular filtration rate (GFR) and area under the curve (AUC). The

Dr Nightingale is Assistant Professor, Department of Pharmacy Practice, Jefferson School of Pharmacy, Thomas Jefferson University, Philadelphia, PA; Dr Trovato is Associate Professor, Department of Pharmacy Practice and Science, University of Maryland School of Pharmacy, Baltimore; Dr Lee is Investigational Drug Specialist, Supervisor, Investigational Drug Service Pharmacy, Department of Pharmacy, University of Maryland Medical Center, Baltimore; and Dr Thompson is Investigational Drug Specialist, Investigational Drug Service Pharmacy, Department of Pharmacy, University of Maryland Medical Center, Baltimore. This study was presented as a poster at the 5th Annual Meeting of the Hematology Oncology Pharmacy Association; June 2009; Miami, FL.

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Carboplatin Dosing in Overweight and Obese Patients

Table 1 Serum Creatinine–Based Formulas Formula Equation Calvert formulaa

Carboplatin total dose, mg = target AUC, mg/mL•min × (GFR, mL/min + 25)

Original Cockcroft-Gaultb

CrCl, mL/min = ([140 – age, y] × [actual body weight, kg]) ÷ [72 × SCr, mg/dL] Females: multiply above result by 0.85

Modification of Diet in Renal Diseasec

GFR (mL/min/1.73 m2) = 170 × [SCr (mg/dL)]–0.999 × [age, y]–0.176 × [0.762 if patient is female] × [1.180 if patient is black] × [BUN, mg/dL]–0.170 × [albumin, g/dL]–0.318

Jelliffe equationd

Males: CrCl (mL/min/1.73 m2) = (98 – {0.8 × [age, y – 20]}) ÷ SCr, mg/dL Females: multiply above result by 0.9

Ideal body weight

Males: 50 kg + 2.3 × (height, in – 60) Females: 45.5 kg + 2.3 × (height, in – 60)

Adjusted body weight

Adjusted body weight (kg) = ideal body weight + [0.4 × (actual body weight, kg – ideal body weight, kg)]

Calvert AH, et al. J Clin Oncol. 1989;7:1748-1756. Cockcroft DW, et al. Nephron. 1976;16:31-41. c Levey AS, et al. Ann Intern Med. 1999;130:461-470. d Jelliffe RW. Ann Intern Med. 1973;79:604-605. b

AUC indicates area under the curve; BUN, blood urea nitrogen; CrCl, creatinine clearance; GFR, glomerular filtration rate; SCr, serum creatinine.

Calvert formula is the preferred method to calculate the dose for a given target AUC.2 Serum creatinine (SCr)-based formulas are used to estimate GFR when calculating carboplatin dosage with the Calvert formula. Individualized dosing is the current practice to control plasma drug exposure of carboplatin. A limitation of the Calvert formula is that the carboplatin dosage can substantially vary, depending on the SCr-based formula used to estimate GFR (ie, Cockcroft-Gault, Jelliffe, or Modification of Diet in Renal Disease [MDRD]). Furthermore, in overweight and obese populations, body weight (actual body weight vs ideal body weight) applied to an SCr-based formula may overestimate GFR. Overestimation of GFR may result in differences in carboplatin dosage that correlate with clinically relevant events, such as dose-limiting thrombocytopenia, treatment delays, and dose reductions. A study by Herrington and colleagues demonstrated that the optimal weight for overweight and obese patients in SCrbased formulas for use in the Calvert formula was adjusted body weight.3 The use of actual body weight in overweight or obese patients resulted in a carboplatin AUC that was 30% to 40% higher than the predicted or targeted carboplatin AUC.3 There are scarce data to guide decision-making regarding the influential variables within the Calvert formula (Table 1). Existing literature is currently limited,4-6 and there is not an established consensus within the oncology community. When actual body weight

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is applied to an SCr-based formula for use in the Calvert formula, overweight and obese patients may have carboplatin AUCs greater than targeted because of overestimation of renal clearance. The purpose of our study was to evaluate carboplatin dosing in overweight and obese patients and to assess clinical outcomes at our institution.

In overweight and obese populations, body weight applied to a SCr-based formula may overestimate GFR. Overestimation of GFR may result in differences in carboplatin dosage that correlate with clinically relevant events. Study Objectives The primary objective of this retrospective analysis was to evaluate physician prescribing practices with the Calvert formula in overweight and obese patients within our institution. Specifically, we identified the SCrbased formula used by the physician prescriber to estimate the GFR and body weight (ie, actual, ideal, adjusted) applied to the SCr-based formula, and whether a maximal/capped creatinine clearance (CrCl) rate was determined at the discretion of the prescriber. This information was gathered from a preprinted

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Figure Consort Diagram of Patients Who Were Screened/Excluded

Screened for eligibility N = 50

Enrolled N = 20

Excluded, N = 30 Reasons for exclusion • Low body weight, n = 3 • Ideal body weight, n = 27 • Missing laboratory values, n = 0

Obese (class I, II) N = 10

Extreme obesity (class III) N=1

Overweight N=9

chemotherapy order form that included calculations for estimated renal function and the body weight descriptor applied. The secondary objectives were to identify the presence of grade 3 or 4 thrombocytopenia (25.0-49.9 × 10e9/L or <25 × 10e9/L) according to the National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events,7 dose modifications, and treatment delays caused by toxicity.

Methods This study was reviewed and approved by the University of Maryland Institutional Review Board. A retrospective analysis was conducted using data from patients who received carboplatin therapy during the period between January 2008 and January 2009. Inclusion criteria were adult patients (aged ≥18 years) who received at least 1 dose of carboplatin with documentation of desired carboplatin AUC for solid tumor malignancies either as monotherapy or as part of combination chemotherapy treatment. Exclusion criteria included patients with incomplete or missing laboratory parameters on the preprinted chemotherapy order form. Patient data were accessed through electronic medical records. Data collection included demographic information, pretreatment and posttreatment complete blood count and nadir, concurrent cytotoxic chemo therapy, and any supporting documentation confirming treatment delays and dose reductions.

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We defined treatment delays as ≥7 days from the planned day of carboplatin administration. A dose reduction was defined as a ≥20% dose decline or a reduction in the target AUC from the previous dose, with supporting documentation on the chemotherapy order confirming a dose reduction secondary to toxicity. The actual carboplatin AUC and actual GFR were not measured as part of this analysis. Stable kidney function was defined by SCr change from baseline of <0.5 mg/dL.8 The SCr-based formula utilized by the prescribing physician, the body weight applied to the formula, the target AUC, and the treatment cycle number were collected from the chemotherapy order. Patients were categorized based on actual body weight (kg) and height (cm) into 1 of 5 groups, including: • Low body weight: body mass index (BMI) <18.5 kg/m2 • Normal/ideal body weight: BMI 18.5-24.9 kg/m2 • Overweight: BMI 25-29.9 kg/m2 • Obese class I: BMI 30-34.9 kg/m2 • Obese class II: BMI 35-39.9 kg/m2 • Extreme obesity/class III: BMI >40 kg/m2. Body weight categories are based on the National Institutes of Health guidelines on the identification of overweight and obese adults.9 Study analysis for end points included overweight, obese, and extremely obese patients.

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Results A sample of 50 patients who received carboplatin during the study period were screened for eligibility, and more than 10 medical oncology prescribers dosed carboplatin with the Calvert formula. Thirty patients were excluded based on criteria for low body weight, ideal body weight, or missing laboratory parameters; therefore, 20 patients were included in the final analysis (Figure). The demographics and baseline laboratory values of the patients are described in Table 2. The study demographics included mean age of 62.3 years, and more whites than blacks comprised the study population. Most patients had a primary diagnosis of non–smallcell lung cancer, followed by malignancy of the head and neck. Fifty percent of the patients were obese, and the mean BMI was 32.059 kg/m2. Based on the target carboplatin AUC, more than two thirds of patients were prescribed a carboplatin target AUC ≥5 mg/mL/min. Kidney function was stable for all patients. Seventy percent of the patients (N = 14) were treated with doublet-combination chemotherapy, and the remaining 30% of patients (N = 6) received a triplecombination chemotherapy regimen. The doubletcombination regimens included paclitaxel (N = 8), gemcitabine (N = 3), pemetrexed (N = 2), and etoposide (N = 1). The triple-combination chemotherapy regimens included paclitaxel (N = 5) and gemcitabine (N = 1) to monoclonal antibodies such as bevacizumab, cetuximab, and an investigational agent. Physician prescribers used the Cockcroft-Gault formula to estimate GFR for use in the Calvert formula in 100% of the patients (N = 20). Prescribers applied the laboratory-derived SCr to all SCr-based formulas. Prescribers did not apply an adjusted SCr value to account for the influence of muscle mass on creatinine concentrations in the elderly. Actual body weight was applied to the SCr-based formula in 19 patients (95%). Mean body weight was applied to the SCr-based formula in 1 patient. Of note, this patient was extremely obese with a BMI of 48.5 kg/m2. A maximum/capped CrCl rate of 125 mL/min was used for 2 patients (10%). Both of these patients had calculated GFR estimates of >150 mL/min based on the CockcroftGault formula, and these patients were enrolled in clinical protocols with amendments for capping CrCl rates. Five patients (25%) experienced grade 3 or 4 thrombocytopenia, 2 patients (10%) experienced a carboplatin treatment delay secondary to toxicity, and these 2 patients subsequently were discontinued from treatment with carboplatin. In addition, 2 patients (10%) had a documented car-

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Table 2 Baseline Characteristics of 20 Patients Variable Result Age, y, mean ± SD 62.30 ± 10.06 Sex, N (%) Male Female

9 (45) 11 (55)

Race, N (%) White Black Other

13 (65) 7 (35) 0 (0)

Cancer, N (%) Lung cancer Head/neck cancer Melanoma Other

14 (70) 3 (15) 2 (10) 1 (5)

Targeted carboplatin AUC, N (%) 2-4 mg/mL/min 5-7 mg/mL/min

7 (35) 13 (65)

Actual body weight, kg, mean ± SD

91.44 ± 17.29

Serum creatinine, mg/dL, mean ± SD

0.99 ± 0.00

Platelets, 10e9/L, mean ± SD

282.15 ± 84.54

AUC indicates area under the curve; SD, standard deviation.

boplatin dose reduction secondary to grade 3 or 4 thrombocytopenia. Overall, there were 9 documented clinical events occurring in 5 (25%) of the patients (Table 3).

An accurate assessment of kidney function is necessary and vital for determination or modification of dosages of chemotherapy agents eliminated through the kidney in an effort to minimize toxicity and maximize efficacy. Discussion An accurate assessment of kidney function is necessary and vital for determination or modification of dosages of chemotherapy agents eliminated through the kidney in an effort to minimize toxicity and maximize efficacy. Traditionally, CrCl has been measured using 12- or 24-hour urine collections for creatinine or using contrast agents such as iohexol or radiolabeled agents. The clearance of chromium 51-ethylenedi-

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Table 3 Clinical Outcomes Patienta 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

BMI, kg/m2 25.3 26.7 26.7 27.5 27.6 28.1 28.7 29.3 29.3 30.4 31.9 32.3 32.8 32.9 34.5 35.3 36.5 37.1 38.2 48.5

Applied SCr, mg/dL

Applied CrCl, mL/min

Grade 3 or 4 thrombocytopenia

1.44 0.87 1.66 1.44 0.89 0.9 1.0 0.8 0.96 0.98 1.11 0.7 0.91 1.18 0.76 0.79 0.95 1.0 0.62 0.9

64.6 81 49.66 67 87.8 93 85 83 75 97 90 118 79 81 104 91 93.2 125 125 112

No No No Yes No No No No No Yes No No Yes No No No Yes No No Yes

Dose reduction No No No No No No No No No No No No No No No No Yes No No Yes

Treatment delay No No No Yes No No No No No Yes No No No No No No No No No No

Listed by BMI ascending order. BMI indicates body mass index; CrCl, creatinine clearance; SCr, serum creatinine.

aminetetraacetic acid (51Cr-EDTA) was originally used for the determination of the GFR in the Calvert formula.2 This method is costly and may be clinically impractical; therefore, GFR is usually estimated from SCr-based formulas.10-12 Although these formulas are convenient to use, and they conserve time, there is a trade-off in accuracy and consistency with regard to the determination of GFR.

Our results demonstrate that physician prescribers utilized the Cockcroft-Gault equation to estimate GFR in all patients. None of our prescribers utilized the MDRD or the Jelliffe formula to estimate GFR. The literature is limited in terms of guiding decisionmaking within the oncology community for addressing the influential variables within the Calvert formula in overweight and obese patients. Our results demonstrate that physician prescribers utilized the Cockcroft-Gault equation to estimate GFR in all patients. None of our prescribers utilized the

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MDRD or the Jelliffe formula to estimate GFR. The Jelliffe equation is used by most gynecologic oncology group protocols, and gynecologic malignancies did not comprise our study population, which explains why the equation may not have been used. Existing data comparing the Cockcroft-Gault equation and the MDRD equation for calculating estimated renal function in the Calvert formula were recently published. Shord and colleagues conducted a retrospective analysis to determine the absolute difference between the dose of carboplatin administered using traditional SCr-based formulas to estimate GFR versus the dose calculated based on the MDRD equation.13 Results showed a carboplatin AUC dose divergence in 48% of the patients, yet the frequency of neutropenia, thrombocytopenia, and dose modifications were similar between the 2 groups using either the SCr-based formulas or the MDRD equation to estimate GFR value. The investigators concluded that the traditional SCr-based formulas used to calculate carboplatin dosage should be used until more data become available regarding the use of the MDRD equation in this population.13 The study conclusions are limited, because the goal was not specifically to evaluate dose divergence and clin-

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ical outcomes in overweight and obese patients, but the study does provide some data regarding surrogate markers within the Calvert formula. The NCIâ&#x20AC;&#x2122;s Cancer Therapy Evaluation Program released 2 action letters in October 2010 to address carboplatin dosing on sponsored protocols and the recent increase in toxicity.14,15 The program recommends utilizing the Cockcroft-Gault equation for calculating CrCl, and commented that the GFR used in the Calvert formula to calculate AUC-based dosing should not exceed 125 mL/min, in an attempt to prevent the erroneous overprediction of renal function estimates when using actual weight in the Cockcroft-Gault equation. These initiatives are limited, because they do not address the body weight that should be applied to the Cockcroft-Gault equation in special populations of overweight and obese patients. Our prescribers applied actual body weight to the Cockcroft-Gault SCr-based formula in 95% of patients. In our study, applying actual body weight to estimate GFR for use in the Calvert formula did correlate with a high percentage of clinical events, including grade 3 or 4 thrombocytopenia and dose reductions secondary to toxicity. The study by Herrington and colleagues demonstrated that the optimal weight to use for obese patients, defined as a BMI >30 kg/m2 with renal function and SCr within normal limits, was adjusted body weight.3 Using actual body weight in SCr-based formulas for the Calvert formula resulted in carboplatin AUCs 30% to 40% higher than predicted or targeted AUCs.3 The study results are limited because, despite evaluating actual versus targeted carboplatin AUC divergence in overweight and obese patients, the investigators did not objectively evaluate the impact of a supratherapeutic carboplatin AUC on clinical outcomes, such as doselimiting myelosuppression or treatment delays.3 Ekhart and colleagues assessed the utility of alternative weight descriptors in the Cockcroft-Gault equation to more accurately predict carboplatin clearance in special body weight populations.5 The results demonstrated that adjusted body weight was the best weight descriptor in overweight and obese patients. The study results suggested that overweight and obese patients with normal renal function should receive a flat carboplatin dose based on population carboplatin clearance. Existing data suggest a strong correlation between carboplatin AUC and dose-limiting myelosuppression, specifically thrombocytopenia.16-18 The incidence of thrombocytopenia in our study population was higher compared with those of standard populations. Based on data from Jodrell and colleagues in patients with ovarian cancer, the expected incidence of grade 3 thrombo-

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cytopenia for carboplatin AUC 4 to 5 is 5%, AUC 5 to 6 is 10%, and AUC 6 to 7 is 20%.19

Limitations There are some limitations to our investigation. This was a retrospective study design, and we were not able to control for the heterogeneity that comprised our small study population. There was also inconsistency with regard to the number of carboplatin treatment cycles that patients received in relation to documented dose reductions or treatment delays. Inconsistency also occurred with the time at which the complete blood count and nadir(s) were taken and evaluated for each patient. The chemotherapy combination regimens that each patient received were not well balanced, thus the addition of other cytotoxic chemotherapy agents, such as paclitaxel, increases the risk and severity of myelosuppression when compared with monotherapy. We did not identify any independent risk factors predicting dose reductions or therapy delays resulting from toxicity (ie, race, sex, age, cancer diagnosis, baseline platelet count, and previous myelotoxic chemotherapy, concurrent radiation therapy, or performance status). Finally, we did not measure actual carboplatin AUC or actual GFR utilizing 51Cr-EDTA.

Our results contribute to existing data regarding prescribing patterns within our institution and highlight unique considerations when calculating carboplatin dosage with the Calvert formula in overweight and obese patients. Conclusion Despite the study limitations, our results contribute to existing data regarding prescribing patterns within our institution and highlight unique considerations when calculating carboplatin dosage with the Calvert formula in overweight and obese patients. The use of actual body weight to estimate GFR in relation to the Calvert formula was associated with a high percentage of adverse clinical events. Increased awareness and education regarding unique considerations with the Calvert formula in overweight and obese populations should be directed to medical oncology physician prescribers, pharmacists, and healthcare providers within the oncology community to establish quality assurance within the institution or practice site. Future considerations include designing a prospective study evaluating body weight descriptors (ideal vs

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ORIGINAL RESEARCH

adjusted) to estimate GFR for use in the Calvert formula incorporating measured carboplatin AUCs compared with target AUCs to identify dose divergence and subsequent adverse clinical events in this population. A prospective study may substantiate these preliminary, clinically relevant data and may be able to establish a consensus in clinical practice, which is critical for patient safety and clinical outcomes. ■ Author Disclosure Statement Drs Nightingale, Trovato, Lee, and Thompson have reported no actual or potential conflicts of interest.

References 1. Alberts DS, Dorr RT. New perspectives on an old friend: optimizing carboplatin for the treatment of solid tumors. Oncologist. 1998;3:15-34. 2. Calvert AH, Newell DR, Gumbrell LA, et al. Carboplatin dosage: prospective evaluation of a simple formula based on renal function. J Clin Oncol. 1989;7:17481756. 3. Herrington JD, Tran HT, Riggs MW. Prospective evaluation of carboplatin AUC dosing in patients with a BMI ≥27 or cachexia. Cancer Chemother Pharmacol. 2005;57:241-247. 4. Chatelut E, Canal P, Brunner V, et al. Prediction of carboplatin clearance from standard morphological and biological patient characteristics. J Natl Cancer Inst. 1995;19:573-580. 5. Ekhart C, Rodenhuis S, Schellens JH, et al. Carboplatin dosing in overweight and obese patients with normal renal function, does weight matter? Cancer Chemother Pharmacol. 2009;64:115-122. 6. Schmitt A, Gladieff L, Lansiaux A, et al. A universal formula based on cystatin C to perform individual dosing of carboplatin in normal weight, underweight, and obese patients. Clin Cancer Res. 2009;15:3633-3639.

Journal of Hematology Oncology Pharmacy

7. Cancer Therapy Evaluation Program. Common Terminology Criteria for Adverse Events, v3.0S. http://ctep.cancer.gov/protocolDevelopment/electronic_ applications/docs/ctcaev3.pdf. August 9, 2006. Accessed August 19, 2011. 8. Thadhani R, Pascual M, Bonventre JV. Acute renal failure (letter). N Engl J Med. 1996;334:1448-1460. 9. National Institutes of Health National Heart, Lung, and Blood Institute. Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults: the Evidence Report. NIH Publication No 984083. September 1998. www.nhlbi.nih.gov/guidelines/obesity/ob_gdlns.pdf. Accessed August 19, 2011. 10. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16:31-41. 11. Levey AS, Bosch JP, Lewis JB, et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Ann Intern Med. 1999;130:461-470. 12. Jelliffe RW. Creatinine clearance: bedside estimate (letter). Ann Intern Med. 1973;79:604-605. 13. Shord SS, Bressler LR, Radhakrishnan L, et al. Evaluation of the Modified Diet in Renal Disease Equation for calculation of carboplatin dose. Ann Pharmacother. 2009;43:235-241. 14. National Institutes of Health, National Cancer Institute. Action letter for protocols sponsored by the National Cancer Institute that use carboplatin. Letter. October 1, 2010. www.cancerletter.com/downloads/20101008/download. Accessed August 19, 2011. 15. National Institutes of Health, National Cancer Institute. Follow-up for information letter regarding AUC-based dosing of carboplatin. Letter. October 22, 2010. http://ctep.cancer.gov/content/docs/Carboplatin_Information_Letter.pdf. Accessed August 19, 2011. 16. Duffull SB, Robinson BA. Clinical pharmacokinetics and dose optimization of carboplatin. Clin Pharmacokinet. 1997;33:161-183. 17. Sørensen BT, Strömgren A, Jakobsen P, Jakobsen A. Dose-toxicity relationship of carboplatin in combination with cyclophosphamide in ovarian cancer patients. Cancer Chemother Pharmacol. 1991;28:397-401. 18. Jakobsen A, Bertelsen K, Andersen JE, et al. Dose-effect study of carboplatin in ovarian cancer: a Danish Ovarian Group study. J Clin Oncol. 1997;15:193-198. 19. Jodrell DI, Egorin MJ, Canetta RM, et al. Relationships between carboplatin exposure and tumor response and toxicity in patients with ovarian cancer. J Clin Oncol. 1992;10:520-528.

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COMMENTARY

Dosing Chemotherapy in Obese Patients: No Clear Answers, Yet Scott Soefje, PharmD, BCOP Associate Director, Oncology Pharmacy Services Smilow Cancer Hospital at Yale University, New Haven, CT

lmost one third of Americans are currently considered obese.1 As the number of patients with cancer who are overweight is increasing, the conventions of chemotherapy dosing are constantly being questioned. Because of the concern for overdosing obese patients, clinicians are routinely tasked with questions such as—Should we use actual body weight, ideal body weight, or something in between? Should we cap doses? Overdosing patients is a concern for all clinicians, but underdosing may be just as problematic. Therefore, we must consider the dose-reduction questions in light of the medical literature, which suggests that such reductions may compromise patient outcomes.2-8

Clinicians spend too much time worrying about doses of chemotherapy. The assumption is that because doses are individualized based on the BSA calculation or the AUC, a more accurate dose is being selected. The reality is, however, that all the dosing calculations are based on an estimate. The use of body surface area (BSA) for dosing chemotherapy was developed in the 1950s as a method to translate animal dosing into humans,9 but no scientific study has demonstrated that BSA is a better dosing measurement than body weight or even fixed doses of chemotherapy. Many pharmacokinetic (PK) studies have demonstrated that the PK parameters do not correlate with BSA,10 and a growing body of evidence suggests that dosing obese patients based on actual body weight is not associated with increased toxicity.11-14 Some have suggested that flat dosing of carboplatin based on population parameters is just as effective as dosing based on the area under the curve (AUC) calculation.15,16 In this issue of the Journal of Hematology Oncology Pharmacy, Nightingale and colleagues address the issue of dosing carboplatin in obese patients.17 This retrospective analysis involves overweight patients receiving carboplatin. The authors’ approach in this study is to

Journal of Hematology Oncology Pharmacy

look at toxicity, which is supposed to be minimized with AUC-based dosing. The conclusion that the use of actual body weight to estimate the glomerular filtration rate (GFR) is associated with high incidence of toxicity is misleading. We know the incidence of toxicity in the 20 obese patients, but normal-weight patients were excluded from this study. How can we know, then, that there would not have been a similar rate of toxicity in normal-weight patients? Of note, the 2 patients whose creatinine clearance was capped at 125 mL/min did not have toxicity. We are, therefore, left with the question of how to calculate the appropriate dose in overweight patients. The common complaint about all studies that examine the effects of obesity on dosing is that those studies are usually retrospective, with small sample sizes, and the patient variability in PK parameters makes any generalized statement difficult. Most often, the goals of therapy are not considered. Furthermore, a little toxicity may be a good thing.18 Clinicians spend too much time worrying about doses of chemotherapy. The assumption is that because doses are individualized based on the BSA calculation or the AUC, a more accurate dose is being selected. The reality is, however, that all the dosing calculations are based on an estimate. Using the BSA consists of measured parameters (height and weight) that are then applied to a population-derived equation to arrive at an estimate. Calculating the Calvert equation for carboplatin does the same thing.19 A measured serum creatinine is used to estimate the GFR. Any additional adjustment that is then made because of obesity (or any other parameter) renders the estimate a guess. The good news is that help may be on the way. The American Society of Clinical Oncology is in the process of developing a practice guideline for dosing chemotherapy in obese patients with cancer.20 Until then—perhaps even beyond that—clinicians will need to balance the risks versus benefits and the efficacy versus toxicity, because the answer to the question of dosing in obese patients is still not clear. ■ Author Disclosure Statement Dr Soefje is on the Speaker’s Bureaus of Amgen, Eisai Pharmaceuticals, and ICU Medical, Inc.

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COMMENTARY

References 1. Flegal KM, Carroll MD, Ogden CL, Curtin LR. Prevalence and trends in obesity among U.S. adults, 1999-2008. JAMA. 2010;303:235-241. Epub 2010 Jan 13. 2. Bonadonna G, Valagussa P, Moliterni A, et al. Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer: the results of 20 years of follow-up. N Engl J Med. 1995;332:901-906. 3. Bonneterre J, Roché H, Kerbrat P, et al. Epirubicin increases long-term survival in adjuvant chemotherapy of patients with poor-prognosis, node-positive, early breast cancer: 10-year follow-up results of the French Adjuvant Study Group 05 randomized trial. J Clin Oncol. 2005;23:2686-2693. 4. Budman DR, Berry DA, Cirrincione CT, et al, for the Cancer and Leukemia Group B. Dose and dose intensity as determinants of outcome in the adjuvant treatment of breast cancer. J Natl Cancer Inst. 1998;90:1205-1211. 5. Lepage E, Gisselbrecht C, Haioun C, et al, for the GELA (Groupe d’Etude des Lymphomes de l’Adulte). Prognostic significance of received relative dose intensity in non-Hodgkin’s lymphoma patients: application to LNH-87 protocol. Ann Oncol. 1993;4:651-656. 6. Griggs JJ, Sorbero ME, Lyman GH. Undertreatment of obese women receiving breast cancer chemotherapy. Arch Intern Med. 2005;165:1267-1273. 7. Mayers C, Panzarella T, Tannock IF. Analysis of the prognostic effects of inclusion in a clinical trial and of myelosuppression on survival after adjuvant chemotherapy for breast carcinoma. Cancer. 2001;91:2246-2257. 8. Lyman GH. Impact of chemotherapy dose intensity on cancer patient outcomes. J Natl Compr Canc Netw. 2009;7:99-108. 9. Pinkel D. The use of body surface area as a criterion of drug dosage in cancer chemotherapy. Cancer Res. 1958;18:853-856. 10. Felici A, Verweij J, Sparreboom A. Dosing strategies for anticancer drugs: the good, the bad and body-surface area. Eur J Cancer. 2002;38:1677-1684. 11. Lopes-Serrao MD, Gressert Ussery SM, Hall RG II, Shah SR. Evaluation of

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chemotherapy-induced severe myelosuppression incidence in obese patients with capped dosing. J Oncol Pract. 2011;7:13-17. 12. Field KM, Kosmider S, Jefford M, et al. Chemotherapy dosing strategies in the obese, elderly and thin patients: results of a nationwide survey. J Oncol Pract. 2008;4:108-113. 13. Shayne M, Culakova E, Wolff D, et al. Dose intensity and hematologic toxicity in older breast cancer patients receiving systemic chemotherapy. Cancer. 2009;115:5319-5328. 14. Griggs JJ, Culakova E, Sorbero ME, et al. Social and racial differences in selection of breast cancer adjuvant chemotherapy regimens. J Clin Oncol. 2007;25:25222527. 15. Ekhart C, Rodenhuis S, Schellens JH, et al. Carboplatin dosing in overweight and obese patients with normal renal function, does weight matter? Cancer Chemother Pharmacol. 2009;64:115-122. Epub 2008 Nov 7. 16. Ekhart C, de Jonge ME, Huitema AD, et al. Flat dosing of carboplatin is justified in adult patients with normal renal function. Clin Cancer Res. 2006;12:65026508. 17. Nightingale G, Trovato JA, Lee M, Thompson J. Carboplatin dosing in overweight and obese patients: a single-center experience. J Hematol Oncol Pharm. 2011;1:18-24. 18. Di Maio M, Gridelli C, Gallo C, et al. Chemotherapy-induced neutropenia and treatment efficacy in advanced non–small-cell lung cancer: a pooled analysis of three randomised trials. Lancet Oncol. 2005;9:669-677. 19. Calvert AH, Newell DR, Gumbrell LA, et al. Carboplatin dosage: prospective evaluation of a simple formula based on renal function. J Clin Oncol. 1989;7:17481756. 20. Lyman GH. Chemotherapy dosing in obese patients with cancer—the need for evidence-based clinical practice guidelines. J Oncol Pract. 2011;7:17-18.

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The Nationâ&#x20AC;&#x2122;s First Peer-Reviewed Clinical Journal for Oncology Pharmacists JOURNAL OF

HEMATOLOGY ONCOLOGY PHARMACY THE PEER-REVIEWED FORUM FOR ONCOLOGY PHARMACY PRACTICE

Submita Manuscript! www.JHOPonline.com/manuscript

Readers are invited to submit the following types of articles: Review Articles Practical Issues in Pharmacy Management Clinical Controversies Commentaries/Opinion Letters to the Editor

For more information please call 732-992-1536 or e-mail JHOP@greenhillhc.com JHOPAsize91411

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AUTHOR GUIDELINES MISSION STATEMENT—The Journal of Hematology Oncology Pharmacy (JHOP) is an independent, peerreviewed journal founded in 2011 to provide hematology and oncology pharmacy practitioners and other healthcare professionals in these fields with high-quality peer-reviewed information relevant to hematologic and oncologic conditions to help them optimize drug therapy for patients.

EDITING—Routine editorial changes are made on all articles to conform to house style, following the AMA Manual of Style, 10th ed.1 The edited manuscript is sent to the corresponding author for a final review and for any outstanding editorial queries. Time from submission to publication is generally 4 to 7 months, but could be longer, depending on the peer-review and revision processes.

GENERAL INFORMATION—Manuscripts submitted to JHOP must be original and must not have been published previously, either in print or in electronic form. Manuscripts cannot be submitted elsewhere while under consideration by JHOP.

AUTHORSHIP/COPYRIGHT—Authors listed on the manuscript should only include those who have made a direct contribution to the content of the article, in accordance with the authorship criteria provided by the International Committee of Medical Journal Editors (ICMJE).2 Credit for authorship is based on a substantial contribution to (1) conception and design, or data analysis/interpretation, (2) drafting or revising the article critically for intellectual content, and (3) approval of the final version to be published. These 3 criteria must all be met.2 Those who have contributed to the article but do not meet these authorship criteria should be acknowledged at the end of the article.

The editors invite readers to submit articles on a variety of points of view and approaches to meet the mission of the journal. Articles will be divided into 4 main categories, including (1) original research, to provide an outlet for translational and practice-based research, including case reports and case series; (2) review articles that focus on drug and disease state as well as on basic science regarding the complex molecular biology of cancer with a pharmacy focus; (3) clinical controversies that discuss common clinical issues for which treatment is unclear, or “point, counterpoint” and “how I treat” type of articles; (4) practical issues in pharmacy management that will focus on realworld issues involving logistics, economics, and other practice-related topics. PEER REVIEW—All articles undergo an initial internal review for topic appropriateness and manuscript format. Manuscripts that are not submitted according to the guidelines in this document will be returned to the author. All manuscripts are subject to a strict, blinded peer review (by 2-3 reviewers), and acceptance is determined by the section editor based on that review. Reviewers look for accuracy of the information and data presented, as well as relevance to the objectives of JHOP. All authors’ identifying information is removed from the article for the purpose of the peer review, but any study funding information is provided to reviewers. Authors are notified as soon as possible regarding the initial decision of acceptance or rejection of the article. The majority of articles that are accepted for publication, however, will require revisions and resubmission.

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Provide authors’ highest academic degree and professional affiliations. Also provide the name, address, telephone number, e-mail, and fax number of the corresponding author. The corresponding author is responsible for securing signatures for all forms from all authors. All authors are required to sign an Authorship/Copyright Transfer Form, assigning all copyrights for the manuscript to Green Hill Healthcare Communications, LLC, publisher of JHOP. For an article to be considered for publication, authors must adhere to the manuscript format described in this document and follow the general ICMJE guidelines.2 DISCLOSURE STATEMENTS—All authors must disclose any relationship that could be viewed as a potential conflict of interest, based on ICMJE guidelines,2 including any financial interests, direct or indirect, and any affiliations or involvement (competitive or amiable) with organizations that have a financial interest in the subject matter or materials discussed in the manuscript. Each author must sign the Financial Disclosure Form in accordance with the ICMJE guidelines.2 JHOP discloses all information regarding employment, consultancies, stock ownership, honoraria, grants, or other financial sources with potential conflict of interest

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AUTHOR GUIDELINES

in relation to a manuscript, or if authors discuss any products or services with such commercial interest. Any information regarding funding, grants, or other financial compensation must be listed on the title page of the manuscript. All published articles will include disclosure statements listing any relationships with real or potential conflict of interest for all authors and for the manuscript/research. PERMISSIONS—Authors must secure written permission to reuse or adapt any graphic elements (table, figure) from a previously published (online or in print) article or from any other source. Provide the letter of permission when submitting the manuscript, or indicate that permission will be provided, and cite the original source with the graphic element in the manuscript. Authors are responsible for acknowledging all information that has been published previously. MANUSCRIPT FORMAT—Manuscripts that do not adhere to the format described in this document will be returned to the author. Title page: Include a proper title for the article and list the names, titles, and affiliations of all authors. Also list the name, address, telephone number, and e-mail address of the corresponding author. List all funding sources for the study/article. Abstract: Articles must include an abstract (200-300 words) that describes the main objectives of the article, why this article is important, and what it adds to the literature. The abstract must be divided into these categories: Background, Objective, Methods (and Study Design, if relevant), Results, and Conclusion. An abstract for an article that does not represent research findings should include the following categories to suggest why the article is important and what its main objective is: Background, Objective, Discussion, Conclusion. Text: The entire text must be provided as a doublespaced Word file and all pages numbered consecutively. Cite any graphic elements (tables, figures, algorithms, appendix) consecutively in the text, but place actual tables/figures at the end of the article, after the references. Limit the length of the text to 3500 words (excluding references, tables, and figures). Conclusion: The conclusion is not a summary of the article. Rather, it should add something new to the

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article, a point of view or comments related to the rationale for the article and what the article adds to the literature. Tables and figures: Cite all figures, tables, algorithms, and other graphics in the text, but place the graphic elements at the end of the article, after the references. Type all tables and all figure heads and captions in the Word document. Figures and other images (excluding tables) must also be provided as individual graphic files, saved at high resolution (300 dpi), as jpg or pdf file. Attach an individual file for each image. Images not saved appropriately will delay the peer-review process significantly. For help with images, please contact JHOP@greenhillhc.com. References: Use most up-to-date, post-1990, primary sources only, cited consecutively in the text (as superscript numbers), then place each complete reference at the end of the article under heading “References.” Avoid automatic numbering or footnote/endnote features. Try to limit the number of references to 35. Use citation format according to the AMA Manual of Style.1 Examples: 1. Peters JL, Sutton AJ, Jones DR, et al. Comparison of two methods to detect publication bias in meta-analysis. JAMA. 2006;295:676-680. 2. McGrath JJ, Murray RM. Risk factors for schizophrenia: from conception to birth. In: Hirsch SR, Weinberger DR, eds. Schizophrenia. Oxford, England: Blackwell Press; 2003. 3. Waters R, Pettypiece S. Drug sales in the US grow at slower pace as generic use surges. Bloomberg news, March 12, 2008. www.bloomberg.com/apps/news? pid=newsarchive&sid=aLfUw7_sYMRY. Accessed March 13, 2008.

HOW TO SUBMIT MANUSCRIPTS—Articles that do not follow the guidelines described in this document will not be considered for publication. Save the manuscript as a Word file and attach individual files for each image or figure. Save images (figures) individually as an image file (jpg or pdf). Submit the entire manuscript and a cover letter stating the objectives of the article to JHOP@greenhill hc.com. For assistance call 732-992-1536. REPRINTS—Reprints may be ordered for a nominal fee by contacting JHOP@greenhillhc.com. 1. AMA Manual of Style, 10th ed. New York, NY: Oxford University Press; 2007. 2. International Committee of Medical Journal Editors. Uniform Requirements for Manuscripts Submitted to Biomedical Journals. Updated April 2010. www.icmje.org/urm_full.pdf. Accessed June 1, 2010.

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Newsletter Series

YOUR QUESTIONS ANSWERED

Editor in Chief

Sagar Lonial, MD

Stephanie A. Gregory, MD

Associate Professor of Hematology and Oncology Emory University School of Medicine

The Elodia Kehm Chair of Hematology Professor of Medicine Director, Section of Hematology Rush University Medical Center/Rush University

Topics include: â&#x20AC;˘ Newly Diagnosed Patients â&#x20AC;˘ Maintenance Therapy â&#x20AC;˘ Transplant-Eligible Patients â&#x20AC;˘ Retreatment â&#x20AC;˘ Transplant-Ineligible Patients â&#x20AC;˘ Cytogenetics â&#x20AC;˘ Side-Effect Management â&#x20AC;˘ Bone Health

Topics include: â&#x20AC;˘ Hodgkin Lymphoma â&#x20AC;˘ Follicular Lymphoma â&#x20AC;˘ Mantle Cell Lymphoma â&#x20AC;˘ Waldenstromâ&#x20AC;&#x2122;s Macroglobulinemia â&#x20AC;˘ Diffuse Large B-Cell Lymphoma â&#x20AC;˘ T-Cell Lymphoma

This activity is supported by an educational grant from Millennium Pharmaceuticals, Inc.

This activity is supported by educational grant from Cephalon Oncology, Millennium Pharmaceuticals, Inc., and Seattle Genetics, Inc.

Target Audience These activities were developed for physicians, nurses, and pharmacists.

Accreditation This activity has been approved for 1.0 AMA PRA Category 1 Creditâ&#x201E;˘ (a total of 14.0 credit hours will be issued for completion of all activities). Nursing and Pharmacy credit hours will also be provided. For complete learning objectives and accreditation information, please refer to each activity. This activity is jointly sponsored by Global Education Group and Medical Learning Institute, Inc. Coordination for this activity provided by Center of Excellence Media, LLC.

For information about the physician accreditation of this activity, please contact Global at 303-395-1782 or inquire@globaleducationgroup.com. COEAsize40611MM

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FROM THE LITERATURE

Concise Reviews from the Literature Relevant to Hematology Oncology Pharmacy By Robert J. Ignoffo, PharmD, FASHP, FCSHP, Section Editor Clinical Professor Emeritus, University of California, San Francisco Professor of Pharmacy, College of Pharmacy, Touro University—California, Mare Island Vallejo, CA

■ Exemestane Effective for the Prevention of Invasive Breast Cancer in Postmenopausal Women Background: Estrogen is a known risk factor for breast cancer in women with a high level of circulating plasma estrogen. Therefore, chemoprevention of breast cancer has centered on the selective estrogen-receptor modulators (SERMs) tamoxifen and raloxifene. However, the majority of postmenopausal women who are at increased risk for breast cancer have not accepted the 2 SERMs for chemoprevention, primarily because of their toxic effects. In patients with early-stage breast cancer, aromatase inhibitors have been shown more effective than tamoxifen in preventing contralateral breast cancer and with fewer side effects. A recent international clinical trial was designed to investigate the benefit of the aromatase inhibitor exemestane for the prevention of invasive breast cancer in postmenopausal women. Design: This international, randomized, placebo-controlled, double-blind clinical trial enrolled 4560 postmenopausal (ie, no menses for 12 months) women (aged ≥35 years; median age, 62.5 years) from Canada, the United States, Spain, and France between February 2004 and March 2010. Postmenopausal women had to have 1 of these eligibility criteria—a 5-year risk for breast cancer (Gail risk score >1.66%); age ≥60 years; or previous atypical ductal or lobular hyperplasia or lobular carcinoma in situ, or ductal carcinoma in situ (DCIS) with mastectomy. The women were randomized to receive exemestane (N = 2285) or placebo (N = 2275) in 1 of 3 groups—exemestane 25 mg plus placebo, exemestane 25 mg plus celecoxib, or placebo—for 5 years or until an unacceptable adverse event occurred, including breast cancer, neoplastic disease, or a serious cardiovascular event. The primary end point was the incidence of invasive breast cancer. The secondary end points included the incidence of DCIS breast cancer; combined incidence of invasive breast cancer and DCIS; and the combined incidence of atypical ductal hyperplasia, atypical lobular hyperplasia, and lobular carcinoma in situ. Summary: At a median 35 months of follow-up, a total of 43 women were diagnosed with invasive breast cancer—11 women in the exemestane groups and 32 women in the placebo group. This translates to an annual breast cancer incidence of 0.19% with exemestane

Journal of Hematology Oncology Pharmacy

compared with a 0.55% incidence rate with placebo, for a 65% relative risk reduction with exemestane (hazard ratio [HR], 0.35; 95% confidence interval [CI], 0.180.70; P <.002). Exemestane was also associated with a lower incidence of invasive breast cancer plus DCIS (0.35%) compared with a 0.77% incidence rate with placebo (HR, 0.47; 95% CI, 0.27-0.79; P = .004). The majority of the tumors were estrogen receptor (ER)-positive, HER2/neu-negative, and node-negative. Adverse event rates were 88% with exemestane and 85% with placebo (P = .003). There were no significant differences in the rates of skeletal fractures, cardiovascular events, other cancers, and treatment-related deaths between the placebo and the active drug groups, and the differences in quality of life were minimal. Takeaway: For postmenopausal women with ER-positive, HER2/neu-negative, node-negative breast cancer who are at moderate risk for future invasive breast cancer, the use of exemestane prophylaxis reduces the annual risk of recurrent invasive breast cancer by 65%, as well as invasive DCIS by 35%. The antiestrogens tamoxifen and raloxifene have been used to also decrease invasive breast cancer, but their acceptance is poor (only 0.08% of women aged 40-79 years currently use these agents), probably because both are associated with rare endometrial cancers and thromboemboli (Ropka ME, et al. J Clin Oncol. 2010;28:3090-3095). With 3 years of follow-up, the absence of serious adverse effects, including bone fractures, is reassuring and may improve the acceptance of this agent for breast cancer chemoprevention. Bone mineral loss was prevented with oral bisphosphonate therapy. Goss PE, Ingle JN, Alés-Martínez JE, et al. Exemestane for breastcancer prevention in postmenopausal women. N Engl J Med. 2011;364:2381-2390.

■ Genotype-Based Dosing of Tamoxifen Improves Therapeutic Response in Invasive Breast Cancer Background: A majority of women diagnosed with invasive breast cancer are estrogen receptor (ER)-positive and therefore are candidates for tamoxifen treatment. However, approximately 50% of them do not derive full benefit from the drug, because genetic variations in the cytochrome P450 2D6 (CYP2D6) limit the ability of

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FROM THE LITERATURE

the enzyme to convert tamoxifen into its primary active metabolite, endoxifen. In a new study, researchers have investigated whether CYP2D6 genotyping could help guide the dosing of tamoxifen to increase the concentration of endoxifen in women who are intermediate or poor metabolizers of the CYP2D6 allele. Design: A total of 119 women (25 black women) aged ≥18 years were enrolled in the study, but only 89 were included in the final analysis of tamoxifen dose intervention. The women had been taking tamoxifen 20 mg daily ≥4 months and no strong CYP2D6inhibiting medications, and were evaluated for the CYP2D6 genotype and for plasma concentration of tamoxifen metabolites. Patients were divided into 3 genotype groups based on their endoxifen concentration—extensive metabolizers, intermediate metabolizers, and poor metabolizers. Patients who were extensive metabolizers of endoxifen continued to take the 20-mg dose of tamoxifen, and those who were intermediate or poor metabolizers had the tamoxifen dose increased to 40 mg daily. After 4 months, patients were measured again for their tamoxifen metabolites. The study primary end point was a change in plasma endoxifen concentration after 4 months of increased tamoxifen dosing for patients who were intermediate metabolizers of the drug. Summary: Among the study population, an unexpectedly high percentage of patients (72%) had one of the CYP450 alleles indicative of intermediate or poor metabolism of tamoxifen. African American women were approximately twice as likely as other women to have the CYP2D6 allele, which has been found to be associated with reduced tamoxifen metabolism (odds ratio, 2.26; 95% confidence interval, 1.17-4.37). Among the 89 patients who completed the study, the median baseline endoxifen concentration was higher in the 32 extensive metabolizers than in the 74 intermediate metabolizers (34.3 ng/mL vs 18.5 ng/mL; P = .004) or in the 11 poor metabolizers (4.2 ng/mL; P <.001). After 4 months of therapy with an increased tamoxifen dose from 20 mg to 40 mg, the median endoxifen concentration increased significantly in the intermediate metabolizers to 21.8 ng/mL (P <.001) and among poor metabolizers to 12.9 ng/mL (P = .020). Of note, after the 4 months, no significant difference was seen between the intermediate and extensive metabolizers in endoxifen concentrations, despite the almost twice as high concentration levels at baseline; in the poor metabolizers, the endoxifen concentration level remained significantly lower than both groups. Takeaway: This study demonstrates that adjusting tamoxifen dosing based on genotyping of CYP2D6 in women with ER-positive breast cancer may lead to

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endoxifen concentrations similar to those in extensive metabolizers. Increasing the dose from 20 to 40 mg in both poor and intermediate metabolizers of tamoxifen was effective and safe in raising endoxifen levels. However, this study was not designed to show whether clinical outcomes were improved with higher endoxifen levels. It may be that the efficacy of tamoxifen is not mediated solely through endoxifen. Until endoxifen concentrations are shown to be strongly associated with improved clinical outcomes in response and survival, the use of CYP2D6 genotyping will remain investigational. Of note is a recent study by Goetz and colleagues from the National Surgical Adjuvant Breast and Bowel Project’s Breast Cancer Prevention Trial (BCPT)-P1 and BCPT-P2 that showed alterations in CYP2D6 metabolism were not associated with either tamoxifen or raloxifene efficacy (Goetz MP, et al. Clin Cancer Res. 2011 Aug 31. Epub ahead of print). As suggested above, there may be other cytochrome alterations that may impact the use of genotyping. A recent study by van Schaik and colleagues from the Netherlands has shown that CYP2C19*2 genotype predicts tamoxifen treatment outcomes in patients with advanced breast cancer (van Schaik RH, et al. Pharmacogenomics. 2011;12:1137-1146). The time to treatment failure was improved by 28% in those who were heterozygous or homozygous for the CYP2C19*2 enzyme. Irvin WJ Jr, Walko CM, Weck KE, et al. Genotype-guided tamoxifen dosing increases active metabolite exposure in women with reduced CYP2D6 metabolism. J Clin Oncol. 2011;29:3232-3239.

■ Vemurafenib Improves Survival in Metastatic Melanoma with BRAF V600E Mutation Background: The prognosis for patients with metastatic melanoma is poor, ranging from 8 to 18 months, and the only chemotherapeutic agent currently approved by the US Food and Drug Administration (FDA) for the treatment of this disease is dacarbazine. A large percentage of cutaneous melanomas involve mutations in the BRAF gene that can activate tumor growth through the mitogen-activated protein kinase pathway. Previous studies have suggested that melanomas with the BRAF V600E mutation are more aggressive and less sensitive to chemotherapy than those with the BRAF wild-type mutation. In earlyphase clinical trials, the investigational agent vemurafenib, a BRAF kinase inhibitor that targets the BRAF V600E mutation, was associated with response rates of >50% in patients with BRAF V600E mutation melanoma. In a recent study, researchers compared the efficacy of dacarbazine and vemurafenib in this patient population.

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FROM THE LITERATURE

Design: In this phase 3 clinical trial, a total of 675 patients with previously untreated, unresectable stage IIIC or stage IV melanoma with the BRAF V600E mutation were randomly assigned to oral vemurafenib (N = 337) 960 mg twice daily or to dacarbazine (N = 338) 1000 mg/m2 infused every 3 weeks. With each drug, intolerable grade 2 toxic effects required dose reduction. Vemurafenib administration was halted until the toxic effect was reduced to grade 1 at least and was resumed at a dosing of 720 mg twice daily; the dose was reduced to 480 mg twice daily if the toxic effect recurred. If the 480-mg dose did not reduce the toxic effect to grade 1 or if the effect recurred, the treatment was stopped permanently. Dacarbazine administration was interrupted if grade 3 or 4 events occurred and was resumed within 1 week of grade 1 or 2, or resumed at a dosing of 75% for grade 4 neutropenia or febrile neutropenia. The primary end points were the rates of overall survival (OS) and progression-free survival (PFS). Secondary end points included the response rate, response duration, and safety. Summary: Patients were examined every 3 weeks and tumors assessed at baseline and at weeks 6, 12, and then every 9 weeks. Response to treatment was assessed with the Response Evaluation Criteria in Solid Tumors, version 1.1. The response rate with vemurafenib was 48% versus 5% with dacarbazine. The hazard ratio for death was 0.37 (95% confidence interval [CI], 0.260.55) with vemurafenib versus dacarbazine (P <.001). At 6 months, the OS was 84% (95% CI, 78-89) among patients receiving vemurafenib compared with 64% (95% CI, 56-73) among those receiving dacarbazine. The estimated median PFS was 5.3 months with vemurafenib and 1.6 months with dacarbazine. Compared with dacarbazine, vemurafenib was associated with a 63% relative risk reduction for death and a 74% risk reduction for either death or disease progression. The data and safety monitoring board recommended that patients in the dacarbazine group be allowed to cross over to receive vemurafenib based on the significant survival benefit with the latter. The most common adverse events associated with vemurafenib were arthralgia, rash, fatigue, alopecia, secondary neoplasia (keratoacanthoma or squamous-cell carcinoma), photosensitivity, nausea, and diarrhea. In all cases of secondary neoplasia (18%) associated with vemurafenib, the lesions were removed by simple excision, and no modifications in drug dose were necessary. Takeaway: The approval of vemurafenib marks the second new drug for metastatic cancer approved by the FDA in the past 13 years. This study showed a significant improvement over dacarbazine in OS. It also

Journal of Hematology Oncology Pharmacy

provides a strong case for the use of pharmacogenomic testing using the cobas 4800 BRAF V600 Mutation Test. Approximately 40% to 60% of cutaneous melanomas carry mutations in BRAF that lead to constitutive activation of downstream signaling through the MAPK pathway. Vemurafenib is an oral agent that is a moderate CYP1A2 inhibitor, a weak CYP2D6 inhibitor, and a CYP3A4 inducer and substrate. Increased monitoring is therefore advised for patients receiving warfarin therapy. Furthermore, strong CYP3A4 inhibitors and inducers may increase or decrease vemurafenibâ&#x20AC;&#x2122;s effects. The role of vemurafenib is still being investigated. Further studies are needed to determine if combinations with chemotherapy or other new agents (eg, ipilimumab) will improve on these results. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507-2516.

â&#x2013; PARP Inhibitor Olaparib a Promising Treatment for Ovarian Cancer Background: In phase 1 and 2 clinical trials, olaparib, a small-molecule poly(ADP-ribose) polymerase (PARP) inhibitor, has demonstrated objective responses in the treatment of tumors with BRCA1 and BRCA2 mutations in women with breast or ovarian cancer. Researchers have set out to assess the impact of BRCA mutations on the benefit of oral olaparib in patients with advanced triple-negative breast cancer or in those with high-grade ovarian cancer. Design: This open-label, nonrandomized phase 2 clinical study was conducted in 6 centers in Canada. A total of 91 women (aged â&#x2030;Ľ18 years) with advanced high-grade serous and/or undifferentiated ovarian carcinoma (N = 65) or triple-negative breast cancer (N = 26) were stratified according to BRCA mutation or lack of mutation; all the patients received oral olaparib 400 mg twice daily. The primary end point was the objective complete or partial response rate, based on the Response Evaluation Criteria in Solid Tumors. Secondary end points were the rate of disease control, percent change from baseline in tumor size, progression-free survival, and for those with ovarian cancer, evaluation of CA-125. Summary: All patients with measurable lesions were included in the objective response analysis, and all patients who received at least 1 dose of olaparib were included in the safety analysis. Of the 91 patients enrolled, 90 were treated between July 8, 2008, and September 24, 2009. Objective responses were not

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FROM THE LITERATURE

reported in patients with breast cancer. Among the 64 patients with ovarian cancer who received treatment, 63 were evaluable, and objective responses were confirmed in 7 (41%; 95% confidence interval [CI], 22-64) of the 17 women with BRCA1 or BRCA2 mutations and in 11 (24%; 95% CI, 14-38) of the 46 patients without BRCA mutations. A total of 13 of the 65 (20%) patients with ovarian cancer discontinued the study early because of worsening disease (N = 3), adverse event (N = 3), voluntary discontinuation (N = 2), and other reasons (N = 5). In addition, 1 of the patients with breast cancer discontinued early because of an adverse event. At study end, 13 of the 65 patients with ovarian cancer and 26 of those with breast cancer were still receiving olaparib. Drug-related adverse events occurred in 56 of 64 (88%) patients with ovarian cancer. The most common adverse events reported were fatigue (70% of patients with ovarian cancer and 50% of patients with breast cancer); nausea (66% and 62%, respectively); vomiting (39% and 35%, respectively); and decreased appetite (36% and 27%, respectively). Takeaway: This is the first study to show that the PARP inhibitor olaparib has activity in a heavily pretreated cohort of patients with high-grade serous ovarian cancer. It was active in patients whether they had germline BRCA mutations or not; it produced responses in 24% to 41% of the patients, which is similar to outcomes observed with the cytotoxic drugs pegylated doxorubicin and topotecan. This study was limited by the small number of patients (ie, 63), but it suggests that additional clinical trials with olaparib in patients with serous ovarian cancer are warranted. Olaparib was very well tolerated in this heavily pretreated group and may be an appropriate option for this aggressive form of ovarian cancer, in which treatment is usually limited to toxic chemotherapies. At the 2009 ASCO annual meeting, Tutt and colleagues reported that single-agent olaparib was active in BRCA-deficient triple-negative breast cancer (Tutt A. J Clin Oncol. 2009;27[suppl]). In that study, however, olaparib had no activity in triplenegative breast cancer, regardless of BRCA status. This may have been because of the small number of patients (ie, 23) in this cohort. Gelmon KA, Tischkowitz M, Mackay H, et al. Olaparib in patients with recurrent high-graded serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer. Lancet Oncol. 2011;12:852-861.

■ Nilotinib Sustains Efficacy Superior to Imatinib for 24 Months in Chronic Myeloid Leukemia Background: Nilotinib is a BCR-ABL inhibitor that was developed as a potent and selective treatment for

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patients with chronic myeloid leukemia (CML) in whom imatinib therapy has not shown appropriate efficacy. The US Food and Drug Administration approved the use of nilotinib 300 mg twice daily for the treatment of patients with newly diagnosed Philadelphia chromosome (Ph)-positive CML in the chronic phase based on results from the Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Newly Diagnosed Patients (ENESTnd) study, which showed superior efficacy for nilotinib over imatinib for up to 12 months. Now researchers from the ENESTnd study published the results of a new 12-month follow-up to the ENESTnd study. Methods: In this phase 3, multicenter, open-label, randomized study, 847 adult patients with chronic phase, Ph-positive CML were randomized (1:1:1) to receive oral therapy with nilotinib 300 mg twice daily (N = 282), nilotinib 400 mg twice daily (N = 281), or imatinib 400 mg once daily (N = 283). The efficacy results are based on the intention-to-treat population of patients. The primary end point was the major molecular response at 12 months, defined as BCR-ABL transcript levels on the International Scale of ≤0.1% by real-time quantitative polymerase chain reaction in peripheral blood. Summary: At 24 months, a major molecular response was seen in 201 (71%) patients receiving nilotinib 300 mg twice daily, in 187 (67%) patients receiving nilotinib 400 mg twice daily, and in only 124 (44%) patients receiving imatinib 400 mg once daily—a significant difference for both comparisons (P <.001). In addition, a complete molecular response was observed significantly more often in both nilotinib groups than in the imatinib group—74 (26%) patients receiving 300 mg nilotinib and 59 (21%) patients receiving 400 mg nilotinib compared with 29 (10%) of patients receiving 300 mg once P <.001 for nilotinib 300 mg twice daily vs imatinib; P = .004 for nilotinib 400 mg twice daily vs imatinib). Progression to accelerated or blast phase CML during treatment, including clonal evolution, occurred in 7 patients in the nilotinib groups and in 17 patients in the imatinib group. At 24 months, survival was comparable in all treatment groups, but there were fewer CMLrelated deaths with nilotinib (N = 8) than with imatinib (N = 10). In addition, the only grade 3 or 4 nonhematologic adverse effects occurring more frequently with nilotinib were headache and rash. However, in the second 12-month follow-up study, 8 additional serious adverse events were reported—7 in the nilotinib group and 1 in the imatinib group. Takeaway: This is an updated report of the ENESTnd trial, the international phase 3 clinical trial of nilotinib versus imatinib in CML with a minimum follow-up of 2 years. More than 90% of patients treated with nilotinib

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FROM THE LITERATURE

who had achieved major molecular response at 12 months were maintained at 24 months. Furthermore, BCR-ABL transcript levels were decreased below the threshold of <0.1% about 1 year earlier with nilotinib than with imatinib. This study demonstrated nilotinib’s superiority over imatinib, with faster, deeper, and more durable molecular responses and a significantly decreased risk of disease progression. In addition, emerging mutations of BCR-ABL in the nilotinib group were half that reported in those treated with imatinib. Nilotinib should be considered a first-line therapy for CML in chronic phase. Kantarijian HM, Hochhaus A, Saglio G, et al. Nilotinib versus imatinib for the treatment of patients with newly diagnosed chronic phase, Philadelphia chromosome–positive, chronic myeloid leukemia. Lancet Oncol. 2011;12:841-851.

■ Radiotherapy plus Short-Term Androgen Deprivation Extend Survival in Men with Intermediate-Risk, Early-Stage Prostate Cancer Background: In patients with locally advanced prostate cancer, radiotherapy added to long-term hormone therapy, or androgen-deprivation therapy (ADT), improves survival but also increases adverse events. Whether short-term ADT used before and during radiotherapy could improve survival in patients with early-stage, localized prostate cancer has not been known. Previous studies have shown that short-term ADT improves survival among patients with later-stage prostate cancer. In a new large clinical trial funded by the National Cancer Institute, researchers investigated the best approach to therapy for men with intermediate-risk, early-stage prostate cancer. Method: This 212-center study included 1979 men with early-stage prostate cancer. All patients had localized prostate cancer and prostate-specific antigen (PSA) levels ≤20 ng/mL. Among the patients, 395 were black men, who are known to have greater rates of prostate cancer than other men. Patients were randomly assigned to treatment with radiotherapy alone (N = 992; 197 black men) or to radiotherapy plus 4 months of ADT that consisted of drugs that block the natural production of testosterone (N = 987; 198 black men). Summary: The median follow-up in this study was 9.1

Journal of Hematology Oncology Pharmacy

years. Results showed that short-term ADT plus radiotherapy significantly improved the 10-year overall survival (OS) compared with radiation therapy alone (62% vs 57%, respectively). The addition of short-term ADT to radiation therapy led to significantly fewer prostate cancer–related deaths (4% vs 8%, respectively; P = .001). The benefits of short-term ADT seen true for white and for black men. In a later analysis looking at the patients by disease risk, participants were divided into 3 groups— high, intermediate, and low risk, using various variables, including PSA levels, tumor grade, and disease stage. The patients with intermediate risk benefited from the combination therapy, unlike those with low or high risk. In those with intermediate risk, the 10-year OS rate significantly increased from 54% with radiotherapy alone to 61% with the combination of short-term ADT plus radiotherapy, and disease-specific death rate was reduced from 10% to 3%. The researchers noted that for now, because of potential side effects with ADT (eg, erectile dysfunction, hot flashes), the evidence does not support longer follow-up therapy for men with low-risk disease. Takeaway: This study of almost 2000 patients shows that men with intermediate-risk prostate cancer (Gleason score of 7 or a Gleason score of ≤6 with a PSA level of >10 and ≤20 ng/mL or clinical stage T2b) benefit from combination ADT and radiotherapy. With 12 years of follow-up, there were more than 60% fewer deaths with combination ADT and radiotherapy. However, in their discussion, the authors noted that this study was performed with a traditional method of radiation therapy. New radiation techniques such as intensity-modulated radiation therapy, intensity-guided radiation therapy, and low-dose-rate and high-dose-rate brachytherapy have resulted in safe delivery of higher doses of radiation than was possible when this study was conducted. Furthermore, they warned that it is uncertain if the addition of ADT to these newer techniques would significantly add benefit to the new radiation methods. The Radiation Therapy Oncology Group has initiated a randomized study to answer this question, but it may be several years before we have the answer to whether combination ADT and radiotherapy is better than current radiation strategies. ■ Jones CU, Hunt D, McGowan DG, et al. Radiotherapy and short-term androgen deprivation for localized prostate cancer. N Engl J Med. 2011;365:107-118.

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BUILDING

pillars of knowledge

IN SUPPORTIVE CARE CINV LOG ON TODAY TO PARTICIPATE

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FACULTY Regina Cunningham, PhD, RN, AOCN Senior Director, Oncology The Tisch Cancer Institute Mount Sinai Medical Center New York, NY

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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Docetaxel Injection safely and effectively. See full prescribing information for Docetaxel.

Docetaxel Injection, For intravenous infusion only. Initial U.S. Approval: 1996

• • • •

• •

WARNING: TOXIC DEATHS, HEPATOTOXICITY, NEUTROPENIA, HYPERSENSITIVITY REACTIONS, and FLUID RETENTION See full prescribing information for complete boxed warning Treatment-related mortality increases with abnormal liver function, at higher doses, and in patients with NSCLC and prior platinumbased therapy receiving docetaxel at 100 mg/m2 (5.1) Should not be given if bilirubin > ULN, or if AST and/or ALT > 1.5 × ULN concomitant with alkaline phosphatase > 2.5 × ULN. LFT elevations increase risk of severe or life-threatening complications. Obtain LFTs before each treatment cycle (8.6) Should not be given if neutrophil counts are < 1500 cells/mm3. Obtain frequent blood counts to monitor for neutropenia (4) Severe hypersensitivity, including very rare fatal anaphylaxis, has been reported in patients who received dexamethasone premedication. Severe reactions require immediate discontinuation of Docetaxel Injection and administration of appropriate therapy (5.4) Contraindicated if history of severe hypersensitivity reactions to docetaxel or to drugs formulated with polysorbate 80 (4) Severe fluid retention may occur despite dexamethasone (5.5)

–––––––––––––––––––––––––––––––––––––––––––––––––– CONTRAINDICATIONS –––––––––––––––––––––––––––––––––––––––––––––– • Hypersensitivity to docetaxel or polysorbate 80 (4) • Neutrophil counts of <1500 cells/mm3 (4) –––––––––––––––––––––––––––––––––––––––––––––– WARNINGS AND PRECAUTIONS –––––––––––––––––––––––––––––––––––––––––– • Acute myeloid leukemia: In patients who received docetaxel doxorubicin and cyclophosphamide, monitor for delayed myelodysplasia or myeloid leukemia (5.6) • Cutaneous reactions: Reactions including erythema of the extremities with edema followed by desquamation may occur. Severe skin toxicity may require dose adjustment (5.7) • Neurologic reactions: Reactions including. paresthesia, dysesthesia, and pain may occur. Severe neurosensory symptoms require dose adjustment or discontinuation if persistent. (5.8) • Asthenia: Severe asthenia may occur and may require treatment discontinuation. (5.9) • Pregnancy: Fetal harm can occur when administered to a pregnant woman. Women of childbearing potential should be advised not to become pregnant when receiving Docetaxel Injection (5.10, 8.1) ––––––––––––––––––––––––––––––––––––––––––––––––– ADVERSE REACTIONS ––––––––––––––––––––––––––––––––––––––––––––––– Most common adverse reactions across all docetaxel indications are infections, neutropenia, anemia, febrile neutropenia, hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, dyspnea, constipation, anorexia, nail disorders, fluid retention, asthenia, pain, nausea, diarrhea, vomiting, mucositis, alopecia, skin reactions, myalgia (6)

To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-441-4100 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

Manufactured by: Hospira Australia Pty., Ltd., Mulgrave, Australia Manufactured by: Zydus Hospira Oncology Private Ltd., Gujarat, India Distributed by: Hospira, Inc., Lake Forest, IL 60045 USA

Reference EN-2761

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Single Vial

Docetaxel Injection (10 mg/mL concentration) • Larger 160 mg Multiple Dose Vial • More convenient 80 mg Multiple Dose Vial • Requires NO dilution with a diluent prior to adding to the infusion solution

Clarity of glass

Barrier sheath

Exclusive Onco-Tain™ packaging for safe handling1

PVC reinforced bottom

WARNING: Toxic Deaths, Hepatotoxicity, Neutropenia, Hypersensitivity Reactions, and Fluid Retention See full prescribing information for complete boxed warning • Treatment-related mortality increases with abnormal liver function, at higher doses, and in patients with NSCLC and prior platinum-based therapy receiving docetaxel at 100 mg/m2 • Should not be given if bilirubin > ULN, or if AST and/or ALT > 1.5 × ULN concomitant with alkaline phosphatase > 2.5 × ULN. LFT elevations increase risk of severe or life-threatening complications. Obtain LFTs before each treatment cycle

• Severe hypersensitivity, including very rare fatal anaphylaxis, has been reported in patients who received dexamethasone premedication. Severe reactions require immediate discontinuation of Docetaxel Injection and administration of appropriate therapy • Contraindicated if history of severe hypersensitivity reactions to docetaxel or to drugs formulated with polysorbate 80 • Severe fluid retention may occur despite dexamethasone

• Should not be given if neutrophil counts are < 1500 cells/mm3. Obtain frequent blood counts to monitor for neutropenia

Indications and Usage

Safety Information

Docetaxel Injection is a microtubule inhibitor indicated for: Breast Cancer (BC): single agent for locally advanced metastatic BC after chemotherapy failure; and with doxorubicin and cyclophosphamide as adjuvant treatment of operable node-positive BC

1. Data on file at Hospira P11-3247-8.125x10.875-Apr., 11

only

Non-Small Cell Lung Cancer (NSCLC): single agent for locally advanced or metastatic NSCLC after platinum therapy failure; and with cisplatin for unresectable, locally advanced or metastatic untreated NSCLC Hormone Refractory Prostate Cancer (HRPC): with prednisone in androgen independent (hormone refractory) metastatic prostate cancer

Most common adverse reactions across all docetaxel indications are infections, neutropenia, anemia, febrile neutropenia, hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, dyspnea, constipation, anorexia, nail disorders, fluid retention, asthenia, pain, nausea, diarrhea, vomiting, mucositis, alopecia, skin reactions, myalgia To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-441-4100 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch See brief Prescribing Information on reverse side.