Journal of Hematology Oncology Pharmacy | December 2012 VOL 2, NO 4

DECEMBER 2012 Vol 2 I No 4

Journal OF

hematology Oncology ™ Pharmacy The Peer-Reviewed Forum for Oncology Pharmacy Practice

TM

ORIGINAL RESEARCH

Early Access to Investigational Agents through the National Cancer Institute’s Treatment Referral Center Tali M. Johnson, PharmD, BCOP; Matthew J. Boron, RPh

Evaluation of Pharmacists’ Interventions in Altering Prescribing Patterns for the Treatment of VTE in Patients with Cancer Vikki M. Steward, PharmD; Hind Hamid, PharmD; Kimberly Hooker, PharmD Review article

Chemotherapy-Induced Diarrhea: Options for Treatment and Prevention Elizabeth Koselke, PharmD; Shawna Kraft, PharmD, BCOP

From the Literature Concise Reviews of Studies Relevant to Hematology Oncology Pharmacy

By Robert J. Ignoffo, PharmD, FASHP, FCSHP, Section Editor

WWW.JHOPONLINE.COM

©2012 Green Hill Healthcare Communications, LLC

XGEVa®, tHe first AnD onLy rAnK LiGAnD inHibitor to preVent sres

inDiCAtion XGEVA® is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors.

XGEVA® is not indicated for the prevention of skeletalrelated events in patients with multiple myeloma.

importAnt sAfety informAtion Hypocalcemia • XGEVA® can cause severe hypocalcemia. Correct pre-existing hypocalcemia prior to XGEVA® treatment.

Monitor calcium levels and administer calcium, magnesium, and vitamin D as necessary. Monitor levels more frequently when XGEVA® is administered with other drugs that can also lower calcium levels.

In the postmarketing setting, severe hypocalcemia has been reported. Advise patients to contact a healthcare professional for symptoms of hypocalcemia.

• Based on clinical trials using a lower dose of denosumab, patients with a creatinine clearance less than 30 mL/min or receiving dialysis are at greater risk of severe hypocalcemia compared to patients with normal renal function. The risk of hypocalcemia at the recommended dosing schedule of 120 mg every 4 weeks has not been evaluated in patients with a creatinine clearance less than 30 mL/min or receiving dialysis.

osteonecrosis of the jaw (onj) • Osteonecrosis of the jaw (ONJ) can occur in patients receiving XGEVA®, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ. • Perform an oral examination and appropriate preventive dentistry prior to the initiation of XGEVA® and periodically during XGEVA® therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with XGEVA®.

• Patients who are suspected of having or who develop ONJ while on XGEVA® should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition.

pregnancy • Women should be advised not to become pregnant when taking XGEVA®. If the patient is pregnant or becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

©2012 Amgen inc. All rights reserved. 07/12 64002-r5-V1 G69091-r1-V1 www.XGeVA.com

superiority XGeVA® delayed the median time to first sre in a prespecified integrated analysis across 3 head-to-head studies vs zoledronic acid1

PERCENTAGE OF PATIENTS WITHOUT SRE

Time to first SRE, evaluated in more than 5,600 patients1,2 XGEVA® 120 mg Q4W (n = 2,862) zoledronic acid 4 mg Q4W (n = 2,861)

100 90

8.2 month delay in time to first SRE

80 70 60 50

Median time: 19.4 months

40 30

17%

Median time: 27.7 months

20 10

RISK REDUCTION

Hr = 0.83 (95% Ci: 0.76–0.90) P < 0.0001†

0 0

3

6

9

12

15

18

21

24

27

reduction in risk of first sre in 3 individual studies • Breast cancer: 18% vs zoledronic acid (P = 0.010, superiority)3 • Prostate cancer: 18% vs zoledronic acid (P = 0.008, superiority)3 • Other solid tumors* or multiple myeloma: 16% vs zoledronic acid (P < 0.001, noninferiority; P = 0.060, NS for superiority)3 – Subanalysis of other solid tumors*: 19% vs zoledronic acid (P = 0.034, superiority)2 – XGEVA® is not indicated for the prevention of SREs in patients with multiple myeloma *Excluding breast and prostate cancer. † P value for superiority.

30

STUDY MONTH Data from three international, phase 3, randomized, double-blind, double-dummy, active-controlled studies comparing XGEVA® with zoledronic acid for the prevention of skeletal-related events in patients with bone metastases from advanced breast cancer (N = 2,046), castration-resistant prostate cancer (N = 1,901), and solid tumors (other than breast or prostate) or multiple myeloma (N = 1,776). Zoledronic acid 4 mg was administered as an IV infusion over a minimum of 15 minutes, once every 4 weeks, in accordance with prescribing information. XGEVA® was administered subcutaneously 120 mg, once every 4 weeks. The primary endpoint was time to first SRE (noninferiority), and the secondary endpoints were time to first SRE (superiority) and time to first and subsequent SREs (superiority). SREs are defined as: radiation to bone, pathologic fracture, surgery to bone, and spinal cord compression.3

subCutAneous injeCtion

no Dose ADjustments

preCise ACtion

XGeVA® is not cleared by the kidneys and does not require dose adjustments, regardless of renal function3-8

XGeVA® acts precisely to bind XGeVA® is administered once to rAnK Ligand, a key mediator every 4 weeks as a single, 120 mg of bone resorption, to inhibit subcutaneous injection3 3 osteoclast activity

Administer calcium and vitamin D as necessary to prevent or treat hypocalcemia.3 Adverse reactions • The most common adverse reactions in patients receiving XGEVA® were fatigue/asthenia, hypophosphatemia, and nausea. The most common serious adverse reaction was dyspnea. The most common adverse reactions resulting in discontinuation were osteonecrosis and hypocalcemia. During post approval use, severe symptomatic hypocalcemia, including fatal cases has been identified.

please see brief summary of prescribing information on the following page.

referenCes: 1. Lipton A, Siena S, Rader M, et al. Comparison of denosumab versus zoledronic acid for treatment of bone metastases in advanced cancer patients: an integrated analysis of 3 pivotal trials. Ann Oncol. 2010;21(suppl 8):viii380.

Abstract 1249P and poster. 2. Data on file, Amgen. 3. XGEVA® (denosumab) prescribing information, Amgen. 4. Bekker PJ, Holloway DL, Rasmussen AS, et al.

A single-dose placebo-controlled study of AMG 162, a fully human monoclonal antibody to RANKL, in postmenopausal women. J Bone Miner Res. 2004;19:10591066. 5. Lewiecki EM. Denosumab: an investigational drug for the management of postmenopausal osteoporosis. Biologics. 2008;2:645-653. 6. Keizer RJ, Huitema ADR, Schellens JHM, Beijnen JH. Clinical pharmacokinetics of therapeutic monoclonal antibodies. Clin Pharmacokinet. 2010;49:493-507. 7. Mould DR, Green B. Pharmacokinetics and pharmacodynamics of monoclonal antibodies: concepts and lessons for drug development. BioDrugs. 2010;24:23-39. 8. Sutjandra L, Rodriguez RD, Doshi S, et al. Population pharmacokinetic meta-analysis of denosumab in healthy subjects and postmenopausal women with osteopenia or osteoporosis.

Clin Pharmacokinet. 2011;50:793-807.

S:6.875” Table 1. Per-patient Incidence of Selecteda Adverse Reactions of Any Animal Data: The effects of denosumab on prenatal development have been studied in both cynomolgus monkeys and genetically engineered mice in Severity (Trials 1, 2, and 3) which RANK ligand (RANKL) expression was turned off by gene removal Xgeva Zoledronic Acid (a “knockout mouse”). In cynomolgus monkeys dosed subcutaneously with Body System n = 2841 n = 2836 denosumab throughout pregnancy at a pharmacologically active dose, there % % was increased fetal loss during gestation, stillbirths, and postnatal mortality.

Other findings in offspring included absence of axillary, inguinal, mandibular, GASTROINTESTINAL and mesenteric lymph nodes; abnormal bone growth, reduced bone Nausea 31 32 strength, reduced hematopoiesis, dental dysplasia and tooth malalignment; and decreased neonatal growth. At birth out to one month of age, infants Diarrhea 20 19 had measurable blood levels of denosumab (22-621% of maternal levels).

GENERAL Following a recovery period from birth out to 6 months of age, the effects on bone quality and strength returned to normal; there were no adverse effects on Fatigue/ Asthenia 45 46 tooth eruption, though dental dysplasia was still apparent; axillary and inguinal INVESTIGATIONS lymph nodes remained absent, while mandibular and mesenteric lymph nodes were present, though small; and minimal to moderate mineralization in Hypocalcemiab 18 9 b multiple tissues was seen in one recovery animal. There was no evidence of Hypophosphatemia 32 20 maternal harm prior to labor; adverse maternal effects occurred infrequently during labor. Maternal mammary gland development was normal. There was NEUROLOGICAL no fetal NOAEL (no observable adverse effect level) established for this study Headache 13 14 because only one dose of 50 mg/kg was evaluated. In RANKL knockout mice, absence of RANKL (the target of denosumab) also caused fetal lymph node RESPIRATORY agenesis and led to postnatal impairment of dentition and bone growth.

Dyspnea 21 18 Pregnant RANKL knockout mice showed altered maturation of the maternal Cough 15 15 mammary gland, leading to impaired lactation (see Use in Nursing Mothers and Nonclinical Toxicology [13.2] in full Prescribing Information). a Adverse reactions reported in at least 10% of patients receiving Xgeva in Nursing Mothers. It is not known whether Xgeva is excreted into human milk.

Trials 1, 2, and 3, and meeting one of the following criteria: Measurable concentrations of denosumab were present in the maternal milk • At least 1% greater incidence in Xgeva-treated patients, or of cynomolgus monkeys up to 1 month after the last dose of denosumab • Between-group difference (either direction) of less than 1% and more (≤ 0.5% milk:serum ratio). Because many drugs are excreted in human milk than 5% greater incidence in patients treated with zoledronic acid and because of the potential for serious adverse reactions in nursing infants compared to placebo (US Prescribing Information for zoledronic acid) from Xgeva, a decision should be made whether to discontinue nursing or b Laboratory-derived and below the central laboratory lower limit of discontinue the drug, taking into account the importance of the drug to the normal [8.3 – 8.5 mg/dL (2.075 – 2.125 mmol/L) for calcium and mother. Maternal exposure to Xgeva during pregnancy may impair mammary gland development and lactation based on animal studies in pregnant 2.2 – 2.8 mg/dL (0.71 – 0.9 mmol/L) for phosphorus] mice lacking the RANK/RANKL signaling pathway that have shown altered Severe Mineral/Electrolyte Abnormalities maturation of the maternal mammary gland, leading to impaired lactation • Severe hypocalcemia (corrected serum calcium less than 7 mg/dL or less postpartum. However, in cynomolgus monkeys treated with denosumab than 1.75 mmol/L) occurred in 3.1% of patients treated with Xgeva and throughout pregnancy, maternal mammary gland development was normal, 1.3% of patients treated with zoledronic acid. Of patients who experienced with no impaired lactation. Mammary gland histopathology at 6 months of severe hypocalcemia, 33% experienced 2 or more episodes of severe age was normal in female offspring exposed to denosumab in utero; however, hypocalcemia and 16% experienced 3 or more episodes (see Warnings and development and lactation have not been fully evaluated (see Nonclinical Precautions and Use in Specific Populations).

Toxicology [13.2] in Full Prescribing Information).

• Severe hypophosphatemia (serum phosphorus less than 2 mg/dL or less Pediatric Use. Xgeva is not recommended in pediatric patients. The safety than 0.6 mmol/L) occurred in 15.4% of patients treated with Xgeva and and effectiveness of Xgeva in pediatric patients have not been established.

7.4% of patients treated with zoledronic acid.

Treatment with Xgeva may impair bone growth in children with open growth plates and may inhibit eruption of dentition. In neonatal rats, inhibition of RANKL Osteonecrosis of the Jaw In the primary treatment phases of Trials 1, 2, and 3, ONJ was confirmed in (the target of Xgeva therapy) with a construct of osteoprotegerin bound to Fc (OPG-Fc) at doses ≤ 10 mg/kg was associated with inhibition of bone growth 1.8% of patients in the Xgeva group and 1.3% of patients in the zoledronic acid group (see Warnings and Precautions). When events occurring during and tooth eruption. Adolescent primates treated with denosumab at doses an extended treatment phase of approximately 4 months in each trial are 5 and 25 times (10 and 50 mg/kg dose) higher than the recommended human included, the incidence of confirmed ONJ was 2.2% in patients who received dose of 120 mg administered once every 4 weeks, based on body weight (mg/kg), had abnormal growth plates, considered to be consistent with the Xgeva. The median time to ONJ was 14 months (range: 4 – 25). pharmacological activity of denosumab. Cynomolgus monkeys exposed in utero Postmarketing Experience. Because postmarketing reactions are to denosumab exhibited bone abnormalities, reduced hematopoiesis, tooth reported voluntarily from a population of uncertain size, it is not always malalignment, decreased neonatal growth, and an absence of axillary, inguinal, possible to reliably estimate their frequency or establish a causal mandibular, and mesenteric lymph nodes. Some bone abnormalities recovered relationship to drug exposure. once exposure was ceased following birth; however, axillary and inguinal lymph The following adverse reactions have been identified during post approval nodes remained absent 6 months post-birth (see Use in Pregnancy). use of Xgeva: Geriatric Use. Of patients who received Xgeva in Trials 1, 2, and 3, 1260 • Hypocalcemia: Severe symptomatic hypocalcemia, including fatal cases. (44%) were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients.

Immunogenicity. As with all therapeutic proteins, there is potential for immunogenicity. Using an electrochemiluminescent bridging immunoassay, Renal Impairment. In a trial of 55 patients without cancer and with varying less than 1% (7/2758) of patients with osseous metastases treated with degrees of renal function who received a single dose of 60 mg denosumab, denosumab doses ranging from 30 – 180 mg every 4 weeks or every 12 weeks patients with a creatinine clearance of less than 30 mL/min or receiving for up to 3 years tested positive for binding antibodies. No patient with positive dialysis were at greater risk of severe hypocalcemia with denosumab binding antibodies tested positive for neutralizing antibodies as assessed using compared to patients with normal renal function. The risk of hypocalcemia at a chemiluminescent cell-based in vitro biological assay. There was no evidence the recommended dosing schedule of 120 mg every 4 weeks has not been of altered pharmacokinetic profile, toxicity profile, or clinical response associated evaluated in patients with a creatinine clearance of less than 30 mL/min or with binding antibody development. The incidence of antibody formation is receiving dialysis (see Warnings and Precautions, Adverse Reactions, and highly dependent on the sensitivity and specificity of the assay. Additionally, Clinical Pharmacology [12.3] in full Prescribing Information). the observed incidence of a positive antibody (including neutralizing antibody) OVERDOSAGE: There is no experience with overdosage of Xgeva. test result may be influenced by several factors, including assay methodology, HOW SUPPLIED/STORAGE AND HANDLING: Xgeva is supplied in a sample handling, timing of sample collection, concomitant medications, and single-use vial. Store Xgeva in a refrigerator at 2°C to 8°C (36°F to 46°F) underlying disease. For these reasons, comparison of antibodies to denosumab in the original carton. Do not freeze. Once removed from the refrigerator, with the incidence of antibodies to other products may be misleading.

Xgeva must not be exposed to temperatures above 25°C/77°F or direct DRUG INTERACTIONS: No formal drug-drug interaction trials have been light and must be used within 14 days. Discard Xgeva if not used within conducted with Xgeva. In clinical trials in patients with breast cancer the 14 days. Do not use Xgeva after the expiry date printed on the label. metastatic to bone, Xgeva was administered in combination with standard Protect Xgeva from direct light and heat. Avoid vigorous shaking of Xgeva. anticancer treatment. Serum denosumab concentrations at 1 and 3 months PATIENT COUNSELING INFORMATION: and reductions in the bone turnover marker uNTx/Cr (urinary N-terminal Advise patients to contact a healthcare professional for any of the following: telopeptide corrected for creatinine) at 3 months were similar in patients with and without prior intravenous bisphosphonate therapy. There was no evidence • Symptoms of hypocalcemia, including paresthesias or muscle that various anticancer treatments affected denosumab systemic exposure and stiffness, twitching, spasms, or cramps (see Warnings and pharmacodynamic effect. Serum denosumab concentrations at 1 and 3 months Precautions and Adverse Reactions) were not altered by concomitant chemotherapy and/or hormone therapy. The • Symptoms of ONJ, including pain, numbness, swelling of or drainage median reduction in uNTx/Cr from baseline to month 3 was similar between from the jaw, mouth, or teeth (see Warnings and Precautions and patients receiving concomitant chemotherapy and/or hormone therapy Adverse Reactions) • Persistent pain or slow healing of the mouth or jaw after dental surgery (see Clinical Pharmacology [12.2] in full Prescribing Information). (see Warnings and Precautions) USE IN SPECIFIC POPULATIONS: • Pregnancy or nursing (see Warnings and Precautions and Use in Pregnancy: Category D [see Warnings and Precautions]. Risk Summary: Specific Populations) Xgeva can cause fetal harm when administered to a pregnant woman based on findings in animals. In utero denosumab exposure in cynomolgus Advise patients of the need for: monkeys resulted in increased fetal loss, stillbirths, and postnatal mortality, • Proper oral hygiene and routine dental care along with evidence of absent lymph nodes, abnormal bone growth and • Informing their dentist that they are receiving Xgeva decreased neonatal growth. There are no adequate and well-controlled • Avoiding invasive dental procedures during treatment with Xgeva studies with Xgeva in pregnant women. Women should be advised not Advise patients that denosumab is also marketed as Prolia®. Patients to become pregnant when taking Xgeva. If this drug is used during should inform their healthcare provider if they are taking Prolia. pregnancy, or if the patient becomes pregnant while taking this drug, the Amgen Manufacturing Limited, a subsidiary of Amgen Inc. patient should be apprised of the potential hazard to the fetus. Women One Amgen Center Drive who become pregnant during Xgeva treatment are encouraged to enroll Thousand Oaks, California 91320-1799 in Amgen’s Pregnancy Surveillance Program. Patients or their physicians ©2012 Amgen Inc. should call 1-800-77-AMGEN (1-800-772-6436) to enroll.

All rights reserved. Printed in USA. Clinical Considerations: The effects of Xgeva are likely to be greater during the second and third trimesters of pregnancy. Monoclonal antibodies are transported across the placenta in a linear fashion as pregnancy progresses, with the largest amount transferred during the third trimester. If the patient becomes pregnant during Xgeva therapy, consider the risks and benefits in 68257-R1-V1 continuing or discontinuing treatment with Xgeva.

DOUS2X0321_Dmab_ONC_ASize_BriefPI_Aug_12_r3_FSU.indd 1

6/25/12 12:07 PM

S:9.875”

Brief Summary: Consult package insert for complete Prescribing Information INDICATIONS AND USAGE: Bone Metastasis from Solid Tumors. Xgeva is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors.

Important Limitation of Use. Xgeva is not indicated for the prevention of skeletal-related events in patients with multiple myeloma (see Clinical Trials [14] in full Prescribing Information).

DOSAGE AND ADMINISTRATION: Recommended Dosage. The recommended dose of Xgeva is 120 mg administered as a subcutaneous injection every 4 weeks in the upper arm, upper thigh, or abdomen. Administer calcium and vitamin D as necessary to treat or prevent hypocalcemia (see Warnings and Precautions).

Preparation and Administration. Visually inspect Xgeva for particulate matter and discoloration prior to administration. Xgeva is a clear, colorless to pale yellow solution that may contain trace amounts of translucent to white proteinaceous particles. Do not use if the solution is discolored or cloudy or if the solution contains many particles or foreign particulate matter. Prior to administration, Xgeva may be removed from the refrigerator and brought to room temperature (up to 25°C/77°F) by standing in the original container. This generally takes 15 to 30 minutes. Do not warm Xgeva in any other way (see How Supplied/ Storage and Handling). Use a 27-gauge needle to withdraw and inject the entire contents of the vial. Do not re-enter the vial. Discard vial after single-use or entry.

CONTRAINDICATIONS: None.

WARNINGS AND PRECAUTIONS: Hypocalcemia. Xgeva can cause severe hypocalcemia. Correct pre-existing hypocalcemia prior to Xgeva treatment.

Monitor calcium levels and administer calcium, magnesium, and vitamin D as necessary. Monitor levels more frequently when Xgeva is administered with other drugs that can also lower calcium levels. In the postmarketing setting, severe symptomatic hypocalcemia has been reported (see Adverse Reactions). Advise patients to contact a healthcare professional for symptoms of hypocalcemia (see Adverse Reactions and Patient Counseling Information [17] in full Prescribing Information). Based on clinical trials using a lower dose of denosumab, patients with a creatinine clearance less than 30 mL/min or receiving dialysis are at greater risk of severe hypocalcemia compared to patients with normal renal function. In a trial of 55 patients, without cancer and with varying degrees of renal impairment, who received a single dose of 60 mg denosumab, 8 of 17 patients with a creatinine clearance less than 30 mL/min or receiving dialysis experienced corrected serum calcium levels less than 8.0 mg/dL as compared to 0 of 12 patients with normal renal function. The risk of hypocalcemia at the recommended dosing schedule of 120 mg every 4 weeks has not been evaluated in patients with a creatinine clearance less than 30 mL/min or receiving dialysis.

Osteonecrosis of the Jaw (ONJ). Osteonecrosis of the jaw (ONJ) can occur in patients receiving Xgeva, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ. In clinical trials, in patients with osseous metastasis, 2.2% of patients receiving Xgeva developed ONJ after a median exposure of 13 doses; of these patients, 79% had a history of tooth extraction, poor oral hygiene, or use of a dental appliance (see Adverse Reactions). In a clinical trial conducted in patients with prostate cancer at high risk for osseous metastasis, a condition for which denosumab is not approved, 5.4% of patients developed ONJ after a median exposure of 20 doses. Perform an oral examination and appropriate preventive dentistry prior to the initiation of Xgeva and periodically during Xgeva therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with Xgeva. Patients who are suspected of having or who develop ONJ while on Xgeva should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition.

PREGNANCY: Xgeva can cause fetal harm when administered to a pregnant woman. Based on findings in animals, Xgeva is expected to result in adverse reproductive effects. In utero denosumab exposure in cynomolgus monkeys resulted in increased fetal loss, stillbirths, and postnatal mortality, along with evidence of absent peripheral lymph nodes, abnormal bone growth and decreased neonatal growth (see Use in Specific Populations). There are no adequate and well controlled studies with Xgeva in pregnant women. Women should be advised not to become pregnant when taking Xgeva. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

ADVERSE REACTIONS: The following adverse reactions are discussed below and elsewhere in the labeling: • Hypocalcemia (see Warnings and Precautions) • Osteonecrosis of the Jaw (see Warnings and Precautions) The most common adverse reactions in patients receiving Xgeva (per-patient incidence greater than or equal to 25%) were fatigue/asthenia, hypophosphatemia, and nausea (see Table 1). The most common serious adverse reaction in patients receiving Xgeva was dyspnea. The most common adverse reactions resulting in discontinuation of Xgeva were osteonecrosis and hypocalcemia.

Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in practice. The safety of Xgeva was evaluated in three randomized, double-blind, double-dummy trials (see Clinical Trials [14] in full Prescribing Information) in which a total of 2841 patients with bone metastasis from prostate cancer, breast cancer, or other solid tumors, or lytic bony lesions from multiple myeloma received at least one dose of Xgeva. In Trials 1, 2, and 3, patients were randomized to receive either 120 mg of Xgeva every 4 weeks as a subcutaneous injection or 4 mg (dose adjusted for reduced renal function) of zoledronic acid every 4 weeks by intravenous (IV) infusion. Entry criteria included serum calcium (corrected) from 8 to 11.5 mg/dL (2 to 2.9 mmol/L) and creatinine clearance 30 mL/min or greater. Patients who had received IV bisphosphonates were excluded, as were patients with prior history of ONJ or osteomyelitis of the jaw, an active dental or jaw condition requiring oral surgery, non-healed dental/oral surgery, or any planned invasive dental procedure.

During the study, serum chemistries including calcium and phosphorus were monitored every 4 weeks. Calcium and vitamin D supplementation was recommended but not required. The median duration of exposure to Xgeva was 12 months (range: 0.1 – 41) and median duration on-study was 13 months (range: 0.1 – 41). Of patients who received Xgeva, 46% were female. Eightyfive percent were White, 5% Hispanic/Latino, 6% Asian, and 3% Black. The median age was 63 years (range: 18 – 93). Seventy-five percent of patients who received Xgeva received concomitant chemotherapy.

Editorial Board

Co-Editors-In-Chief Patrick J. Medina, PharmD, BCOP Associate Professor Department of Pharmacy University of Oklahoma College of Pharmacy Oklahoma City, OK

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

Section Editors Clinical Controversies

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

Original Research

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

Review Articles

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

Practical Issues in Pharmacy Management

Timothy G. Tyler, PharmD, FCSHP Director of Pharmacy Comprehensive Cancer Center Desert Regional Medical Center Palm Springs, CA

From the Literature

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

editors-At-Large Joseph Bubalo, PharmD, BCPS, BCOP Assistant Professor of Medicine Oncology Clinical Specialist and Oncology Lead OHSU Hospital and Clinics Portland, OR

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

Sandra Cuellar, PharmD, BCOP Director Oncology Specialty Residency University of Illinois at Chicago Medical Center Chicago, IL

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

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

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

Vol 2, No 4

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December 2012

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Journal of Hematology Oncology Pharmacy

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Whoâ&#x20AC;&#x2122;s Your

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Pharmacist Nominee?

The Oncology Pharmacist is pleased to announce the 2013 T.O.P. Pharmacist Award, sponsored by Teva Oncology.

This annual award recognizes an oncology pharmacist for outstanding contributions to oncology pharmacy practice, research, or education in 2012.

Nominate a pharmacist before December 31, 2012.

The 6 leading nominees will be 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, March 20â&#x20AC;&#x201C;23, 2013 in Los Angeles, CA, and profiled in the April 2013 issue of The Oncology Pharmacist.

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DECEMBER 2012

Volume 2, number 4

Journal OF

Publishing Staff

hematology Oncology Pharmacy™

Senior Vice President, Sales & Marketing Philip Pawelko phil@greenhillhc.com Publisher John W. Hennessy john@greenhillhc.com 732.992.1886 Editorial Director Dalia Buffery dalia@greenhillhc.com 732.992.1889

The Peer-Reviewed Forum for Oncology Pharmacy Practice

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Associate Editor Lara J. Lorton

Table of Contents

Editorial Assistant Jennifer Brandt jbrandt@the-lynx-group.com 732.992.1536

ORIGINAL RESEARCH

120 Early Access to Investigational Agents through the National Cancer

Institute’s Treatment Referral Center

Tali M. Johnson, PharmD, BCOP; Matthew J. Boron, RPh

Associate Publishers Joe Chanley joe@greenhillhc.com 732.992.1524 Cris Pires cris@engagehc.com 732.992.1896

132 Evaluation of Pharmacists’ Interventions in Altering Prescribing

Patterns for the Treatment of VTE in Patients with Cancer

Production Manager Stephanie Laudien

Vikki M. Steward, PharmD; Hind Hamid, PharmD; Kimberly Hooker, PharmD

Quality Control Director Barbara Marino

Review article

Business Manager Blanche Marchitto blanche@greenhillhc.com

143 Chemotherapy-Induced Diarrhea: Options for Treatment

and Prevention

From the Literature 153 Concise Reviews of Studies Relevant to Hematology

Oncology Pharmacy

Editorial Contact: Telephone: 732.992.1536 Fax: 732.656.7938 E-mail: JHOP@greenhillhc.com

Elizabeth Koselke, PharmD; Shawna Kraft, PharmD, BCOP

By Robert J. Ignoffo, PharmD, FASHP, FCSHP, Section Editor

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

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The ideas and opinions expressed in Journal of Hematology Oncology Pharmacy™ do not necessarily reflect those of the Editorial Board, the Editorial Director, or the Publisher. Publication of an advertisement or other product mention in Journal of Hematology Oncology Pharmacy™ should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturer with questions about the features or limitations of the products mentioned. Neither the Editorial Board nor the Publisher assumes any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this periodical. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosage, the method and duration of administration, or contraindications. It is the responsibility of the treating physician or other healthcare professional, relying on independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Every effort has been made to check generic and trade names, and to verify dosages. The ultimate responsibility, however, lies with the prescribing physician.

Please convey any errors to the Editorial Director.

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Early Access to Investigational Agents through the National Cancer Institute’s Treatment Referral Center Tali M. Johnson, PharmD, BCOP; Matthew J. Boron, RPh

Background: The National Cancer Institute’s (NCI) Division of Cancer Treatment and Diagnosis (DCTD), as an investigational new drug sponsor, may provide early access to investigational agents for treatment use. Until recently, the NCI had 3 protocol mechanisms for distributing investigational agents through the Treatment Referral Center (TRC), a service provided by the Pharmaceutical Management Branch (PMB) within the Cancer Therapy Evaluation Program of the NCI’s DCTD. The first mechanism is the Group C protocol, the second mechanism is the TRC protocol, and the third, and most common, mechanism is the Special Exception protocol.

Objectives: The purpose of this article is to describe and report on the activities of the TRC at the PMB since 2000 through the end of 2011.

Methods: Capital Technology Information Services performed PMB data mining for all treatment protocols from January 1, 2000, to December 31, 2011. Requests to PMB were sorted in spreadsheet format by disposition, either as referred, approved, or denied, and were counted by type, either as Group C, TRC, or Special Exception.

Results: More than 60% of requests were either referred or approved between 2000 and 2011. The peak number of requests was 1664 between 2000 and 2011 and occurred in 2003.

The peak was mostly a result of Special Exception requests; however, more than 400 TRC requests and 20 Group C requests were approved that year. The total number of requests dropped precipitously after 2003, and since 2008 have totaled fewer than 50 annually. All Group C and TRC protocols were completed by March 2006. The lowest number of treatment use requests occurred in 2011.

J Hematol Oncol Pharm.

Conclusion: Providing agents through the Special Exception mechanism is one way that prom2012;2(4):120-127. ising investigational new drug agents can get to patients with life-threatening illnesses. In general, www.JHOPonline.com Disclosures are at end of text the PMB’s TRC is a useful drug information resource for sites conducting clinical research in oncology, and it provides a valuable service to the oncology community.

A

lthough medical oncology has furthered effective cancer treatment for many decades, finding effective treatment for patients with advanced cancer is challenging. Millions of dollars support publicly funded cancer research every year, and patients expect that the latest cancer research will bring us one step closer to discovering a cure.

Instances often exist when patients have exhausted all standard therapies, and they are ineligible for any active research studies. The National Cancer Institute’s (NCI) Division of Cancer Treatment and Diagnosis (DCTD) has a long history of providing early access to investigational agents for patients with cancer for treatment or for

Dr Johnson is Senior Clinical Research Pharmacist and Mr Boron is Senior Clinical Research Pharmacist at the National Cancer Institute, National Institutes of Health, Rockville, MD.

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nonresearch use. DCTD, as an investigational new drug (IND) sponsor for dozens of agents, may approve early access to investigational agents that (1) show evidence of therapeutic activity in a specific cancer diagnosis and (2) have reasonably acceptable risks of toxicity.

Treatment use is frequently referred to as “compassionate use,” “expanded access,” “treatment IND,” or “single-patient IND,” and is regulated under 21 Code of Federal Regulations Part 312, subpart I.1,2 The NCI’s Treatment Referral Center (TRC), a service provided by the Pharmaceutical Management Branch (PMB) within the Cancer Therapy Evaluation Program DCTD, distributes investigational agents through multiple protocol mechanisms. Although the following mechanisms differ somewhat, all of them require adverse event reporting as a basic requirement of IND sponsorship.

One such mechanism was the Group C designation

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Table 1 Special Exception Procedures Checklist ****SPECIAL EXCEPTION PROTOCOL CHECKLIST**** Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy require the following steps to be completed as indicated: ****Statement of Investigator (FDA 1572), Supplemental Investigator Data Form (IDF), and Financial Disclosure Form (FDF): A physician must be registered with the National Cancer Institute as an investigator by having completed a “Statement of Investigator” (FDA Form 1572), IDF, and FDF. A copy of the most recent Curriculum Vitae is also needed. If the physician’s NCI investigator registration is not current and the Form 1572, IDF, and FDF have been faxed to the NCI, then they must be followed by the signed originals within 10 working days.****  Protocol: A brief protocol must be submitted, for each patient, which describes the treatment plan, expected adverse events, efficacy, and monitoring procedures. For your convenience we have devised a standard protocol form, which is included. After completion, the original must be returned to the address below within 10 working days of receipt of the investigational agent.  Institutional Review Board (IRB) Approval: You must obtain Institutional Review Board Approval before treating your patient and retain documentation of this approval in the patient’s medical records.  Informed Consent: You must obtain a written informed consent, which must be signed by the patient or their guardian prior to treatment. The informed consent does not need to be forwarded to NCI, but should be retained in the patient’s medical records. For certain agents we also provide a Model Informed Consent to be used as a guideline to writing your own.  Final Patient Report: Upon completion of therapy you must provide NCI a report of the treatment experience, which describes any adverse events and efficacy. We have enclosed The Report of the Independent Investigator form OR other Data Collection Forms, to be used. These forms can be returned to the NCI by fax at 301-402-4870 or mail.  NCI must also be notified, in writing, if the patient is NOT treated under the Special Exception Protocol, with a brief explanation.  Adverse Events: Adverse events should be graded by the Common Terminology Criteria for Adverse Events, and then reported to the NCI via Adverse Event Expedited Reporting System (AdEERS). The procedure for reporting the adverse event is dependent on the grading, the attribution, and if the event is expected or unexpected.

All life-threatening and fatal (grade 4 and 5) adverse events should be reported via AdEERS. If this grade 4 and 5 adverse event is not listed on the agent-specific toxicity list (ie, unexpected), then the investigator should also call the Investigational Drug Branch at 301-230-2330. Grade 2 and 3 unexpected events and any serious event leading to hospitalization should also be reported via AdEERS. Computer-based training and detailed instructions on reporting of adverse events can be found at http://ctep.cancer.gov, and then click on Reporting Guidelines. A summary is also included in this packet. Special Exception Protocol adverse event reporting guidelines should follow those developed for phase 2 clinical trials. Please call the AdEERS Help Line at 301-897-7497 for any problems while submitting adverse event reports.  When reporting in AdEERS use the Special Exception Protocol number as the patient ID in the patient information section.  All Serious Adverse Events must be reported within 10 days of occurrence  If the protocol does not appear in the AdEERS application contact the Treatment Referral Center at 301-496-5725 or AdEERSMD at 301-897-7497 or adeersmd@tech-res.com.  Investigational Drug Accountability: Investigational drug accountability records (enclosed) must be maintained and retained in your records. An authorized representative of the FDA, NCI, or drug manufacturer may inspect these records upon request.  Agent Reorders: Additional agent may be requested by completing the enclosed Clinical Drug Request Form and faxing it to 301-480-4612. You may only order more agent for the patient specifically named on this protocol. The patient’s first name and initial of last name should be indicated on the Clinical Drug Request. Telephone orders will not be accepted.

Failure to comply with any of the above procedures may result in suspension of an investigator’s status thus preventing or delaying future shipments of all investigational agents.

If there are any questions concerning this packet of information, contact the Special Exceptions Coordinator by phone at 301-496-5725, or by fax at 301-402-4870. If the Coordinator is unavailable, then contact the Special Exceptions Pharmacist at the same numbers.

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established in 1976 by the NCI, with US Food and Drug Administration (FDA) approval. The agents that were considered worthy of altering the standard of care, but were not yet available commercially, were handled through this program.1,3 Since 1975, the NCI has approved or distributed 21 agents under the Group C protocol mechanism.3,4 The Group C protocol mechanism is no longer active, and the last protocol was closed to accrual in 2005. Historically, Group C–designated agents: • Had reproducible efficacy in specific tumor types • Were considered likely to change standard of care practice • Could safely be administered by a properly trained healthcare provider • Did not require a specialized supportive care facility for treatment • Were likely to have a New Drug Application (NDA) or a Biologics License Application (BLA) approval in the near future.

A second mechanism is the TRC protocol. These protocols are written for medications that show efficacy in a certain disease and can be used in a large population with relative ease of use. Eligibility criteria and study objectives are written simply so as to capture patients who are not eligible for available clinical trials.3,4 TRC agents: • Have highly promising activity in high-priority tumor types • Have limited availability that necessitates an equitable distribution system • Have participation generally limited to NCI-designated cancer centers • May have an NDA or a BLA submitted, but time to approval and marketing may be delayed.

The most common treatment protocol, the Special Exception protocol, is approved on a case-by-case basis and is written for individual patients.3,4 Special Exception agents: • Vary from patient to patient • Have therapeutic activity in a specific cancer diagnosis • Must have a justification provided by the requesting investigator • Must have a well-established and acceptable safety profile.

The Cancer Therapy Evaluation Program has received thousands of treatment use requests from mostly domestic investigators, but also some from international investigators. The submitted requests are reviewed and are assigned a disposition within the Cancer Therapy Evaluation Program. Since 1994, 1 or more pharmacists within the PMB served as the point of contact for treatment use requests and as a general resource for the oncology research community. The pharmacist reviews the request and asks for additional information if needed. The pharmacist evaluates active studies that may be suitable based on the

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patient’s history. If the patient is eligible for 1 or more ongoing studies, the investigator is referred to the appropriate studies. If the patient is not eligible for any active studies and the request is justified, then the pharmacist collaborates with Cancer Therapy Evaluation Program senior investigators to assess eligibility for one of the treatment use mechanisms. If suitable, the Cancer Therapy Evaluation Program requests approval from the pharmaceutical collaborator. Once all parties have approved the request, the documentation is authorized, and arrangements are made to send the agent to the investigator so the patient can start treatment as soon as possible.

The Special Exception Checklist (Table 1) outlines the regulatory requirements that the investigator must meet to access a Special Exception protocol. Requests that do not meet the appropriate conditions that are described above are denied.

The purpose of this article is to describe and report on the activities of the TRC at the PMB since 2000 through the end of 2011. It is an update to an article published in 2000 by 4 pharmacists at the Cancer Therapy Evaluation Program.3 Our database query begins in January 2000.

The Shalabi and colleagues report ended with a total of 1015 requests for 1999.3

Methods Capital Technology Information Services performed the PMB data mining for all treatment protocols from January 1, 2000, to December 31, 2011. Requests to PMB were sorted in spreadsheet format by disposition, either as referred, approved, or denied, and were counted by type, either as Group C, TRC, or Special Exception; requests that were not categorized as such were not counted for the analysis, but counted instead as “other.” Request disposition was only prospectively recorded in the PMB database after 2002, when the database became fully functional.

Gaps in data from requests before 2002 were completed from internal annual reports that were manually collated at the end of each respective year. All discrepancies were reconciled between paper reports and the PMB database.

Results The results of the database query by request disposition from January 1, 2000, to December 31, 2011, are displayed by year in Figure 1. The total numbers of annual requests by type are displayed in Figure 2. The peak request total for this time period occurred in 2003, with 1664 requests. The peak was mostly a result of Special Exception requests; however, more than 400 TRC and 20 Group C requests were approved that year—more than any other single year in the analysis.

The total number of requests dropped precipitously after 2003, and since 2008 they have totaled fewer than

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Figure 1 Total Treatment Use Requests, by Disposition 1800

1664 1600

Approvals

1400

Treatment use requests, N

Denials Referrals

1200

1080

Total

1000

819 800

814

725

600

395

400

271 200

105

48

38

41

28

0

2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 Year

50 annually. Both bevacizumab and 5-azacitidine were FDA approved in 2004, accounting for 350 TRC protocol requests and 708 Special Exception protocol requests in 2003, respectively. All other Group C and TRC protocols were completed by March 2006 (Table 2). The lowest number of requests through the TRC occurred in 2011.

With the exception of 2011, the PMB either referred or approved more than two thirds of the requests annually between 2000 and 2011. Requests that were counted as “other” came from either the public or healthcare professionals outside of the NCI. Most inquiries involved agent availability and available clinical trials for specific diseases at the NCI. Table 3 provides examples of these inquiries from 2000 to 2011.

Discussion The PMB’s TRC has seen a significant change in the total number of treatment use requests over the past decade. With a peak of 1664 requests in 2003, the PMB currently only receives a few dozen requests for a variety of agents in clinical development. The days of enrolling hundreds of patients into an NCI-sponsored treatment use protocol are in the past, because the requests through

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the TRC to provide early access to cancer therapies has diminished.

Of note, the number of FDA-approved oncology agents increased annually, and there is certainly no shortage in the number of practice-changing therapies that emerge from clinical research. Why then the decrease in requests? Two phenomena are likely responsible for this change—a reduced NDA approval time and a smaller number of investigational agents that are either manufactured by the NCI or for which the NCI is the sole source.

The days of enrolling hundreds of patients into an NCI-sponsored treatment use protocol are in the past, because the requests through the TRC to provide early access to cancer therapies has diminished.

Before the Prescription Drug User Fee Act (PDUFA) of 1992, the median time from first NDA submission to FDA approval for new molecular entities and significant bio-

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Figure 2 Treatment Use Requests, by Type 1195

1200

1061 1000

Treatment use requests, N

SPEX 798

800

698

TRC 729

Group C

600

371

400

271 200

105 48

38

40

28

0

2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 Year

SPEX indicates Special Exception; TRC, Treatment Referral Center.

logic agents was 2.7 years between 1985 and 1989.5 Since 1992, the approval times gradually decreased, and the most recent 5-year increment (2005-2009) demonstrated a median approval time of 1.2 years.5 Antineoplastic agents in particular have a median approval time of 0.5 years for the same period, and have generally seen reduced times in overall drug development (IND filing to FDA approval) since 1980. This is despite more than a 4-fold increase in the number of antineoplastic agents that have been approved since 1980—11 from 1980 to 1989, 38 from 1990 to 1999, and 47 from 2000 to 2009.5 Based on the timing of the TRC and Group C protocols as shown in Table 2, all of these protocols were closed to accrual approximately the same time as the NDAs were approved. The TRC and Group C protocols successfully bridged the gap between positive clinical trial results and NDA approval, without interfering with marketing approval. Many patients benefited from practice-changing therapies that would not have been otherwise accessible to them.

Early drug development was the mainstay of the NCI’s Cancer Chemotherapy National Service Center, a congressionally mandated initiative that was started in 1955.

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Its mission was to screen and evaluate novel compounds for the treatment of cancer. By 1976, it was consolidated within the Developmental Therapeutics Program (DTP).6 Over the years, the DTP collected hundreds of thousands of compounds, some of which reached clinical development.6 The NCI was responsible for developing a number of agents with unique mechanisms of action, often with minimal industry collaboration.7 The NCI’s Frederick facility manufactured agents, and, in a few instances, the NCI was the only source of drug available for clinical research.

Although most of the agents that were developed at the NCI were not responsible for the bulk of the treatment requests, 5-azacitidine, developed at the NCI was provided to thousands of patients via the Group C and Special Exception protocols. Table 4 lists agents developed by the NCI that the PMB received Special Exception requests between 2000 and 2011. One of the agents listed in Table 4, chimeric 14.18, has been requested for treatment use from the PMB in the past year for pediatric patients with neuroblastoma. These requests accounted for more than 20% of requests in 2011.

In the past 25 years, pharmaceutical companies have stepped up investment in anticancer drug development,

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Table 2 TRC and Group C Protocols from 2000 to 2011 Closed to accrual date

Number of accrued patients

NDA approval date

3/10/2006

36

2005

Oxaliplatin (NSC 266046) in combination with 8/5/2004 5-FU and leucovorin (FOLFOX4) for patients who have not received prior chemotherapy for advanced CRC

37

2002

Bevacizumab

A multicenter study of the anti-VEGF monoclonal antibody bevacizumab plus 5-FU/leuco­ vorin in patients with metastatic CRC that has progressed after standard chemotherapy

2/27/2004

350

2004

5-azacitidine

Guidelines for the clinical use of 5-azacitidine (NSC 102816) in AML

6/29/2005

170

2004

Protocol number

IND agent

Protocol title

TRC-9701

Nelarabine (506U78)

CPD 506U78 (686673) in patients with relapsed or refractory T-cell ALL or T-cell lymphoblastic lymphoma

TRC-0201

Oxaliplatin

TRC-0301

I91-6 (Group C)

5-FU indicates 5-fluorouracil; ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; CPD, compound; CRC, colorectal cancer; IND, investigational new drug; NDA, New Drug Application; NSC, National Service Code; TRC, Treatment Referral Center; VEGF, vascular endothelial growth factor.

Table 3 Types of “Other” Inquiries Received at the Pharmaceutical Management Branch From healthcare professionals

From patients through Cancer Information Service

Miscellaneous

Availability of investigational agents Available disease-specific clinical in the United States and other trials countries

IRB requesting guidance for treatment use protocol review

Availability of commercial agents that were formerly investigational at the NCI

List of available agents in NCI development

IRB requesting package insert for former investigational agent

Availability of ancillary commercial agents for active studies

Patient financial assistance for commercial drugs

Private physician’s office requesting name of suitable IRB for cooperative group studies

Nonhuman use request of agents for animal or in vitro studies

Expediting clinical trial screening at NIH Clinical Center

Investigator requesting permission to publish case report using SPEX drug

Temperature excursion data for former investigational agents

Filling prescriptions in the United States from other countries where drug is not available

Local physician request for cooperative group study

Other formulations of active investigational agents IRB indicates Institutional Review Board; NCI, National Cancer Institute; NIH, National Institutes of Health; SPEX, Special Exception.

resulting in more industry-directed development.8 It is not unheard of for the pharmaceutical company to have a pending NDA approval for the agent of interest, while simultaneously developing it with the NCI, in less prevalent malignancies. As a result of increased industry focus on cancer drug development, the DCTD holds fewer active INDs. For example, the DCTD held INDs for 200

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agents in 1997 compared with approximately 90 agents today.7 As pharmaceutical industry drug development plans become more comprehensive, companies evaluate the need for their own early access programs, and this, along with the ability to prescribe commercially available agents off label, have led to a diminished need for NCI treatment use protocols.

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Table 4 National Cancer Institute Manufactured Drugs Drug name

Pharmaceutical collaborators

Outcome and year

17-AAG

Pharmacia

IND withdrawn 2012

5-azacitidine

Pharmion/Celgene

FDA approved 2004 (Vidaza-Pharmion/ Celgene)

9-Aminocamptothecin (9-AC)

Pharmacia

IND withdrawn 2005

BL22

IND withdrawn 2008

CAI

IND withdrawn 2010

Carboxypeptidase

Microbiological Research Establishment (CAMR)/Protherics

Chimeric 14.18

FDA approved 2012 (VoraxazeProtherics/BTG) NCI development ongoing (United Therapeutics, Inc)

COL-3

Collagenex Pharmaceuticals, Inc

IND withdrawn 2010

Depsipeptide (romidepsin)

Celgene

FDA approved 2009 (Istodax-Celgene)

Fenretinide

R.W. Johnson Pharmaceuticals

NCI development ongoing

Flavopiridol (Alvocidib)

NCI development ongoing

gp100:209-217(210M) peptide

NCI development ongoing

Halichondrin B analog (eribulin)

Eisai, Inc

FDA approved 2010 (Halaven-Eisai, Inc)

Homoharringtonine

IND withdrawn 2008

LMB-2

NCI development ongoing

MART-1:26-35(27L) peptide

IND withdrawn 2008

Nelarabine (506U78)

GlaxoSmithKline

FDA approved 2005 (ArranonGlaxoSmithKline)

O6-BG PANVAC

NCI development ongoing Therion

NCI development ongoing

Proteinase 3:PR1 peptide

IND withdrawn 2010

PS-341 (bortezomib)

Millennium

FDA approved 2003 (VelcadeMillennium)

rF-gp100P209 (recombinant fowlpox-gp100P209)

Therion

IND withdrawn 2012

Sodium phenylbutyrate

Elan Pharmaceutical Research Corporation/Virium Pharmaceuticals

IND withdrawn 2008

Suramin

Parke Davis and Company

IND withdrawn 2008

Thymidine XL119 (becatecarin, rebeccamycin analog)

IND withdrawn 2004 Exelixis/Bristol Myers Squibb

IND withdrawn 2008

FDA indicates US Food and Drug Administration; IND, investigational new drug; NCI, National Cancer Institute.

The PMB TRC pharmacist serves as a drug information resource for the cancer community inside and outside of the NCI. Not only is this pharmacist the point of contact for PMB-directed drug information questions, but also for relevant inquiries that come through the Cancer Information Service, the NCIâ&#x20AC;&#x2122;s

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community hotline. The types of questions have varied over the years, but they mostly pertain to agent or clinical trial availability.

Conclusions Although the activities of the TRC at the PMB have

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decreased over the past several years, the infrastructure at the DCTD is available to meet the demand for larger-scale, expanded-use protocols if necessary. The current trends in the pharmaceutical industry obviate a lot of the need at the present time, but future circumstances may change that as early drug development enters new frontiers.

The DCTD is the IND sponsor for more than 90 investigational agents, a number of which have unique mechanisms of action. As an IND sponsor, the DCTD has the privilege and the responsibility to further develop these agents, especially those that demonstrate positive clinical trial results. Providing agents through the Special Exception mechanism is one way that effective agents get to patients with life-threatening illnesses who may benefit from these agents. The PMB reviews requests serves as the liaison with the pharmaceutical collaborator and coordinates with other Cancer Therapy Evaluation Program branches and the requesting investigator. In general, the PMB’s TRC is a useful drug information resource for sites that are conducting clinical research in oncology, and it provides a valuable service to the oncology community.

Clinical pharmacists at sites have a role in the Special Exception process. They can help identify patients who are neither suitable for standard care treatment nor eligible for active clinical trials. As drug therapies grow more complex, clinical pharmacists can assist investigators who are navigating the details and determine the best options for a patient. In addition, pharmacists can be instrumental in preparing the Special Exception protocol for submission, obtaining Institutional Review Board

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approval, securing drug supply, monitoring toxicities, and ensuring patient follow-up.

Special Exception requests for DCTD-held IND agents are directed to the PMB at the Cancer Therapy Evaluation Program. See http://ctep.cancer.gov/branches/pmb/referral_ center.htm for current contact information. n

Acknowledgment The authors would like to thank Patricia R. Schettino, RPh, MS, for her writing assistance.

Author Disclosure Statement Dr Johnson reported no conflicts of interest. Mr Boron has a stock benefit at MedImmune/AstraZeneca through his spouse’s employment.

References

1. Wittes RE. Noninvestigational uses of investigational drugs: some implications of FDA’s revised regulations. J Natl Cancer Inst. 1988;80:301-304.

2. Food and Drug Administration, HHS. Expanded access to investigational drugs for treatment use. Final rule. Fed Regist. 2009;74:40900-40945.

3. Shalabi AM, High J, Edwards MS, Montello M. Obtaining investigational agents from the National Cancer Institute: when clinical trials are not an option.

Highlights Oncol Pract. 2000;18:8-14.

4. Montello MJ, Greenblatt JJ, Fallavollita A, Shoemaker D. Accessing investigational anticancer agents outside of clinical trials. Am J Health Syst Pharm.

1998;55:651-652, 660.

5. Kaitin KI, DiMasi JA. Pharmaceutical innovation in the 21st century: new drug approvals in the first decade, 2000-2009. Clin Pharmacol Ther. 2011;89:183-188.

6. Monga M, Sausville EA. Developmental therapeutics program at the NCI: molecular target and drug discovery process. Leukemia. 2002;16:520-526.

7. Christian MC, Pluda JM, Ho PT, et al. Promising new agents under development by the Division of Cancer Treatment, Diagnosis, and the centers of the National Cancer Institute. Semin Oncol. 1997;24:219-240.

8. Collins M. The NCI Developmental Therapeutics Program. Clin Adv Hematol Oncol. 2006;4:271-273.

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TREANDA速 (bendamustine HCI) for Injection is his chemo.

This is his therapy.

Single-agent TREANDA tripled median PFS* 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.

Survival distribution function

PROGRESSION-FREE SURVIVAL (PFS): CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) TREANDA (n=153)

1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1

Chlorambucil (n=148)

18 months median PFS

6 months median PFS

P<.0001

HR†=0.27 (95% CI‡: 0.17, 0.43)

0

5

10

15

20

25

30

35

40

45

Months *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) • TREANDA is administered with a convenient dosing schedule – The recommended dose for TREANDA is 100 mg/m2 administered intravenously over 30 minutes on Days 1 and 2 of a 28-day treatment cycle, up to 6 cycles – In the phase 3 trial, patients received chlorambucil at a dose of 0.8 mg/kg orally on Days 1 and 15 (n=148) of a 28-day treatment cycle, up to 6 cycles • In the pivotal phase 3 trial, the most common non-hematologic adverse reactions (frequency ≥15%) were pyrexia (24%), nausea (20%), and vomiting (16%) (n=153). The most common hematologic abnormalities (frequency ≥15%) were anemia (89%), thrombocytopenia (77%), neutropenia (75%), lymphopenia (68%), and leukopenia (61%) (n=150) 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 • 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

Discover the elements of efficacy and safety LEARN MORE AT WWW.TREANDA.COM Please see accompanying brief summary of full Prescribing Information.

©2012 Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd.

All rights reserved. TRE-2510b August 2012

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

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-2500 TRE-2511b (Label Code: 00016287.06) This brief summary is based on TRE-2527 TREANDAfull fullPrescribing PrescribingInformation.

Information.

TRE-006 TREANDA

April 2012 August

ORIGINAL RESEARCH

Impact of Pharmacists’ Interventions on Prescribing Patterns for the Treatment of VTE in Patients with Cancer Vikki M. Steward, PharmD; Hind Hamid, PharmD; Kimberly Hooker, PharmD

Background: Venous thromboembolism (VTE) is a common comorbidity and a significant complication among patients with cancer. Its management can be quite problematic for medical oncologists. Guidelines recommend low-molecular-weight heparin (LMWH) monotherapy for 6 months as the preferred treatment, and it is important for the prescribing patterns of medical oncologists to align with these recommendations to ensure optimal patient care.

Objectives: The main objectives of this study were to assess the medical oncologists’ prescribing patterns for VTE treatment among patients with cancer at DCH Regional Medical Center, to make clinical interventions in an effort to comply with the guideline recommendations, and to assess the impact of these clinical interventions.

Methods: A retrospective chart review of patients with cancer who were diagnosed with VTE between January 2010 and June 2010 was conducted to assess their prescribed treatment regimens. Pharmacists made clinical interventions consisting of education to healthcare providers, development of VTE treatment preprinted order forms, and direct recommendations to align prescribing patterns with the preferred guidelines’ recommendation. Thereafter, prospective data of medical oncologists’ prescribing patterns were collected during three 5-week segments (15 weeks).

Results: Thirty-nine of the 54 patients with cancer in the retrospective chart review met the inclusion criteria. Three (8%) patients were prescribed LMWH monotherapy for the treatment of VTE. After pharmacists’ educational interventions and collaboration with medical oncologists, 70% of patients who were assessed were prescribed LMWH monotherapy (P = .001) in accordance with the guidelines’ recommendation for VTE treatment. This desired prescribing pattern decreased to 59% in the absence of a pharmacist’s collaboration. Nevertheless, a significant J Hematol Oncol Pharm. difference (P <.05) was found for the prescribing of LMWH monotherapy by medical oncologists 2012;2(4):132-139. after pharmacists’ interventions compared with the initial review of such prescribing patterns. www.JHOPonline.com Disclosures are at end of text Conclusion: This study shows that although initially sporadically prescribed, LMWH monotherapy for VTE treatment in patients with cancer significantly increases after interventions by pharmacists.

V

enous thromboembolism (VTE) is a common comorbidity among patients with cancer. It is often one of the initial signs for the presence of malignancy, and its presence increases the complexity of patient care within this patient population. Studies have shown that 15% to 20% of all acute VTE cases are associated with malignancy, 2% to 5% of cases are diagnosed concurrently with cancer, and 5% to 10% of cases are diagnosed during a cancer follow-up visit.1 Therefore, VTE is a significant complication affecting

Dr Steward is Pharmacy Practice Resident, Dr Hamid is Oncology Pharmacy Clinician at the Cancer Center, and Dr Hooker is Clinical Pharmacy Manager, all at DCH Regional Medical Center, Tuscaloosa, AL.

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quality of life and patient prognosis. In fact, VTE is known to represent one of the leading causes of death in this patient population,2 and it is discovered at autopsy in at least 50% of patients with cancer.3,4 This percentage is thought to be underestimated; therefore, it is imperative to recognize this medical problem and to appropriately deploy effective treatment to reduce morbidity and mortality.

The management of VTE among patients with cancer can be problematic for medical oncologists because of the complexity of the cancer process, and because of patient-specific and treatment-related risk factors. Patients with cancer who are aged ≥65 years, are of African American ethnicity, are of female sex, and whose medical history includes other comorbid conditions, such as

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obesity, pulmonary, renal, and/or cardiac disease, are at increased risk for VTE.5,6 Chemotherapy or hormone therapy and indwelling central venous catheters, which are often used in the medical oncology setting, also present as clinical risk factors for developing VTE.7 Chemotherapy increases the risk of VTE and recurrent VTE by 6-fold and 2-fold, respectively.8 Specifically, the agents thalidomide and lenalidomide, which are frequently used for the treatment of multiple myeloma and myelodysplastic syndrome, are strongly associated with the risk of VTE.9-11 For patients receiving these agents, prophylactic anticoagulation is typically initiated to lower the incidence of VTE.7,12,13 Although the pathophysiology of thrombosis formation and blood coagulation in patients with cancer has been studied for many years, it remains poorly understood. Research suggests that the cause of thrombosis is associated with malignant cells that are potentially secreting procoagulants (cysteine protease that directly activates factor X) and are stimulating the immune system to secrete cytokines that increase coagulopathy.14 Endothelial cell injury and inflammation associated with malignancy can result in coagulation activation and elevated clotting factors.15 This may explain why patients with cancer exhibit a high rate of resistance to the oral anticoagulant warfarin. In addition, solid tumors compressing vessels can cause turbulent blood flow, which increases the risk of coagulation.14 The standard regimen for VTE treatment among the general medically ill patient population typically consists of unfractionated heparin, fondaparinux, or low-molecular-weight heparin (LMWH) for the initial 5 to 10 days, overlapping with warfarin to bridge to subsequent extended anticoagulant therapy (≥3 months).1,7,16 This regimen has been shown to be effective for most patients pending appropriate compliance to therapy. Therefore, it is logical to think of this approach as an appropriate option for a patient with cancer who is presenting with VTE. However, in the recently published American College of Chest Physicians (ACCP) Guidelines (9th edition), the ACCP suggests the use of LMWH extended anticoagulant therapy over vitamin K antagonist therapy as the preferred treatment of VTE in patients with cancer.17 LMWHs are favored over other treatment options, because they can conveniently be administered in an outpatient setting and are associated with a reduced risk of developing adverse effects, such as heparin-induced thrombocytopenia.1 Publication of the Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anti­ coagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) trial demonstrated evidence for LMWH superiority over warfarin without increasing the risk of bleeding.18

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Patients with cancer exhibit a high rate of resistance to warfarin, and there are other significant issues associated with the use of warfarin to treat patients with cancer. Variability in dietary intake, potential liver dysfunction, and chemotherapy-induced nausea and vomiting make it difficult to achieve the target international normalized ratio (INR) of 2.0 to 3.0.1,19 Anticoagulation with warfarin can also be hazardous because the chemotherapy regimens, as well as the supportive therapy, are more likely to have drug interactions with oral anticoagulants, thereby altering the dose requirement.19 Therefore, warfarin therapy requires more frequent monitoring than the guidelines’ recommended LMWH monotherapy. Invasive surgical procedures, concomitant radiation therapy, and metastases, particularly those to the brain, often lead to interruption in oral anticoagulation to avoid supratherapeutic INRs and potential hemorrhage.19,20 This interruption in oral anticoagulation therapy can, in turn, place the patient at significant risk for recurrent thrombosis.

Patients with cancer exhibit a high rate of resistance to warfarin, and there are other significant issues associated with the use of warfarin to treat patients with cancer.

Despite the known issues regarding VTE management in patients with cancer, we hypothesized that the prescribing patterns of the medical oncologists at DCH Regional Medical Center (RMC) do not correspond with preferred treatment guidelines for VTE, but instead mimic treatment options for acute VTE among the medically ill patient population. This study evaluated prescribing practices, while allowing the principal investigator the opportunity to make patient-specific recommendations and to provide education for all healthcare providers involved in the care of patients with cancer.

Methods This research was a single-center study conducted at DCH RMC, which is located in Tuscaloosa, AL, and is a community owned, not-for-profit hospital licensed for approximately 600 beds. It is the flagship hospital within the DCH Health System and a major referral center, serving 11 western Alabama counties. Oncology is an area of specialty provided at DCH Cancer Center, a hospital-based cancer center affiliated with M.D. Anderson Physicians Network. The research was approved by the DCH Health System Institutional Review Committee in December 2010. Throughout all parts of the study, 4 medical oncologists were staffed at the institution. The

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principal investigator was a postgraduate year 1 pharmacy practice resident.

Part 1 Part 1 of the study was a retrospective chart review.

Diagnosis-related group (DRG) codes were used to identify all patients with cancer between January 2010 and June 2010 who had a primary or secondary documented diagnosis of VTE. The documented VTE could be either a deep-vein thrombosis (DVT; DRG code 453.4) and/or a pulmonary embolism (PE; DRG code 415.19). Patients were excluded if they met any of the following criteria: age >18 years; diagnosis of benign tumors; diagnosis of myeloproliferative disorders, multiple myeloma, or myelodysplastic syndrome, as well as any other diagnosis for which thalidomide or lenalidomide was included within the chemotherapy regimen; and laboratory work performed at a facility other than DCH RMC. Data collection included patient demographics, cancer type, documented date of VTE event(s), number of VTE events during part 1 of the study, prescribed VTE treatment regimen, length of LMWH therapy (if available), and details regarding warfarin therapy if used within the VTE treatment regimen.

The primary objective of part 1 was to assess whether the prescribing patterns of the medical oncologists corresponded with the preferred guidelines for the treatment of VTE in patients with cancer. At the time the study was conducted, the preferred guidelines referred to the most current guidelines published by the American Society of Clinical Oncology, the ACCP, and the National Comprehensive Cancer Network, all of which recommend the use of LMWH monotherapy for 6 months.3,21,22 Concomitant use of warfarin within the majority of VTE treatment regimens was anticipated. Therefore, the secondary objective was to evaluate the frequency of optimal INRs among the physician-managed oral anticoagulation therapy. INR collection began 5 to 7 days after initiation of warfarin therapy or once the INR was ≥2.0, and all subsequent INRs were collected for 6 months.

The INRs were reviewed and classified as therapeutic (target range, 2.0-3.0) or nontherapeutic (<2.0 or >3.0).

Patients receiving thalidomide or lenalidomide as a part of their chemotherapy regimen were excluded, because they were likely receiving prophylactic anticoagulation.

Parts 2 and 3 In parts 2 and 3 of the study, the principal investigator made clinical recommendations for LMWH monotherapy in an effort to establish the evidence-based guidelines’ recommendation as the standard of care at the institution. Specifically, in part 2, both inpatient and outpatient oncology VTE treatment preprinted order forms

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were developed and approved by the medical oncologists and the DCH Forms Committee. Each form included an indication for LMWH use, dosing information (including dosage adjustments), duration of therapy, monitoring parameters, orders for patient self-administration education, orders for case management and/or medication assistance involvement, and scheduled follow-up visits. The primary objective of part 2 was to help make prescribing LMWH monotherapy more convenient for medical oncologists.

Part 3 of the study consisted of the principal investigator providing an educational series of presentations and newsletter articles to all healthcare providers involved in the care of patients with cancer. The medical oncologists were presented with the results of the part 1 retrospective chart review revealing their prescribing patterns and a detailed explanation of the evidence-based literature supporting the preferred recommendation for the treatment of VTE in patients with cancer. The pharmacy and nursing staffs were presented with an overview of VTE among patients with cancer, the preferred treatment recommendation and suggestions on how to identify patients at risk and how to intervene to optimize patient care, and, finally, they were introduced to the inpatient and outpatient VTE treatment preprinted order forms.

Pharmacists were instructed to determine whether orders and prescriptions for LMWH were for treatment or for prophylaxis therapy, and to make clinical interventions to ensure optimal dosing and use of the preprinted order forms when appropriate. Furthermore, education involved composing an article for Chemo Savvy, the newsletter for DCH Cancer Center Physicians, as well as another article for P&T News, the hospital’s Pharmacy and Therapeutics Committee newsletter. The primary objective of part 3 was to increase the multidisciplinary team’s awareness of the evidence-based guideline recommendation for VTE treatment among patients with cancer.

Part 4 The final part of the study, part 4, was a 15-week prospective period divided into three 5-week segments. The initial 5-week segment consisted of an evaluation of the medical oncologists’ prescribing patterns for the post–educational intervention-only period. During this segment, any patient with cancer and suspected VTE was reported to the principal investigator by the oncology nursing staff.

The principal investigator would then follow the patient to confirm the VTE diagnosis and to collect the treatment regimen that was prescribed by the medical oncologist.

Pharmacists did not engage in any collaborative efforts with medical oncologists during this segment.

During the second 5-week segment of part 4, the principal investigator screened and followed patients with

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Table 1 Characteristics of Patient Population in Parts 1 and 4

Figure 1 Patient Population in Part 1 75 patients identified through database search 21 met exclusion criteria

Patient characteristics

Part 1, retrospective (N = 39)

Part 4, prospective (N = 27)

Age, mean, yrs

66.2

62.9

24 (62)

11 (41)

Bladder

0 (0)

2 (7)

Brain

1 (3)

0 (0)

Breast

2 (5)

0 (0)

Cervical

0 (0)

1 (4)

Colon

4 (10)

5 (19)

Esophagus

1 (3)

0 (0)

Kidney

0 (0)

1 (4)

Leukemia

1 (3)

1 (4)

Liver

1 (3)

0 (0)

Lung

12 (31)

7 (26)

Lymphoma

2 (5)

1 (4)

Ovarian

1 (3)

0 (0)

Pancreas

0 (0)

2 (7)

Prostate

10 (26)

0 (0)

Rectal

0 (0)

1 (4)

Skin

1 (3)

0 (0)

Stomach

2 (5)

2 (7)

Uterine

1 (3)

0 (0)

Other

0 (0)

4 (15)

DVT

13 (33)

20 (74)

PE

19 (49)

3 (11)

DVT + PE

7 (18)

4 (15)

Recurrent VTE

6 (15)

3 (11)

Male sex, N (%) Cancer type, N (%) 54 patient charts were reviewed 15 were excluded because of: • Insufficient data • VTE diagnosis outside the study period Study population (part 1) N = 39

VTE indicates venous thromboembolism.

cancer concurrently with the 4 medical oncologists. If an acute VTE was documented, the principal investigator collaborated with the patient’s medical oncologist regarding the patient and made a direct recommendation for the guidelines’ preferred treatment, LMWH monotherapy, as appropriate.

After the second 5-week segment, there was a 3-week dormant period during which the principal investigator discontinued concurrent interventions and collaboration with the medical oncologists.

Thereafter began the third and final 5-week segment of part 4. This segment was similar to the second 5-week segment; however, the principal investigator did not discuss the patients with the medical oncologists if an acute VTE was documented and did not intervene regarding their prescribing patterns. In turn, the medical oncologists did not consult the principal investigator for VTE treatment recommendations. Instead, the principal investigator observed and recorded the medical oncologists’ prescribing patterns. The primary objective of part 4 was to evaluate the impact of the previous clinical interventions. Data collected for each patient in part 4 were the same as previously defined for the retrospective chart review in part 1 of the study.

All data were collected and interpreted by the principal investigator. The hospital statistician and the principal investigator analyzed the data. Statistical analysis using Pearson’s chi-squared test was performed for nonparametric data to evaluate the impact of the clinical interventions. The P value of significance was .05.

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a

VTE event, N (%)

Other cancer types include adenocarcinoma of unknown primary origin, hepatobiliary cancers, and Kaposi’s sarcoma.

DVT indicates deep-vein thrombosis; PE, pulmonary embolism; VTE, venous thromboembolism.

a

Results Part 1 A total of 75 patients were identified through the hospital database search for having a diagnosis of cancer, as well as a diagnosis of VTE, between January 2010 and June 2010. Of these, 54 patients met the inclusion crite-

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Figure 2 VTE Treatment Regimens for the Patient Population in Part 1 (N = 39) LMWH plus warfarin 41%

Heparin, LMWH, and warfarin 13%

Heparin plus LMWH 2% Heparin plus warfarin 20%

Inferior vena cava filter 8% Heparin only 8%

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67 46

50

66

54 33

34

25

0 Heparin plus Heparin,

warfarin LMWH, plus

warfarin

l

LMWH plus warfarin

Treatment regimen

ria for the retrospective chart review. During the retrospective chart review, it was discovered that 15 of these patients met the exclusion criteria. Therefore, the study population for part 1 consisted of 39 patients (Figure 1).

Patients within the part 1 study population were predominantly male (62%) and aged 22 to 89 years (mean, 66 years). This population consisted of a variety of cancer types. The 2 types representing the majority of patients were lung (31%) and prostate (26%) cancer.

PE was the most prevalent (49%) type of VTE event among the part 1 study population; however, 18% of the patients were diagnosed with a DVT and a PE during the study period. Six patients (15%) experienced a recurrent VTE event during the study period, 5 of whom had the same type of VTE event as before. The characteristics of the part 1 study population are shown in Table 1.

A total of 7 treatment regimens were prescribed by the medical oncologists when managing VTE in the observed patients with cancer, including: (1) heparin only; (2) heparin plus warfarin; (3) heparin plus LMWH; (4) heparin, LMWH, and warfarin; (5) LMWH only; (6) LMWH plus warfarin; and (7) inferior vena cava filter only. The LMWH-only treatment regimen represents the guidelines’ preferred recommendation of LMWH monotherapy. Of the 39 patients, 3 (8%) were prescribed the guidelines’ preferred recommendation of LMWH monotherapy. The majority (41%) of the part 1 study population received LMWH with concomitant warfarin to bridge into long-term anticoagulation therapy (Figure 2).

The vast majority (74%) of patients in part 1 were prescribed a VTE treatment regimen that involved warfarin as a component of their anticoagulation therapy.

l

INR nontherapeutic level

75

LMWH indicates low-molecular-weight heparin; VTE, venous thromboembolism.

136

INR therapeutic level

100

Patients, %

LMWH only 8%

Figure 3 INR Levels of Patients with VTE Treatment Regimen Involving Warfarin

INR indicates international normalized ratio; LMWH, low-molecular-weight heparin; VTE, venous thromboembolism.

INRs were collected for the 6 months immediately after the documented VTE event for those patients, to assess whether they were being maintained within the therapeutic range of 2.0 to 3.0 for appropriate anticoagulation.

The number of INRs collected per patient was inconsistent; however, more than 50% of the INRs were nontherapeutic for the heparin plus warfarin treatment regimen, and more than 65% were nontherapeutic for the remaining regimens (Figure 3). Of the nontherapeutic INRs, 69% of those obtained were subtherapeutic (INR <2.0), and the highest INR level obtained was 14.8.

Parts 2 and 3 The VTE inpatient and outpatient oncology treatment preprinted order forms were approved and implemented in February 2011. The educational presentation series was conducted by the principal investigator in January and February 2011, and it consisted of 7 total presentations to the medical oncologists, pharmacists, and nursing staff. Of the 4 medical oncologists, 3 at­ tended at least 1 of the educational presentations. The inpatient pharmacists, cancer center pharmacists, and nursing staff each had 2 opportunities to attend an educational presentation. Approximately 20 pharmacists and 30 nurses attended the educational presentation. In addition, the educational newsletter articles were published in the February 2011 issue of Chemo Savvy and in the February/March 2011 issue of P&T News.

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Impact of Pharmacists’ Interventions on Prescribing Patterns

Part 4 The impact of the pharmacists’ interventions was assessed throughout the 15 weeks of part 4 of the study, which was divided into three 5-week segments. The first 5-week segment consisted of the evaluation of the medical oncologists’ prescribing patterns for the post–educational intervention-only period. Of the 12 patients with cancer who were reported to the principal investigator by the oncology nursing staff, 7 patients were screened for VTE, all of whom had a documented VTE (Table 2).

Of these patients, 5 (71%) were prescribed the LMWHonly treatment regimen. Compared with the retrospective chart review in part 1, a significant difference (P = .001) was found among medical oncologists’ prescribing of LMWH monotherapy.

Data collected from the second 5-week segment involved direct collaboration with the medical oncologists regarding patient care. A total of 214 patients were screened on the inpatient and the outpatient medical oncology services. Among these 214 patients, 54 patients had a cancer diagnosis, 11 of whom were identified as having had a VTE event (Table 2). Of 11 documented VTE events, 8 (73%) were treated with the LMWH-only regimen, which again was significant (P = .001) compared with part 1 of the study. Only 1 patient

Table 2 Part 4 Patient Population for Each 5-Week Segment First 5-week segment

Second 5-week segment

Third 5-week segment

Total patients identified, N

12

214

217

Excluded patients, N

2

109

101

Total patients with cancer, N

10

105

116

Total patients with cancer screened for VTE, N

7

54

68

Total documented VTEs, N

7

11

14

VTE indicates venous thromboembolism.

from the initial 5-week segment and 1 patient from the second 5-week segment (14% and 9%, respectively) received therapy with LMWH plus warfarin, which was the most prevalent treatment regimen in part 1.

A 3-week dormant period was allowed before the beginning of the third 5-week segment of part 4 to transition to independent prescribing of VTE treatment by the medical oncologists. In the final 5-week segment, 217 patients were screened on the oncology service and 68 of them were actual patients with cancer. Of

Table 3 Summary of Prescribing Patterns for VTE in Patients with Cancer Part 1 results, retrospective

Part 4 results, prospective

Treatment regimens

Before pharmacist’s intervention (N = 39)

First 5-week segment, posteducation onlya (N = 7)

Second 5-week segment, pharmacist’s concurrent interventions (N = 11)

Third 5-week segment, after pharmacist’s concurrent interventions (N = 14)

Heparin only, N (%)

3 (8)

1 (14)

—

—

Heparin plus warfarin, N (%)

8 (20)

—

1 (9)

—

Heparin plus LMWH, N (%)

1 (2)

—

—

3 (21)

Heparin, LMWH, plus warfarin, N (%)

5 (13)

—

—

1 (7)

LMWH onlyb, N (%)

3 (8)

5 (71) P = .001

8 (73) P = .001

6 (43) P = .068

LMWH plus warfarin, N (%)

16 (41)

1 (14)

1 (9)

2 (14)

IVC filter only, N (%)

3 (8)

—

1 (9)

2 (14)

P <.05. a Period between educational presentations to medical oncologist’s and pharmacist’s concurrent intervention. b Significant difference between prescribing LMWH only in part 1 and in all components of part 4.

IVC indicates inferior vena cava; LMWH, low-molecular-weight heparin; VTE, venous thromboembolism.

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ORIGINAL RESEARCH

the patients with cancer, 14 were found to have had a documented VTE event (Table 2), 6 (43%) of whom had VTE events that were treated with LMWH only.

Although still significant, this percentage of LMWH monotherapy treatment regimens prescribed is slightly decreased from when there was a pharmacist’s collaboration. A summary of the results of parts 1 and 4 of the study are outlined in Table 3.

Discussion This study demonstrates that the medical oncologists at DCH RMC are receptive to pharmacists’ interventions to comply with evidence-based guidelines in the form of education and patient-specific recommendations. This statement is supported by the statistical significance found in the increased prescribing of the guidelines’ preferred recommendation, LMWH monotherapy, after pharmacists’ interventions compared with previous prescribing patterns (from 8% to 73%). This is important, because patients with cancer are at an increased risk for developing VTE and recurrent VTE. Therefore, medical oncologists should be aware of this evidence to optimize patient care.

This study demonstrates that the medical oncologists at DCH RMC are receptive to pharmacists’ interventions to comply with evidence-based guidelines in the form of education and patient-specific recommendations.

There are several strengths to our study. First, the study has used evidence-based recommendations to optimize patient care. Studies have already demonstrated the effectiveness of 6-month LMWH monotherapy in patients with cancer18,23,24; this is the rationale supporting the acceptance of this recommendation, which is in accordance with current guidelines.

Second, the assessment of INRs in part 1 for patients who had received warfarin within their VTE treatment regimen is also a strength. Although warfarin has already been shown to present significant problems when used in patients with cancer, collecting these data within our institution demonstrated to our medical oncologists the need to improve anticoagulation therapy in the majority of their patients with cancer. The medical oncologists were the same throughout all parts of the study; however, the methods for monitoring and adjusting warfarin therapy varied among medical oncologists. Therefore, the INR data collection was important, because it showed

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the results of this nonstandardized physician-managed oral anticoagulation therapy.

Finally, the multidisciplinary education and preprinted order forms were vital for this study, because they reinforced the evidence-based guidelines’ recommendation and helped improve adherence to the guidelines in an effort to make this recommendation the standard of care at DCH RMC. In addition, the LMWH on the formulary changed during this study, and the education and preprinted order forms helped eliminate confusion about which LMWH to prescribe to the patients with cancer.

Limitations The limitations of our study include the possibility of VTE events not accounted for during the initial 5-week post–educational intervention-only segment of part 4.

This is believed to be true, because the identification and the reporting of potential patients were exclusively voluntary for the nursing staff.

Furthermore, because of the multiple tasks involved in caring for patients with cancer, as well as the distractions, it is quite possible that some patients were missed, especially because reporting patients with suspected VTE to the principal investigator was not part of the nurses’ daily routine.

Some VTE events could have been attributed to the presence of central venous catheters, which was also viewed as a limitation to the study, because the primary cause of the VTE event was not investigated.

In addition, the indication for warfarin was not investigated; therefore, warfarin therapy could have been for anticoagulation related to conditions such as atrial fibrillation or artificial heart valves. However, these patients were not excluded from our study. Finally, given the limitation of being a hypothesis-generated pilot study with a small sample size, a larger confirmatory study to be conducted over a longer duration of time is warranted.

Conclusions Our future directions include continued pharmacists’ inventions within the area of VTE in patients with cancer to increase adherence to evidence-based guidelines.

This may consist of follow-up educational series for new staff members and reminders for the current staff.

Clinical updates should be presented, as appropriate, to keep the staff abreast of the most recent guideline recommendations. This study did not evaluate the impact of changing prescribing patterns on the long-term out­comes of our patients. Therefore, outcome studies evaluating the 6-month duration of LMWH monotherapy is a future direction. These outcome studies should address the clinical validity of adherence to the guidelines’ recommendation and determine whether patients at our institution

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Impact of Pharmacists’ Interventions on Prescribing Patterns

experience less bleeding and fewer recurrent VTEs as a result of these educational/intervention efforts.

As pharmacists continue to become more prevalent in the clinical setting, it is imperative that we are aware of this high-risk population and of the appropriate treatment. In addition to continued education and interventions to the medical staff, patient education can certainly be performed by pharmacists, because the feasibility of long-term self-injections of LMWH remains a practical issue. This study offers a positive contribution to the practice of pharmacy and supplements the existing literature that demonstrates the impact of clinical pharmacists on patient care. n

As pharmacists continue to become more prevalent in the clinical setting, it is imperative that we are aware of this high-risk population and of the appropriate treatment.

Acknowledgments The authors would like to express their gratitude to Timothy Martin, PharmD, Director of Pharmacy; Ariel Anguiano, Jr, MD, Medical Oncologist; Sandy Barger, Oncology Nurse Manager; Robin Tidmore, Medication Assistance Coordinator; Tom Wyatt, Research Statistician; and members of the DCH Residency Advisory Group for their help in the successful completion of this study.

Author Disclosure Statement Dr Steward, Dr Hamid, and Dr Hooker have reported no conflicts of interest.

References

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2. Khorana AA, Francis CW, Culakova E, et al. Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. J Thromb Haemost. 2007;5:632-634.

3. Lyman GH, Khorana AA, Falanga A, et al. American Society of Clinical Oncology guideline: recommendations for venous thromboembolism prophy-

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laxis and treatment in patients with cancer. J Clin Oncol. 2007;25:5490-5505.

4. Falanga A, Zacharski L. Deep vein thrombosis in cancer: the scale of the problem and approaches to management. Ann Oncol. 2005;16:696-701.

5. Khorana AA, Francis CW, Culakova E, et al. Frequency, risk factors, and trends for venous thromboembolism among hospitalized cancer patients. Cancer. 2007;110: 2339-2346.

6. Khorana AA, Connolly GC. Assessing risk of venous thromboembolism in the patient with cancer. J Clin Oncol. 2009;27:4839-4847.

7. Mandalà M, Falanga A, Roila F; ESMO Guidelines Working Group.

Management of venous thromboembolism in cancer patients: ESMO clinical recommendations. Ann Oncol. 2009;20(suppl4):182-184.

8. Karimi M, Cohan N. Cancer-associated thrombosis. Open Cardiovasc Med J. 2010;4:78-82.

9. Rajkumar SV, Blood E, Vesole D, et al. Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: a clinical trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol. 2006;24:431-436.

10. Zangari M, Barlogie B, Thertulien R, et al. Thalidomide and deep vein thrombosis in multiple myeloma: risk factors and effect on survival. Clin Lymphoma.

2003;4:32-35.

11. Zonder JA, Barlogie B, Durie BG, et al. Thrombotic complications in patients with newly diagnosed multiple myeloma treated with lenalidomide and dexamethasone: benefit of aspirin prophylaxis. Blood. 2006;108:403; author reply 404.

12. ten Cate-Hoek AJ, Prins MH. Low molecular weight heparins in cancer.

Management and prevention of venous thromboembolism in patients with malignancies. Thromb Res. 2008;122:584-598.

13. Goldsmith M, Whitelaw G, Jewell K, et al. The role of community oncologists in the prevention and treatment of VTE: clinical guidelines and CMS payment policy. Commun Oncol. 2009;6:563-568.

14. Zacharski LR. Malignancy as a solid-phase coagulopathy: implications for the etiology, pathogenesis, and treatment of cancer. Semin Thromb Hemost.

2003;29:239-246.

15. Deitcher SR. Cancer-related deep venous thrombosis: clinical importance, treatment challenges, and management strategies. Semin Thromb Hemost. 2003;29:247-258.

16. McRae SJ, Ginsberg JS. Initial treatment of venous thromboembolism.

Circulation. 2004;110(9 suppl 1):I3-I9.

17. Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th Ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest.

2012;141(2 suppl):e419S-e494S. 18. Lee AYY, Levine MN, Baker RI, et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003;349:146-153.

19. Rhodes S, Bond S. A review of the practical advantages of low molecular weight heparin in the treatment of cancer-related venous thromboembolism. Eur J Oncol Nurs. 2008;12:425-429.

20. Zacharski LR, Prandoni P, Monreal M. Warfarin versus low-molecular-weight heparin therapy in cancer patients. Oncologist. 2005;10:72-79.

21. Kearon C, Kahn SR, Agnelli G, et al. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest. 2008;133(6 suppl):454S-545S. 22. National Comprehensive Cancer Network. Clinical Practice Guidelines in Onco­ logy. Venous thromboembolic disease. Version 1.2010. www.nccn.org/professionals/ physician_gls/PDF/vte.pdf. Accessed September 28, 2012.

23. Meyer G, Marjanovic Z, Valcke J, et al. Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: a randomized controlled study. Arch Intern Med. 2002;162:1729-1735.

24. Deitcher SR, Kessler CM, Merli G, et al. Secondary prevention of venous thromboembolic events in patients with active cancer: enoxaparin alone versus initial enoxaparin followed by warfarin for a 180-day period. Clin Appl Thromb Hemost. 2006;12:389-396.

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R D IV O F AN D E US ION V O EO AT R P AN STR P A UT INI BC DM U S A

VELCADEHCP.COM

If you define value as an overall survival advantage: VELCADE® (bortezomib) DELIVERED A >13-MONTH OVERALL SURVIVAL ADVANTAGE At 5-year median follow-up, VELCADE (bortezomib)+MP* provided a median overall survival of 56.4 months vs 43.1 months with MP alone (HR=0.695 [95% CI, 0.57-085]; p<0.05)† At 3-year median follow-up, VELCADE+MP provided an overall survival advantage over MP that was not regained with subsequent therapies

If you define value as defined length of therapy: Results achieved using VELCADE twice-weekly followed by weekly dosing for a median of 50 weeks (54 planned)1

If you define value as medication cost: Medication cost is an important factor when considering overall drug spend. The Wholesale Acquisition Cost for VELCADE is $1,471 per 3.5-mg vial as of January 2012 Health plans should consider medication cost, length of therapy, and dosing regimens when determining the value of a prescription drug regimen. This list of considerations is not meant to be all-inclusive; there are multiple other factors to consider when determining value for a given regimen

VELCADE Indication and Important Safety Information INDICATION VELCADE is indicated for the treatment of patients with multiple myeloma.

CONTRAINDICATIONS VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. VELCADE is contraindicated for intrathecal administration.

WARNINGS, PRECAUTIONS AND DRUG INTERACTIONS Peripheral neuropathy, including severe cases, may occur — manage with dose modification or discontinuation. Patients with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment Hypotension can occur. Use caution when treating patients receiving antihypertensives, those with a history of syncope, and those who are dehydrated Closely monitor patients with risk factors for, or existing heart disease Acute diffuse infiltrative pulmonary disease has been reported Nausea, diarrhea, constipation, and vomiting have occurred and may require use of antiemetic and antidiarrheal medications or fluid replacement Thrombocytopenia or neutropenia can occur; complete blood counts should be regularly monitored throughout treatment Tumor Lysis Syndrome, Reversible Posterior Leukoencephalopathy Syndrome, and Acute Hepatic Failure have been reported Women should avoid becoming pregnant while being treated with VELCADE. Pregnant women should be apprised of the potential harm to the fetus Closely monitor patients receiving VELCADE in combination with strong CYP3A4 inhibitors. Concomitant use of strong CYP3A4 inducers is not recommended

ADVERSE REACTIONS Most commonly reported adverse reactions (incidence ≥30%) in clinical studies include asthenic conditions, diarrhea, nausea, constipation, peripheral neuropathy, vomiting, pyrexia, thrombocytopenia, psychiatric disorders, anorexia and decreased appetite, neutropenia, neuralgia, leukopenia, and anemia. Other adverse reactions, including serious adverse reactions, have been reported Please see Brief Summary for VELCADE on the next page of this advertisement.

To contact a reimbursement specialist: Please call 1-866-VELCADE, Option 2 (1-866-835-2233). *Melphalan+prednisone. † VISTA: a randomized, open-label, international phase 3 trial (N=682) evaluating the efficacy and safety of VELCADE administered intravenously in combination with MP vs MP in previously untreated multiple myeloma. The primary endpoint was TTP. Secondary endpoints were CR, ORR, PFS, and overall survival. At a pre-specified interim analysis (median follow-up 16.3 months), VELCADE+MP resulted in significantly superior results for TTP (median 20.7 months with VELCADE+MP vs 15.0 months with MP [p=0.000002]), PFS, overall survival, and ORR. Further enrollment was halted and patients receiving MP were offered VELCADE in addition.

Updated analyses were performed.

Reference: 1. Mateos M-V, Richardson PG, Schlag R, et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial. J Clin Oncol. 2010;28(13):2259-2266.

Brief Summary INDICATIONS: VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma.

VELCADE is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy.

CONTRAINDICATIONS: VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol.

VELCADE is contraindicated for intrathecal administration.

WARNINGS AND PRECAUTIONS: VELCADE should be administered under the supervision of a physician experienced in the use of antineoplastic therapy. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory. However, cases of severe sensory and motor peripheral neuropathy have been reported.

Patients with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥ Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. In the Phase 3 relapsed multiple myeloma trial comparing VELCADE subcutaneous vs. intravenous the incidence of Grade ≥ 2 peripheral neuropathy events was 24% for subcutaneous and 41% for intravenous. Grade ≥ 3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 16% in the intravenous treatment group. Starting VELCADE subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy.

Patients experiencing new or worsening peripheral neuropathy during VELCADE therapy may benefit from a decrease in the dose and/or a less dose-intense schedule. In the single agent phase 3 relapsed multiple myeloma study of VELCADE vs. Dexamethasone following dose adjustments, improvement in or resolution of peripheral neuropathy was reported in 51% of patients with ≥ Grade 2 peripheral neuropathy in the relapsed multiple myeloma study. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥ Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma.

Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 13%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics.

Cardiac Disorders: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have been reported, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart disease should be closely monitored. In the relapsed multiple myeloma study of VELCADE vs. dexamethasone, the incidence of any treatment-emergent cardiac disorder was 15% and 13% in the VELCADE and dexamethasone groups, respectively. The incidence of heart failure events (acute pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock, pulmonary edema) was similar in the VELCADE and dexamethasone groups, 5% and 4%, respectively. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established.

Pulmonary Disorders: There have been reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome (ARDS) in patients receiving VELCADE. Some of these events have been fatal. In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, a prompt comprehensive diagnostic evaluation should be conducted.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): There have been reports of RPLS in patients receiving VELCADE. RPLS is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing RPLS, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing RPLS is not known.

Gastrointestinal Adverse Events: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration.

Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia.

The mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study of VELCADE vs. dexamethasone, the incidence of significant bleeding events (≥Grade 3) was similar on both the VELCADE (4%) and dexamethasone (5%) arms. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. There have been reports of gastrointestinal and intracerebral hemorrhage in association with VELCADE. Transfusions may be considered. The incidence of febrile neutropenia was <1%.

Tumor Lysis Syndrome: Because VELCADE is a cytotoxic agent and can rapidly kill malignant cells, the complications of tumor lysis syndrome may occur. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.

Hepatic Events: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic events include increases in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible upon discontinuation of VELCADE. There is limited re-challenge information in these patients.

Hepatic Impairment: Bortezomib is metabolized by liver enzymes. Bortezomib exposure is increased in patients with moderate or severe hepatic impairment; these patients should be treated with VELCADE at reduced starting doses and closely monitored for toxicities.

Use in Pregnancy: Pregnancy Category D. Women of childbearing potential should avoid becoming pregnant while being treated with VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses.

3832_milpro_fa3_val_ahdb.indd 2

ADVERSE EVENT DATA: Safety data from phase 2 and 3 studies of single-agent VELCADE (bortezomib) 1.3 mg/m2/dose administered intravenously twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously treated multiple myeloma (N=1008, not including the phase 3, VELCADE plus DOXIL® [doxorubicin HCI liposome injection] study) and previously treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma.

In the integrated analysis, the most commonly reported adverse events were asthenic conditions (including fatigue, malaise, and weakness); (64%), nausea (55%), diarrhea (52%), constipation (41%), peripheral neuropathy NEC (including peripheral sensory neuropathy and peripheral neuropathy aggravated); (39%), thrombocytopenia and appetite decreased (including anorexia); (each 36%), pyrexia (34%), vomiting (33%), anemia (29%), edema (23%), headache, paresthesia and dysesthesia (each 22%), dyspnea (21%), cough and insomnia (each 20%), rash (18%), arthralgia (17%), neutropenia and dizziness (excluding vertigo); (each 17%), pain in limb and abdominal pain (each 15%), bone pain (14%), back pain and hypotension (each 13%), herpes zoster, nasopharyngitis, upper respiratory tract infection, myalgia and pneumonia (each 12%), muscle cramps (11%), and dehydration and anxiety (each 10%).

Twenty percent (20%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (5%) and neutropenia (3%). A total of 50% of patients experienced serious adverse events (SAEs) during the studies. The most commonly reported SAEs included pneumonia (7%), pyrexia (6%), diarrhea (5%), vomiting (4%), and nausea, dehydration, dyspnea and thrombocytopenia (each 3%).

In the phase 3 VELCADE + melphalan and prednisone study in previously untreated multiple myeloma, the safety profile of VELCADE administered intravenously in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone. The most commonly reported adverse events in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (52% vs 47%), neutropenia (49% vs 46%), nausea (48% vs 28%), peripheral neuropathy (47% vs 5%), diarrhea (46% vs 17%), anemia (43% vs 55%), constipation (37% vs 16%), neuralgia (36% vs 1%), leukopenia (33% vs 30%), vomiting (33% vs 16%), pyrexia (29% vs 19%), fatigue (29% vs 26%), lymphopenia (24% vs 17%), anorexia (23% vs 10%), asthenia (21% vs 18%), cough (21% vs 13%), insomnia (20% vs 13%), edema peripheral (20% vs 10%), rash (19% vs 7%), back pain (17% vs 18%), pneumonia (16% vs 11%), dizziness (16% vs 11%), dyspnea (15% vs 13%), headache (14% vs 10%), pain in extremity (14% vs 9%), abdominal pain (14% vs 7%), paresthesia (13% vs 4%), herpes zoster (13% vs 4%), bronchitis (13% vs 8%), hypokalemia (13% vs 7%), hypertension (13% vs 7%), abdominal pain upper (12% vs 9%), hypotension (12% vs 3%), dyspepsia (11% vs 7%), nasopharyngitis (11% vs 8%), bone pain (11% vs 10%), arthralgia (11% vs 15%) and pruritus (10% vs 5%).

In the phase 3 VELCADE subcutaneous vs. intravenous study in relapsed multiple myeloma, safety data were similar between the two treatment groups. The most commonly reported adverse events in this study were peripheral neuropathy NEC (38% vs 53%), anemia (36% vs 35%), thrombocytopenia (35% vs 36%), neutropenia (29% vs 27%), diarrhea (24% vs 36%), neuralgia (24% vs 23%), leukopenia (20% vs 22%), pyrexia (19% vs 16%), nausea (18% vs 19%), asthenia (16% vs 19%), weight decreased (15% vs 3%), constipation (14% vs 15%), back pain (14% vs 11%), fatigue (12% vs 20%), vomiting (12% vs 16%), insomnia (12% vs 11%), herpes zoster (11% vs 9%), decreased appetite (10% vs 9%), hypertension (10% vs 4%), dyspnea (7% vs 12%), pain in extremities (5% vs 11%), abdominal pain and headache (each 3% vs 11%), abdominal pain upper (2% vs 11%). The incidence of serious adverse events was similar for the subcutaneous treatment group (36%) and the intravenous treatment group (35%). The most commonly reported SAEs were pneumonia (6%) and pyrexia (3%) in the subcutaneous treatment group and pneumonia (7%), diarrhea (4%), peripheral sensory neuropathy (3%) and renal failure (3%) in the intravenous treatment group.

DRUG INTERACTIONS: Bortezomib is a substrate of cytochrome P450 enzyme 3A4, 2C19 and 1A2. Co-administration of ketoconazole, a strong CYP3A4 inhibitor, increased the exposure of bortezomib by 35% in 12 patients. Therefore, patients should be closely monitored when given bortezomib in combination with strong CYP3A4 inhibitors (e.g. ketoconazole, ritonavir). Co-administration of omeprazole, a strong inhibitor of CYP2C19, had no effect on the exposure of bortezomib in 17 patients. Co-administration of rifampin, a strong CYP3A4 inducer, is expected to decrease the exposure of bortezomib by at least 45%. Because the drug interaction study (n=6) was not designed to exert the maximum effect of rifampin on bortezomib PK, decreases greater than 45% may occur. Efficacy may be reduced when VELCADE is used in combination with strong CYP3A4 inducers; therefore, concomitant use of strong CYP3A4 inducers is not recommended in patients receiving VELCADE. St. John’s Wort (Hypericum perforatum) may decrease bortezomib exposure unpredictably and should be avoided. Co-administration of dexamethasone, a weak CYP3A4 inducer, had no effect on the exposure of bortezomib in 7 patients. Co-administration of melphalan-prednisone increased the exposure of bortezomib by 17% in 21 patients.

However, this increase is unlikely to be clinically relevant.

USE IN SPECIFIC POPULATIONS: Nursing Mothers: It is not known whether bortezomib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VELCADE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use: The safety and effectiveness of VELCADE in children has not been established.

Geriatric Use: No overall differences in safety or effectiveness were observed between patients ≥age 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out.

Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, VELCADE should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer’s prescribing information.

Patients with Hepatic Impairment: The exposure of bortezomib is increased in patients with moderate and severe hepatic impairment. Starting dose should be reduced in those patients.

Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication.

Please see full Prescribing Information for VELCADE at VELCADEHCP.com.

VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners.

Millennium Pharmaceuticals, Inc., Cambridge, MA 02139 Copyright © 2012, Millennium Pharmaceuticals, Inc. All rights reserved.

Printed in USA

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Chemotherapy-Induced Diarrhea: Options for Treatment and Prevention Elizabeth Koselke, PharmD; Shawna Kraft, PharmD, BCOP

Background: Chemotherapy-induced diarrhea (CID) is a predictable yet undertreated side effect of several frequently used chemotherapy agents and can lead to delays in treatment and poor quality of life. Although the exact cause of CID is not completely understood, various theories point to a multifactorial process resulting in an imbalance between the absorption and the secretion of fluid in the gastrointestinal tract. Medications such as loperamide and diphenoxylate plus atropine are frequently used along with nonpharmacologic measures to treat mild CID. Objectives: To discuss the currently recommended treatment for CID, as well as other potential medications for the treatment and the prevention of CID. With the emergence of new therapeutic alternatives for severe CID, an update of the current treatment options is warranted.

Discussion: Although guidelines exist for the treatment of CID, patient needs often exceed these recommendations. Through different mechanisms of action, medications such as cortiJ Hematol Oncol Pharm. costeroids, antibiotics, glutamine, palifermin, and activated charcoal have been studied for the 2012;2(4):143-151. prevention of CID. For patients with treatment-resistant CID, small clinical trials suggest that www.JHOPonline.com probiotics or octreotide long-acting release may be an effective alternative.

Disclosures are at end of text Conclusion: Further investigations should be conducted with promising therapies for validation before being recommended for guideline inclusion for the treatment of CID.

D

iarrhea is a well-recognized side effect that is associated with various phases of a patient with cancerâ&#x20AC;&#x2122;s treatment cycle. Radiotherapy, chemotherapy, infection, and graft-versus-host disease can all potentially augment this dose-limiting toxicity. Some regimens, especially those targeting colorectal cancer (CRC) and other malignancies of the gastrointestinal (GI) tract, are associated with an increased incidence of severe or refractory chemotherapy-induced diarrhea (CID). In some studies, CID has been reported as a side effect in up to 82% of patients with cancer, with up to 33% experiencing grades 3 and 4 diarrhea.1 GI toxicity has also been linked to many cases of death and is often an underrecognized and undertreated complication of chemotherapy.2 Severe diarrhea resulting in dehydration, neutro­ penia, fever, malnutrition, renal insufficiency, infectious complications, or severe electrolyte imbalances can lead to hospitalization.2 The presence of CID can influence providers to change chemotherapy agents, reduce treatment doses, delay therapy, or even to discontinue ther-

apy, leading to potentially worsened clinical outcomes.2 A study by Arbuckle and colleagues demonstrated that grades 1 and 2 diarrhea may lead to an alteration in chemotherapy for 11% of patients, whereas approximately 45% of patients experiencing any-grade CID required dose reduction in chemotherapy.3,4 Although it is well known that CID can result in significant morbidity and mortality, no comprehensive treatment guidelines exist for historically used and newly evaluated medications for the treatment of CID.

Dr Koselke is Hematology/Oncology Pharmacy Resident, and Dr Kraft is Hematology/Oncology Clinical Pharmacist and Clinical Assistant Professor, University of Michigan Hospitals and Health Centers, Pharmacy Services, Ann Arbor, MI.

Mechanism of Fluorouracil-Induced Diarrhea Up to 50% of patients treated with weekly 5-fluorouracil in combination with leucovorin experience CID.6 Fluorouracil therapy results in mitotic arrest and apop-

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Mechanism of Chemotherapy-Induced Diarrhea The exact mechanism of CID is not completely understood; however, various theories point to a multifactorial process resulting in an imbalance between the absorption and the secretion of fluid in the GI tract.5 Other contributing factors, such as diet, concomitant medications, and infectious complications, can enhance diarrhea in patients with cancer.4 The frequency of CID varies based on the chemotherapy regimen and on the administration schedule.

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Table 1 Common Terminology Criteria for Adverse Events for Diarrhea Grade 1

Grade 2

Grade 3

Grade 4

Grade 5

Increase of <4 stools per day over baseline; mild increase in ostomy output compared with baseline

Increase of 4-6 stools per day over baseline; moderate increase in ostomy output compared with baseline

Increase of â&#x2030;Ľ7 stools per day over baseline; incontinence; hospitalization indicated; severe increase in ostomy output compared with baseline; limiting self-care activities of daily life

Life-threatening consequences; urgent intervention indicated

Death

Source: Reference 11.

tosis of the crypt cells in the GI tract.5 Necrosis of this tissue enhances the imbalance of the ratio of immature secretory crypt cells to mature villus enterocytes.7 It also causes bowel wall inflammation, thereby stimulating additional secretion of fluid and electrolytes into the intestinal lumen5 and significantly altering the osmotic gradient in the GI tract, which contributes to the increased secretion of fluid into the stool.8

Mechanism of Irinotecan-Induced Diarrhea Irinotecan, a cornerstone in the management of CRC, with a 2-pronged effect, can induce acute (within 24 hours) and delayed (2-14 days postadministration) diarrhea.6 Irinotecan is a prodrug converted into its active form, SN-38, both of which are released into the feces by hepatobiliary and intestinal secretions.4 SN-38 is inactivated in the liver to SN-38G. As it eventually reaches the intestinal lumen, SN-38G is transformed back into its active form by beta-glucuronidase, an enzyme secreted by intestinal microflora, causing direct mucosal damage and toxicity.4 Irinotecan also induces the production of prostaglandin E2 and thromboxane A2, inflammatory cytokines, and tumor necrosis factor alpha, all causing additional mucosal damage.4 Additional Drugs Causing ChemotherapyInduced Diarrhea Other chemotherapeutic regimens have been associated with diarrhea, although at a considerably lower rate than either fluorouracil or irinotecan. Epidermal growth factor receptor (EGFR)-targeted therapies result in grade 3 or greater diarrhea in <10% of cases.6 Patients treated with EGFR tyrosine kinase inhibitors (eg, erlotinib, gefitinib, or lapatinib) experience diarrhea in up to 60% of cases, with grades 3 and 4 diarrhea occurring much less often.6 Unlike irinotecan- and fluorouracil-based regimens, EGFR therapies rarely need to be dose-reduced as a result of severe diarrhea.6 The mechanism of CID for these therapies has not been adequately investigated.6

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Therapy with ipilimumab, a human monoclonal antiâ&#x20AC;&#x201C; cytotoxic T-lymphocyte antigen (CTLA)-4 antibody used for the treatment of metastatic melanoma, often results in GI and skin toxicities.9 Weber and colleagues estimated the incidence of grade 2 or greater diarrhea between 32% and 35%.10 Blockade of CTLA-4 in the GI tract causes dysregulation of the mucosal immune system, resulting in colitis and diarrhea.9 This mechanism of diarrhea is significantly different from fluorouracil or irinotecan and is often not adequately treated with conventional therapies.

Assessment of Chemotherapy-Induced Diarrhea Currently, there is a lack of comprehensive standardized assessment methods for CID.5 The most frequently used criteria for categorizing CID is the Common Terminology Criteria for Adverse Events, which assesses patient symptoms on a scale of 1 to 5 (Table 1).8,11 CID is classified into 2 categories, complicated and uncomplicated. Uncomplicated diarrhea is defined as patients with grade 1 or 2 diarrhea and no additional signs or symptoms. Complicated CID is classified by patients with grade 3 or 4 diarrhea or patients with grade 1 or 2 diarrhea and 1 additional risk factor, such as moderateto-severe cramping, grade 2 or greater nausea and vomiting, decreased performance status, fever, sepsis, neutropenia, frank bleeding, or dehydration.

Guideline-Recommended Therapy for Uncomplicated Chemotherapy-Induced Diarrhea The last consensus conference for the management of CID was published in 1998,7 and the resulting guidelines were last updated in 2004.2 Loperamide, tincture of opium, and octreotide remain the only agents currently recommended by treatment guidelines, because of the lack of data supporting other therapies for CID (Figure).2 These guidelines recommend dietary modification, along with loperamide (4 mg initially, followed by 2 mg every 4 hours or after every unformed stool), as the

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standard first-line therapy for the treatment of uncomplicated CID (Table 2).2,4,12-21 Patients can discontinue loperamide therapy when they have been free of diarrhea for at least 12 hours.2 If diarrhea persists for more than 24 hours, high-dose loperamide (2 mg every 2 hours) is recognized as an appropriate therapeutic option in addition to initiating oral antibiotics for the prevention of infectious complications.2 If diarrhea persists for more than 48 hours with highdose loperamide therapy, loperamide should be stopped and a second-line treatment should be considered when the patient is evaluated by a physician; options include subcutaneous (SC) octreotide, tincture of opium, or oral budesonide.2

Figure Proposed Algorithm: Primary Treatment Options for Uncomplicated Chemotherapy-Induced Diarrhea Uncomplicated CIDa Yes No Standard-dose loperamide

Reassess 12-24 hours later; CID unresolved (grades 1-2)

Loperamide Loperamide, a synthetic opiate derivative, is the initial drug of choice for CID; it has reduced the incidence of irinotecan-induced diarrhea from 80% to 9% in several studies.5,8 Loperamide acts as an antidiarrheal agent by exerting agonistic effects on opioid receptors in the GI tract, resulting in decreased peristalsis and increased fluid reabsorption.5 Loperamide is minimally absorbed and produces a limited side-effect profile.6 Although rare, loperamide can cause a paralytic ileus, and patients should be routinely monitored while using high-dose loperamide.5 Other side effects include abdominal pain, dry mouth, drowsiness, and dizziness.4 Although loper足 amide has been proved to be extremely effective in uncomplicated diarrhea, its utility as monotherapy for severe diarrhea is limited.8,22 Tincture of Opium Tincture of opium, like loperamide, works by slowing GI peristalsis and increasing intestinal transit time.4 No studies have specifically evaluated tincture of opium in the treatment of CID; however, it is frequently used as an antidiarrheal agent and can safely be used as a second-line therapy for refractory diarrhea.4 Common side effects are usually mild and include nausea and vomiting.4 Atropine In the treatment of irinotecan-induced, acute-onset diarrhea, atropine monotherapy works as a competitive antagonist at anticholinergic receptors, typically dosed as 0.25 to 1 mg intravenous (IV) or SC.4 Grades 1 to 4 and grades 3 to 4 acute-onset diarrhea are typically seen in 51% and 8% of patients receiving irinotecan infusions, respectively.12 In a study by Yumuk and colleagues, 66 patients with metastatic CRC who received irinotecan were premedicated with 0.5 mg of SC atropine before their infusion. In a total of 444 infusions, acute-onset diarrhea was not seen in any of these patients.12

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Atropine

Patient received irinotecan?

Yes Ipilimumab-induced CID?

Consider steroids; CID unresolved

No High-dose loperamide and/or diphenoxylate/atropine combination

Reassess 12-24 hours later; CID unresolved (grades 1-2)

Change to or add on: diphenoxylate/atropine (if not done before, or tincture of opium)

Reassess 12-24 hours later; CID unresolved (grades 1-2)

Consider changing to, or adding, nonguideline-based therapies

For grade 3 or 4 (complicated CID), or for grades 1 and 2 CID with additional symptoms, the patient should be medically evaluated.

CID indicates chemotherapy-induced diarrhea.

Note: This proposed algorithm is based, in part, on Reference 2.

a

Diphenoxylate plus Atropine There are little efficacy data supporting the use of diphenoxylate plus atropine compared with loperamide for the treatment of CID8; however, one double-blind study comparing these agents suggests that loperamide is the more effective agent.7 In one study of 614 patients who experienced acute diarrhea, the efficacy of lopera-

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Table 2 Dosing Guidelines for Selected Medications Medication

Suggested dosing guidelines

Loperamide

4 mg orally initially, then 2 mg every 4 hrs or after every unformed stool; can increase to 2 mg every 2 hrs if needed2

Deodorized tincture of opium (10 mg/mL)

10-15 drops in water orally every 3-4 hrs3

Atropine

0.25-1 mg IV or SC3

Diphenoxylate/atropine

1-2 tablets by mouth every 6-8 hrs3

Octreotide

100-150 mcg SC 3 times daily, or 25-50 mcg/hr by continuous infusion4

Budesonide

9 mg by mouth daily, or 3 mg by mouth 3 times daily13,14

Glutamine

0.3 mg/kg IV daily, or 20 g by mouth daily15,16

Celecoxib

400 mg by mouth twice daily12

Octreotide LAR

30-40 mg SC every 28 days17

Probiotics (Lactobacillus rhamnosus GG)

1-2 Ă&#x2014; 1010 by mouth twice daily18

Activated charcoal

250 mg by mouth every 8 hrs19

Kampo medicine

7.5 mg by mouth 3 times daily20

Palifermin

40 mcg/kg IV daily21

IV indicates intravenous; LAR, Long-acting release; SC, subcutaneous.

Sources: References 2-4, 12-21.

mide was compared with diphenoxylate plus atropine.23 Patients were initially treated with loperamide 2 mg or with diphenoxylate 2.5 mg plus atropine 0.025 mg and were instructed to take an additional tablet after each unformed stool. Of patients in the loperamide group, 42% required 2 to 3 tablets to control diarrhea, whereas 2 to 3 tablets of diphenoxylate plus atropine controlled diarrhea in only 23% of patients. Diarrhea was controlled within 24 hours in 47% of patients in the loperamide group compared with 37% of patients in the diphenoxylate plus atropine group. In addition, within the 72-hour study period, fewer tablets of loperamide were required versus in the diphenoxylate plus atropine group (4.37 vs 5.75 tablets; P = .01).23 Diphenoxylate plus atropine can be used in combination with loperamide for the treatment of grade 1 or 2 diarrhea at a dosage of 1 to 2 tablets every 6 to 8 hours.4 Side effects include dry mouth, blurred vision, insomnia, and dyspepsia.4

Guideline-Recommended Therapy for Aggressive Chemotherapy-Induced Diarrhea Standard- or high-dose loperamide therapy is often unsuccessful in the treatment of aggressive (complicated) CID in 9% to 30% of cases.7,22 Patients experiencing refractory grade 1 or 2 CID, as well as grade 3 or 4 CID can be treated more aggressively with SC octreotide

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acetate (100-150 mcg 3 times daily).2 The octreotide dose can be titrated until the symptoms of diarrhea are under control.2 In addition, patients should receive fluids and antibiotic therapy according to the guidelines.2 Hospitalization is often required for patients who are unable to be adequately rehydrated orally or those who have other complicating symptoms.1 Antidiarrheal treatment should be continued until the patient is symptom free for at least 24 hours.2 Patients experiencing grade 2 or greater diarrhea before a scheduled chemotherapy session should have treatment suspended until complete symptom resolution for at least 24 hours.4

Octreotide Octreotide is a synthetic somatostatin analogue that regulates intestinal fluid and electrolyte transport.24 Octreotide inhibits the secretion of hormones in the gut, including serotonin, gastrin, insulin, and secretin.24 Through these mechanisms, octreotide increases GI tran­ sit time and reduces intestinal secretions.8 Numerous studies have displayed the effectiveness of short-acting SC octreotide for the treatment of CID.25 In a study by Gebbia and colleagues, patients were treated with 500 mcg of SC octreotide 3 times daily compared with oral loperamide 4 mg 3 times daily in patients with grade 3 or 4 diarrhea.26 Complete resolution of diarrhea was seen in 80% of patients receiving octreotide compared with only

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30% of patients treated with loperamide (P <.001).26 A dosage of SC octreotide 100 to 150 mcg 3 times daily has been shown in clinical trials to reduce grades 3 and 4 CID by 60% to 95%.1 As of the last revision (in 2004), the guidelines recommend a dose of 100 to 150 mcg of SC octreotide 3 times daily or 25 to 50 mcg hourly by continuous infusion.2 This dose can be increased up to 0.5 mg 3 times daily until diarrhea is under control.2 A study by Goumas and colleagues evaluated 100 mcg versus 500 mcg of SC octreotide in patients with grades 3 or 4 diarrhea after loperamide failure.27 Patients treated with 500 mcg had significantly more symptom control than those treated with the 100-mcg dose (approximately 90% vs 61%, respectively; P <.05), with a similar side-effect profile.2 Drawbacks for the use of octreotide include the administration of SC injection and a high cost profile.8 Side effects of SC octreotide include GI symptoms and, rarely, injection-site reactions.4

Antibiotics Widespread inflammation and necrosis in the bowel predisposes patients to infections from opportunistic pathogens, especially if they are immunocompromised or neutropenic.5 Increased epithelial permeability, as well as a reduced immune system, enable microflora to translocate out of the GI tract, predisposing patients to potential life-threatening gram-negative sepsis.4 The guidelines suggest the initiation of antibiotics for patients who are experiencing diarrhea for more than 24 hours for the prevention of septic complications.2 An oral fluoroquinolone, such as ciprofloxacin, for 7 days, has been recommended by the Independent Panel for Management of Chemotherapy-Induced Diarrhea.2,4 Nonguideline-Based Therapies Budesonide Budesonide, an oral, topically active synthetic glucocorticoid, provides anti-inflammatory activity within the intestines.4,13 Historically, budesonide has been used as an anti-inflammatory agent in the treatment of inflammatory bowel disease (IBD). Of note, when patients with irinotecan-induced diarrhea underwent colonoscopy, findings were similar to those seen in patients with IBD.13 Budesonide decreases inflammation through the inhibition of mucosal prostaglandins within the intestines, restoring mucosal function and leading to intestinal fluid absorption.4 With a 90% first-pass effect in the liver, budesonide presents an improved safety profile compared with traditional oral glucocorticoids.14 In a study of 21 patients with loperamide-refractory diarrhea, budesonide decreased the severity of grade 3-4 diarrhea by at least 2 grades in 86% of patients treated with irinotecan.13 The dosage studied in this trial was 9

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mg, given once daily for 3 to 5 days, starting the day of chemotherapy. Most patients saw a reduction in diarrhea within 24 to 48 hours.13 A second study evaluated the effects of budesonide (3 mg 3 times daily) in patients with advanced CRC.14 Patients in the budesonide arm experienced a shorter duration (1.8 vs 4.2 days, respectively) and fewer episodes (0.7 vs 2.2, respectively) of diarrhea than patients receiving placebo. Patients treated with budesonide also required fewer doses of loperamide (24.9 vs 36.2 capsules, respectively). Although findings were not statistically significant, a trend toward clinical improvement with budesonide therapy was demonstrated.14 Budesonide prophylaxis has been studied in the prevention of severe colitis, a common adverse effect of therapy with ipilimumab. However, Weber and colleagues found no difference between the treatment arms of ipilimumab plus budesonide or ipilimumab plus placebo in patients with grade 2 or higher diarrhea (33% vs 35%, respectively).10 Likewise, Berman and colleagues demonstrated that prophylactic oral budesonide did not prevent GI toxicity in patients undergoing treatment with ipilimumab.9 The authors theorized that the lack of effect was a result of insufficient amounts of budesonide reaching the distal colon.9

Corticosteroids in Ipilimumab-Induced Colitis Although ipilimumab-associated colitis did not show response to prophylaxis with oral budesonide, response has been demonstrated with drug withdrawal and with systemic steroid administration.9,28 In 676 patients who were treated with ipilimumab for metastatic melanoma, the most common immune-related adverse event was diarrhea, with up to 32% of patients experiencing any grade of CID.29,30 Thirty-four patients experienced grade 3 to 5 enterocolitis.30 Of these patients, 29 (85%) were treated with high-dose corticosteroids (â&#x2030;Ľ40-mg prednisone equivalent daily), with a median dose of 80 mg daily of prednisone or an equivalent.29,30 Complete resolution was seen in 74% of patients treated with steroids, 3% of patients improved to grade 2 severity, and 24% did not improve their Common Toxicity Criteria (CTC) score.30 Ipilimumabâ&#x20AC;&#x2122;s package insert recommends the discontinuation of therapy in patients experiencing severe enterocolitis and the initiation of systemic corticosteroids at a dose of 1 to 2 mg/kg daily of prednisone or an equivalent.30 When CID improves to grade 1 or less, steroids can be tapered over a duration of at least 1 month. Trials have shown that rapid steroid tapering can result in the recurrence or the worsening of CID in some patients.30 Glutamine Glutamine, the most abundant amino acid in the body, serves as oxidative fuel for enterocytes.22 It is es-

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sential for normal intestinal structure, and it enhances nutrient transport in the GI tract.4 Over time, marked glutamine depletion develops in patients with cancer, enhancing the incidence and the severity of diarrhea. It has been proposed that glutamine supplementation may aid in protecting the gut mucosa from toxic chemotherapeutic agents.

In a randomized, double-blind, crossover study, Li and colleagues evaluated the prophylactic effect of glutamine in 54 patients with GI cancer.31 Patients were administered 20 g of IV alanyl-glutamine dipeptide (0.3 g/kg daily) on day 1 of chemotherapy and continued therapy for 5 days. Nausea and vomiting, as well as diarrhea, decreased significantly in patients treated with glutamine (P <.05). A 2001 study by Daniele and colleagues demonstrated that 18 g of oral glutamine daily increased intestinal absorption (P = .02) and decreased intestinal permeability (P = .04) to a greater extent than placebo in patients with CRC.16 Although the exact mechanism and extent with regard to decreasing CID remain uncertain, these studies have shown promise for patients with CID who are undergoing treatment for GI cancer.16,31

Octreotide is generally reserved as a second-line treatment of CID after patients fail treatment with loperamide, based on the increased drug cost of octreotide. Octreotide LAR could be considered for patients with refractory CID as a part of their CID management when other alternatives fail.

COX-2 Inhibitors Clinical trials suggest that diarrhea may be induced by the overproduction of thromboxane A and prostaglandins in the GI tract.32 The body uses cyclooxygenase (COX), an enzyme found in normal tissue, to convert arachidonic acid into prostaglandins.32 The prostaglandin PGE2 stimulates mucous and chloride secretion from the epithelial cells in the colon, leading to significant diarrhea.22 In preclinical data, both COX-2 and PGE2 levels increased in a direct relationship to diarrhea incidence in rats given irinotecan.22 In this trial, celecoxib, a COX-2 selective inhibitor, at doses of â&#x2030;Ľ10 mg/kg daily was shown to reduce PGE2 levels, ameliorate diarrhea, and reduce weight loss while enhancing the anticancer effect of irinotecan.22 However, in a study by Maiello and colleagues, 81 patients with advanced CRC were randomized to receive

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FOLFIRI or FOLFIRI plus celecoxib.33 Celecoxib was given continuously as a 400-mg twice-daily dose starting on the first day of chemotherapy.33 No significant toxicity differences were seen between groups. Although preclinical trials suggest that celecoxib may be beneficial in alleviating CID, human studies have yet to show significant benefit of adding celecoxib to traditional chemotherapy.

Long-Acting Octreotide In the GI tract, octreotide suppresses gastric emptying and inhibits active chloride secretion in the small intestine, allowing for water and electrolyte reabsorption.25 Octreotide long-acting release (LAR) is the intramuscular form of octreotide, which is slowly released over a period of 4 to 6 weeks.25 A case series by Rosenoff and colleagues evaluated 3 patients with severe refractory diarrhea who were treated with 30 mg of octreotide LAR every 28 days.34 All 3 patients experienced prompt resolution of diarrhea, improved quality of life, and completion of full-dose chemotherapy.34 In regard to the dosing of octreotide LAR, data supporting the use of 30-mg versus 40-mg dosing every 28 days has not been convincing.17 In the STOP trial, an open-label, randomized multicenter study by Rosenoff and colleagues, 147 patients with active or previous CID were randomized to receive 30 mg or 40 mg of octreotide LAR every 28 days.17 The primary end point was the proportion of patients with grade 3 or 4 diarrhea during the study period; secondary end points included the number of patients requiring IV fluids or changes in chemotherapy dosage, as well as a quality-of-life survey.17 Although fewer patients in the 40-mg treatment group experienced CID (48.4% vs 61.7% in the 30-mg group), differences did not reach significance (P = .14); however, with both dosages, the amount of CID was reduced significantly, because all patients experienced CID with previous cycles. The authors concluded that although octreotide LAR can be used safely and effectively for CID, no specific prophylactic dosing recommendations (30 mg vs 40 mg) can be made at this time.17 Octreotide is generally reserved as a second-line treatment of CID after patients fail treatment with loperamide, based on the increased drug cost of octreotide.6 Octreotide LAR could be considered for patients with refractory CID as a part of their CID management when other alternatives fail.17 Probiotics Probiotics, nonpathogenic microorganisms such as Lactobacillus rhamnosus, Lactobacillus acidophilus, and bifidobacterium, have been extensively studied in the prevention of diarrhea associated with irritable bowel syndrome and Crohnâ&#x20AC;&#x2122;s disease.4,6 The possible mechanisms of action include providing a protective physical barrier

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from infectious bacteria, degrading carcinogens, and producing anti-inflammatory effects on the bowel mucosa.35 One clinical trial assessed the efficacy of Lactobacillus rhamnosus GG in reducing fluorouracil-induced CID in patients with CRC.18 L rhamnosus GG was administered orally twice daily at a dosage of 1 to 2 Ă&#x2014; 1010 daily for 24 weeks. A significant reduction in grade 3 to 4 diarrhea (22% vs 37% in the control group, respectively; P = .027) was seen with probiotic therapy.18 In addition, decreased abdominal discomfort and fewer dosage reductions in chemotherapy were seen with the use of probiotics.18 Immunocompromised patients should, however, be cautious of severe infections, such as sepsis, resulting from the use of probiotics.4 In that trial, no blood cultures from any of the patients grew Lactobacillus during the study period18; however, case reports have identified probiotics as a source of clinical bloodstream infections, especially in immunocompromised patients.36

Activated Charcoal Activated charcoal, an adsorbent, has been used in the acute treatment of drug overdoses and poisonings.4 Its use as a prophylactic CID agent presents mechanistic potential, because it decreases enterohepatic cycling and increases SN-38 (irinotecanâ&#x20AC;&#x2122;s toxic form) clearance from the gut.6 A 2008 study by Sergio and colleagues evaluated the use of activated charcoal prophylaxis in children who were receiving a chemotherapy regimen of irinotecan plus either cisplatin plus doxorubicin (N = 20) or carboplatin (N = 2).19 Activated charcoal was given as a 250-mg capsule starting the evening before chemotherapy and every 8 hours thereafter until the end of the cycle.19 Loperamide was given at the onset of diarrhea (2 mg every 2 hours). Twenty-eight events of diarrhea were recorded, with a frequency of 28.88% in the activated charcoal group and 71.42% in the control group (P = .002).19 Grade 3 diarrhea was significantly more frequent in the control group (42.85% vs 2.22%, respectively). Children in the activated charcoal group completed their chemotherapy cycles more often, and compliance was nearly doubled. No significant adverse events to activated charcoal were reported in this trial.19 Michael and colleagues completed a similar study of activated charcoal in adults.37 Patients received 5 mL of aqueous Charcodote (1000 mg activated charcoal) plus 25 mL of water the evening before and subsequently every 8 hours for 48 hours postirinotecan chemotherapy during their first cycle.37 The patients then served as their own control, and they received no activated charcoal during their second cycle. Grade 3 to 4 diarrhea was present in 7.1% versus 25% of patients in cycles 1 and 2, respectively. The use of loperamide increased to more than 10 tablets in 25% of patients and in 54% of patients in cycles

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1 and 2, respectively. The patients received 98% of their planned chemotherapy in the first cycle as opposed to only 70% in the second cycle. Again, activated charcoal was well tolerated and had excellent patient compliance.37 In these 2 trials, prophylactic use of activated charcoal has shown decreased grades 3 and 4 diarrhea and loperamide use, while optimizing the amount of irinotecan that could be administered.19,37 A phase 3, randomized controlled trial should be considered to validate these results.

Neomycin Irinotecan-induced diarrhea is enhanced by the intestinal bacterial production of beta-glucuronidases, causing the transformation of SN38-G into its active form, SN-38.38 Several trials have evaluated the use of neomycin, a poorly absorbed aminoglycoside antibiotic, in its effect in treating CID through the reduction of intestinal microflora.39 In patients with CRC who are experiencing delayed-type diarrhea after their first irinotecan cycle, 1000-mg neomycin 3 times daily was administered for 2 days before and for 5 days after their second cycle.39 Of the 7 patients in the trial, 5 experienced no diarrhea after the second treatment course with neomycin (P = .03).39 Fecal cultures did not reveal any neomycin-resistant or pathogenic microorganisms.

In addition, neomycin did not alter the plasma kinetics of SN-38 or irinotecan, and thus did not alter the efficacy of chemotherapy.39 Another study evaluated the combination of neomycin 25,000 IU plus bacitracin 2500 IU dosed 1000 mg 3 times daily for days 2 to 5 and days 16 to 19 of each cycle.40 All 15 patients with diarrhea in the first cycle had complete resolution of diarrhea for cycles 2 to 4.40 Neomycin was also studied as a prophylactic regimen at a dose of 660 mg 3 times daily for 3 days, starting 2 days before receiving irinotecan (350 mg/m2 once every 3 weeks).41 The overall incidence, severity, and duration of diarrhea were not statistically significant between the neomycin arm and placebo (P = .33); however, neomycin did show a 45% lower incidence of grade 3 delayed-onset diarrhea and a reduced duration of diarrhea by 0.9 days.41 The variation seen among trials could result from a difference in the treatment dose and duration of neomycin.

Cefpodoxime Despite the potential risk for antibiotic-induced diarrhea, a number of antibiotics have shown promise in decreasing the incidence and the severity of CID.4 The third-generation cephalosporin, cefpodoxime, possesses the benefit of eliminating Escherichia coli, a known beta-glucuronidase producer, while not eradicating the anaerobes that are important for intestinal coloniza-

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tion. A phase 1, prospective, pediatric study performed

by McGregor and colleagues investigated if this oral cephalosporin would allow for the dose escalation of irinotecan.42 In this study, 17 patients were treated with escalating levels of irinotecan starting at 20 mg/m2 per dose, the previously established maximum tolerated dose, for days 1 to 5 and days 8 to 12 of a 21-day course.

Cefpodoxime (10 mg/kg daily, divided twice daily) was given to patients starting 2 days before chemotherapy and was continued as long as the patient was participating in the study.42 This study demonstrated that with the addition of cefpodoxime, the maximum tolerated dose of irinote­ can could be increased to 30 mg/m2 per dose; however, diarrhea and diarrhea-associated dehydration remained the major dose-limiting toxicities when doses exceeded 30 mg/m2. Although prolonged administration of antibiotics may have the ability to increase the incidence of infections, none were demonstrated in this trial.42 Based on these results, further trials with cefpodoxime in children and adults are warranted and are under way.

Levofloxacin plus Cholestyramine Flieger and colleagues hypothesized that the combination of cholestyramine, a bile acid chelator that reduces enterohepatic recirculation, plus levofloxacin to inhibit beta-glucuronidase production would be beneficial in patients with CID.43 Of patients with colorectal adenocarcinoma, 51 were treated with levofloxacin 500 mg daily and cholestyramine 4 g 3 times daily beginning the day before irinotecan administration and continuing for 3 days thereafter. The treatment of acute-onset diarrhea and delayed-onset diarrhea with standard doses of atropine and loperamide, respectively, was offered if necessary. Of the total patients in this trial, 78% reported no diarrhea. Only 22% of patients developed grade 1 to 2 diarrhea, 2% developed grade 3 diarrhea, and no patients developed grade 4 diarrhea.43 This prospective study illustrated that intestinal microflora suppression in combination with the reduction of enterohepatic recirculation of active chemotherapy provides suppression of diarrhea to well below the normal incidence of 40%.43 In addition, the short duration of antibiotic therapy supports a prompt recovery time of intestinal microflora, thereby decreasing potential adverse effects.

Kampo Medicine (Hangeshashin-To) Hangeshashin-to (TJ-14) is a Chinese herbal product that is used in the treatment of acute gastroenteritis and that contains baicalin, a beta-glucuronidase inhibitor.44,45 Based on same mechanistic theory proposed for the use of oral antibiotics, TJ-14 may reduce active SN-38 concentrations in the intestine.44 A randomized, single-center

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trial by Mori and colleagues was conducted to investigate if the administration of TJ-14 would prevent and control CID.20 The trial included 41 patients with advanced nonâ&#x20AC;&#x201C;small-cell lung cancer who were treated with irinotecan and cisplatin.20 The patients in the treatment arm were given TJ-14 at a dose of 7.5 g 3 times daily beginning more than 3 days before chemotherapy.20 Treatment with TJ-14 continued for a minimum of 21 days after the start of treatment with irinotecan plus cisplatin.20 Loperamide was administered to patients with severe diarrhea (grade â&#x2030;Ľ2). All but 2 patients (95%) in the TJ-14 group experienced some grade of diarrhea; however, the treatment arm did show an improved overall grade of diarrhea (P = .044) and a significantly lower incidence of grades 3 and 4 diarrhea (P = .018).20 The frequency and duration of diarrhea between the groups showed no difference. The major side effect of TJ-14, constipation, occurred in 11% of patients.20

Palifermin Palifermin, a recombinant form of human keratinocyte growth factor (KGF), has been approved to reduce the incidence and the duration of severe oral mucositis in patients with hematologic malignancies who are receiving myelotoxic therapy that requires hematopoietic stem-cell support.46 The binding of KGF to its receptor results in the proliferation and differentiation of epithelial cells in multiple tissues, including the buccal mucosa, esophagus, stomach, and small intestine.46 Gibson and colleagues tested the efficacy of palifermin as an antidiarrheal agent in rats that were treated with irinotecan chemotherapy.47 One large dose (10 mg/kg) of palifermin was compared with multiple small doses (3 mg/kg daily for 3 days) or with placebo before administration of chemotherapy. The animals receiving palifermin prophylaxis had less severe diarrhea (single dose, 5%; multiple dose, 11%; and placebo, 28%; P <.05) in addition to maintaining their body weight.47 In a study by Rosen and colleagues, 64 patients with metastatic CRC being treated with fluorouracil plus leucovorin were receiving palifermin (40 mcg/kg) for 3 consecutive days before 2 chemotherapy cycles.21 Although the incidence of severe mucositis in patients treated with palifermin was half that of the placebo control group (P = .016) and reduced the need for chemotherapy dose reductions, the incidence of diarrhea did not differ between the groups.21 Grade 2 or higher CTC was observed in 20% of patients receiving placebo and in 18% of patients receiving palifermin during cycle 1.21 The most common adverse reactions to palifermin include skin toxicities (ie, rash, erythema) and oral toxicities (ie, reversible tongue thickening and tongue discoloration and alteration in taste).46

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Other Treatments for Chemotherapy-Induced Diarrhea Although not included in this review because of limited human data and the severity of side-effect profiles, thalidomide, cyclosporine, and racecadotril have been considered and have been used in limited studies as treatment options for CID. Conclusion Although guidelines exist for the treatment of CID, patient needs often exceed these recommendations. The majority of the clinical trials discussed in this article were limited by their small population size and their short-term follow-up. Further investigation should be conducted with promising therapies for validation before recommendation for guideline inclusion. Furthermore, with the emergence of new therapeutic alternatives in patients with severe CID, an update to the current treatment guidelines is warranted. n Author Disclosure Statement Dr Koselke and Dr Kraft reported no conflicts of interest.

References

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2. Benson AB 3rd, Ajani JA, Catalano RB, et al. Recommended guidelines for the treatment of cancer treatment-induced diarrhea. J Clin Oncol. 2004;22:2918-2926.

3. Arbuckle RB, Huber SL, Zacker C. The consequences of diarrhea occurring during chemotherapy for colorectal cancer: a retrospective study. Oncologist. 2000;5:250-259.

4. Richardson G, Dobish R. Chemotherapy induced diarrhea. J Oncol Pharm Pract.

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5. Kornblau S, Benson AB, Catalano R, et al. Management of cancer treatment-related diarrhea. Issues and therapeutic strategies. J Pain Symptom Manage. 2000;19:118-129.

6. Stein A, Voigt W, Jordan K. Chemotherapy-induced diarrhea: pathophysiology, frequency and guideline-based management. Ther Adv Med Oncol. 2010;2:51-63.

7. Wadler S, Benson AB 3rd, Engelking C, et al. Recommended guidelines for the treatment of chemotherapy-induced diarrhea. J Clin Oncol. 1998;16:3169-3178.

8. Saltz LB. Understanding and managing chemotherapy-induced diarrhea. J Support Oncol. 2003;1:35-46; discussion 38-41, 45-46.

9. Berman D, Parker SM, Siegel J, et al. Blockade of cytotoxic T-lymphocyte antigen-4 by ipilimumab results in dysregulation of gastrointestinal immunity in patients with advanced melanoma. Cancer Immun. 2010;10:11.

10. Weber J, Thompson JA, Hamid O, et al. A randomized, double-blind, placebo-controlled, phase II study comparing the tolerability and efficacy of ipilimumab administered with or without prophylactic budesonide in patients with unresectable stage III or IV melanoma. Clin Cancer Res. 2009;15:5591-5598.

11. National Cancer Institute. Common Terminology Criteria for Adverse Events, v4.03. National Cancer Institute, National Institutes of Health, Department of Health and Human Services; June 14, 2010.

12. Yumuk PF, Aydin SZ, Dane F, et al. The absence of early diarrhea with atropine premedication during irinotecan therapy in metastatic colorectal patients. Int J Colorectal Dis. 2004;19:609-610 13. Lenfers BH, Loeffler TM, Droege CM, Hausamen TU. Substantial activity of budesonide in patients with irinotecan (CPT-11) and 5-fluorouracil induced diarrhea and failure of loperamide treatment. Ann Oncol. 1999;10:1251-1253.

14. Karthaus M, Ballo H, Abenhardt W, et al. Prospective, double-blind, placebo-controlled, multicenter, randomized phase III study with orally administered budesonide for prevention of irinotecan (CPT-11)-induced diarrhea in patients with advanced colorectal cancer. Oncology. 2005;68:326-332.

15. Howard A, Hoffman J, Sheth A. Clinical application of voriconazole concentrations in the treatment of invasive aspergillosis. Ann Pharmacother. 2008;42:1859-1864.

16. Daniele B, Perrone F, Gallo C, et al. Oral glutamine in the prevention of fluorouracil induced intestinal toxicity: a double blind, placebo controlled, randomised trial. Gut. 2001;48:28-33.

17. Rosenoff SH, Gabrail NY, Conklin R, et al. A multicenter, randomized trial of long-acting octreotide for the optimum prevention of chemotherapy-induced diar-

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rhea: results of the STOP trial. J Support Oncol. 2006;4:289-294.

18. Österlund P, Ruotsalainen T, Korpela R, et al. Lactobacillus supplementation for diarrhoea related to chemotherapy of colorectal cancer: a randomised study. Br J Cancer. 2007;97:1028-1034.

19. Sergio GC, Felix GM, Luis JV. Activated charcoal to prevent irinotecaninduced diarrhea in children. Pediatr Blood Cancer. 2008;51:49-52.

20. Mori K, Kondo T, Kamiyama Y, et al. Preventive effect of kampo medicine (hangeshashin-to) against irinotecan-induced diarrhea in advanced non-small-cell lung cancer. Cancer Chemother Pharmacol. 2003;51:403-406.

21. Rosen LS, Abdi E, Davis ID, et al. Palifermin reduces the incidence of oral mucositis in patients with metastatic colorectal cancer treated with fluorouracil-based chemotherapy. J Clin Oncol. 2006;24:5194-5200.

22. Yang X, Hu Z, Chan SY, et al. Novel agents that potentially inhibit irinotecaninduced diarrhea. Curr Med Chem. 2005;12:1343-1358.

23. Dom J, Leyman R, Schuermans V, Brugmans J. Loperamide (R 18 553), a novel type of antidiarrheal agent. Part 8: clinical investigation. Use of a flexible dosage schedule in a double-blind comparison of loperamide with diphenoxylate in 614 patients suffering from acute diarrhea. Arzneimittelforschung. 1974;24:1660-1665.

24. Rubenstein EB, Peterson DE, Schubert M, et al. Clinical practice guidelines for the prevention and treatment of cancer therapy-induced oral and gastrointestinal mucositis. Cancer. 2004;100(9 suppl):2026-2046.

25. Prommer EE. Established and potential therapeutic applications of octreotide in palliative care. Support Care Cancer. 2008;16:1117-1123.

26. Gebbia V, Carreca I, Testa A, et al. Subcutaneous octreotide versus oral loper­ amide in the treatment of diarrhea following chemotherapy. Anticancer Drugs.

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27. Goumas P, Naxakis S, Christopoulou A, et al. Octreotide acetate in the treatment of fluorouracil-induced diarrhea. Oncologist. 1998;3:50-53.

28. Kahler KC, Hauschild A. Treatment and side effect management of CTLA-4 antibody therapy in metastatic melanoma. J Dtsch Dermatol Ges. 2011;9:277-286.

29. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711-723.

30. Yervoy (ipilimumab) [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2011.

31. Li Y, Ping X, Yu B, et al. Clinical trial: prophylactic intravenous alanyl-glutamine reduces the severity of gastrointestinal toxicity induced by chemotherapy— a randomized crossover study. Aliment Pharmacol Ther. 2009;30:452-458.

32. Fakih MG, Rustum YM. Does celecoxib have a role in the treatment of patients with colorectal cancer? Clin Colorectal Cancer. 2009;8:11-14.

33. Maiello E, Giuliani F, Gebbia V, et al. FOLFIRI with or without celecoxib in advanced colorectal cancer: a randomized phase II study of the Gruppo Oncologico dell’Italia Meridionale (GOIM). Ann Oncol. 2006;17 (suppl 7):vii55-vii59.

34. Rosenoff SH. Octreotide LAR resolves severe chemotherapy-induced diarrhoea (CID) and allows continuation of full-dose therapy. Eur J Cancer Care (Engl).

2004;13:380-383.

35. Miller AC, Elamin EM. Use of probiotics for treatment of chemotherapyinduced diarrhea: is it a myth? JPEN J Parenter Enteral Nutr. 2009;33:573-574.

36. Salminen MK, Tynkkynen S, Rautelin H, et al. Lactobacillus bacteremia during a rapid increase in probiotic use of lactobacillus rhamnosus GG in Finland. Clin Infect Dis. 2002;35:1155-1160.

37. Michael M, Brittain M, Nagai J, et al. Phase II study of activated charcoal to prevent irinotecan-induced diarrhea. J Clin Oncol. 2004;22:4410-4417.

38. Schmittel A, Jahnke K, Thiel E, Keilholz U. Neomycin as secondary prophylaxis for irinotecan-induced diarrhea. Ann Oncol. 2004;15:1296.

39. Kehrer DF, Sparreboom A, Verweij J, et al. Modulation of irinotecan-induced diarrhea by cotreatment with neomycin in cancer patients. Clin Cancer Res. 2001;7:1136-1141.

40. Alimonti A, Satta F, Pavese I, et al. Prevention of irinotecan plus 5-fluorouracil/ leucovorin-induced diarrhoea by oral administration of neomycin plus bacitracin in first-line treatment of advanced colorectal cancer. Ann Oncol. 2003;14:805-806.

41. de Jong FA, Kehrer DF, Mathijssen RH, et al. Prophylaxis of irinotecan-induced diarrhea with neomycin and potential role for UGT1A1*28 genotype screening: a double-blind, randomized, placebo-controlled study. Oncologist. 2006;11:944-954.

42. McGregor LM, Stewart CF, Crews KR, et al. Dose escalation of intravenous irinotecan using oral cefpodoxime: a phase I study in pediatric patients with refractory solid tumors. Pediatr Blood Cancer. 2012;58:372-379.

43. Flieger D, Klassert C, Hainke S, et al. Phase II clinical trial for prevention of delayed diarrhea with cholestyramine/levofloxacin in the second-line treatment with irinotecan biweekly in patients with metastatic colorectal carcinoma. Oncology.

2007;72:10-16.

44. Sharma R, Tobin P, Clarke SJ. Management of chemotherapy-induced nausea, vomiting, oral mucositis, and diarrhoea. Lancet Oncol. 2005;6:93-102.

45. Kase Y, Hayakawa T, Takeda S, et al. Pharmacological studies on antidiarrheal effects of hange-shashin-to. Biol Pharm Bull. 1996;19:1367-1370.

46. Kepivance (palifermin injection) [package insert]. Thousand Oaks, CA: Amgen; 2012.

47. Gibson RJ, Bowen JM, Keefe DM. Palifermin reduces diarrhea and increases survival following irinotecan treatment in tumor-bearing DA rats. Int J Cancer.

2005;116:464-470.

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Concise Reviews of Studies Relevant to Hematology Oncology Pharmacy

By Robert J. Ignoffo, PharmD, FASHP, FCSHP, Section Editor Clinical Professor Emeritus, University of California, San Francisco Professor of Pharmacy, College of Pharmacy, Touro University-California, Mare Island, Vallejo, CA

n Enzalutamide Prolongs Overall Survival in Prostate Cancer after Chemotherapy Background: The once-daily oral androgen receptor signaling inhibitor enzalutamide differs from current antiandrogen therapies by its ability to inhibit nuclear translocation of the androgen receptor and its coactivator recruitment, in addition to other benefits in prostate cancer. This novel agent is administered without the need for concomitant prednisone, which has been postulated to activate androgen-receptor signaling.

Design: In this phase 3, double-blind, placebo-controlled clinical trial, enzalutamide significantly prolonged survival in patients with castration-resistant prostate cancer (CRPC) after standard chemotherapy. A total of 1199 men with CRPC who had received chemotherapy were randomized in a 2:1 ratio to oral enzalutamide 160 mg daily or to placebo. The primary end point was overall survival (OS).

Results: Based on the study design, the trial was stopped when 520 deaths occurred, and an interim analysis was conducted. At that point, the OS was not reached with enzalutamide. The median OS was 18.4 months in the group receiving enzalutamide (confidence interval [CI], 18.3-not reached) compared with 13.6 months with placebo (CI, 11.3-15.8). Enzalutamide was significantly (P <.001) superior to placebo in all the secondary end points. These secondary measures showed that 54% of patients who received enzalutamide had reduced prostate-specific antigen (PSA) levels by more than 50% versus by 2% in the placebo group; the quality-of-life response rate was 43% with enzalutamide versus 18% with placebo; time to PSA progression was 8.3 months versus 3.0 months, respectively; radiographic progression-free survival was 8.3 months versus 2.9 months (hazard ratio, 0.40), respectively; and time to first skeletal-related event was 16.7 months versus 13.3 months (hazard ratio, 0.69), respectively.

The rates of adverse events (AEs) were similar in the 2 groups, with the exception of higher rates of fatigue, diarrhea, and hot flashes reported with enzalutamide than with placebo. In addition, 5 patients (0.6%) had seizures while taking enzalutamide. Of note, AEs of

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grade â&#x2030;Ľ3 occurred 8.4 months earlier with placebo than with enzalutamideâ&#x20AC;&#x201D;the median time to such events was 4.2 months with placebo and 12.6 months with enzalu­ tamide. Enzalutamide is currently being investigated in clinical trials of men with earlier-stage prostate cancer.

Takeaway: The results are impressive and show that enzalutamide is as effective as other second-line therapies for advanced CRPC. Of note, prednisone, a known stimulator of androgen receptor and receptor signaling, is not required with this drug, thereby avoiding its AEs. Another valuable result was that the clinical benefits occurred in the presence of castrate levels of testosterone and that androgen-receptor signaling and overexpression play an important role in CRPC. It may be rational to combine enzalutamide and antiandrogens in CRPC, but follow-up studies are needed. Enzalutamide may be added to the other drugs that prolong survival in CRPC. It is clear that enzalutamide has a safer toxicity profile than the cytotoxic drugs mitoxantrone and docetaxel, but it should be used with caution in patients with a history of seizures or those receiving drugs that lower the seizure threshold.

Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367:1187-1197.

n Anastrozole-Fulvestrant Combination Improves Overall Survival in Metastatic Breast Cancer Background: Fulvestrant downgrades the estrogen receptor and may therefore improve survival in postmenopausal women with hormone-receptor (HR)-positive metastatic breast cancer.

Design: The Southwest Oncology Group (SWOG) study randomized 707 postmenopausal patients with previously untreated HR-positive metastatic breast cancer to anastrozole alone or to a combination of anastrozole plus fulvestrant. All patients received 1 mg of anastrozole; those in the combination group also received a 500-mg loading dose of fulvestrant on day 1, followed by 250 mg on days 14, 28, and every 28 days thereafter.

Patients in the anastrozole-alone group whose disease progressed were strongly encouraged to cross over to receive fulvestrant alone. Early in 2011, when the 500 mg of fulvestrant was approved by the US Food and Drug

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Administration, all patients were allowed to receive the 500-mg dose.

Results: In the SWOG study, the median progression-free survival (PFS) was 15.0 months with the combination therapy and 13.5 months with anastrozole alone, representing a significant difference (P = .007); the overall survival (OS) was 41.3 months with anastrozole alone and 47.7 months with the combination therapy, also a significant difference (P = .049), although 41% of these patients crossed over to fulvestrant after progression. This is the first study of first-line hormone therapy used for HRpositive metastatic breast cancer that shows an improvement in OS. It is also the first study to show the superiority of concurrent therapy with 2 hormonal modulators over monotherapy, especially an improvement in OS. Toxic effects were mild and similar between the 2 groups.

However, more patients who received the combination therapy discontinued treatment because of toxicity.

Takeaway: Although this study shows a significant difference in PFS for the combination of anastrozole and fulvestrant, the difference was only 1.5 months.

The anastrozole group was allowed to cross over to lowdose fulvestrant, which did not improve OS versus the combination group. Three other studies have shown that high-dose fulvestrant after an aromatase inhibitor improved OS. In an unplanned subset analysis in the current study, the greatest benefit was seen in patients previously untreated with tamoxifen. This study contrasts with another recent study that showed no benefit from the combination of low-dose fulvestrant plus anastrozole (Bergh J, et al. J Clin Oncol. 2012;30:1919-1925).

Mehta and colleagues suggest that further studies should be performed, combining an aromatase inhibitor and high-dose fulvestrant in comparison to an aromatase inhibitor or high-dose fulvestrant alone. Therefore, this study has too many confounding variables, and it is unclear whether the combination of low-dose fulvestrant plus anastrozole cannot be recommended at this time.

Mehta RS, Barlow WE, Albain KS, et al. Combination anastrozole and fulvestrant in metastatic breast cancer. N Engl J Med. 2012;367:435-444.

n Adding Cetuximab to Chemotherapy Improves Outcomes in Patients with KRAS G13D Mutation Background: Although epidermal growth factor receptor (EGFR) monoclonal antibodies were initially indicated for the treatment of EGFR-expressing metastatic colorectal cancer (mCRC), studies conducted in patients with mCRC have failed to show benefits of the EGFR monoclonal antibodies cetuximab and panitumumab for patients with KRAS mutations. About 40% of patients have a KRAS mutation; most frequent mutations are G12D (13%), G12V (9%), and G13D (8%).

Design: This new analysis of pooled data from previ-

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ously published studies evaluated progression-free survival (PFS), overall survival (OS), and response to therapy using published results from 1378 patients in the 2 randomized clinical trials, CRYSTAL and OPUS. Among the 533 patients (39%) with KRAS mutations, 83 (16%) had the G13D mutation, 125 (23%) had the G12V mutation, and 325 (61%) had other mutations.

Results: Previous comparisons between patients with KRAS wild-type tumors and patients with KRAS mutations have not differentiated between subtypes of KRAS mutations, but this analysis shows significant variations in treatment effects in terms of the response rate and duration of PFS in patients with the KRAS G13D mutation compared with all the other mutations (including KRAS G12V). There was no significant OS difference between the groups; median OS was 15.4 months with the combination versus 14.7 months with chemotherapy alone (hazard ratio, 0.89; P = .68) in patients with the G13D mutation. Patients with G12V and other mutations did not benefit from the combination. However, in the subgroups of patients with the KRAS G13D mutation, PFS improved significantly by adding cetuximab to standard chemotherapy, leading to a median PFS of 7.4 months with the combination compared with 6.0 months with placebo (hazard ratio, 0.47; P = .039); similarly, tumor response rate was 40.5% versus 22.0%, respectively (odds ratio [OR], 3.38; P = .042). Of note, patients with the KRAS G13D mutation who received chemotherapy alone had worse outcomes than those with other mutations receiving chemotherapy alone (response rate, 22.0% vs 43.2%; OR, 0.40; P = .032).

Takeaway: This study confirms the results from a previous report by the same authors, indicating that the type of KRAS mutation plays a role in the response of the EGFR inhibitors cetuximab and pantimumab. The results show that tumor response and PFS were significantly better with cetuximab plus FOLFOX or FOLFIRI in patients with mCRC and KRAS G13D mutation compared with chemotherapy alone. These outcomes were comparable to those of patients with the KRAS wild-type. Of note, patients with KRAS G13D treated with chemotherapy alone had a worse response rate and PFS than patients with other KRAS mutations. However, patients with the G12V mutation treated with the combination had worse OS compared with the wild-type mutation group.

Further research is ongoing to determine the mechanism associated with these differences. The lesson is that KRAS mutation subtypes affect the tumor biology of CRC and should be considered in treatment planning. This study suggests that KRAS screening should be broadened to include KRAS subtypes.

Tejpar S, Celik I, Schlichting M, et al. Association of KRAS G13D tumor mutations with outcome in patients with metastatic colorectal cancer treated with firstline chemotherapy with or without cetuximab. J Clin Oncol. 2012;30:3570-3577.

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BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

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

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

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

Docetaxel Injection, USP

Gemcitabine Injection

Oxaliplatin for Injection,

For intravenous infusion only.

Initial U.S. Approval: 1996

For Intravenous Infusion Only.

Must Be Diluted Before Use. Initial U.S. Approval: 1996

Oxaliplatin Injection,

WARNING: TOXIC DEATHS, HEPATOTOXICITY, NEUTROPENIA, HYPERSENSITIVITY REACTIONS, and FLUID RETENTION See full prescribing information for complete boxed warning • Treatment-related mortality increases with abnormal liver function, at higher doses, and in patients with NSCLC and prior platinum-based therapy receiving docetaxel at 100 mg/m2 (5.1) • Should not be given if bilirubin > ULN, or if AST and/or ALT > 1.5 x ULN concomitant with alkaline phosphatase > 2.5 x ULN. LFT elevations increase risk of severe or life-threatening complications. Obtain LFTs before each treatment cycle (8.6) • Should not be given if neutrophil counts are < 1500 cells/mm3. Obtain frequent blood counts to monitor for neutropenia (4) • Severe hypersensitivity, including very rare fatal anaphylaxis, has been reported in patients who received dexamethasone premedication. Severe reactions require immediate discontinuation of Docetaxel Injection, USP and administration of appropriate therapy (5.4) • Contraindicated if history of severe hypersensitivity reactions to docetaxel or to drugs formulated with polysorbate 80 (4) • Severe fluid retention may occur despite dexamethasone (5.5) CONTRAINDICATIONS • Hypersensitivity to docetaxel or polysorbate 80 (4) • Neutrophil counts of <1500 cells/mm3 (4) WARNINGS AND PRECAUTIONS • Acute myeloid leukemia: In patients who received docetaxel doxorubicin and cyclophosphamide, monitor for delayed myelodysplasia or myeloid leukemia (5.6) • Cutaneous reactions: Reactions including erythema of the extremities with edema followed by desquamation may occur.

Severe skin toxicity may require dose adjustment (5.7) • Neurologic reactions: Reactions including. paresthesia, dysesthesia, and pain may occur. Severe neurosensory symptoms require dose adjustment or discontinuation if persistent. (5.8) • Asthenia: Severe asthenia may occur and may require treatment discontinuation. (5.9) • Pregnancy: Fetal harm can occur when administered to a pregnant woman. Women of childbearing potential should be advised not to become pregnant when receiving Docetaxel Injection, USP (5.10, 8.1) ADVERSE REACTIONS Most common adverse reactions across all docetaxel indications are infections, neutropenia, anemia, febrile neutropenia, hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, dyspnea, constipation, anorexia, nail disorders, fluid retention, asthenia, pain, nausea, diarrhea, vomiting, mucositis, alopecia, skin reactions, myalgia (6) To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-441-4100 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

INDICATIONS AND USAGE Gemcitabine is a nucleoside metabolic inhibitor indicated for: • Ovarian cancer in combination with carboplatin (1.1) • Breast cancer in combination with paclitaxel (1.2) • Non-small cell lung cancer in combination with cisplatin (1.3) • Pancreatic cancer as a single-agent (1.4) DOSAGE AND ADMINISTRATION Gemcitabine Injection is for intravenous use only.

• Ovarian cancer: 1000 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle (2.1) • Breast cancer: 1250 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle (2.2) • Non-small cell lung cancer: 4-week schedule, 1000 mg/m2 over 30 minutes on Days 1, 8, and 15 of each 28-day cycle: 3-week schedule; 1250 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle (2.3) • Pancreatic cancer: 1000 mg/m2 over 30 minutes once weekly for up to 7 weeks (or until toxicity necessitates reducing or holding a dose), followed by a week of rest from treatment.

Subsequent cycles should consist of infusions once weekly for 3 consecutive weeks out of every 4 weeks (2.4) • Dose Reductions or discontinuation may be needed based on toxicities (2.1-2.4) DOSAGE FORMS AND STRENGTHS • 200 mg/5.26 mL injection vial (3) • 1 g/26.3 mL injection vial (3) • 2 g/52.6 mL injection vial (3) CONTRAINDICATIONS Patients with a known hypersensitivity to gemcitabine (4) WARNINGS AND PRECAUTIONS • Infusion time and dose frequency: Increased toxicity with infusion time >60 minutes or dosing more frequently than once weekly. (5.1) • Hematology: Monitor for myelosuppression, which can be dose-limiting. (5.2, 5.7) • Pulmonary toxicity: Discontinue Gemcitabine Injection immediately for severe pulmonary toxicity. (5.3) • Renal: Monitor renal function prior to initiation of therapy and periodically thereafter. Use with caution in patients with renal impairment. Cases of hemolytic uremic syndrome (HUS) and/or renal failure, some fatal, have occurred. Discontinue Gemcitabine Injection for HUS or severe renal toxicity. (5.4) • Hepatic: Monitor hepatic function prior to initiation of therapy and periodically thereafter. Use with caution in patients with hepatic impairment. Serious hepatotoxicity, including liver failure and death, have occurred. Discontinue Gemcitabine Injection for severe hepatic toxicity. (5.5) • Pregnancy: Can cause fetal harm. Advise women of potential risk to the fetus. (5.6, 8.1) • Radiation toxicity. May cause severe and life-threatening toxicity. (5.8)

powder for solution for intravenous use solution for intravenous use Initial U.S. Approval: 2002

WARNING: ANAPHYLACTIC REACTIONS See full prescribing information for complete boxed warning.

Anaphylactic reactions to Oxaliplatin have been reported, and may occur within minutes of Oxaliplatin administration. Epinephrine, corticosteroids, and antihistamines have been employed to alleviate symptoms. (5.1) INDICATIONS AND USAGE Oxaliplatin is a platinum-based drug used in combination with infusional 5-fluorouracil /leucovorin, which is indicated for: • adjuvant treatment of stage III colon cancer in patients who have undergone complete resection of the primary tumor.

• treatment of advanced colorectal cancer. (1) •

• • • • •

CONTRAINDICATIONS Known allergy to Oxaliplatin or other platinum compounds. (4, 5.1) WARNINGS AND PRECAUTIONS Allergic Reactions: Monitor for development of rash, urticaria, erythema, pruritis, bronchospasm, and hypotension. (5.1) Neuropathy: Reduce the dose or discontinue Oxaliplatin if necessary. (5.2) Pulmonary Toxicity: May need to discontinue Oxaliplatin until interstitial lung disease or pulmonary fibrosis are excluded. (5.3) Hepatotoxicity: Monitor liver function tests. (5.4) Pregnancy. Fetal harm can occur when administered to a pregnant woman. Women should be apprised of the potential harm to the fetus. (5.5, 8.1)

ADVERSE REACTIONS Most common adverse reactions (incidence ≥ 40%) were peripheral sensory neuropathy, neutropenia, thrombocytopenia, anemia, nausea, increase in transaminases and alkaline phosphatase, diarrhea, emesis, fatigue and stomatitis. Other adverse reactions, including serious adverse reactions, have been reported. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Hospira Inc. at 1-800-441-4100, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

See 17 for PATIENT COUNSELING INFORMATION and FDA approved patient labeling.

Revised: 04/2011

ADVERSE REACTIONS The most common adverse reactions for the single-agent (≥20%) are nausea and vomiting, anemia, ALT, AST, neutropenia, leukopenia, alkaline phosphatase, proteinuria, fever, hematuria, rash, thrombocytopenia, dyspnea (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-441-4100 or electronically at ProductComplaintsPP@hospira.com, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

See 17 for PATIENT COUNSELING INFORMATION Revised: 09/2011

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

Manufactured by: Zydus Hospira Oncology Private Ltd. Ahmedabad 382-213, Gujarat, India. for Hospira, Inc. Lake Forest, IL 60045 USA

GUJ DRUGS/G/28/1267

Product of India

Manufactured by: Hospira Australia Ltd Mulgrave VIC 3170 Australia Manufactured for: Hospira, Inc. Lake Forest, IL 60045 USA

AVA I L A B L E F R O M HOSPIRA

OXALIPLATIN IN JECTION (5 m g/m L)

50 mg/10 mL single-dose vial

As the complexity of healthcare evolves, we’re doing our part to improve cost savings, optimize workflow and enhance patient care.

With our generic oncology portfolio we provide

100 mg/20 mL single-dose vial See Black Box Warning Below

ONE solution for ALL.

FOR PHARMACISTS—FAMILIAR STRENGTHS AND FLEXIBLE DOSING

FOR ADMINISTRATORS—MULTIPLE-DOSE VIALS LEAD TO LESS WASTE

FOR CLINICIANS—UNIQUE ONCO-TAIN™ VIALS REINFORCE SAFETY1

FOR YOUR INSTITUTION—HIGH-QUALITY MEDICATION AT A LOWER COST

UNIQUE ONCO-TAI N S AF ET Y F EAT UR ES 1

PVC BOTTOM offers shatter resistance.

2

SHRINK-WRAPPED SLEEVE provides surface protection that acts as a barrier between any cytotoxic residue that may remain on the surface of the vial and persons handling the products.

3

GLASS CLARITY allows for easy inspection of the vial as a final safety check before administration.

4

PREWASHED VIALS reduce cytotoxic residue.

DOCETAXEL IN JECTION (1 0 m g/m L)

160 mg/16 mL multiple-dose vial 80 mg/8 mL multiple-dose vial 20 mg/2 mL single-dose vial See Black Box Warning Below

For more information, contact your

Hospira representative or call 1-877-946-7747.

Or visit us at products.hospira.com.

Docetaxel: WARNING: TOXIC DEATHS, HEPATOTOXICITY, NEUTROPENIA, HYPERSENSITIVITY REACTIONS, and FLUID RETENTION Oxaliplatin: WARNING: ANAPHYLACTIC REACTIONS Please refer to Black Box Warnings and see Brief Prescribing Informations on back page.

2 g/52.6 mL single-dose vial

Reference: 1. Data on file. Hospira, Inc. Hospira, Inc., 275 North Field Drive, Lake Forest, IL 60045

GEMCITABIN E IN JECTION (3 8 m g/m L)

P12-3707-8.125x10.875-Jul., 12

1 g/26.3 mL single-dose vial 200 mg/5.26 mL single-dose vial