VOL 6, NO 1
KOELLER’S CORNER The Cost of Cancer Drugs: How High Is Too High? see page 27
SIDE EFFECTS MANAGEMENT
CANCER CENTER PROFILE
Smilow Cancer Hospital at Yale-New Haven Oncology Pharmacy: Designing Pathways and Guidelines for Disease Management
he Smilow Cancer Hospital treats more cancer patients than any other hospital in the state of Connecticut. Smilow offers a comprehensive treatment plan for each patient that can include surgery, medical oncology, radiation oncology, a combination of treatments, or conservative monitoring. One of Smilow’s 12 multidisciplinary disease state specialty teams is available to discuss each patient’s diagnosis and therapy options. Smilow Cancer Hospital is a leader in personScott Soefje, PharmD, MBA, BCOP alized cancer care through innovative tumor profiling techniques used to analyze every patient’s cancer. In addition, Smilow continues to expand its clinical research and involvement in clinical trials. The Oncology Pharmacist spoke with Scott Soefje, PharmD, MBA, BCOP, the Associate Director of Oncology Pharmacy Services at the Smilow Cancer Hospital at Yale-New Haven.
What is your role at the Smilow Cancer Center? Scott Soefje (SS): I am the associate director in charge of the oncology service line at the Smilow Cancer Hospital at Yale New Haven Health System. I manage both the inpatient and outpatient services as well as 9 satellite sites for our health network. We are in the process of integrating our network for the Yale New Haven Health System, and when this process is completed, there will be 4 hospitals and 9 or 10 satellite sites. What approach does your institution take to treating people with cancer? SS: We are an NCI-designated comprehensive cancer center, but we are not part of the National Comprehensive Cancer Network. On the medical side, we have divided the physicians’ practices into 12 disease state specialty teams.
SNP Networks Identify Risk for Adverse Effects of Chemotherapy By Caroline Helwick
ayesian networks based on single nucleotide polymorphisms (SNPs), developed from saliva-sourced DNA, can be used to predict the occurrence of adverse effects associated with chemotherapy, according to investigators who presented studies at both the 2012 CTRC-AACR San Antonio Breast Cancer Symposium and the 54th Annual Meeting of the American Society of Hematology (ASH).1,2 Given the biological basis for many toxic adverse effects of chemotherapy,
Bisphosphonates Should Not Be Routine in Early Breast Cancer By Caroline Helwick
or preventing bone metastases in women with early breast cancer, the current body of evidence does not support the use of osteoclast-targeting agents, ie, bisphosphonates, according to Julie Gralow, MD, director of Breast Medical Oncology at the Fred Hutchinson Cancer Research Center in Seattle, Washington. Gralow presented her thoughts on this controversial topic at the American
THE WHOLE PATIENT. . . . . . . . . . . .
Approaches to Sexual Dysfunction in Breast Cancer Survivors
By Alice Goodman
LEUKEMIA . . . . . . . . . . . . . . . . . . . . . . . .
professionals from around the world gathered to discuss the latest clinical developments in research, therapies, and practice strategies. Below are some of the highlights from that meeting.
Society of Clinical Oncology 2012 Breast Cancer Symposium, held in San Francisco, California.1 “There is no question that breast cancer treatment can cause accelerated bone loss, most commonly among patients receiving aromatase inhibitors,” she acknowledged. But studies have failed to show significant differences in the occurrence of the more clinically relevant end Continued on page 8
American Society of Hematology wealth of abstracts were presented at the 54th Annual Meeting of the American Society of Hematology (ASH), held in Atlanta, Georgia, on December 8-11, 2012. More than 18,000 hematologists and other healthcare
Continued on page 6
Continued on page 7
genotypically based risk assessments make sense, the investigators said. “It is clear that genetics plays a significant role in determining individual patient risk for side effects, and it seems most likely that the genetic impact on risk is a result of teams of genes functioning synergistically,” said Lee Schwartzberg, MD, of the West Clinic in Memphis, Tennessee. “In these investigations, we determined if we could construct SNP networks using an innovative Bayesian
Liposomal Vincristine Allows for Greater Dose Density Without Increased Neurotoxicity ASH HIGHLIGHTS
. . . . . . . . . . . . . . . .
Abstracts of Interest From the 54th Annual Meeting
Continued on page 15 ©2013 Green Hill Healthcare Communications, LLC
THE PATIENT’S VOICE . . . . . . . . . . .
Adherence to Therapy at Home
VOTE NOW The 2013
T.O.P. Award Make Your Choice at www.TheOncologyPharmacist.com/award
See Our 6 Finalists on Page 18
EDITORIAL BOARD EDITOR-IN-CHIEF
Patrick Medina, PharmD, BCOP Oklahoma University College of Pharmacy Tulsa, OK
Anjana Elefante, PharmD, BSc, BSc Pharm, RPh
Dwight Kloth, PharmD, FCCP, BCOP
Timothy G. Tyler, PharmD, FCSHP
Beth Faiman, PhD(c), MSN, APRN-BC, AOCN
Jim Koeller, MS
John M. Valgus, PharmD, BCOP
Christopher Fausel, PharmD
Christopher J. Lowe, PharmD
Roswell Park Cancer Institute Buffalo, NY
Fox Chase Cancer Center Philadelphia, PA
Desert Regional Medical Center Palm Springs, CA
Steve Stricker, PharmD, MS, BCOP Samford University McWhorter School of Pharmacy Birmingham, AL
John F. Aforismo, BSc Pharm, RPh, FASCP RJ Health Systems International, LLC Wethersfield, CT
Cleveland Clinic Taussig Cancer Institute Cleveland, OH
Indiana University Simon Cancer Center Indianapolis, IN
Indiana University Hospital Indianapolis, IN
David Baribeault, RPh, BCOP
Rebecca S. Finley, PharmD, MS
Emily Mackler, PharmD, BCOP
Betty M. Chan, PharmD, BCOP
David C. Gammon, BSPh
Laura Boehnke Michaud, PharmD, BCOP, FASHP
Boston Medical Center Boston, MA
USC/Norris Cancer Hospital Los Angeles, CA
Steven L. Dâ€™Amato, RPh, BCOP Maine Center for Cancer Medicine Scarborough, ME
University of Texas at Austin San Antonio, TX
FEBRUARY 2013 I VOL 6, NO 1
Jefferson School of Pharmacy Philadelphia, PA
OncologyPharmacist.net Warwick, RI
Lew Iacovelli, BS, PharmD, BCOP, CPP
Moses H. Cone Health System Greensboro, NC
University of Michigan Health System & College of Pharmacy Ann Arbor, MI
University of North Carolina Hospitals and Clinics Chapel Hill, NC
Gary C. Yee, PharmD, FCCP, BCOP University of Nebraska College of Pharmacy Omaha, NE
Burt Zweigenhaft, BS
OncoMed Onco360 Great Neck, NY
Marlo Blazer, PharmD, BCOP James Cancer Hospital & Solove Research Institute Columbus, OH
The University of Texas MD Anderson Cancer Center Houston, TX
Heidi D. Gunderson, PharmD, BCOP
LeAnn Best Norris, PharmD, BCPS, BCOP
Kamakshi V. Rao, PharmD, BCOP
South Carolina College of Pharmacy Columbia, SC
Mayo Clinic Cancer Center Rochester, MN
University of North Carolina Hospitals and Clinics Chapel Hill, NC
For the treatment of patients with chronic lymphocytic leukemia (CLL). Efficacy relative to first-line therapies other than chlorambucil has not been established.
Start with TREANDA® (bendamustine HCI) for Injection for established front-line CLL therapy Single-agent TREANDA tripled median PFS Progression-free survival (PFS)* Survival distribution function
0.7 0.6 0.5 0.4
0.2 P<.0001 HR=0.27 (95% CI: 0.17, 0.43)
0.1 0 0
*TREANDA (95% CI: 11.7, 23.5) vs chlorambucil (95% CI: 5.6, 8.6). HR=hazard ratio. CI=confidence interval.
TREANDA was compared with chlorambucil in a randomized, open-label, phase 3 trial in treatment-naïve patients with Binet stage B or C (Rai stages I–IV) CLL who required treatment (N=301). Patients were scheduled to receive either TREANDA 100 mg/m2 intravenously on Days 1 and 2 (n=153) or chlorambucil 0.8 mg/kg orally on Days 1 and 15 (n=148) of a 28-day treatment cycle, up to 6 cycles. The most common non-hematologic adverse reactions for CLL (frequency ≥15%) are pyrexia, nausea and vomiting. The most common hematologic abnormalities (frequency ≥15%) are anemia, thrombocytopenia, neutropenia, lymphopenia, and leukopenia.
TREANDA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). Efficacy relative to first-line therapies other than chlorambucil has not been established. • TREANDA is administered with a convenient dosing schedule – The recommended CLL dose is 100 mg/m2 administered intravenously over 30 minutes on Days 1 and 2 of a 28-day treatment cycle, up to 6 cycles Important Safety Information • Serious adverse reactions, including myelosuppression, infections, infusion reactions and anaphylaxis, tumor lysis syndrome, skin reactions including SJS/TEN, other malignancies, and extravasation, have been associated with TREANDA. Some reactions, such as myelosuppression, infections, and SJS/TEN (when TREANDA was administered concomitantly with allopurinol and other medications known to cause SJS/TEN), have been fatal. Patients should be monitored closely for these reactions and treated promptly if any occur • Adverse reactions may require interventions such as decreasing the dose of TREANDA, or withholding or delaying treatment • TREANDA is contraindicated in patients with a known hypersensitivity to bendamustine or mannitol. Women should be advised to avoid becoming pregnant while using TREANDA
Learn more at TREANDAHCP.com © 2012 Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved. TRE-2545a December 2012
Please see accompanying brief summary of full Prescribing Information.
Job Number: 16001 Revision No: 2 Date: 12/13/12
NOTEWORTHY NUMBERS Cancer Prevention According to the World Health Organization, onethird of all cancer cases are preventable.1 When individuals choose the right health behaviors and avoid exposure to certain
environmental risk factors, prevention becomes the most long-term cost-effective approach for curtailing cancer.2 The following statistics examine policy factors and behavioral prevention strategies.
Brief Summary of Prescribing Information for Chronic Lymphocytic Leukemia INDICATIONS AND USAGE: TREANDA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). Efficacy relative to first line therapies other than chlorambucil has not been established. CONTRAINDICATIONS: TREANDA is contraindicated in patients with a known hypersensitivity (eg, anaphylactic and anaphylactoid reactions) to bendamustine or mannitol. [See Warnings and Precautions] WARNINGS AND PRECAUTIONS: Myelosuppression. Patients treated with TREANDA are likely to experience myelosuppression. In the two NHL studies, 98% of patients had Grade 3-4 myelosuppression. Three patients (2%) died from myelosuppression-related adverse reactions; one each from neutropenic sepsis, diffuse alveolar hemorrhage with Grade 3 thrombocytopenia, and pneumonia from an opportunistic infection (CMV). In the event of treatment-related myelosuppression, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils closely. In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs were observed predominantly in the third week of therapy. Hematologic nadirs may require dose delays if recovery to the recommended values have not occurred by the first day of the next scheduled cycle. Prior to the initiation of the next cycle of therapy, the ANC should be ≥ 1 x 109/L and the platelet count should be ≥ 75 x 109/L. [See Dosage and Administration]. Infections. Infection, including pneumonia and sepsis, has been reported in patients in clinical trials and in post-marketing reports. Infection has been associated with hospitalization, septic shock and death. Patients with myelosuppression following treatment with TREANDA are more susceptible to infections. Patients with myelosuppression following TREANDA treatment should be advised to contact a physician if they have symptoms or signs of infection. Infusion Reactions and Anaphylaxis. Infusion reactions to TREANDA have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe reactions. Patients should be asked about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who experienced Grade 3 or worse allergic-type reactions were not typically rechallenged. Measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids should be considered in subsequent cycles in patients who have previously experienced Grade 1 or 2 infusion reactions. Discontinuation should be considered in patients with Grade 3 or 4 infusion reactions. Tumor Lysis Syndrome. Tumor lysis syndrome associated with TREANDA treatment has been reported in patients in clinical trials and in post-marketing reports. The onset tends to be within the first treatment cycle of TREANDA and, without intervention, may lead to acute renal failure and death. Preventive measures include maintaining adequate volume status, and close monitoring of blood chemistry, particularly potassium and uric acid levels. Allopurinol has also been used during the beginning of TREANDA therapy. However, there may be an increased risk of severe skin toxicity when TREANDA and allopurinol are administered concomitantly. Skin Reactions. A number of skin reactions have been reported in clinical trials and post-marketing safety reports. These events have included rash, toxic skin reactions and bullous exanthema. Some events occurred when TREANDA was given in combination with other anticancer agents, so the precise relationship to TREANDA is uncertain. In a study of TREANDA (90 mg/m2) in combination with rituximab, one case of toxic epidermal necrolysis (TEN) occurred. TEN has been reported for rituximab (see rituximab package insert). Cases of Stevens-Johnson syndrome (SJS) and TEN, some fatal, have been reported when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. The relationship to TREANDA cannot be determined. Where skin reactions occur, they may be progressive and increase in severity with further treatment. Therefore, patients with skin reactions should be monitored closely. If skin reactions are severe or progressive, TREANDA should be withheld or discontinued. Other Malignancies. There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial carcinoma. The association with TREANDA therapy has not been determined. Extravasation. There are postmarketing reports of bendamustine extravasations resulting in hospitalizations from erythema, marked swelling, and pain. Precautions should be taken to avoid extravasations, including monitoring of the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA. Use in Pregnancy. TREANDA can cause fetal harm when administered to a pregnant woman. Single intraperitoneal doses of bendamustine in mice and rats administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations, and decreased fetal body weights. ADVERSE REACTIONS: The data described below reflect exposure to TREANDA in 153 patients who participated in an actively-controlled trial for the treatment of CLL. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The following serious adverse reactions have been associated with TREANDA in clinical trials and are discussed in greater detail in other sections [See Warnings and Precautions] of the label: Myelosuppression; Infections; Infusion Reactions and Anaphylaxis; Tumor Lysis Syndrome; Skin Reactions; Other Malignancies. Clinical Trials Experience in CLL. The data described below reflect exposure to TREANDA in 153 patients. TREANDA was studied in an active-controlled trial. The population was 45-77 years of age, 63% male, 100% white, and had treatment naïve CLL. All patients started the study at a dose of 100 mg/m2 intravenously over 30 minutes on days 1 and 2 every 28 days. Adverse reactions were reported according to NCI CTC v.2.0. In the randomized CLL clinical study, non-hematologic adverse reactions (any grade) in the TREANDA group that occurred with a frequency greater than 15% were pyrexia (24%), nausea (20%), and vomiting (16%). Other adverse reactions seen frequently in one or more studies included asthenia, fatigue, malaise, and weakness; dry mouth; somnolence; cough; constipation; headache; mucosal inflammation; and stomatitis. Worsening hypertension was reported in 4 patients treated with TREANDA in the randomized CLL clinical study and none treated with chlorambucil. Three of these 4 adverse reactions were described as a hypertensive crisis and were managed with oral medications and resolved. The most frequent adverse reactions leading to study withdrawal for patients receiving TREANDA were hypersensitivity (2%) and pyrexia (1%). Table 1 contains the treatment emergent adverse reactions, regardless of attribution, that were reported in ≥ 5% of patients in either treatment group in the randomized CLL clinical study. Table 1: Non-Hematologic Adverse Reactions Occurring in Randomized CLL Clinical Study in at Least 5% of Patients Number (%) of patients TREANDA Chlorambucil (N=153) (N=143) System organ class Preferred term All Grades Grade 3/4 All Grades Grade 3/4 Total number of patients with at least 1 adverse reaction 121 (79) 52 (34) 96 (67) 25 (17) Gastrointestinal disorders Nausea 31 (20) 1 (<1) 21 (15) 1 (<1) Vomiting 24 (16) 1 (<1) 9 (6) 0 Diarrhea 14 (9) 2 (1) 5 (3) General disorders and administration site conditions Pyrexia 36 (24) 6 (4) 8 (6) 2 (1) Fatigue 14 (9) 2 (1) 8 (6) 0 Asthenia 13 (8) 0 6 (4) 0 Chills 9 (6) 0 1 (<1) 0 Immune system disorders Hypersensitivity 7 (5) 2 (1) 3 (2) 0 Infections and infestations Nasopharyngitis 10 (7) 0 12 (8) 0 Infection 9 (6) 3 (2) 1 (<1) 1 (<1) Herpes simplex 5 (3) 0 7 (5) 0 Investigations Weight decreased 11 (7) 0 5 (3) 0 Metabolism and nutrition disorders Hyperuricemia 11 (7) 3 (2) 2 (1) 0 Respiratory, thoracic and mediastinal disorders Cough 6 (4) 1 (<1) 7 (5) 1 (<1) Skin and subcutaneous tissue disorders Rash 12 (8) 4 (3) 7 (5) 3 (2) Pruritus 8 (5) 0 2 (1) 0
Tobacco Use Approximately 30% of all deaths from cancer in the United States are a result of smoking,2 and about 70% of lung cancer cases can be attributed to smoking alone.1
The Grade 3 and 4 hematology laboratory test values by treatment group in the randomized CLL clinical study are described in Table 2. These findings confirm the myelosuppressive effects seen in patients treated with TREANDA. Red blood cell transfusions were administered to 20% of patients receiving TREANDA compared with 6% of patients receiving chlorambucil. Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA or Chlorambucil in the Randomized CLL Clinical Study TREANDA Chlorambucil (N=150) (N=141) All Grades Grade 3/4 All Grades Grade 3/4 Laboratory Abnormality n (%) n (%) n (%) n (%) Hemoglobin Decreased 134 (89) 20 (13) 115 (82) 12 (9) Platelets Decreased 116 (77) 16 (11) 110 (78) 14 (10) Leukocytes Decreased 92 (61) 42 (28) 26 (18) 4 (3) Lymphocytes Decreased 102 (68) 70 (47) 27 (19) 6 (4) Neutrophils Decreased 113 (75) 65 (43) 86 (61) 30 (21) In the randomized CLL clinical study, 34% of patients had bilirubin elevations, some without associated significant elevations in AST and ALT. Grade 3 or 4 increased bilirubin occurred in 3% of patients. Increases in AST and ALT of Grade 3 or 4 were limited to 1% and 3% of patients, respectively. Patients treated with TREANDA may also have changes in their creatinine levels. If abnormalities are detected, monitoring of these parameters should be continued to ensure that significant deterioration does not occur. Post-Marketing Experience. The following adverse reactions have been identified during post-approval use of TREANDA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: anaphylaxis; and injection or infusion site reactions including phlebitis, pruritus, irritation, pain, and swelling. Skin reactions including SJS and TEN have occurred when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. [See Warnings and Precautions] OVERDOSAGE: The intravenous LD of bendamustine HCl is 240 mg/m2 in the mouse and rat. Toxicities included sedation, tremor, ataxia, convulsions and respiratory distress. Across all clinical experience, the reported maximum single dose received was 280 mg/m2. Three of four patients treated at this dose showed ECG changes considered dose-limiting at 7 and 21 days post-dosing. These changes included QT prolongation (one patient), sinus tachycardia (one patient), ST and T wave deviations (two patients), and left anterior fascicular block (one patient). Cardiac enzymes and ejection fractions remained normal in all patients. No specific antidote for TREANDA overdose is known. Management of overdosage should include general supportive measures, including monitoring of hematologic parameters and ECGs. DOSAGE AND ADMINISTRATION: Dosing Instructions for CLL. Recommended Dosage: The recommended dose is 100 mg/m2 administered intravenously over 30 minutes on Days 1 and 2 of a 28-day cycle, up to 6 cycles. Dose Delays, Dose Modifications and Reinitiation of Therapy for CLL: TREANDA administration should be delayed in the event of Grade 4 hematologic toxicity or clinically significant ≥ Grade 2 non-hematologic toxicity. Once non-hematologic toxicity has recovered to ≤ Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) ≥ 1 x 109/L, platelets ≥ 75 x 109/L], TREANDA can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted. [See Warnings and Precautions] Dose modifications for hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 25 mg/m2 on Days 1 and 2 of each cycle. Dose modifications for non-hematologic toxicity: for clinically significant Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle. Dose re-escalation in subsequent cycles may be considered at the discretion of the treating physician. Reconstitution/Preparation for Intravenous Administration. • Aseptically reconstitute each TREANDA vial as follows: • 25 mg TREANDA vial: Add 5 mL of only Sterile Water for Injection, USP. • 100 mg TREANDA vial: Add 20 mL of only Sterile Water for Injection, USP. Shake well to yield a clear, colorless to a pale yellow solution with a bendamustine HCl concentration of 5 mg/mL. The lyophilized powder should completely dissolve in 5 minutes. If particulate matter is observed, the reconstituted product should not be used. • Aseptically withdraw the volume needed for the required dose (based on 5 mg/mL concentration) and immediately transfer to a 500 mL infusion bag of 0.9% Sodium Chloride Injection, USP (normal saline). As an alternative to 0.9% Sodium Chloride Injection, USP (normal saline), a 500 mL infusion bag of 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, may be considered. The resulting final concentration of bendamustine HCl in the infusion bag should be within 0.2–0.6 mg/mL. The reconstituted solution must be transferred to the infusion bag within 30 minutes of reconstitution. After transferring, thoroughly mix the contents of the infusion bag. The admixture should be a clear and colorless to slightly yellow solution. • Use Sterile Water for Injection, USP, for reconstitution and then either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, for dilution, as outlined above. No other diluents have been shown to be compatible. • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Any unused solution should be discarded according to institutional procedures for antineoplastics. Admixture Stability. TREANDA contains no antimicrobial preservative. The admixture should be prepared as close as possible to the time of patient administration. Once diluted with either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, the final admixture is stable for 24 hours when stored refrigerated (2-8°C or 36-47°F) or for 3 hours when stored at room temperature (15-30°C or 59-86°F) and room light. Administration of TREANDA must be completed within this period. DOSAGE FORMS AND STRENGTHS: TREANDA for Injection single-use vial containing either 25 mg or 100 mg of bendamustine HCl as white to off-white lyophilized powder. HOW SUPPLIED/STORAGE AND HANDLING: Safe Handling and Disposal. As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of solutions prepared from TREANDA. The use of gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage. If a solution of TREANDA contacts the skin, wash the skin immediately and thoroughly with soap and water. If TREANDA contacts the mucous membranes, flush thoroughly with water. Procedures for the proper handling and disposal of anticancer drugs should be considered. Several guidelines on the subject have been published. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. How Supplied. TREANDA (bendamustine hydrochloride) for Injection is supplied in individual cartons as follows: NDC 63459-390-08 TREANDA (bendamustine hydrochloride) for Injection, 25 mg in 8 mL amber singleuse vial and NDC 63459-391-20 TREANDA (bendamustine hydrochloride) for Injection, 100 mg in 20 mL amber single-use vial. Storage. TREANDA may be stored up to 25°C (77°F) with excursions permitted up to 30°C (86°F) (see USP Controlled Room Temperature). Retain in original package until time of use to protect from light. 50
Distributed by: Cephalon, Inc. Frazer, PA 19355 TREANDA is a trademark of Cephalon, Inc., or its affiliates. All rights reserved. ©2008-2012 Cephalon, Inc., or its affiliates. TRE-2511e (Label Code: 00016287.06) This brief summary is based on TRE-2527 TREANDA full Prescribing Information.
A study by the American Cancer Society Cancer Action Network revealed that enacting comprehensive smoke-free legislation in states without such laws could decrease deaths by more than 624,000 over the long term and save $1.32 billion in treatment costs over 5 years.3 Also, the United States could save $1.05 billion in treatment costs, generate close to $9 billion in new state government revenue over 5 years, and save 1.32 million deaths over the long term with the passage of a one-time $1 increase in cigarette excise taxes in all US states and the District of Columbia.3 Diet, Physical Activity, and Weight One-third of the more than 500,000 cancer deaths in the US per year can be attributed to poor diet, physical inactivity, and obesity.3 To prevent cancer, individuals should achieve and maintain a healthy weight throughout life, adopt a physically active lifestyle, consume a healthy diet, and limit consumption of alcoholic beverages.3 In 2010, the Affordable Care Act created the Prevention and Public Health Fund, a source of annual funding for prevention and public health initiatives, which provided $103 million for community-based policy and environmental change initiatives dedicated to decreasing obesity, improving nutrition, and increasing physical activity through the Community Transformation Grant program.3 Continued on page 8
FEBRUARY 2013 I VOL 6, NO 1
FROM THE EDITOR PUBLISHING STAFF Senior Vice President, Sales & Marketing Philip Pawelko firstname.lastname@example.org Publisher John W. Hennessy email@example.com
Patrick Medina, PharmD, BCOP Editor-in-Chief
elcome to the first issue of The Oncology Pharmacist (TOP) for 2013. We’ll be publishing 4 issues this year, keeping you up-to-date about what is happening in the world of oncology research and bringing you information that helps you in your day-to-day practice. In this issue, we tell you about some of the news coming out of the American Society of Hematology annual meeting and the San Antonio Breast Cancer Symposium. Our coverage includes research indicating that single nucleotide polymorphisms, developed from saliva-sourced DNA, can be used to predict the occurrence of adverse effects associated with chemotherapy. Be sure to read MMA’s article about how she struggled
Steve Stricker, PharmD, MS, BCOP Associate Editor-in-Chief
to adhere to her medication regimen at home after more than 8 months of hospital-based treatment. She writes about not wanting to be a “cancer patient” anymore and how this affected her feelings toward taking her medications. This month’s Reader Poll asks if your patients talk to you about how to adhere to their medication regimen when they return home (see page 26). Please tell us what your patients are telling you and how you respond to their concerns. As always, we encourage you to visit our website, www. TheOncologyPharmacist.com. Be sure to tell us what topics you want to see covered in TOP. We want to hear from you, and we appreciate your feedback—positive and negative— about what you see in print and on the website. l
RECENT FDA NEWS Generic Doxorubicin Hydrochloride Liposome Approved The US Food and Drug Administration (FDA) approved doxorubicin hydrochloride liposome injection (Sun Pharma Global FZE) for the treatment of patients with ovarian cancer with disease progression after platinum-based chemotherapy and for the treatment of AIDS-related sarcoma in patients after failure of systemic chemotherapy or intolerance to that therapy. Approval for doxorubicin hydrochloride liposome injection was granted on February 4, 2013. The review of this generic application was expedited by the FDA’s Office of Generic Drugs because of the continuing drug shortage of Doxil Injection (doxorubicin hydrochloride liposome; Janssen Products, LP). Doxil is under shortage because of manufacturing issues. To meet patient needs, the FDA exercised its regulatory discretion with regard to alternative doxorubicin hydrochloride liposome products. Bevacizumab for Metastatic Colorectal Cancer Bevacizumab (Avastin; Genentech) received FDA approval on January 23, 2013, for use in combination with fluoropyrimidine-irinotecan–based or fluoropyrimidine-oxaliplatin– based chemotherapy for treating patients with metastatic colorectal cancer (mCRC) with disease that has progressed on a regimen containing first-line bevacizumab.
The FDA approval was granted based on the results of a randomized, open-label, multinational clinical trial that enrolled patients with mCRC whose disease progressed during or within 3 months of discontinuation of first-line bevacizumab-based combination chemotherapy. The 820 patients accrued for the trial were randomized to receive chemotherapy alone or chemotherapy in combination with bevacizumab. Depending on their prior treatment, patients received either fluoropyrimidine-irinotecan–based or fluoropyrimidine-oxaliplatin–based chemotherapy, with treatment cycles for both groups repeated every 2 or 3 weeks. For those patients in the chemotherapy plus bevacizumab arm, bevacizumab was administered by intravenous infusion at a dose of 5 mg/kg every 2 weeks or 7.5 mg/kg every 3 weeks. Patients received bevacizumab until disease progression or unacceptable toxicity. Overall survival (OS) was the primary end point, with a statistically significant improvement in OS observed in patients who received chemotherapy plus bevacizumab compared with those who received chemotherapy alone. Median OS was 11.2 months for patients in the chemotherapy plus bevacizumab arm and 9.8 months for patients in the chemotherapy-alone arm. l Sources
GET INVOLVED: HAVE YOU EVER WANTED TO WRITE AN ARTICLE FOR TOP? We’re interested in articles about the everyday issues that affect pharmacists—everything from chemotherapy safe handling to supportive care for patients to challenging cases.
Contact firstname.lastname@example.org for information. www.TheOncologyPharmacist.com
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FEBRUARY 2013 I VOL 6, NO 1
SIDE EFFECTS MANAGEMENT
SNP Networks Identify Risk... Continued from cover methodology that would be able to identify patients being treated for cancer who were at risk for side effects.” “The development of SNP-based Bayesian networks for risk assessment offers significant advantages over classic candidate gene and genome-wide association studies (GWAS),” added Ed Rubenstein, MD, president and chief executive officer of Inform Genomics, Inc., Boston, Massachusetts, which is developing the test. “Instead of looking for a single ‘master gene or SNPs’ or individually acting genes that ‘fit’ with phenotype (the GWAS approach) to predict side effects, the new concept recognizes a network of SNPs working cooperatively,” he said. The investigators have found a range of around 20 to 100 SNPs per network, and each network is associated with a particular moderate-to-severe toxicity. Advances in bioinformatics and computational power have enabled the development of learned networks using a Bayesian methodology, which is a means of estimating probabilities. Rubenstein explained the approach. “We start out with 2.5 million SNPs per person plus the clinical data, and all this goes into the network. The Bayesian algorithm removes the 99% of the SNPs that have no association with the side effect, ie, the ‘noise.’ We then take the remaining SNPs and the clinical data
and build an interaction SNP network, and this is then cross-validated.” Predicting Breast Cancer Risk The study presented in San Antonio involved 78 patients with breast cancer who received at least 3 cycles of dose-dense doxorubicin/cyclophosphamide plus paclitaxel and the recommended prophylaxis and supportive care. A validated patient-reported symptom
tic curve (AUROC) >0.80. The investigators were able to identify SNP networks associated with moderate-to-severe adverse effects of the standard breast cancer regimen. The occurrence of toxicity and the model’s accuracy at predicting it are shown in the Table. Schwartzberg explained that the AUROC shows tight correlation between the SNP networks and the occurrence of
“We have alternative regimens for many kinds of cancer, especially breast cancer, and they differ substantially in toxicity, if not necessarily in efficacy. In an attempt to personalize treatment, this is a potentially exciting tool for selecting patients for particular regimens that will be less toxic for them.” Lee Schwartzberg, MD
assessment tool was used to measure oral mucositis, chemotherapy-induced nausea and vomiting, the severity and frequency of diarrhea, fatigue, cognitive dysfunction, and peripheral neuropathy. Predictive SNP networks were developed for each of the 6 adverse effects. The primary end point was an area under the receiver operating characteris-
these adverse effects. For example, the presence of the SNP network associated with oral mucositis can predict with 97% accuracy that an individual is likely to be among the 49% who will develop this adverse effect, he explained. He said the test could possibly be very useful in the clinic. “We have alternative regimens for many kinds of cancer, espe-
Table Adverse Effects and Predictive Accuracy of SNP Network Measurement
Abbreviations: AUROC, area under the receiver operating characteristic curve; SNP, single nucleotide polymorphism. AVBCC_2013Conf_horizontalV2_91312_Layout 1 9/13/12 12:03 PM Page 1
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Predicting the Risk for Oral Mucositis The oral mucositis study presented at ASH comprised 153 patients in the discovery set, including 82 patients with myeloma and 71 with Hodgkin disease or non-Hodgkin lymphoma undergoing conditioning regimens. The genetic analysis revealed 82 SNPs within a network, and these identified patients developing mucositis with an accuracy of 99.3%, reported Stephen Sonis, DMSc, professor of Oral Medicine and Diagnostic Science at Harvard School of Dental Medicine, Boston, Massachusetts. Sonis has pioneered much of the research on oral mucositis and its prevention and treatment. In a prospective validation study of 16 patients who were demographically similar to the discovery cohort, the network predicted mucositis with an accuracy of 81%. Of 8 patients without mucositis, all were accurately identified and there were no false-positives. Of 8 patients who did not develop mucositis, 5 were accurately identified and there were 3 false-negatives. The SNPs network is “more robust” and “more likely to be accurate in subsequent validation studies.” There is less chance for false-positives compared with the “old paradigm,” Sonis said. According to Rubenstein, having a predictive test would streamline the selection of patients who could benefit from expensive prophylaxis such as palifermin. “You don’t want to give this expensive drug to patients who will never need it.” The commercial custom chip could become available for routine patient care if results from these studies can be validated in a multicenter study, he added. l References
May 2-5, 2013 Westin Diplomat • Hollywood, Florida
cially breast cancer, and they differ substantially in toxicity, if not necessarily in efficacy. In an attempt to personalize treatment, this is a potentially exciting tool for selecting patients for particular regimens that will be less toxic for them,” he said. Schwartzberg added that the model reveals intrinsic predispositions based on different germline SNPs. “It makes biological sense, and that is key,” he said.
1. Schwartzberg LS, Sonis ST, Walker MS, et al. Single nucleotide polymorphism (SNP) Bayesian networks (BNs) predict risk of chemotherapy-induced side effects in patients with breast cancer receiving dose dense (DD) doxorubicin/cyclophosphamide plus paclitaxel (AC+T). Presented at: 2012 CTRC-AACR San Antonio Breast Cancer Symposium; December 4-8, 2012; San Antonio, TX. Poster P1-15-12. 2. Sonis ST, Antin JH, Alterovitz G. SNP-based Bayesian networks define oral mucositis risk in patients receiving stomatotoxic conditioning regimens for autologous hematopoietic stem cell transplantation. Presented at: 54th Annual Meeting of the American Society of Hematology; December 8-11, 2012; Atlanta, GA. Abstract 735.
CANCER CENTER PROFILE
Smilow Cancer Hospital at Yale-New Haven Continued from cover In pharmacy, we don’t have enough staff to supply 1 pharmacist for every disease team. We have pharmacists who cover medical oncology (solid tumors), hematology (including bone marrow transplant), the women’s infusion center for gynecologic oncology and breast cancer, and pediatrics.
How does this approach translate to better outcomes? SS: We have multidisciplinary teams in the disease clinics that include surgeons, radiation oncologists, and medical oncologists. Our eventual goal is to have a pharmacist on each multidisciplinary team, and we think this is an achievable goal. Our facility has the ability to analyze 400 genes in a relatively rapid period of time and customize patient care according to the results of the genetic analysis of the patient’s tumor. We believe that in the near future, we will be able to analyze 1000 genes, and in the next few years the whole genome in a cost-effective manner. We are using the genetic analysis to improve drug selection accordingly. This strategy helps us to identify the drugs that have a better chance of working. It’s been said that the most expensive drug is the one that does not work. We can therefore provide a patient with personalized therapy with an improved chance of working, resulting in improved outcomes and reduction in waste.
At Smilow, the oncology pharmacy is positioning itself to help design pathways and guidelines for disease management. This should improve quality of care and reduce costs. What are you excited about right now in the field? SS: I am focused on 2 things. One is the personalizing of oncology care, with the ability to target therapies to the patient’s tumor type and genetics. I am also interested in the transition in healthcare moving from fee for service to a disease management strategy. Part of this movement is due to healthcare reform, but a large part is due to the need to reduce cost and improve patient care. The focus is no longer on what we did to the patient,
A projected shortage of oncologists in the coming years means that pharmacists will have the opportunity to give clinical care and in some instances become primary providers for patients. Pharmacists will have to get ready to manage that role.
but what we are doing to improve the patient’s outcome. At Smilow, the oncology pharmacy is positioning itself to help design pathways and guidelines for disease management. This should improve quality of care and reduce costs. We hope to develop standardized pathways for the approximately 80% of patients with cancer who can be treated with standard protocols and customize therapies for the remaining 20% who do not fit the standard approach. This breakdown comes from managed care strategies, where the goal was standardization of approaches.
As we learn about new abnormalities and have newer targeted therapies, these would be accounted for in the pathways. The pathways actually get easier to build and follow as we learn more about the targets that are driving tumor growth.
How has the role of the oncology pharmacist changed in the past 5 years? SS: At Smilow, we are moving away from focusing on making sure chemotherapy is being delivered to working with providers to make sure we are getting the right drug to the right patient with the right protocol. This trend in pharmacy is evident across What about the genetic abnormalthe country—moving away from a ities found in patients’ tumors? product focus to focusing on the How would you standardize that? clinical outcomes of the patient. We SS: Genetic abnormalities and their are seeing more emphasis on making targets would be incorporated into sure our patients are educated about WCMC_2013Conf_horizontalV382012_Layout 1 8/20/12 9:44 AM Page 1 the pathways for disease management. their drugs and how to take them.
This is particularly important with oral therapies. We let patients know what to expect, when they should call their doctors, and which side effects can be discussed at a regular clinic visit. Discussions with pharmacists tend to have patients direct their attention to the drugs they are receiving, whereas discussions with physicians are focused on the disease, and discussions with nurses are focused on administration of the drug.
What advice would you give pharmacists entering the field of oncology? SS: It is important to learn about the clinical aspects of oncology. A projected shortage of oncologists in the coming years means that pharmacists will have the opportunity to give clinical care and in some instances become primary providers for patients. Pharmacists will have to get ready to manage that role. I would encourage new graduates to enter residence programs, get as much training as possible, and get board certification if they want to take on a clinical role. This education will prepare them to become clinical care providers. If you weren’t a pharmacist, what would you be doing? SS: Teaching chemistry in high school and coaching football or baseball. l
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FEBRUARY 2013 I VOL 6, NO 1
Bisphosphonates Should Not Be Routine... Continued from cover point of fracture, and the prevention of recurrences and deaths from breast cancer, she noted. To the point, Gralow reviewed key data from several important trials evaluating the benefit of adjuvant bisphosphonates. No Real Benefit for Fracture Prevention The Z-FAST trial compared upfront use of zoledronic acid with its delayed use in postmenopausal women receiving adjuvant letrozole. Whereas bone mineral density (BMD) was better with the immediate use of zoledronic acid—with gain observed with upfront use and decline observed without it—fracture rates were similar between the arms: approximately 6% at 36 months and 9% to 11% at 61 months, the recent update showed.2 “Zoledronic acid preserved BMD but did not impact fractures,” she said. “There is also a rebound effect in BMD that is important,” Gralow noted. In the ABCSG-12 trial, premenopausal patients received ovarian suppression for 3 years plus adjuvant hormonal therapy, with or without zoledronic acid.3 The bisphosphonate was protective against BMD loss. However, a natural rebound in BMD occurred once the ovarian suppression was stopped, she said. “Just because we are suppressing the ovaries, especially temporarily, or starting an aromatase inhibitor, we don’t need to impact on BMD immediately,” she explained. “There’s a significant rebound of BMD once you take away the pressures from these treatments.” Although zoledronic acid did reduce recurrences by 28% and deaths by 36%, the death rate at 84 months was already
“The results of these trials will be critical in better defining the efficacy of bone-modifying agents for preventing recurrence and may provide data regarding which patients and tumors are most likely to benefit from treatment.” Julie Gralow, MD
very low (6%) among patients not receiving chemotherapy or zoledronic acid (and in spite of allowing up to 10 positive nodes). A task force of the National Com p rehensive Cancer Network, led by Gralow, defined patients who may be at increased risk for fracture and who therefore might be candidates for bisphosphonates. The algorithm suggests that drug therapy be considered for patients with a T-score between -1.5 and -2.0, and that it be initiated in those with a T-score ≤-2.0 or who have a 10-year risk >20% for a major fracture or >3% for a hip fracture by FRAX analysis (WHO Fracture Risk Assessment Tool). “The task force clearly did not say that all patients should start drug therapy up front,” she emphasized. No Real Protection From Recurrence Studies investigating whether bisphosphonates can prevent bone metastases and improve survival have produced conflicting results. Two randomized trials of oral clodronate showed a reduction in bone metastases, while a third demonstrated an equivalent rate of bone metastases between the arms. A meta-analysis using the 5-year data from these 3 adjuvant clodronate trials
failed to show a statistically significant difference in overall survival or bone metastasis-free survival,4 although heterogeneity among the trial was noted, she said. “The largest and most recently reported trial of clodronate, NSABP B-345 (the 2011 San Antonio Breast Cancer Symposium), was flat-out negative for the primary end point, disease-free survival,” she added.
Studies investigating whether bisphosphonates can prevent bone metastases and improve survival have produced conflicting results. The German GAIN trial of ibandronate6 also was completely negative for a benefit in terms of recurrence or survival, she added. Trials of the more potent aminobisphosphonate, zoledronic acid, also have produced conflicting results. Whereas the ABCSG-12 trial3 and the ZO-FAST trial7 both showed improvements in dis-
Noteworthy Numbers... Continued from page 4 UV Radiation It is estimated that approximately 76,250 cases of melanoma were diagnosed in 2012, with likely 9180 deaths.3 Behavioral strategies for the prevention of skin cancer include wearing ultraviolet (UV)-protective clothing, seeking shade when outdoors, applying sunscreen of SPF 15 or higher to exposed skin, and avoiding indoor tanning booths.3
In 2010, 60.4% of adults said that they usually or always protected themselves from the sun by practicing at least 1 of 3 sun-protective behaviors: • 31.0% reported usually applying SPF 15 or higher sunscreen • 19.7% reported usually wearing sun-protective clothing • 37.2% usually sought shade2
Sources 1. www.WHO.int/cancer/prevention/en/. 2. http://progressreport.cancer.gov/doc.asp?pid=1&did=2007&mid=vcol&chid=71. 3. http://www.cancer.org/search/index?QueryText=033423.
FEBRUARY 2013 I VOL 6, NO 1
ease-free survival in patients receiving zoledronic acid, the Z-FAST trial, with the same design as ZO-FAST, did not.2 The AZURE trial, which evaluated an “intensive” adjuvant zoledronic acid regimen, also failed to show a diseasefree or overall survival benefit.8 “The largest trial in the highest risk patients using the most intensive dosing (AZURE) was flat-out negative,” Gralow emphasized. There was a suggestion of an overall survival benefit among women who were 5 years past menopause prior to randomization—a statistically significant 25% risk reduction—suggesting that an estrogen-deficient environment might be more susceptible to the effect of zoledronic acid, but these results must be interpreted with caution, she said. Gralow added, “If there is a direct antitumor effect, I don’t know why we have not seen a hint of this in metastat ic studies.” A number of ongoing trials are further evaluating clodronate, ibandronate, zoledronic acid, and the newest osteoclast inhibitor denosumab. “The results of these trials will be critical in better defining the efficacy of bone-modifying agents for preventing recurrence and may provide data regarding which patients and tumors are most likely to benefit from treatment,” Gralow said. l References
1. Gralow J. Debate: bone health/role of bisphosphonates in early-stage breast cancer—con. Presented at: American Society of Clinical Oncology 2012 Breast Cancer Symposium; September 13-15, 2012; San Francisco, CA. 2. Brufsky AM, Harker WG, Beck JT, et al. Final 5-year results of Z-FAST trial: adjuvant zoledronic acid maintains bone mass in postmenopausal breast cancer patients receiving letrozole. Cancer. 2012;118(5): 1192-1201. 3. Gnant M, Mlineritsch B, Luschin-Ebengreuth G, et al. Long-term follow-up in ABCSG-12: significantly improved overall survival with adjuvant zoledronic acid in premenopausal patients with endocrine-receptor-positive early breast cancer. Presented at: 34th Annual San Antonio Breast Cancer Symposium; December 6-11, 2011; San Antonio, TX. Abstract S1-2. 4. Ha TC, Li H. Meta-analysis of clodronate and breast cancer survival. Br J Cancer. 2007;96(12):1796-1801. 5. Paterson AHG, Anderson SJ, Lembersky BC, et al. NSABP protocol B-34: a clinical trial comparing adjuvant clodronate vs. placebo in early stage breast cancer patients receiving systemic chemotherapy and/ or tamoxifen or no therapy—final analysis. Presented at: 34th Annual San Antonio Breast Cancer Symposium; December 6-11, 2011; San Antonio, TX. Abstract S2-3. 6. Möbus V, Diel IJ, Harbeck N, et al. GAIN (German Adjuvant Intergroup Node Positive) study: a phase-III multicenter trial to compare dose dense, dose intense ETC (iddETC) vs. EC-TX and ibandronate vs. observation in patients with node-positive primary breast cancer—1st interim EFFICACY analysis. Presented at: 34th Annual San Antonio Breast Cancer Symposium; December 6-11, 2011; San Antonio, TX. Abstract S2-4. 7. de Boer R, Bundred N, Eidtmann H, et al. Long-term survival outcomes among postmenopausal women with hormone receptor-positive early breast cancer receiving adjuvant letrozole and zoledronic acid: 5-year follow-up of ZO-FAST. Presented at: 34th Annual San Antonio Breast Cancer Symposium; December 6-11, 2011; San Antonio, TX. Abstract S1-3. 8. Coleman RE, Marshall H, Cameron D, et al. Breastcancer adjuvant therapy with zoledronic acid. N Engl J Med. 2011;365(15):1396-1405.
CONFERENCE NEWS: SABCS No Benefit for Extending Trastuzumab Another Year Two years of trastuzumab provide no benefit over the standard of 1 year of trastuzumab therapy for human epidermal growth factor receptor 2–positive (HER2+) breast cancer, according to an 8-year follow-up of the Herceptin Adjuvant (HERA) trial reported by Martine Piccart, MD, president of the European Society for Medical Oncology and chair of the Breast International Group, Institut Jules Bordet, Brussels, Belgium. “One year of trastuzumab should remain the standard of care,” she said. HERA was a large international trial that accrued 5102 women with HER2+ breast cancer in a little more than 3 years. Oncologists had the choice of neoadjuvant or adjuvant therapy, and patients were randomized to receive 1 or 2 years of trastuzumab following chemotherapy. For the primary end point of the trial, disease-free survival (DFS) was significantly better for 1 year versus
observation. The secondary end point was DFS after 1 year versus 2 years of trastuzumab. At 8 years, no difference in DFS was observed between the 2 arms, and both were significantly better than observation. At baseline, all patients had left ventricular ejection fraction of 55%; the cumulative incidence of cardiac end points showed no difference between the 2 arms. “Severe cardiac end points are rare,” Piccart said. Most cardiac events occurred during the first year of treatment and then the curves of both arms reached a plateau. Few women experienced cardiac events after stopping trastuzumab, she said. “We were concerned that there would be a progressively smaller effect of 1 year of treatment with trastuzumab over time. Now with 8 years of follow-up, there is no further attenuation of benefit as was seen at 1 year, and a very robust
Photo from SABCS 2012.
By Alice Goodman
Martine Piccart, MD
effect with 1 year of trastuzumab.” No difference was seen between hormone receptor–positive and hormone
receptor–negative patients. No attenuation of overall survival benefit was seen at 8 years.
Extending Adjuvant Tamoxifen to 10 Years Improves Survival
In the second decade after diagnosis, those who took tamoxifen for 10 years had a 25% lower recurrence rate and a 29% lower breast cancer mortality rate compared with those who had only 5 years of tamoxifen. The cumulative risk of death from
Photo from SABCS 2012.
Extending tamoxifen treatment for 10 years reduced the risk of dying by 29% compared with the standard 5 years of tamoxifen for estrogen receptor–positive (ER+) breast cancer, but these benefits of longer-duration tamoxifen did not emerge until the second decade after diagnosis, according to results of the international Adjuvant Tamoxifen— Longer Against Shorter (ATLAS) study. “Five years of tamoxifen is very effective, and there is a carryover effect after stopping, with about a 30% reduction in mortality over the next 5 years. In the period 10 to 14 years after diagnosis, we found many fewer recurrences: 617 in the group receiving 10 years of tamoxifen versus 711 in patients treated with 5 years of tamoxifen. Breast cancer mortality and overall were similarly affected by longer duration of tamoxifen,” stated lead author Richard Gray, MSc, Clinical Trial Service Unit, University of Oxford, United Kingdom. He reported 331 breast cancer–related deaths in the 10-year group versus 397 in the 5-year group, and 539 versus 722 deaths from all causes, respectively. ATLAS enrolled 6846 women with ER+ breast cancer from 36 countries between 1996 and 2005. About 50% had node-positive disease, and all women had been taking tamoxifen for 5 years. Women were randomized to either continue 5 more years of tamoxifen or to receive no more tamoxifen. In the period 5 to 14 years after diagnosis, the risk of breast cancer death was 12.2% for 10-year users versus 15% for 5-year users, for an absolute gain of 2.8% favoring the longer treatment duration.
0.2% for those who did not continue. “The reduction in breast cancer deaths far outweighs this small risk of endometrial cancer and other adverse events. Contrary to expectations, no excess risk of endometrial cancer was observed in younger women who took 10 years of
“The reduction in breast cancer deaths far outweighs this small risk of endometrial cancer and other adverse events.” Richard Gray, MSc
endometrial cancer between 5 and 14 years after diagnosis was 0.4% for the continuing tamoxifen users versus
tamoxifen,” Gray said. “The absolute mortality gain with 10 years of tamoxifen at 15 years after diagnosis is 12% or 1 in
8 balanced against 1 in 250 cases of endometrial cancer deaths,” he noted. These findings are likely to be more relevant for premenopausal women. In the United States, postmenopausal women are generally given aromatase inhibitors (AIs), whereas tamoxifen is preferred for younger women with hormone receptor–positive breast cancer. However, some postmenopausal women are intolerant of AIs and may prefer to take tamoxifen, and the results are relevant for that group, stated Peter Ravdin, MD, director of the Breast Health Clinic at the Cancer Therapy & Research Center at the University of Texas Health Science Center in San Antonio. With any patient, risks versus benefits must be discussed, and low-risk women may prefer to stay with 5 years of treatment, he noted. —AG
Higher Doses of Fulvestrant Better Than Lower Doses A 500-mg dose of fulvestrant improved survival compared with a 250-mg dose in women with estrogen receptor–positive (ER+) metastatic breast cancer with no increase in toxicity, according to an update of the Comparison of Faslodex in Recurrent or Metastatic Breast Cancer (CONFIRM) trial. “For postmenopausal women with recurrent or progressing ER+ locally advanced or metastatic breast cancer for whom fulvestrant is appropriate, the standard of care has been 250 mg. Our results indicate that this should be modified to a 500-mg dose,” said lead author Angelo Di Leo, MD, PhD, head of the department of medical oncology at the Hospital of Prato, Istituto Toscano Tumoria, Prato, Italy. CONFIRM was a double-blind, parallel-group, multicenter, phase 3 trial that randomized 736 women from 128 centers in 17 countries to receive either 250 mg or 500 mg of fulvestrant. Women were observed until 75% of the patients died; at the time of analysis, 554 died, 63 were lost to follow-up, and 16 withdrew consent. The 500-mg dose achieved a clinically relevant 4.1-month difference in median overall survival compared with a 250-mg dose: 26.4 months and 22.3 months, respectively. The relative risk reduction in death was 19% for those taking the higher dose of fulvestrant. Serious adverse events were reported in 8.9% of the 500-mg dose group and 6.7% of those receiving the lower dose. —AG
FEBRUARY 2013 I VOL 6, NO 1
THE WHOLE PATIENT
Approaches to Sexual Dysfunction in Breast Cancer Survivors By Alice Goodman
“Sexual and intimacy issues are the white elephant in the room for women with breast cancer,” stated Susan W. Rafte, of the Pink Ribbons Project, Houston, Texas. Rafte, an 18-year survivor of metastatic breast cancer, intro-
duced an expert in sexuality to discuss approaches to sexual problems in breast cancer patients at the first session to be planned and moderated by a patient advocate (herself) at the San Antonio Breast Cancer Symposium.1
CCC Asize_112112_TON0210 11/29/12 2:21 PM Page 1
“Intimacy is vital for the breast cancer survivor, and she needs comprehensive sexual care that involves communication with the team of health care providers who treat the patient,” stated Michael Krychman, MD, executive director of
nc seri Vie olo es w gy on the Ph lin ar e a m t ac ist .co
CONQUERING THE CANCER CARE
CONQUERING THE CANCER CARE CONTINUUM CONQUERING CANCER CARTHE C E CONT I
A 6-part series
The publishers of The Oncology Nurse-APN/PA, The Oncology Pharmacist, and Personalized Medicine in Oncology are proud to present our 2nd annual Conquering the Cancer Care Continuum series. Upcoming topics include:
Challenges Patients Face in Cancer Care: Implications for the Healthcare Team Lea Ann Hansen, PharmD, BCOP Associate Professor, Virginia Commonwealth University
cancer.1 More than half are living well beyond 5 years ancer is an illness associated with substantial physical, emotional, social, and financial ramafter diagnosis. Women comprise a majority of longifications for affected individuals and their term survivors due to the favorable outcomes with families. In a significant number of cases, the diagnosis breast, cervical, and uterine cancers.2 The number of of cancer is either preceded by a period people living with a history of cancer of gradual, nonspecific symptoms or is projected to grow considerably over discovered by routine screening, and the next 20 years for 2 major reasons. individuals are then thrust into a First, the number of Americans over whirlwind of diagnostic testing, inage 65 is predicted to double between vasive procedures, and complicated the years 2000 and 2030.3 Consetreatments with very little warning or Lea Ann Han quently, as a disease primarily of older sen, Pha Associat rmD, BCO adults, cancer will also increase. Sece Professo opportunity to assimilate their circumP r, Virginia Common stances. 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The purp dolsion, requ ose of this ire special isdistress to expand or rsity BCOP into care in order to minimize their maxiThese statistics underscore the need for a wide variety are han artic D, lain Unive used dlin le the evolutio g, en, Pharm for complex 80%, monwealth ia Com cialty pha n ens Lea Ann Hans ssor, Virgin from 17% toand other support personnel torequire of range the mize their clinical outcomes. of health professionals spermacy ation Profe regim special mon diseases that and the Associate on assumption oral medic can itoring. 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THE QUERING N O C ANCER CARE
C O N T I NT U U M C
“The foremost issue is breaking the silence. If you don’t see sexual problems in your practice, you are not asking the right questions.” Michael Krychman, MD
imizing Ad herence to Cancer Therapy
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TO VIEW THE SERIES ONLINE PLEASE LOG ON TO:
FEBRUARY 2013 I VOL 6, NO 1
CONQUERING T CANCER CAREHE
er nce to Canc Nonadhere Impact of
Conveni en The Impa ce, Challeng es Patient ct of Specialty , and Cost Con Care Pharmac tainmen ies on t:
Best Prac tices in M ax
• Palliation • Pain management • Hospice care • Treatment planning • Survivorship care • Biosimilars in supportive care
the Southern California Cancer Center for Sexual Health and Survivorship Medicine in Newport Beach, California.2 “We do a disservice when we don’t address sexual care,” he added. “The foremost issue is breaking the silence. If you don’t see sexual problems in your practice, you are not asking the right questions. Ninety percent of breast cancer survivors have some sort of sexual complaint, either immediate or long-lasting,” he continued. Sexual issues need to be addressed in the context of patients’ ethnicity and choice of partners—whether gay or straight, he continued. Also, overall health and wellness should be addressed. Several nonpharmacologic interventions can improve sexual health. “Data support that the Mediterranean diet can improve indices of sexual health function. Body mass index [BMI] and BMI maintenance is vital for overall general health and for sexual health as well. Mindfulness has been found effective for sexual desire and arousal disorders as part of a larger treatment program. Meditation can improve response and decrease sexual distress,” Krychman said.
Vulvovaginal atrophy (VVA) is a common problem that affects sexual function in sexually active postmenopausal women and breast cancer survivors, and reducing symptoms of VVA may help sexual function, he said. Lubricants and moisturizers can be used. There is a difference between these 2 products; lubricants are used at the time of sexual intercourse and moisturizers promote long-term relief of VVA. Over-the-counter lubricants include K-Y Jelly, Astroglide, olive oil, and other types of oils. Moisturizers, such as Replens, need to be used consistently to help improve plasticity of the vaginal lining. “A woman with VVA should be prescribed vaginal dilators to increase the circumference of the vagina. They come in sets and require instruction and monitoring. We see patients every
THE WHOLE PATIENT 4 weeks to increase compliance. They need constant encouragement to use these dilators, but this helps the woman increase her sexual self-esteem,â€? he said. Turning to pharmacologic approaches, the use of estrogen preparations to manage VVA is controversial for breast cancer survivors, because estrogen fuels some breast cancers. Some newer versions of these preparations have less estrogen. â€œI tread cautiously about advising use of minimally absorbed local estrogen for breast cancer survivors,â€? Krychman said. â€œThe vagina is not cement. The vaginal epithelium does have some absorption. It is important to emphasize that the effects of minimally absorbed local estrogen
â€œI tread cautiously about advising use of minimally absorbed local estrogen for breast cancer survivors.â€? Michael Krychman, MD
Document all discussions with patients, and get informed consent. Consider following estradiol levels and tailor the treatment regimen accordingly. See your patients regularly,â€? he advised. Potential off-label approaches to treatment of sexual dysfunction include bupropion (an antidepressant with prosexual effects) and flibanserin, a nonhormonal serotonin modulator. In studies of more than 10,000 women, flibanserin
improved sexual interest and was very well tolerated. A study by Katz and colleagues called BEGONIA is in press in the Journal of Sexual Medicine, he added. Other compounds in clinical trials include a nonhormonal vulvar soothing cream called cellular lysate cream; Femprox (alprostadil), a topical cream that improves blood flow to the clitoris and response; Lybrido (testosterone with a phosphodiesterase inhibitor);
Lybridos (testosterone with a 5-HT1A agonist); and bremelanotide (a melanocortin receptor agonist). l References
1. Rafte SW. Navigating the obstacles and risks of survivorship. Presented at: 2012 CTRC-AACR San Antonio Breast Cancer Symposium; December 4-8, 2012; San Antonio, TX. 2. Krychman M. Emerging sexual pharmacology for the breast cancer survivor. Presented at: 2012 CTRCAACR San Antonio Breast Cancer Symposium; December 4-8, 2012; San Antonio, TX.
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â€˘ Melanoma â€˘ Basal Cell Carcinoma â€˘ Cutaneous T-Cell Lymphoma
â€˘ Squamous Cell Carcinoma â€˘ Merkel Cell Carcinoma
July 26-28, 2013
Hyatt Regency La Jolla â€˘ San Diego, California
A 2-day congress dedicated to informing, educating, and fostering the exchange of clinically relevant information in the field of cutaneous malignancies on topics in melanoma, basal cell carcinoma, cutaneous T-cell lymphoma, squamous cell carcinoma, and Merkel cell carcinoma, including: â€˘ Epidemiology and genetic/environmental factors â€˘ Molecular biology and cytogenetics related to the pathogenesis of cutaneous malignancies â€˘ Risk stratification based on patient and tumor characteristics â€˘ Principles of cancer prevention of melanoma and basal cell carcinoma
remain to be elucidated in breast cancer patients,â€? he stated. Several nonhormonal products are in development for VVA and will be suitable for breast cancer survivors if approved by the US Food and Drug Administration (FDA). These include intravaginal testosterone (no systemic increase in estradiol levels, he said) and intravaginal dehydroepiandrosterone (DHEA; suppositories given daily with no increase in systemic estradiol levels, under review at the FDA). Ospemifene (a vaginal receptor agonist, or selective estrogen receptor modulator [SERM]) just completed phase 3 clinical trials and is under review by the FDA. This is a first-inclass oral agent that targets the vaginal epithelium, Krychman said, which â€œmay be interesting for the breast cancer population. I think it is very exciting. Oncology teams are more comfortable using SERMs than local estrogens,â€? he commented. In Europe, Vagitocin (intravaginal oxytocin) is in phase 2 testing for VVA, while estriol, a weak endogenous estrogen, has been used for many years. Estriol is safe for the endometrium and reverses VVA, Krychman added. However, â€œThese 2 products are not FDA approved. Some of my colleagues are using estriol in a compounded formulation. This has not been studied in breast cancer survivors,â€? he stated. â€œThe approach to the breast cancer survivor with VVA should always begin with nonpharmacologic strategies. Alternatives should be tried first.
â€˘ Current treatment guidelines â€˘ Emerging treatment options for personalized therapy â€˘ Future strategies in management based on translational data from current clinical trials and basic research
LEARNING OBJECTIVES Upon completion of this activity, the participant will be able to: â€˘ Review the molecular biology and pathogenesis of cutaneous malignancies as they relate to the treatment of cutaneous T-cell lymphoma, basal cell carcinoma, Merkel cell tumors, and malignant melanoma â€˘ Compare risk stratification of patients with cutaneous malignancies, and how to tailor treatment based on patient and tumor characteristics â€˘ Summarize a personalized treatment strategy that incorporates current standards of care and emerging treatment options for therapy of patients with cutaneous malignancies
TARGET AUDIENCE This activity was developed for medical and surgical oncologists, dermatologists, radiation oncologists, and pathologists actively involved in the treatment of cutaneous malignancies. Advanced practice oncology or dermatololgy nurses, oncology pharmacists, and researchers interested in the molecular biology and management of cutaneous malignancies are also encouraged to participate.
DESIGNATION OF CREDIT STATEMENTS SPONSORS This activity is jointly sponsored by Medical Learning Institute Inc, Center of Excellence Media, LLC, and Core Principle Solutions, LLC.
COMMERCIAL SUPPORT ACKNOWLEDGMENT Grant requests are currently being reviewed by numerous supporters. Support will be acknowledged prior to the start of the educational activities.
Sanjiv S. Agarwala, MD Professor of Medicine Temple University School of Medicine Chief, Oncology & Hematology St. Lukeâ€™s Cancer Center Bethlehem, Pennsylvania
REGISTERED NURSE DESIGNATION Medical Learning Institute Inc Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 12.0 contact hours.
REGISTERED PHARMACY DESIGNATION The Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Completion of this knowledge-based activity provides for 12.0 contact hours (1.2 CEUs) of continuing pharmacy education credit. The Universal Activity Number for this activity is (To be determined).
CONFERENCE REGISTRATION EARLY BIRD REGISTRATION NOW OPEN! $175.00 UNTIL APRIL 30, 2013
Professor Dr. Med. Axel Hauschild Professor, Department of Dermatology University of Kiel Kiel, Germany
AGENDA* FRIDAY, JULY 26, 2013 3:00 pm â€“ 7:00 pm
5:30 pm â€“ 7:30 pm
SATURDAY, JULY 27, 2013 7:00 am â€“ 8:00 am
Breakfast Symposium/Product Theater/Exhibits
8:00 am â€“ 8:15 am
8:15 am â€“ 8:30 am
Welcome to the Second Annual World Cutaneous Malignancies Congress â€” Setting the Stage for the Meeting - Sanjiv S. Agarwala, MD
8:30 am â€“ 11:45 am General Session I: A Clinicianâ€™s Primer on the Molecular Biology of Cutaneous Malignancies â€˘ Keynote Lecture Understanding the Basic Biology and Clinical Implications of the Hedgehog Pathway â€˘ Keynote Lecture Pathogenesis of Merkel Cell Carcinoma: An Infectious Etiology? - Paul Nghiem, MD, PhD 12:00 pm â€“ 1:00 pm Lunch Symposium/Product Theater/Exhibits 1:00 pm â€“ 1:15 pm
1:15 pm â€“ 4:30 pm
General Session II: Current Treatment Guidelines in Cutaneous Malignancies â€˘ Case Studies Optimal, Value-Based Therapy of Cutaneous Malignancies: The Expertâ€™s Perspective on How I Treat My Patients â€˘ Panel Discussion Management Controversies and Accepted Guidelines for the Personalized Management of Cutaneous Malignancies â€˘ Keynote Lecture New Combinations in Melanoma: A Role for MEK + BRAF and Antiâ€“PD-1
4:30 pm â€“ 6:30 pm
Meet the Experts/Networking/Exhibits
PHYSICIAN CREDIT DESIGNATION The Medical Learning Institute Inc designates this live activity for a maximum of 12.0 AMA PRA Category 1 Credits â„˘. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of the Medical Learning Institute Inc and the Center of Excellence Media, LLC. The Medical Learning Institute Inc is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.
Steven J. Oâ€™Day, MD Hematology/Oncology Director of Clinical Research Director of Los Angeles Skin Cancer Institute at Beverly Hills Cancer Center Clinical Associate Professor of Medicine USC Keck School of Medicine Los Angeles, California
SUNDAY, JULY 28, 2013 7:00 am â€“ 8:00 am
Breakfast Symposium/Product Theater/Exhibits
8:00 am â€“ 8:15 am
8:15 am â€“ 8:30 am
Review of Saturdayâ€™s Presentations and Preview of Todayâ€™s Sessions
8:30 am â€“ 11:45 am General Session III: Review of Emerging Treatment Options for Cutaneous Malignancies General Session IV: Challenges for the Cutaneous Malignancies Clinician â€˘ Panel Discussion How Can the Healthcare Team Work Best Together to Deliver Value-Based Care in Cutaneous Malignancies? 12:00 pm â€“ 1:00 pm Lunch Symposium/Product Theater/Exhibits 1:00 pm â€“ 1:15 pm
1:15 pm â€“ 2:45 pm
General Session V: â€œHot Dataâ€? â€” What I Learned at Recent Meetings: Focus on Cutaneous Malignancies
2:45 pm â€“ 3:00 pm
Closing Remarks - Steven J. Oâ€™Day, MD
*Agenda is subject to change.
For complete agenda please visit www.CutaneousMalignancies.com
FEBRUARY 2013 I VOL 6, NO 1
Benefit for Neoadjuvant Chemotherapy Seen in Very Young Patients With Triple-Negative and Luminal-Like Breast Cancer By Alice Goodman
oung women with triple-negative and luminal-type breast cancer were more likely to respond to neoadjuvant chemotherapy than were older women with these cancers, and improved outcomes were observed for young women with luminal-A–like tumors who achieved a pathologic complete response (pCR) versus those who did not. The study suggests that neoadjuvant chemotherapy is beneficial for young women with triple-negative and luminal-type breast cancer, even those with favorable biological features that include hormone receptor positivity (HR+) and human epidermal growth factor 2–negative (HER2–) disease. “Breast cancer is less common in women age 35 or younger, and some data suggest that these younger patients
have a worse prognosis. This is not only because they tend to have more aggressive breast cancers, but because tumors that arise in younger women
leagues reported at the CTRC-AACR San Antonio Breast Cancer Symposium included a total of 8949 women from 8 German studies. All women had oper-
“Breast cancer is less common in women age 35 or younger, and some data suggest that these younger patients have a worse prognosis.” Sibylle Loibl, MD, PhD
appear to have different biological features,” stated Sibylle Loibl, MD, PhD, associate professor at the University of Frankfurt, Germany. The meta-analysis that Loibl and col-
able or locally advanced nonmetastatic breast cancer and received neoadjuvant chemotherapy. Among these women, 704 were aged 35 years or younger. pCR and disease-free survival (DFS) were
Venlafaxine Lowers Endoxifen Levels, May Affect Tamoxifen Effectiveness By Caroline Helwick
he antidepressant venlafaxine is often prescribed to dominantly CYP2D6 extensive and ultrarapid metabolizers. patients with breast cancer who are taking tamoxifen, Venlafaxine significantly decreased endoxifen concentrations. to help reduce the side effect of hot flashes. But accord- Across all genetic subgroups, levels were depressed by a mediing to research presented at the 2012 CTRC-AACR San an of about 1.6 ng/mL over time (P = .04). Limited evidence Antonio Breast Cancer Symposium, venlafaxine may reduce suggests that at least 6 ng/mL is needed for the prevention of the effectiveness of the drug. breast cancer events; in the present study, 3 women with low The findings came from a multicenter prospective phar- CYP2D6 activity had levels drop below that. macologic study that analyzed paired blood samples from Goetz acknowledged that the optimal endoxifen concen30 women taking venlafaxine for at least 4 weeks for the tration needed for benefit is still unknown, as is the effect of treatment of hot flashes. Blood was taken before starting venlafaxine on breast cancer outcomes. “The bottom line is venlafaxine and 8 to 16 weeks afterthat there is a decrease [in concenward. Genotyping was conducted for tration]. It’s small but it’s statisticalWomen with tamoxifenalleles associated with no, reduced, and ly significant. The question really ultrarapid metabolism. The aim was to is, ‘Are there subgroups of patients induced vasomotor examine whether venlafaxine altered in which this is important?’” symptoms requiring the pharmacokinetics of tamoxifen He concluded that “given prior and to determine the distribution of data linking low endoxifen conameliorative treatment CYP2D6 genotypes in this population. centrations with recurrence, venlawith venlafaxine were CYP2D6 is the rate-limiting faxine should be used with caution enzyme responsible for the metabolic in tamoxifen-treated patients.” predominantly CYP2D6 activation of tamoxifen to endoxifen. Session moderator Hiltrud extensive and ultrarapid Among women taking tamoxifen, Brauch, PhD, of the Margarete those who are extensive metabolizers Fischer-Bosch Institute of Clinimetabolizers. of CYP2D6 have higher endoxifen cal Pharmacology in Stuttgart, concentrations, have more vasomoGermany, led a 2009 study showtor symptoms, and are more likely to discontinue treat- ing that variations in CYP2D6 metabolism have an effect on ment, compared with poor metabolizers. disease-free and event-free survival in patients taking tamoxi“The data regarding CYP2D6 genotype and cancer recur- fen. “Poor metabolizers do not benefit from tamoxifen as well rence [have] been mixed,” said lead investigator Matthew as extensive metabolizers,” she said. “The long and the short Goetz, MD, of the Mayo Clinic in Rochester, Minnesota. of it is that this matters to women.” l “Venlafaxine is a weak CYP2D6 inhibitor not known to alter tamoxifen pharmacokinetics and is commonly recommended Reference Goetz MP, Suman V, Henry NL, et al. Venlafaxine inhibits the CYP2D6 medifor tamoxifen-induced hot flashes.” ated metabolic activation of tamoxifen: results of a prospective multicenter study: Women with tamoxifen-induced vasomotor symptoms (NCT00667121). Presented at: 2012 CTRC-AACR San Antonio Breast Cancer requiring ameliorative treatment with venlafaxine were pre- Symposium; December 4-8, 2012; San Antonio, TX. Abstract PD10-08.
FEBRUARY 2013 I VOL 6, NO 1
compared for the younger patients (aged ≤35 years) versus women aged 36 to 50 years and women aged 51 years or older. A greater percentage of younger women had triple-negative breast cancer (32% for younger women, about 25% for those aged 26-50 years, and 21% for those aged 51 years and older). Compared with older women, a smaller percentage of younger women had luminal-A–type breast cancer (27% vs 21%, respectively). pCR was significantly higher in younger women compared with older women: 23.6% versus 17.5% of women in the 36- to 50-year-old age group and 13.5% of those aged 51 years and older (P <.001); this difference in pCR was confined to triple-negative and luminal-like breast cancer (HR+/HER2–). More in-depth analysis showed that this difference was restricted to women with triple-negative breast cancer: the pCR rate was 45% for younger patients versus 31% for older patients (P <.001). For all patients, regardless of subtype of breast cancer, DFS and local recurrence-free survival were significantly worse for the very young patients (aged ≤35 years) compared with middle-aged patients (aged 36-50 years; P = .031 and P = .018, respectively). No difference in DFS according to age was observed among patients who achieved pCR. However, DFS was significantly worse among women who failed to achieve pCR. Tumor biology appeared to be important in predicting pCR and survival in younger women. Age but not pCR predicted DFS in women with luminal-A– type cancer. However, the worst DFS rate was seen among those women with luminal-A–type breast cancer who were younger than age 35 years and did not achieve pCR. The most favorable DFS was observed among younger women who did achieve pCR. Loibl said the investigators were surprised to find that younger women with luminal-type cancer (HR+ and HER2–) who achieved pCR had improved survival compared with patients with nonpathologic CR. “This is not seen in other age groups, indicating that breast cancer in the young women is chemosensitive, even when it is a luminal-type breast cancer,” she stated. l Reference
Loibl S, Jackisch C, Gade S, et al. Neoadjuvant chemotherapy in the very young 35 years of age or younger. Presented at: 2012 CTRC-AACR San Antonio Breast Cancer Symposium; December 4-8, 2012; San Antonio, TX.
Liposomal Vincristine Allows for Greater Dose Density Without Increased Neurotoxicity By Caroline Helwick
90 80 70 60 50 40 30 20 10 0
Dose Density (mg/week)
1.4 mg/m2/3 wk
4 mg/3 wk
2 mg/3 wk
2.25 mg/m /wk
Figure Higher VSLI Dose Without Increase in PN
Increased Delivery of Vincristine to Target Tissue Dose capping is intended to reduce the risk of drug-induced neuropathy, but may also limit clinical efficacy, said Jeffrey A. Silverman, PhD, Vice President of Clinical Pharmacology and Translational Research at Talon Therapeutics, South San Francisco, California. “In addition to dose capping, standard VCR is limited by a very rapid distribution half-life and large volume of distribution that suggests there is wide and diffuse tissue distribution,” he said. “VSLI is designed to overcome the dosing and pharmacokinetic limitations of standard VCR. It is intended to take advantage of fenestrated (leaky) vasculature found in bone marrow, lymph nodes, the spleen, and many tumors…to preferentially penetrate, accumulate, and deliver VCR to cancer tissues,” he pointed out. At ASH, Silverman described plasma pharmacokinetics in rats that received standard VCR or VSLI 2 mg/m2 by slow IV bolus.3 VSLI increased VCR
plasma circulation time and area under the curve, delivered more VCR to tissues that are important in hematologic malignancies, and slowly released VCR in tumors over days, he reported.
Paraesthesia Rate (%)
n August 2012, vincristine sulfate LIPOSOME injection (VSLI) (Marqibo) was granted accelerated approval by the US Food and Drug Administration (FDA) for the treatment of adult patients with Philadelphia chromosome-negative (Ph-) acute lymphoblastic leukemia (ALL) in second or greater relapse or whose disease has progressed after 2 or more regimens.1 At the 54th Annual Meeting of the American Society of Hematology (ASH), investigators further described its pharmacokinetics and neurotoxicity profile of the new drug and reported data in pediatric patients. Standard vincristine sulfate (VCR) is a component of treatment regimens for pediatric and adult hematologic and solid malignancies,2 including ALL, non-Hodgkin lymphoma, Hodgkin lymphoma, Wilms’ tumor, sarcomas, and brain tumors. Dosing of VCR is limited by significant neurotoxicity, which occurs at doses higher than 1.4 mg/m2 and has led to capping of the total dose at 2.0 mg.2 The newly approved vincristine product is a sphingomyelin/cholesterol liposome-encapsulated formulation of VCR.2 Liposomal carriers are capable of increasing the therapeutic index of anticancer drugs by altering the pharmacokinetic behavior of standard agents. VSLI is administered at 2.25 mg/m2 by IV infusion over 1 hour once every 7 days with no dose cap.1
Paraesthesia Rate (%)
Neurotoxicity Profile Marqibo facilitates >2 fold higher dose density without a concomitant Stable, In Spite of High 0 1 2 3 4 5 increase in paraesthesia rate Doses Delivered Dose Density (mg/week) Peripheral neuropathy is the major toxicity associ- Figure used with permission of Jeffrey A. Silverman. ated with the use of VCR, and this limits the individual dose, VCR showed much higher paresthe- of 10 received the VSLI dose that cumulative exposure, and dose density sia rates at much lower dose densities exceeded the 2-mg dose cap for standard VCR. Of 7 patients evaluable for of the drug. (Figure)4,5: • 78% with a dose density of 0.84 mg/ response, 1 patient achieved a complete “Attempts to increase the dose [of week (1.4 mg/m2 every 3 weeks) remission, 3 had stable disease, 2 had standard VCR] have been met with a • 34% with a dose density of 0.67 mg/ progressive disease, and 1 was too early 100% incidence of peripheral neuropaweek (2 mg every 3 weeks) to assess for response. thy,” Silverman said. • 60% at a dose density of 1.33 mg/ Most treatment-related adverse events Due to VCR’s dose-dependent antiweek (4 mg every 3 weeks) were grade 1 and 2 and reversible, the tumor activity, it would be beneficial VSLI facilitated more than a 2-fold most common of which were hepatic to be able to increase the dose and dose density without increasing neuropathy, higher dose density without a concomi- transaminase elevations, paresthesias, tant increase in paresthesia rate. neutropenia, and fatigue. No patient he added. discontinued treatment due to neurotoxicity. “VSLI appears to be safe and tolerable. Liposomal carriers are capable of increasing The toxicity spectrum appears similar in children and adults,” Shah said. “VSLI the therapeutic index of anticancer drugs may allow for intensification of vincrisby altering the pharmacokinetic behavior of tine therapy in children with cancer.” “Clearance of total vincristine in our standard agents. study was approximately 100-fold lower in comparison to previously observed values for the administration of standard “One of the advantages of VSLI is no vincristine,” she added. Investigators dosed VSLI at 2.25 mg/m2 (the FDA-approved dose) with- dose cap, so we can administer more vinAccrual at the adult recommended out a dose cap and evaluated the cristine, and what we saw in this study is dose is ongoing and an expanded phase emergence of neuropathy in 83 adults that higher dosing does not translate into 2 cohort in pediatric patients with ALL with relapsed/refractory ALL and prior greater neurotoxicity. With the conven- is being planned. l VCR exposure; 80% of the subjects tional drug, we see more neurotoxicity had residual neuropathy.2 Peripheral even at much lower doses and lower dose References 1. Marqibo [package insert]. South San Francisco, CA: neuropathy was proactively assessed density,” Silverman said. Talon Therapeutics, Inc; August 2012. weekly with a detailed evaluation of 16 There were no new or unexpected 2. Deitcher SR, Silverman JA; on behalf of the RALLY signs and symptoms. toxicities observed with VSLI dosed at Trial Investigators. Neurotoxicity profile of vinCRIStine sulfate LIPOSOME injection (VSLI, Marqibo®) The investigators observed that the 2.25 mg/m2, he added. monotherapy in adults with relapsed acute lymphoblasHe acknowledged that the study tic leukemia and universal prior standard vincristine occurrence of peripheral neuropathy exposure. Poster presented at: 54th American Society was consistent with the labeled dose of compared neurotoxicity with VSLI to of Hematology Annual Meeting; December 8-11, 2012; standard VCR, despite the delivery of historical data on VCR. “A head-to- Atlanta, GA. Abstract 3568. 3. Silverman JA, Deitcher SR. Vincristine sulfate lipolarger, normally unachievable individu- head study is ongoing,” he added. some injection (VSLI, Marqibo®) facilitates increased delivery of vincristine sulfate to target cancer tissues. al and cumulative doses of VCR. Presented at: 54th American Society of Hematology Peripheral neuropathy of any grade VSLI in Pediatric Patients Annual Meeting; December 8-11, 2012; Atlanta, GA. occurred in 23% of patients but only 1% “The pediatric experience with VSLI Abstract 2457. Haim N, Epelbaum R, Ben-Shahar M, et al. Full dose was grade 4 and 22% was grade 3, despite has been limited,” said Nirali N. Shah, 4. vincristine (without 2-mg dose limit) in the treatment a dose density of 4.04 mg/week (2.25 MD, of the National Institutes of Health of lymphomas. Cancer. 1994;73:2515-2519. mg/m2/week). This included peripheral Pediatric Oncology Branch, Bethesda, 5. Verstappen CC, Koeppen S, Heimans JJ, et al. Dose-related vincristine-induced peripheral neuropamotor neuropathy, pain in the extrem- Maryland. thy with unexpected off-therapy worsening. Neurology. ity, areflexia, decreased vibratory sense, At ASH, Shah presented the results 2005;64:1076-1077. 6. Shah NN, Merchant M, Cole D, et al. Vincristine gait disturbance, hypoesthesia, muscu- of a phase 1 single-institution dose sulfate liposomes injection (VSLI, Marqibo): interim lar weakness, neuralgia, paresthesia, and escalation trial of 10 children and young results from a phase I study in children and adolescents refractory cancer. Presented at: 54th American peripheral sensory neuropathy. adults (2-20 years old) with relapsed or with Society of Hematology Annual Meeting; December In comparison, previous studies of refractory ALL or solid tumors.6 Seven 8-11, 2012; Atlanta, GA. Abstract 1497.
FEBRUARY 2013 I VOL 6, NO 1
MLN9708 May Revolutionize Treatment of Multiple Myeloma By Alice Goodman
n investigational oral proteasome drug is expected to be approved as soon inhibitor known as MLN9708 as 2014. had such promising results in MLN9708 is an oral drug taken once phase 1 and 2 trials that it is currently in weekly, and will be an alternative to GBC2013Asize20813_Layout 1 2/8/13 11:12 the AM Page 1 phase 3 testing. If results are positive, bortezomib, the first proteasome inhib-
itor developed for multiple myeloma. Bortezomib is administered by intravenous infusion or subcutaneous injection. MLN9708 appears to have a more favorable adverse-effect profile than bortezo-
"! ! !
! Professor Rob Coleman, MBBS, MD, FRCP Yorkshire Cancer Research Professor of Medical Oncology Director, Sheffield Cancer Research Centre Associate Director, National Institute for Health Research Cancer Research Network Department of Oncology, Weston Park Hospital Sheffield, United Kingdom
* 3:00 pm - 7:00 pm
5:30 pm - 7:30 pm
Welcome Reception and Exhibits
7:00 am - 8:00 am
8:15 am - 8:30 am
Welcome to the Second Annual Conference of the Global Biomarkers Consortiumâ€”Setting the Stage for the Meeting Professor Rob Coleman, MBBS, MD, FRCP
8:15 am - 11:45 am
General Session I â€˘ Personalized Medicine in Oncology: Evolution of Cancer Therapy from Nonspecific Cytotoxic Drugs to Targeted Therapies â€˘ Taking Stock of Molecular Oncology Biomarkers â€˘ Genomics â€˘ Bioinformatics â€˘ Validating Biomarkers for Clinical Use in Solid Tumors - Professor Rob Coleman, MBBS, MD, FRCP â€˘ Validating Biomarkers for Clinical Use in Hematologic Malignancies Jorge E. Cortes, MD â€˘ The Challenges of Biomarker-Based Clinical Trials â€˘ Keynote Lecture: Understanding Cancer at the Molecular Level
12:00 pm - 1:00 pm
1:15 pm - 4:30 pm
This activity is jointly sponsored by Medical Learning Institute Inc, Center of Excellence Media, LLC, and Core Principle Solutions, LLC.
General Session II â€˘ Introduction to Case Studies - Jorge E. Cortes, MD â€˘ Case Studies: Optimal, Value-Based Use of Molecular Biomarkers in Oncology: The Expertâ€™s Perspective on How I Treat My Patients, Part I â€˘ Lung Cancer â€˘ Breast Cancer â€˘ Multiple Myeloma â€˘ Prostate Cancer â€˘ Leukemia â€˘ Lymphoma â€˘ Panel Discussion: Management Controversies and Accepted Guidelines for the Personalized Management of Solid Tumors and Hematologic Malignancies â€˘ Keynote Lecture: The Medical-Legal Issues Surrounding the Use of Biomarkers in Oncology
4:30 pm - 6:30 pm
Meet the Experts/Networking/Exhibits
Jorge E. Cortes, MD Chair, CML and AML Sections D.B. Lane Cancer Research Distinguished Professor for Leukemia Research Department of Leukemia, Division of Cancer Medicine The University of Texas MD Anderson Cancer Center Houston, TX
The only global meeting dedicated to advancing the understanding of value and clinical impact of biomarker research in oncology. Guided by the expertise of leaders in this field, participants will receive a thorough understanding of the current and future landscape of the relevance of tumor biomarkers and how to effectively personalize cancer care in the clinical setting.
This meeting will be directed toward medical oncologists and hematologists, pathologists, geneticists, advanced practice oncology nurses, research nurses, clinical oncology pharmacists, and genetic counselors involved in the management of patients with solid tumors or hematologic malignancies, and interested in the use of molecular tumor biomarkers to help optimize patient care.
Upon completion of this activity, the participant will be able to: â€˘ Assess emerging data and recent advances in the discovery of molecular biomarkers and their impact on the treatment of patients with solid tumors or hematologic malignancies â€˘ Discuss the role of molecular biomarkers in designing personalized therapy for patients with solid tumors or hematologic malignancies â€˘ Outline the practical aspects of integrating molecular biomarkers into everyday clinical practice in the treatment of patients with cancer
Grant requests are currently being reviewed by numerous supporters. Support will be acknowledged prior to the start of the educational activities.
8:15 am - 11:45 am
General Session III â€˘ Review of Saturdayâ€™s Presentations and Preview of Today - Jorge E. Cortes, MD â€˘ Case Studies: Optimal, Value-Based Use of Molecular Biomarkers in Oncology: The Expertâ€™s Perspective on How I Treat My Patients, Part II â€˘ Melanoma â€˘ Colorectal Cancer and Other GI Malignancies â€˘ MDS â€˘ Myeloproliferative Neoplasms â€˘ Keynote Lecture: Promises and Challenges of Personalized Medicine in Improving Cancer Care â€˘ Tumor Board: Challenging Cases in the Use of Biomarkers in Managing Solid Tumors (attendee-contributed cases) â€˘ Tumor Board: Challenging Cases in the Use of Biomarkers in Managing Hematologic Malignancies (attendee-contributed cases)
12:00 pm - 1:00 pm
1:15 pm - 3:00 pm
General Session IV â€˘ Keynote Lecture: Making Personalized Medicine a Reality: The Realization of Genomic Medicine â€˘ The Future of Personalized Medicine: Measuring Clinical Outcomes â€˘ Cost-Effective Technologies That Can Drive Therapeutic Decision Making â€˘ Regulatory Perspectives on PMO â€˘ PMO: The Payerâ€™s Perspective â€˘ Panel Discussion: Can We Afford PMO? A Value-Based Analysis â€˘ Practical Considerations in Incorporating PMO into Everyday Cinical Management â€˘ Reimbursement Challenges â€˘ Closing Remarks
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*Agenda is subject to change.
FEBRUARY 2013 I VOL 6, NO 1
Minor adverse events were reported in 40% of patients, including fatigue, nausea, and rash. Seven patients discontinued treatment due to adverse events. The major serious adverse events of grade 3 or higher were gastrointestinal upset and skin rash (about 5% of patients for each adverse event). Two grade 4 events occurred: end-stage renal disease in 1 patient, which was attributed to the disease itself, and deep vein thrombosis in 1 patient. One patient died from pneumonia. Mild grade 1 neuropathy occurred in 8.45%, and grade 3 neuropathy developed in only 2.07%. The overall response rate was 92%; 55% had very good partial response and 23% had complete response. Longer treatment increased the depth of response. For those patients who finished 12 cycles of therapy, the complete response rate increased to 67%, while 33% had very good partial response. l Reference
PMPMERSONALIZED EDICINE IN ONCOLOGY O
MLN9708 had such promising results in phase 1 and 2 trials that it is currently in phase 3 testing.
7:00 am - 8:00 am
The Medical Learning Institute Inc designates this live activity for a maximum of 12.5 AMA PRA Category 1 Creditsâ„˘. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of the Medical Learning Institute Inc and the Center of Excellence Media, LLC. The Medical Learning Institute Inc is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.
mib; specifically, peripheral neuropathy has been greatly reduced with the oral agent in trials thus far. To put this into context, bortezomib given intravenously twice weekly has been associated with peripheral neuropathy in 30% to 40% of patients, compared with rates of about 10% to 15% for MLN9708 in preliminary trials. Shaji Kumar, MD, of the Mayo Clinic, Rochester, Minnesota, presented results of the phase 1/2 trial at the 54th Annual Meeting of the American Society of Hematology (ASH) after a median of 6 cycles of therapy. The study had 2 parts. Phase 1 enrolled 15 patients and established 4 mg orally once weekly as the maximum tolerated dose of the investigational agent. Phase 2 included 55 patients with newly diagnosed multiple myeloma. MLN9708 4 mg was given on days 1, 8, and 15, in combination with lenalidomide 25 mg once daily on days 1 to 21 and dexamethasone 40 mg on days 1, 8, 15, and 22. Twenty patients went on to attempt stem-cell harvesting for transplant. The other 30 remained on therapy at the time of ASH.
Kumar SK, Berdeja JG, Niesvizky R, et al. A phase 1/2 study of weekly MLN9708, an investigational oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma (MM). Presented at: 54th American Society of Hematology Annual Meeting; December 8-11, 2012; Atlanta, GA. Abstract 332.
CONFERENCE NEWS: ASH Continued from cover
Ibrutinib Encouraging in CLL According to expert opinion, ibrutinib is one of the most important treatments to emerge in the past 3 decades. This investigational agent has the promise to change the natural history of chronic lymphocytic leukemia (CLL) and lymphomas, if the results of several phase 2 trials are confirmed in the phase 3 studies currently in progress. Ibrutinib, an investigational Bruton’s tyrosine kinase (BTK) inhibitor, achieved excellent results in clinical trials of patients with CLL, indolent non-Hodgkin lymphoma, and mantle cell lymphoma (MCL). “Rarely does a drug come along that helps patients this much. This drug is highly effective and very well tolerated. We are looking forward to Pharmacyclics bringing this drug forward. The quicker we get this drug across the finish line, the better,” stated John C. Byrd, MD, the D. Warren Brown Chair of Leukemia Research and director of the Division of Hematology at the Ohio State University Comprehensive Cancer Center in Columbus. Byrd presented the results of a phase 2 trial of 116 patients with CLL/small lymphocytic leukemia (SLL) including elderly treatment-naive, relapsed/refractory, and high-risk relapsed/refractory patients.1 At 26 months, single-agent ibrutinib achieved excellent progression-free survival (PFS) both in elderly treatment-naive individuals (estimated PFS, 96%) and in those with relapsed/refractory high-risk CLL/SLL (estimated PFS, 75%). Ibrutinib is also being studied in combination with rituximab in CLL and lymphoma. A separate phase 2 study in 40 patients with high-risk CLL treated with the combination of ibrutinib plus rituximab achieved an overall response rate of 83% and no evidence of disease progression in 38 of 40 patients, who are continuing on therapy.2 “These patients typically have inferior outcomes compared with low- and intermediate-risk patients,” stated Jan Burger, MD, PhD, lead author of this phase 2 trial and associate professor at the University of Texas MD Anderson Cancer Center in Houston. “This study shows profound activity for this combination in high-risk patients with CLL. The overall response rate is favorable compared with standard treatment, and the toxicity compares favorably to other treatment options.” Interim results of an international phase 2 study of ibrutinib in relapsed/refractory MCL were extremely positive, according to another presentation at the 54th ASH annual meeting by Michael Wang, MD, also of the MD Anderson Cancer Center.3 The phase 2 study enrolled 115 patients (65 bortezomib naive and 50 bortezomib exposed) with relapsed/refractory
MCL. In these difficult-to-treat patients, ibrutinib achieved an overall response rate of 70% and a complete response rate of 20%, which increased to 50% at 14 months.
the National Cancer Institute in Bethesda, Maryland, showed that ibrutinib achieved an overall response rate of about 28% in 70 patients with relapsed diffuse large B-cell lymphoma
Ibrutinib, an investigational Bruton’s tyrosine kinase inhibitor, achieved excellent results in clinical trials of patients with chronic lymphocytic leukemia, indolent non-Hodgkin lymphoma, and mantle cell lymphoma. “With other molecular compounds, response rates in this group of patients are about 30% and progression-free survival is about 6 months. The difference between ibrutinib and other molecular compounds is outrageous,” stated an expert not involved in these studies, Martin Dreyling, MD, of the University of Munich, Germany. A separate study presented at ASH by Wyndham Wilson, MD, PhD, of
(DLBCL).4 However, when patients were stratified according to genetic expression, response rates in activated B-cell (ABC)-like DLBCL were 40% (this group has the worst prognosis) and in germinal center B-cell–like DLBCL were 5.3%. These results in the ABC subgroup of patients with relapsed DLBCL are considered unprecedented. Wilson and his coinvestigators concluded that future clinical
trials of ibrutinib in DLBCL should be confined to the ABC subtype. References
1. Byrd JC, Furman RR, Coutre S, et al. The Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib (PCI-32765) promotes high response rate, durable remissions, and is tolerable in treatment naïve (TN) and relapsed or refractory (RR) chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) patients including patients with high-risk (HR) disease: new and updated results of 116 patients in a phase Ib/II study. Presented at: 54th American Society of Hematology Annual Meeting; December 8-11, 2012; Atlanta, GA. Abstract 189. 2. Burger JA, Keating MJ, Wierda WG, et al. The Btk inhibitor ibrutinib (PCI-32765) in combination with rituximab is well tolerated and displays profound activity in high-risk chronic lymphocytic leukemia (CLL) patients. Presented at: 54th American Society of Hematology Annual Meeting; December 8-11, 2012; Atlanta, GA. Abstract 187. 3. Wang M, Rule SA, Martin P, et al. Interim results of an international, multicenter, phase 2 study of Bruton’s tyrosine kinase (BTK) inhibitor, ibrutinib (PCI-32765), in relapsed or refractory mantle cell lymphoma (MCL): durable efficacy and tolerability with longer follow-up. Presented at: 54th American Society of Hematology Annual Meeting; December 8-11, 2012; Atlanta, GA. Abstract 904. 4. Wilson WH, Gerecitano JF, Goy A, et al. The Bruton’s tyrosine kinase (BTK) inhibitor, ibrutinib (PCI32765), has preferential activity in the ABC subtype of relapsed/refractory de novo diffuse large B-cell lymphoma (DLBCL): interim results of a multicenter, open-label, phase 2 study. Presented at: 54th American Society of Hematology Annual Meeting; December 8-11, 2012; Atlanta, GA. Abstract 686.
Daunorubicin-Free Regimen Effective A study presented at the 54th ASH annual meeting minimize their risk of experiencing cardiac damage showed showed that daunorubicin could be safely omitted later in life.” from an induction regimen without compromising survival The FRALLE 2000-A study, conducted at 20 centers in children with standard-risk acute lymphocytic leukemia in France and 1 center in Belgium, randomized 1128 (ALL). Daunorubicin is already omitted in this setting pediatric patients with standard-risk B-cell ALL to 2 at many cancer centers in the United States and Europe, treatment arms: arm A (n = 560) received standard-dose but until now there has been little evidence to support daunorubicin during induction therapy, and arm B (n = this practice. The French Acute Lymphoblastic Leukemia 568) did not. The induction regimen included vincris(FRALLE) 2000-A study is the first randomized controlled tine, dexamethasone, and asparaginase. Patients received trial in the modern era to provide scientific evidence to doxorubicin during delayed intensification (ie, the last support daunorubicin-free induction therapy. treatment phase before maintenance therapy) and standard The current cure rate for stan24-month maintenance therapy from dard-risk ALL in pediatric patients December 2000 through June 2010. is 90%. For many years, daunoFive-year event-free survival (EFS) and rubicin—an anthracycline that is overall survival (OS) were evaluated The current cure associated with myelosuppression during that period. rate for standard-risk and potential long-term cardiac Standard-risk ALL of the B-cell lindamage—was part of the induction eage was defined as children between acute lymphocytic protocol. However, this practice 1 and 10 years of age and white blood leukemia in pediatric was based on only 3 studies that cell count <50 g/L. Five-year EFS was were more than 20 years old. 92.9% in arm A and 93.3% in arm B. OS patients is 90%. An anthracycline-free inducrates were 97.2% for arm A and 98.2% tion regimen can achieve the for arm B. The amount of minimal same positive outcomes without residual disease (MRD) was similar in putting children at risk for both myelosuppression both arms: MRD ≥1% was observed in 1.8% of arm A and and cardiac toxicities associated with daunorubicin, in 1.9% of arm B; MRD ≥0.1% was seen in 6.5% and 9.3%, said lead author Andre Baruchel, MD, head of the respectively. The rates of cumulative incidence of relapse Department of Pediatric Hematology at the Robert and site of relapse were also similar in both arms. Debré University Hospital in Paris, France. “These “These results show similar efficacy rates in children data can potentially benefit children with ALL in 2 with standard-risk ALL for induction regimens with and important ways. First, we now have strong evidence without daunorubicin,” Baruchel emphasized. that reducing the amount of chemotherapy initially administered to these children with standard-risk ALL Reference [the majority of ALL patients] does not have a nega- Baruchel A, Petit A, Leblanc T, et al. Daunorubicin or not during the inductreatment of childhood standard-risk B-cell precursor acute lymphoblastic tive effect on their immediate outcome. Perhaps more tion leukemia (SR-BCP-ALL): the randomized Fralle 2000-A protocol. Presented at: importantly, we know and anticipate that removing 54th American Society of Hematology Annual Meeting; December 8-11, 2012; harmful chemotherapy from their treatment can help Atlanta, GA. Abstract 135.
FEBRUARY 2013 I VOL 6, NO 1
CONFERENCE NEWS: ASH Apixaban Reduced Thromboembolic Events In the randomized, placebo-controlled Apixaban After the Initial Management of Pulmonary Embolism and Deep Vein Thrombosis With FirstLine Therapy–Extended Treatment (AMPLIFY-EXT) trial, oral apixaban taken for another year after a standard course of treatment for venous thromboembolism (VTE) reduced the risk
of fatal and nonfatal recurrent VTE without increasing the risk of major bleeding. Extended treatment with oral apixaban was associated with death or recurrent VTE in about 4% of patients who received either 2.5-mg or 5-mg doses of the drug, compared with 12% in the group assigned to placebo. “Both doses of anticoagulant reduced
the risk of recurrent fatal or nonfatal VTE by about 80%, and the rates of major bleeding on apixaban were low and comparable to those in the placebo group. The number of patients needed to treat [NNT] to prevent 1 episode of recurrent or nonfatal VTE is only 14, while the NNT to cause 1 episode of major or clinically relevant
AVBCC2013Asize13013_AVBCC 2/4/13 2:10 PM Page 1
Association for Value-Based Cancer Care Conference Influencing the Patient-Impact Factor
This activity is jointly sponsored by the Florida Society of Clinical Oncology, Medical Learning Institute Inc, Association for Value-Based Cancer Care, Inc., Center of Excellence Media, LLC, and Core Principle Solutions, LLC.
nonmajor bleeding is 200,” stated lead author Giancarlo Agnelli, MD, of the University of Perugia, Italy. Warfarin is standard treatment for VTE, and after patients discontinue warfarin the risk of recurrent VTE ranges from 6% to 10% in patients without reversible risk factors, he explained. Apixaban is a new oral Xa inhibitor that is rapidly absorbed, with the kidney excreting about 25%. Unlike warfarin, no monitoring is necessary with apixaban. In the AMPLIFY-EXT trial, patients with deep vein thrombosis or VTE treated for 6 to 12 months with anticoagulant therapy were randomized to receive either apixaban 2.5 mg or 5 mg twice daily versus placebo. Patients were treated for 12 additional months, and safety was assessed at 30 days after treatment initiation.
May 2-5, 2013 • Westin Diplomat • Hollywood, Florida CONFERENCE CO-CHAIRS
Apixaban is a new oral Xa inhibitor that is rapidly absorbed, with the kidney excreting about 25%.
THURSDAY, MAY 2, 2013 8:00 am - 5:00 pm
FRIDAY, MAY 3, 2013
Craig K. Deligdish, MD Hematologist/Oncologist Oncology Resource Networks
Gary M. Owens, MD President Gary Owens Associates
Burt Zweigenhaft, BS President and CEO OncoMed
7:00 am - 8:00 am
Simultaneous Symposia/Product Theaters
8:15 am - 9:15 am
Session 1: Welcome, Introductions, and Opening Remarks Conference Co-Chairs - Craig K. Deligdish, MD; Gary M. Owens, MD; Burt Zweigenhaft, BS
9:15 am - 10:15 am
10:15 am - 10:30 am
10:30 am - 11:45 am
Session 2: Trends in Treatment Decision-Making: Pathways and Stakeholder Collaborations Marcus Neubauer, MD; Michael Kolodziej, MD
12:00 pm - 1:00 pm
Exclusive Lunch Symposium/Product Theater
1:15 pm - 2:00 pm
Session 3: Cost of Cure: When, How, and How Much? John Fox, MD; John Hennessy
2:00 pm - 2:45 pm
Session 4: Where Is Oncology Care Headed in the Future? Jayson Slotnick, JD, MPH (Moderator); Barbara L. McAneny, MD
Upon completion of this activity, the participant will be able to: • Discuss the current trends and challenges facing all stakeholders in optimizing value in cancer care delivery. • Define the barriers associated with cost, quality, and access as they relate to healthcare reform and what solutions are currently being considered. • Compare and contrast the different approaches/tools providers and payers are utilizing to manage and deliver care collaboratively. • Examine the current trends in personalized care and companion diagnostics. • Analyze the patient issues around cost, quality, and access to care.
2:45 pm - 3:30 pm
Session 5: What Will the Cancer Delivery System Look Like in 2015? Ted Okon; John D. Sprandio, MD
Following on the success of our Second Annual Conference, AVBCC will be coming to Hollywood, Florida, on May 2-5, 2013. We continue to be guided by the expertise of leaders in these fields providing attendees with a thorough understanding of the evolution of the value equation as it relates to cancer therapies. Our goal is to be able to assist them in implementing, improving, and sustaining their organizations and institutions, while improving access for patients and ultimately quality patient care.
3:30 pm - 3:45 pm
3:45 pm - 4:30 pm
Session 6: Employers and Oncology Care F. Randy Vogenberg, PhD, RPh (Moderator); Bridget Eber, PharmD; Patricia Goldsmith; Darin Hinderman
4:30 pm - 5:15 pm
Session 7: Advanced Care Directives: Palliative Care, Hospice, Ethics J. Russell Hoverman, MD, PhD; Thomas Smith, MD, FACP, FASCO
5:15 pm - 5:45 pm
Summary/Wrap-Up of Day 1
This conference is intended for medical oncologists, practice managers/administrators, and managed care professionals. Stakeholders in a position to impact cancer patient care, such as advanced practice nurses, pharmacists, and medical directors, are also invited to join this exciting forum.
6:00 pm - 8:00 pm
Cocktail Reception in the Exhibit Hall
DESIGNATION OF CREDIT STATEMENTS
8:15 am - 8:30 am
8:30 am - 9:15 am
Session 8: The Role of Government in the Future of Oncology Care Jayson Slotnick, JD, MPH
9:15 am - 10:00 am
Session 9: Medicaid: A Healthcare Delivery System Review Matthew Brow
10:00 am - 10:15 am
10:15 am - 11:00 am
Session 10: Payer, Government, and Industry Insights: Balancing Cost and Quality Kip Piper
11:00 am - 11:45 am
Session 11: National Coalition for Cancer Survivorship: Medication Nonadherence Issues Pat McKercher; Lillie Shockney, RN, BS, MAS
This activity is jointly sponsored by the Florida Society of Clinical Oncology, Medical Learning Institute Inc, Association for Value-Based Cancer Care, Inc., Center of Excellence Media, LLC, and Core Principle Solutions, LLC.
COMMERCIAL SUPPORT ACKNOWLEDGMENT
Grant requests are currently being reviewed by numerous supporters. Support will be acknowledged prior to the start of the educational activities.
SATURDAY, MAY 4, 2013 7:00 am - 8:00 am
PHYSICIAN CREDIT DESIGNATION
The Medical Learning Institute Inc designates this live activity for a maximum of 17.25 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of the Medical Learning Institute Inc and the Center of Excellence Media, LLC. The Medical Learning Institute Inc is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.
REGISTERED NURSE DESIGNATION
Simultaneous Symposia/Product Theaters
12:00 pm - 1:00 pm
Exclusive Lunch Symposium/Product Theater
1:15 pm - 3:00 pm
Session 12: Meet the Experts Networking Roundtable Session
3:00 pm - 3:45 pm
Session 13: Personalized Medicine, Companion Diagnostics, Molecular Profiling, Genome Sequencing—The Impact on Cost, Treatment, and the Value Proposition Mark S. Boguski, MD, PhD; Gary Palmer, MD, JD, MBA, MPH
3:45 pm - 4:15 pm
Summary/Wrap-Up of Day 2
4:30 pm - 6:30 pm
Cocktail Reception in the Exhibit Hall
Medical Learning Institute Inc. Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 17.25 contact hours.
SUNDAY, MAY 5, 2013
REGISTERED PHARMACY DESIGNATION
8:15 am - 8:30 am
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Session 14: Cancer Rehabilitation: The Next Frontier in Survivorship Care Julie Silver, MD
9:15 am - 10:00 am
Session 15: Current and Future Considerations for the Oncology Practice Manager Dawn Holcombe, MBA, FACMPE, ACHE; Leonard Natelson
The Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Completion of this knowledge-based activity provides for 17.25 contact hours (1.725 CEUs) of continuing pharmacy education credit. The Universal Activity Number for this activity is (To be determined).
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FEBRUARY 2013 I VOL 6, NO 1
7:00 am - 8:00 am
Simultaneous Symposia/Product Theaters
10:00 am - 10:15 am
10:15 am - 11:00 am
Session 16: Access to Drugs—Shortages, Biosimilars Douglas Burgoyne, PharmD; James T. Kenney, Jr., RPh, MBA
11:00 am - 11:45 am
Session 17: Perspectives from Oncology Group Practices—Successes, Issues, and Challenges Thomas Marsland, MD; David Eagle, MD
11:45 am - 12:00 pm
Summary and Conclusion of Conference
*Agenda is subject to change. AVBCCAsize20413
Recurrence of VTE or all-cause death was 3.8% for the 2.5-mg dose of apixaban, 4.2% for the 5-mg dose, and 11.6% for placebo, for a risk reduction of 65%. Recurrent VTE or VTE-related deaths were 1.7%, 1.7%, and 8.8% for the 2.5-mg dose, the 5-mg dose, and placebo, respectively. Myocardial infarction, stroke, or cardiovascular-related deaths were reported in 2.1%, 2.3%, and 10%, respectively. The rates of major bleeding were 0.2% for the 2.5-mg dose, 0.1% for the 5-mg dose, and 0.5% for placebo. The rates of clinically relevant nonmajor bleeding were 3%, 4.2%, and 2.3%, respectively. Agnelli said the optimal treatment duration for apixaban has not yet been determined. In the AMPLIFY-EXT trial, patients were treated for 1 year and achieved risk reduction in recurrent VTE without an increase in major bleeding, but further study of a longer treatment duration would be needed to establish a benefit. Going forward, the 2.5-mg dose will be preferred, because the 5-mg dose did not provide further benefit. Apixaban will be reviewed by the US Food and Drug Administration in the future. Reference
Agnelli G, Buller HR, Cohen A, et al. Two doses of apixaban for the extended treatment of venous thromboembolism. Presented at: 54th American Society of Hematology Annual Meeting; December 8-11, 2012; Atlanta, GA. Abstract LBA-1.
Donâ€™t Forget to Cast Your
Pharmacist Vote Remember to vote for the 2013 T.O.P. Pharmacist Award, sponsored by Teva Oncology. This annual award recognizes an oncology pharmacist nominated by his/her peers for outstanding contributions to oncology pharmacy practice, research, or education in 2012. The 6 leading nominees are profiled online and in the February issue of The Oncology Pharmacist. Vote for the winner at TheOncologyPharmacist.com/award. The winner will be announced at the 2013 Hematology/Oncology Pharmacy Association (HOPA) meeting and profiled in the April issue of The Oncology Pharmacist.
T.O.P. Pharmacist Award Finalists Vote Now for Your Choice www.TheOncologyPharmacist.com/award
Below are descriptions of the 6 finalists for the 2013 T.O.P. Pharmacist Award. These people were chosen from an outstanding group of pharmacists nominated by their peers. Although every nominee was impressive, these 6 stood out for their commitment to teamwork, embrace of evidence-based practice, and compassion for their patients. After reading the summaries, you can place your vote for the lucky winner by going to www.TheOncologyPharmacist.com/award. The winner will be announced in the April issue of The Oncology Pharmacist.
is a trained oncolo- als, consulting on dosing and dose reductions, and gy pharmacist with mixing of chemotherapy drugs, as well as all clina background in laboratory work and ical trials for blinded studies. She clinical training at the US Food and is also the point person for trying Drug Administration. She uses this to obtain compassionate drugs for expanded knowledge base to inform her patients who meet certain requireconsultations about problems and hurments. “I am a jack of all trades,” dles that arise during cancer treatment, she said. some of which go beyond the traditional Amini is spearheading a major initiaareas of oncology pharmacy. tive to develop an oral chemotherapy At The Angeles Clinic and Research pharmacy on site, which would provide Institute, Amini is responsible for order“one-stop shopping” for patients. “This ing all of the drugs for both the research would make it easier and more comsite and general clinic, and for overseeing forting for cancer patients and ease the infusions at both sites. In addition, she Nanaz F. Amini, PharmD, psychological burdens,” she said. oversees the dispensing of drugs for the RPh, MS Amini’s goals in treating patients are 25 or 30 clinical trials in various phases The Angeles Clinic and Research to make the treatment as pleasant as of development. She participates in dis- Institute possible, manage the side effects, provide cussions about eligibility for clinical tri- Los Angeles, California patient education at a level that patients
“We want to give every patient we treat individualized care.…Building a good rapport with patients is essential, and I am always available to discuss any concerns.”
can understand, and overcome hurdles to accessing the best care driven by evidence-based medicine. This can mean negotiating with insurance companies to approve certain off-label treatments. “We want to give every patient we treat individualized care,” she emphasized. Patience and empathy are key professional skills in her role as oncology pharmacist. “Building a good rapport with patients is essential, and I am always available to discuss any concerns. Many are not drug related,” she added, for example, anxiety about a port-a-cath. “A patient is not just a number. The human touch is key. You need to consider the is an oncology pharThe ability to succeed at providing nondispensing serpatient’s context, that is, age-related macist at the Seidman vices to patients, doctors, and nurses depends on developing concerns. An older patient has differCancer Center at Geauga Medical Center, a community out- good “people skills.” “No matter how proficient you are at ent issues than a middle-aged one,” patient cancer center that is part of a large healthcare system. the science, if you can’t establish a good rapport, then you she noted. He is responsible for the safe and efficient preparation and won’t be able to collaborate and become a valued team Amini is involved in clinical trials dispensing of chemotherapy and other cancer-related medica- member,” Brown commented. of cutting-edge therapies, including tions to outpatients. He also works at an infusion center within For most of his 23-year career, Brown worked on the manBRAF inhibitors, MEK inhibitors, Seidman Cancer Center, where both patients agement side of hospital pharmacy. As part of and PD-1 antibodies. About 35% to with cancer and noncancer patients are treated. his master’s degree, he had a 2-year residency 50% of these trials are in early stages. Some of these patients receive biologic therain pharmacy training, and particularly enjoyed Omid Hamid, MD, Chief of pies for rheumatoid arthritis. the clinical training in oncology at that time. Clinical Research at The Angeles “For the dispensing part of my job, we do “I always was drawn to being an oncology Clinic, nominated Amini for the a pharmacist double-check for every medicapharmacist, and had it in the back of my mind 2013 T.O.P. Pharmacist Award based tion we prescribe and monitor patients closely,” as a potential career change. I got that opporon the following: “She has integrated Brown explained. In addition to dispensing sertunity 2.5 years ago and am happy I made the herself into the fabric of clinical care vices for medications, his job encompasses nonchange,” he said. “A great day is a day that I and research in our institute. With dispensing services, providing consultations and help a patient, doctor, or nurse with treatment the advent of new treatments, such counseling to patients, and answering questions and making the patient more comfortable.” as PD-1 antibodies, she has worked to from nurses and oncologists that can be related Lacey Minnick, who nominated Brown for assure patients will receive these parto dosing, monitoring, and expected side effects. George E. Brown, RPh, the 2013 T.O.P. Pharmacist Award, comadigm-shifting therapies and helped “Our goal is to improve upon safe dispensing MS mended him for his dedication to oncology patient accrual to clinical trials and of drugs and to develop strategies to lever- Seidman Cancer Center pharmacy. “He is always extremely thorough, patients’ understanding of therapy. age oncology pharmacy to expand services University Hospitals Geauga taking the time to triple-check his own work Through her conduct and dedicaand achieve cost savings. I am involved in Medical Center along with the preparing technician. Every tion, our small research institute has initiatives to achieve those goals, mainly to Chardon, Ohio step of the process is carefully calculated and done many special things, including expand the role of the pharmacist from the thought through to ensure there is the least multiple national and international traditional one of drug dispensing to include more patient possible chance for error. He is also a team player for the rest presentations. Amini has continued contact and consultation as a team player with nurses and of the department…he is always willing to lend an extra hand educating her peers and become a doctors,” Brown said. in the regular day-to-day running of our pharmacy,” she wrote. leader in her field. We are fortunate to have this special person.”
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T.O.P. Pharmacist Bradley Burton
has a num- clinical pharmacy services in the GI oncology clin- ly impressed by his dedication and motivation to ber of re- ic, where he provides patient counseling, drug ther- advance oncology pharmacy practice. He is a pracsponsibilities for both inpatient and outpatient care apy recommendations, and monitoring. Another tice innovator and knowledge facilitator.” at The Johns Hopkins Hospital. On the inpatient facet of Burton’s practice is precepting residents Burton says that he was initially hesitant about side, he does daily rounds with the inpatient medical and students through a variety of rotations. He the oncology module in pharmacy school, because oncology team; provides drug therapy recommen- participates on an institutional multidisdations; educates nurses, physicians, and other ciplinary Antithrombotic Subcommittee trainees; and acts as a drug informaof the Clinical Practice tion resource to the service. On the Council. He provides guidoutpatient side, he participates in a ance on quality improveweekly half-day gastrointestinal (GI) ments and medication oncology clinic and does checkups safety for oncology-spefor patients along the full spectrum cific practice issues. As a of management—newly diagnosed, CACP-certified pharmacurrently in treatment, and colon cist, he also effectively cancer survivors. He makes sure these trains colleagues as part patients are compliant with medicaof The Johns Hopkins Hospital he heard it was challenging. However, once he tions for other chronic conditions, inpatient anticoagulation service. was working in oncology, this module became his such as hypertension and diabetes; His impact has been felt not only favorite. “There have been so many new advances schedules screenings; and ensures that Bradley Burton, PharmD, within his institution, but also by in oncology drugs in recent years, and with this, they are not at risk for additional BCOP, CACP his peers throughout the oncology oncology pharmacists have become so much more problems, such as unfavorable drug The Johns Hopkins Hospital pharmacy community.” Thompson of an important piece of patient care. I am glad I Baltimore, Maryland interactions. continues, “I have been consistent- made the choice,” he said. “One of the things I love about oncology is that I get the overview of watching the whole patient. As an oncology pharmacist, I educate patients about the side effects of chart is shared throughout their therapies and also how their cancer therapies the clinic and answers most is the manager of the oncology pharcan have implications on chronic comorbidities, questions that can arise. “The macy at Tripler Army Medical Center and an informed patient is more likely to be able flowchart enhances patient where his staff, including himself, anothto have better outcomes; for example, to increase safety and the nurses really er pharmacist, and a technician, provide their exposure to potentially life-saving chemolike it,” DeFreitas said. chemotherapy for ambulatory patients, therapy,” Burton explained. “I want patients to In his role as an oncoloinpatients, and pediatric patients who understand why they are getting a treatment, so gy pharmacist at a military are on active military duty, family memthat they are motivated to stay on that treatcenter, DeFreitas feels he has bers, retired military personnel, and referment, as missing treatments could potentially have the opportunity to excel as an rals from the Veterans Administration. life-altering consequences.” integral member of the medAdditionally, through a unique program, Erik F. DeFreitas, Jennifer Thompson, who nominated Burton for ical team. He has prescribing the center provides chemotherapy for PharmD, BCOP, MAJ, MS privileges and oversees adverse the 2013 T.O.P. Pharmacist Award, lists his many Pacific Islanders from Federated States Tripler Army Medical Center significant contributions in oncology pharmacy events and chemotherapy dose of Micronesia, Palau, Guam, Marshall Honolulu, Hawaii practice. “Through collaboration, he established reductions. Islands, Northern Marianas, and When asked what led him American Samoa. The pharmacy departto become a pharmacist, DeFreitas ment has a graduate medical education mission― said, “As a first-generation American, my parents overseeing pharmacy residents during their 6-week wanted me to pursue a safe career path. They rotations. This year, they have 4 first-year pharma- wouldn’t have liked my becoming an artist.” He cy residents. had a long-standing interest in the medical profesAs an oncology pharmacist, DeFreitas’s top sion, and particularly enjoyed high school chempriority is patient safety and efficiency. “We istry. Then he enlisted in the army as a pharmacy want to enhance patient care and avoid acci- technician, and subsequently went to pharmacy dents,” he stated. His small pharmacy department is dependent on 3 staff members, so the emphasis is on “next man up,” he explained. This means standardizing operating and documentation procedures so that a newly trained pharmacist can easily take over, if necessary. To this end, DeFreitas developed a flowchart that is an easy-to-visualize “snapshot” college at Northeastern University. An oncology for each patient coming in for chemotherapy. rotation at Boston Medical Center in Boston, The flowchart includes patient diagnosis, type Massachusetts, inspired him to become involved of chemotherapy, cycle of chemotherapy, pre- in that field, because it was evident he could make medications, postmedications, laboratory tests, a difference and be a valued team member in hepatitis status, and oncologist’s name. This caring for patients.
“I want patients to understand why they are getting a treatment, so that they are motivated to stay on that treatment, as missing treatments could potentially have life-altering consequences.”
VOTE NOW Don’t Forget to Cast Your T.O.P. Pharmacist Vote
DeFreitas’s top priority is patient safety and efficiency. “We want to enhance patient care and avoid accidents,” he stated. His small pharmacy department is dependent on 3 staff members, so the emphasis is on “next man up.”
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T.O.P. Pharmacist Jeffrey Weiss
Weiss says that the field of oncology has transformed over the past 15 years at “breakneck speed,” with numerous new targeted therapies for malignancy. “It is almost a full-time job to keep up with all the changes. Fortunately, we have NCCN guidelines, but we used to have to memorize chemotherapy regimens.”
is hardly a novice in “breakneck speed.” There are numerous the field of oncology new targeted therapies for malignanpharmacy. He was a member of the first class of Board cy, including hematologic malignanCertified Oncology Pharmacists in 1998 and was prac- cies, that include a number of tyrosine ticing for 15 years before that. He strongly supports kinase inhibitors. There are also new board certification as a means of differentiating oneself diagnostic criteria for leukemia, and from other pharmacists and keeping up with the many new targets for therapy and prognosis. advances in the field through continuing education to “It is almost a full-time job to keep up maintain certification. with all the changes. Fortunately, we At NCH (Naples Community Hospital), Weiss have NCCN [National Comprehensive is responsible for all chemotherapy orders for both Cancer Network] guidelines, but we outpatients and inpatients, and he used to have to memois based in the inpatient unit, which rize chemotherapy regiencompasses a large leukemia service. mens,” he said. His job involves ordering chemotherWeiss’s goal in treatapy, getting an oncologist to sign off ing patients with cancer on the order, reviewing laboratory is to provide state-of-the-art medresults, and deciding if the patient ical care in a safe environment. should go forward with chemotherTo that end, he works with a team apy. If there is a problem with the that includes an oncology hospitalist laboratory tests, he discusses it with and 3 oncology physician assistants. an oncologist. In addition to these Within the team, he is responsible responsibilities, he does rounds every for accurate calculation of the drug morning and orders supportive care Jeffrey P. Weiss, RPh, regimen and planning the sequence medications including antibiotics. of events once a patient is admitted BCOP Weiss says that the field of oncology NCH Healthcare System to the hospital. has transformed over the past 15 years at Naples, Florida Kimberly Thorp, the colleague
was nominated for the 2013 T.O.P. Pharmacist Award by her colleagues at BioScrip, Chicago, Illinois, where she was a pharmacist in the oncology division for several years. She has recently moved to a new job. What comes through in the emails from her colleagues at BioScrip is the humanity and empathy she brings to her job, and this is also evident in speaking to her over the telephone. “I could tell you all about safety and efficacy of cancer drugs, compliance with therapy, flow sheets for efficiency, and other challenges in the day-to-day world of oncology pharmacy. But at the end of the day, a patient is standing in front of you and none of
those buzzwords matter. What matters is the one-on-one care―to find a way to let a patient know that he or she can trust you, and help to get that patient through a challenging time and to provide some comfort,” Drury said. Drury sees pharmacy and medicine as a vehicle for self-growth, both personally and professionally. Her approach is patient-centered. “Cancer can be the best of times and the worst of times for an oncology professional, with highs and Jill Drury, PharmD, BCOP lows. I have learned as much from my AstraZeneca (formerly with BioScrip) patients as from my mentors,” she stated. Chicago, Illinois
Frequently Asked Questions (FAQs) We asked the 6 finalists to list the most common questions they get in their practice. Below is a composite of their responses. Finalists agreed that patients are savvy consumers and that they do research on the Internet and come in with questions. The main questions patients ask are: 1. W hat side effects does this chemotherapy have? (It is helpful to provide written information about the drug[s] at an 8th-grade level.) 2. How will you manage the side effects? 3. Will these drugs cause nausea, vomiting, hair loss, or fatigue? Patients on clinical trials are often the sickest patients. Their most FAQs are: 1. Will this chemotherapy help me? 2. Will I be on this therapy for the rest of my life? The questions from doctors relate to supply issues and side effects: 1. Do we have sufficient supplies of this drug? 2. What are your thoughts about some of the newer drugs (eg, carfilzomib for multiple myeloma)? 3. What side effects did this patient develop and how is he/she doing?
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who nominated Weiss for the 2013 T.O.P. Pharmacist Award, wrote: “Jeff is a well-respected and valued member of the clinical care team, and is an excellent liaison between pharmacy and prescribers to promote safe and effective hematology/ oncology services for the patients we serve. The NCH Department of Pharmacy Services, as well as the entire NCH Healthcare System, are extremely proud of the excellent program we have developed, with the clinical expertise and professional dedication contributed by Jeff Weiss.” At BioScrip, Drury’s job as a pharmacist entailed medication management and patient counseling. BioScrip was recently bought out by a larger company and is now a home infusion company. She hopes to bring her patient-centered skills to her new position. Here is what her colleague, Joan L., had to say about Jill: “We have had the pleasure of working with Jill Drury for a number of years. As a pharmacist, Jill has assisted us in our independent clinical practice with oncology and general pharmacy management. Her knowledge and expertise is greatly appreciated. Jill really does take pride in being a pharmacist, and that is reflected in her skillset and likability. Her students and patients are a priority, and her ability to assist has been beyond rewarding to the healthcare system. It is our honor as fellow healthcare professionals to confirm and recommend her for this award.” Another colleague, Rebecca S., said that working with patients on a journey of living with cancer has made Jill reevaluate her life without a diagnosis [of cancer]. Rebecca wrote: “Patients with cancer have a ‘bucket list,’ but it is often too late for them to fulfill this wish list, so when Jill travels to places that patients wish they could visit, she uses her own money to bring back photos, culture, videos, authentic recipes, and many stories of adventure and astonishment. In return, she has been able to see her patients mentally check off a destination with a smile. Patients have taught Jill something about themselves and herself. It’s beyond rewarding and inspirational that she can live out some of their dreams.”
T.O.P. Pharmacist Help us congratulate the 2013
T.O.P. Pharmacist Nominees
Angel Also, PharmD The Mark H. Zangmeister Center
Teresa Fisher, BS Pharm Banter Borwell Medical Center
Cindy O’Bryant, PharmD, BCOP University of Colorado Cancer Center
Jay Tipps, PharmD All Saints Home Medical
Lamya Bakoss, BCOP New York Methodist Hospital
Carolyn Hall, PharmD Jordan Hospital
Kerry Parsons, PharmD, BCOP Children’s of Alabama
Laura Tsy, PharmD, BCPS Midwestern University-Glendale
Jeffrey Barletta, PharmD, FCCM Midwestern University-Glendale
Shadman Hosseini, PharmD Walgreen Arizona Drug Company
Angela Pearson, PharmD Lakeland Regional Medical Center
Stephen Valentine, RPh Strong Memorial Hospital, University of Rochester
Joanne Bell, PharmD Santa Rosa Memorial Hospital
Thomas Hughes, PharmD, BCOP National Institutes of Health Clinical Center
Diana Perez, PharmD Doctors Hospital at Renaissance
Jeffrey Betcher, RPh Mayo Clinic
Sarah Larson, PharmD, BCPS Sanford Roger Maris Cancer Center
Steve Breckenridge, RPh Central Valley Medical Center
Lois Leister, BS, MS, MBA Mendocino Coast District Hospital
Royston Browne, PharmD Montefiore Medical Center
Richard Maietta, RPh, BCOP Eastern Maine Medical Center
Francois Cauchon, PharmD, MSC, MBA BCE Pharma Michelle Chan, PharmD New York Presbyterian Hospital
Jane McConnell, BS Pharm Gifford Medical Center
Mei Chen, PharmD, BCOP Frederick Memorial Hospital
Jeanette Mills, PharmD Carolinas Medical Center-Northeast
Maryann Cooper, PharmD, BCOP Massachusetts College of Pharmacy & Health Services Isabelle Cote, PharmD Hôpital du Saint-Sacrement David Eckart Jordan Hospital
Robert Mancini, PharmD St. Luke’s Mountain States Tumor Institute
Robin Mower, PharmD Centura Health-Porter Adventist Hospital LeAnn Norris, PharmD, BCPS South Carolina College of Pharmacy
Antony Pham, PharmD Long Island University Eileen Marley, PharmD, BCOP Parkland Health & Hospital System Elizabeth Poirier, PharmD Northside Hospital Sean Reily, PharmD Harris Health System Grant Segall, BS Pharm Moog Medical Devices Kate Simondsen, PharmD University of Wisconsin Hospital and Clinics Jeffrey Sivik, PharmD, BCOP Penn State Hershey Medical Center Dominic Solimando, Jr, MA, RPh Walter Reed National Military Medical Center
Daniel Wandres, PharmD University of California, San Francisco Medical Center Ellen Wang, BCOP UCDANS Pamela Waring, PharmD Kaiser Permanente Celine Water, BCOP, RPh Arnett Cancer Care Bennett Westjuha, PharmD Reid Hospital Bryan White, PharmD St. Francis Hospital Elaine Yam, PharmD Memorial Sloan-Kettering Cancer Center Daniel Zlott, PharmD, BCOP National Institutes of Health Clinical Center
Lisa Stanley, RPh Thomas Hospital
VOTE NOW Don’t Forget to Cast Your T.O.P. Pharmacist Vote TheOncologyPharmacist.com/award www.TheOncologyPharmacist.com
FEBRUARY 2013 I VOL 6, NO 1
Abstracts of Interest From the 54th Annual Meeting of the American Society of Hematology By Caroline Helwick
Evidence Grows for Bendamustine-Rituximab Combination for Lymphoma Several studies presented at the 54th Annual Meeting of the American Society of Hematology (ASH) found
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that a regimen that combines bendamustine with rituximab (B-R) may result in superior outcomes compared with the
current standard of care, rituximab plus cyclophosphamide/doxorubicin/vincristine/prednisone (R-CHOP) or ritux-
Individualizing Treatment for DCIS of the Breast: New Molecular Approaches LOG ON TODAY TO PARTICIPATE
TARGET AUDIENCE This initiative will target medical oncologists, hematologists, breast surgeons, radiation oncologists, oncology nurses, advanced practice nurses, nurse practitioners, physician assistants, oncology pharmacists, managed care professionals, and others with clinical research and management interest in treatment of ductal carcinoma in situ (DCIS) and early-stage breast cancer.
STATEMENT OF NEED Ability to detect DCIS has dramatically improved in recent decades, and the current incidence of DCIS is several-fold higher than in the 1970s and 1980s, largely due to increased use of mammography screening.1,2 However, attempts to identify subsets of DCIS women who may be spared radiotherapy and perhaps treated with surgery alone have heretofore been unsuccessful. This inability to predict which patients will develop recurrent DCIS or invasive disease has complicated DCIS management. Many clinicians and other healthcare professionals dealing with patients diagnosed with DCIS are unaware or incompletely knowledgeable about the most recent results from a clinical trial examining the ability of the 12-gene assay, using a prespecified DCIS algorithm, to predict recurrence risk, and the implications these findings may have for management of their patients with DCIS. 1. Kerlikowske K. Epidemiology of ductal carcinoma in situ. J Natl Cancer Inst Monogr. 2010;2010:139-141. 2. Virnig BA, Tuttle TM, Shamliyan T, Kane RL. Ductal carcinoma in situ of the breast: a systematic review of incidence, treatment, and outcomes. J Natl Cancer Inst. 2010;102:170-178.
EDUCATIONAL OBJECTIVES After completion of this activity, participants will be better able to: • Identify approaches currently available or in development to predict recurrence risk in DCIS patients • Explain how the 12-gene expression assay for DCIS was developed and how it compares with the 21-gene assay for early invasive breast cancer • Describe the design and findings of the ECOG 5194 validation study • Apply the 12-gene assay for DCIS into clinical decision-making • Explain relevant information about the 12-gene DCIS assay and DCIS score to patients
Release Date: May 8, 2012 Expiration Date: May 7, 2013
FACULTY Chair: Lawrence J. Solin, MD, FACR, FASTRO
Chairman Department of Radiation Oncology Albert Einstein Medical Center Philadelphia, PA
E. Shelley Hwang, MD, MPH
Professor and Chief, Breast Surgery Duke University Medical Center Durham, NC
Kathy D. Miller, MD
Associate Professor Department of Medicine IU School of Medicine Indianapolis, IN This activity is supported by an educational grant from Genomic Health, Inc.
Physicians: Creative Educational Concepts, Inc. (CEC) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. CEC designates this enduring educational activity for a maximum of 1.0 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation in the activity. Nurses: CEC is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s (ANCC) Commission on Accreditation. CEC provides this activity for 1.0 contact hour. Learners are advised that accredited status does not imply endorsement by the provider or ANCC of any commercial products displayed in conjunction with an activity. Case Managers: This activity has been approved for 1.0 clock hour through 12/31/12 by the Commission for Case Manager Certification. Case Managers number 790005057. AstuteDCIS_Ksize 50712
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Regardless of the quality of response, first-line treatment with B-R resulted in superior progression-free survival. In a different noninferiority study—the Bendamustine Rituximab Investigational Non-Hodgkin’s Trial (BRIGHT) of 447 patients—treatment with B-R was associated with CR rate that was noninferior to R-CHOP/R-CVP: 31% versus 25%, meeting the primary objective of the study. The CR rate was significantly higher with B-R in the subgroup of patients with MCL, and quality-of-life scores were higher overall with B-R.2 Investigators for both studies noted that the toxicity profiles of these regimens are very different, which thus can help guide treatment selection. References
imab plus cyclophosphamide/vincristine/prednisone (R-CVP), in patients with non-Hodgkin lymphoma (NHL) and mantle cell lymphoma (MCL). A subanalysis of the Study Group on Indolent Lymphomas (StiL) NHL 1-2003 study, which indicated a substantial benefit for B-R in a study presented at ASH in 2011, showed that complete responses (CRs) were more frequent with B-R (39.8%) than with R-CHOP/R-CVP (30.0%). Regardless of the quality of response, first-line treatment with B-R resulted in superior progression-free survival (PFS). In patients with CRs, median PFS exceeded the 5-year evaluation point with B-R, compared with 53.7 months for patients receiving standard therapy.1
1. Rummel MJ, Niederle N, Maschmeyer G, et al. Subanalysis of the StiL NHL 1-2003 study: achievement of complete response with bendamustine-rituximab (B-R) and CHOP-R in the first-line treatment of indolent and mantle cell lymphomas results in superior survival compared to partial response. Presented at: 54th American Society of Hematology Annual Meeting; December 8-11, 2012; Atlanta, GA. Abstract 2724. 2. Flinn IW, van der Jagt RH, Kahl BS. An open-label, randomized study of bendamustine and rituximab (BR) compared with rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP) or rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in first-line treatment of patients with advanced indolent non-Hodgkin’s lymphoma (NHL) or mantle cell lymphoma (MCL): the Bright study. Presented at: 54th American Society of Hematology Annual Meeting; December 8-11, 2012; Atlanta, GA. Abstract 902.
ASH HIGHLIGHTS Genetic Profile Predicts Mortality in African American and Asian Pediatric Patients With AML Among children with acute myeloid leukemia (AML), the presence of a specific genetic marker known as WT1 SNP rs16754 may be associated with reduced chemotherapy-related toxicity and reduced treatment-related toxic deaths if they are African American or Asian, a phase 2 Childrenâ€™s Oncology Group trial suggested.
The WT1 gene can be subject to loss-offunction mutations that lead to the development of AML. The WT1 gene, a tumor suppressor that regulates cell growth, can be subject to loss-of-function mutations that lead to the development of AML. Researchers have recently discovered that a certain single nucleotide polymorphism (SNP, a naturally occurring variation in DNA)â€”SNP rs16754 in the WT1 geneâ€”is correlated with
improved outcomes in pediatric patients with AML. The frequency of this SNP varies by race/ethnicity. The study examined how the presence of SNP rs16754, which was observed in 28% overall, affected outcomes and treatment-related mortality in 492 young AML patients of different races/ethnicities. Patients who
were SNP-positive had higher 5-year overall survival rates than did those who were not (61% vs 44%, respectively). Among African Americans and Asians, SNP-positive patients had significantly lower treatment-related mortality rates than did SNP-negative patients: 0% versus 25% for African Americans and 0% versus 43% for Asians, respectively.
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These results suggest that the protective effect of the presence of SNP rs16754 in reducing chemotherapy-related toxicity in pediatric patients with AML is more pronounced among these racial/ethnic groups than among whites. Reference
Ho PA, Alonzo TA, Gerbing RB, et al. WT1 sp rs16754 genotype predicts treatment related mortality (TRM) in African-American and Asian pediatric AML patients: a report from the Childrenâ€™s Oncology Group. Presented at: 54th American Society of Hematology Annual Meeting; December 8-11, 2012; Atlanta, GA. Abstract 1385.
nc seri Vie olo es w gy on the Ph lin ar e a m t ac ist .
CONQUERING THE CANCER CARE
CONQUERING THE CANCER CARE CONTINUUM CONQUERING CANCER CARTHE C E CONT I
Genes Linked to AnthracyclineRelated Congestive Heart Failure In patients who have undergone hematopoietic stem cell transplants, genetic factors may influence susceptibility to congestive heart failure related to anthracyclines used prior to transplant, City of Hope researchers found. A case-control study of 77 persons with hematologic cancers identified certain genetic pathways that were present in patients who developed heart failure compared with those who did not. Patients who had variations in the MRP2, RAC2, and HFE genes had up to a 3-fold higher risk for heart failure. These genes are responsible for key proteins that regulate the metabolism of anthracyclines and defend against oxidative stress. Females with â‰Ľ2 genetic variations were at highest risk, compared with males with one or none of them. Reference
Armenian SH, Ding Y, Mills G III, et al. Genetic susceptibility to anthracycline-related congestive heart failure (CHF) in survivors of hematopoietic cell transplantation (HCT). Presented at: 54th American Society of Hematology Annual Meeting; December 8-11, 2012; Atlanta, GA. Abstract 589.
A 6-part series
The publishers of The Oncology Nurse-APN/PA, The Oncology Pharmacist, and Personalized Medicine in Oncology are proud to present our 2nd annual Conquering the Cancer Care Continuum series. Upcoming topics include:
Challenges Patients Face in Cancer Care: Implications for the Healthcare Team Lea Ann Hansen, PharmD, BCOP Associate Professor, Virginia Commonwealth University
cancer.1 More than half are living well beyond 5 years ancer is an illness associated with substantial physical, emotional, social, and financial ramafter diagnosis. Women comprise a majority of longifications for affected individuals and their term survivors due to the favorable outcomes with families. In a significant number of cases, the diagnosis breast, cervical, and uterine cancers.2 The number of of cancer is either preceded by a period people living with a history of cancer of gradual, nonspecific symptoms or is projected to grow considerably over
discovered by routine screening, and the next 20 years for 2 major reasons. individuals are then thrust into a First, the number of Americans over whirlwind of diagnostic testing, inage 65 is predicted to double between vasive procedures, and complicated the years 2000 and 2030.3 Consetreatments with very little warning or Lea Ann Han quently, as a disease primarily of older sen, Associat e ProfessoPharmD, BCOP adults, cancer will also increase. Secopportunity to assimilate their circumr, Virginia Common stances. Frequently, a multidisciplinary ond, as the effectiveness of cancer wea ersity the number of â„˘lth Univ approach to treatment is necessary, retreatments improves, he past deca de quiring patients to engage with numerpatients cured of the disease will inthe utilizatio has seen a dram atic upsu
n of spec several ous medical teams comprising crease, andrge an in even larger ialty pha types of Medpercentage rmacies for icare Mo ther Lea Ann Hansen, ape thos utic e for cancer. different specialties, often in different will be living all longer with diseasedernization Act modaliti as â€œathe PharmD, es, includin part D drug The BCOP defined a cost of can specialty g locations. Many patients have beenabout $125 billi while receiving multiple cer care may ceed â€œlinesâ€? of with plan-negotia drug on in 201 0 rise from etc) over $40 ted prices 0 to (first-line, relatively healthy prior to the cancer lion eventbyand second-line, time. per Themonth.â€? 2 Oth thethere7 bilthat exend of the therapy$20 fine spec er health ialty drug deca plans may de. demand fore are not sophisticated consumerstim ofe,medical overall specialtyserBy that for oncology services is expected to ins different dedrugs are ly. In gen acco predby eral, they unthealthcare icte48% vices. 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FEBRUARY 2013 I VOL 6, NO 1
ASH HIGHLIGHTS In PACE Update, Ponatinib Benefit Confirmed Updated findings from the pivotal phase 2 Ponatinib Ph+ ALL and CML Evaluation (PACE) trial found robust activity and sustained benefit for the investigational tyrosine kinase inhibitor ponatinib in heavily pretreated patients with accelerated or blastphase chronic myeloid leukemia (CML) or Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL). Twelve-month data were presented for 179 patients who were resistant to or intolerant of dasatinib or nilotinib, or had the T315I mutation.
Updated findings from the pivotal phase 2 PACE trial found robust activity and sustained benefit for the investigational tyrosine kinase inhibitor ponatinib in heavily pretreated patients with accelerated or blast-phase CML or Ph+ ALL. Major hematologic response, the primary end point, was as follows: for accelerated-phase patients, 58% for the resistant group and 50% for the mutation group; for blast-phase and Ph+
ALL patients, 35% for the resistant group and 33% for the mutated group. Cytologic responses were obtained in 52%, 67%, 40%, and 43%, respectively. Progression-free survival at 12
months was 55% for patients with accelerated-phase CML and 15% for those with blast-phase/Ph+ ALL, while overall survival was 84% and 33%, respectively. Reference
Kantarjian HM, Kim D-W, Pinilla-Ibarz J; the PACE Study Group. Efficacy and safety of ponatinib in patients with accelerated phase or blast phase chronic myeloid leukemia (AP-CML or BP-CML) or Philadelphia chromosome–positive acute lymphoblastic leukemia (PH+ ALL): 12-month follow-up of the PACE trial. Presented at: 54th American Society of Hematology Annual Meeting; December 8-11, 2012; Atlanta, GA. Abstract 915.
GVHD Reduced With Vorinostat The administration of the histone deacetylase inhibitor vorinostat in patients undergoing matched related donor reduced-intensity conditioning allogeneic hematopoietic stem cell transplants could be an effective approach to reducing graft-versus-host disease (GVHD), according to the firstin-human clinical trial of 45 patients. The drug was added on days 10 to 100 to standard GVHD prophylaxis consisting of mycophenolate mofetil and tacrolimus. After treatment, patients who received vorinostat had a significantly lower incidence of GVHD than their historical
controls (22% vs 42%). They also had lower rates of grade 3 and 4 GVHD (4% vs 19%) as well as transplant-related mortality at 1 year (13% vs 19%). There were no significant differences in rates of infectious complications or incidence of relapse, indicating that vorinostat helped reduce the risk of GVHD in patients without further compromise. Reference Choi SW, DiPersio JF, Braun TM, et al. Targeting histone deacetylases as a new strategy for graft versus host disease prevention. Presented at: 54th American Society of Hematology Annual Meeting; December 8-11, 2012; Atlanta, GA. Abstract 740.
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SAVE THE DATE SECOND ANNUAL CONFERENCE
2013 WORLD CUTANEOUS MALIGNANCIES CONGRESS
July 26-28, 2013 Hyatt Regency La Jolla at Aventine 3777 La Jolla Village Drive San Diego, California
Cryotherapy Effective for Oral Mucositis Memorial Sloan-Kettering Cancer Center (MSKCC) researchers showed that cryotherapy given at the time of high-dose melphalan reduced the incidence of severe oral mucositis and the need for pain medicine in patients with multiple myeloma who are undergoing autologous stem cell support. In 2011, MSKCC adopted the use of ice chips given for 30 minutes before, during, and after melphalan ≥140 mg/m2. The retrospective analysis from the pharmacy database sought to determine if this practice reduced the incidence of oral mucositis. Eighty-five patients who received cryotherapy were compared with 129 similar patients who did not. Investigators found that mucositis (all grades) occurred in 34% who received cryotherapy and 47% who did not (P = .08). Grade 3 and 4 mucositis occurred in 2% and 16%, respectively (P = .004), and grade 4 mucositis was not observed at all in the cryotherapy group. Cryotherapy was also associated with less use of patient-controlled analgesia (19% vs 37%; P = .01). The authors suggested that because cryotherapy is readily available, it should be offered to all patients receiving high-dose melphalan. Reference
Melanoma • Basal Cell Carcinoma • Cutaneous T-Cell Lymphoma Squamous Cell Carcinoma • Merkel Cell Carcinoma
FEBRUARY 2013 I VOL 6, NO 1
Rodriguez M, Adel NG, Devlin S, et al. Cryotherapy reduces mucositis in multiple myeloma patients receiving high-dose melphalan conditioning prior to autologous stem cell transplantation. Presented at: 54th American Society of Hematology Annual Meeting; December 8-11, 2012; Atlanta, GA. Abstract 4265.
SIDE EFFECTS MANAGEMENT
Peripheral Arterial Disease Seen With Nilotinib By Audrey Andrews
eripheral artery occlusive disease (PAOD) may be an adverse effect of nilotinib treatment in patients with chronic-phase chronic myeloid leukemia (CML), according to a study presented at the 54th Annual Meeting of the American Society of Hematology.1 A significantly higher frequency of PAOD was observed in patients taking nilotinib than in patients taking imatinib, as measured by prospective, sequential ankle-brachial index (ABI) and duplex ultrasonography monitoring, said Philipp le Coutre, MD, of Charité, Universitätsmedizin Berlin in Germany. The occurrence of PAOD was most notable among patients with ≥2 underlying cardiovascular risk factors, and this patient group “should be treated with caution,” le Coutre advised. Based on a suggestion of risk from previous studies, le Coutre and colleagues assessed 159 patients with CML who received first-line imatinib (n = 53), firstline nilotinib (n = 31), or second-line nilotinib (n = 32), and those who were previously exposed to nilotinib (n = 23) or never treated with nilotinib and currently not on imatinib (n = 7). Patients received nilotinib 300 mg or 400 mg twice daily for 6 months or longer. Laboratory parameters were measured as early as 4 weeks in some patients. A pathologic ABI, defined as <0.9, occurred in 31 of 129 patients with available ABI data (24%), and was found to occur more frequently among those treated with nilotinib, le Coutre reported. At baseline, patients who received first-line imatinib tended to have a significantly longer duration of CML than those who received nilotinib (P <.0001) and a significantly longer firstline treatment duration—a median duration of 97.5 months versus 29 months with nilotinib (P <.0001). The higher risk for PAOD was observed with nilotinib, despite much shorter treatment exposure, he pointed out.
Risk of PAOD in Subgroups PAOD was diagnosed in 6.3% of patients on first-line imatinib, compared
with 26% on first-line nilotinib (P = .0297), 35.7% on second-line nilotinib (P = .0029), 16.6% of those previously exposed to nilotinib, and 12.5% who never received nilotinib.
abolic problems,” le Coutre said. These risk factors may have contributed to the development of PAOD, the investigators maintained. In a subgroup analysis of 17 patients with severe PAOD
A significantly higher frequency of PAOD was observed in patients taking nilotinib than in patients taking imatinib. The rate of PAOD in patients receiving imatinib has been reported to be essentially the same as the upper limit observed historically in the non-CML population: 6.7%.2 “There is no decrease in PAOD frequency in imatinib-treated patients, when compared to historical non-CML cohorts. We believe our findings are therefore not due to a reduction in PAOD with imatinib, but that it’s a nilotinib issue,” le Coutre suggested. Five PAOD-related events occurred, all in patients who received nilotinib. Risk Factors Associated With Nilotinib Increases in cholesterol and low-density lipoprotein were observed with nilotinib over imatinib, but there were no significant differences in high-density lipoprotein, triglycerides, glucose, or hemoglobin A1C levels among the treatment cohorts. Total cholesterol was 164 mg/dL among the first-line imatinib cohort, but was 209 mg/dL with first-line nilotinib (P <.0001), 222 mg/dL with second-line nilotinib (P <.0001), and 193 mg/dL after any nilotinib exposure (P <.034). Low-density lipoprotein values were 95 mg/dL, 135 mg/dL (P <.0003), 139 mg/ dL (P <.0001), and 117 mg/dL (P <.03), respectively. “Although nilotinib may cause hyperglycemia and dyslipidemia, the exact mechanism leading to PAOD is unclear. We think that atherosclerotic disease caused by dyslipidemia should take longer to develop, and we may be seeing the effect of nilotinib accelerating these met-
that was newly diagnosed while they were on treatment, 94% had received nilotinib and only 1 patient (6%) had received
imatinib. Of these patients, 53% had 1 or 2 underlying risk factors (tobacco, hypertension, diabetes, and dyslipidemia) and 47% had 3 or 4 risk factors. “At present, we are recommending baseline and follow-up ABI and lab chemistries before nilotinib is given, and in patients with 2 or more cardiovascular risk factors, nilotinib should be given with caution,” he concluded. l References
1. Schwartz M, Kim T, Mirault T, et al. Elevated risk of peripheral artery occlusive disease (PAOD) in nilotinib treated chronic phase chronic myeloid leukemia (CML) patients assessed by ankle-brachial-index (ABI) and duplex ultrasonography. Presented at: 54th American Society of Hematology Annual Meeting; December 8-11, 2012; Atlanta, GA. Abstract 914. 2. Lamina C, Meisinger C, Heid IM, et al. Association of ankle-brachial index and plaques in the carotid and femoral arteries with cardiovascular events and total mortality in a population-based study with 13 years of follow-up. Eur Heart J. 2006;27(21):2580-2587.
What inspired you to enter the oncology field?
he Oncology Pharmacist (TOP) asked its online reading community to share their inspiration for entering the oncology field. We received responses that made it clear that those involved in the field are passionate about the profession and challenged by its complexity. Some of the responses highlighted a single person who inspired a career choice and a desire to help those living with cancer. Below, we share with you excerpts from several of the responses. My father. The complexity of cancer pathology. I was the only PharmD that didn’t threaten to quit if he or she had to round with the oncologists. Now I can’t imagine doing anything else. Love for the constantly changing learning environment!
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FEBRUARY 2013 I VOL 6, NO 1
THE PATIENT’S VOICE
Adherence to Therapy at Home: The Personal Touch By MMA
spent 8 long months in a city far from my own, undergoing intense chemotherapy and then an autologous stem cell transplant. Eventually, after a longer-than-I-would-have-liked stay in the hospital and another few weeks living close to the hospital in case of emergency, I was sent back home with a bagful of medicines and instructions on how/when/ with what to take them. Much discussion exists around the issue of how to get patients to adhere to their treatment regimen at home. I must admit I worried about this, too. When I first arrived back in my city, I felt a complete disconnect from the turmoil and commotion associated with being a cancer patient at a major cancer treatment center. I did not want to be that cancer patient anymore. I wanted to go back to my life precancer—progress in my career, energy to shuttle my children to and from their activities, enough resources to actually save some money, and the freedom to eat at my favorite restaurants. Though many friends kept in close contact with me during my treatment, during my absence their lives continued—as did mine—on parallel, but no longer interconnected, tracks: their kids kept going to the same schools, they got promotions at work, they continued to save some money, and they hung out at our favorite coffee shop. My kids and I saw our entire routine interrupted: some of them stayed in the same schools and flew back and forth to see me, others left school to be with me, we moved into a rented apartment in the hospital city while paying a mortgage in our home city, and we quickly descended to the bottom of the middle class from our once-secure financial position. Now home, I just wanted my old life back! Yet, I could not have it back. Exhausted, I found that even some of the easiest tasks seemed beyond my capabilities. Standing up for more than 5 minutes was an ordeal. Keeping the house clean was absolutely impossible. Going back to the office seemed like a pipe dream. The side effects from the chemotherapy and the stem cell transplant continued to haunt me. Nausea remained the norm, controlled only by the miracle drug prescribed to me to stop it. I tried to go out for nightly walks around the block, but after 2 days of attempts, I stopped, discouraged by my inability to make it without gasping for air, even at a pace that if it were any slower, could factually be called reverse. My first few weeks at home, rather than giving me tranquility, offered
FEBRUARY 2013 I VOL 6, NO 1
me little but treasured memories of how things were before cancer invaded our life and the bitter reality of what now was. I knew I did not want to keep living like this. That did not mean, though, that I wanted to end my life. Certainly, I had some moments of severe sadness, sitting in my bed, too tired to get up, weeping. How could this have happened? Why did it happen? What would happen from here? But those moments were few and far between.
Also, admittedly, during my first couple of weeks at home, I wanted to disassociate completely from my role as cancer patient and the pain associated with my treatment. I took my “easy” medications (for me this meant the medications in pill form) rather regularly (if I was asleep I would miss a dose and not take one until I woke up). But I resisted taking my painful medication—a self-injection I was supposed to take twice a day—on more than a few occasions. Oh, certainly I had many justifications: it hurt and I did not want any more pain; I was not even supposed to have to take it, because the condition I was being treated for (a pulmonary embolism) happened 5 months ago, and though my doctor told me that I would need the medication for at least 6 months, a nurse at the hospital had once told me that some doctors required only 4 months of the medication, and I preferred to be in that category regardless of what anyone said; and that particular medicine, I convinced myself, was causing all my nausea and making my recovery much more difficult. And regardless of what patients actually tell their doctors, I found out that my reaction to being home was rather common, or, at least, not uncommon, particularly for patients like myself who live in areas with negligible access to healthcare and with healthcare professionals of dubious merit. I spoke to a woman who, once sent home from the same cancer center where I was treated,
took the “I no longer want to be a cancer patient” attitude to an extreme: she stopped taking her medicines completely after only a few weeks at home. As she told me, “Hey, if no one is watching, no one will know.” Last week I found out she was back in the hospital with another blood clot that most probably could have been avoided had she kept taking those darn injections. I spoke to a colleague at work who, unknown to me, was a cancer survivor. We got to talking about our experiences, and he mentioned the pros and cons of being sent home. He shared with me that had it not been for his wife, who every morning put his pills in one of those pill dispenser trays, he would never have taken his medication. “It was hard enough to get those giant pills down when I already did not feel well,” he shared. “If it had not been for her, I would have said to heck (he used a different word) with the whole medication thing. I didn’t want this cancer thing haunting me for the rest of my days, and those pills just reminded me of how sick I really was.” So, at least in my case, what strategies would have been helpful to keep me motivated to follow my medication regimen exactly, at least during those first few weeks of being home (I now religiously take all my medications)? I think the solution would have been rather easy: a series of phone calls— maybe once a week or so—from the pharmacist or another member of my medical team to check up on me. You see, when I was a cancer patient receiving care at the cancer center, I went to the hospital several times a
week. There, I was always asked about which medicines I was taking, when I took them, and when I took them last. Someone actually looked over that information and asked me questions to clarify it. I shared with them that I hated doing the self-injection, and though given sympathy, I was also encouraged to continue the injections and I did so. Once I got home, though, I felt like I was thrown to the wolves, alone, to fend for myself. I was no longer amongst a swarm of cancer patients, all waging their private battles against an evil disease yet all united by the obligation to take pills and injections. No one was asking me if I was taking my medicines or if I had any concerns about them. At home, I was “the” cancer patient—different, weaker, and sicker than the rest. I was waging this battle completely alone, now, and I really did not want to be so unique. Consider it a kind of culture shock. Patients who are sent home go from being checked up on several times a week to almost complete neglect. At first, we are not used to the neglect. It feels like “Out of sight, out of mind.” Though I do not consider my case of nonadherence extreme, and I did get myself back on track rather quickly, it all could have been avoided if I had just had someone, anyone, from my team personally check up on me. So, if you want your patients to adhere to their prescribed therapy at home, pick up the phone, and give them a call to ask if they are doing so. Even in this age of high technology, you might be surprised at how incredibly important a little human contact can actually be! l MMA is undergoing treatment for cancer. She wishes to use her initials.
READER POLL Do patients talk to you about how best to adhere to their medication regimen when at home? o Yes
MMA discusses the many issues she confronted when she returned home with “a bagful of medicines.” Do patients talk to you about similar concerns? How do you talk to patients about the issues they may confront?
Go to www.TheOncologyPharmacist.com to answer the question.
Koeller’s Corner Shooting from the Hip
The Cost of Cancer Drugs: How High Is Too High? By Jim Koeller
irst, it has been awhile since my last column and I want to apologize for the hiatus. So, you are then probably wondering what possibly could have coaxed me back into writing another column? Well, the mother lode of all controversial topics has risen to the top of the gossip and Internet chatter lists: a too expensive cancer drug! All the commotion is over a drug named Zaltrap (ziv-aflibercept), which was recently approved by the US Food and Drug Adminstration (FDA) for second-line treatment of metastatic colon cancer, at an average monthly cost of just over $11,000. As an economics guy, this truly is in my “sweet spot.” How can I resist making some comments concerning the prices and pricing of cancer drugs. Again, not to get anyone else in trouble, the comments I make are mine alone (we live in a world of disclaimers!). With that being said, let’s dig into the price and pricing of drugs, specifically, cancer drugs, which also fit into the category called specialty drugs. First, let’s put drug cost into perspective from a macroeconomic standpoint, then look at what are the “really” expensive drugs, then look at cancer drugs specifically, and finally address Zaltrap and all the hoopla. In the United States, we spend roughly $300 billion (with a B) per year on prescription drugs! According to a report by Barclays Capital, the prices for the top 130 brand drugs rose 6.9% in 2010.While that may hold true for the “average” prescription drug, Novartis AG’s Gleevec rose 20.9%. Express Scripts PBM noted in 2012 that prescription drugs shot up 13%; they also noted that specialty drugs (includes our cancer drugs) rose 16% in 2011. Others have noted that specialty drugs rose by 23% in 2012. The Pharmaceutical Research and Manufacturers of America says that the big rise in prescription drugs is “skewed by a handful of high-priced specialty drugs.” Specialty drugs current-
ly make up 17% of all prescription drugs but are expected to make up 40% of drugs by 2020. So, that doesn’t sound promising for the future of drug price increases! So, are cancer drugs REALLY expensive? I guess the answer would be a resounding YES as a collective group, but there are individual drugs that are in a category by themselves. If you google “most expensive prescription drugs,” which I did, you will see various lists presented. Depending on which list you used, the most expensive drug in the US is either Soliris (eculizu-
What do all these really expensive drugs have in common? The answer is, “it’s the math, stupid!” All these drugs have a limited number of treated individuals to spread the cost over, and this holds true especially for most cancers, which affect patients only in the thousands each year, with only a few cancers affecting 100,000 or more people. Compare that with hypertension, diabetes, or other more common maladies, whose patients generally number in the millions, if not tens of millions, making it easier to spread the cost across a larger number of patients to generate the
The mother lode of all controversial topics has risen to the top of the gossip and Internet chatter lists: a too expensive cancer drug!
mab) at $409,500 per year for hemoglobinuria, which affects roughly 8000 individuals, or Elaprase (idursulfase), which treats a rare metabolic disorder (500 people) called Hunter syndrome and costs either $375,000 or $657,000 per year, depending on dose. Following those 2 are Naglazyme (galsulfase) at $365,000 per year, for a connective tissue disorder that affects a population in the thousands; Cinryze (C1 esterase inhibitor) at $350,000 per year for hereditary angioedema, which affects several thousand (6000 in the US); and finally the cancer agent Folotyn (pralatrexate) at $300,000+ per year, for peripheral T-cell lymphoma. Not to be outdone, H.P. Acthar Gel (repository corticotropin injection), a natural formulation of adrenocorticotropic hormone or ACTH, goes for $23,000 a vial, at a cost of $115,000 per month (6-7 vials). So, as you can see, there are a select few other therapies besides cancer drugs that can hit that 6-figure cost yearly.
expected revenue. For drugs to generate hundreds of millions or even billions of dollars in revenue, X number of dollars must be charged per product unit to generate that amount of money. So, it really comes down to just math and what the market will bear (more on that later). Now, back to cancer drugs. First, for a little history, do you know which cancer drug (and when) was the first to break the 4-digit cost barrier per dose? The answer is Taxol (paclitaxel), which was approved by the FDA at the end of 1992 and ended up costing just over $1000 a dose, a new high! Realize that this was just 20 years ago! We now have cancer drugs that can reach 5 to 6 figures per dose. So, for intravenous (IV) cancer drugs that are generally given once or twice monthly, per-dose costs are usually higher than many of our more recent oral cancer drugs, which seem to fit into a range of $5000 to $8000 per month. Because these drugs are generally taken daily, the per-dose
costs are less, but the monthly cost often gets close to the monthly cost of IV cancer drugs, which have tended to stay in that same $5000 to $8000 permonth range, up through 2010 (with only a few exceptions). From 2011 to now, however, the bar seems to have been raised significantly, to the point where the monthly or total costs of a few of the exceptions mentioned above became the new normal in pricing equivalence, with monthly costs commonly exceeding $10,000, some monthly costs of $30,000 popping up, and yearly costs of $100,000 now being seen. With several new drugs having been introduced in the past 24 months, the price escalation is readily apparent. Also remember that many of the newer agents go after second- or third-line indications, thus limiting the population size, which again puts pressure on the per-dose price. Let’s take a look (these are my rough calculations, so don’t throw a fit if your numbers are a little different): • Provenge (sipuleucel-T): $31,000/ dose × 3 doses ≈ $93,000/year • Caprelsa (vandetanib): ≈ $10,500/ month • Yervoy (ipilimumab): $30,000/dose × 4 doses ≈ $120,000/year • Zelboraf (vemurafenib): $9400/ month × 6 doses ≈ $56,400/year • Halaven (eribulin mesylate): ≈ $75,000/year • Adcetris (brentuximab vedotin): $13,500/dose × 7-9 doses ≈ $94,500-$121,500/year • Xalkori (crizotinib): $9600/dose × 12 doses ≈ $115,000/year • Zaltrap (ziv-aflibercept): $11,063/ dose Yes, cancer drugs per treatment or per year are expensive, but are they worth that expense? Are these reasonable prices to pay? If the public is willing to pay $X for a product, then it is viewed as worth that cost (this is a market-driven principle). In healthcare, because individuals do not generContinued on page 28
FEBRUARY 2013 I VOL 6, NO 1
The Cost of Cancer Drugs... Continued from page 27 ally pay for the complete cost of their to pay for their own medicines, drugs drugs except for, potentially, a copay costing more than a couple hundred (rather, insurance or government pays), dollars a month would be problematic. the issue of worth (what a person The market would not bear it, because would pay) becomes extremely distort- the average income would not support ed. How many patients would actually it—but healthcare does not follow pay $10,000 to $30,000 for a treatment individual market rules. if they had to pay for it out of their own If society—that is, insurance compapockets? If individuals1 actually hadPagenies and/or taxpayers—is being asked VBCC0112_VBMAsize_Layout 2/9/12 4:12 PM 1
to pay for these drugs, is there another way to determine what is “worth the cost” or what is fair? Yes: it can be determined by what the payers are willing to pay for a product. This concept goes back many years, when it was determined that the government paid for a significant portion of dialysis (ie, $50,000 per life-year [LY]
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gained); thus, if they were willing to pay for dialysis, they must also be willing to pay for other treatments that would also be deemed cost-effective (ie, $50,000/LY)—it’s only fair! This was the start of using economics (cost per LY or quality-adjusted life-year [QALY]) in determining what would be paid for and what would be seen as too much. We can argue what that current cost-per-LY value is, but most would agree it is somewhere in the $100,000/year range. With that being said, for many if not most of the newer cancer drugs that extend overall survival by only weeks to a few months and yet cost what they do, the cost-per-LY gained generally exceeds several hundreds of thousands of dollars (example: Provenge extends survival by 4 months at a cost of $93,000-$279,000/ LY gained). So, you can do your own math for the rest of the agents listed above. These, by definition, would not be viewed as cost-effective. This begs the question, is it reasonable to pay up to 6 figures for only a month or so of additional life? The easy answer is, it depends on whose perspective. According to that definition of an acceptable societal cost and a reasonable value, one could argue that many of today’s cancer drugs are not worth the cost. Unlike in many countries where government pays for healthcare and can set societal rules regarding what is paid for and what is not (many using a calculation of cost-effectiveness, eg, the United Kingdom’s National Institute for Health and Clinical Excellence, or NICE, Guidelines), where the cost-effective cut points eliminate many of the agents that are available in the US. That is because the rules in the US are different. First off, once the FDA approves a drug (and by law, they cannot take the cost of the product into consideration, only efficacy and toxicity), Medicare, by law, must pay for it; then other payers fall into line and also pay. This truly distorts pricing and allows industry to price their products against other products currently being paid for (using the logic that, if you are paying for other products already, and the market will bear it, then you will also pay for ours…). Before the pharmaceutical industry goes ballistic and adamantly defends their prices because of the cost of doing research and other industry-related issues and inherent risks, etc (of which there are many), I will be the first to admit that a good portion of their pricing may in fact be justified. One can argue indefinitely as to what the true cost is of bringing a drug to market, and it can be substantial, but that discussion is for another time. With all that being said, and I
KOELLER’S CORNER have said plenty, it’s time to return to Zaltrap and its $11,063/dose cost, and to address all the commotion. Is its cost really out of line with that of some of the other outliers? Some would say yes and some would say no, but it appears the market—and in this case I mean Memorial Sloan-Kettering Cancer Center (MSKCC), one of the largest cancer centers in the United States—put its foot down and said, enough is enough; this price is just too high, and if payers cannot say no and must pay, we do not have to prescribe! On October 14, 2012, the New York Times published an op-ed piece by 3 physicians from MSKCC, who stated that they would not use Zaltrap in second-line colon cancer treatment because its $11,063 average monthly cost was twice that of a similar medicine (Avastin) and its efficacy was no better (both increase survival by 1.4 months); they also stated that “[i] gnoring the cost of care…is no longer tenable,” and that they are obligated to consider the financial strains that result. This single action has now elevated the discussion of cost and value to mainstream oncology practice. If oncologists throughout the US start to include the cost and the value of treatment in their decision process, it could be a game changer. Sanofi has admitted that they “pegged” the price of Zaltrap at the 10-mg/kg dose of Avastin (bevacizumab), seemingly confirming that matching pricing to what similar products cost, or what the market is already bearing, appears to have driven the price. However, data have shown that the 5-mg/kg dose of Avastin in colon cancer is equivalent to the 10-mg/kg dose, and general oncology practice has basically accepted this. Please note that this does not let Avastin off the hook as being a good value and costeffective; in second-line colon cancer treatment, the cost-per-QALY gained is still $300,000, so it is no bargain either. The action by MSKCC no doubt set off an explosion (nuclear) at Sanofi central. Within 1 week, Sanofi came out and defended their price, saying it was the right price, a responsible price, and priced competitively. Nevertheless, Sanofi went on to say that there was “some market resistance” to the perceived price (ie, value) of Zaltrap, and the company would thus cut the price. However, please realize that Sanofi did not cut the price, but instead simply offered a 50% rebate to physicians, which many publications erroneously reported as a price decrease. This 50% rebate can, in fact, be argued to actually encourage drug use due to the margin generated to physicians and institutions, though, at least for some time, it will not change patients’ copay or what payers
pay (we can thank Medicare’s ASP [average sale price] reimbursement process for that). The actions taken by MSKCC may have actually been perfectly timed, because the American Society of Clinical Oncology (ASCO) is currently putting value and cost-effective cancer care on the front burner as a key initiative. ASCO, which already has its Quality Oncology Practice
Initiative, or QOPI, program, is now moving forward to develop criteria for defining the benefit of cancer treatment—including such metrics as survival, toxicity, cost, and quality—in an attempt to establish and define value in cancer care. It appears that the cancer community will finally start to include cost in the equation for drug use, and do it seriously. My take on this whole thing is that
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cancer care may be entering a whole new paradigm in establishing which treatments are given to patients. It’s certainly a start, but we have a long way to go before this is mainstream practice. I can now imagine that every company that comes out with a new cancer drug in the future will absolutely think twice before pricing their product, and that’s a good thing…. l
Pushing Your Limits
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USAGE INDICATIONS AND USAGE EMEND for Injection is a substance P/neurokinin 1 Prevention of Chemotherapy-Induced Nausea and (NK1) receptor antagonist in adults Vomiting (CINV): EMEND,indicated in combination withforother use in combination other for antiemetic agents for antiemetic agents, iswith indicated prevention of acute the prevention of acute delayed nauseawith and and delayed nausea and and vomiting associated vomiting withofinitial and repeat courses initial andassociated repeat courses highly emetogenic cancerof highly emetogenic cancer chemotherapy (HEC) and chemotherapy (HEC), including high-dose cisplatin; CAPSULES including high-dose cisplatin. for prevention of nausea and vomiting associated with initial and repeat courses of moderately cancer chemotherapy (MEC). Limitations of Use: EMEND for Injectionemetogenic has not been studied for the treatment of established nausea and vomiting. Prevention of Postoperative Nausea and Vomiting (PONV): EMEND isand indicated for prevention of postoperative Chronic continuous administration is not recommended [see Warnings Precautions]. nausea and vomiting. CONTRAINDICATIONS Limitations of Use: EMEND has not been studied for treatment of established nausea and vomiting. Hypersensitivity: EMEND for Injection is contraindicated in patients who are hypersensitive to EMEND for Chronic continuous administration is not recommended. Injection, aprepitant, polysorbate 80, or any other components of the product. Known hypersensitivity reactions CONTRAINDICATIONS include flushing, erythema, dyspnea, and anaphylactic reactions [see Adverse Reactions]. EMEND is contraindicated in patientsorwho are hypersensitive any component of the product. Concomitant Use With Pimozide Cisapride: Aprepitant,towhen administered orally, is a moderate EMEND is a dose-dependent inhibitor of cytochrome P450 isoenzyme 3A4 (CYP3A4). EMENDregimen should not used cytochrome P450 isoenzyme 3A4 (CYP3A4) inhibitor following the 3-day antiemetic dosing forbe CINV. concurrently with pimozide, terfenadine, or cisapride. of CYP3A4 by aprepitant could result Since fosaprepitant is rapidly convertedastemizole, to aprepitant, do not useInhibition fosaprepitant concurrently with pimozide or in elevated plasma concentrations of these drugs,could potentially serious or life-threatening Drug cisapride. Inhibition of CYP3A4 by aprepitant resultcausing in elevated plasma concentrationsreactions of these[see drugs, Interactions]. potentially causing serious or life-threatening reactions [see Drug Interactions]. WARNINGS AND AND PRECAUTIONS WARNINGS PRECAUTIONS CYP3A4 Interactions: EMEND, a dose-dependent inhibitor of CYP3A4, should be used with caution in patients CYP3A4 Interactions: Fosaprepitant is rapidly converted to aprepitant, which is a moderate inhibitor of CYP3A4 receiving concomitant medications that are primarily metabolized through CYP3A4. Moderate inhibition of CYP3A4 when administered as a 3-day antiemetic dosing regimen for CINV. Fosaprepitant should be used with caution in by aprepitant, 125-mg/80-mg regimen, could result in elevated plasma concentrations of these concomitant patients receiving concomitant medications that are primarily metabolized through CYP3A4. Inhibition of CYP3A4 medications. by aprepitant or fosaprepitant could result in elevated plasma concentrations of these concomitant medications. Weak inhibition of CYP3A4 a single 40-mg dose of aprepitant not expected to alterplasma the plasma concentrations When fosaprepitant is usedbyconcomitantly with another CYP3A4isinhibitor, aprepitant concentrations of concomitant medications that are primarily metabolized through CYP3A4 to athat clinically degree. could be elevated. When aprepitant is used concomitantly with medications inducesignificant CYP3A4 activity, When aprepitant is concentrations used concomitantly aprepitant plasmaefficacy concentrations could be aprepitant plasma couldwith be another reduced,CYP3A4 and thisinhibitor, may result in decreased of aprepitant elevated. EMEND is used concomitantly with medications that induce CYP3A4 activity, aprepitant plasma [see DrugWhen Interactions]. concentrations could be reduced and this may result in decreased efficacy of EMEND [see Drug Interactions]. Chemotherapy agents that are known to be metabolized by CYP3A4 include docetaxel, paclitaxel, etoposide, Chemotherapy agents that are known to be metabolized CYP3A4 includeIn docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide, imatinib, vinorelbine, vinblastine,byand vincristine. clinical studies, the oral aprepitant irinotecan, ifosfamide, imatinib, vinorelbine, and vincristine. In clinical studies, EMEND (125-mg/80-mg regimen was administered commonly with vinblastine, etoposide, vinorelbine, or paclitaxel. The doses of these agents were regimen) wastoadministered with interactions. etoposide, vinorelbine, or paclitaxel. The doses of these agents were not not adjusted account forcommonly potential drug adjusted to account for potential drug interactions. In separate pharmacokinetic studies, no clinically significant change in docetaxel or vinorelbine pharmacokinetics In separate pharmacokinetic studies no clinically significant change in docetaxel or vinorelbine pharmacokinetics was observed when the oral aprepitant regimen was coadministered. Due to the small number of patients in was observed when EMEND (125-mg/80-mg regimen) was coadministered. clinical studies who received the CYP3A4 substrates vinblastine, vincristine, or ifosfamide, particular caution and Due to the small number of patients in clinical studies these who received theother CYP3A4 substrates vinblastine, vincristine, careful monitoring are advised in patients receiving agents or chemotherapy agents metabolized or ifosfamide, particular andstudied careful monitoring are advised in patients receiving these agents or other primarily by CYP3A4 thatcaution were not [see Drug Interactions]. chemotherapy agents metabolized primarily by CYP3A4 that were not studied [see Drug Interactions]. Hypersensitivity Reactions: Isolated reports of immediate hypersensitivity reactions including flushing, Coadministration (a CYP2C9 substrate): of EMENDThese with warfarin may result erythema, dyspnea,With and Warfarin anaphylaxis have occurred duringCoadministration infusion of fosaprepitant. hypersensitivity in a clinically significant decrease in international normalized ratio (INR) of prothrombin time. In patients on chronic reactions have generally responded to discontinuation of the infusion and administration of appropriate therapy. warfarin therapy, the INR should be closely monitored in the 2-week period, particularly at 7 to 10 days, following Reinitiation of the infusion is not recommended in patients who experience these symptoms during first-time use. initiation of the 3-day regimen of EMEND with each chemotherapy cycle, or following administration of a single Coadministration WithforWarfarin (a of CYP2C9 substrate): Coadministration of Drug fosaprepitant or aprepitant with 40-mg dose of EMEND prevention postoperative nausea and vomiting [see Interactions]. warfarin may result in a clinically significant decrease in international normalized ratio (INR) of prothrombin time. Coadministration With Hormonal Contraceptives: Upon coadministration with EMEND, the efficacy of hormonal In patients on chronic warfarin the INRthe should be closely monitored the 2-week period,orparticularly contraceptives during and for 28therapy, days following last dose of EMEND may beinreduced. Alternative backup at 7methods to 10 days, following initiation of fosaprepitant with eachwith chemotherapy cycle [see Drug Interactions]. of contraception should be used during treatment EMEND and for 1 month following the last dose of Coadministration With Hormonal Contraceptives: Upon coadministration with fosaprepitant or aprepitant, EMEND [see Drug Interactions]. the efficacy of hormonal contraceptives may There be reduced for 28 days following last dose either Patients With Severe Hepatic Impairment: are noduring clinicaland or pharmacokinetic data inthe patients withofsevere fosaprepitant or aprepitant. Alternative or backup methods contraception should be used during treatment hepatic impairment (Child-Pugh score >9). Therefore, cautionofshould be exercised when EMEND is administered with andpatients. for 1 month following the last dose of fosaprepitant or aprepitant [see Drug Interactions]. in these Chronic Continuous Continuous Use: Use: Chronic Chronic continuous continuoususe useofofEMEND EMENDfor forprevention Injection for prevention of nauseais and of nausea and vomiting not vomiting is not recommended because it has been studied and because drug interaction profile mayduring change recommended because it has not beennotstudied and because the drug the interaction profile may change during continuous chronicchronic continuous use. use. ADVERSE REACTIONS The overall safety of aprepitant was evaluated approximately 5300under individuals. Clinical Trials Experience: Because clinical in trials are conducted widely varying conditions, adversereaction the clinical trialswidely of a drug cannot be directly compared ratesobserved in the clinical of Because rates clinicalobserved trials areinconducted under varying conditions, adverse reactiontorates in thetrials clinical another maybenotdirectly reflectcompared the rates to observed in clinical trials of adrug drugand cannot rates in the clinicalpractice. trials of another drug and may not reflect the rates observed in clinical practice.is converted to aprepitant, those adverse reactions associated with aprepitant might Since EMEND for Injection Clinical Trials Experience: Chemotherapy-Induced Nausea and Vomiting: Highly Emetogenic Chemotherapy: In 2 also be expected to occur with EMEND for Injection. well-controlled clinical trials in patients highly emetogenic cancer 544 treated The overall safety of fosaprepitant wasreceiving evaluated in approximately 1,100chemotherapy, individuals and thepatients overallwere safety of with aprepitant Cyclein1approximately of chemotherapy and individuals. 413 of these patients continued into the Multiple-Cycle extension aprepitant wasduring evaluated 6,500 for up to 6 cycles of chemotherapy. EMEND was given in combination with ondansetron and dexamethasone. Oral Aprepitant: Highly Emetogenic Chemotherapy (HEC): In 2 well-controlled clinical trials in patients In Cycle 1,highly clinicalemetogenic adverse experiences were reported544 in approximately of patients treated with the aprepitant receiving cancer chemotherapy, patients were69% treated with aprepitant during Cycle 1 regimen compared with approximately 68% of patients treated with standard therapy. Following are the percentage of chemotherapy and 413 of these patients continued into the multiple-cycle extension for up to 6 cycles of of patients receiving highly emetogenic chemotherapy in Cycle 1 with clinical adverse experiences reported at an chemotherapy. Oral aprepitant was given in combination with ondansetron and dexamethasone. incidence of ≥3% for the aprepitant regimen (n=544) and standard therapy (n=550), respectively: In Cycle 1, adverse reactions were reported in approximately 17% of patients treated with the aprepitant Body as a whole/Site unspecified: asthenia/fatigue: 17.8, 11.8; dizziness: 6.6, 4.4; dehydration: 5.9, 5.1; abdominal regimen 13% of patients treated with standard therapy. Treatment was pain: 4.6,compared 3.3; fever:with 2.9,approximately 3.5; mucous membrane disorder: 2.6, 3.1 discontinued due to adverse reactions in 0.6% of patients treated with the aprepitant regimen compared with Digestive system: treated nausea:with 12.7,standard 11.8; constipation: 0.4% of patients therapy. 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 The most common adverse reactions reported in patients treated with the aprepitant regimen (n=544) with an Eyes, ears, nose, and throat: tinnitus: 3.7, 3.8 incidence of >1% and greater than with standard therapy (n=550), respectively, are listed below: Hemic and lymphatic system: neutropenia: 3.1, 2.9 Respiratory system: hiccups 4.6 vs 2.9 Metabolism and nutrition: anorexia: 10.1, 9.5 Body as a whole/Site unspecified: asthenia/fatigue 2.9 vs 1.6 Nervous system: headache: 8.5, 8.7; insomnia: 2.9, 3.1 Investigations: increased ALT 2.8 vs 1.5, increased AST 1.1 vs 0.9 Respiratory system: hiccups: 10.8, 5.6 Digestive 2.2 vs 2.0, dyspepsia 1.5 regardless vs 0.7, diarrhea 1.1 vs of 0.9bradycardia, disorientation, In addition,system: isolatedconstipation cases of serious adverse experiences, of causality, Nervous system:duodenal headache 2.2were vs 1.8 and perforating ulcer reported in highly emetogenic CINV clinical studies. Metabolism and nutrition: anorexia 2.0During vs 0.5Cycle 1 of 2 moderately emetogenic chemotherapy studies, 868 Moderately Emetogenic Chemotherapy: treatedreactions with the aprepitant regimenregimen and 686(incidence of these patients continued intoatextensions for up to 4 Apatients listing were of adverse in the aprepitant <1%) that occurred a greater incidence cycleswith of chemotherapy. In the of Cycle 1 data Adverse for theseReactions 2 studies, subsection adverse experiences than standard therapy arecombined presentedanalysis in the Less Common below. were reported in approximately 69% of patients treated with the aprepitant regimen compared with approximately 72% In an additional active-controlled clinical study in 1,169 patients receiving aprepitant and HEC, the adverseof patients treated with standard therapy. experience profile was generally similar to that seen in the other HEC studies with aprepitant. In the combined analysis of Cycle 1 data for these 2 studies, the adverse-experience profile in both moderately Less Common Adverse Reactions: Adverse reactions reported or moderately emetogenic emetogenic chemotherapy studies was generally comparable to in theeither highlyHEC emetogenic chemotherapy studies. chemotherapy (MEC) studiesofinpatients patientsreceiving treated with the aprepitant regimen with an incidence <1%clinical and Following are the percentage moderately emetogenic chemotherapy in Cycle 1ofwith greater than with standard therapy are listed below. adverse experiences reported at an incidence of ≥3% for the aprepitant regimen (n=868) and standard therapy Infection infestations: candidiasis, staphylococcal infection (n=846),and respectively: neutropenia: 5.8, 5.6 Blood and and lymphatic lymphaticsystem systemdisorders: disorders: anemia, febrile neutropenia Metabolism and 6.2, 7.2 Metabolism andnutrition nutritiondisorders: disorders:anorexia: weight gain, polydipsia Psychiatric disorders: 2.6, 3.7 Psychiatric disorders:insomnia: disorientation, euphoria, anxiety Nervous system disorders: headache: 14.3; dizziness:cognitive 2.8, 3.4 disorder, lethargy, somnolence Nervous system disorders: dizziness,13.2, dream abnormality, Gastrointestinal disorders: constipation: 10.3, 15.5; diarrhea: 7.6, 8.7; dyspepsia: 5.8, 3.8; nausea: 5.8, 5.1; Eye disorders: conjunctivitis stomatitis: 3.1, 2.7 Ear and labyrinth disorders: tinnitus Skin and subcutaneous tissue disorders: alopecia: 12.4, 11.9 Cardiac disorders: bradycardia, cardiovascular disorder, palpitations Brief Summary Summaryofofthe thePrescribing PrescribingInformation Informationforfor
(aprepitant) capsules dimeglumine) for Injection EMEND® (fosaprepitant
Brief Summary of the Prescribing Info
Vascular disorders:and hotgeneral flush, flushing General disorders administration site conditions: fatigue: 15.4, 15.6; asthenia: 4.7, 4.6 Respiratory, thoracic, mediastinal disorders: sneezing, cough, postnasal drip,similar throatinirritation In a combined analysisand of these 2 studies, isolatedpharyngitis, cases of serious adverse experiences were the 2 treatment groups. Gastrointestinal disorders: nausea, acid reflux, dysgeusia, epigastric discomfort, obstipation, gastroesophageal Highlydisease, and Moderately Emetogenic Chemotherapy: Theabdominal following additional clinical adverse experiences (incidence reflux perforating duodenal ulcer, vomiting, pain, dry mouth, abdominal distension, hard >0.5% and greatercolitis, than standard therapy), regardless of causality, were reported in patients treated with CAPSULES the feces, neutropenic flatulence, stomatitis aprepitant regimen in either HEC or MEC studies: Skin and subcutaneous tissue disorders: rash, acne, photosensitivity, hyperhidrosis, oily skin, pruritus, initial and repeat courses of moderate Infections skin lesionand infestations: candidiasis, herpes simplex, lower respiratory infection, oral candidiasis, pharyngitis, Prevention of Postoperative Nause septic shock, upper respiratory infection, urinary tract infection Musculoskeletal and connective tissue disorders: muscle cramp, myalgia, muscular weakness nausea and vomiting. Neoplasms benign, malignant, and unspecified (including cysts and polyps): malignant neoplasm, non–small-cell Renal and urinary disorders: polyuria, dysuria, pollakiuria Limitations of Use: EMEND has not lung carcinoma Chronic continuous administration is General disorders and administration site conditions: edema, chest discomfort, malaise, thirst, chills, Blood and lymphatic system disorders: anemia, febrile neutropenia, thrombocytopenia gait disturbance CONTRAINDICATIONS Metabolism and nutrition disorders: appetite decreased, diabetes mellitus, hypokalemia Investigations: increased alkaline phosphatase, hyperglycemia, microscopic hematuria, hyponatremia, EMEND is contraindicated in patients Psychiatric disorders: anxiety disorder, confusion, depression decreased weight, decreased neutrophil count EMEND is a dose-dependent inhibitor Nervous system: peripheral neuropathy, sensory neuropathy, taste disturbance, tremor concurrently with pimozide, terfenadi In another chemotherapy-induced nausea and vomiting (CINV) study, Stevens-Johnson syndrome was reported Eyea disorders: conjunctivitis elevated plasma concentrations of the as serious adverse reaction in a patient receiving aprepitant with cancer chemotherapy. Cardiac disorders: myocardial infarction, palpitations, tachycardia The adverse-experience profiles in the multiple-cycle extensions of HEC studies for up to 6 cycles of Interactions]. Vascular disorders: venous thrombosis, hot flush, hypertension, hypotension WARNINGS AND PRECAUTIONS chemotherapy weredeep similar to that observed flushing, in Cycle 1. Respiratory, thoracic, and mediastinal disorders: cough, dyspnea, nasal secretion, pharyngolaryngeal pain, CYP3A4 Interactions: EMEND, a do Fosaprepitant: In an active-controlled clinical study in patients receiving HEC, safety was evaluated for 1,143 pneumonitis, pulmonary embolism, respiratory disturbance receiving concomitant medications th patients receiving the 1-day regimen of EMENDinsufficiency, for Injectionvocal 150 mg compared with 1,169 patients receiving by aprepitant, 125-mg/80-mg regime Gastrointestinal disorders: abdominal pain profile upper, was acid generally reflux, deglutition disorder, dry inmouth, dysgeusia, the 3-day regimen of EMEND. The safety similar to that seen prior HEC studiesdysphagia, with medications. eructation,However, flatulence,infusion-site obstipation, reactions salivation occurred increasedat a higher incidence in patients in the fosaprepitant aprepitant. Weak inhibition of CYP3A4 by a single Skin and subcutaneous disorders: diaphoresis, rashreported infusion-site reactions included group (3.0%) comparedtissue with those in theacne, aprepitant grouppruritus, (0.5%). The of concomitant medications that are p infusion-site erythema, infusion-site infusion-site pain, pain, infusion-site infusion-site Musculoskeletal and connective tissuepruritus, disorders: arthralgia, back muscularinduration, weakness,and musculoskeletal pain, thrombophlebitis. When aprepitant is used concomitant myalgia elevated. The following additional adverse reactions occurred with fosaprepitant 150 mg and were not reported with the When EMEND is used conc Renal and urinary disorders: dysuria, renal insufficiency concentrations could be reduced and oral aprepitantsystem regimen the corresponding section Reproductive andinbreast disorders: pelvic pain above: Chemotherapy agents that are known General and administrative administrationsite siteconditions: conditions: infusion-site infusion-site pruritus, infusion-site General disorders disorders and edema, malaise,erythema, pain, rigors irinotecan, ifosfamide, imatinib, vinore induration, infusion-site pain Investigations: weight loss regimen) was administered commonl Investigations: increased blood pressure Stevens-Johnson syndrome was reported as a serious adverse experience in a patient receiving aprepitantadjusted with to account for potential drug Skin andchemotherapy subcutaneousintissue disorders: erythema cancer another CINV study. In separate pharmacokinetic studies n Laboratory Adverse thrombophlebitis Experiences: Following are the percentage of patients receiving highly emetogenic chemotherapy was observed when EMEND (125-mg Vascular disorders: (predominantly infusion-site thrombophlebitis) in Cycle 1 withAngioedema laboratory adverse experiences incidence of ≥3% for the in aprepitant (n=544) Due to the small number of patients in Other Studies: and urticaria were reported reported atasanserious adverse reactions a patientregimen receiving and standard (n=550), respectively: or ifosfamide, particular caution and c aprepitant in atherapy non-CINV/non-PONV study. Proteinuria: 6.8, 5.3 agents metabolized pr Postmarketing Experience: The following adverse reactions have been identified during postapproval chemotherapy use of ALT increased: 6.0, 4.3 Coadministration With Warfarin (a fosaprepitant and aprepitant. Because these reactions are reported voluntarily from a population of uncertain a clinically significant decrease in in Bloodit urea 3.5 estimate their frequency or establish a causal relationship to thein drug. size, is notnitrogen always increased: possible to4.7, reliably warfarin therapy, the INR should be c Serum creatinine increased: 3.7, 4.3 Skin and subcutaneous tissue disorders: pruritus, rash, urticaria, rarely Stevens-Johnson syndrome/toxic initiation of the 3-day regimen of EME epidermal necrolysis AST increased: 3.0, 1.3 40-mg dose of EMEND for prevention The following additional laboratory adverse experiences (incidence >0.5% andreactions greater than standard therapy), Immune system disorders: hypersensitivity reactions including anaphylactic Coadministration With Hormonal C regardless of causality, were reported in patients treated with the aprepitant regimen: alkaline phosphatase DRUG INTERACTIONS contraceptives during and for 28 days increased, hyperglycemia, hyponatremia, leukocytes increased, erythrocyturia, leukocyturia. methods Drug interactions following administration of fosaprepitant are likely to occur with drugs that interact with oral of contraception should be u The adverse-experience profiles in the Multiple-Cycle extensions of HEC and MEC studies for up to 6 cycles of [see Drug Interactions]. EMEND aprepitant. chemotherapy were generally similar to that observed in Cycle 1. Aprepitant is a substrate, a moderate inhibitor, and an inducer of CYP3A4 when administered as a 3-dayPatients With Severe Hepatic Impa Postoperative Nausea and Vomiting: In well-controlled clinical studies in patients receiving general anesthesia, 564impairment (Child-Pugh score hepatic antiemetic dosing regimen for CINV. Aprepitant is also an inducer of CYP2C9. patients were administered 40-mg aprepitant orally and 538 patients were administered 4-mg ondansetron IV. patients. in these Fosaprepitant 150 mg, given were as a single dose, is a weak inhibitor CYP3A4treated and does induce Clinical adverse experiences reported in approximately 60% ofofpatients withnot 40-mg aprepitant Chronic Continuous Use: Chronic c CYP3A4. Fosaprepitant and aprepitant are unlikely to interact with drugs thatIV. areFollowing substrates compared with approximately 64% of patients treated with 4-mg ondansetron arefor thethe percentage recommended because it has not bee P-glycoprotein transporter. of patients receiving general anesthesia with clinical adverse experiences reported at an incidence of ≥3%chronic in the continuous use. The following information was derived dataand withondansetron oral aprepitant, 2 studies conducted with fosaprepitant combined studies for aprepitant 40 mg from (n=564) (n=538), respectively: ADVERSE REACTIONS and oral midazolam, and 1 urinary study conducted with 2.3, fosaprepitant and dexamethasone. Infections and infestations: tract infection: 3.2 The overall safety of aprepitant was e Effect of Fosaprepitant/Aprepitant on the Pharmacokinetics of Other Agents: CYP3A4 Substrates: Blood and lymphatic system disorders: anemia: 3.0, 4.3 Because clinical trials are conducted Aprepitant, a moderate inhibitor CYP3A4, and fosaprepitant 150 mg, as a weak inhibitor of CYP3A4, can Psychiatric as disorders: insomnia: 2.1,of3.3 trials of a drug cannot be directly com increase plasma concentrations of concomitantly coadministered oral medications that are metabolized through observed in clinical practice. Nervous system disorders: headache: 5.0, 6.5 CYP3A4 [see Contraindications]. Clinical Trials Experience: Chemoth Cardiac disorders: bradycardia: 4.4, 3.9 5-HT3 antagonists: In clinical drug interaction studies, aprepitant did not have clinically important effects on the Vascular disorders:ofhypotension: 4.6; hypertension: 2.1, 3.2 (the active metabolite of dolasetron).well-controlled clinical trials in patient pharmacokinetics ondansetron,5.7, granisetron, or hydrodolasetron with aprepitant during Cycle 1 of chem Gastrointestinal disorders: nausea: 8.5, 8.6; constipation: 8.5, 7.6; flatulence: 4.1, 5.8; vomiting 2.5, 3.9 Corticosteroids: Dexamethasone: Fosaprepitant 150 mg administered as a single intravenous dose on Day 1 to 6 cycles of chemotherapy. EM for up Skin and subcutaneous disorders: pruritus: 7.6, 8.4as a single 8-mg oral dose on Days 1, 2, and 3, by increased the AUC0–24hr oftissue dexamethasone, administered In Cycle 1, clinical adverse experience General disorders andon general site dexamethasone conditions: pyrexia: 5.9, approximately 2-fold Days administration 1 and 2. The oral dose on10.6 Days 1 and 2 should be reduced by compared with approximatel regimen approximately 50% whenclinical coadministered with fosaprepitant mg I.V. Day 1.than ondansetron), regardless The following additional adverse experiences (incidence150 >0.5% andongreater of patients receiving highly emetogen of oral causality, were reported aprepitant: incidence of ≥3% for the aprepitant re An aprepitant regimen in of patients 125 mg treated on Daywith 1 and 80 mg/day on Days 2 through 5, coadministered with 20-mg oraland dexamethasone on Day 1 andinfection 8-mg oral dexamethasone on Days 2 through 5, increased theBody as a whole/Site unspecified: ast Infections infestations: postoperative AUC of dexamethasone 2.2-fold hypokalemia, on Days 1 andhypovolemia 5. The oral dexamethasone doses should be reducedpain: by 4.6, 3.3; fever: 2.9, 3.5; mucou Metabolism and nutritionbydisorders: approximately 50% when coadministered with a regimen of fosaprepitant 115 mg followed by aprepitant. Digestive system: nausea: 12.7, 11.8; Nervous system disorders: dizziness, hypoesthesia, syncope Methylprednisolone: An oral aprepitant regimen of 125 mg on Day 1 and 80 mg/day on Days 2 and 3 increased 5.3, 4.9; gastritis: 4.2, 3.1; epigastric Vascular disorders: hematoma the AUC of methylprednisolone by 1.34-fold on Day 1 and by 2.5-fold on Day 3, when methylprednisolone Eyes, ears, nose, and throat: tinnitus: Respiratory, thoracic, and mediastinal disorders: dyspnea, hypoxia, respiratory depression was coadministered intravenously as 125 mg on Day 1 and orally as 40 mg on Days 2 and 3. The intravenous Hemic and lymphatic system: neutrop Gastrointestinal disorders: abdominal pain, abdominal pain upper,25% dry and mouth, methylprednisolone dose should be reduced by approximately thedyspepsia oral methylprednisolone dose Metabolism and nutrition: anorexia: 10 Skin and subcutaneous tissue disorders: urticaria should be reduced by approximately 50% when coadministered with a regimen of fosaprepitant 115 mg Nervous system: headache: 8.5, 8.7; followed by aprepitant. General disorders and administrative site conditions: hypothermia, pain Investigations: blood pressure decreased Chemotherapeutic agents: Docetaxel: In a pharmacokinetic study, oral aprepitant (CINV regimen) did notRespiratory system: hiccups: 10.8, 5. In addition, isolated cases of serious a influence the pharmacokinetics of docetaxel [see Warnings and Precautions]. Injury, poisoning, and procedural complications: operative hemorrhage, wound dehiscence and perforating duodenal ulcer were r Vinorelbine: In aexperiences pharmacokinetic study, oral aprepitant regimen) notaprepitant influence40 themg pharmacokinetics Other adverse (incidence ≤0.5%) reported in(CINV patients treateddid with for postoperative Moderately Emetogenic Chemotherapy ofnausea vinorelbine to a clinically significant degree [see Warnings and Precautions]. and vomiting included: patients were treated with the aprepit Nervous system disorders: sensory disturbanceand dexamethasone were coadministered with an oral Oral contraceptives: When dysarthria, oral aprepitant, ondansetron, cycles of chemotherapy. In the combi contraceptive containing ethinyl estradiol and norethindrone, the trough concentrations of both ethinyl estradiol Eye disorders: miosis, visual acuity reduced reported in approximately 69% of pat and norethindrone were by as much aswheezing 64% for 3 weeks posttreatment. Respiratory, thoracic, andreduced mediastinal disorders: of patients treated with standard ther The coadministration of fosaprepitant orabnormal, aprepitantstomach may reduce the efficacy of hormonal contraceptivesIn the combined analysis of Cycle 1 d Gastrointestinal disorders: bowel sounds discomfort (these can include birth control pills, skin patches, implants, and certain IUDs) during and for 28 days after emetogenic There were no serious adverse drug-related experiences reported in the postoperative nausea and vomiting clinical chemotherapy studies wa administration of the last dose of fosaprepitant or aprepitant. Alternative or backup methods of contraception Following are the percentage of patie studies in patients taking 40-mg aprepitant. should be used during treatment with and for 1 month following the last dose of fosaprepitant or aprepitant. adverse experiences reported at an in Laboratory Adverse Experiences: One laboratory adverse experience, hemoglobin decreased (40-mg aprepitant (n=846), respectively: Midazolam: Interactions between aprepitant orincidence fosaprepitant are listed below 3.8%, ondansetron 4.2%), was reported at an ≥3%and in a coadministered patient receivingmidazolam general anesthesia. (increase is indicated as h, decrease as i, no change as 1 ): The following additional laboratory adverse experiences (incidence >0.5% and greater than ondansetron),Blood and lymphatic system disorders Fosaprepitant 150 mg onwere Dayreported 1, oral midazolam 2 mg onwith Days 1 and 4:40 AUC 1.8-fold on Day 1 and Metabolism and nutrition disorders: an h blood regardless of causality, in patients treated aprepitant mg: albumin decreased, AUC on Dayincreased, 4 1bilirubin blood blood glucose increased, blood potassium decreased, glucose urine present. Psychiatric disorders: insomnia: 2.6, 3 Fosaprepitant 100 mg onofDay 1, oral ALT midazolam mg: oral midazolam h 1.6-fold The adverse experience increased occurred2 with similar incidenceAUC in patients treated with aprepitant 40 mgsystem disorders: headache: Nervous (1.1%) as in patients treated with1 ondansetron 4 mg (1.0%). Oral aprepitant 125 mg on Day and 80 mg on Days 2 to 5, oral midazolam 2 mg SD on Days 1 and 5: Gastrointestinal oral disorders: constipatio midazolam AUCInhaddition, 2.3-fold2onserious Day 1adverse and h 3.3-fold on Day 5 reported in postoperative nausea and vomiting Other Studies: experiences were stomatitis: 3.1, 2.7 (PONV) clinical125 studies taking higher dose2ofand aprepitant: 1 case midazolam of constipation, 1 case ofSkin subileus. Oral aprepitant mg in onpatients Day 1 and 80 amg on Days 3, intravenous 2 mgand prior to 3-day and subcutaneous tissue disorde
INDICATIONS AND USAGE (aprepitant) capsules dimeglumine) for Injection EMEND® (fosaprepitant Prevention Chemotherapy-Induced regimen of of aprepitant and on Days 4, 8,Nausea and 15: and intravenous midazolam AUC h 25% on Day 4, AUC i 19% on were treated with oral doses ranging from 2.5 to 2000 mg/kg/day. The highest dose produced a systemic Vomiting (CINV): in combination with other General disorders and general administration site conditions: exposure fatigue: 15.4, 15.6;2.8 asthenia: 4.7, 4.6 Day 8, and AUC iEMEND, 4% on Day 15 of about to 3.6 times the human exposure at the recommended dose. Treatment with aprepitant antiemetic agents, is indicated for prevention of acute In a combined analysis of these 2 studies, isolated cases of serious adverse experiences were similar the mg/kg/day 2 produced skin fibrosarcomas at 125 andin500 doses in male mice. Carcinogenicity studies were not Oral aprepitant 125 mg, intravenous midazolam 2 mg given 1 hour after aprepitant: intravenous midazolam and delayed nausea and vomiting associated with treatment groups. conducted with fosaprepitant. AUC h 1.5-fold initial and repeat courses of highly emetogenic cancer Highly and Moderately Emetogenic Chemotherapy: The following additional adverse were experiences (incidence Aprepitant andclinical fosaprepitant not genotoxic in the Ames test, the human lymphoblastoid cell (TK6) A difference of(HEC), less than 2-foldhigh-dose increase cisplatin; of midazolam chemotherapy including and AUC was not considered clinically important. >0.5% and greater than standard therapy), regardless of causality, were reported treated with the break test, the Chinese hamster ovary (CHO) cell chromosome mutagenesis test, the inratpatients hepatocyte DNA strand for prevention of nausea and vomiting associated with The potential effects of increased plasma concentrations ofaprepitant midazolam or other regimen in benzodiazepines either HEC or MECmetabolized studies: aberration test and the mouse micronucleus test. ely emetogenic cancer chemotherapy (MEC). via CYP3A4 (alprazolam, triazolam) should be considered when coadministering these agents with fosaprepitant Infections and infestations: candidiasis, herpes simplex, lowerFosaprepitant, respiratory infection, oral candidiasis, pharyngitis,is rapidly converted to aprepitant. In the fertility studies when administered intravenously, or aprepitant. ea and Vomiting (PONV): EMEND is indicated for prevention of postoperative septic shock, upper respiratory infection, urinary tract infection conducted with fosaprepitant and aprepitant, the highest systemic exposures to aprepitant were obtained CYP2C9 Substrates (Warfarin, Tolbutamide): Warfarin: A single 125-mgbenign, dose ofmalignant, oral aprepitant was administered Neoplasms and unspecified (including cysts and polyps): malignant neoplasm, non–small-cell following oral administration of aprepitant. Oral aprepitant did not affect the fertility or general reproductive been studied for treatment of established nausea and vomiting. on Day 1 and 80 mg/day on Days 2 and 3 to healthy subjects who were stabilized on chronic warfarin therapy. lung carcinoma performance of male or female rats at doses up to the maximum feasible dose of 1000 mg/kg twice daily Although there was no effect of oral aprepitant on the plasma AUC of R(+) or S(–) warfarin determined on Day not recommended. (providing exposure in male rats lower than the exposure at the recommended human dose and exposure in Blood and lymphatic system disorders: anemia, febrile neutropenia, thrombocytopenia 3, there was a 34% decrease in S(–) warfarin trough concentration accompanied by a 14% decrease in the female rats at about 1.6 times the human exposure). and oral nutrition disorders: appetite on decreased, prothrombin time (reported as INR) 5 days after completionMetabolism of dosing with aprepitant. In patients chronic diabetes mellitus, hypokalemia s who are hypersensitive to any component of the product. PATIENT COUNSELING INFORMATION Psychiatric disorders: anxiety disorder, confusion, depression warfarin therapy, the prothrombin time (INR) should be closely monitored in the 2-week period, particularly at 7 r of cytochrome P450 isoenzyme 3A4 (CYP3A4). EMEND not be used to 10 days, following initiation of should fosaprepitant with each chemotherapy cycle. Patient Labeling]: Physicians should instruct their patients to read the patient package Nervous system: peripheral neuropathy, sensory neuropathy,[See tasteFDA-Approved disturbance, tremor ine, astemizole, or cisapride. Inhibition of CYP3A4 by aprepitant could result in insert before starting therapy with EMEND for Injection and to reread it each time the prescription is renewed. Tolbutamide: Oral aprepitant, when given as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, decreased the Eye disorders: conjunctivitis ese drugs, potentially causing serious or life-threatening reactions [see Drug AUC of tolbutamide by 23% on Day 4, 28% on Day 8, and 15% on Day 15, when a singleinfarction, dose of tolbutamide Patients should follow the physician’s instructions for the regimen of EMEND for Injection. Cardiac disorders: myocardial palpitations, tachycardia 500 mg was administered orally prior to the administration Vascular of the 3-day regimen oral aprepitant andflushing, on Days hot flush, Allergic reactions,hypotension which may be sudden and/or serious, and may include hives, rash, itching, redness of the disorders: deepofvenous thrombosis, hypertension, 4, 8, and 15. face/skin, may cause difficulty in breathing Respiratory, thoracic, and mediastinal disorders: cough, dyspnea, nasal and secretion, pharyngolaryngeal pain, or swallowing, have been reported. Physicians should instruct ose-dependent inhibitor of CYP3A4, should be used with caution in patients Effect of Other Agents on the Pharmacokinetics of Aprepitant: Aprepitant is a substrate CYP3A4; insufficiency,their to stop using EMEND and call their doctor right away if they experience an allergic reaction. In pneumonitis, pulmonary embolism,forrespiratory vocalpatients disturbance hat are primarily metabolized through CYP3A4. Moderate inhibition of CYP3A4 therefore, fosaprepitant or aprepitant with drugs that inhibit CYP3A4 activity may result addition, severe skin reactions may occur rarely. en, could result in elevated plasmacoadministration concentrations ofofthese concomitant Gastrointestinal disorders: abdominal pain upper, acid reflux, deglutition disorder, dry mouth, dysgeusia, dysphagia, in increased plasma concentrations of aprepitant. Consequently, concomitant administration of fosaprepitant Patients who develop an infusion-site reaction such as erythema, edema, pain, or thrombophlebitis should be eructation, flatulence, obstipation, salivation increased or aprepitant with strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, nefazodone, troleandomycin, instructed on how to care for the local reaction and when to seek further evaluation. e 40-mg dose of aprepitant is not expected to alter the plasma concentrations Skincaution. and subcutaneous tissue disorders: diaphoresis, pruritus, rash clarithromycin, ritonavir, nelfinavir) should be approached with Because moderate CYP3A4acne, inhibitors EMEND formuscular Injectionweakness, may interact with some drugs, primarily metabolized through CYP3A4 to a clinically significant degree. Musculoskeletal and connective tissue disorders: arthralgia, back pain, musculoskeletal pain,including chemotherapy; therefore, patients should (eg, diltiazem) result in a 2-fold increase in plasma concentrations of aprepitant, concomitant administration be advised to report to their doctor the use of any other prescription or nonprescription medication or tly with another CYP3A4should inhibitor, aprepitant plasma with concentrations myalgia also be approached caution. could be herbal products. omitantly with medications that induce CYP3A4 activity, aprepitant plasma Renal and urinary disorders: dysuria, renal Aprepitant is a substrate for CYP3A4; therefore, coadministration of fosaprepitant or aprepitant with insufficiency drugs d this may result in decreased efficacy of EMEND [see Drug Interactions]. Patients on chronic warfarin therapy should be instructed to have their clotting status closely monitored in the Reproductive systemmay and result breastindisorders: pain that strongly induce CYP3A4 activity (eg, rifampin, carbamazepine, phenytoin) reducedpelvic plasma 2-week period, particularly at 7 to 10 days, following initiation of fosaprepitant with each chemotherapy cycle. n to be metabolized by CYP3A4 include docetaxel, paclitaxel, etoposide, concentrations and decreased efficacy. General disorders and administrative site conditions: edema, malaise, pain, rigors elbine, vinblastine, and vincristine. In clinical studies, EMEND (125-mg/80-mg Administration of EMEND for Injection may reduce the efficacy of hormonal contraceptives. Patients should be Ketoconazole: When single of 125-mg dose ofwere oralnot aprepitant was administered Day 5 of a 10-day regimen Investigations: weighton loss ly with etoposide, vinorelbine, or paclitaxel. Thea doses these agents advised to use alternative or backup methods of contraception during treatment with and for 1 month following of 400 mg/day of ketoconazole, a strong CYP3A4 inhibitor, the AUC of aprepitant increased approximately 5-fold adverse experience in a patient receiving aprepitant with Stevens-Johnson syndrome was reported as a serious g interactions. the last dose of fosaprepitant or aprepitant. and the mean terminal half-life of aprepitant increased approximately 3-fold. Concomitant cancer chemotherapy in another administration CINV study. of no clinically significant change in docetaxel or vinorelbine pharmacokinetics fosaprepitant or aprepitant with strong CYP3A4 inhibitors should be approached cautiously. Laboratory Adverse Experiences: Following are the percentage patients information, receiving highly emetogenic Forofdetailed please read thechemotherapy Prescribing Information. g/80-mg regimen) was coadministered. Rifampin: a single 375-mg dose of vincristine, oral aprepitant was administered on Day 9adverse of a 14-day regimenreported of 600 at anRxincidence in Cycle 1 with laboratory experiences n clinical studies who received the When CYP3A4 substrates vinblastine, only of ≥3% for the aprepitant regimen (n=544) mg/dayinofpatients rifampin, a strong CYP3A4 inducer, decreased 11-fold and the and standard therapyapproximately (n=550), respectively: careful monitoring are advised receiving these agents or otherthe AUC of aprepitant meannot terminal decreased approximately 3-fold. Proteinuria: 6.8, 5.3 rimarily by CYP3A4 that were studiedhalf-life [see Drug Interactions]. CoadministrationofofEMEND fosaprepitant or aprepitant with drugs that CYP3A4 activity may result in reduced ALT induce increased: 6.0, 4.3 a CYP2C9 substrate): Coadministration with warfarin may result concentrations and decreased efficacy. nternational normalized plasma ratio (INR) of prothrombin time. In patients on chronic Blood urea nitrogen increased: 4.7, 3.5 closely monitored in the 2-week period, particularly Diltiazem: at 7 to 10 days, following Additional Interactions: In a study in 10 patients with creatinine mild to moderate hypertension, Serum increased: 3.7, 4.3 intravenous END with each chemotherapy cycle, or following administrationwith of adiltiazem single 120 mg 3 times daily resulted in a 1.5-fold increase of infusion of 100 mg of fosaprepitant Copyright © 2012 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. AST increased: 3.0, 1.3 n of postoperative nauseaaprepitant and vomiting Interactions]. AUC[see and Drug a 1.4-fold increase in diltiazem AUC. It also resulted in a small but clinically meaningful All rights reserved. ONCO-1029338-0014 The following additional laboratory adverse experiences (incidence >0.5% and greater than standard therapy), further maximum decrease diastolic pressure (mean [SD] of 24.3 [±10.2] mmHg with fosaprepitant vs Contraceptives: Upon coadministration with EMEND,inthe efficacyblood of hormonal regardless of causality, were reported in patients treated with the aprepitant regimen: alkaline phosphatase [±4.1]may mmHg without fosaprepitant) and resulted in a small further maximum decrease in systolic blood s following the last dose 15.6 of EMEND be reduced. Alternative or backup increased, hyperglycemia, hyponatremia, leukocytes increased, erythrocyturia, leukocyturia. used during treatment with EMEND(mean and for 1 month the lastwith dosefosaprepitant of pressure [SD] of 29.5following [±7.9] mmHg vs 23.8 [±4.8] mmHg without fosaprepitant), The adverse-experience profiles in the which may be clinically meaningful, but did not result in a clinically meaningful further change in Multiple-Cycle heart rate or extensions of HEC and MEC studies for up to 6 cycles of chemotherapy were generally similar to that observed in Cycle 1. PR interval beyond those data changes induced bysevere diltiazem alone. airment: There are no clinical or pharmacokinetic in patients with Postoperative Nausea and Vomiting: to In 230 well-controlled e >9). Therefore, cautionIn should be exercised when EMENDofisaprepitant administered the same study, administration once daily as a tablet formulation comparable mg of the clinical studies in patients receiving general anesthesia, 564 administered 40-mg aprepitant orally and 538 patients were administered 4-mg ondansetron IV. capsule formulation, with diltiazem 120 mg 3 times daily forpatients 5 days,were resulted in a 2-fold increase of aprepitant experiences weredid reported in approximately 60% of patients treated with 40-mg aprepitant and a simultaneous increase These adverse pharmacokinetic effects not result in continuous use of EMENDAUC for prevention of nausea 1.7-fold and vomiting is notof diltiazem AUC.Clinical compared with approximately 64% of patients treated with 4-mg ondansetron IV. Following are the percentage en studied and because clinically the drug interaction mayinchange duringrate, or blood pressure meaningfulprofile changes ECG, heart beyond those changes induced by diltiazem of patients receiving general anesthesia with clinical adverse experiences reported at an incidence of ≥3% in the alone. combined studies for aprepitant 40 mg (n=564) and ondansetron (n=538), respectively: Paroxetine: Coadministration of once-daily doses of aprepitant as a tablet formulation comparable to 85 mg Infections and resulted infestations: tractininfection: 2.3, 3.2 or 5300 170 mg of the capsule formulation, with paroxetine 20 mg once daily, in aurinary decrease AUC by apevaluated in approximately individuals. Blood andand lymphatic system disorders: anemia: 3.0, 4.3 by approximately 20% of both aprepitant paroxetine. proximately 25% and C max under widely varying conditions, adverse reaction rates observed in the clinical Psychiatric disorders: insomnia: 2.1, 3.3 mpared to rates in the clinical of another drug and may not reflect the rates USE trials IN SPECIFIC POPULATIONS Nervous system disorders: headache:with 5.0, 6.5 Pregnancy: Teratogenic effects: Pregnancy Category B: In the reproduction studies conducted Cardiac disorders:were bradycardia: 3.9 oral herapy-Induced Nausea and Vomiting: Highly Emetogenicthe Chemotherapy: In 2 exposures fosaprepitant and aprepitant, highest systemic to aprepitant obtained 4.4, following ts receiving highly emetogenic cancer chemotherapy, patients were treated administration of aprepitant.544 Reproduction studies performed in ratsdisorders: at oral doses of aprepitant of uphypertension: to Vascular hypotension: 5.7, 4.6; 2.1, 3.2 motherapy and 413 of these patients into(plasma the Multiple-Cycle 1000 mg/kgcontinued twice daily AUC0–24hr of extension 31.3 mcg•hr/mL, about 1.6 times the human exposure at constipation: the Gastrointestinal disorders: nausea: 8.5, 8.6; 8.5, 7.6; flatulence: 4.1, 5.8; vomiting 2.5, 3.9 MEND was given in combination with ondansetron and dexamethasone. recommended dose) and in rabbits at oral doses of up to 25 mg/kg/day (plasma AUC0–24hr of 26.9 mcg•hr/mL, Skin and subcutaneous tissue disorders: pruritus: 7.6, 8.4 es were reported in approximately patients withatthethe aprepitant about 1.4 69% timesofthe humantreated exposure recommended dose) revealed no evidence of impaired fertility disorders general administration ly 68% of patients treated therapy. are the percentage or with harmstandard to the fetus due Following to aprepitant. There are, however, General no adequate and and well-controlled studies in site conditions: pyrexia: 5.9, 10.6 additionalofclinical adverse experiences nic chemotherapy in Cyclepregnant 1 with clinical adverse experiences reported at an women. Because animal reproduction studies areThe not following always predictive human response, this drug(incidence >0.5% and greater than ondansetron), regardless egimen (n=544) and standard respectively: should therapy be used(n=550), during pregnancy only if clearly needed. of causality, were reported in patients treated with aprepitant: and infestations: postoperative infection thenia/fatigue: 17.8, 11.8; dizziness: 6.6, 4.4; dehydration: 5.9, 5.1;inabdominal Nursing Mothers: Aprepitant is excreted the milk of rats.Infections It is not known whether this drug is excreted in us membrane disorder: 2.6, 3.1 milk. Because many drugs are excreted in human milk Metabolism and nutrition disorders:for hypokalemia, hypovolemia human and because of the potential possible serious ; constipation: 10.3, 12.2; diarrhea: 10.3, 7.5; vomiting: 7.5, 7.6; adverse reactions in nursing infants fromheartburn: aprepitant and because the potential for dizziness, tumorigenicity shown forsyncope Nervousofsystem disorders: hypoesthesia, c discomfort: 4.0, 3.1 aprepitant in rodent carcinogenicity studies, a decision should be made whether to discontinue nursing or to Vascular disorders: hematoma discontinue the drug, taking into account the importance ofRespiratory, the drug tothoracic, the mother. 3.7, 3.8 and mediastinal disorders: dyspnea, hypoxia, respiratory depression Pediatric Use: Safety and effectiveness of EMEND for Injection in pediatricdisorders: patients have not been penia: 3.1, 2.9 Gastrointestinal abdominal pain,established. abdominal pain upper, dry mouth, dyspepsia 10.1, 9.5 Geriatric Use: In 2 well-controlled CINV clinical studies, of the of patients Skintotal and number subcutaneous tissue(N=544) disorders:treated urticaria with oral aprepitant, 31% were 65 and over, while 5% were 75 and over. No overall differences in safety or insomnia: 2.9, 3.1 General disorders and administrative site conditions: hypothermia, pain effectiveness were observed between these subjects and younger subjects. Greater sensitivity of some older .6 Investigations: blood pressure decreased individuals cannot be ruled out. Dosage adjustment in the elderly is not necessary. adverse experiences, regardless of causality, of bradycardia, disorientation, Injury, poisoning, and procedural complications: operative hemorrhage, wound dehiscence Patients With Severe Hepatic Impairment: There are no clinical or pharmacokinetic data in patients with reported in highly emetogenic CINV clinical studies. Other adverse experiences (incidence reported in patients treated with aprepitant 40 mg for postoperative severe hepatic impairment (Child-Pugh score >9). Therefore, caution should be exercised when ≤0.5%) fosaprepitant py: During Cycle 1 of 2 moderately emetogenic chemotherapy studies, 868 nausea and vomiting included: or aprepitant is administered in these patients. tant regimen and 686 of these patients continued into extensions for up to 4 Nervous system disorders: dysarthria, sensory disturbance OVERDOSAGE ined analysis of Cycle 1 data for these 2 studies, adverse experiences were Eye disorders: miosis, visual acuity reduced tients treated with the aprepitant regimen compared with approximately 72% There is no specific information on the treatment of overdosage with fosaprepitant or aprepitant. Respiratory, thoracic, and mediastinal disorders: wheezing rapy. In the event of overdose, fosaprepitant and/or oral aprepitant should be discontinued and general supportive Gastrointestinal disorders: bowel sounds abnormal, stomach discomfort data for these 2 studies, the adverse-experience profile in both moderately treatment and monitoring should be provided. Because of the antiemetic activity of aprepitant, drug-induced as generally comparableemesis to the highly emetogenic chemotherapy were no serious adverse drug-related experiences reported in the postoperative nausea and vomiting clinical may not be effective. Aprepitantstudies. cannot be removedThere by hemodialysis. ents receiving moderately emetogenic chemotherapy in Cycle 1 with clinical studies in patients taking both 40-mg aprepitant. 150 mg Thirteen patients in the randomized controlled trial of EMEND for Injection received fosaprepitant ncidence of ≥3% for the aprepitant regimen (n=868) and standard therapy Adverse Experiences: laboratory and at least one dose of oral aprepitant, 125 mg or 80 mg. Laboratory Three patients reported adverseOne reactions thatadverse were experience, hemoglobin decreased (40-mg aprepitant similar to those experienced by the total study population. 3.8%, ondansetron 4.2%), was reported at an incidence ≥3% in a patient receiving general anesthesia. s: neutropenia: 5.8, 5.6 The following additional laboratory adverse experiences (incidence >0.5% and greater than ondansetron), NONCLINICAL TOXICOLOGY norexia: 6.2, 7.2 regardless of causality, were reported in patients treated with aprepitant 40 mg: blood albumin decreased, Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies were conducted in blood bilirubin increased, blood glucose increased, blood potassium decreased, glucose urine present. 3.7 Sprague-Dawley rats and in CD-1 mice for 2 years. In the rat carcinogenicity studies, animals were treated The adverse experience of increased ALT occurred with similar incidence in patients treated with aprepitant 40 mg : 13.2, 14.3; dizziness: 2.8, 3.4 with oral doses ranging from 0.05 to 1000 mg/kg twice daily. The highest dose produced a systemic exposure (1.1%) as in patients treated with ondansetron 4 mg (1.0%). on: 10.3, 15.5; diarrhea:to7.6, 8.7; dyspepsia: nausea: 5.8, 5.1; aprepitant (plasma5.8, AUC3.8; 0–24hr) of 0.7 to 1.6 times the human exposure (AUC0–24hr=19.6 mcg•hr/mL) at the Other serious adverse were reported in postoperative nausea and vomiting recommended dose of 125 mg/day. Treatment with aprepitant at Studies: doses ofIn5addition, to 1000 2mg/kg twice dailyexperiences caused (PONV) studiesininmale patients a higher ers: alopecia: 12.4, 11.9 an increase in the incidences of thyroid follicular cell adenomas andclinical carcinomas rats.taking In female rats,dose it of aprepitant: 1 case of constipation, and 1 case of subileus.
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
For appropriate patients receiving highly emetogenic chemotherapy who are at risk of chemotherapy-induced nausea and vomiting (CINV)
PREVENTION BEGINS WHERE TRIPLE THERAPY STARTS On Cycle 1, Day 1, start with Triple Therapy—EMEND® (fosaprepitant dimeglumine) for Injection, a 5-HT3 antagonist, and a corticosteroid—for first-line prevention of CINV. EMEND for Injection, 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. EMEND for Injection has not been studied for treatment of established nausea and vomiting. Chronic continuous administration of EMEND for Injection is not recommended.
Selected Important Safety Information • EMEND for Injection is contraindicated in patients who are hypersensitive to EMEND for Injection, aprepitant, polysorbate 80, or any other components of the product. Known hypersensitivity reactions include flushing, erythema, dyspnea, and anaphylactic reactions. • Aprepitant, when administered orally, is a moderate cytochrome P450 isoenzyme 3A4 (CYP3A4) inhibitor. Because fosaprepitant is rapidly converted to aprepitant, neither drug should be used concurrently with pimozide or cisapride. Inhibition of CYP3A4 by aprepitant could result in elevated plasma concentrations of these drugs, potentially causing serious or life-threatening reactions. • EMEND for Injection should be used with caution in patients receiving concomitant medications, including chemotherapy agents, that are primarily metabolized through CYP3A4. Inhibition of CYP3A4 by EMEND for Injection could result in elevated plasma concentrations of these concomitant medications. Conversely, when EMEND for Injection is used concomitantly with another CYP3A4 inhibitor, aprepitant plasma concentrations could be elevated. When EMEND for Injection 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® (aprepitant) 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 did not influence 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.
Selected Important Safety Information (continued) • There have been isolated reports of immediate hypersensitivity reactions including flushing, erythema, dyspnea, and anaphylaxis during infusion of fosaprepitant. These hypersensitivity reactions have generally responded to discontinuation of the infusion and administration of appropriate therapy. It is not recommended to reinitiate the infusion in patients who have experienced these symptoms during first-time use. • Coadministration of EMEND for Injection 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 for Injection with each chemotherapy cycle. • The efficacy of hormonal contraceptives may be reduced during coadministration with and for 28 days after the last dose of EMEND for Injection. Alternative or backup methods of contraception should be used during treatment with and for 1 month after the last dose of EMEND for Injection. • Chronic continuous use of EMEND for Injection 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® (aprepitant) in patients receiving highly emetogenic chemotherapy, the most common adverse events reported at a frequency greater than with standard therapy, and at an incidence of 1% or greater were hiccups (4.6% EMEND vs 2.9% standard therapy), asthenia/fatigue (2.9% vs 1.6%), increased ALT (2.8% vs 1.5%), increased AST (1.1% vs 0.9%), constipation (2.2% vs 2.0%), dyspepsia (1.5% vs 0.7%), diarrhea (1.1% vs 0.9%), headache (2.2% vs 1.8%), and anorexia (2.0% vs 0.5%). • In a clinical trial evaluating safety of the 1-day regimen of EMEND for Injection 150 mg compared with the 3-day regimen of EMEND, the safety profile was generally similar to that seen in prior highly emetogenic chemotherapy studies with aprepitant. However, infusion-site reactions occurred at a higher incidence in patients who received fosaprepitant (3.0%) than in those who received aprepitant (0.5%). Those infusion-site reactions included infusion-site erythema, infusion-site pruritus, infusion-site pain, infusion-site induration, and infusion-site thrombophlebitis. Please see the adjacent Brief Summary of the Prescribing Information.
An antiemetic regimen including
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February 2013 Vol 6 No 1