journal of hematology oncology pharmacy

HEMATOLOGYONCOLOGYPHARMACY™

JOURNAL OFVOL 1 I NO 3

SEPTEMBER 2011

THE PEER-REVIEWED FORUM FOR ONCOLOGY PHARMACY PRACTICETM

©2011 Green Hill Healthcare Communications, LLCwww.JHOPonline.com

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

ORIGINAL RESEARCHIfosfamide 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 ExperienceGinah Nightingale, PharmD, BCOP; James A. Trovato, PharmD, MBA, BCOP, FASHP; Myounghee Lee, PhD, PharmD; Jennifer Thompson, PharmD, BCOP

COMMENTARYDosing Chemotherapy in Obese Patients: No Clear Answers, YetScott Soefje, PharmD, BCOP

From the LiteratureConcise Reviews from the Literature Relevant to Hematology Oncology PharmacyRobert J. Ignoffo, PharmD, FASHP, FCSHP

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EDITORIAL BOARD

CLINICAL CONTROVERSIESChristopher Fausel, PharmD, BCPS, BCOP Clinical DirectorOncology Pharmacy ServicesIndiana University Simon Cancer CenterIndianapolis, IN

PRACTICAL ISSUES IN PHARMACY MANAGEMENT Timothy G. Tyler, PharmD, FCSHP Director of PharmacyComprehensive Cancer CenterDesert Regional Medical CenterPalm Springs, CA

ORIGINAL RESEARCH Gary C. Yee, PharmD, FCCP, BCOP Professor, Department of Pharmacy PracticeCollege of Pharmacy, University of Nebraska MedicalCenter, Omaha, NE

REVIEW ARTICLESR. Donald Harvey, PharmD, FCCP, BCPS, BCOPAssistant Professor, Hematology/Medical Oncology Department of Hematology/Medical OncologyDirector, Phase 1 UnitWinship Cancer InstituteEmory University, Atlanta, GA

FROM THE LITERATURERobert J. Ignoffo, PharmD, FASHP, FCSHPProfessor of Pharmacy, College of Pharmacy, Touro University–California Mare Island Vallejo, CA

Patrick J. Medina, PharmD, BCOPAssociate ProfessorDepartment of PharmacyUniversity of Oklahoma College of PharmacyOklahoma City, OK

Val R. Adams, PharmD, BCOP, FCCPAssociate Professor, Pharmacy Program Director, PGY2 Specialty ResidencyHematology/OncologyUniversity of Kentucky College of PharmacyLexington, KY

SECTION EDITORS

CO-EDITORS-IN-CHIEF

Sandra Cueller, PharmD, BCOPDirectorOncology Specialty ResidencyUniversity of Illinois at Chicago Medical CenterChicago, IL

Sachin Shah, PharmD, BCOPAssociate ProfessorTexas Tech University Health Sciences CenterDallas, TX

Scott Soefje, PharmD, BCOPAssociate Director, Oncology PharmacySmilow Cancer Hospital at Yale New HavenYale New Haven HospitalNew Haven, CT

Steve Stricker, PharmD, MS, BCOP Assistant Professor of Pharmacy PracticeSamford University McWhorter School of PharmacyBirmingham, AL

John M. Valgus, PharmD, BCOPHematology/Oncology Senior Clinical PharmacySpecialistUniversity of North Carolina Hospitals and ClinicsChapel Hill, NC

Daisy Yang, PharmD, BCOP Clinical Pharmacy SpecialistUniversity of Texas M. D. Anderson Cancer CenterHouston, TX

EDITORS-AT-LARGE

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4 l Journal of Hematology Oncology Pharmacy l www.JHOPonline.com September 2011 l Vol 1, No 3

Senior Vice President, Sales & Marketing

Philip [email protected]

PublisherJohn W. Hennessy

[email protected]

Editorial DirectorDalia Buffery

[email protected]

Associate EditorsBrett KaplanLara J. Lorton

Editorial AssistantJennifer Brandt732.992.1536

Directors, Client ServicesJoe Chanley

[email protected]

Jack [email protected]

732.992.1537

Production ManagerStephanie Laudien

Quality Control DirectorBarbara Marino

Business ManagerBlanche Marchitto

[email protected]

Editorial Contact:Telephone: 732.992.1536

Fax: 732.656.7938E-mail: [email protected]

TABLE OF CONTENTS

SEPTEMBER 2011 VOLUME 1, NUMBER 3

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 ofHematology Oncology Pharmacy™ logo is a trademark of Green Hill Healthcare Com munications, LLC. No part of this publication may be reproduced or transmitted in any form or by anymeans 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, NJ08831. E-mail: [email protected]. YEARLY SUBSCRIPTION RATES: United States and possessions: individuals, $105.00; institutions, $135.00; single issues, $17.00. Orders will bebilled 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 inthis journal should be addressed to REPRINT PERMISSIONS DEPARTMENT, Green Hill Healthcare Commun i cations, 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 ofan 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 areencouraged to contact the manufacturer with questions about the features or limitations of the products mentioned. Neither the Editorial Board nor the Publisher assumes any responsibilityfor 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 lit-erature 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 contraindi-cations. 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 thebest 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.

EDITORIAL7 Brother, Can You Spare Some Chemotherapy? No End in Sight for Drug Shortages

Timothy G. Tyler, PharmD, FCSHP

ORIGINAL RESEARCH12 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

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

COMMENTARY26 Dosing Chemotherapy in Obese Patients: No Clear Answers, Yet

Scott Soefje, PharmD, BCOP

FROM THE LITERATURE32 Concise Reviews from the Literature Relevant to Hematology Oncology Pharmacy

Robert J. Ignoffo, PharmD, FASHP, FCSHP

PUBLISHING STAFF

MISSION STATEMENTThe Journal of Hematology Oncology Pharm -acy is an independent, peer-reviewed jour-nal founded in 2011 to provide hematologyand oncology pharmacy practitioners andother healthcare professionals with high-quality peer-reviewed information rele-vant to hematologic and oncologic condi-tions to help them optimize drug therapyfor patients.


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The Journal of Hematology Oncology Pharmacy is the nation’s first peer-reviewed clini-cal journal for oncology pharmacists. As pharmacy practice and research become integral to improvingboth the clinical care of cancer patients as well as expanding the research literature in contemporaryoncology pharmacy, new avenues are necessary to ensure this information gets disseminated to the pro-fession.

The recently launched Journal of Hematology Oncology Pharmacy provides a new avenue for the publica-tion of peer-reviewed, high-quality pharmacy reviews and original research to help oncology pharmacypractitioners 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 issuesin oncology pharmacy. All articles will undergo a blind peer-review process, and acceptance is based onthat review.

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

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

COMMENTARIES

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

PRACTICAL ISSUES IN PHARMACY MANAGEMENT• Logistics• Economics• Practice-influencing issues

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.

CALL FOR PAPERS

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EDITORIAL

7www.JHOPonline.com l Journal of Hematology Oncology Pharmacy lVol 1, No 3 l September 2011

It was on the front page of my newspaper. It is in thedata services I subscribe to for the American Societyof Health-System Pharmacists and the American

Society of Clinical Oncology. It is the feature of a newsurvey from the Hematology Oncology PharmacyAssociation and is the lead-in for the Pharmacists’Newsletter. It is on the nightly news, and it was exploredin depth in the last issue of the Journal of HematologyOncology Pharmacy (JHOP).

What exactly is this “it,” you may wonder. The drugshortage, of course. For pharmacists involved in anyway with drug procurement, this shortage has been asource of extreme consternation, fear, apprehension,and frustration. Even the general population is becom-ing alarmed by drugs that are no longer readily avail-able. We have an advanced civilization, but we appar-ently cannot figure out how to reliably provide some ofthe cheaper drugs that have significant impact onpatient care. Or at least that seems to be the messagethat is promulgated today.

During a 30-minute newspaper interview on thisissue at the end of August, I had to redirect the inter-viewer on 3 separate occasions to avoid inaccurateand sensational tendencies in the story. I reiterated 3times that this was a national issue not unique to mycenter, 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 thepublished article was that my hospital was unable totreat patients with cancer, because of my inability toget drugs. Ironically, the day the story appeared inprint, I received shipments of the main 2 drugs (lipo-somal doxorubicin and paclitaxel) that had caused usserious problems.

I have read stories about drug mark-ups in the gray market, and about the concern with the safety of the cur-rent drug supply. Michael R. Cohen, RPh, MS, presidentof the Institute for Safe Medication Practices(www.ismp.org), has just presented a teleconference onthis subject. MSNBC posted a story on the drug shortageonline in late August, and the more than 600 reader com-

ments were vitriolic, bashing everyone from the currentand past federal administrations to the evils of capitalism,and complaining that hospitals and doctors are “stickingit” to patients. Having now been involved as a SectionEditor of JHOP and the author of the article on this topicthat ran in the June 2011 issue of the journal, I believe Ihave some credibility in this regard. As such, the vastmajority of the comments in the media were off base.

The drug shortage problems are complex and multi-factorial; no single issue can be blamed alone. TheCenter for Drug Evaluation and Research is planning apublic workshop titled “Approach to Addressing DrugShortage” for September 26, 2011, but to date, the onlyexpedient solutions appear to be focused on givingmore authority to the government. Knowing that aproblem is forthcoming may allow professionals to havebetter communication and planning, but giving morecontrol to those in government who cannot balance asingle budget (eg, the US Postal Service Office, Med -icare, Social Security) makes me uneasy at best.

In addition, some colleagues in the pharmaceuticalindustry are worried that confidential marketing plansand strategies would be required to be divulged to fed-eral agencies. Finally, although the US Food and DrugAdministration (FDA) is not the primary culprit, it iscertainly playing a role in this crisis with the increasedregulatory scrutiny. Furthermore, the FDA has admittedthat it only has 4 employees who are dedicated to work-ing with generic approvals.

Brother, Can You Spare SomeChemotherapy? No End in Sight for DrugShortagesTimothy G. Tyler, PharmD, FCSHP, Section EditorDirector of Pharmacy Services, Comprehensive Cancer Center Desert Regional Medical Center, Palm Springs, CA

For pharmacists involved in any way with drug procurement, this shortage has been a source of extremeconsternation, fear, apprehension, andfrustration. Even the general population is becoming alarmed by drugs that are no longer readily available.

5-TylerCommentary_Cover 9/13/11 11:05 AM

EDITORIAL


The pharmaceutical companies also have some bur-den to bear, but in a capitalistic system such as ours, theproblem arises from taking a product that has littleprofit and removing whatever remains of that profitincentive, by imposing new rules and increased regula-tory compliance. Add to the mix the unstable world inwhich many of these drugs are sourced and manufac-tured, and the situation gets even worse. Many genericmanufacturers can no longer afford to compete if thedrugs are manufactured in the United States, with laborcosts being more affordable elsewhere.

The other concern is not controlled by manufac -turers, but by payers. The federal government—viaMedicare and Medicaid reimbursement—is the singlelargest payer in the world today. Remember that theaverage sales price (ASP) system is only a few years old,and all drug manufacturers must submit (or suffer egre-gious fines) the prices for all the drugs they sell to the

United States, and the US government then publishesthe ASP for each drug based on these drug prices.

That has a devastating effect on contracting andnegotiating a drug price. The effect on profits has beencurtailed by companies succumbing to pressure andconforming to a mean, even with a minimal profit for atime, but eventually looking for a better use of the com-pany’s resources. Many times that means exiting exist-ing markets, which results in the current drug shortagethat is plaguing our system today.

Solutions are neither easy nor obvious, but we can hopethat the coming summit will provide more than just giv-ing the federal government even more power. In themeantime—brother, can you spare some paclitaxel? ■

Author Disclosure StatementDr Tyler is on the Speaker’s Bureau of Bristol-Myers

Squibb and Eisai Pharmaceuticals.


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) ± rituximabCVP (cyclophosphamide + vincristine + prednisone)

Lung Cancer1,3

Carbo-Tax (carboplatin + paclitaxel)Cisplatin + vinorelbineCisplatin + gemcitabineCisplatin + pemetrexed

Colorectal Cancer1,6,7

FOLFOX (oxaliplatin + leucovorin + 5-fluorouracil) FOLFIRI (irinotecan + leucovorin + 5-fluorouracil)CapeOX (capecitabine + oxaliplatin)IrinotecanCisplatin-based regimens

Head and Neck Cancer1,4

Cisplatin-based regimensCarboplatin-based regimens

Ovarian Cancer1,8

Carbo-Tax (carboplatin + paclitaxel) IP cis (intraperitoneal cisplatin)Cisplatin

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

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 InformationEMEND should be used with caution in patients receiv ing c o n c o m i t a n t m e d i c a t i o n s , i n c l u d i n g c h e m o t h e r a p y agents, that are pr imar i ly metabol ized through CYP3A4. Inhib i t ion of CYP3A4 by EMEND could result in e levated plasma concentrations of these concomitant medications. Conversely, when EMEND is used concomitantly with another CYP3A4 inhibitor, aprepitant plasma concentrations couldbe 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 / 80 mg did not inf luence the pharmacokinetics 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% EMEND vs 11.9% standard therapy) , dyspepsia (5.8% vs 3.8%), nausea (5.8% vs 5.1%), neutropenia (5.8% vs 5.6%), asthenia (4.7% vs 4.6%), and stomatit is (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.

Have you included

EMEND from Cycle 1?

CINV=chemotherapy-induced nausea and vomiting.

Copyright © 2011 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.All rights reserved. 21050812(2)(901)-EME emend.com

An antiemetic regimen including


Brief Summary of the Prescribing Information for INDICATIONS AND USAGEPrevention 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 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.

CONTRAINDICATIONSEMEND 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 PRECAUTIONSCYP3A4 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 signifi cant 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 effi cacy 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 signifi cant 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 signifi cant 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 effi cacy 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 profi le may change during chronic continuous use.

ADVERSE REACTIONSThe 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 refl ect 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 unspecifi ed: 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 profi le 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 unspecifi ed (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, fl ushing, hot fl ush, hypertension, hypotension

Respiratory, thoracic, and mediastinal disorders: cough, dyspnea, nasal secretion, pharyngolaryngeal pain, pneumonitis, pulmonary embolism, respiratory insuffi ciency, vocal disturbance

Gastrointestinal disorders: abdominal pain upper, acid refl ux, deglutition disorder, dry mouth, dysgeusia, dysphagia, eructation, fl atulence, 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 insuffi ciency

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 profi les 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; fl atulence: 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.

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 identifi ed 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 signifi cant degree. However, higher aprepitant doses or repeated dosing at any aprepitant dose may have a clinically signifi cant 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 refl ects 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 signifi cant 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 infl uence the pharmacokinetics of docetaxel.

Vinorelbine: In a pharmacokinetic study, EMEND (125-mg/80-mg regimen) did not infl uence the pharmacokinetics of vinorelbine to a clinically signifi cant 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 effi cacy 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, nelfi navir) 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 effi cacy 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 effi cacy 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 POPULATIONSPregnancy: Teratogenic effects: Pregnancy Category B: Reproduction studies have been performed in rats at oral doses up to 1000 mg/kg twice daily (plasma AUC0–24hr 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 AUC0–24hr 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 TOXICOLOGYCarcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies were conducted in Sprague-Dawley 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 AUC0–24hr) of 0.7 to 1.6 times the human exposure (AUC0–24hr=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 fi brosarcomas 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 fi rst 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 diffi culty 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 effi cacy 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

Copyright © 2010 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.All rights reserved. 21050812(2)(901)-EME

EMEND® (aprepitant) capsules


ORIGINAL RESEARCH


Ifosfamide is a chemotherapeutic agent frequently usedin the treatment of sarcomas and hematologic malig-nancies. Ifosfamide is associated with unique neuro-

toxicity that may include confusion, seizures, hallucina-tions, incontinence, and cranial nerve abnormalities.Currently, ifosfamide is available commercially as eithera lyophilized powder or a liquid formulation. Since therelease of aqueous ifosfamide in 2002, several institutionshave transitioned to utilizing this formulation as a cost-saving measure, but ifosfamide dosing strategies have

essentially remained the same. Previous pharmacologicstudies have not identified any distinct differences inmetabolism between these 2 formulations.1 The mecha-nisms related to ifosfamide-induced neurotoxicityremain unclear; however, reports suggest an associationwith accumulation of neurotoxic metabolites such aschloroacetaldehyde (CAA), concurrent use of aprepi-tant, cisplatin exposure, reduced thiamine bioavailabili-ty, hypoalbuminemia, low hemoglobin level, low totalbilirubin 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 ClinicalPharmacist, 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/OncologyClinical Pharmacist, Florida Hospital for Children, Orlando; Dr Schwartz is Chief, Pediatric Hematology/Oncology, NemoursChildren’s Clinic, Pensacola, FL; Dr Smith is Clinical Pharmacy Manager, Pediatrics, Sacred Heart Women and Children’sHospital, Pensacola, FL; and Dr Assanasen is Assistant Professor, Pediatric Hematology-Oncology, University of Texas HealthScience Center at San Antonio, CHRISTUS Santa Rosa Children’s Hospital.

Ifosfamide Neurotoxicity in PediatricPatients: A Multi-Institutional CaseSeries ReportAmy 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

Background: Ifosfamide is a frequently used nitrogen mustard chemotherapeutic alkylatingagent that is available commercially in either an aqueous or powder formulation. Documented tox-icities related to ifosfamide include a unique neurotoxicity that has been associated with hypo -albuminemia, previous or concurrent administration of other neurotoxic agents, and renal dys-function. Although data regarding ifosfamide neurotoxicity are available in adult medical oncologyliterature, studies regarding pediatric neurotoxicity are limited. Objective: To review the clinical and pharmacologic characteristics of ifosfamide-induced neu-rotoxicity associated with the use of aqueous ifosfamide in pediatric patients.Methods: Retrospective chart review was used to identify cases of ifosfamide-induced enceph -alopathy at 5 pediatric oncology centers. Results: This multi-institutional case series evaluates 13 pediatric cases of ifosfamide-inducedencephalopathy. The patients exhibited confusion, lethargy, aphasia, incontinence, and auditoryhallucinations. Less than half of the patients had hypoalbuminemia, and none had renal dysfunc-tion at the onset of neurotoxicity that was associated with ifosfamide administration. Threepatients had previous exposure to cisplatin. New anecdotal evidence presented in this study sug-gests that the aqueous formulation of ifosfamide may be associated with higher incidence of neu-rotoxicity than the powder formulation. A total of 5 patients were rechallenged with the powderformulation, without recurrence of neurotoxicity. Conclusion: Our observation lends credence to the clinical opinion that the aqueous formulationof ifosfamide may be a risk factor for neurotoxicity.

J Hematol Oncol Pharm.2011;1(3):12-17www.JHOPonline.com

Disclosures are at end of text

6-Lee_Cover 9/13/11 11:05 AM

Ifosfamide Neurotoxicity in Pediatric Patients

13www.JHOPonline.com l Journal of Hematology Oncology PharmacyVol 1, No 3 l September 2011

MethodsThis retrospective chart review of patients diag-

nosed with ifosfamide-induced neurotoxicity was con-ducted at 5 pediatric oncology centers—Children’sHospital of Alabama, Birmingham; Wolfson Child -ren’s Hospital, Jacksonville, FL; Sacred HeartChildren’s Hospital, Pensacola, FL; Florida Hospital,Orlando; and University of Kansas Hospital, KansasCity. Pertinent data reviewed for this study includedpatient age, diagnosis, treatment regimen, ifosfamidedose and formulation, description of neurotoxicitysymptoms, concurrent use of aprepitant, cisplatinexposure, serum albumin levels, serum creatinine, andthe use of methylene blue, an electron acceptor.

ResultsWe reviewed 13 cases of ifosfamide-induced neurotox-

icity in children and teens aged 4 to 19 years who werediagnosed between 2002 and 2010 (Table). The predom-inant diagnosis was sarcoma (N = 11), although 2 otherpatients received ifosfamide as therapy for pre–B-cellacute lymphocytic leukemia (ALL) and primitive neuro -ectodermal tumor. All patients initially received the aque-ous formulation of ifosfamide.

Daily dosages of ifosfamide ranged from 1.8 g/m2 perdose to 3.5 g/m2 per dose. Only 1 patient received con-current therapy with aprepitant.

All patients exhibited multiple symptoms of neurotox-icity: confusion (N = 7), lethargy (N = 5), aphasia (N =4), and incontinence (N = 4). One patient experiencedauditory hallucinations. Data were analyzed for possibleorganic predisposing factors for neurotoxicity.

Of the 13 patients, 9 received intravenous methyleneblue as treatment, and all patients experienced abatementof symptoms within 5 days. After the resolution of neuro-toxicity, 5 patients who had previously received the aque-ous compound received subsequent dosing with the pow-der formulation of ifosfamide, without further recurrenceof neuropsychiatric symptoms.

DiscussionIncidence of Ifosfamide-Induced Neurotoxicity

Approximately 10% to 40% of pediatric and adultpatients who receive ifosfamide experience en ceph -alopathy.2-4,6 Although widely reported in adult med-ical oncology literature, this phenomenon is less frequent in the pediatric population.7 Ifosfamide neuro -toxicity in the pediatric patient varies in presentationbut most often consists of confusion, hallucinations,and incontinence.8

Predisposing Factors Risk factors for ifosfamide neurotoxicity, such as

hypoalbuminemia, renal dysfunction, concurrent use ofaprepitant, and a history of cisplatin exposure, wereidentified in our patient population (Table). Other lessreported risk factors, such as low hemoglobin and lowtotal bilirubin levels, were not evaluated in our study.

Currently, the greatest risk factor for neurotoxicity ishypoalbuminemia, predominantly a serum albumin level<3.3 g/dL.2,3 Recent reports show that prophylaxis withan albumin infusion has no apparent effect on the devel-opment of ifosfamide-related neurotoxicity, suggestingthat hepatic dysfunction rather than albumin depletionmay account for such a predisposition.

Of the often implicated risk factors, hypoalbumin -emia was the most frequently identified risk factor in ourstudy. A total of 7 patients had hypoalbuminemia withalbumin levels of ≤3.3 g/dL at the time of ifosfamideadministration. In addition, 3 of the 5 patients who wererechallenged with the powder remained hypoalbumin -emic but did not experience recurrent symptoms of neu-rotoxicity when the powder formulation was used.

Renal dysfunction was not identified as a risk factor inour patient population, because only 1 patient experi-enced elevated creatinine level (1.3 mg/dL) throughoutthe course of therapy. Only 1 patient had concurrent useof aprepitant, suggesting that this is also difficult to iden-tify as a predisposing factor in the pediatric population.

Although 3 patients had a history of previous cis-platin exposure, they had normal renal function at thetime of ifosfamide administration. Of these patients, 2did not experience encephalopathy when rechallengedwith a powder formulation. Therefore, in our populationit is difficult to determine if cisplatin exposure is relatedto ifosfamide neurotoxicity, particularly in the setting ofnormal renal function.

Mechanism of NeurotoxicityThe metabolism of ifosfamide by the hepatic

cytochrome (CY) P450 system results in inactivemetabolites, toxic metabolites, and the active form ofthe drug, isophosphoramide, a nitrogen mustard.Neurotoxic effects are thought to be associated with dis-ruption of the mitochondrial respiratory chain and the

Currently, the greatest risk factor forneurotoxicity is hypoalbuminemia,predominantly a serum albumin level <3.3 g/dL. Recent reports show thatprophylaxis with an albumin infusion hasno apparent effect on the development ofifosfamide-related neurotoxicity.

6-Lee_Cover 9/13/11 11:05 AM

ORIGINAL RESEARCH


Tabl

eCh

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tics

of P

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Pat

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ith If

osfa

mid

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ity

Age

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Sex

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isIf

osfa

mid

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se (

liqui

d)

Con

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apr

epita

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Histo

ryof

cisp

latin

expo

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?If

osfa

mid

e sy

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Seru

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min

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ne,

mg/

LM

ethy

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blue

Com

men

ts

4M

Clear-cell sarcoma

of kidney with

central n

ervous

system

relapse

3 g/m

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3 days

No/No

Ataxia,

vertigo,

lethargy

3.5

0.7

Yes �

2Head CT negative

Neurotoxicity occurred on

last

cycle of chemotherapy

Did not re

challenge

7M

Pre–B-cell A

LL1.8 g/m

2�

5 days

No/No

Lethargy,

confusion,

incontinence

2.1

0.3

No

Head MRI n

egative

Symptom

s experienced after

dose 4

Powder formulation used fo

rdose 5 witho

ut re

current

symptom

s

8M

Metastatic

desm

oplastic

roun

d cell

tumor

1.8 g/m

2�

5 days

No/No

Alternating

agitation and

lethargy,

unable to

am

bulate,

disorientation

3.2

0.8

Yes �

1 Head CT negative

Dose 3 held

Returned to baseline status and

discharged on ho

spital day 5

Not re

challenged

11F

Clear-cell

sarcom

a right

medial thigh

3 g/m

2�

3 days

No/No

Con

fusion

,asthenia,

presyncope

3.8

0.5

Yes �

4Symptom

s resolved after 2

4 hrs

of treatm

ent

Finished proton beam

therapy,

transferred back to

referral

center

Not re

challenged

11F

Osteosarcom

a2.8 g/m

2�

5 days

No/Yes

Disorientation,

aphasia, new

trem

or,

emotional

lability

3.7

0.71

Yes �

2 Head CT and

MRI n

egative

EEG in

dicativ

e of encephal -

o pathy

Powder formulation used on

later d

ate and no

neurotoxicity

14F

Rhabdom

yosarcom

a1.8 g/m

2�

5 days

No/No

Aph

asia,

confusion,

aggression

2.7

0.8

No

MRI a

nd LP negative

Returned to baseline on

ho

spital day 4

Rechalle

nged 2 m

onths later

with same regimen witho

utrecurrent sym

ptom

s

6-Lee_Cover 9/13/11 11:05 AM



Tabl

e(C

ontin

ued)

Age

,yr

Sex

Dia

gnos

isIf

osfa

mid

e do

se (

liqui

d)

Con

curr

ent us

eof

apr

epita

nt?/

Histo

ryof

cisp

latin

expo

sure

?If

osfa

mid

e sy

mpt

oms

Seru

m

albu

min

,g/

dL

Seru

m

crea

tini

ne,

mg/

LM

ethy

lene

blue

Com

men

ts

15F

Osteosarcoma

2.8 g/m

2�5 days

Yes/Yes

Incontinence,

tremor, auditory

hallucinations

2.9

0.6

Yes �

6Powder formulation used on

subsequent admission, no

neurotoxicity

17M

Osteosarcoma

3 g/m

2�3 days

No/Yes

Agitation,

aphasia,

incontinence

2.9

0.5

Yes �

8Completed course with fre-

quent dosing methylene blue

Not rechallenged

17F

Metastatic PNET

3 g/m

2�2 days

No/No

Aphasia,

lethargy, facial

twitch and

myoclonic jerks

3.1

0.5

Yes �

1 Head CT negative

Returned to baseline on

hospital day 4

Not rechallenged

Last course of chemotherapy

before expiration

17F

Osteosarcoma

3.5 g/m

2�5 days

No/No

Disorientation,

confusion

3.2

1.3

Yes �

8Course shortened because of

symptoms

Returned to baseline within

4 days

Rechallenged with dose

reduction without recurrent

symptoms

19M

Undifferentiated

sarcoma

2.8 g/m

2�5 days

No/No

Aphasia,

lethargy,

confusion

3.6

0.8

No

Last 2 doses ifosfamide held

Returned to baseline within

5 days

Rechallenged with dose

reduction without recurrent

symptoms

19M

Alveolar

rhabdomyosarcoma1.8 g/m

2�5 days

No/No

Amnesia,

confusion

4.1

0.7

No

Ifosfamide discontinued

Switched to nonifosfamide-

containing regimen

19F

Spinal

osteosarcoma

3.5 g/m

2�5 days

No/No

Disorientation,

confusion

3.5

0.7

Yes �

8Returned to baseline within

48 hrs

Ifosfamide discontinued

Not rechallenged

ALL indicates acute lymphocytic leukemia; CT, computed tomography; EEG, electroencephalogram; LP, lumbar puncture; MRI, magnetic resonance

imaging; PNET, primitive neuroectodermal tumor.

6-Lee_Cover 9/13/11 11:16 AM

ORIGINAL RESEARCH


accumulation of nicotinamide adenine dinucleotidehydride, which prevents dehydrogenation of the neuro-toxic metabolite CAA.9,10 Therefore, factors that mayaccount for predisposition to neurotoxicity include mark-ers of hepatic function, such as albumin, or concurrentadministration of substances that affect the CYP450enzymes, including aprepitant.

Recent reports show that prophylaxis with an albu-min infusion has no apparent effect on the developmentof ifosfamide-related neurotoxicity, further suggestingthat hepatic dysfunction rather than albumin depletionmay account for this predisposition.11 The treatment ofifosfamide-induced neurotoxicity is focused on thereduction of excess electrons and restoration of the mito-

chondrial respiratory chain, resulting in increasedmetabolism of CAA (Figure).

Methylene blue has traditionally been used to accom-plish this.9,10,12 Methylene blue may also reduce the for-mation of CAA by blocking activity of monoamine oxi-dases. Although not as well described, intravenousthiamine administration has been reported in the litera-ture as an intervention for ifosfamide-induced neurotox-icity. The proposed mechanism of action has been pos-tulated to be related to ifosfamide-induced thiaminedysfunction or reduced thiamine availability.13-15Alternatively, attempts have been made to prevent neu-rotoxicity by modifying the ifosfamide molecule, alteringmetabolism so that CAA production is hindered.16

Patient CharacteristicsCharacteristics of rechallenged patients are also

shown in the Table. For several years, anecdotal obser-vations suggesting a higher incidence of encephalopathywith the aqueous formulation of ifosfamide have beendiscussed among oncologists and oncologic pharmacists.In this case series, we report 5 cases in which patientswho developed encephalopathy with an aqueous ifos-

The treatment of ifosfamide-inducedneurotoxicity is focused on the reduction ofexcess electrons and restoration of themitochondrial respiratory chain, resulting inincreased metabolism of CAA.

Ifosfamide ExtrahepaticMAO activity CAA

NADH

CAA catabolism

Neurotoxicity

Chloroethylamine-induced inhibitionof mitochondrial respiratory chain

Competitive inhibition of thiamine pyrophosphate

and/or thiamine triphosphate

Other metabolites

Isophosphoramidemustard (active)

Methylene blue

Methylene blue

Thiamine

Mechanism of Ifosfamide-Induced NeurotoxicityFigure

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

6-Lee_Cover 9/14/11 11:35 AM



famide formulation did not experience recurrence ofsuch symptoms when rechallenged with the powderformulation.A 19-year-old male with undifferentiated sarcoma

and an 11-year-old female with osteosarcoma experi-enced neurotoxicity with the liquid formulation andlater during therapy received the powder formulationwithout adverse effects. Neither had hypoalbuminemiaor renal dysfunction when encephalopathy occurred.The 11-year-old female did have a history of cisplatinexposure. Both patients had normal serum albumin lev-els at the time of infusion with powder formulation.Two additional patients, a 14-year-old female with

rhabdomyosarcoma and a 15-year-old female withosteosarcoma, both of whom had also had hypoalbu-minemia, developed encephalopathy with the liquid for-mulation. Both patients were rechallenged at a later datewith the powder formulation, which did not result in anyadverse effect. The patients remained hypoalbuminemicat the time of infusion with the powder formulation(serum albumin levels, 3.3 g/dL and 3.1 g/dL, respective-ly). It is interesting to note that the 15-year-old femalewho was rechallenged had 3 known risk factors for ifos-famide-associated neurotoxicity—hypoalbuminemia,previous cisplatin exposure, and concurrent use ofaprepitant. However, she did not experience recurrentencephalopathy with the powder formulation.A 7-year-old male with pre–B-cell ALL experienced

lethargy, confusion, and incontinence after 4 doses ofthe liquid formulation of ifosfamide. He was persistentlyhypoalbuminemic throughout his hospital course andhad no history of cisplatin exposure or renal dysfunction.He was not administered methylene blue. Rather, thepatient’s next dose of ifosfamide was held, and his symp-toms resolved within 24 hours. He was then adminis-tered the fifth dose of ifosfamide, using the powder for-mulation, and did not experience neurotoxicity.

ConclusionIfosfamide-induced neurotoxicity has been frequently

reported in the literature. Our case series raises someinteresting questions regarding this phenomenon. Serumalbumin has been reported as a risk factor, and this wasidentified in patients in this pediatric case series.However, low serum albumin levels were not consistent-ly associated with neurotoxicity. Other risk factors, suchas renal dysfunction or previous cisplatin exposure, could

not be identified in our small population. In addition,the lack of neurotoxicity in patients rechallenged withthe powder formulation of ifosfamide suggests a possibleincreased incidence of ifosfamide neurotoxicity with theliquid formulation of the drug. The current aqueous formulation of ifosfamide could

be a contributing factor to neurotoxicity, and furtherstudies are warranted to evaluate this trend. In -vestigation utilizing high-performance light chromatog-raphy or nuclear magnetic resonance spectroscopy toanalyze possible differences in toxic metabolite forma-tion between formulations may be helpful. ■

Author Disclosure StatementDr 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 orpotential conflicts of interest.

References1. Gilard V, Martino R, Malet-Martino M, Niemeyer U. Stability of commercialformulations 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 ifosfamideencephalopathy. Am J Clin Oncol. 2005;28:277-280.3. Sweiss KI, Beri R, Shord SS. Encephalopathy after high-dose ifosfamide: a ret-rospective 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 theoccurrence 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 withchemotherapy 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: 15observations. Arch Pediatr. 2006;13:140-145. 8. Di Cataldo A, Astuto M, Rizzo G, et al. Neurotoxicity during ifosfamide treat-ment 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 treatmentand prevention of ifosfamide-induced encephalopathy: report of 12 cases and areview of the literature. Br J Cancer. 2000;82:291-294.10. Alici-Evcimen Y, Breitbart WS. Ifosfamide neuropsychiatric toxicity inpatients with cancer. Psychooncology. 2007;16:956-960.11. Kettle JK, Grauer D, Folker TL, et al. Effectiveness of exogenous albuminadministration for the prevention of ifosfamide-induced encephalopathy.Pharmacotherapy. 2010;30:812-817.12. Küpfer A, Aeschlimann C, Wermuth B, Cerny T. Prophylaxis and reversal ofifosfamide encephalopathy with methylene blue. Lancet. 1994;343:763-764.13. Buesa JM, Garcia-Teijido P, Losa R, Fra J. Treatment of ifosfamideencephalopathy with intravenous thiamin. Clin Cancer Res. 2003;9:4636-4637.14. Hamadani M, Awan F. Role of thiamine in managing ifosfamide-inducedencephalopathy. J Oncol Pharm Pract. 2006;12:237-239.15. Lombardi G, Zustovich F, Nicoletto MO, et al. Important role of thiamine inpreventing ifosfamide-induced encephalopathy. J Oncol Pharm Practice.2010;16:135-136.16. Storme T, Deroussent A, Mercier L, et al. New ifosfamide analogs designed forlower associated neurotoxicity and nephrotoxicity with modified alkylating kinet-ics leading to enhanced in vitro anticancer activity. J Pharmacol Exp Ther.2009;328:598-609.

6-Lee_Cover 9/13/11 11:05 AM

ORIGINAL RESEARCH


Carboplatin has been approved by the US Foodand Drug Administration for the treatment ofovarian cancer and has been used off-label for the

treatment of many solid tumors, including lung, head andneck, endometrial, breast, and cervical cancers.1 As anonclassical alkylating agent, carboplatin acts by cova-lently 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 iseliminated as intact carboplatin in the urine during thefirst 12 to 16 hours after administration.1

Carboplatin dosage relies on glomerular filtrationrate (GFR) and area under the curve (AUC). The

Dr Nightingale is Assistant Professor, Department of Pharmacy Practice, Jefferson School of Pharmacy, Thomas JeffersonUniversity, Philadelphia, PA; Dr Trovato is Associate Professor, Department of Pharmacy Practice and Science, University ofMaryland School of Pharmacy, Baltimore; Dr Lee is Investigational Drug Specialist, Supervisor, Investigational Drug ServicePharmacy, Department of Pharmacy, University of Maryland Medical Center, Baltimore; and Dr Thompson is InvestigationalDrug 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.

Carboplatin Dosing in Overweight andObese Patients: A Single-CenterExperienceGinah Nightingale, PharmD, BCOP; James A. Trovato, PharmD, MBA, BCOP, FASHP; Myounghee Lee, PhD, PharmD; Jennifer Thompson, PharmD, BCOP

Background: Serum creatinine–based formulas are used to estimate glomerular filtrationrate when calculating carboplatin dosage with the Calvert formula. In overweight and obesepatients, body weight applied to serum creatinine–based formulas may overestimateglomerular filtration rate. Overestimation may result in divergent carboplatin dosages thatcorrelate with dose-limiting thrombocytopenia, treatment delays, and dose reductions.Objective: The primary objective of this study was to evaluate physician prescribing practiceswith the Calvert formula in overweight and obese patients. The secondary objective was toidentify presence of grade 3 or 4 thrombocytopenia, per the National Cancer Institute CommonToxicity Criteria for Adverse Events, treatment delays, and dose reductions.Method: A retrospective analysis was conducted using data from a total of 20 patients whoreceived carboplatin therapy. Adults who received at least 1 dose of carboplatin with documen-tation of desired area under the concentration-time curve were included. Patients were excludedif baseline laboratory values were not available. We identified the serum creatinine–based formu-la utilized, the body weight descriptor applied to the glomerular filtration rate formula, and whethera maximal/capped creatinine clearance rate was determined.Results: A total of 50 patients were screened for eligibility, and 20 were included in the final analy-sis. 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 carboplatindose reduction secondary to toxicity.Conclusion: The use of actual body weight in the Cockcroft-Gault equation to estimate glomeru-lar filtration rate in the Calvert formula was associated with a high percentage of adverse clinicalevents. Increased awareness is needed in the oncology community to highlight unique consider-ations and confirm quality assurance when estimating renal clearance in the Calvert formula inoverweight and obese patients. Prospective studies are needed to substantiate these preliminaryclinical data.

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

7-Nightingale_Cover 9/13/11 11:06 AM

Carboplatin Dosing in Overweight and Obese Patients


Calvert formula is the preferred method to calculatethe dose for a given target AUC.2 Serum creatinine(SCr)-based formulas are used to estimate GFR whencalculating carboplatin dosage with the Calvert formu-la. Individualized dosing is the current practice to controlplasma drug exposure of carboplatin. A limitation of the Calvert formula is that the carboplatin dosage cansubstantially vary, depending on the SCr-based formulaused to estimate GFR (ie, Cockcroft-Gault, Jelliffe, orModification 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 overestimateGFR. Overestimation of GFR may result in differencesin carboplatin dosage that correlate with clinically rel-evant events, such as dose-limiting thrombocytopenia,treatment delays, and dose reductions. A study byHerrington and colleagues demonstrated that the opti-mal weight for overweight and obese patients in SCr-based formulas for use in the Calvert formula wasadjusted body weight.3 The use of actual body weight inoverweight or obese patients resulted in a carboplatinAUC that was 30% to 40% higher than the predictedor targeted carboplatin AUC.3

There are scarce data to guide decision-makingregarding the influential variables within the Calvertformula (Table 1). Existing literature is currently lim-ited,4-6 and there is not an established consensus with-in the oncology community. When actual body weight

is applied to an SCr-based formula for use in theCalvert formula, overweight and obese patients mayhave carboplatin AUCs greater than targeted becauseof overestimation of renal clearance. The purpose ofour study was to evaluate carboplatin dosing in over-weight and obese patients and to assess clinical out-comes at our institution.

Study ObjectivesThe primary objective of this retrospective analysis

was to evaluate physician prescribing practices with theCalvert formula in overweight and obese patients with-in our institution. Specifically, we identified the SCr-based formula used by the physician prescriber to esti-mate the GFR and body weight (ie, actual, ideal,adjusted) applied to the SCr-based formula, and whethera maximal/capped creatinine clearance (CrCl) rate wasdetermined at the discretion of the prescriber.

This information was gathered from a preprinted

Table 1 Serum Creatinine–Based FormulasFormula 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 inRenal 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/dLFemales: 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 – idealbody weight, kg)]

aCalvert AH, et al. J Clin Oncol. 1989;7:1748-1756.bCockcroft DW, et al. Nephron. 1976;16:31-41.cLevey AS, et al. Ann Intern Med. 1999;130:461-470.dJelliffe RW. Ann Intern Med. 1973;79:604-605.

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

In overweight and obese populations, bodyweight applied to a SCr-based formula mayoverestimate GFR. Overestimation of GFRmay result in differences in carboplatindosage that correlate with clinicallyrelevant events.


chemotherapy order form that included calculations forestimated renal function and the body weight descrip-tor applied. The secondary objectives were to identifythe presence of grade 3 or 4 thrombocytopenia (25.0-49.9 × 10e9/L or <25 × 10e9/L) according to theNational Cancer Institute (NCI) Common ToxicityCriteria for Adverse Events,7 dose modifications, andtreatment delays caused by toxicity.

MethodsThis study was reviewed and approved by the

University of Maryland Institutional Review Board.A retrospective analysis was conducted using datafrom patients who received carboplatin therapy dur-ing the period between January 2008 and January2009. Inclusion criteria were adult patients (aged ≥18years) who received at least 1 dose of carboplatin withdocumentation of desired carboplatin AUC for solidtumor malignancies either as monotherapy or as partof com bination chemotherapy treatment. Exclusioncriteria included patients with incomplete or missinglaboratory parameters on the preprinted chemothera-py order form. Patient data were accessed through electronic med-

ical records. Data collection included demographicinformation, pretreatment and posttreatment completeblood count and nadir, concurrent cytotoxic chemo -therapy, and any supporting documentation confirmingtreatment delays and dose reductions.

We defined treatment delays as ≥7 days from theplanned day of carboplatin administration. A dosereduction was defined as a ≥20% dose decline or areduction in the target AUC from the previous dose,with supporting documentation on the chemothera-py order confirming a dose reduction secondary totoxicity.The actual carboplatin AUC and actual GFR were

not measured as part of this analysis. Stable kidneyfunction was defined by SCr change from baseline of<0.5 mg/dL.8The SCr-based formula utilized by the prescribing

physician, the body weight applied to the formula, thetarget AUC, and the treatment cycle number were col-lected from the chemotherapy order. Patients were cat-egorized 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 ofoverweight and obese adults.9 Study analysis for endpoints included overweight, obese, and extremelyobese patients.

ORIGINAL RESEARCH


Screened for eligibilityN = 50

EnrolledN = 20

Obese (class I, II)N = 10

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

Consort Diagram of Patients Who Were Screened/ExcludedFigure

Extreme obesity (class III)N = 1

OverweightN = 9




ResultsA sample of 50 patients who received carboplatin dur-

ing the study period were screened for eligibility, and morethan 10 medical oncology prescribers dosed carboplatinwith the Calvert formula. Thirty patients were excludedbased on criteria for low body weight, ideal body weight,or missing laboratory parameters; therefore, 20 patientswere included in the final analysis (Figure).The demographics and baseline laboratory values of

the patients are described in Table 2. The study demo-graphics included mean age of 62.3 years, and more whitesthan blacks comprised the study population.Most patients had a primary diagnosis of non–small-

cell lung cancer, followed by malignancy of the headand 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 tar-get AUC ≥5 mg/mL/min. Kidney function was stablefor all patients.Seventy percent of the patients (N = 14) were treat-

ed with doublet-combination chemotherapy, and theremaining 30% of patients (N = 6) received a triple-combination chemotherapy regimen. The doublet-combination regimens included paclitaxel (N = 8),gemcitabine (N = 3), pemetrexed (N = 2), and etopo-side (N = 1). The triple-combination chemotherapyregimens included paclitaxel (N = 5) and gemcitabine(N = 1) to monoclonal antibodies such as bevacizu -mab, cetuximab, and an investigational agent. Physician prescribers used the Cockcroft-Gault for-

mula to estimate GFR for use in the Calvert formula in100% of the patients (N = 20). Prescribers applied thelaboratory-derived SCr to all SCr-based formulas.Prescribers did not apply an adjusted SCr value toaccount for the influence of muscle mass on creatinineconcentrations in the elderly.Actual body weight was applied to the SCr-based for-

mula in 19 patients (95%). Mean body weight was appliedto the SCr-based formula in 1 patient. Of note, thispatient 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 calcu latedGFR estimates of >150 mL/min based on the Cockcroft-Gault formula, and these patients were enrolled in clini-cal protocols with amendments for capping CrCl rates.Five patients (25%) experienced grade 3 or 4 throm-

bocytopenia, 2 patients (10%) experienced a carbo-platin treatment delay secondary to toxicity, and these2 patients subsequently were discontinued from treat-ment with carboplatin.In addition, 2 patients (10%) had a documented car-

boplatin dose reduction secondary to grade 3 or 4 throm-bocytopenia. Overall, there were 9 documented clinicalevents occurring in 5 (25%) of the patients (Table 3).

DiscussionAn accurate assessment of kidney function is neces-

sary and vital for determination or modification ofdosages of chemotherapy agents eliminated throughthe kidney in an effort to minimize toxicity and maxi-mize efficacy. Traditionally, CrCl has been measuredusing 12- or 24-hour urine collections for creatinine orusing contrast agents such as iohexol or radiolabeledagents. The clearance of chromium 51-ethylenedi-

Table 2 Baseline Characteristics of 20 PatientsVariable Result

Age, y, mean ± SD 62.30 ± 10.06

Sex, N (%)MaleFemale

9 (45)11 (55)

Race, N (%)WhiteBlackOther

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

Cancer, N (%)Lung cancerHead/neck cancerMelanomaOther

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

Targeted carboplatin AUC,N (%)2-4 mg/mL/min5-7 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.

An accurate assessment of kidney functionis necessary and vital for determination ormodification of dosages of chemotherapyagents eliminated through the kidney inan effort to minimize toxicity andmaximize efficacy.


aminetetraacetic acid (51Cr-EDTA) was originally usedfor the determination of the GFR in the Calvert for-mula.2 This method is costly and may be clinicallyimpractical; therefore, GFR is usually estimated fromSCr-based formulas.10-12

Although these formulas are convenient to use, andthey conserve time, there is a trade-off in accuracy andconsistency with regard to the determination of GFR.

The literature is limited in terms of guiding decision-making within the oncology community for addressingthe influential variables within the Calvert formula inoverweight and obese patients.

Our results demonstrate that physician prescribersutilized the Cockcroft-Gault equation to estimate GFRin all patients. None of our prescribers utilized the

MDRD or the Jelliffe formula to estimate GFR. TheJelliffe equation is used by most gynecologic oncologygroup protocols, and gynecologic malignancies did notcomprise our study population, which explains why theequation may not have been used.

Existing data comparing the Cockcroft-Gault equa-tion and the MDRD equation for calculating estimatedrenal function in the Calvert formula were recentlypublished. Shord and colleagues conducted a retrospec-tive analysis to determine the absolute differencebetween the dose of carboplatin administered using tra-ditional SCr-based formulas to estimate GFR versus thedose calculated based on the MDRD equation.13 Resultsshowed a carboplatin AUC dose divergence in 48% ofthe patients, yet the frequency of neutropenia, thrombo-cytopenia, and dose modifications were similar betweenthe 2 groups using either the SCr-based formulas or theMDRD equation to estimate GFR value. The investiga-tors concluded that the traditional SCr-based formulasused to calculate carboplatin dosage should be used untilmore data become available regarding the use of theMDRD equation in this population.13

The study conclusions are limited, because the goalwas not specifically to evaluate dose divergence and clin-

ORIGINAL RESEARCH


Table 3 Clinical Outcomes

Patienta BMI, kg/m2Applied

SCr, mg/dLApplied

CrCl, mL/minGrade 3 or 4

thrombocytopenia Dose reduction Treatment delay1 25.3 1.44 64.6 No No No2 26.7 0.87 81 No No No3 26.7 1.66 49.66 No No No4 27.5 1.44 67 Yes No Yes5 27.6 0.89 87.8 No No No6 28.1 0.9 93 No No No7 28.7 1.0 85 No No No8 29.3 0.8 83 No No No9 29.3 0.96 75 No No No10 30.4 0.98 97 Yes No Yes11 31.9 1.11 90 No No No12 32.3 0.7 118 No No No13 32.8 0.91 79 Yes No No14 32.9 1.18 81 No No No15 34.5 0.76 104 No No No16 35.3 0.79 91 No No No17 36.5 0.95 93.2 Yes Yes No18 37.1 1.0 125 No No No19 38.2 0.62 125 No No No20 48.5 0.9 112 Yes Yes NoaListed by BMI ascending order.BMI indicates body mass index; CrCl, creatinine clearance; SCr, serum creatinine.

Our results demonstrate that physicianprescribers utilized the Cockcroft-Gaultequation to estimate GFR in all patients.None of our prescribers utilized the MDRDor the Jelliffe formula to estimate GFR.


ical outcomes in overweight and obese patients, but thestudy does provide some data regarding surrogate markerswithin the Calvert formula.The NCI’s Cancer Therapy Evaluation Program

released 2 action letters in October 2010 to address carbo-platin dosing on sponsored protocols and the recentincrease in toxicity.14,15 The program recommends utiliz-ing the Cockcroft-Gault equation for calculating CrCl,and commented that the GFR used in the Calvert formu-la to calculate AUC-based dosing should not exceed 125mL/min, in an attempt to prevent the erroneous overpre-diction of renal function estimates when using actualweight in the Cockcroft-Gault equation.These initiatives are limited, because they do not

address the body weight that should be applied to theCockcroft-Gault equation in special populations ofoverweight and obese patients.Our prescribers applied actual body weight to the

Cockcroft-Gault SCr-based formula in 95% of pa -tients. In our study, applying actual body weight toestimate GFR for use in the Calvert formula did corre-late with a high percentage of clinical events, includ-ing grade 3 or 4 thrombocytopenia and dose reductionssecondary to toxicity.The study by Herrington and colleagues demonstrat-

ed that the optimal weight to use for obese patients,defined as a BMI >30 kg/m2 with renal function and SCrwithin normal limits, was adjusted body weight.3 Usingactual body weight in SCr-based formulas for theCalvert formula resulted in carboplatin AUCs 30% to40% higher than predicted or targeted AUCs.3 Thestudy results are limited because, despite evaluatingactual versus targeted carboplatin AUC divergence inoverweight and obese patients, the investigators did notobjectively evaluate the impact of a supratherapeuticcarboplatin AUC on clinical outcomes, such as dose-limiting myelosuppression or treatment delays.3Ekhart and colleagues assessed the utility of alternative

weight descriptors in the Cockcroft-Gault equation tomore accurately predict carboplatin clearance in specialbody weight populations.5 The results demonstrated thatadjusted body weight was the best weight descriptor inoverweight and obese patients. The study results suggestedthat overweight and obese patients with normal renal func-tion should receive a flat carboplatin dose based on popu-lation carboplatin clearance.Existing data suggest a strong correlation between

carboplatin AUC and dose-limiting myelosuppression,specifically thrombocytopenia.16-18 The incidence ofthrombocytopenia in our study population was highercompared with those of standard populations. Based ondata from Jodrell and colleagues in patients with ovari-an cancer, the expected incidence of grade 3 thrombo-

cytopenia for carboplatin AUC 4 to 5 is 5%, AUC 5 to6 is 10%, and AUC 6 to 7 is 20%.19

LimitationsThere are some limitations to our investigation. This

was a retrospective study design, and we were not able tocontrol for the heterogeneity that comprised our smallstudy population.There was also inconsistency with regard to the num-

ber of carboplatin treatment cycles that patientsreceived in relation to documented dose reductions ortreatment delays.Inconsistency also occurred with the time at which the

complete blood count and nadir(s) were taken and evalu-ated for each patient. The chemotherapy combination reg-imens 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 myelo-suppression when compared with monotherapy. We didnot identify any independent risk factors predicting dosereductions or therapy delays resulting from toxicity (ie,race, sex, age, cancer diagnosis, baseline platelet count, andprevious myelotoxic chemotherapy, concurrent radiationtherapy, or performance status).Finally, we did not measure actual carboplatin AUC or

actual GFR utilizing 51Cr-EDTA.

ConclusionDespite the study limitations, our results contribute

to existing data regarding prescribing patterns withinour institution and highlight unique considerationswhen calculating carboplatin dosage with the Calvertformula in overweight and obese patients. The use ofactual body weight to estimate GFR in relation to theCalvert formula was associated with a high percentage ofadverse clinical events.Increased awareness and education regarding unique

considerations with the Calvert formula in overweight andobese populations should be directed to medical oncologyphysician prescribers, pharmacists, and healthcare pro -viders within the oncology community to establish qualityassurance within the institution or practice site.Future considerations include designing a prospective

study evaluating body weight descriptors (ideal vs



Our results contribute to existing dataregarding prescribing patterns within ourinstitution and highlight uniqueconsiderations when calculatingcarboplatin dosage with the Calvertformula in overweight and obese patients.


adjusted) to estimate GFR for use in the Calvert for-mula incorporating measured carboplatin AUCs com-pared with target AUCs to identify dose divergenceand subsequent adverse clinical events in this popula-tion. A prospective study may substantiate these pre-liminary, clinically relevant data and may be able toestablish a consensus in clinical practice, which is crit-ical for patient safety and clinical outcomes. ■

Author Disclosure StatementDrs Nightingale, Trovato, Lee, and Thompson have

reported no actual or potential conflicts of interest.

References1. Alberts DS, Dorr RT. New perspectives on an old friend: optimizing carboplatinfor the treatment of solid tumors. Oncologist. 1998;3:15-34.2. Calvert AH, Newell DR, Gumbrell LA, et al. Carboplatin dosage: prospectiveevaluation of a simple formula based on renal function. J Clin Oncol. 1989;7:1748-1756.3. Herrington JD, Tran HT, Riggs MW. Prospective evaluation of carboplatin AUCdosing 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 fromstandard 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 overweightand obese patients with normal renal function, does weight matter? CancerChemother Pharmacol. 2009;64:115-122.6. Schmitt A, Gladieff L, Lansiaux A, et al. A universal formula based on cystatinC to perform individual dosing of carboplatin in normal weight, underweight, andobese patients. Clin Cancer Res. 2009;15:3633-3639.

7. Cancer Therapy Evaluation Program. Common Terminology Criteria forAdverse 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 JMed. 1996;334:1448-1460. 9. National Institutes of Health National Heart, Lung, and Blood Institute.Clinical Guidelines on the Identification, Evaluation, and Treatment ofOverweight and Obesity in Adults: the Evidence Report. NIH Publication No 98-4083. 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 cre-atinine. Nephron. 1976;16:31-41.11. Levey AS, Bosch JP, Lewis JB, et al. A more accurate method to estimateglomerular filtration rate from serum creatinine: a new prediction equation. AnnIntern 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 Dietin 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 pro-tocols sponsored by the National Cancer Institute that use carboplatin. Letter.October 1, 2010. www.cancerletter.com/downloads/20101008/download. AccessedAugust 19, 2011. 15. National Institutes of Health, National Cancer Institute. Follow-up for infor-mation 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 ofcarboplatin. Clin Pharmacokinet. 1997;33:161-183.17. Sørensen BT, Strömgren A, Jakobsen P, Jakobsen A. Dose-toxicity relationshipof 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 carboplatinin 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 carboplatinexposure and tumor response and toxicity in patients with ovarian cancer. J ClinOncol. 1992;10:520-528.

ORIGINAL RESEARCH



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COMMENTARY


Almost one third of Americans are currently con-sidered obese.1 As the number of patients withcancer who are overweight is increasing, the

conventions of chemotherapy dosing are constantly beingquestioned. Because of the concern for overdosing obesepatients, clinicians are routinely tasked with questionssuch as—Should we use actual body weight, ideal bodyweight, or something in between? Should we cap doses?Overdosing patients is a concern for all clinicians, butunderdosing may be just as problematic. Therefore, wemust consider the dose-reduction questions in light of themedical literature, which suggests that such reductionsmay compromise patient outcomes.2-8

The use of body surface area (BSA) for dosing chemo -therapy was developed in the 1950s as a method totranslate animal dosing into humans,9 but no scientif-ic study has demonstrated that BSA is a better dosingmeasurement than body weight or even fixed doses of chemotherapy. Many pharmacokinetic (PK) studieshave demonstrated that the PK parameters do not cor-relate with BSA,10 and a growing body of evidencesuggests that dosing obese patients based on actualbody weight is not associated with increased toxici-ty.11-14 Some have suggested that flat dosing of carbo-platin based on population parameters is just as effec-tive 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 issueof dosing carboplatin in obese patients.17 This retro-spective analysis involves overweight patients receivingcarboplatin. The authors’ approach in this study is to

look at toxicity, which is supposed to be minimized withAUC-based dosing. The conclusion that the use of actu-al body weight to estimate the glomerular filtration rate(GFR) is associated with high incidence of toxicity is mis-leading. We know the incidence of toxicity in the 20obese patients, but normal-weight patients were excludedfrom this study. How can we know, then, that there wouldnot have been a similar rate of toxicity in normal-weightpatients? Of note, the 2 patients whose creatinine clear-ance was capped at 125 mL/min did not have toxicity. Weare, therefore, left with the question of how to calculatethe appropriate dose in overweight patients. The common complaint about all studies that exam-

ine the effects of obesity on dosing is that those studiesare usually retrospective, with small sample sizes, andthe patient variability in PK parameters makes any gen-eralized statement difficult. Most often, the goals oftherapy are not considered. Furthermore, a little toxic-ity may be a good thing.18Clinicians spend too much time worrying about

doses of chemotherapy. The assumption is that becausedoses are individualized based on the BSA calculationor the AUC, a more accurate dose is being selected.The reality is, however, that all the dosing calculationsare based on an estimate. Using the BSA consists ofmeasured parameters (height and weight) that are thenapplied to a population-derived equation to arrive at anestimate. Calculating the Calvert equation for carbo-platin does the same thing.19 A measured serum creati-nine is used to estimate the GFR. Any additionaladjustment that is then made because of obesity (or anyother 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 theprocess of developing a practice guideline for dosingchemotherapy in obese patients with cancer.20 Untilthen—perhaps even beyond that—clinicians will needto balance the risks versus benefits and the efficacy ver-sus toxicity, because the answer to the question of dos-ing in obese patients is still not clear. ■

Author Disclosure StatementDr Soefje is on the Speaker’s Bureaus of Amgen, Eisai

Pharmaceuticals, and ICU Medical, Inc.

Dosing Chemotherapy in Obese Patients: No Clear Answers, YetScott Soefje, PharmD, BCOPAssociate Director, Oncology Pharmacy ServicesSmilow Cancer Hospital at Yale University, New Haven, CT

Clinicians spend too much time worryingabout doses of chemotherapy. Theassumption is that because doses areindividualized based on the BSA calculationor the AUC, a more accurate dose is beingselected. The reality is, however, that all thedosing calculations are based on an estimate.

8-SoefieCommentary_Cover 9/14/11 11:39 AM

References 1. Flegal KM, Carroll MD, Ogden CL, Curtin LR. Prevalence and trends in obesi-ty 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 20years of follow-up. N Engl J Med. 1995;332:901-906.3. Bonneterre J, Roché H, Kerbrat P, et al. Epirubicin increases long-term survivalin adjuvant chemotherapy of patients with poor-prognosis, node-positive, earlybreast cancer: 10-year follow-up results of the French Adjuvant Study Group 05randomized trial. J Clin Oncol. 2005;23:2686-2693.4. Budman DR, Berry DA, Cirrincione CT, et al, for the Cancer and LeukemiaGroup B. Dose and dose intensity as determinants of outcome in the adjuvant treat-ment 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 desLymphomes de l’Adulte). Prognostic significance of received relative dose intensi-ty in non-Hodgkin’s lymphoma patients: application to LNH-87 protocol. AnnOncol. 1993;4:651-656.6. Griggs JJ, Sorbero ME, Lyman GH. Undertreatment of obese women receivingbreast cancer chemotherapy. Arch Intern Med. 2005;165:1267-1273. 7. Mayers C, Panzarella T, Tannock IF. Analysis of the prognostic effects of inclu-sion in a clinical trial and of myelosuppression on survival after adjuvantchemotherapy 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 cancerchemotherapy. Cancer Res. 1958;18:853-856.10. Felici A, Verweij J, Sparreboom A. Dosing strategies for anticancer drugs: thegood, 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

chemotherapy-induced severe myelosuppression incidence in obese patients withcapped dosing. J Oncol Pract. 2011;7:13-17.12. Field KM, Kosmider S, Jefford M, et al. Chemotherapy dosing strategies in theobese, 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 toxici-ty 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 selec-tion of breast cancer adjuvant chemotherapy regimens. J Clin Oncol. 2007;25:2522-2527.15. Ekhart C, Rodenhuis S, Schellens JH, et al. Carboplatin dosing in overweightand obese patients with normal renal function, does weight matter? CancerChemother Pharmacol. 2009;64:115-122. Epub 2008 Nov 7.16. Ekhart C, de Jonge ME, Huitema AD, et al. Flat dosing of carboplatin is justi-fied in adult patients with normal renal function. Clin Cancer Res. 2006;12:6502-6508.17. Nightingale G, Trovato JA, Lee M, Thompson J. Carboplatin dosing in over-weight 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 andtreatment efficacy in advanced non–small-cell lung cancer: a pooled analysis ofthree randomised trials. Lancet Oncol. 2005;9:669-677.19. Calvert AH, Newell DR, Gumbrell LA, et al. Carboplatin dosage: prospectiveevaluation of a simple formula based on renal function. J Clin Oncol. 1989;7:1748-1756.20. Lyman GH. Chemotherapy dosing in obese patients with cancer—the need forevidence-based clinical practice guidelines. J Oncol Pract. 2011;7:17-18.

COMMENTARY


8-SoefieCommentary_Cover 9/13/11 11:07 AM

aSubmitManuscript!

HEMATOLOGYONCOLOGY PHARMACY�

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MISSION STATEMENT—The Journal of HematologyOncology Pharmacy (JHOP) is an independent, peer-reviewed journal founded in 2011 to provide hema-tology and oncology pharmacy practitioners andother healthcare professionals in these fields withhigh-quality peer-reviewed information relevant tohematologic and oncologic conditions to help themoptimize drug therapy for patients.

GENERAL INFORMATION—Manuscripts submit-ted to JHOP must be original and must not have beenpublished previously, either in print or in electronicform. Manuscripts cannot be submitted elsewherewhile under consideration by JHOP.

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FROM THE LITERATURE


■ Exemestane Effective for the Prevention ofInvasive Breast Cancer in Postmenopausal Women

Background: Estrogen is a known risk factor for breastcancer in women with a high level of circulating plasmaestrogen. Therefore, chemoprevention of breast cancerhas centered on the selective estrogen-receptor modula-tors (SERMs) tamoxifen and raloxifene. However, themajority of postmenopausal women who are at increasedrisk for breast cancer have not accepted the 2 SERMs for chemoprevention, primarily because of their toxiceffects. In patients with early-stage breast cancer, aro-matase inhibitors have been shown more effective thantamoxifen in preventing contralateral breast cancer andwith fewer side effects. A recent international clinicaltrial was designed to investigate the benefit of the aro-matase inhibitor exemestane for the prevention of inva-sive breast cancer in postmenopausal women.

Design: This international, randomized, placebo-con-trolled, double-blind clinical trial enrolled 4560 post-menopausal (ie, no menses for 12 months) women (aged≥35 years; median age, 62.5 years) from Canada, theUnited States, Spain, and France between February 2004and March 2010. Postmenopausal women had to have 1of these eligibility criteria—a 5-year risk for breast can-cer (Gail risk score >1.66%); age ≥60 years; or previousatypical ductal or lobular hyperplasia or lobular carcino-ma in situ, or ductal carcinoma in situ (DCIS) with mas-tectomy. The women were randomized to receiveexemestane (N = 2285) or placebo (N = 2275) in 1 of 3groups—exemestane 25 mg plus placebo, exemestane 25mg plus celecoxib, or placebo—for 5 years or until anunacceptable adverse event occurred, including breastcancer, neoplastic disease, or a serious cardiovascularevent. The primary end point was the incidence of inva-sive breast cancer. The secondary end points includedthe incidence of DCIS breast cancer; combined inci-dence of invasive breast cancer and DCIS; and the com-bined incidence of atypical ductal hyperplasia, atypicallobular hyperplasia, and lobular carcinoma in situ.

Summary: At a median 35 months of follow-up, atotal of 43 women were diagnosed with invasive breastcancer—11 women in the exemestane groups and 32women in the placebo group. This translates to an annu-al breast cancer incidence of 0.19% with exemestane

compared with a 0.55% incidence rate with placebo, fora 65% relative risk reduction with exemestane (hazardratio [HR], 0.35; 95% confidence interval [CI], 0.18-0.70; P <.002). Exemestane was also associated with alower incidence of invasive breast cancer plus DCIS(0.35%) compared with a 0.77% incidence rate withplacebo (HR, 0.47; 95% CI, 0.27-0.79; P = .004). Themajority of the tumors were estrogen receptor (ER)-pos-itive, HER2/neu-negative, and node-negative. Adverseevent rates were 88% with exemestane and 85% withplacebo (P = .003). There were no significant differencesin the rates of skeletal fractures, cardiovascular events,other cancers, and treatment-related deaths between theplacebo and the active drug groups, and the differencesin quality of life were minimal.

Takeaway: For postmenopausal women with ER-pos-itive, HER2/neu-negative, node-negative breast cancerwho are at moderate risk for future invasive breast can-cer, the use of exemestane prophylaxis reduces theannual risk of recurrent invasive breast cancer by 65%,as well as invasive DCIS by 35%. The antiestrogenstamoxifen and raloxifene have been used to alsodecrease invasive breast cancer, but their acceptance ispoor (only 0.08% of women aged 40-79 years currentlyuse these agents), probably because both are associatedwith 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 seriousadverse effects, including bone fractures, is reassuringand may improve the acceptance of this agent for breastcancer chemoprevention. Bone mineral loss was pre-vented with oral bisphosphonate therapy.

Goss PE, Ingle JN, Alés-Martínez JE, et al. Exemestane for breastcancer pre-vention in postmenopausal women. N Engl J Med. 2011;364:2381-2390.

■ Genotype-Based Dosing of Tamoxifen ImprovesTherapeutic Response in Invasive Breast Cancer

Background: A majority of women diagnosed with inva-sive breast cancer are estrogen receptor (ER)-positive andtherefore are candidates for tamoxifen treatment.However, approximately 50% of them do not derive fullbenefit from the drug, because genetic variations in thecytochrome P450 2D6 (CYP2D6) limit the ability of

Concise Reviews from the Literature Relevantto Hematology Oncology PharmacyBy Robert J. Ignoffo, PharmD, FASHP, FCSHP, Section EditorClinical Professor Emeritus, University of California, San Francisco Professor of Pharmacy, College of Pharmacy, Touro University—California, Mare Island Vallejo, CA

10-From theLit_Cover 9/14/11 11:36 AM

FROM THE LITERATURE


the enzyme to convert tamoxifen into its primary activemetabolite, endoxifen. In a new study, researchers haveinvestigated whether CYP2D6 genotyping could helpguide the dosing of tamoxifen to increase the concen-tration of endoxifen in women who are intermediate orpoor metabolizers of the CYP2D6 allele.

Design: A total of 119 women (25 black women)aged ≥18 years were enrolled in the study, but only 89were included in the final analysis of tamoxifen doseintervention. The women had been taking tamoxifen20 mg daily ≥4 months and no strong CYP2D6-inhibiting medications, and were evaluated for theCYP2D6 genotype and for plasma concentration oftamoxifen metabolites. Patients were divided into 3genotype groups based on their endoxifen concentra-tion—extensive metabolizers, intermediate metaboliz-ers, and poor metabolizers. Patients who were exten-sive metabolizers of endoxifen continued to take the20-mg dose of tamoxifen, and those who were inter-mediate or poor metabolizers had the tamoxifen doseincreased to 40 mg daily. After 4 months, patients weremeasured again for their tamoxifen metabolites. Thestudy primary end point was a change in plasma endox-ifen concentration after 4 months of increased tamox-ifen dosing for patients who were intermediate metab-olizers of the drug.

Summary: Among the study population, an unex-pectedly high percentage of patients (72%) had one ofthe CYP450 alleles indicative of intermediate or poormetabolism of tamoxifen. African American womenwere approximately twice as likely as other women tohave the CYP2D6 allele, which has been found to beassociated with reduced tamoxifen metabolism (oddsratio, 2.26; 95% confidence interval, 1.17-4.37).Among the 89 patients who completed the study, themedian baseline endoxifen concentration was higherin the 32 extensive metabolizers than in the 74 inter-mediate 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 increasedtamoxifen dose from 20 mg to 40 mg, the medianendoxifen concentration increased significantly in theintermediate metabolizers to 21.8 ng/mL (P <.001) andamong poor metabolizers to 12.9 ng/mL (P = .020). Ofnote, after the 4 months, no significant difference wasseen between the intermediate and extensive metabo-lizers in endoxifen concentrations, despite the almosttwice as high concentration levels at baseline; in thepoor metabolizers, the endoxifen concentration levelremained significantly lower than both groups.

Takeaway: This study demonstrates that adjustingtamoxifen dosing based on genotyping of CYP2D6 inwomen with ER-positive breast cancer may lead to

endoxifen concentrations similar to those in extensivemetabolizers. Increasing the dose from 20 to 40 mg inboth poor and intermediate metabolizers of tamoxifenwas effective and safe in raising endoxifen levels.However, this study was not designed to show whetherclinical outcomes were improved with higher endox-ifen levels. It may be that the efficacy of tamoxifen isnot mediated solely through endoxifen. Until endox-ifen concentrations are shown to be strongly associatedwith improved clinical outcomes in response and sur-vival, the use of CYP2D6 genotyping will remain inves-tigational. Of note is a recent study by Goetz and col-leagues from the National Surgical Adjuvant Breastand Bowel Project’s Breast Cancer Prevention Trial(BCPT)-P1 and BCPT-P2 that showed alterations inCYP2D6 metabolism were not associated with eithertamoxifen or raloxifene efficacy (Goetz MP, et al. ClinCancer Res. 2011 Aug 31. Epub ahead of print). As suggested above, there may be other cytochrome

alterations that may impact the use of genotyping. Arecent study by van Schaik and colleagues from theNetherlands has shown that CYP2C19*2 genotype pre-dicts tamoxifen treatment outcomes in patients withadvanced breast cancer (van Schaik RH, et al.Pharmacogenomics. 2011;12:1137-1146). The time totreatment failure was improved by 28% in those who wereheterozygous or homozygous for the CYP2C19*2 enzyme.

Irvin WJ Jr, Walko CM, Weck KE, et al. Genotype-guided tamoxifendosing increases active metabolite exposure in women with reducedCYP2D6 metabolism. J Clin Oncol. 2011;29:3232-3239.

■ Vemurafenib Improves Survival in MetastaticMelanoma with BRAF V600E Mutation

Background: The prognosis for patients with metasta-tic melanoma is poor, ranging from 8 to 18 months,and the only chemotherapeutic agent currentlyapproved by the US Food and Drug Administration(FDA) for the treatment of this disease is dacarbazine.A large percentage of cutaneous melanomas involvemutations in the BRAF gene that can activate tumorgrowth through the mitogen-activated protein kinasepathway. Previous studies have suggested that mela -nomas with the BRAF V600E mutation are moreaggressive and less sensitive to chemotherapy thanthose with the BRAF wild-type mutation. In early-phase clinical trials, the investigational agent vemu-rafenib, a BRAF kinase inhibitor that targets theBRAF V600E mutation, was associated with responserates of >50% in patients with BRAF V600E mutationmelanoma. In a recent study, researchers comparedthe efficacy of dacarbazine and vemurafenib in thispatient population.


FROM THE LITERATURE


Design: In this phase 3 clinical trial, a total of 675patients with previously untreated, unresectable stageIIIC or stage IV melanoma with the BRAF V600Emutation were randomly assigned to oral vemurafenib (N = 337) 960 mg twice daily or to dacarbazine (N = 338) 1000 mg/m2 infused every 3 weeks. Witheach drug, intolerable grade 2 toxic effects requireddose reduction. Vemurafenib administration was halteduntil the toxic effect was reduced to grade 1 at least andwas resumed at a dosing of 720 mg twice daily; the dosewas reduced to 480 mg twice daily if the toxic effectrecurred. If the 480-mg dose did not reduce the toxiceffect to grade 1 or if the effect recurred, the treatmentwas stopped permanently. Dacarbazine administrationwas interrupted if grade 3 or 4 events occurred and wasresumed within 1 week of grade 1 or 2, or resumed at adosing of 75% for grade 4 neutropenia or febrile neu-tropenia. The primary end points were the rates ofoverall survival (OS) and progression-free survival(PFS). Secondary end points included the responserate, response duration, and safety.

Summary: Patients were examined every 3 weeksand tumors assessed at baseline and at weeks 6, 12, andthen every 9 weeks. Response to treatment was assessedwith the Response Evaluation Criteria in Solid Tumors,version 1.1. The response rate with vemurafenib was48% versus 5% with dacarbazine. The hazard ratio fordeath was 0.37 (95% confidence interval [CI], 0.26-0.55) with vemurafenib versus dacarbazine (P <.001).At 6 months, the OS was 84% (95% CI, 78-89) amongpatients receiving vemurafenib compared with 64%(95% CI, 56-73) among those receiving dacarbazine.The estimated median PFS was 5.3 months with vemu-rafenib and 1.6 months with dacarbazine. Comparedwith dacarbazine, vemurafenib was associated with a63% relative risk reduction for death and a 74% riskreduction for either death or disease progression. Thedata and safety monitoring board recommended thatpatients in the dacarbazine group be allowed to crossover to receive vemurafenib based on the significantsurvival benefit with the latter. The most commonadverse events associated with vemurafenib werearthralgia, rash, fatigue, alopecia, secondary neoplasia(keratoacanthoma or squamous-cell carcinoma), pho-tosensitivity, nausea, and diarrhea. In all cases of sec-ondary neoplasia (18%) associated with vemurafenib,the lesions were removed by simple excision, and nomodifications in drug dose were necessary.

Takeaway: The approval of vemurafenib marks thesecond new drug for metastatic cancer approved bythe FDA in the past 13 years. This study showed a sig-nificant improvement over dacarbazine in OS. It also

provides a strong case for the use of pharmacogenom-ic testing using the cobas 4800 BRAF V600 MutationTest. Approximately 40% to 60% of cutaneousmelanomas carry mutations in BRAF that lead to con-stitutive activation of downstream signaling throughthe MAPK pathway. Vemurafenib is an oral agent thatis a moderate CYP1A2 inhibitor, a weak CYP2D6inhibitor, and a CYP3A4 inducer and substrate.Increased monitoring is therefore advised for patientsreceiving warfarin therapy. Furthermore, strongCYP3A4 inhibitors and inducers may increase ordecrease vemurafenib’s effects. The role of vemu-rafenib is still being investigated. Further studies areneeded to determine if combinations with chemother-apy or other new agents (eg, ipilimumab) will improveon these results.

Chapman PB, Hauschild A, Robert C, et al. Improved survival withvemurafenib in melanoma with BRAF V600E mutation. N Engl J Med.2011;364:2507-2516.

■ PARP Inhibitor Olaparib a Promising Treatment forOvarian Cancer

Background: In phase 1 and 2 clinical trials, olaparib,a small-molecule poly(ADP-ribose) polymerase (PARP)inhibitor, has demonstrated objective responses in thetreatment of tumors with BRCA1 and BRCA2 muta-tions in women with breast or ovarian cancer.Researchers have set out to assess the impact of BRCAmutations on the benefit of oral olaparib in patientswith advanced triple-negative breast cancer or in thosewith high-grade ovarian cancer.

Design: This open-label, nonrandomized phase 2clinical study was conducted in 6 centers in Canada. Atotal of 91 women (aged ≥18 years) with advancedhigh-grade serous and/or undifferentiated ovarian carci-noma (N = 65) or triple-negative breast cancer (N =26) were stratified according to BRCAmutation or lackof mutation; all the patients received oral olaparib 400mg twice daily. The primary end point was the objec-tive complete or partial response rate, based on theResponse Evaluation Criteria in Solid Tumors.Secondary end points were the rate of disease control,percent change from baseline in tumor size, progres-sion-free survival, and for those with ovarian cancer,evaluation of CA-125.

Summary: All patients with measurable lesions wereincluded in the objective response analysis, and allpatients who received at least 1 dose of olaparib wereincluded in the safety analysis. Of the 91 patientsenrolled, 90 were treated between July 8, 2008, andSeptember 24, 2009. Objective responses were not


FROM THE LITERATURE


reported in patients with breast cancer. Among the 64patients with ovarian cancer who received treatment, 63were evaluable, and objective responses were confirmedin 7 (41%; 95% confidence interval [CI], 22-64) of the17 women with BRCA1 or BRCA2 mutations and in 11(24%; 95% CI, 14-38) of the 46 patients without BRCAmutations. A total of 13 of the 65 (20%) patients withovarian cancer discontinued the study early because ofworsening disease (N = 3), adverse event (N = 3), vol-untary discontinuation (N = 2), and other reasons (N =5). In addition, 1 of the patients with breast cancer dis-continued early because of an adverse event. At studyend, 13 of the 65 patients with ovarian cancer and 26 ofthose with breast cancer were still receiving olaparib.Drug-related adverse events occurred in 56 of 64 (88%)patients with ovarian cancer. The most common adverseevents reported were fatigue (70% of patients with ovar-ian cancer and 50% of patients with breast cancer); nau-sea (66% and 62%, respectively); vomiting (39% and35%, respectively); and decreased appetite (36% and27%, respectively).

Takeaway: This is the first study to show that thePARP inhibitor olaparib has activity in a heavily pre-treated cohort of patients with high-grade serous ovari-an cancer. It was active in patients whether they hadgermline BRCA mutations or not; it produced respons-es in 24% to 41% of the patients, which is similar tooutcomes observed with the cytotoxic drugs pegylateddoxorubicin and topotecan. This study was limited bythe small number of patients (ie, 63), but it suggeststhat additional clinical trials with olaparib in patientswith serous ovarian cancer are warranted. Olaparib wasvery well tolerated in this heavily pretreated group andmay be an appropriate option for this aggressive form ofovarian cancer, in which treatment is usually limited totoxic chemotherapies. At the 2009 ASCO annualmeeting, Tutt and colleagues reported that single-agentolaparib was active in BRCA-deficient triple-negativebreast cancer (Tutt A. J Clin Oncol. 2009;27[suppl]). Inthat study, however, olaparib had no activity in triple-negative breast cancer, regardless of BRCA status. Thismay 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 withrecurrent high-graded serous or poorly differentiated ovarian carcinomaor triple-negative breast cancer. Lancet Oncol. 2011;12:852-861.

■ Nilotinib Sustains Efficacy Superior to Imatinib for24 Months in Chronic Myeloid Leukemia Background: Nilotinib is a BCR-ABL inhibitor thatwas developed as a potent and selective treatment for

patients with chronic myeloid leukemia (CML) inwhom imatinib therapy has not shown appropriate effi-cacy. The US Food and Drug Administration approvedthe use of nilotinib 300 mg twice daily for the treatmentof patients with newly diagnosed Philadelphia chromo-some (Ph)-positive CML in the chronic phase based onresults from the Evaluating Nilotinib Efficacy and Safetyin Clinical Trials–Newly Diagnosed Patients (ENESTnd)study, which showed superior efficacy for nilotinib overimatinib for up to 12 months. Now researchers from theENESTnd study published the results of a new 12-monthfollow-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 receiveoral therapy with nilotinib 300 mg twice daily (N =282), nilotinib 400 mg twice daily (N = 281), or imatinib400 mg once daily (N = 283). The efficacy results arebased on the intention-to-treat population of patients.The primary end point was the major molecular responseat 12 months, defined as BCR-ABL transcript levels onthe International Scale of ≤0.1% by real-time quantita-tive polymerase chain reaction in peripheral blood.

Summary: At 24 months, a major molecular responsewas seen in 201 (71%) patients receiving nilotinib 300mg twice daily, in 187 (67%) patients receiving nilotinib400 mg twice daily, and in only 124 (44%) patientsreceiving imatinib 400 mg once daily—a significant dif-ference for both comparisons (P <.001). In addition, acomplete molecular response was observed significantlymore often in both nilotinib groups than in the imatinibgroup—74 (26%) patients receiving 300 mg nilotiniband 59 (21%) patients receiving 400 mg nilotinib com-pared with 29 (10%) of patients receiving 300 mg onceP <.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 duringtreatment, including clonal evolution, occurred in 7 patients in the nilotinib groups and in 17 patients inthe imatinib group. At 24 months, survival was compa-rable in all treatment groups, but there were fewer CML-related deaths with nilotinib (N = 8) than with imatinib(N = 10). In addition, the only grade 3 or 4 nonhemato-logic adverse effects occurring more frequently with nilo-tinib were headache and rash. However, in the second12-month follow-up study, 8 additional serious adverseevents were reported—7 in the nilotinib group and 1 inthe imatinib group.

Takeaway: This is an updated report of the ENESTndtrial, the international phase 3 clinical trial of nilotinibversus imatinib in CML with a minimum follow-up of 2years. More than 90% of patients treated with nilotinib


FROM THE LITERATURE


who had achieved major molecular response at 12months were maintained at 24 months. Furthermore,BCR-ABL transcript levels were decreased below thethreshold of <0.1% about 1 year earlier with nilotinibthan with imatinib. This study demonstrated nilotinib’ssuperiority over imatinib, with faster, deeper, and moredurable molecular responses and a significantlydecreased risk of disease progression. In addition,emerging mutations of BCR-ABL in the nilotinibgroup were half that reported in those treated with ima-tinib. Nilotinib should be considered a first-line thera-py for CML in chronic phase.

Kantarijian HM, Hochhaus A, Saglio G, et al. Nilotinib versus imatinibfor the treatment of patients with newly diagnosed chronic phase,Philadelphia chromosome–positive, chronic myeloid leukemia. LancetOncol. 2011;12:841-851.

■ Radiotherapy plus Short-Term AndrogenDeprivation Extend Survival in Men withIntermediate-Risk, Early-Stage Prostate Cancer

Background: In patients with locally advanced pros -tate cancer, radiotherapy added to long-term hormonetherapy, or androgen-deprivation therapy (ADT),improves survival but also increases adverse events.Whether short-term ADT used before and duringradiotherapy could improve survival in patients withearly-stage, localized prostate cancer has not beenknown. Previous studies have shown that short-termADT improves survival among patients with later-stageprostate cancer. In a new large clinical trial funded bythe National Cancer Institute, researchers investigatedthe best approach to therapy for men with intermedi-ate-risk, early-stage prostate cancer.

Method: This 212-center study included 1979 menwith early-stage prostate cancer. All patients had local-ized prostate cancer and prostate-specific antigen (PSA)levels ≤20 ng/mL. Among the patients, 395 were blackmen, who are known to have greater rates of prostate can-cer than other men. Patients were randomly assigned totreatment with radiotherapy alone (N = 992; 197 blackmen) or to radiotherapy plus 4 months of ADT that con-sisted of drugs that block the natural production of testos-terone (N = 987; 198 black men).

Summary: The median follow-up in this study was 9.1

years. Results showed that short-term ADT plus radio-therapy significantly improved the 10-year overall sur-vival (OS) compared with radiation therapy alone (62%vs 57%, respectively). The addition of short-term ADTto radiation therapy led to significantly fewer prostatecancer–related deaths (4% vs 8%, respectively; P = .001).The benefits of short-term ADT seen true for white andfor black men. In a later analysis looking at the patientsby disease risk, participants were divided into 3 groups—high, intermediate, and low risk, using various variables,including PSA levels, tumor grade, and disease stage. Thepatients with intermediate risk benefited from the combi-nation therapy, unlike those with low or high risk. Inthose with intermediate risk, the 10-year OS rate signifi-cantly increased from 54% with radiotherapy alone to61% with the combination of short-term ADT plusradiotherapy, and disease-specific death rate was reducedfrom 10% to 3%. The researchers noted that for now,because of potential side effects with ADT (eg, erectiledysfunction, hot flashes), the evidence does not supportlonger follow-up therapy for men with low-risk disease.

Takeaway: This study of almost 2000 patients showsthat men with intermediate-risk prostate cancer (Gleasonscore of 7 or a Gleason score of ≤6 with a PSA level of >10and ≤20 ng/mL or clinical stage T2b) benefit from combi-nation ADT and radiotherapy. With 12 years of follow-up,there were more than 60% fewer deaths with combinationADT and radiotherapy. However, in their discussion, theauthors noted that this study was performed with a tradi-tional method of radiation therapy. New radiation tech-niques such as intensity-modulated radiation therapy,intensity-guided radiation therapy, and low-dose-rate andhigh-dose-rate brachytherapy have resulted in safe deliv-ery of higher doses of radiation than was possible whenthis study was conducted. Furthermore, they warned thatit is uncertain if the addition of ADT to these newer tech-niques would significantly add benefit to the new radia-tion methods. The Radiation Therapy Oncology Grouphas initiated a randomized study to answer this question,but it may be several years before we have the answer towhether combination ADT and radiotherapy is betterthan current radiation strategies. ■

Jones CU, Hunt D, McGowan DG, et al. Radiotherapy and short-termandrogen deprivation for localized prostate cancer. N Engl J Med.2011;365:107-118.


BUILDINGpillars of knowledgeIN SUPPORTIVE CARE CINVLOG ON TODAY TO PARTICIPATE

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TARGET AUDIENCEThe educational series is intended for nurses, pharmacists, and otherswith clinical, research, and management interests in CINV treatment

EDUCATIONAL OBJECTIVESOn completion of this activity, participants, should be able to:• Describe recent advances in the treatment of cancer patientswith chemotherapy-induced nausea and vomiting (CINV)

• Outline key barriers and challenges that impact the supportivecare of patients with CINV

• Examine strategies for achieving optimal control of CINV, basedon recent evidence-based data and updated clinical practiceguidelines

ACCREDITATION STATEMENTSCreative Educational Concepts, Inc. (CEC) is accredited bythe Accreditation Council for Pharmacy Education as aprovider of continuing pharmacy education.

This knowledge-based activity has been assigned ACPE # 0245-0000-11-019-H01-P and will award 1.0 contact hour (0.10 CEUs) of contin-uing pharmacy education credit. CEC complies with the Criteria forQuality for continuing education programming.

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CEC provides this activity for 1.0 contact hour.

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Your statement of credit will be issued immediately upon successful completion of the posttest and evaluation form.

For further information and to participate, please go to:www.coexm.com/ace07

FACULTYRegina Cunningham, PhD, RN, AOCNSenior Director, Oncology The Tisch Cancer InstituteMount Sinai Medical CenterNew York, NY

Shawna Kraft, PharmD, BCOPClinical Pharmacist/OncologyAdjunct Clinical Assistant ProfessorDepartment of Pharmacy ServicesCollege of PharmacyUniversity of MichiganAnn Arbor, MI

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

www.coexm.com/ace07Release Date: July 11, 2011 Expiration Date: July 10, 2012

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

Timothy G. Tyler, PharmD, FCSHPORIGINAL RESEARCHIfosfamide 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, BCOPCOMMENTARYDosing Chemotherapy in Obese Patients: No Clear Answers, Yet

Scott Soefje, PharmD, BCOPFrom the LiteratureConcise Reviews from the Literature Relevant to Hematology Oncology Pharmacy

Robert J. Ignoffo, PharmD, FASHP, FCSHP

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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 informationfor Docetaxel.

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

–––––––––––––––––––––––––––––––––––––––––––––––––– 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

WARNING: TOXIC DEATHS, HEPATOTOXICITY, NEUTROPENIA, HYPERSENSITIVITY REACTIONS, and FLUID RETENTIONSee 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 (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. LFTelevations 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)

Manufactured by: Hospira Australia Pty., Ltd., Mulgrave, AustraliaManufactured by: Zydus Hospira Oncology Private Ltd., Gujarat, IndiaDistributed by: Hospira, Inc., Lake Forest, IL 60045 USA Reference EN-2761

1-Cover_Layout 1 9/13/11 11:10 AM

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

Exclusive Onco-Tain™ packaging for safe handling1

Clarity of glass

Barrier sheath

PVC reinforced bottom

P11-3247-8.125x10.875-Apr., 11 � only

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

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

1. Data on fi le at Hospira

Indications and Usage Safety Information

Most common adverse reactions across all docetaxel indications are infections, neutropenia, anemia, febrile neutropenia, hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, dyspnea, constipation, anorexia, nail disorders, fl uid 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.

WARNING: Toxic Deaths, Hepatotoxicity, Neutropenia, Hypersensitivity Reactions, and Fluid RetentionSee 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

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

• 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 fl uid retention may occur despite dexamethasone

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