Cancer Therapy Advisor September/October 2015 Issue

SEPTEMBER/OCTOBER 2015 | VOL 2, ISSUE 1

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A16 CME ACTIVITY

Clinical Considerations in the Management of Chronic Lymphocytic Leukemia Novel and emerging treatment options for relapsed/refractory disease.

FEATURING Cancer Therapy Regimens and Oncology Drug Monographs from

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1 Bone Cancer 7 Brain Cancer 9 Breast Cancer 22 Endocrine Cancer

 25 Gastrointestinal Cancer

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New Drug Approvals Bring Hope, Challenges in the Treatment of Patients With CLL

37 Genitourinary Cancer 45 Gynecologic Cancer

 47 Head and Neck Cancer

A28 IN THE CLINIC SEPTEMBER/OCTOBER 2015 | VOL 2, ISSUE 1

Managing Pain in Patients With Cancer: Considerations When Prescribing Opioids

 53 Hematologic Cancer 73 Lung Cancer 78 Sarcoma 79 Skin Cancer

A31 VIEWPOINT

Study Suggests Using Caution When Sharing Information of Adult Patients Over 75

83 Associated Hematological

Disorders

 Regimen included

A30 EXPERT PERSPECTIVE We Can Treat Hodgkin’s Lymphoma Like Melanoma?

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DID YOU KNOW?

CLIENT: Lilly

FINISH SIZE: 8.5” wide x 10.875” high

JOB#: ELCONG 34903_5 (Asize_SinglePP)

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NSCLC=non-small cell lung cancer.

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For nearly 15 years (1999-2014), no FDAapproved, second-line regimen extended overall survival versus docetaxel across a broad population of patients with metastatic NSCLC.1-4

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Visit www.CYRAMZAHCP.com for more information CYRAMZA® (ramucirumab), in combination with docetaxel, is indicated for the treatment of patients with metastatic NSCLC with disease progression on or after platinum-based chemotherapy. Patients with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving CYRAMZA.

aDvancing the seconD-line treatment oF metastatic nsclc5 CYRAMZA is the first antiangiogenic agent FDA approved in combination with docetaxel for the second-line treatment of metastatic NSCLC, including nonsquamous and squamous histologies.5

IMPORTANT SAFETY INFORMATION FOR CYRAMZA

Warnings and Precautions Hemorrhage • CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. In study 3, which evaluated CYRAMZA plus docetaxel in metastatic non-small cell lung cancer (NSCLC), the incidence of severe bleeding was 2.4% for CYRAMZA plus docetaxel and 2.3% for placebo plus docetaxel. Patients with NSCLC receiving therapeutic anticoagulation or chronic therapy with NSAIDs or other antiplatelet therapy other than once-daily aspirin or with radiographic evidence of major airway or blood vessel invasion or intratumor cavitation were excluded from study 3; therefore, the risk of pulmonary hemorrhage in these groups of patients is unknown. Permanently discontinue CYRAMZA in patients who experience severe bleeding.

Arterial Thromboembolic Events (ATEs)

• Serious, sometimes fatal, ATEs including myocardial infarction,

cardiac arrest, cerebrovascular accident, and cerebral ischemia occurred in clinical trials. Permanently discontinue CYRAMZA in patients who experience a severe ATE.

Hypertension

• An increased incidence of severe hypertension occurred in patients

receiving CYRAMZA plus docetaxel (6%) as compared to placebo plus docetaxel (2%). Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every 2 weeks or more frequently as indicated during treatment. Temporarily suspend CYRAMZA for severe hypertension until medically controlled.

Permanently discontinue CYRAMZA if medically significant hypertension cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy.

of gastrointestinal perforation, a potentially fatal event. In study 3, the incidence of gastrointestinal perforation was 1% for CYRAMZA plus docetaxel versus 0.3% for placebo plus docetaxel.

Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.

Impaired Wound Healing

• Impaired wound healing can occur with antibodies inhibiting the VEGF pathway. CYRAMZA has not been studied in patients with serious or nonhealing wounds. CYRAMZA, as an antiangiogenic therapy, has the potential to adversely affect wound healing. Withhold CYRAMZA prior to surgery. Resume CYRAMZA following the surgical intervention based on clinical judgment of adequate wound healing. If a patient develops wound healing complications during therapy, discontinue CYRAMZA until the wound is fully healed.

Clinical Deterioration in Child-Pugh B or C Cirrhosis

• Clinical deterioration, manifested by new onset or worsening

encephalopathy, ascites, or hepatorenal syndrome, was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA. Use CYRAMZA in patients with Child-Pugh B or C cirrhosis only if the potential benefits of treatment are judged to outweigh the risks of clinical deterioration.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

• RPLS has been reported at a rate of <0.1% in clinical studies with

CYRAMZA. Confirm the diagnosis of RPLS with MRI and discontinue CYRAMZA in patients who develop RPLS. Symptoms may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death.

Proteinuria Including Nephrotic Syndrome

• Monitor proteinuria by urine dipstick and/or urinary protein

creatinine ratio for the development of worsening of proteinuria during CYRAMZA therapy. Withhold CYRAMZA for urine protein levels that are ≥2 g over 24 hours. Reinitiate CYRAMZA at a reduced dose once the urine protein level returns to <2 g over 24 hours.

Permanently discontinue CYRAMZA for urine protein levels >3 g over 24 hours or in the setting of nephrotic syndrome.

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Impaired Wound Healing: Impaired wound healing can occur with antibodies inhibiting the VEGF pathway. Discontinue CYRAMZA therapy in patients with impaired wound healing.

Withhold CYRAMZA prior to surgery and discontinue CYRAMZA if a patient develops wound healing complications.

Gastrointestinal Perforations

• CYRAMZA is an antiangiogenic therapy that can increase the risk

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Gastrointestinal Perforation: CYRAMZA can increase the risk of gastrointestinal perforation, a potentially fatal event.

Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.

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WARNING: HEMORRHAGE, GASTROINTESTINAL PERFORATION, AND IMPAIRED WOUND HEALING Hemorrhage: CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. Permanently discontinue CYRAMZA in patients who experience severe bleeding.

Infusion-Related Reactions (IRRs) • Prior to the institution of premedication recommendations across clinical trials of CYRAMZA, IRRs occurred in 6 out of 37 patients (16%), including 2 severe events. The majority of IRRs across trials occurred during or following a first or second CYRAMZA infusion. Symptoms of IRRs included rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia.

In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension. Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue CYRAMZA for grade 3 or 4 IRRs.

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CYRAMZA plus docetaxel demonstrated a statistically significant improvement in overall survival vs docetaxel5 OVERALL SURVIVAL: MEDIAN - MONTHS (95% CI) CYRAMZA + docetaxel (n=628)

1.0

OS PROBABILITY

0.8

MAJOR OUTCOME MEASURE

10.5

15% INCREASE IN MEDIAN OS

MONTHS

(9.5, 11.2) Hazard Ratio (95% CI)=0.86 (0.75, 0.98); P=0.024

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Placebo + docetaxel (n=625)

MONTHS (8.4, 10.0)

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TIME FROM RANDOMIZATION (MONTHS)

Number at Risk

CYRAMZA + docetaxel 628 Placebo + docetaxel 625

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156

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• The percentage of deaths at the time of analysis was 68% (428 patients) and 73% (456 patients) in the CYRAMZA plus docetaxel and placebo plus docetaxel arms, respectively 5

Demonstrated improvements across all three efficacy outcomes (OS, PFS, ORR)5 • Median PFS with CYRAMZA plus docetaxel was 4.5 months (95% CI: 4.2, 5.4) vs 3.0 months (95% CI: 2.8, 3.9) with placebo plus docetaxel (hazard ratio 0.76 [95% CI: 0.68, 0.86]; P<0.001) — The percentage of events at the time of analysis was 89% (558 patients) and 93% (583 patients) in the CYRAMZA plus docetaxel and placebo plus docetaxel arms, respectively • ORR with CYRAMZA plus docetaxel was 23% (95% CI: 20, 26) vs 14% (95% CI: 11, 17) with placebo plus docetaxel (P<0.001)* CI=confidence interval; OS=overall survival; PFS=progression-free survival; ORR=objective response rate. *Intent-to-treat population. Disease progression and tumor response were assessed by investigators in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.6 ORR is defined as complete plus partial response.

REVEL TRIAL DESIGN (N=1253)

The phase III REVEL trial evaluated the efficacy and safety of CYRAMZA plus docetaxel vs placebo plus docetaxel in patients with metastatic NSCLC with disease progression on or after platinum-based chemotherapy. Major efficacy outcome measure was OS. Supportive efficacy outcome measures were PFS and ORR. All patients were required to have Eastern Cooperative Oncology Group performance status 0 or 1. Patients were randomized 1:1 (N=1253) to receive either CYRAMZA 10 mg/kg or placebo, in combination with docetaxel at 75 mg/m2 every 21 days.5 Thyroid Dysfunction • Monitor thyroid function during treatment with CYRAMZA. Embryofetal Toxicity

• The most commonly reported adverse reactions (all grades; grade

3/4) occurring in ≥5% of patients receiving CYRAMZA plus docetaxel and ≥2% higher than placebo plus docetaxel in study 3 were neutropenia (55% vs 46%; 49% vs 40%), fatigue/asthenia (55% vs 50%; 14% vs 11%), stomatitis/mucosal inflammation (37% vs 19%; 7% vs 2%), epistaxis (19% vs 7%; <1% vs <1%), febrile neutropenia (16% vs 10%; 16% vs 10%), peripheral edema (16% vs 9%; 0% vs <1%), thrombocytopenia (13% vs 5%; 3% vs <1%), lacrimation increased (13% vs 5%; <1% vs 0%), and hypertension (11% vs 5%; 6% vs 2%).

• The most common serious adverse events with CYRAMZA plus

docetaxel in study 3 were febrile neutropenia (14%), pneumonia (6%), and neutropenia (5%). The use of granulocyte colony-stimulating factors was 42% in CYRAMZA plus docetaxel-treated patients versus 37% in patients who received placebo plus docetaxel.

• In patients ≥65 years of age, there were 18 (8%) deaths on treatment

or within 30 days of discontinuation for CYRAMZA plus docetaxel and 9 (4%) deaths for placebo plus docetaxel. In patients <65 years of age, there were 13 (3%) deaths on treatment or within 30 days of discontinuation for CYRAMZA plus docetaxel and 26 (6%) deaths for placebo plus docetaxel.

• Treatment discontinuation due to adverse reactions occurred more

frequently in CYRAMZA plus docetaxel-treated patients (9%) than in placebo plus docetaxel-treated patients (5%). The most common adverse events leading to treatment discontinuation of CYRAMZA were infusion-related reaction (0.5%) and epistaxis (0.3%).

• For patients with nonsquamous histology, the overall incidence of

pulmonary hemorrhage was 7% and the incidence of grade ≥3 pulmonary hemorrhage was 1% for CYRAMZA plus docetaxel compared to 6% overall incidence and 1% for grade ≥3 pulmonary hemorrhage for placebo plus docetaxel. For patients with squamous histology, the overall incidence of pulmonary hemorrhage was 10% and the incidence of grade ≥3 pulmonary hemorrhage was 2% for CYRAMZA plus docetaxel compared to 12% overall incidence and 2% for grade ≥3 pulmonary hemorrhage for placebo plus docetaxel.

• Clinically relevant adverse reactions reported in ≥1% and <5% of

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• No pharmacokinetic interactions were observed between ramucirumab and docetaxel.

Use in Specific Populations

• Pregnancy: Based on its mechanism of action, CYRAMZA can cause

fetal harm. Animal models link angiogenesis, VEGF, and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no available data on CYRAMZA use in pregnant women to inform any drug-associated risks. No animal studies have been conducted to evaluate the effect of ramucirumab on reproduction and fetal development. Advise females of reproductive potential of the potential risk for maintaining pregnancy, risk to the fetus, and risk to newborn and infant development, and to use effective contraception during CYRAMZA therapy and for at least 3 months following the last dose of CYRAMZA.

• Lactation: Because of the potential risk for serious adverse

reactions in nursing infants from ramucirumab, advise women that breastfeeding is not recommended during treatment with CYRAMZA.

• Females of Reproductive Potential: Advise females of reproductive potential that based on animal data CYRAMZA may impair fertility.

Please see Brief Summary of Prescribing Information for CYRAMZA, including Boxed Warnings for hemorrhage, gastrointestinal perforation, and impaired wound healing, on next page.

RB-L HCP ISI 24APR2015 References: 1. Reck M, Kaiser R, Mellemgaard A, et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. Lancet Oncol.

2014;15:143-155. 2. Supplement to: Reck M, Kaiser R, Mellemgaard A, et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. Lancet Oncol. 2014;15:143-155. 3. National Cancer Institute. Cancer drug information. FDA approval for docetaxel. http://www.cancer.gov/cancertopics/druginfo/ fda-docetaxel/print. Accessed August 26, 2014. 4. National Cancer Institute. Cancer drug information. FDA approval for ramucirumab. http://www.cancer.gov/cancertopics/ treatment/drugs/fda-ramucirumab#nsclc. Accessed May 4, 2015. 5. CYRAMZA (ramucirumab) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2015. 6. Garon EB, Ciuleanu T-E, Arrieta O, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet. 2014;384(9944):665-673.

RB96552 05/2015 PRINTED IN USA © Lilly USA, LLC 2015. All rights reserved.

CYRAMZA is a trademark owned by or licensed to Eli Lilly and Company, its subsidiaries, or affiliates.

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Most Common Adverse Reactions

Drug Interactions

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when administered to pregnant women. Animal models link angiogenesis, VEGF, and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with CYRAMZA and for at least 3 months after the last dose of CYRAMZA.

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• Based on its mechanism of action, CYRAMZA can cause fetal harm

CYRAMZA plus docetaxel-treated patients in study 3 were hyponatremia (4.8% CYRAMZA plus docetaxel versus 2.4% for placebo plus docetaxel) and proteinuria (3.3% CYRAMZA plus docetaxel versus 0.8% placebo plus docetaxel).

CYRAMZA® (ramucirumab) injection BRIEF SUMMARY: For complete safety, please consult the full Prescribing Information.

WARNING: HEMORRHAGE, GASTROINTESTINAL PERFORATION, AND IMPAIRED WOUND HEALING Hemorrhage: CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events.

Permanently discontinue CYRAMZA in patients who experience severe bleeding.

Gastrointestinal Perforation: CYRAMZA can increase the risk of gastrointestinal perforation, a potentially fatal event. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.

Impaired Wound Healing: Impaired wound healing can occur with antibodies inhibiting the VEGF pathway. Discontinue CYRAMZA therapy in patients with impaired wound healing. Withold CYRAMZA prior to surgery and discontinue CYRAMZA if a patient develops wound healing complications.

INDICATIONS AND USAGE Non-Small Cell Lung Cancer: CYRAMZA, in combination with docetaxel, is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with disease progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving CYRAMZA. CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Hemorrhage CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. In Study 1, the incidence of severe bleeding was 3.4% for CYRAMZA and 2.6% for placebo. In Study 2, the incidence of severe bleeding was 4.3% for CYRAMZA plus paclitaxel and 2.4% for placebo plus paclitaxel. Patients with gastric cancer receiving nonsteroid anti-inflammatory drugs (NSAIDs) were excluded from enrollment in Studies 1 and 2; therefore, the risk of gastric hemorrhage in CYRAMZA-treated patients with gastric tumors receiving NSAIDs is unknown. In Study 3, the incidence of severe bleeding was 2.4% for CYRAMZA plus docetaxel and 2.3% for placebo plus docetaxel. Patients with NSCLC receiving therapeutic anticoagulation or chronic therapy with NSAIDS or other antiplatelet therapy other than once daily aspirin or with radiographic evidence of major airway or blood vessel invasion or intratumor cavitation were excluded from Study 3; therefore the risk of pulmonary hemorrhage in these groups of patients is unknown. In Study 4, the incidence of severe bleeding was 2.5% for CYRAMZA plus FOLFIRI and 1.7% for placebo plus FOLFIRI. Permanently discontinue CYRAMZA in patients who experience severe bleeding.

Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATEs) including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia occurred in clinical trials including 1.7% of 236 patients who received CYRAMZA as a single agent for gastric cancer in Study 1. Permanently discontinue CYRAMZA in patients who experience a severe ATE. Hypertension An increased incidence of severe hypertension occurred in patients receiving CYRAMZA as a single agent (8%) as compared to placebo (3%) and in patients receiving CYRAMZA plus paclitaxel (15%) as compared to placebo plus paclitaxel (3%), in patients receiving CYRAMZA plus docetaxel (6%) as compared to placebo plus docetaxel (2%), and in patients receiving CYRAMZA plus FOLFIRI (11%) as compared to placebo plus FOLFIRI (3%). Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every two weeks or more frequently as indicated during treatment. Temporarily suspend CYRAMZA for severe hypertension until medically controlled. Permanently discontinue CYRAMZA if medically significant hypertension cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy.

Infusion-Related Reactions Prior to the institution of premedication recommendations across clinical trials of CYRAMZA, infusion-related reactions (IRRs) occurred in 6 out of 37 patients (16%), including two severe events. The majority of IRRs across trials occurred during or following a first or second CYRAMZA infusion. Symptoms of IRRs included rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia. In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension. Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue CYRAMZA for Grade 3 or 4 IRRs. Gastrointestinal Perforations CYRAMZA is an antiangiogenic therapy that can increase the risk of gastrointestinal perforation, a potentially fatal event. Four of 570 patients (0.7%) who received CYRAMZA as a single agent in clinical trials experienced gastrointestinal perforation. In Study 2, the incidence of gastrointestinal perforations was also increased in patients that received CYRAMZA plus paclitaxel (1.2%) as compared to patients receiving placebo plus paclitaxel (0.3%). In Study 3, the incidence of gastrointestinal perforation CYRAMZA® (ramucirumab) injection RB-L HCP BS 04MAY2015

CYRAMZA RB-L HCP BS 04MAY2015 - 7 x 10

was 1% for CYRAMZA plus docetaxel and 0.3% for placebo plus docetaxel. In Study 4, the incidence of gastrointestinal perforation was 1.7% for CYRAMZA plus FOLFIRI and 0.6% for placebo plus FOLFIRI. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.

Impaired Wound Healing Impaired wound healing can occur with antibodies inhibiting the VEGF pathway. CYRAMZA has not been studied in patients with serious or non-healing wounds. CYRAMZA, as an antiangiogenic therapy, has the potential to adversely affect wound healing. Withhold CYRAMZA prior to surgery. Resume following the surgical intervention based on clinical judgment of adequate wound healing. If a patient develops wound healing complications during therapy, discontinue CYRAMZA until the wound is fully healed.

Clinical Deterioration in Patients with Child-Pugh B or C Cirrhosis Clinical deterioration, manifested by new onset or worsening encephalopathy, ascites, or hepatorenal syndrome was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA. Use CYRAMZA in patients with Child-Pugh B or C cirrhosis only if the potential benefits of treatment are judged to outweigh the risks of clinical deterioration.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS has been reported with a rate of <0.1% in clinical studies with CYRAMZA. Confirm the diagnosis of RPLS with MRI and discontinue CYRAMZA in patients who develop RPLS. Symptoms may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death.

Proteinuria Including Nephrotic Syndrome In Study 4, severe proteinuria occurred more frequently in patients treated with CYRAMZA plus FOLFIRI compared to patients receiving placebo plus FOLFIRI. Severe proteinuria was reported in 3% of patients treated with CYRAMZA plus FOLFIRI (including 3 cases [0.6%] of nephrotic syndrome) compared to 0.2% of patients treated with placebo plus FOLFIRI. Monitor proteinuria by urine dipstick and/or urinary protein creatinine ratio for the development of worsening of proteinuria during CYRAMZA therapy. Withhold CYRAMZA for urine protein levels that are 2 or more grams over 24 hours. Reinitiate CYRAMZA at a reduced dose once the urine protein level returns to less than 2 grams over 24 hours. Permanently discontinue CYRAMZA for urine protein levels greater than 3 grams over 24 hours or in the setting of nephrotic syndrome.

Thyroid Dysfunction Monitor thyroid function during treatment with CYRAMZA. In Study 4, the incidence of hypothyroidism reported as an adverse event was 2.6% in the CYRAMZA plus FOLFIRI treated patients and 0.9% in the placebo plus FOLFIRI treated patients.

Embryofetal Toxicity Based on its mechanism of action, CYRAMZA can cause fetal harm when administered to pregnant women. Animal models link angiogenesis, VEGF and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with CYRAMZA and for at 3 least months after the last dose of CYRAMZA. ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

CYRAMZA Administered in Combination with Docetaxel Study 3 was a multinational, randomized, double-blind study conducted in patients with NSCLC with disease progression on or after one platinum-based therapy for locally advanced or metastatic disease. Patients received either CYRAMZA 10 mg/kg intravenously plus docetaxel 75 mg/m2 intravenously every 3 weeks or placebo plus docetaxel 75 mg/m2 intravenously every 3 weeks. Due to an increased incidence of neutropenia and febrile neutropenia in patients enrolled in East Asian sites, Study 3 was amended and 24 patients (11 CYRAMZA plus docetaxel, 13 placebo plus docetaxel) at East Asian sites received a starting dose of docetaxel at 60 mg/m2 every 3 weeks.

Study 3 excluded patients with an ECOG PS of 2 or greater, bilirubin greater than the upper limit of normal (ULN), uncontrolled hypertension, major surgery within 28 days, radiographic evidence of major airway or blood vessel invasion by cancer, radiographic evidence of intra-tumor cavitation, or gross hemoptysis within the preceding 2 months, and patients receiving therapeutic anticoagulation or chronic anti-platelet therapy other than once daily aspirin. The study also excluded patients whose only prior treatment for advanced NSCLC was a tyrosine kinase (epidermal growth factor receptor [EGFR] or anaplastic lymphoma kinase [ALK]) inhibitor. The data described below reflect exposure to CYRAMZA plus docetaxel in 627 patients in Study 3. Demographics and baseline characteristics were similar between treatment arms. Median age was 62 years; 67% of patients were men; 84% were White and 12% were Asian; 33% had ECOG PS 0; 74% had non-squamous histology and 25% had squamous histology. Patients received a median of 4.5 doses of CYRAMZA; the median duration of exposure was 3.5 months, and 195 (31% of 627) patients received CYRAMZA for at least six months.

In Study 3, the most common adverse reactions (all grades) observed in CYRAMZA plus docetaxel-treated patients at a rate of ≥30% and ≥2% higher than placebo plus docetaxel were neutropenia, fatigue/asthenia, and stomatitis/mucosal inflammation.

Treatment discontinuation due to adverse reactions occurred more frequently in CYRAMZA plus docetaxel-treated patients (9%) than in placebo plus docetaxel-treated patients (5%). The most common adverse events leading to treatment discontinuation of CYRAMZA were infusion-related reaction (0.5%) and epistaxis (0.3%). For patients with non-squamous histology, the overall incidence of pulmonary hemorrhage was 7% and the incidence of ≥Grade 3 pulmonary hemorrhage was 1% for CYRAMZA plus docetaxel compared to 6% overall incidence and 1% for ≥Grade 3 pulmonary CYRAMZA® (ramucirumab) injection RB-L HCP BS 04MAY2015

PRINTER VERSION 1 OF 3

hemorrhage for placebo plus docetaxel. For patients with squamous histology, the overall incidence of pulmonary hemorrhage was 10% and the incidence of ≥Grade 3 pulmonary hemorrhage was 2% for CYRAMZA plus docetaxel compared to 12% overall incidence and 2% for ≥Grade 3 pulmonary hemorrhage for placebo plus docetaxel.

The most common serious adverse events with CYRAMZA plus docetaxel were febrile neutropenia (14%), pneumonia (6%), and neutropenia (5%). The use of granulocyte colony-stimulating factors was 42% in CYRAMZA plus docetaxel-treated patients

versus 37% in patients who received placebo plus docetaxel. In patients ≥65 years, there were 18 (8%) deaths on treatment or within 30 days of discontinuation for CYRAMZA plus docetaxel and 9 (4%) deaths for placebo plus docetaxel. In patients <65 years, there were 13 (3%) deaths on treatment or within 30 days of discontinuation for CYRAMZA plus docetaxel and 26 (6%) deaths for placebo plus docetaxel. Table 4 provides the frequency and severity of adverse reactions in Study 3.

Table 4: Adverse Reactions Occurring at Incidence Rate ≥5% and a ≥2% Difference Between Arms in Patients Receiving CYRAMZA in Study 3 Adverse Reactions (MedDRA) System Organ Class Blood and Lymphatic System Disorders Febrile neutropenia Neutropenia Thrombocytopenia Gastrointestinal Disorders Stomatitis/Mucosal inflammation Eye Disorders Lacrimation increased General Disorders and Administration Site Disorders Fatigue/Asthenia Peripheral edema Respiratory, Thoracic, and Mediastinal Disorders Epistaxis Vascular Disorders Hypertension

CYRAMZA plus docetaxel (N=627) All Grades Grade 3-4 (Frequency %) (Frequency %) 16 55 13

16 49 3

10 46 5

10 40 <1

37

7

19

2

13

<1

5

0

55 16

14 0

50 9

11 <1

19

<1

7

<1

11

6

5

2

Clinically relevant adverse drug reactions reported in ≥1% and <5% of the CYRAMZA plus docetaxel-treated patients in Study 3 were hyponatremia (4.8% CYRAMZA plus docetaxel versus 2.4% for placebo plus docetaxel) and proteinuria (3.3% CYRAMZA plus docetaxel versus 0.8% placebo plus docetaxel).

Immunogenicity As with all therapeutic proteins, there is the potential for immunogenicity. In 23 clinical trials, 86/2890 (3.0%) of CYRAMZA-treated patients tested positive for treatmentemergent anti-ramucirumab antibodies by an enzyme-linked immunosorbent assay (ELISA). Neutralizing antibodies were detected in 14 of the 86 patients who tested positive for treatment-emergent anti-ramucirumab antibodies.

The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to CYRAMZA with the incidences of antibodies to other products may be misleading.

DRUG INTERACTIONS No pharmacokinetic (PK) interactions were observed between ramucirumab and docetaxel.

USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary Based on its mechanism of action, CYRAMZA can cause fetal harm. Animal models link angiogenesis, VEGF and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no available data on CYRAMZA in pregnant women to inform any drug-associated risks.

No animal studies have been conducted to evaluate the effect of ramucirumab on reproduction and fetal development. The background risk of major birth defects and miscarriage for the indicated populations are unknown. In the U.S. general population the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Advise pregnant women of the potential risk to a fetus.

Animal Data No animal studies have been specifically conducted to evaluate the effect of ramucirumab on reproduction and fetal development. In mice, loss of the VEGFR2 gene resulted in embryofetal death and these fetuses lacked organized blood vessels and blood islands in the yolk sac. In other models, VEGFR2 signaling was associated with development and maintenance of endometrial and placental vascular function, successful blastocyst implantation, maternal and feto-placental vascular differentiation, and development during early pregnancy in rodents and non-human primates.

Disruption of VEGF signaling has also been associated with developmental anomalies including poor development of the cranial region, forelimbs, forebrain, heart, and blood vessels.

CYRAMZA® (ramucirumab) injection RB-L HCP BS 04MAY2015

CYRAMZA RB-L HCP BS 04MAY2015 - 7 x 10

Placebo plus docetaxel (N=618) All Grades Grade 3-4 (Frequency %) (Frequency %)

Lactation Risk Summary There is no information on the presence of ramucirumab in human milk, the effects on the breast-fed infant, or the effects on milk production. Human IgG is present in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because of the potential risk for serious adverse reactions in nursing infants from ramucirumab, advise women that breastfeeding is not recommended during treatment with CYRAMZA. Females and Males of Reproductive Potential Contraception Females Based on its mechanism of action, CYRAMZA can cause fetal harm. Advise females of reproductive potential to use effective contraception while receiving CYRAMZA and for at least 3 months after the last dose of CYRAMZA. Infertility Females Advise females of reproductive potential that based on animal data CYRAMZA may impair fertility.

Pediatric Use The safety and effectiveness of CYRAMZA in pediatric patients have not been established.

In animal studies, effects on epiphyseal growth plates were identified. In cynomolgus monkeys, anatomical pathology revealed adverse effects on the epiphyseal growth plate (thickening and osteochondropathy) at all doses tested (5-50 mg/kg). Ramucirumab exposure at the lowest weekly dose tested in the cynomolgus monkey was 0.2 times the exposure in humans at the recommended dose of ramucirumab as a single agent.

Geriatric Use Of the 563 CYRAMZA-treated patients in two randomized gastric cancer clinical studies, 36% were 65 and over, while 7% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Of the 1253 patients in Study 3, 455 (36%) were 65 and over and 84 (7%) were 75 and over.

Of the 627 patients who received CYRAMZA plus docetaxel in Study 3, 237 (38%) were 65 and over, while 45 (7%) were 75 and over. In an exploratory subgroup analysis of Study 3, the hazard ratio for overall survival in patients less than 65 years old was 0.74 (95% CI: 0.62, 0.87) and in patients 65 years or older was 1.10 (95% CI: 0.89, 1.36).

Renal Impairment No dose adjustment is recommended for patients with renal impairment based on population pharmacokinetic analysis.

Hepatic Impairment No dose adjustment is recommended for patients with mild (total bilirubin within upper limit of normal [ULN] and aspartate aminotransferase [AST] >ULN, or total bilirubin >1.0-1.5 times ULN and any AST) or moderate (total bilirubin >1.5-3.0 times ULN and any AST) hepatic impairment based on population pharmacokinetic analysis. Clinical deterioration was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA. CYRAMZA® (ramucirumab) injection RB-L HCP BS 04MAY2015

PRINTER VERSION 2 OF 3

DOSAGE AND ADMINISTRATION Do not administer CYRAMZA as an intravenous push or bolus.

Recommended Dose and Schedule The recommended dose of CYRAMZA is 10 mg/kg administered by intravenous infusion over 60 minutes on day 1 of a 21-day cycle prior to docetaxel infusion. Continue CYRAMZA until disease progression or unacceptable toxicity.

Premedication Prior to each CYRAMZA infusion, premedicate all patients with an intravenous histamine H1 antagonist (e.g., diphenhydramine hydrochloride). For patients who have experienced a Grade 1 or 2 infusion reaction, also premedicate with dexamethasone (or equivalent) and acetaminophen prior to each CYRAMZA infusion.

Dose Modifications Infusion-Related Reactions (IRR) • Reduce the infusion rate of CYRAMZA by 50% for Grade 1 or 2 IRRs. • Permanently discontinue CYRAMZA for Grade 3 or 4 IRRs. Hypertension • Interrupt CYRAMZA for severe hypertension until controlled with medical management.

• Permanently discontinue CYRAMZA for severe hypertension that cannot be controlled with antihypertensive therapy.

Proteinuria • Interrupt CYRAMZA for urine protein levels ≥2 g/24 hours. Reinitiate treatment at a reduced dose of 8 mg/kg every 3 weeks once the urine protein level returns to <2 g/24 hours. If the protein level ≥2 g/24 hours reoccurs, interrupt CYRAMZA and reduce the dose to 6 mg/kg every 3 weeks once the urine protein level returns to <2 g/24 hours.

• Permanently discontinue CYRAMZA for urine protein level >3 g/24 hours or in the setting of nephrotic syndrome.

Wound Healing Complications • Interrupt CYRAMZA prior to scheduled surgery until the wound is fully healed.

Arterial Thromboembolic Events, Gastrointestinal Perforation, or Grade 3 or 4 Bleeding • Permanently discontinue CYRAMZA. For toxicities related to docetaxel, refer to the current respective prescribing information.

PATIENT COUNSELING INFORMATION • Hemorrhage: Advise patients that CYRAMZA can cause severe bleeding. Advise patients to contact their health care provider for bleeding or symptoms of bleeding including lightheadedness.

• Arterial thromboembolic events: Advise patients of an increased risk of an arterial thromboembolic event.

• Hypertension: Advise patients to undergo routine blood pressure monitoring and to contact their health care provider if blood pressure is elevated or if symptoms from hypertension occur including severe headache, lightheadedness, or neurologic symptoms.

• Gastrointestinal perforations: Advise patients to notify their health care provider for severe diarrhea, vomiting, or severe abdominal pain.

• Impaired wound healing: Advise patients that CYRAMZA has the potential to impair wound healing. Instruct patients not to undergo surgery without first discussing this potential risk with their health care provider.

• Pregnancy and fetal harm: Advise females of reproductive potential of the potential risk for maintaining pregnancy, risk to the fetus, and risk to postnatal newborn and infant development and to use effective contraception during CYRAMZA therapy and for at least 3 months following the last dose of CYRAMZA. • Lactation: Advise patients not to breastfeed during CYRAMZA treatment.

• Infertility: Advise females of reproductive potential regarding potential infertility effects of CYRAMZA. Additional information can be found at www.CYRAMZAhcp.com.

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RB-L HCP BS 04MAY2015 CYRAMZA® (ramucirumab) injection

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A9 LATEST NEWS

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REGIMEN & MONOGRAPH INDEX

Headlines in Oncology Research and Practice

A11 IN THE PIPELINE The Latest on Oncology Drugs

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Highlighted topics () contain both treatment regimens and drug monographs.

CME ACTIVITY Clinical Considerations in the Management of Chronic Lymphocytic Leukemia

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1-100 CANCER THERAPY REGIMENS & DRUG MONOGRAPHS

 1 Bone Cancer 7

Brain Cancer

FEATURE

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Breast Cancer

New Drug Approvals Bring Hope, Challenges in the Treatment of Patients With CLL

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Endocrine Cancer

 25 Gastrointestinal Cancer

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IN THE CLINIC Managing Pain in Patients With Cancer: Considerations When Prescribing Opioids C. ANDREW KISTLER, MD, PharmD, RPh

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Genitourinary Cancer

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Gynecologic Cancer

 47 Head and Neck Cancer

 53 Hematologic Cancer

EXPERT PERSPECTIVE We Can Treat Hodgkin’s Lymphoma Like Renal Cell Carcinoma and Melanoma?

ISABEL CUNNINGHAM, MD

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VIEWPOINT Study Suggests Using Caution When Sharing Information of Adult Patients Over 75 JOHN SCHIESZER

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Lung Cancer

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Sarcoma

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Skin Cancer

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Associated Hematological Disorders

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ALPHABETICAL INDEX

Cancer Therapy Advisor (ISSN 2375-558X), September/October 2015, Volume 2, Number 1. Published 6 times annually by Haymarket Media, Inc., 114 West 26th Street, 4th Floor, New York, NY 10001. For Advertising Sales, Editorial and Subscription information call (646) 638-6000 (M–F, 9am–5pm, ET). Standard Postage paid at Orem, UT. Postmaster: Send changes of address to Cancer Therapy Advisor, c/o Direct Medical Data, 10255 W. Higgins Rd., Suite 280, Rosemont, IL 60018.

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CancerTherapyAdvisor.com | SEPTEMBER/OCTOBER 2015 | CANCER THERAPY ADVISOR A7

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EDITORIAL & BUSINESS STAFF

EDITORIAL ADVISORY BOARD

Managing Editor, Haymarket Oncology

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Yale Cancer Center  New Haven, CT

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Fox Chase Cancer Center  Philadelphia, PA

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A8 CANCER THERAPY ADVISOR | SEPTEMBER/OCTOBER 2015 | CancerTherapyAdvisor.com

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LATEST NEWS

An analysis has found that using oral contraceptives for even a few years can give long-term protection against endometrial cancer, showing greater risk reduction with longer use. Findings from the study are published in The Lancet Oncology.

Over the past 50 years (1965–2014), researchers estimate that about 400,000 cases of endometrial cancer have been prevented by oral contraceptive use in high-income countries with about 200,000 from 2005 to 2014 alone. Study authors from the Collaborative Group on Epidemiological Studies on Endometrial Cancer analyzed data on 27,276 women with endometrial cancer across 36 studies.

They found that every five years of oral contraceptive use lowered the risk of endometrial cancer by about a quarter.

Ten years of oral contraceptive use was found to lower the risk of developing endometrial cancer before the age of 75 from 2.3 to 1.3 cases per 100 users. Specifically, the risk reduction was at least as great for women who took the pill during the 1980s as for women who took it in earlier decades. This shows that the hormone content in the lower-dose pills is still enough to reduce the incidence of endometrial cancer. Study authors added that the proportional risk reduction did not change substantially with women’s reproductive history, adiposity, alcohol use, tobacco use, or ethnicity.

Women who use oral contraceptives in their 20s or younger may see the protective benefits continue into their 50s and older even after stopping the pill, they concluded.

Adjunctive Telotristat Demonstrates Efficacy in Carcinoid Syndrome Lexicon Pharmaceuticals announced that the pivotal TELESTAR phase 3 clinical trial met its primary endpoint, showing the benefit of oral telotristat etiprate in treating patients with cancer with carcinoid syndrome that is not adequately controlled by the current standard of care, somatostatin analog depot injection (SSA) therapy.

TELESTAR (Telotristat Etiprate for Somatostatin Analogue Not Adequately Controlled Carcinoid Syndrome) is a double-blind, three-arm study that evaluated 250 mg and 500 mg doses of oral telotristat etiprate against placebo over

a 12-week period and measured the reduction from baseline in the average number of daily bowel movements. Patients in both the treatment and placebo arms continued their SSA therapy throughout the study.

Results show that patients who added telotristat etiprate to SSA therapy at both the 250 mg and 500 mg doses experienced a statistically significant reduction from baseline compared to placebo in the average number of daily bowel movements over the 12-week study period (P<0.001).

Telotristat etiprate is the first investigational drug in clinical studies to target tryptophan hydroxylase (TPH), an enzyme that triggers the excess serotonin production within mNET cells that leads to carcinoid syndrome.

If approved, telotristat etiprate would be the first oral treatment successfully developed for carcinoid syndrome and the first addition to the standard of care in more than 16 years.

PTSD, Cancer Not Linked in Largest Study to Date While the potential relationship between stress and cancer has been a topic of discussion and research for over 70 years, no association between post-traumatic stress disorder (PTSD) and cancer was found in the largest study to date, which was published in the European Journal of Epidemiology.

Jaimie L. Gradus, DSc, MPH, from the Boston University School of Medicine, and colleagues designed a nationwide cohort study of all Danish-born residents of Denmark from 1995 to 2011 using data from the Danish national medical and social registers. The exposure was PTSD diagnoses (4,131 patients) and the primary outcomes were all malignant neoplasms, hematologic malignancies, immune-related cancers, smoking- and alcohol-related cancers, and cancers at all other sites.

No association was found between PTSD and cancer diagnoses overall and stratified by gender, age, substance abuse history, and time since PTSD diagnosis. These results are consistent with other population-based studies that found no link between stressful life events and cancer incidence.

The authors note that the large sample size and length of study period allowed them to examine associations that had not been previously evaluated, such as rare cancer outcomes and associations among demographic subgroups.

© THINKSTOCK

Oral Contraceptives Could Protect Against Endometrial Cx for Decades

CancerTherapyAdvisor.com | SEPTEMBER/OCTOBER 2015 | CANCER THERAPY ADVISOR A9

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LATEST NEWS EDO-S101 NDA Accepted for Relapsed or Refractory Malignancies

Does Pioglitazone Increase Bladder Cancer Risk?

Mundipharma EDO (Early Development in Oncology) has announced that the U.S. Food and Drug Administration (FDA) has accepted the New Drug Application (NDA) for EDO-S101 for the treatment of relapsed or refractory hematologic malignancies and solid tumors.

The primary goal of the first clinical trial is to evaluate the safety and tolerability of EDO-S101 and its pharmacokinetic profile. This information will be used to establish the dose of EDO-S101 to be used in subsequent phase 1b and phase 2 trials. Gene expression profiles correlated with response or resistance to EDO-S101 will also be evaluated. A phase 1 trial in solid tumors will be developed once the dose escalation part of the first-in-human study has been completed.

EDO-S101 is a first-in-class fusion molecule that combines the DNA damaging effect of bendamustine with the panhistone deacetylase inhibitor (HDACi) vorinostat, with the aim of increasing the efficacy of the alkylator through the HDACi-mediated chromatin relaxation.

A statistically significant increased risk of bladder cancer was not found with the use of pioglitazone, although a small increased risk could not be excluded, according to an analysis published in JAMA. Prior st udies have suggested an increased risk of bladder cancer in patients with diabetes receiving pioglitazone.

Study authors from Kaiser Permanente Northern California assessed several cohorts of patients with diabetes, including a bladder cancer cohort (193,099 patients) until December 2012, and an additional cohort of 10 cancers (236,507 patients) until June 2012.

The results showed no statistically significant increase in bladder cancer with use of pioglitazone. Among the bladder cancer cohort, 34,181 patients received pioglitazone for a mean duration of 2.8 years, and 1,261 had bladder cancer. In casecontrol analyses, pioglitazone use was seen in 19.6% of case patients and 17.5% of control patients. In addition, though there was no association of increased cancer risk in eight of the 10 additional cancers, use of pioglitazone was associated with an increased risk of pancreatic and prostate cancer.

Targeting the bacteria Helicobacter pylori (H. pylori) with a short course of combination therapy may help decrease the risk of gastric cancer, study findings published in the Cochrane Library suggest.

Researchers conducted a systematic review and meta-analysis of all published randomized controlled trials that compared at least one week of H. pylori therapy with placebo or no treatment in healthy and asymptomatic H. pylori-positive adults to assess whether eradicating H. pylori could reduce the incidence of gastric cancer. The final review included six trials, which included close to 6,500 patients. The studies included a combination of antibiotics with proton pump inhibitors that suppress gastric acid production. Study authors found that this combination therapy given for one to two weeks prevented the development of gastric acid vs placebo or no treatment.

Specifically, 1.6% of patients treated for H. pylori developed gastric cancer vs 2.4% of patients untreated or given a placebo.

Study findings support the existing research that eliminating H. pylori in the general population can potentially prevent gastric cancer, researchers concluded. More studies are needed on the extent of the effect and any possible harms that are associated with H. pylori treatment.

Routine Clinical Genetic Testing Should Include RAD51C, RAD51D, Study Suggests RAD51C and RAD51D are moderate ovarian cancer susceptibility genes, a study in the Journal of Clinical Oncology has shown.

Researchers sought to estimate the contribution of deleterious mutations in the RAD51B, RAD51C, and RAD51D genes to the risk of invasive epithelial ovarian cancer in the population and in high-risk individuals who participated in a screening trial.

Using a case-control study of 3,429 patients with invasive epithelial ovarian cancer and 2,772 controls, researchers identified predicted deleterious mutations in 0.82% of ovarian cancer cases compared with 0.11% of controls (P<0.001).

Results showed that patients with RAD51C and RAD51D mutations were 5.2 and 12 times, respectively, more likely to develop ovarian cancer than the controls.

The findings suggest that RAD51C and RAD51D confer levels of risk of invasive epithelial ovarian cancer “that may warrant their use alongside BRCA1 and BRCA2 in routine clinical genetic testing,” the authors concluded.

© THINKSTOCK

Can Eliminating H. pylori Prevent Gastric Cancer?

A10 CANCER THERAPY ADVISOR | SEPTEMBER/OCTOBER 2015 | CancerTherapyAdvisor.com

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IN THE PIPELINE Kyprolis sNDA for Expanded Multiple Myeloma Indication Amgen announced the submission of a supplemental New Drug Application (sNDA) to the U.S. Food and Drug Administration (FDA) for Kyprolis (carfilzomib) for injection for the treatment of patients with relapsed multiple myeloma who have received at least one prior therapy.

The sNDA submission is based on dat a f rom t he ra ndom iz ed, global phase 3 ENDEAVOR trial evaluating carfilzomib in combination w it h dexamet hasone vs Velcade (bortezomib) with dexamethasone in patients whose multiple myeloma has relapsed after at least one, but not more than three prior therapeutic regimens.

The primary endpoint of the trial was progression-free survival (PFS).

R e l a p s e d m u lt i p l e m y e l o m a patients treated with carfilzomib and dexamethasone in the study lived twice as long without their disease worsening, demonstrating statistically and clinically significant superiority over bortezomib.

For more information call (800) 772-6436 or visit Amgen.com.

Nanoparticle Drug Delivery System Orphan Drug Designation n NanoSmart Pharmaceuticals has received Orphan Drug designation f rom t he U.S. Food a nd Dr ug Administration (FDA) for a second drug product that uses its nanoparticle drug delivery system.

The drug product is a formulation of dactinomycin for the treatment of Ew i ng’s sa rcoma. The FDA

granted NanoSmart’s Orphan Drug Designation on the basis of a plausible hypothesis that the novel formulation may be clinically superior to the original drug.

NanoSmart’s formulation is expected to localize drug delivery to the tumor site, thereby increasing effectiveness at the tumor while simultaneously improving safety.

For more information visit NanoSmartPharma.com.

metastat ic renal cell carcinoma.

Lenvatinib is a receptor t yrosine kinase (RTK) inhibitor that inhibits t he k inase act iv it ies of vascular endothelial growth factor (VEGF) receptors VEGFR1-3. It also inhibits other RTKs that have been implicated in pathogenic angiogenesis, tumor growth, and cancer progression in addition to their normal cellular functions, including fibroblast growth factor (FGF) receptors FGFR1-4; the platelet derived growth factor receptor alpha (PDGFRα), KIT, and RET.

Lenvima Granted Breakthrough Therapy for Advanced RCC

For more information call (888) 422–4743 or visit Eisai.com.

Eisai announced that the U.S. Food and Drug Administration (FDA) g r a nt e d L e n v i m a ( le n v at i n ib) Breakthrough Therapy designation for use in patients with advanced or metastatic renal cell carcinoma (RCC) who were previously treated with a vascular endothelial growth factor (VEGF)-targeted therapy.

The Brea k t h rough Therapy designation for lenvatinib was based on results of a phase 2 open-label, mult icenter st udy involv ing 153 patients who were previously treated with a VEGF-targeted therapy and randomized 1:1:1 to receive lenvatinib in combination everolimus, lenvatinib alone, or everolimus alone. Nearly all patients (99%) had received one prior VEGF-targeted therapy, 1% had received two prior VEGF-targeted therapies, and 18% had received prior immunotherapy treatment.

Lenvatinib is approved for the treatment of patients with locally recurrent or metastatic, progressive, rad ioact ive iod i ne-ref ractor y differentiated thyroid cancer (DTC).

It is not indicated for patients with

Melphalan Designated Orphan Drug for Bile Duct Cancer Delcath Systems announced that the U.S. Food and Drug Administration (FDA) has granted Orphan Drug designation to melphalan for the treatment of cholangiocarcinoma.

Recently Delcath Systems announced the expansion of its global phase 2 clinical study in primary liver cancer (HCC) to include an intrahepatic cholangiocarcinoma (ICC) cohort, which is investigating the safet y and eff icacy of Melphalan / HDS treatment in patients with unresectable ICC confined to the liver. The ICC cohort will evaluate tumor response (objective response rate), progressionfree survival, and safety. Additional a n a ly se s w i l l be conduc ted to characterize the systemic exposure of melph a l a n ad m i n i stered b y Melphalan/HDS, as well as to assess patient-reported clinical outcomes, or quality-of-life.

For more information visit Delcath.com.

CancerTherapyAdvisor.com | SEPTEMBER/OCTOBER 2015 | CANCER THERAPY ADVISOR A11

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JOINING FORCES In PALOMA-1, first-line IBRANCE® (palbociclib) + letrozole doubled median progression-free survival (mPFS) in postmenopausal women with estrogen receptor positive (ER+)/human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer1 An innovative combination of the first-in-class CDK4/6 inhibitor and an antihormonal therapy

Compelling 10-month improvement in mPFS with first-line IBRANCE + letrozole vs letrozole alone1 HR=0.488 (95% CI: 0.319–0.748)

100 90 80

PFS probability (%)

1 pathway. 2 targets. TWICE THE IMPACT

20.2 months

70 60

with IBRANCE + letrozole (n=84) (95% CI: 13.8–27.5)

50

PALOMA-1 was a randomized 1:1, open-label, multicenter Phase II study designed to evaluate the efficacy and safety of IBRANCE 125 mg in combination with letrozole 2.5 mg compared with letrozole alone in the first-line treatment of postmenopausal women with ER-positive, HER2negative advanced breast cancer (N=165).2

10.2 months

40

with letrozole (n=81) (95% CI: 5.7–12.6)

30 20

PFS=progression-free survival; ER=estrogen receptor; HR=hazard ratio; CI=confidence interval.

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4

8

12

16

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84 81

67 48

20

24

28

32

36

40

21 6

13 3

8 3

5 1

1

Months 60 36

47 28

36 19

28 14

IBR=Ibrance; LET=letrozole.

PALOMA-1: overall response • 55.4% overall response (OR)* with IBRANCE + letrozole vs 39.4% with letrozole alone in the measurable disease population Neutropenia: Neutropenia was the most frequently reported adverse reaction in the combination arm (all grades, 75%). Grade 3 (57%) or 4 (5%) decreased neutrophil counts were reported in patients receiving IBRANCE plus letrozole in PALOMA-1. Febrile neutropenia events have been reported in the IBRANCE clinical program, although no cases of febrile neutropenia have been observed in PALOMA-1. Monitor complete blood count prior to starting IBRANCE therapy and at the beginning of each cycle, as well as on Day 14 of the first two cycles, and as clinically indicated. Dose interruption, dose reduction or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia.

In the first-line setting, start with IBRANCE + letrozole • Unique MOA: Dual inhibition of CDK4/6 and the ER pathway demonstrated increased growth arrest in untreated ER+ cell lines compared with treatment with each drug alone • Dosing: Once-daily oral regimen: 125-mg IBRANCE once daily for 3 weeks on, 1 week off plus 2.5-mg letrozole once daily, continuously —Please see General dosing information and the Dosing and Administration section of the Brief Summary on the following page for more details regarding proper dosing

Indication IBRANCE is a kinase inhibitor indicated in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease.

To learn more, visit IbranceHCP.com, which includes access and coverage details and the full Prescribing Information. *OR, defined as number (%) of patients with complete response (CR) or partial response (PR), was analyzed in the evaluable patients with measurable disease at baseline (IBRANCE + letrozole n=65; letrozole alone n=66).1

This indication is approved under accelerated approval based on progression-free survival (PFS). Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

References: 1. Data on file. Pfizer Inc, New York, NY. 2. Finn RS, Crown JP, Lang I, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study [published online ahead of print December 16, 2014]. Lancet Oncol. http://dx.doi.org/10.1016/S1470-2045(14)71159-3.

Important Safety Information

Pregnancy and lactation: Based on the mechanism of action, IBRANCE can cause fetal harm. Advise females with reproductive potential to use effective contraception during therapy with IBRANCE and for at least 2 weeks after the last dose. Advise females to contact their healthcare provider if they become pregnant or if pregnancy is suspected during treatment with IBRANCE. Advise women not to breastfeed while on IBRANCE therapy because of the potential for serious adverse reactions in nursing infants from IBRANCE. Additional hematologic abnormalities: Decreases in hemoglobin (83% vs 40%), leukocytes (95% vs 26%), lymphocytes (81% vs 35%), and platelets (61% vs 16%) occurred at a higher rate in patients treated with IBRANCE plus letrozole vs letrozole alone.

Adverse reactions: The most common all causality adverse reactions (≥10%) of any grade reported in patients treated with IBRANCE plus letrozole vs letrozole alone in the phase II study included neutropenia (75% vs 5%), leukopenia (43% vs 3%), fatigue (41% vs 23%), anemia (35% vs 7%), upper respiratory infection (31% vs 18%), nausea (25% vs 13%), stomatitis (25% vs 7%), alopecia (22% vs 3%), diarrhea (21% vs 10%), thrombocytopenia (17% vs 1%), decreased appetite (16% vs 7%), vomiting (15% vs 4%), asthenia (13% vs 4%), peripheral neuropathy (13% vs 5%), and epistaxis (11% vs 1%).

Neutropenia: Neutropenia is frequently reported with IBRANCE therapy. In the randomized phase II study, Grade 3 (57%) or 4 (5%) decreased neutrophil counts were reported in patients receiving IBRANCE plus letrozole. Febrile neutropenia can occur.

Monitor complete blood count prior to starting IBRANCE and at the beginning of each cycle, as well as Day 14 of the first two cycles, and as clinically indicated. For patients who experience Grade 3 neutropenia, consider repeating the complete blood count monitoring 1 week later. Dose interruption, dose reduction, or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia.

Infections: Infections have been reported at a higher rate in patients treated with IBRANCE plus letrozole (55%) compared with letrozole alone (34%). Grade 3 or 4 infections occurred in 5% of patients treated with IBRANCE plus letrozole vs no patients treated with letrozole alone. Monitor patients for signs and symptoms of infection and treat as medically appropriate.

Pulmonary embolism (PE): PE has been reported at a higher rate in patients treated with IBRANCE plus letrozole (5%) compared with no cases in patients treated with letrozole alone. Monitor patients for signs and symptoms of PE and treat as medically appropriate.

Please see additional Important Safety Information and Brief Summary on following pages.

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JOINING FORCES In PALOMA-1, first-line IBRANCE® (palbociclib) + letrozole doubled median progression-free survival (mPFS) in postmenopausal women with estrogen receptor positive (ER+)/human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer1 An innovative combination of the first-in-class CDK4/6 inhibitor and an antihormonal therapy

Compelling 10-month improvement in mPFS with first-line IBRANCE + letrozole vs letrozole alone1 HR=0.488 (95% CI: 0.319–0.748)

100 90 80

PFS probability (%)

1 pathway. 2 targets. TWICE THE IMPACT

20.2 months

70 60

with IBRANCE + letrozole (n=84) (95% CI: 13.8–27.5)

50

PALOMA-1 was a randomized 1:1, open-label, multicenter Phase II study designed to evaluate the efficacy and safety of IBRANCE 125 mg in combination with letrozole 2.5 mg compared with letrozole alone in the first-line treatment of postmenopausal women with ER-positive, HER2negative advanced breast cancer (N=165).2

10.2 months

40

with letrozole (n=81) (95% CI: 5.7–12.6)

30 20

PFS=progression-free survival; ER=estrogen receptor; HR=hazard ratio; CI=confidence interval.

10 0 0

4

8

12

16

Number of patients at risk IBR+LET LET

84 81

67 48

20

24

28

32

36

40

21 6

13 3

8 3

5 1

1

Months 60 36

47 28

36 19

28 14

IBR=Ibrance; LET=letrozole.

PALOMA-1: overall response • 55.4% overall response (OR)* with IBRANCE + letrozole vs 39.4% with letrozole alone in the measurable disease population Neutropenia: Neutropenia was the most frequently reported adverse reaction in the combination arm (all grades, 75%). Grade 3 (57%) or 4 (5%) decreased neutrophil counts were reported in patients receiving IBRANCE plus letrozole in PALOMA-1. Febrile neutropenia events have been reported in the IBRANCE clinical program, although no cases of febrile neutropenia have been observed in PALOMA-1. Monitor complete blood count prior to starting IBRANCE therapy and at the beginning of each cycle, as well as on Day 14 of the first two cycles, and as clinically indicated. Dose interruption, dose reduction or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia.

In the first-line setting, start with IBRANCE + letrozole • Unique MOA: Dual inhibition of CDK4/6 and the ER pathway demonstrated increased growth arrest in untreated ER+ cell lines compared with treatment with each drug alone • Dosing: Once-daily oral regimen: 125-mg IBRANCE once daily for 3 weeks on, 1 week off plus 2.5-mg letrozole once daily, continuously —Please see General dosing information and the Dosing and Administration section of the Brief Summary on the following page for more details regarding proper dosing

Indication IBRANCE is a kinase inhibitor indicated in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease.

To learn more, visit IbranceHCP.com, which includes access and coverage details and the full Prescribing Information. *OR, defined as number (%) of patients with complete response (CR) or partial response (PR), was analyzed in the evaluable patients with measurable disease at baseline (IBRANCE + letrozole n=65; letrozole alone n=66).1

This indication is approved under accelerated approval based on progression-free survival (PFS). Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

References: 1. Data on file. Pfizer Inc, New York, NY. 2. Finn RS, Crown JP, Lang I, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study [published online ahead of print December 16, 2014]. Lancet Oncol. http://dx.doi.org/10.1016/S1470-2045(14)71159-3.

Important Safety Information

Pregnancy and lactation: Based on the mechanism of action, IBRANCE can cause fetal harm. Advise females with reproductive potential to use effective contraception during therapy with IBRANCE and for at least 2 weeks after the last dose. Advise females to contact their healthcare provider if they become pregnant or if pregnancy is suspected during treatment with IBRANCE. Advise women not to breastfeed while on IBRANCE therapy because of the potential for serious adverse reactions in nursing infants from IBRANCE. Additional hematologic abnormalities: Decreases in hemoglobin (83% vs 40%), leukocytes (95% vs 26%), lymphocytes (81% vs 35%), and platelets (61% vs 16%) occurred at a higher rate in patients treated with IBRANCE plus letrozole vs letrozole alone.

Adverse reactions: The most common all causality adverse reactions (≥10%) of any grade reported in patients treated with IBRANCE plus letrozole vs letrozole alone in the phase II study included neutropenia (75% vs 5%), leukopenia (43% vs 3%), fatigue (41% vs 23%), anemia (35% vs 7%), upper respiratory infection (31% vs 18%), nausea (25% vs 13%), stomatitis (25% vs 7%), alopecia (22% vs 3%), diarrhea (21% vs 10%), thrombocytopenia (17% vs 1%), decreased appetite (16% vs 7%), vomiting (15% vs 4%), asthenia (13% vs 4%), peripheral neuropathy (13% vs 5%), and epistaxis (11% vs 1%).

Neutropenia: Neutropenia is frequently reported with IBRANCE therapy. In the randomized phase II study, Grade 3 (57%) or 4 (5%) decreased neutrophil counts were reported in patients receiving IBRANCE plus letrozole. Febrile neutropenia can occur.

Monitor complete blood count prior to starting IBRANCE and at the beginning of each cycle, as well as Day 14 of the first two cycles, and as clinically indicated. For patients who experience Grade 3 neutropenia, consider repeating the complete blood count monitoring 1 week later. Dose interruption, dose reduction, or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia.

Infections: Infections have been reported at a higher rate in patients treated with IBRANCE plus letrozole (55%) compared with letrozole alone (34%). Grade 3 or 4 infections occurred in 5% of patients treated with IBRANCE plus letrozole vs no patients treated with letrozole alone. Monitor patients for signs and symptoms of infection and treat as medically appropriate.

Pulmonary embolism (PE): PE has been reported at a higher rate in patients treated with IBRANCE plus letrozole (5%) compared with no cases in patients treated with letrozole alone. Monitor patients for signs and symptoms of PE and treat as medically appropriate.

Please see additional Important Safety Information and Brief Summary on following pages.

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Important Safety Information (continued) Grade 3/4 adverse reactions reported (≥10%) occurring at a higher incidence in the IBRANCE® (palbociclib) plus letrozole vs letrozole alone group include neutropenia (54% vs 1%) and leukopenia (19% vs 0%). The most frequently reported serious adverse events in patients receiving IBRANCE were pulmonary embolism (4%) and diarrhea (2%).

General dosing information: The recommended dose of IBRANCE is 125 mg taken orally once daily for 21 days followed by 7 days off treatment in 28-day cycles. IBRANCE should be taken with food and in combination with letrozole 2.5 mg once daily continuously.

Patients should be encouraged to take their dose at approximately the same time each day.

Capsules should be swallowed whole. No capsule should be ingested if it is broken, cracked, or otherwise not intact. If a patient vomits or misses a dose, an additional dose should not be taken that day. The next prescribed dose should be taken at the usual time.

Management of some adverse reactions may require temporary dose interruption/delay and/or dose reduction, or permanent discontinuation. Dose modification of IBRANCE is recommended based on individual safety and tolerability.

Drug interactions: Avoid concurrent use of strong CYP3A inhibitors. If patients must be administered a strong CYP3A inhibitor, reduce the IBRANCE dose to 75 mg/day. If the strong inhibitor is discontinued, increase the IBRANCE dose (after 3–5 half-lives of the inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor. Grapefruit or grapefruit juice may increase plasma concentrations of IBRANCE and should be avoided.

Avoid concomitant use of strong and moderate CYP3A inducers. The dose of the sensitive CYP3A substrates with a narrow therapeutic index may need to be reduced as IBRANCE may increase their exposure.

Hepatic and renal impairment: IBRANCE has not been studied in patients with moderate to severe hepatic impairment or in patients with severe renal impairment (CrCl <30 mL/min).

Brief Summary of Prescribing Information

Dose Modification and Management – Non-Hematologic Toxicities

IBRANCE® (palbociclib) capsules Initial US Approval: 2015

CTCAE Grade

INDICATIONS AND USAGE IBRANCE is indicated in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease.

This indication is approved under accelerated approval based on progression-free survival (PFS) [see Clinical Studies]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

DOSAGE AND ADMINISTRATION General Dosing Information. The recommended dose of IBRANCE is a 125 mg capsule taken orally once daily for 21 consecutive days followed by 7 days off treatment to comprise a complete cycle of 28 days. IBRANCE should be taken with food in combination with letrozole 2.5 mg once daily given continuously throughout the 28-day cycle. [see Clinical Pharmacology]. Patients should be encouraged to take their dose at approximately the same time each day.

If the patient vomits or misses a dose, an additional dose should not be taken that day.

The next prescribed dose should be taken at the usual time. IBRANCE capsules should be swallowed whole (do not chew, crush or open them prior to swallowing). No capsule should be ingested if it is broken, cracked, or otherwise not intact.

Dose Modification. Dose modification of IBRANCE is recommended based on individual safety and tolerability.

Management of some adverse reactions [see Warnings and Precautions] may require temporary dose interruptions/delays and/or dose reductions, or permanent discontinuation.

If dose reduction is required the first recommended dose reduction is 100 mg/day and the second dose reduction is 75 mg/day. If further dose reduction below 75 mg/day is required, discontinue the treatment.

Dose Modification and Managementa – Hematologic Toxicities CTCAE Grade

Dose Modifications

Grade 1 or 2

No dose adjustment is required.

Grade 3b

No dose adjustment is required.

Consider repeating complete blood count monitoring one week later.

Withhold initiation of next cycle until recovery to Grade ≤2.

Grade 3 ANC (<1000 to 500/mm3) + Fever ≥38.5ºC and/or infection

Withhold IBRANCE and initiation of next cycle until recovery to Grade ≤2 (≥1000/mm3).

Resume at next lower dose.

Grade 4b

Withhold IBRANCE and initiation of next cycle until recovery to Grade ≤2.

Resume at next lower dose.

Grading according to CTCAE Version 4.0.

ANC=absolute neutrophil count; CTCAE=Common Terminology Criteria for Adverse Events. a Monitor complete blood count prior to the start of IBRANCE therapy and at the beginning of each cycle, as well as on Day 14 of the first two cycles, and as clinically indicated. b E xcept lymphopenia (unless associated with clinical events, e.g., opportunistic infections).

Dose Modifications

Grade 1 or 2

No dose adjustment is required.

Grade ≥3 non-hematologic toxicity (if persisting despite medical treatment)

Withhold until symptoms resolve to: • Grade ≤1; • Grade ≤2 (if not considered a safety risk for the patient) Resume at the next lower dose.

See manufacturer’s prescribing information for the coadministered product, letrozole, dose adjustment guidelines in the event of toxicity and other relevant safety information or contraindications.

Dose Modifications for Use With Strong CYP3A Inhibitors. Avoid concomitant use of strong CYP3A inhibitors and consider an alternative concomitant medication with no or minimal CYP3A inhibition. If patients must be coadministered a strong CYP3A inhibitor, reduce the IBRANCE dose to 75 mg once daily. If the strong inhibitor is discontinued, increase the IBRANCE dose (after 3–5 half-lives of the inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor [see Drug Interactions and Clinical Pharmacology].

DOSAGE FORMS AND STRENGTHS 125 mg capsules: opaque hard gelatin capsules, size 0, with caramel cap and body, printed with white ink “Pfizer” on the cap, “PBC 125” on the body.

100 mg capsules: opaque hard gelatin capsules, size 1, with caramel cap and light orange body, printed with white ink “Pfizer” on the cap, “PBC 100” on the body.

75 mg capsules: opaque hard gelatin capsules, size 2, with light orange cap and body, printed with white ink “Pfizer” on the cap, “PBC 75” on the body.

CONTRAINDICATIONS: None WARNINGS AND PRECAUTIONS Neutropenia. Decreased neutrophil counts have been observed in clinical trials with IBRANCE. Grade 3 (57%) or 4 (5%) decreased neutrophil counts were reported in patients receiving IBRANCE plus letrozole in the randomized clinical trial (Study 1).

Median time to first episode of any grade neutropenia per laboratory data was 15 days (13–117 days). Median duration of Grade ≥3 neutropenia was 7 days [see Adverse Reactions].

Febrile neutropenia events have been reported in the IBRANCE clinical program, although no cases of febrile neutropenia have been observed in Study 1. Monitor complete blood count prior to starting IBRANCE therapy and at the beginning of each cycle, as well as on Day 14 of the first two cycles, and as clinically indicated.

Dose interruption, dose reduction or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia [see Dosage and Administration].

Infections. Infections have been reported at a higher rate in patients treated with IBRANCE plus letrozole compared to patients treated with letrozole alone in Study 1. Grade 3 or 4 infections occurred in 5% of patients treated with IBRANCE plus letrozole whereas no patients treated with letrozole alone experienced a Grade 3 or 4 infection. Monitor patients for signs and symptoms of infection and treat as medically appropriate.

Pulmonary Embolism. Pulmonary embolism has been reported at a higher rate in patients treated with IBRANCE plus letrozole (5%) compared with no cases in patients treated with letrozole alone in Study 1. Monitor patients for signs and symptoms of pulmonary embolism and treat as medically appropriate.

Embryo-Fetal Toxicity. Based on findings in animals and mechanism of action, IBRANCE can cause fetal harm. IBRANCE caused embryo-fetal toxicities in rats and rabbits at maternal exposures that were greater than or equal to 4 times the human clinical exposure based on area under the curve (AUC). Advise females of reproductive potential to use effective contraception during therapy with IBRANCE and for at least two weeks after the last dose [see Use in Specific Populations and Clinical Pharmacology].

ADVERSE REACTIONS Clinical Studies Experience. Because clinical trials are conducted under varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice.

The safety of IBRANCE (125 mg/day) plus letrozole (2.5 mg/day) versus letrozole alone was evaluated in Study 1. The data described below reflect exposure to IBRANCE in 83 out of 160 patients with ER-positive, HER2-negative advanced breast cancer who received at least 1 dose of treatment in Study 1. The median duration of treatment for palbociclib was 13.8 months while the median duration of treatment for letrozole on the letrozole-alone arm was 7.6 months.

Dose reductions due to an adverse reaction of any grade occurred in 38.6% of patients receiving IBRANCE plus letrozole. No dose reduction was allowed for letrozole in Study 1.

Permanent discontinuation due to an adverse event occurred in 7 of 83 (8%) patients receiving IBRANCE plus letrozole, and in 2 of 77 (3%) patients receiving letrozole alone. Adverse reactions leading to discontinuation for those patients receiving IBRANCE plus letrozole included neutropenia (6%), asthenia (1%), and fatigue (1%).

The most common adverse reactions (≥10%) of any grade reported in patients in the IBRANCE plus letrozole arm were neutropenia, leukopenia, fatigue, anemia, upper respiratory infection, nausea, stomatitis, alopecia, diarrhea, thrombocytopenia, decreased appetite, vomiting, asthenia, peripheral neuropathy, and epistaxis.

The most frequently reported serious adverse reactions in patients receiving IBRANCE plus letrozole were pulmonary embolism (3 of 83; 4%) and diarrhea (2 of 83; 2%).

An increased incidence of infections events was observed in the palbociclib plus letrozole arm (55%) compared to the letrozole alone arm (34%). Febrile neutropenia events have been reported in the IBRANCE clinical program, although no cases were observed in Study 1. Grade ≥3 neutropenia was managed by dose reductions and/or dose delay or temporary discontinuation consistent with a permanent discontinuation rate of 6% due to neutropenia [see Dosage and Administration].

The following table presents adverse drug reactions (≥10%) reported in patients who received IBRANCE plus letrozole or letrozole alone.

Adverse Reactions* (≥10%) in Study 1 IBRANCE + Letrozole (N=83) Letrozole Alone (N=77) System Organ Class All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 Any Adverse Drug Reaction (%) (%) (%) (%) (%) (%) Infections and infestations URIa 31 1 0 18 0 0 Blood and lymphatic system disorders Neutropenia 75 48 6 5 1 0 Leukopenia 43 19 0 3 0 0 Anemia 35 5 1 7 1 0 Thrombocytopenia 17 2 0 1 0 0 Metabolism and nutrition disorders Decreased appetite 16 1 0 7 0 0 Nervous system disorders b Peripheral neuropathy 13 0 0 5 0 0 Respiratory, thoracic, and mediastinal disorders Epistaxis 11 0 0 1 0 0 Gastrointestinal disorders Stomatitisc 25 0 0 7 1 0 Nausea 25 2 0 13 1 0 Diarrhea 21 4 0 10 0 0 Vomiting 15 0 0 4 1 0 Skin and subcutaneous tissue disorders Alopecia 22d N/A N/A 3e N/A N/A General disorders and administration site conditions Fatigue 41 2 2 23 1 0 Asthenia 13 2 0 4 0 0

* Adverse Reaction rates reported in the table include all reported events regardless of causality.

Grading according to CTCAE Version 3.0.

CTCAE=Common Terminology Criteria for Adverse Events; N=number of subjects; N/A=not applicable; URI=Upper respiratory infection. a URI includes: Influenza, Influenza like illness, Laryngitis, Nasopharyngitis, Pharyngitis, Rhinitis, Sinusitis, Upper respiratory tract infection. b Peripheral neuropathy includes: Neuropathy peripheral, Peripheral sensory neuropathy. c Stomatitis includes: Aphthous stomatitis, Cheilitis, Glossitis, Glossodynia, Mouth ulceration, Mucosal inflammation, Oral pain, Oropharyngeal discomfort, Oropharyngeal pain, Stomatitis. d Grade 1 events - 21%; Grade 2 events - 1%. e Grade 1 events - 3%.

Laboratory Abnormality for Patients in Study 1 Laboratory Abnormality White blood cells decreased Neutrophils decreased Lymphocytes decreased Hemoglobin decreased Platelets decreased N=number of patients.

IBRANCE + Letrozole (N=83) Letrozole Alone (N=77) All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 (%) (%) (%) (%) (%) (%) 95 44 0 26 0 0 94 57 5 17 3 0 81 17 1 35 3 0 83 5 1 40 3 0 61 3 0 16 3 0

DRUG INTERACTIONS Effect of CYP3A Inhibitors. Coadministration of a strong CYP3A inhibitor (itraconazole) increased the plasma exposure of palbociclib in healthy subjects by 87%. Avoid concomitant use of strong CYP3A inhibitors (e.g., clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, verapamil, and voriconazole). Avoid grapefruit or grapefruit juice during IBRANCE treatment. If

coadministration of IBRANCE with a strong CYP3A inhibitor cannot be avoided, reduce the dose of IBRANCE [see Dosage and Administration and Clinical Pharmacology].

Effect of CYP3A Inducers. Coadministration of a strong CYP3A inducer (rifampin) decreased the plasma exposure of palbociclib in healthy subjects by 85%. Avoid concomitant use of strong CYP3A inducers (e.g., phenytoin, rifampin, carbamazepine and St John’s Wort) [see Clinical Pharmacology].

Coadministration of moderate CYP3A inducers may also decrease the plasma exposure of IBRANCE. Avoid concomitant use of moderate CYP3A inducers (e.g., bosentan, efavirenz, etravirine, modafinil, and nafcillin) [see Clinical Pharmacology].

Drugs That May Have Their Plasma Concentrations Altered by Palbociclib.

Coadministration of midazolam with multiple doses of IBRANCE increased the midazolam plasma exposure by 61%, in healthy subjects, compared with administration of midazolam alone. The dose of the sensitive CYP3A substrate with a narrow therapeutic index (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, everolimus, fentanyl, pimozide, quinidine, sirolimus and tacrolimus) may need to be reduced as IBRANCE may increase their exposure [see Clinical Pharmacology].

USE IN SPECIFIC POPULATIONS Pregnancy. Based on findings in animals and mechanism of action, IBRANCE can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology]. In animal studies, palbociclib was teratogenic and fetotoxic at maternal exposures that were ≥4 times the human clinical exposure based on AUC at the recommended human dose. There are no available human data informing the drug-associated risk. Advise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is 2–4% and of miscarriage is 15–20% of clinically recognized pregnancies.

Lactation. There are no data on the presence of palbociclib in human milk, the effects of IBRANCE on the breastfed child, or the effects of IBRANCE on milk production.

Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from IBRANCE, advise a nursing woman to discontinue breastfeeding during treatment with IBRANCE. Females and Males of Reproductive Potential. Advise females of reproductive potential to use effective contraception during treatment with IBRANCE and for at least two weeks after the last dose. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with IBRANCE [see Use in Specific Populations].

Based on findings in animals, male fertility may be compromised by treatment with IBRANCE [see Carcinogenesis, Mutagenesis, Impairment of Fertility].

Pediatric Use. The safety and efficacy of IBRANCE in pediatric patients have not been studied.

Geriatric Use. Of 84 patients who received IBRANCE in Study 1, 37 patients (44%) were ≥65 years of age and 8 patients (10%) were ≥75 years of age. No overall differences in safety or effectiveness of IBRANCE were observed between these patients and younger patients but greater sensitivity of some older individuals cannot be ruled out.

Hepatic Impairment. Based on a population pharmacokinetic analysis that included 183 patients, where 40 patients had mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin >1.0 to 1.5 × ULN and any AST), mild hepatic impairment had no effect on the exposure of palbociclib. The pharmacokinetics of palbociclib have not been studied in patients with moderate or severe hepatic impairment (total bilirubin >1.5 × ULN and any AST) [see Clinical Pharmacology].

Renal Impairment. Based on a population pharmacokinetic analysis that included 183 patients, where 73 patients had mild renal impairment (60 mL/min ≤ CrCl <90 mL/min) and 29 patients had moderate renal impairment (30 mL/min ≤ CrCl <60 mL/min), mild and moderate renal impairment had no effect on the exposure of palbociclib. The pharmacokinetics of palbociclib have not been studied in patients with severe renal impairment [see Clinical Pharmacology].

OVERDOSAGE There is no known antidote for IBRANCE. The treatment of overdose of IBRANCE should consist of general supportive measures.

PATIENT COUNSELING INFORMATION • Advise patients to immediately report any signs or symptoms of myelosuppression or infection, such as fever, chills, dizziness, shortness of breath, weakness or any increased tendency to bleed and/or to bruise [see Warnings and Precautions].

• Advise patients to immediately report any signs or symptoms of pulmonary embolism, such as shortness of breath, chest pain, tachypnea, and tachycardia [see Warnings and Precautions].

• Advise patients to take IBRANCE with food and swallow IBRANCE capsules whole.

• I BRANCE may interact with grapefruit. Patients should not consume grapefruit products while on treatment with IBRANCE. • I nform patients to avoid strong CYP3A inhibitors and strong CYP3A inducers.

• Advise patients to inform their health care providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Drug Interactions].

• I f the patient vomits or misses a dose, an additional dose should not be taken that day. The next prescribed dose should be taken at the usual time. IBRANCE capsules should be swallowed whole (do not chew, crush or open them prior to swallowing).

No capsule should be ingested if it is broken, cracked, or otherwise not intact.

• Advise females of reproductive potential to use effective contraception during IBRANCE therapy and for at least two weeks after the last dose. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with IBRANCE [see Warnings and Precautions and Use in Specific Populations].

Rx only Issued: February 2015 ULN=upper limit of normal.

705404-01 © 2015 Pfizer Inc. All rights reserved. May 2015

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Important Safety Information (continued) Grade 3/4 adverse reactions reported (≥10%) occurring at a higher incidence in the IBRANCE® (palbociclib) plus letrozole vs letrozole alone group include neutropenia (54% vs 1%) and leukopenia (19% vs 0%). The most frequently reported serious adverse events in patients receiving IBRANCE were pulmonary embolism (4%) and diarrhea (2%).

General dosing information: The recommended dose of IBRANCE is 125 mg taken orally once daily for 21 days followed by 7 days off treatment in 28-day cycles. IBRANCE should be taken with food and in combination with letrozole 2.5 mg once daily continuously.

Patients should be encouraged to take their dose at approximately the same time each day.

Capsules should be swallowed whole. No capsule should be ingested if it is broken, cracked, or otherwise not intact. If a patient vomits or misses a dose, an additional dose should not be taken that day. The next prescribed dose should be taken at the usual time.

Management of some adverse reactions may require temporary dose interruption/delay and/or dose reduction, or permanent discontinuation. Dose modification of IBRANCE is recommended based on individual safety and tolerability.

Drug interactions: Avoid concurrent use of strong CYP3A inhibitors. If patients must be administered a strong CYP3A inhibitor, reduce the IBRANCE dose to 75 mg/day. If the strong inhibitor is discontinued, increase the IBRANCE dose (after 3–5 half-lives of the inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor. Grapefruit or grapefruit juice may increase plasma concentrations of IBRANCE and should be avoided.

Avoid concomitant use of strong and moderate CYP3A inducers. The dose of the sensitive CYP3A substrates with a narrow therapeutic index may need to be reduced as IBRANCE may increase their exposure.

Hepatic and renal impairment: IBRANCE has not been studied in patients with moderate to severe hepatic impairment or in patients with severe renal impairment (CrCl <30 mL/min).

Brief Summary of Prescribing Information

Dose Modification and Management – Non-Hematologic Toxicities

IBRANCE® (palbociclib) capsules Initial US Approval: 2015

CTCAE Grade

INDICATIONS AND USAGE IBRANCE is indicated in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease.

This indication is approved under accelerated approval based on progression-free survival (PFS) [see Clinical Studies]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

DOSAGE AND ADMINISTRATION General Dosing Information. The recommended dose of IBRANCE is a 125 mg capsule taken orally once daily for 21 consecutive days followed by 7 days off treatment to comprise a complete cycle of 28 days. IBRANCE should be taken with food in combination with letrozole 2.5 mg once daily given continuously throughout the 28-day cycle. [see Clinical Pharmacology]. Patients should be encouraged to take their dose at approximately the same time each day.

If the patient vomits or misses a dose, an additional dose should not be taken that day.

The next prescribed dose should be taken at the usual time. IBRANCE capsules should be swallowed whole (do not chew, crush or open them prior to swallowing). No capsule should be ingested if it is broken, cracked, or otherwise not intact.

Dose Modification. Dose modification of IBRANCE is recommended based on individual safety and tolerability.

Management of some adverse reactions [see Warnings and Precautions] may require temporary dose interruptions/delays and/or dose reductions, or permanent discontinuation.

If dose reduction is required the first recommended dose reduction is 100 mg/day and the second dose reduction is 75 mg/day. If further dose reduction below 75 mg/day is required, discontinue the treatment.

Dose Modification and Managementa – Hematologic Toxicities CTCAE Grade

Dose Modifications

Grade 1 or 2

No dose adjustment is required.

Grade 3b

No dose adjustment is required.

Consider repeating complete blood count monitoring one week later.

Withhold initiation of next cycle until recovery to Grade ≤2.

Grade 3 ANC (<1000 to 500/mm3) + Fever ≥38.5ºC and/or infection

Withhold IBRANCE and initiation of next cycle until recovery to Grade ≤2 (≥1000/mm3).

Resume at next lower dose.

Grade 4b

Withhold IBRANCE and initiation of next cycle until recovery to Grade ≤2.

Resume at next lower dose.

Grading according to CTCAE Version 4.0.

ANC=absolute neutrophil count; CTCAE=Common Terminology Criteria for Adverse Events. a Monitor complete blood count prior to the start of IBRANCE therapy and at the beginning of each cycle, as well as on Day 14 of the first two cycles, and as clinically indicated. b E xcept lymphopenia (unless associated with clinical events, e.g., opportunistic infections).

Dose Modifications

Grade 1 or 2

No dose adjustment is required.

Grade ≥3 non-hematologic toxicity (if persisting despite medical treatment)

Withhold until symptoms resolve to: • Grade ≤1; • Grade ≤2 (if not considered a safety risk for the patient) Resume at the next lower dose.

See manufacturer’s prescribing information for the coadministered product, letrozole, dose adjustment guidelines in the event of toxicity and other relevant safety information or contraindications.

Dose Modifications for Use With Strong CYP3A Inhibitors. Avoid concomitant use of strong CYP3A inhibitors and consider an alternative concomitant medication with no or minimal CYP3A inhibition. If patients must be coadministered a strong CYP3A inhibitor, reduce the IBRANCE dose to 75 mg once daily. If the strong inhibitor is discontinued, increase the IBRANCE dose (after 3–5 half-lives of the inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor [see Drug Interactions and Clinical Pharmacology].

DOSAGE FORMS AND STRENGTHS 125 mg capsules: opaque hard gelatin capsules, size 0, with caramel cap and body, printed with white ink “Pfizer” on the cap, “PBC 125” on the body.

100 mg capsules: opaque hard gelatin capsules, size 1, with caramel cap and light orange body, printed with white ink “Pfizer” on the cap, “PBC 100” on the body.

75 mg capsules: opaque hard gelatin capsules, size 2, with light orange cap and body, printed with white ink “Pfizer” on the cap, “PBC 75” on the body.

CONTRAINDICATIONS: None WARNINGS AND PRECAUTIONS Neutropenia. Decreased neutrophil counts have been observed in clinical trials with IBRANCE. Grade 3 (57%) or 4 (5%) decreased neutrophil counts were reported in patients receiving IBRANCE plus letrozole in the randomized clinical trial (Study 1).

Median time to first episode of any grade neutropenia per laboratory data was 15 days (13–117 days). Median duration of Grade ≥3 neutropenia was 7 days [see Adverse Reactions].

Febrile neutropenia events have been reported in the IBRANCE clinical program, although no cases of febrile neutropenia have been observed in Study 1. Monitor complete blood count prior to starting IBRANCE therapy and at the beginning of each cycle, as well as on Day 14 of the first two cycles, and as clinically indicated.

Dose interruption, dose reduction or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia [see Dosage and Administration].

Infections. Infections have been reported at a higher rate in patients treated with IBRANCE plus letrozole compared to patients treated with letrozole alone in Study 1. Grade 3 or 4 infections occurred in 5% of patients treated with IBRANCE plus letrozole whereas no patients treated with letrozole alone experienced a Grade 3 or 4 infection. Monitor patients for signs and symptoms of infection and treat as medically appropriate.

Pulmonary Embolism. Pulmonary embolism has been reported at a higher rate in patients treated with IBRANCE plus letrozole (5%) compared with no cases in patients treated with letrozole alone in Study 1. Monitor patients for signs and symptoms of pulmonary embolism and treat as medically appropriate.

Embryo-Fetal Toxicity. Based on findings in animals and mechanism of action, IBRANCE can cause fetal harm. IBRANCE caused embryo-fetal toxicities in rats and rabbits at maternal exposures that were greater than or equal to 4 times the human clinical exposure based on area under the curve (AUC). Advise females of reproductive potential to use effective contraception during therapy with IBRANCE and for at least two weeks after the last dose [see Use in Specific Populations and Clinical Pharmacology].

ADVERSE REACTIONS Clinical Studies Experience. Because clinical trials are conducted under varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice.

The safety of IBRANCE (125 mg/day) plus letrozole (2.5 mg/day) versus letrozole alone was evaluated in Study 1. The data described below reflect exposure to IBRANCE in 83 out of 160 patients with ER-positive, HER2-negative advanced breast cancer who received at least 1 dose of treatment in Study 1. The median duration of treatment for palbociclib was 13.8 months while the median duration of treatment for letrozole on the letrozole-alone arm was 7.6 months.

Dose reductions due to an adverse reaction of any grade occurred in 38.6% of patients receiving IBRANCE plus letrozole. No dose reduction was allowed for letrozole in Study 1.

Permanent discontinuation due to an adverse event occurred in 7 of 83 (8%) patients receiving IBRANCE plus letrozole, and in 2 of 77 (3%) patients receiving letrozole alone. Adverse reactions leading to discontinuation for those patients receiving IBRANCE plus letrozole included neutropenia (6%), asthenia (1%), and fatigue (1%).

The most common adverse reactions (≥10%) of any grade reported in patients in the IBRANCE plus letrozole arm were neutropenia, leukopenia, fatigue, anemia, upper respiratory infection, nausea, stomatitis, alopecia, diarrhea, thrombocytopenia, decreased appetite, vomiting, asthenia, peripheral neuropathy, and epistaxis.

The most frequently reported serious adverse reactions in patients receiving IBRANCE plus letrozole were pulmonary embolism (3 of 83; 4%) and diarrhea (2 of 83; 2%).

An increased incidence of infections events was observed in the palbociclib plus letrozole arm (55%) compared to the letrozole alone arm (34%). Febrile neutropenia events have been reported in the IBRANCE clinical program, although no cases were observed in Study 1. Grade ≥3 neutropenia was managed by dose reductions and/or dose delay or temporary discontinuation consistent with a permanent discontinuation rate of 6% due to neutropenia [see Dosage and Administration].

The following table presents adverse drug reactions (≥10%) reported in patients who received IBRANCE plus letrozole or letrozole alone.

Adverse Reactions* (≥10%) in Study 1 IBRANCE + Letrozole (N=83) Letrozole Alone (N=77) System Organ Class All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 Any Adverse Drug Reaction (%) (%) (%) (%) (%) (%) Infections and infestations URIa 31 1 0 18 0 0 Blood and lymphatic system disorders Neutropenia 75 48 6 5 1 0 Leukopenia 43 19 0 3 0 0 Anemia 35 5 1 7 1 0 Thrombocytopenia 17 2 0 1 0 0 Metabolism and nutrition disorders Decreased appetite 16 1 0 7 0 0 Nervous system disorders b Peripheral neuropathy 13 0 0 5 0 0 Respiratory, thoracic, and mediastinal disorders Epistaxis 11 0 0 1 0 0 Gastrointestinal disorders Stomatitisc 25 0 0 7 1 0 Nausea 25 2 0 13 1 0 Diarrhea 21 4 0 10 0 0 Vomiting 15 0 0 4 1 0 Skin and subcutaneous tissue disorders Alopecia 22d N/A N/A 3e N/A N/A General disorders and administration site conditions Fatigue 41 2 2 23 1 0 Asthenia 13 2 0 4 0 0

* Adverse Reaction rates reported in the table include all reported events regardless of causality.

Grading according to CTCAE Version 3.0.

CTCAE=Common Terminology Criteria for Adverse Events; N=number of subjects; N/A=not applicable; URI=Upper respiratory infection. a URI includes: Influenza, Influenza like illness, Laryngitis, Nasopharyngitis, Pharyngitis, Rhinitis, Sinusitis, Upper respiratory tract infection. b Peripheral neuropathy includes: Neuropathy peripheral, Peripheral sensory neuropathy. c Stomatitis includes: Aphthous stomatitis, Cheilitis, Glossitis, Glossodynia, Mouth ulceration, Mucosal inflammation, Oral pain, Oropharyngeal discomfort, Oropharyngeal pain, Stomatitis. d Grade 1 events - 21%; Grade 2 events - 1%. e Grade 1 events - 3%.

Laboratory Abnormality for Patients in Study 1 Laboratory Abnormality White blood cells decreased Neutrophils decreased Lymphocytes decreased Hemoglobin decreased Platelets decreased N=number of patients.

IBRANCE + Letrozole (N=83) Letrozole Alone (N=77) All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 (%) (%) (%) (%) (%) (%) 95 44 0 26 0 0 94 57 5 17 3 0 81 17 1 35 3 0 83 5 1 40 3 0 61 3 0 16 3 0

DRUG INTERACTIONS Effect of CYP3A Inhibitors. Coadministration of a strong CYP3A inhibitor (itraconazole) increased the plasma exposure of palbociclib in healthy subjects by 87%. Avoid concomitant use of strong CYP3A inhibitors (e.g., clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, verapamil, and voriconazole). Avoid grapefruit or grapefruit juice during IBRANCE treatment. If

coadministration of IBRANCE with a strong CYP3A inhibitor cannot be avoided, reduce the dose of IBRANCE [see Dosage and Administration and Clinical Pharmacology].

Effect of CYP3A Inducers. Coadministration of a strong CYP3A inducer (rifampin) decreased the plasma exposure of palbociclib in healthy subjects by 85%. Avoid concomitant use of strong CYP3A inducers (e.g., phenytoin, rifampin, carbamazepine and St John’s Wort) [see Clinical Pharmacology].

Coadministration of moderate CYP3A inducers may also decrease the plasma exposure of IBRANCE. Avoid concomitant use of moderate CYP3A inducers (e.g., bosentan, efavirenz, etravirine, modafinil, and nafcillin) [see Clinical Pharmacology].

Drugs That May Have Their Plasma Concentrations Altered by Palbociclib.

Coadministration of midazolam with multiple doses of IBRANCE increased the midazolam plasma exposure by 61%, in healthy subjects, compared with administration of midazolam alone. The dose of the sensitive CYP3A substrate with a narrow therapeutic index (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, everolimus, fentanyl, pimozide, quinidine, sirolimus and tacrolimus) may need to be reduced as IBRANCE may increase their exposure [see Clinical Pharmacology].

USE IN SPECIFIC POPULATIONS Pregnancy. Based on findings in animals and mechanism of action, IBRANCE can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology]. In animal studies, palbociclib was teratogenic and fetotoxic at maternal exposures that were ≥4 times the human clinical exposure based on AUC at the recommended human dose. There are no available human data informing the drug-associated risk. Advise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is 2–4% and of miscarriage is 15–20% of clinically recognized pregnancies.

Lactation. There are no data on the presence of palbociclib in human milk, the effects of IBRANCE on the breastfed child, or the effects of IBRANCE on milk production.

Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from IBRANCE, advise a nursing woman to discontinue breastfeeding during treatment with IBRANCE. Females and Males of Reproductive Potential. Advise females of reproductive potential to use effective contraception during treatment with IBRANCE and for at least two weeks after the last dose. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with IBRANCE [see Use in Specific Populations].

Based on findings in animals, male fertility may be compromised by treatment with IBRANCE [see Carcinogenesis, Mutagenesis, Impairment of Fertility].

Pediatric Use. The safety and efficacy of IBRANCE in pediatric patients have not been studied.

Geriatric Use. Of 84 patients who received IBRANCE in Study 1, 37 patients (44%) were ≥65 years of age and 8 patients (10%) were ≥75 years of age. No overall differences in safety or effectiveness of IBRANCE were observed between these patients and younger patients but greater sensitivity of some older individuals cannot be ruled out.

Hepatic Impairment. Based on a population pharmacokinetic analysis that included 183 patients, where 40 patients had mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin >1.0 to 1.5 × ULN and any AST), mild hepatic impairment had no effect on the exposure of palbociclib. The pharmacokinetics of palbociclib have not been studied in patients with moderate or severe hepatic impairment (total bilirubin >1.5 × ULN and any AST) [see Clinical Pharmacology].

Renal Impairment. Based on a population pharmacokinetic analysis that included 183 patients, where 73 patients had mild renal impairment (60 mL/min ≤ CrCl <90 mL/min) and 29 patients had moderate renal impairment (30 mL/min ≤ CrCl <60 mL/min), mild and moderate renal impairment had no effect on the exposure of palbociclib. The pharmacokinetics of palbociclib have not been studied in patients with severe renal impairment [see Clinical Pharmacology].

OVERDOSAGE There is no known antidote for IBRANCE. The treatment of overdose of IBRANCE should consist of general supportive measures.

PATIENT COUNSELING INFORMATION • Advise patients to immediately report any signs or symptoms of myelosuppression or infection, such as fever, chills, dizziness, shortness of breath, weakness or any increased tendency to bleed and/or to bruise [see Warnings and Precautions].

• Advise patients to immediately report any signs or symptoms of pulmonary embolism, such as shortness of breath, chest pain, tachypnea, and tachycardia [see Warnings and Precautions].

• Advise patients to take IBRANCE with food and swallow IBRANCE capsules whole.

• I BRANCE may interact with grapefruit. Patients should not consume grapefruit products while on treatment with IBRANCE. • I nform patients to avoid strong CYP3A inhibitors and strong CYP3A inducers.

• Advise patients to inform their health care providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Drug Interactions].

• I f the patient vomits or misses a dose, an additional dose should not be taken that day. The next prescribed dose should be taken at the usual time. IBRANCE capsules should be swallowed whole (do not chew, crush or open them prior to swallowing).

No capsule should be ingested if it is broken, cracked, or otherwise not intact.

• Advise females of reproductive potential to use effective contraception during IBRANCE therapy and for at least two weeks after the last dose. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with IBRANCE [see Warnings and Precautions and Use in Specific Populations].

Rx only Issued: February 2015 ULN=upper limit of normal.

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CME ACTIVITY

EDUCATIONAL OBJECTIVES: After participating in this activity, clinicians should be better able to: • Determine the optimal management for treatment-naïve and relapsed/refractory patients with CLL • Apply novel and emerging treatment options when treating patients with relapsed or refractory CLL • Use updated CLL response assessment guidelines to guide treatment decisions when treating patients with emerging novel agents TO COMPLETE THE ACTIVITY, PRE-TEST, POST-TEST, EVALUATION FORM, AND CLAIM YOUR CERTIFICATE: Go to myCME.com/CLLConsiderations

This program is provided by Haymarket Medical Education.

Program Faculty:

Faculty Disclosures: Dr. Stone has no relevant financial relationships to disclose. Dr. Nashed has no relevant financial relationships to disclose.

CME Editor Christine Stone, PhD, MBA Associate Medical Director, Hematology/Oncology Haymarket Medical Education

Planners’ and Managers’ Disclosures: The Haymarket staff involved in the planning and content review of this activity have no relevant financial relationships to disclose.

CME Reviewer Sylvia Nashed, PharmD Associate Medical Director Haymarket Medical Education

Disclosure of Unlabeled Use: This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. Haymarket Medical Education (HME) does not recommend the use of any agent outside of the labeled indications.

Release Date: May 5, 2015 Expiration Date: May 4, 2016 Estimated time to complete the educational activity: 1 hour Target Audience: This activity has been designed to meet the educational needs of hematologists and oncologists.

Accreditation Statement: Haymarket Medical Education is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

Designation Statement: Haymarket Medical Education designates this enduring material for a maximum of 1.00 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of HME. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

Disclaimer: Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient’s conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

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CME ACTIVITY

Clinical Considerations in the Management of Chronic Lymphocytic Leukemia

CLINICAL CONTEXT Chronic lymphocytic leukemia (CLL) is a lymphoproliferative disorder characterized by progressive expansion of monoclonal B lymphocytes.1,2 With an estimated prevalence of approximately 126,000 individuals, CLL is the most common form of adult leukemia in the United States.3 In 2015, an estimated 14,620 people in the US will be diagnosed with CLL, and over 4,650 will die of the disease.4 Patients with CLL have highly variable disease presentations and cytogenetics; life expectancies range from months to years.5 Approximately 25% of patients with CLL have no symptoms at the time of diagnosis and are only diagnosed when a routine blood count uncovers an absolute lymphocytosis.1 In

Blood smear that depicts chronic lymphocytic leukemia.

the remaining 75% of patients, there is a wide range of presenting features as well as physical and laboratory abnormalities (eg, constitutional symptoms, lymphadenopathy, splenomegaly, anemia, and/or bleeding).1,6,7 Due to the introduction of chemoimmunotherapy standards of care, the primary goal of CLL treatment has been altered from palliation of symptoms to the attainment of complete responses (CR) to prolong patient survival outcomes.1,8 However, increased duration

© THINKSTOCK

Identification of the role of B-cell receptor signaling in chronic lymphocytic leukemia has led to the approval of several novel targeted therapies.

of responses and survival have not been experienced equally among all patient populations, even with current standards of care. Currently, chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) is considered by many to be the standard of care in previously untreated and physically fit CLL patients aged <70 years, except for those with a 17p deletion.24 However, most patients with CLL are elderly and/or have comorbidities that may make them ineligible for

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CME ACTIVITY fludarabine-based treatment.8-12 Those with high-risk cytogenetic or molecular features typically have a short duration of responses and survival outcomes, while the very elderly (≥ 70 years of age) typically cannot tolerate full-dose therapy.13-16 Clinical trials have demonstrated that several newly approved and emerging non-chemotherapy agents (eg, obinutuzumab, ofatumumab, idelalisib, and ibrutinib, among others) have promising clinical activity in these “difficultto-treat” populations.17-18 Furthermore, clinical trial results show that these new targeted agents are redefining the benefit-to-toxicity risk paradigm, which suggests that future treatment regimens will not need to rely solely on cytotoxic chemotherapy-based options.19 Clinical Application Therapy is a highly individualized choice and should be based on age, extent of disease, comorbidities, and treatment goals. Despite recent advances, there is an ongoing need for active and tolerable therapies for patients who fail to respond to or cannot tolerate treatment with commonly used agents.8,19 This has led to intense research to better understand the molecular pathways that are important for survival and proliferation of malignant B cells. Identification of the key role that B-cell receptor (BCR) signaling plays in these diseases has led to the approval and continued investigation of several novel targeted therapies, including monoclonal antibodies and small-molecule inhibitors.18,20 Anti-CD20 Monoclonal Antibodies Obinutuzumab

The third‐generation antibody obinutuzumab was approved in November 2013 for previously untreated CLL in combination with chlorambucil (Table 1).21 Obinutuzumab is a glycoengineered,

TABLE 1. Newly Approved Anti-CD20 Monoclonal Key Aspects

Obinutuzumab27

Description

• A CD20-directed cytolytic antibody

CLL Indication

• In combination with chlorambucil, is indicated for the treatment of patients with previously untreated CLL

Efficacy Findings in CLL Clinical Trials

• Obinutuzumab was evaluated in 781 patients with previously untreated CD20+ CLL requiring treatment • In the Stage 1 analysis of Study 1, the median PFS in the obinutuzumab in combination with chlorambucil arm was 27.2 months and 11.2 months in the chlorambucil alone arm • The median OS was not yet reached with a total of 46 deaths: 22 (9%) in the obinutuzumab in combination with chlorambucil arm and 24 (20%) in the chlorambucil arm • In the Stage 2 analysis of Study 1, the median PFS was 26.7 months in the obinutuzumab arm and 14.9 months in the rituximab arm with a median observation time of 18.7 months • Secondary endpoints included ORR, CR, and response duration

Adverse Event Findings in CLL Clinical Trials

• The most common adverse reactions (incidence ≥10%) were: infusion reactions (66%), neutropenia (38%), thrombocytopenia (14%), nausea (12%), anemia (11%), pyrexia (10%), cough (10%), and diarrhea (10%)

Dosing and Administration

• Each dose of obinutuzumab is 1000 mg, administered intravenously, with the exception of the first infusions in Cycle 1, which are administered on day 1 (100 mg) and day 2 (900 mg) • Infusion reactions occurred in 65% of patients treated with obinutuzumab –G rade 3/4 infusion reactions were seen in 20% of patients, with 7% discontinuing therapy. Infusion reactions were experienced by 47 of the first 53 patients (89%) enrolled in the study, warranting an early adjustment to study protocol to require premedication with a corticosteroid, antihistamine, and acetaminophen along with dose adjustments • Refer to prescribing information for dose adjustments related to adverse events • Regular blood count monitoring for neutropenia is also necessary

type 2, fully humanized antibody that targets a CD20 epitope distinct from that targeted by rituximab. 21-23 Compared with type 1 antibodies, type 2 antibodies induce increased tumor death, primarily through enhancement of antibody‐dependent cellular cytotoxicity. In vitro studies have demonstrated that obinutuzumab induces significantly

more lysis of CLL cells compared with rituximab, through both complement‐ dependent and antibody‐dependent cellular cytoxicity.22 Stage 1 of the CLL11 study showed that obinutuzumab, in combination with chlorambucil, significantly improved progression-free survival (PFS) (15.2 mo vs 26.7 mo, P < .0001). Importantly, the PFS benefit was

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CME ACTIVITY Antibodies With Indications for the Treatment of CLL Ofatumumab

21

• A CD20-directed cytotoxic monoclonal antibody • In combination with chlorambucil, for the treatment of previously untreated patients with CLL for whom fludarabine-based therapy is considered inappropriate • For the treatment of patients with CLL refractory to fludarabine and alemtuzumab

• 447 patients previously untreated for CLL were randomized to receive either ofatumumab as monthly intravenous infusions in combination with chlorambucil or chlorambucil alone – This trial enrolled patients for whom fludarabine-based therapy was considered to be inappropriate by the investigator for reasons that included advanced age or presence of co-morbidities –O fatumumab plus chlorambucil resulted in statistically significant improvement in independent review committee (IRC)-assessed median PFS compared with chlorambucil alone (22.4 months versus 13.1 months; HR: 0.57 [0.45, 0.72]) –S econdary efficacy endpoints, including ORR, CR, and duration of response, were also assessed by the IRC using the 2008 IWCLL Guidelines • 154 patients with relapsed or refractory CLL received ofatumumab intravenously – The investigator determined ORR in patients with CLL refractory to fludarabine and alemtuzumab was 42% (99% CI: 26, 60) with a median duration of response of 6.5 months (95% CI: 5.8, 8.3). There were no complete responses • In the previously untreated CLL clinical trial, the most common adverse reactions (≥10%, all grades) were infusion reactions (67% for ofatumumab plus chlorambucil vs 0% for chlorambucil) and neutropenia (27% vs 18%) • In the single-arm refractory CLL clinical trial, the most common adverse reactions (≥10%, all grades) were neutropenia, pneumonia (23%), pyrexia (20%), cough (19%), diarrhea (18%), anemia (16%), fatigue (15%), dyspnea (14%), rash (14%), nausea (11%), bronchitis (11%), and upper respiratory tract infections (11%) • For previously untreated CLL, the recommended dosage and schedule is: –3 00 mg on Day 1 followed 1 week later by – 1 000 mg on Day 8 (Cycle 1) followed by – 1 000 mg on Day 1 of subsequent 28-day cycles for a minimum of 3 cycles until best response or a maximum of 12 cycles • For refractory CLL, the recommended dosage and schedule is 12 doses administered as follows: –3 00 mg initial dose (Dose 1), followed 1 week later by –2 000 mg weekly for 7 doses (Doses 2 through 8), followed 4 weeks later by –2 000 mg every 4 weeks for 4 doses (Doses 9 through 12) • Ofatumumab should be diluted and administered as an intravenous infusion according to the above schedules • In patients with previously untreated CLL, overall, 67% of patients who received ofatumumab in combination with chlorambucil experienced 1 or more symptoms of infusion reactions – I nfusion reactions that were either ≥Grade 3, serious, or led to treatment interruption or discontinuation occurred most frequently during Cycle 1 (56% on Day 1 [6% were ≥Grade 3] and 23% on Day 8 [3% were ≥Grade 3]) and decreased with subsequent infusions. Infusion reactions led to discontinuation of treatment in 3% of patients. Serious adverse events of infusion reactions occurred in 2% of patients • In patients with refractory CLL treated with ofatumumab monotherapy, infusion reactions occurred in 44% of patients on the day of the first infusion (300 mg), 29% on the day of the second infusion (2000 mg), and less frequently during subsequent infusions • Premedication with acetaminophen, an antihistamine, and a corticosteroid is required • Refer to prescribing information for dose adjustments related to adverse events • Regular blood count monitoring for neutropenia is also necessary

observed across all cytogenetic risk subgroups, including del(17p) and del(11q).

While median overall survival (OS) had not been reached in either arm, obinutuzumab plus chlorambucil demonstrated an OS benefit over chlorambucil alone (HR = 0.41, CI 0.23-0.74, P = .002).

While there were a greater number of ≥ grade 3 infusion reactions (20% vs 4%)

and neutropenia (33% vs 27%) compared with chlorambucil alone, there was no difference in the incidence of infections with the use of obinutuzumab (7%).24,25 Recently, the label for obinutuzumab plus chlorambucil was updated to include data from stage 2 of the phase 3 CLL11 study, which demonstrated an improvement in PFS compared with

rituximab plus chlorambucil as a frontline treatment for patients with CLL.21 Obinutuzumab plus chlorambucil led to a median PFS of 26.7 months compared with 14.9 months with rituximab and chlorambucil (HR = 0.42; 95% CI, 0.330.54; P <.0001). Enrolled patients had not received prior treatments for CLL and had a median Cumulative Illness Rating Scale (CIRS) score of 8 and/or an estimated creatinine clearance <70 mL/min. For reference, the CIRS score is often used to classify patient fitness regardless of age. The overall response rate (ORR) in the obinutuzumab arm was 79.6%, compared with 66.3% with rituximab and the CR rate with obinutuzumab was 26.1%, compared with 8.8% with rituximab. The median duration of response with obinutuzumab was 19.6 versus 9.7 months with rituximab. The most common grade 3/4 adverse events with obinutuzumab versus rituximab were neutropenia (46% vs 41%), lymphopenia (39% vs 16%), leukopenia (35% vs 16%), and thrombocytopenia (13% vs 8%).26 Ofatumumab

Ofatumumab was approved for the treatment of alemtuzumab‐ and fludarabine‐refractory CLL in 2009 and in combination with chlorambucil for previously untreated CLL patients for whom fludarabine-based therapy is considered inappropriate in April 2014 (Table 1). 27 The second‐generation antibody ofatumumab is a type 1 anti‐CD20 antibody, which, unlike rituximab, is fully humanized and binds to both loops of the CD20 receptor.27,28 The increased cytotoxicity of ofatumumab compared with rituximab against both rituximab‐sensitive and ‐resistant cells is hypothesized to be a result of ofatumumab’s increased binding affinity to CD20 and enhanced complement activation.

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CME ACTIVITY TABLE 2. Newly Approved Small Molecule Inhibitors With Indications for the Treatment of CLL Key Aspects

Ibrutinib36,38

Idelalisib41,42

Description

• Bruton’s tyrosine kinase (BTK) inhibitor that blocks BTK activity by irreversibly bonding to a cystein residue

• A reversible, highly selective phosphoinositide 3 kinase δ (PI3Kδ) inhibitor

CLL Indication

• For the treatment of patients with CLL who have received at least 1 prior therapy • For the treatment of patients with CLL with 17p deletion

• In combination with rituximab for the treatment of patients with CLL for whom rituximab alone would be considered appropriate therapy due to other comorbidities

Efficacy Findings in CLL Clinical Trials

• The safety and efficacy of ibrutinib in patients with CLL who have received at least 1 prior therapy were demonstrated in 1 uncontrolled trial and 1 randomized, controlled trial – The randomized, multicenter, open-label Phase 3 study of ibrutinib versus ofatumumab was conducted in 391 patients with previously treated CLL or SLL (n=373 patients with CLL, n=18 patients with SLL) • Ibrutinib significantly prolonged the duration of PFS, with the median not reached at a median follow-up of 9.4 months, as compared with a median duration of PFS of 8.1 months with ofatumumab – The hazard ratio for progression or death in the ibrutinib group was 0.22 (95% confidence interval [CI], 0.15 to 0.32; P<0.001) – This represents a 78% reduction in the risk of progression or death among patients treated with ibrutinib, as compared with ofatumumab – Among patients with a chromosome 17p13.1 deletion, the median duration of PFS was not reached in the ibrutinib group, as compared with a median of 5.8 months in the ofatumumab group (hazard ratio for progression or death, 0.25; 95% CI, 0.14 to 0.45) • I brutinib, as compared with ofatumumab, significantly prolonged the rate of OS (hazard ratio for death in the ibrutinib group, 0.43; 95% CI, 0.24 to 0.79; P=0.005), with the risk of death reduced by 57% – At 12 months, the OS rate was 90% in the ibrutinib group and 81% in the ofatumumab group • The independently assessed response rate was significantly higher in the ibrutinib group than in the ofatumumab group – Overall, 43% of the patients in the ibrutinib group had a PR, as compared with 4% in the ofatumumab group (odds ratio, 17.4; 95% CI, 8.1 to 37.3; P<0.001) – In addition, 20% of the patients receiving ibrutinib had a partial response with lymphocytosis (resulting in a 63% response rate)

• At 24 weeks, the rate of PFS was 93% in the idelalisib group, as compared with 46% in the placebo group (adjusted hazard ratio for progression or death in the idelalisib group, 0.15; 95% CI, 0.08 to 0.28; unadjusted P<0.001, which crossed the prespecified stopping – The median duration of PFS among patients in the idelalisib group was not reached, whereas the median PFS was 5.5 months in the placebo group – The treatment effect of idelalisib and rituximab was similarly favorable in all prespecified subgroups, including those stratified according to the presence or absence of the 17p deletion or TP53 mutation and IGHV mutational status • The rate of OS in the idelalisib group was superior to that in the placebo group (92% vs 80% at 12 months), with an adjusted hazard ratio for death of 0.28 (95% CI, 0.09 to 0.86; P=0.02) – The median duration of overall survival in the 2 groups had not yet been reached at the time of analysis • The ORR was 81% (95% CI, 71 to 88) in the idelalisib group, as compared with 13% (95% CI, 6 to 21) in the placebo group (odds ratio, 29.92; P<0.001). All responses were partial responses

Adverse-Event Findings in CLL Clinical Trials

• Most common adverse events (≥20%): thrombocytopenia, neutropenia, diarrhea, anemia, fatigue, musculoskeletal pain, upper respiratory tract infection, rash, nausea, and pyrexia

• Most common adverse events (≥20%) in combination with rituximab: pyrexia, nausea, pneumonia, diarrhea, and chills

Dosing and Administration

• The recommended dose of ibrutinib for CLL is 420 mg (3 140 mg capsules) orally once daily • Ibrutinib capsules should be swallowed whole with a glass of water

• The recommended maximum starting dose of idelalisib is 150 mg administered orally twice daily • Idelalisib can be taken with or without food. Tablets should be swallowed whole

In the trial for previously untreated patients with CLL, fludarabine-based therapy was designated as inappropriate by the investigator for reasons that included advanced age or presence of comorbidities. The median age was 69 years (35 to 92 years) and 72% of patients had ≥2 comorbidities. Median PFS was 22.4 months for patients who received ofatumumab in combination with chlorambucil (95% confidence

interval [CI] = 19.0–25.2 months), compared with 13.1 months (95% CI = 10.6–13.8 months) for patients who received single-agent chlorambucil.

Overall, 67% of patients who received ofatumumab experienced one or more symptoms of infusion reaction.

Currently, ofatumumab is one of the few options approved for patients with fludarabine‐ and alemtuzumab‐refractory CLL. 8 More than 90% of the

patients enrolled in the pivotal study in this subpopulation had also received prior therapy that included an alkylating agent and had received a median of 5 treatments prior to enrollment.19 The investigator-determined ORR in patients with CLL refractory to fludarabine and alemtuzumab was 42% (99% CI: 26, 60) with a median duration of response of 6.5 months (95% CI: 5.8, 8.3). The most common adverse reactions (≥10%) in

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CME ACTIVITY the study were neutropenia, pneumonia, pyrexia, cough, diarrhea, anemia, fatigue, dyspnea, rash, nausea, bronchitis, and upper respiratory tract infections.27 Minimal Residual Disease and Novel Anti-CD20s Leukemic burden can be quantified by minimal residual disease (MRD) technology with a 1000-fold higher sensitivity compared with clinical staging.28 MRD is an independent predictor of PFS and OS after conventional induction therapy, adding significantly to the prognostic power of known pretreatment prognostic factors.28-30 For instance, treatment with fludarabine-based chemoimmunotherapy that results in MRD-negative CR has been shown to predict longer time to treatment failure and prolonged PFS and OS.31 Prognosis is poor for patients who fail to achieve at least a PR after fludarabine-chlorambucil-rituximab therapy, especially for patients with genetically high-risk disease. Studies investigating more recently approved monoclonal antibodies like obinutuzumab and ofatumumab show that MRD-negative may be an achievable CR; it is possible that these agents may play a role in either induction therapy or MRD-tailored maintenance therapy.32-34 In stage 2 of the CLL11 trial, MRD negativity in the bone marrow for patients who achieved a CR with or without complete recovery from abnormal blood cell counts (CR, CRi) was 19% with obinutuzumab versus 6% with rituximab. In peripheral blood, 41% of patients treated with obinutuzumab were MRD negative compared with 12% with rituximab.21,35 BCR Signaling Pathway Inhibitors Ibrutinib

Ibrutinib is a Bruton’s tyrosine kinase (BTK) inhibitor that blocks BTK kinase activity by irreversible bonding

to a cystein residue (Table 2).36-40 BTK is expressed primarily in B cells, is recruited to activate BCR molecules, and is central to promoting downstream signaling, resulting in activation of MAPK and NF‐κB. This agent was approved in July 2014 to treat relapsed CLL patients who have received at least 1 prior treatment and to treat individuals with a 17p deletion.38 Approval was based on a clinical study of 391 previously treated participants, 127 of whom had CLL with 17p deletion, randomized to receive either ibrutinib or ofatumumab. The trial was stopped early for efficacy after a preplanned interim analysis showed ibrutinib-treated participants experienced a 78% reduction in risk of disease progression or death. Results also showed a 57% reduction in risk of death (OS) in participants treated with ibrutinib.

Of the 127 people who had CLL with

Bruton’s tyrosine kinase is expressed primarily in B cells and is recruited to activate BCR molecules.

17p deletion, those treated with ibrutinib experienced a 75% reduction in risk of disease progression or death and the objective response rate was 47.6% vs 4.7%, favoring ibrutinib.

When evaluating PFS, all patients responded equally to ibrutinib regardless of prognostic factor status in the pivotal Phase 3 study for ibrutinib. The most common adverse effects associated with ibrutinib observed in the clinical study included thrombocytopenia, neutropenia, diarrhea, anemia, fatigue, musculoskeletal pain, upper respiratory

tract infection, rash, nausea, and pyrexia.

Adverse events of grade 3 or higher that occurred more frequently in the ibrutinib group than in the ofatumumab group included diarrhea (4% vs 2%) and atrial fibrillation (3% vs 0%). Bleedingrelated adverse events of any grade (most commonly, petechiae, and including ecchymoses) were more common in the ibrutinib group than in the ofatumumab group (44% vs 12%). The data suggest that ibrutinib can be safely administered even in a heavily pretreated and elderly CLL patient population with baseline coexisting conditions.37-40 Idelalisib

Idelalisib, a reversible, highly selective inhibitor of the δ isoform of phosphoinositide 3 kinase (PI3K), was also approved in July 2014 in combination with rituximab to treat relapsed CLL patients for whom rituximab alone would be considered appropriate therapy traceable to other comorbidities (Table 2).41,42 Research into the tumor biology of indolent non-Hodgkin’s lymphoma (NHL) shows that PI3K plays an important role in activating regulators of cell proliferation, survival, and motility. PI3K is also activated by BCR signaling, as well as other signals in the microenvironment.

PI3K activation drives downstream activation of AKT as well as NF‐κB. The α and β isoforms are commonly expressed in many tissues, while the γ and δ isoforms are only found in hematopoietic cells. In B lymphocytes, the δ isoform (PI3Kδ) is known to play a key role in normal development and function and this pathway is hyperactive in B-cell malignancies.37 This approval was based on data from a phase 3 trial of idelalisib plus rituximab in 220 patients with relapsed CLL who were not able to undergo standard chemotherapy.

The patients were defined as less able to receive cytotoxic chemotherapy on

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CME ACTIVITY the basis of severe myelosuppression from previous chemotherapy, reduced kidney function, or a CIRS score of more than 6 for non–CLL-related coexisting illnesses. The study was terminated after the first prespecified interim analysis due to significant improvement in the rate of PFS as compared with placebo and rituximab (hazard ratio = 0.18 (95% CI: 0.10, 0.32), P < .0001). PFS improvement was also achieved in all subgroups examined, including patients with poor prognostic features, such as 17p deletion or TP53 mutations and unmutated IGHV. When evaluating PFS by prognostic group, all patients responded independent of their prognostic marker in the pivotal Phase 3 study for idelalisib. The rate of OS in the idelalisib group was superior to that in the placebo group (92% vs 80% at 12 months), with an adjusted hazard ratio for death of 0.28 (95% CI, 0.09-0.86; P = .02). There was no overall increase in the rate of adverse events with the addition of idelalisib to rituximab, as compared with placebo and rituximab. In the idelalisib group, the 5 most common adverse events were pyrexia, fatigue, nausea, chills, and diarrhea. These results show that the addition of idelalisib to rituximab in a population of frail, difficult-to-treat patients with CLL, including those with adverse genetic features, was superior to rituximab monotherapy, which is commonly used in such patients.43 Assessing Response to Novel BCR Signaling Inhibitors Consistent assessment of response to treatment is critical in determining the appropriate treatment pathway in CLL.8 Based on surrogate tumor burden markers that include blood lymphocyte counts, lymph node/spleen size, and circulating tumor cells, CLL treatment outcomes are defined as complete remission, partial remission, and progressive disease. Depth of response

to traditional chemotherapy correlates with survival outcomes, and a downgrade of response based on laboratory values is generally seen as a symptom of disease progression necessitating therapeutic intervention through intensification or addition of new agents.43,44 Standard response criteria serve as a measure of treatment efficacy and exist to provide the means for determining need for treatment discontinuation.

CLL outcomes are defined as either complete remission, partial remission, or progressive disease.

Under the iwCLL2008 criteria for treatment response, lymphocytosis was registered as a disease exacerbation, not an improvement. Specifically, per the guidelines, a ≥50% increase in absolute lymphocyte count (ALC) (with a total ALC of ≥5.0 x 109 cells/L) represented CLL progression.44 However, for novel agents, current response criteria are not adequate. Administration of newly approved agents for CLL, ibrutinib and idelalisib, as well as other BCR and Akt/ mTOR inhibitors, has resulted in treatment-induced lymphocytosis.44-46 This increase may indicate a mobilization of CLL cells from tissues, rather than a proliferative event.44 Studies have shown that BCR signaling, in addition to playing a role in survival and proliferation, modulates the movement of B cells to the bone marrow and lymph nodes. Thus, inhibition of the BCR may release these cells back into the circulation.

These studies suggest that the ALC alone is not adequate as a determinant of disease status when evaluating these

agents and have resulted in a modification of the iwCLL response criteria.44,45 Application of the current iwCLL2008 or National Cancer Institute Working Group 1996 criteria in these patients would result in incorrect assessment as progressive disease, which might mandate early treatment discontinuation. The guidelines now indicate that an increase in ALC caused by treatment-induced redistribution of CLL cells should not be confused with progressive disease, especially when other disease parameters are improving. Lymphocytosis alone should not be considered an indicator of progressive disease in the absence of other objective evidence of progressive disease. Patients with lymphocytosis alone should continue therapy until they develop other definitive signs of progressive disease or the occurrence of another reason to discontinue therapy. The recommendations also note that tumor flare should not be used inappropriately to describe lymphocytosis in a patient who also shows other signs of progression while receiving a BCR antagonist.44 Furthermore, patients meeting all of the criteria for partial response except for persistent lymphocytosis may be considered “partial responders.”44,45 MRD is also being reevaluated in the context of these new agents. BCR inhibitors have been proven to be effective for the treatment of relapsed CLL; MRDnegative CRs, though, have rarely been observed after single-agent therapy.36,41 Most patients treated with BCR inhibitors ultimately achieve durable—but no better than partial—remissions.

Long-term remissions are observed in patients treated with BCR inhibitors, even among those who never achieved resolution of peripheral blood lymphocytosis. With these therapies, the duration of response may not correlate with depth of response, and remission

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CME ACTIVITY may not be necessary to create durable clinical benefit, provided therapy is continued. BCR inhibitors are differentiated from chemotherapy in that extended treatment with BCR inhibitors is generally not prohibitively toxic.

Thus, a more general re-examination of the end points for CLL therapy may be required. Intermediate end points, such as response, which is appropriate for a relapsing/remitting natural history, may ultimately prove inappropriate when the disease is chronically controlled and the treatment is continuous rather than episodic.36,41 Questions remain regarding more meaningful outcome measures and new intermediate end points predictive of disease outcome are warranted.

Conclusion The increased scientific understanding of the pathophysiology contributing to CLL tumor proliferation and survival has led to the development of promising novel agents. Research continues to investigate the mechanisms of action and is attempting to elucidate the cross talk between malignant B cells and the tissue microenvironment.37 The data presented represent a snapshot of clinical data from emerging agents for the treatment of patients with CLL, and demonstrate that the treatment landscape for indolent lymphomas is constantly evolving.

Studies are ongoing for these agents as alternative drug combinations, possible resistance, improvements in quality of life, and optimal duration of therapy continue to be investigated.48-52 ■ References

Advisory Committee meeting-Airlie House,

11. Satram-Hoang S, Reyes C, Hoang KQ,

Virginia, November 1997. J Clin Oncol.

et al. Treatment practice in the elderly

1999;17:3835-3849.

patient with chronic lymphocytic leu-

3. Facts 2014-2015. Leukemia & Lymphoma

kemia—analysis of the combined SEER

Society®. http://www.lls.org/content/

and Medicare database. Ann Hematol.

nationalcontent/resourcecenter/freeeducationmaterials/generalcancer/pdf/facts. pdf. Accessed on March 12, 2015.

2014;93:1335-1344.

12. Gribben JG. Chronic lymphocytic leukemia: planning for an aging population. Expert

4. Siegel RL, Miller KD, Jemal A. Cancer statis-

Rev Anticancer Ther. 2010;10(9):1389-1394.

tics, 2015. CA Cancer J Clin. 2015;65(1):5-29.

13. Shanafelt TD, Geyer SM, Kay NE. Prognosis

5. Schultz RA, Delioukina M, Gaal K, et al.

Evaluation of chronic lymphocytic leukemia

by BAC-based microarray analysis. Mol

Cytogenet. 2011;4:4.

6. Hallek M, Cheson BD, Catovsky D, et

at diagnosis: integrating molecular biologic insights into clinical practice for patients with CLL. Blood. 2004;103:1202-1210.

14. Shanafelt TD, Witzig TE, Fink SR, et al.

Prospective evaluation of clonal evolution

al; International Workshop on Chronic

during long-term follow-up of patients with

Lymphocytic Leukemia. Guidelines

untreated early-stage chronic lymphocytic

for the diagnosis and treatment of chronic lymphocytic leukemia: a report

leukemia. J Clin Oncol. 2006;24:4636-4641.

15. Rassenti LZ, Jain S, Keating MJ, et al.

from the International Workshop on

Relative value of ZAP-70, CD38, and immu-

Chronic Lymphocytic Leukemia updat-

noglobulin mutation status in predicting

ing the National Cancer Institute-

aggressive disease in chronic lymphocytic

Working Group 1996 guidelines. Blood.

leukemia. Blood. 2008;112:1923-1930.

2008;111:5446-5456.

7. Kipps TJ. Chronic lymphocytic leu-

16. Brenner H, Gondos A, Pulte D. Trends in long-term survival of patients with

kemia and related diseases. Williams

chronic lymphocytic leukemia from the

Hematology. In: Lichtman MA, ed. New

1980s to the early 21st century. Blood.

York, NY: McGraw-Hill Companies.

2010;1431-1481.

2008;111:4916-4921.

17. Roche’s obinutuzumab (GA101) delayed

8. NCCN Clinical Practice Guidelines in

disease progression longer than MabThera/

Oncology (NCCN Guidelines®) Non-

Rituxan in people with one of the most common

Hodgkin’s Lymphomas. (Version 2.2015).

forms of blood cancer. http://www.roche.com/

©2015 National Comprehensive Cancer

media/media_releases/med-cor-2013-07-24.

Network, Inc. http://www.nccn.org/

htm. Accessed October 20, 2013.

professionals/physician_gls/pdf/nhl.pdf.

Accessed March 12, 2015.

18. Choi MY, Kipps TJ. Inhibitors of B-cell receptor signaling for patients with B-cell malig-

9. Hallek M, Fischer K, Fingerle-Rowson G,

nancies. Cancer J. 2012;18:404-410.

et al. Addition of rituximab to fludarabine

19. Chao MP. Treatment challenged in the

and cyclophosphamide in patients with

management of relapsed or refractory

chronic lymphocytic leukaemia: a ran-

non-Hodgkin’s lymphoma – novel and

domised, open-label, phase 3 trial. Lancet.

emerging therapies. Cancer Manag Res.

2010;376(9747):1164-1174.

2013;5:251-269.

1. Shanshal M, Haddad RY. Chronic lympho-

10. Hillmen P, Gribben JG, Follows GA, et al.

cytic leukemia. Dis Mon. 2012;58:153-167.

Rituximab Plus Chlorambucil As First-

agents in indolent lymphomas. Ther Adv

Line Treatment for Chronic Lymphocytic

Hematol. 2013;4:133-148.

2. Harris NL, Jaffe ES, Diebold J, et al. World Health Organization classification of neo-

Leukemia: Final Analysis of an Open-

20. Merli M, Ferrario A, Basilico C, et al. Novel

21. GAZYVA (obinutuzumab). Prescribing

plastic diseases of the hematopoietic and

Label Phase II Study. J Clin Oncol.

Information. South San Francisco, CA:

lymphoid tissues: report of the Clinical

2014;32(12):1236-1241.

Genentech, Inc.; 2014.

CancerTherapyAdvisor.com | SEPTEMBER/OCTOBER 2015 | CANCER THERAPY ADVISOR A23

CTA_CME_1015.indd 23

8/14/15 2:19 PM

CME ACTIVITY 22. Bologna L, Gotti E, Manganini M, et al.

an independent predictor of progression-

with relapsed/refractory chronic

Mechanism of action of type II, glycoengi-

free and overall survival in chronic lympho-

lymphocytic leukemia/small lympho-

neered, anti-CD20 monoclonal antibody

cytic leukemia: a multivariate analysis from

cytic leukemia: RESONATE. J Clin Oncol.

GA101 in B-chronic lymphocytic leukemia

the randomized GCLLSG CLL8 trial. J Clin

2013;31:abstract tps8619.

whole blood assays in comparison with rituximab and alemtuzumab. J Immunol.

2011;186:3762-3769.

23. Radford J, Davies A, Carron G, et al.

Oncol. 2012;30(9):980-988.

41. Furman RR, Sharman JP, Coutre SE, et al.

31. Boettcher A et al. Quantitative minimal

Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med.

residual disease assessments predict

2014;370(11):997-1007.

progression-free survival in CLL patients

Obinutuzumab (GA101) plus CHOP or FC in

treated with FC with or without rituximab:

relapsed/refractory follicular lymphoma:

a prospective analysis in 471 patients from

results of the GAUDI study (BO21000).

the CLL-8 trial. Blood. 2008;112:abs 326.

Blood. 2013;122:1137-1143.

ASH Annual Meeting.

24. Cavallo J. Partnering With Community

32. Cerquozzi S, Owen C. Clinical role of obinu-

Centers to Advance Oncology Care—A

tuzumab in the treatment of naïve patients

42. Zydelig (idelalisib). Prescribing Information.

Foster City, CA: Gilead Sciences, Inc.; 2014.

43. Gopal AK, Kahl BS, de Vos S, et al. PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med. 2014;370:1008-1018.

Conversation With Richard R. Barakat,

with chronic lymphocytic leukemia.

44. Cheson BD, Byrd JC, Rai KR, et al. Novel tar-

MD, FACS. The ASCO Post. 2014;5(17).

Biologics: Targets Ther. 2015;9:13-22.

geted agents and the need to refine clinical

http://www.ascopost.com/issues/novem-

33. Shanafelt T, Lanasa MC, Call TG, et al.

ber-1,-2014/partnering-with-community-

Ofatumumab-based chemoimmunotherapy

centers-to-advance-oncology-care.aspx.

is effective and well tolerated in patients

Accessed November 4, 2014.

with previously untreated CLL. Cancer.

25. Goede V, Fischer K, Busch R, et al. Head-

end points in chronic lymphocytic leukemia.

J Clin Oncol. 2012;30:2820-2822.

45. Rossi D, Gaidano G. Lymphocytosis and ibrutinib treatment of CLL. Blood.

2013;119(21):3788-3796.

2014;123(12):1772-1774.

To-Head Comparison Of Obinutuzumab

34. Ma Shuo, Rosen ST, Frankfurt O, et al. 4686 a

46. Brown JR, Furman RR, Flinn I, et al. Final

(GA101) Plus Chlorambucil (Clb) Versus

Phase 2 study of alemtuzumab-ofatumumab

results of a phase I study of Idelalisib

Rituximab Plus Clb In Patients With

(A+O) combination in patients with previ-

(GS-1101) a selective inhibitor of PI3Kδ in

Chronic Lymphocytic Leukemia (CLL)

ously untreated chronic lymphocytic leuke-

patients with relapsed or refractory CLL. J

and Co-Existing Medical Conditions

mia (CLL). Presented at: 56th ASH® Annual

Clin Oncol. 2013;31(15s):abstract 7003.

(Comorbidities): Final Stage 2 Results Of

Meeting and Exposition; December 6-9,

47. Garber K. Kinase inhibitors overachieve in CLL.

The CLL11 Trial. Presented at: 55th ASH®

Nature Rev Drug Discov. 2014;13(3):162-164.

2014; San Francisco, CA. Abstract 4686.

Annual Meeting and Exposition; December

35. Data on file. Genentech, Inc.

7-10, 2013; New Orleans, LA. Abstract 6.

36. Byrd JC, Brown JR, O’Brien S, et al.

48. Byrd JC, Jones JJ, Woyach JA, et al.

Entering the era of targeted therapy for

26. Smolej L. Targeted treatment for chronic lym-

Ibrutinib versus ofatumumab in previously

chronic lymphocytic leukemia: impact

phocytic leukemia: clinical potential of obinutu-

treated chronic lymphoid leukemia. N Engl J

on the practicing clinician. J Clin Oncol.

zumab. Pharmacogenom Pers Med. 2015;8:1-7.

Med. 2014;371(3):213-223.

27. ARZERRA (ofatumumab). Prescribing

2014;32(27):3039-2047.

37. ten Hacken E, Burger JA. Microenvironment

49. Riches JC, Gribben JG. Immunomodulation and

Information. Research Triangle Park, NC:

dependency in chronic lymphocytic leuke-

immune reconstitution in chronic lymphocytic

GlaxoSmithKline; 2014.

mia: The basis for new targeted therapies.

leukemia. Semin Hematol. 2014;51:228-234.

Pharmacol Ther. 2014;144(3):338-348.

50. Komarova NL, Burger JA, Wodarz D.

role of minimal residual disease measure-

38. Imbruvica (ibrutinib). Prescribing Information.

Evolution of ibrutinib resistance in

ments in the therapy for CLL: is it ready for

Sunnyvale, CA: Pharmacyclics, Inc.; 2014.

28. Böttcher S, Hallek M, Ritgen M, et al. The

prime time? Hematol Oncol Clin North Am. 2013;27(2):267-288.

29. Strati P, Keating MJ, O’Brien SM, et al.

Eradication of bone marrow minimal residual disease may prompt early treat-

Targeting BTK with ibrutinib in relapsed

Idelalisib, an inhibitor of phosphatidylinosi-

Med. 2013;369:32-42.

tol 3-kinase p110δ for relapsed/refractory chronic lymphocytic leukemia. Blood.

40.Byrd JC, Barrientos JC, Devereux S, et al.

A randomized, multicenter, open-label,

2014;123(24):3727-3732.

phase III study of the Bruton tyrosine

Minimal residual disease quantification is

51. Brown JR, Byrd JC, Coutre SE, et al.

chronic lymphocytic leukemia. N Engl J

ment discontinuation in CLL. Blood.

30. Böttcher S, Ritgen M, Fischer K, et al.

chronic lymphocytic leukemia (CLL). PNAS. 2014;111(38);13906-13911.

39. Byrd JC, Furman RR, Coutre SE, et al.

2014;123(22):3390-3397.

52. Young RM, Staudt LM. Ibrutinib treatment

kinase (BTK) inhibitor ibrutinib (PCI-

of CLL: the cancer fights back. Cancer Cell.

32765) versus ofatumumab in patients

2014;26:11-13.

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FEATURE

BY ANDREA S. BLEVINS PRIMEAU, PhD, MBA

T

he paradigm of the treatment of chronic lymphocytic leukemia (CLL) has shifted, with the recent addition of obinutuzumab, idelalisib, and ibrutinib to the armamentarium.

“These agents underscore our advancement in the understanding of the biology of CLL and will improve outcomes for many patients with CLL,” wrote David S. Sanford, MD, of the University of Texas MD Anderson Cancer Center in Houston, TX, and colleagues in Clinical Lymphoma, Myeloma, and Leukemia.1

Obinutuzumab Approved by the U.S. Food and Drug Administration (FDA) in November 2013 in combination with chlorambucil for treatment-naive patients with CLL, obinutuzumab is a humanized type II immunoglobulin G1 antibody that targets CD20. Its cytotoxic effect is likely a result of antibody-dependent cell-mediated toxicity.2 T h e f r o nt l i n e e f f i c a c y w a s demonstrated in the randomized, open-label, phase 3 CLL11 trial, in which obinutuzumab plus chlorambucil resulted in greater complete (20.7% vs. 7.0%) and molecular response rates compared with rituximab plus

Despite advances in treatment options for CLL, determining how to best incorporate novel, targeted agents into practice remains a challenge for clinicians.

chlorambucil.3 In addition, treatment wit h chlorambucil resulted in a prolonged median progression-free survival (PFS) of 26.7 months compared with 16.3 months in the rituximab plus chlorambucil arm (hazard ratio [HR]=0.44; 95% CI, 0.34-0.57; P<0.001) and 11.1 months in the chlorambucil monotherapy arm (HR=0.18; 95% CI, 0.13-0.24; P<0.001). In addition, overall survival (OS) was significantly greater in the obinutuzumab arm compared w it h chlorambucil monot herapy (HR=0.41; 95% CI, 0.23-0.74; P=0.002), but was not significant compared with the rituximab arm (HR=0.66; 95% CI, 0.41-1.06; P=0.08). Median OS has not yet been reached. However, the improved efficacy with obinutuzumab did not carry over to patients with a 17p deletion.

The addition of obinut uzumab did result in greater rates of adverse events (AEs) including grade 3 to 4 neutropenia and thrombocytopenia, but rates of infection were similar compared with the addition of rituximab.3 In addition, 20% of patients experienced infusion-site reactions during their first infusion of obinutuzumab, compared with 4% of patients who received rituximab. Furthermore, patients in the obinutuzumab arm were more likely to discontinue therapy compared with the rituximab or chlorambucil monotherapy arms.

© THINKSTOCK

New Drug Approvals Bring Hope, Challenges in the Treatment of Patients With CLL

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FEATURE Ibrutinib Ibrutinib was approved by the FDA in February 2014 for the treatment of patients with CLL whose disease did not respond to at least one prior therapy.

Ibrutinib is an irreversible Bruton’s tyrosine kinase (BTK) inhibitor, leading to the decreased activity of downstream signaling events and, ultimately, the proliferation of leukemic cells.4,5 Furthermore, ibrutinib has been shown to suppress the expression adhesion proteins in the bone marrow microenvironment, impairing B-cell homing.6 The efficacy of ibrutinib in relapsed and heavily pretreated patients with CLL was demonstrated in a multicenter, nonrandomized, open-label, phase 1b/2 trial.7 In this trial, the overall response rate was 71% in both the 420mg and 840-mg arms. Importantly,

Recent approvals underscore the advancement in the understanding of the biology of CLL. the response rate among patients with a 17p deletion was similar at 68%; however, patients with a mutated immunoglobulin heavy-chain (IGHV ) variable region gene had a significantly lower response rate (P=0.005).

The PFS and OS rates were 75% and 83%, respectively, at 26 months. In addition, among patients with the 17p deletion, the 26-month PFS rate was 57% and OS rate was 70%.

The most common AEs included diarrhea, upper respirator y tract infection, and fatigue. Pneumonia, dehydration, and neutropenia were the most common grade 3 or higher AEs.

The phase 2 RESONATE-17 trial further demonstrated ibrutinib’s efficacy in patients with a 17p deletion.8 In this nonrandomized trial, patients with relapsed CLL or small lymphocytic leukemia (SLL) with a 17p deletion received ibrutinib monotherapy for a median follow-up of 13 months. The 12-month PFS rate was 79.3%, and the median duration of response had not yet been reached.

Idelalisib In July 2015, the FDA approved the use of idelalisib in combination with rituximab in patients with relapsed CLL in whom rituximab monotherapy is considered appropriate due to the presence of comorbidities. Idelalisib specifically and reversibly binds to the p110δ isoform of PI3 k inase (PI3K), reducing the phosphorylation of downstream signaling factors such as Akt. As a result, the tumor microenvironment within the bone marrow and chemokine signaling is disrupted, thereby promoting apoptosis of leukemic cells.9,10 A randomized, double-blind, phase 3 trial demonstrated that idelalisib plus rituximab improved overall response rates compared with placebo plus rituximab.11 Median PFS was not reached in the idelalisib arm but was 5.5 months in the placebo arm (HR=0.15; P<0.001). In addition, the 12-month OS rate was 92% in the idelalisib arm compared with 80% in the placebo arm (HR=0.21; P=0.02).

A second interim analysis of the trial demonstrated that the addition of idelalisib improved PFS for patients w it h u n favorable c y togenet ic s, including a 17p delet ion, T P53 mutation, or ZAP70 positivity.12 Furthermore, a nonrandomized, open-label, phase 2 extension of study 101-08 of front-line idelalisib monotherapy resulted in a 90% response rate.13

Serious AEs were more common in the idelalisib arm, and the most common AEs included diarrhea, nausea, pyrexia, fatigue, and chills. Anemia, neutropenia, thrombocytopenia, and liver enzyme elevation were more common in the idelalisib arm compared with the placebo arm.

New Options for High-Risk CLL Ibrutinib and idelalisib demonstrated efficacy in patients with CLL who harbor a chromosome 17p deletion—a feature that is notorious for difficult-totreat disease, as chemoimmunotherapy typically elicits low response rates compared with wild-type 17p.13 As a result, ibrutinib is recommended by the National Comprehensive Cancer Network as the preferred first-line agent for patients with a 17p deletion.

Obinutuzumab plus chlorambucil may also be used as first-line therapy, and idelalisib with or without rituximab is recommended for relapsed or refractory disease.

Incorporating Into Practice The approval of obinut uzumab, ibrutinib, and idelalisib, as well as potential approvals of additional novel, targeted agents in the future provide clinicians with new and improved opt ions for pat ient s w it h CLL. However, how to best incorporate them into clinical practice remains a challenge. For example, clinicians may be surprised at the extent of lymphocytosis that may occur in patients who receive one of these agents; however, lymphocytosis is generally asymptomatic and slowly normalizes.

“Many questions remain about their use including long-term efficacy, safety, and how and when to best incorporate these treatments into therapy,” wrote Dr. Sanford and colleagues.1 ■

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FEATURE References

6. Chang BY, Francesco M, De Rooij MF,

10. Lannutti BJ, Meadows SA, Herman SE,

et al. Egress of CD19(þ)CD5(þ)

et al. CAL-101, a p110delta selective

Three newly approved drugs for chronic

cells into peripheral blood following

phosphatidylinositol-3-kinase inhibitor

lymphocytic leukemia: incorporating

treatment with the Bruton tyrosine

for the treatment of B-cell malignancies,

ibrutinib, idelalisib, and obinutuzumab into

kinase inhibitor ibrutinib in mantle

inhibits PI3K signaling and cellular viability.

clinical practice. Clin Lymphoma Myeloma

cell lymphoma patients. Blood.

Leuk. 2015;15(7):385-391.

2013;122(14):2412-2424.

1. Sanford DS, Wierda WG, Burger JA, et al.

2. Beers SA, Chan CH, French RR, et al. CD20

7. Byrd JC, Brown JR, O’Brien S, et al. Ibrutinib

as a target for therapeutic type I and II

versus ofatumumab in previously treated

monoclonal antibodies. Semin Hematol.

chronic lymphoid leukemia. N Engl J Med.

2010;47(2):107-114.

2014;371(3):213-223.

3. Goede V, Fischer K, Busch R, et al.

8. O’Brien S, Jones JA, Coutre S, et al.

Blood. 2011;117(2):591-594.

11. Furman RR, Sharman JP, Coutre SE, et al.

Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014;370(11):997-1007.

12. Sharman JP, Coutre SE, Furman RR, et al.

Second interim analysis of a phase 3 study

Obinutuzumab plus chlorambucil in

Efficacy and safety of ibrutinib in patients

of idelalisib (ZYDELIG) plus rituximab

patients with CLL and coexisting conditions.

with relapsed or refractory chronic

(R) for relapsed chronic lymphocytic

N Engl J Med. 2014;370(12):1101-1110.

lymphocytic leukemia or small lymphocytic

leukemia (CLL): efficacy analysis of patient

4. Honigberg LA, Smith AM, Sirisawad M, et

leukemia with 17p deletion from the phase

subpopulations with del(17p) and other

al. The Bruton tyrosine kinase inhibitor

II RESONATE-17 trial. 56th ASH Annual

adverse prognostic factors. 56th ASH

PCI-32765 blocks B-cell activation and

Meeting and Exposition; San Francisco, CA.

Annual Meeting and Exposition;

is efficacious in models of autoimmune

Abstract 327.

San Francisco, CA. Abstract 330.

disease and B-cell malignancy. Proc Natl

9. Hoellenriegel J, Meadows SA, Sivina M, et

13. Zelenetz AD, Gordon LI, Wierda WG, et

Acad Sci USA. 2010;107(29):13075-13080.

al. The phosphoinositide 3’-kinase delta

al. NCCN Clinical Practice Guidelines

5. Cheng S, Ma J, Guo A, et al. BTK inhibition

inhibitor, CAL-101, inhibits B-cell receptor

in Oncology. Non-Hodgkin Lymphoma.

targets in vivo CLL proliferation through its

signaling and chemokine networks in

Version 2.2015. 2015. Available at: http://

effects on B-cell receptor signaling activity.

chronic lymphocytic leukemia. Blood.

www.nccn.org/professionals/physician_

Leukemia. 2014;28(3):649-657.

2011;118(13):3603-3612.

gls/pdf/nhl.pdf. Accessed July 21, 2015.

Cancer Therapy Advisor’s Publishers Alliance Cancer Therapy Advisor has partnered with leading medical publishers, including Dove Press, Libertas Academica, and Moffit Cancer Center, to present Publishers Alliance, a selection of oncology-focused articles from a number of clinically relevant research journals.

Visit CancerTherapyAdvisor.com/PublishersAlliance to review the most recent selections.

Publishers Alliance CancerTherapyAdvisor.com | SEPTEMBER/OCTOBER 2015 | CANCER THERAPY ADVISOR A27

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IN THE CLINIC | BY C. ANDREW KISTLER, MD, P

harmD, RPh

Managing Pain in Patients With Cancer: Considerations When Prescribing Opioids

management. Clinicans from these groups may have more experience in managing opioids and developing a pain treatment plan specifically aimed at reducing the risk for opioid dependence in patients with cancer.■

There are numerous factors to consider when determining the best strategy for treating pain in patients receiving chemotherapy.

References

A

2. Greco MT, Roberto A, Corli O, et al. Quality

population, health care professionals may consider using them prior to initiating opioid treatment.3,4 Opioid-sparing medications may be useful in certain scenarios, however some non-opioids still carry the risk for dependence. Medications such as tramadol and pregabalin are still classified as controlled substances, so there is a potential for dependence.5 If a health care practitioner does not feel comfortable managing a patient’s opioid medications, they can also consider discussing the case with a specialist in palliative care or pain

al. Symptom prevalence in patients with incurable cancer: a systematic review. J Pain

Symptom Manage. 2007;34(1):94-104. of cancer pain management: an update of a systematic review of undertreatment of patients with cancer. J Clin Oncol.

2014;32(36):4149-4154.

3. Miaskowski C. The use of risk-management approaches to protect patients with cancer-related pain and their healthcare providers. Oncol Nurs Forum. 2008;35 Suppl:20-4.

4. Bruera E, Paice JA. Cancer pain management: safe and effective use of opioids. Am Soc Clin Oncol Educ Book.

2015;35:e593-e599.

5. Portenoy RK. Treatment of cancer pain.

Lancet. 2011;377(9784):2236-2247

© THINKSTOCK

dequate pain control for patients with cancer can be extremely challenging, especially in pat ients receiv ing chemotherapy or radiation therapy and/or in patients with end-stage disease. Up to 50% of patients receiving chemotherapy and 90% of patients with end-stage disease will require opioids.1 Despite treatment options, pain is frequently undertreated in patients with cancer. Research indicates that up to 32% of patients with cancer are undertreated for their pain. While that percentage is smaller than the 43.4% in a prior review, it still reinforces that undertreated pain is a significant issue in the cancer population. 2 There can be confusion regarding the terminology used when describing certain symptoms associated with opioid use. This confusion can make patients uncomfortable with taking an opioid, and can also make physicians uncomfortable with prescribing them. When prescribing opioids, it is important to ensure that patients and their families understand syndromes associated with opiod use such as dependence, tolerance, abuse, and addiction.3 There are numerous questionnaires and scales to assess a patient’s potential risk for negative drug behavior.

While many of these tools have not been studied or validated in the cancer

1. Teunissen SC, Wesker W, Kruitwagen C, et

A28 CANCER THERAPY ADVISOR | SEPTEMBER/OCTOBER 2015 | CancerTherapyAdvisor.com

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Innovation in squamous non-small cell lung cancer therapy There is an urgent need for effective treatment options to improve outcomes for patients with squamous non-small cell lung cancer (NSCLC). The importance of incremental improvements in squamous carcinoma therapies should not be underestimated.

Despite the wealth of medical knowledge afforded by years of scientific research, lung cancer continues to have one of the highest incidence rates and the highest mortality rate of any cancer.1 In 2012, lung cancer was responsible for 1.825 million new cases and 1.59 million deaths worldwide.1 Despite changes in patient behaviors, such as reduced tobacco smoking, the number of people dying from this disease is expected to increase to 2.95 million over the next 20 years.1 Squamous NSCLC is an aggressive form of lung cancer that is hard to treat.

For the majority of patients with advanced squamous NSCLC, platinum-based doublet chemotherapy remains the standard of care in 1st line,11,12 with an OS of approximately 8 to 10 months.9,10 This is in contrast to the progress made in nonsquamous NSCLC, where treatment advances—including therapies targeting oncogenic drivers—have extended survival.10,13,14 These oncogenic drivers— mutations in the epidermal growth factor receptor kinase and fusions involving anaplastic lymphoma kinase—rarely occur in squamous NSCLC, and as a result, few patients with squamous NSCLC can benefit from these treatments.15,16 Improved outcomes for patients with squamous NSCLC are needed.

CONTRIBUTING AUTHORS: David R. Spigel, MD SCRI (Sarah Cannon Research Institute) Nashville, TN Philip Bonomi, MD Rush University Medical Center Chicago, IL Edward Kim, MD Levine Cancer Institute Carolinas HealthCare System Charlotte, NC

References 1. From Ferlay J., Soerjomataram I., Ervik M., Dikshit R., Eser S., Mathers C., Rebelo M., Parkin D.M., Forman D., Bray, F. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 2013. Available from: http://globocan.iarc.fr, accessed on 23/02/2015. 2. American Cancer Society. What is non-small cell lung cancer? http://www.cancer.org/cancer/lungcancer-non-smallcell/detailedguide/non-small-cell-lung-cancerwhat-is-non-small-cell-lung-cancer. Accessed December 4, 2014. 3. Rosado-de-Christenson ML, Templeton PA, Moran CA. Bronchogenic carcinoma: radiologic-pathologic correlation. Radiographics. 1994;14(2):429-446. 4. Nichols L, Saunders R, Knollmann FD. Causes of death of patients with lung cancer. Arch Pathol Lab Med. 2012;136(12):1552-1557. 5. Wilson DO, Ryan A, Fuhrman C, et al. Doubling times and CT screen-detected lung cancers in the Pittsburgh lung screening study. Am J Respir Crit Care Med. 2012;185(1):85-89. 6. Veronesi G, Maisonneuve P, Bellomi M, et al. Estimating overdiagnosis in low-dose computed tomography screening for lung cancer: a cohort study. Ann Intern Med. 2012;157(11):776-784. 7. Rubin E, Reisner HM, eds. Essentials of Rubin’s Pathology. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2009:268-270. 8. Asmis TR, Ding K, Seymour L, et al. Age and comorbidity as independent prognostic factors in the treatment of non small-cell lung cancer: a review of National Cancer Institute of Canada Clinical Trials Group trials. J Clin Oncol. 2008;26(1):54-59. 9. Hoang T, Dahlberg SE, Schiller JH, Johnson DH. Does histology predict survival of advanced non-small cell lung cancer patients treated with platin-based chemotherapy? An analysis of the Eastern Cooperative Oncology Group Study E1594. Lung Cancer. 2013;81(1):47-52. 10. Ellis LM, Bernstein DS, Voest EE, et al. American Society of Clinical Oncology perspective: raising the bar for clinical trials by defining clinically meaningful outcomes. J Clin Oncol. 2014;32(12):1277-1280. 11. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.5.2015. © National Comprehensive Cancer Network, Inc 2015. All rights reserved.

Accessed December 4, 2014. To view the most recent and complete version of the guidelines, go online to http://nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN content are trademarks owned by the National Comprehensive Cancer Network, Inc. 12. Reck M, Popat S, Reinmuth N, et al. Metastatic non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014;25(suppl 3):iii27-iii39. 13. Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2008;26:3543-3551. 14. Morgensztern D, Waqar S, Subramanian J, Gao F, Govindan R. Improving survival for stage IV non-small cell lung cancer: a surveillance, epidemiology, and end results survey from 1990 to 2005. J Thorac Oncol. 2009;4:1524-1529. 15. Pao W, Girard N. New driver mutations in non-smallcell lung cancer. Lancet Oncol. 2011;12(2):175-180. 16. Perez-Moreno P, Brambilla E, Thomas R, Soria JC. Squamous cell carcinoma of the lung: molecular subtypes and therapeutic opportunities. Clin Cancer Res. 2012;18(9):2443-2451 17. Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002;346:92-98. 18. Socinski MA, Bondarenko I, Karaseva NA, et al. Weekly nab-paclitaxel in combination with carboplatin versus solvent-based paclitaxel plus carboplatin as first-line therapy in patients with advanced non-small-cell lung cancer: final results of a phase III trial. J Clin Oncol. 2012;30:2055-2062. 19. Aydiner A, Yildiz I, Seyidova A. Clinical outcomes and prognostic factors associated with the response to erlotinib in non-small-cell lung cancer patients with unknown EGFR mutational status. Asian Pac J Cancer Prev. 2013;14:3255-3261. 20. Creelan BC. Update on immune checkpoint inhibitors in lung cancer. Cancer Control. 2014;21:80-89.

21. Cancer Genome Atlas Research Network. Comprehensive genomic characterization of squamous cell lung cancers. Nature. 2012;489:519-525.

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While chemotherapy produces a moderate survival improvement in patients with advanced squamous NSCLC, no regimen is associated with a clear survival benefit in this group of patients.9 It is likely that improved outcomes will continue to occur in modest, stepwise increments in unselected squamous NSCLC patients,13,14,17,18 although efforts to identify clinical or molecular signatures with potential predictive value for currently available treatments are continuing.19,20 Ongoing genomic studies may identify novel therapeutic targets.21 Current clinical trials testing immune checkpoint inhibitors and agents to improve supportive care20 may also provide new, individual therapeutic strategies that have the potential to enhance the effectiveness of currently available treatments. More treatment options are needed for patients with squamous NSCLC.

S:10 in

Tumors in squamous NSCLC are often centrally located, making them more likely to invade larger blood vessels and bronchi, leading to potentially fatal complications.3,4 Squamous NSCLC tumors also grow quickly5,6 and commonly metastasize to other parts of the body.7 Furthermore, patients with squamous NSCLC are more likely to have a history of smoking and serious comorbidities, factors that make the disease more challenging to treat.8 In the 1st-line treatment of this disease, overall survival (OS) is approximately 8 to 10 months.9,10 There is, therefore, an

In the 1st-line setting, progress in squamous NSCLC is lagging behind progress in nonsquamous NSCLC.

T:10.5 in

NSCLC accounts for 85% to 90% of all lung cancers and comprises several subtypes.2 These subtypes include nonsquamous and squamous, which represent two-thirds and one-third of all NSCLC cases, respectively.2 Nonsquamous NSCLC can be further divided into different subtypes, including adenocarcinoma (approximately 40% of all NSCLC cases), large cell carcinoma (approximately 10% to 15% of all NSCLC cases), and other less common subtypes.2

urgent need for effective therapies that will improve outcomes for patients with squamous NSCLC.

EXPERT PERSPECTIVE | BY ISABEL CUNNINGHAM, MD

We Can Treat Hodgkin’s Lymphoma Like Renal Cell Carcinoma and Melanoma?

Isabel Cunningham, MD, Cancer Therapy Advisor Advisory Board member reviews recent discoveries in the treatment of hematologic cancers.

T

he news that agents effective in melanoma, renal cell, and non-small cell lung cancers can achieve complete remissions in heavily pretreated, mainly nodular sclerosis Hodgkin’s lymphoma1 should not surprise anyone familiar with medical history.

Cancers were not separated until the 19th century when, in 1919, Dr. James Ewing’s 1,000-page book contained a detailed chapter for each tumor by organ. He envisioned the 20th century as “promising to widely separate many neoplastic diseases formerly held to be closely related...[and] proving to be the era of successful therapeutics and prophylaxis.” And his prediction came true; separation by tumor site led to some success and knowledge about prevention, but not nearly all we need. Dr. Ewing did not foresee that our century’s therapeutic focus would turn from organ site classification back to the concept of “closely related” cancers and the ancient Greek belief in a human body’s ability to heal itself, but using 21st century technology.

Focus is now back on the host’s evident inability to mount the immune response required to recognize cancer and eradicate it. Our target is now not the tumor, but the host. Means tumors may use to escape immune surveillance include immune checkpoints such as CTLA-4 and programmed death (PD)1/PD-L1.

Regulatory T cells, activated B cells, and

NK cells express the checkpoint receptor PD-1. Tumors that overexpress the ligands PD-L1 and PD-L2 can engage these receptors on activated T cells that can cause T cell exhaustion, allowing unimpeded tumor growth. Tumor PD-L1 expression is correlated with poor prognosis in many tumors. Many new antibody therapies are being developed to block the interaction of PD-1 and PD-L1, the first of which are nivolumab and pembrolizumab. Responses and their long durations have been great news in typically resistant tumors that bear PD-L1.

However, responses have also been seen among tumors considered PD-L1 negative, as in some significant radiologic response in PD-L1-negative melanoma. The optimal means of quantifying PD-L1 and understanding unexplained responses are being explored.

The exciting results with nivolumab include the New Englad Journal of Medicine study of 23 patients with resistant Hodgkin’s lymphoma, the majority with the nodular sclerosis type and after failure of autotransplant. It found responses in 20 (87%), four of which were complete, with 86% progression-free survival at 6 months.1 It may or may not be noteworthy that three of the four patients with complete responses had not received brentuximab. Is there something specific about Hodgkin’s lymphoma or can any hematologic malignancy be effectively

treated? PD-L1 is overexpressed on Reed-Sternberg cells and, particular to the nodular sclerosis type, chromosome 9p24.1 amplification is associated with increase in PD-1 ligands. Viruses can also use the PD-1 axis to avoid immune attack. In Epstein-Barr virus-related Hodgkin’s lymphoma, post-transplant lymphoma, and nasopharyngeal cancer, PD-1 blockade has been used successfully but not in Burkitt lymphoma or human herpesvirus-8 Kaposi sarcoma, possibly explained by differences in protein signaling. Clinical trials are ongoing in most hematologic malignancies.

Results in non-Hodgkin’s lymphoma presented at the 2014 American Society of Hematology annual meeting by the same Hodgkin’s lymphoma investigators

Focus is now back on the host’s inability to mount the immune response required to recognize cancer. showed 15% to 40% responses in small patient numbers, and studies are continuing in diffuse large B-cell lymphoma and follicular lymphoma.

Although it has taken a long time to discover, cancer’s been using the same tricks in its various manifestations, which we couldn’t identify while we separated them by histology. As we continue to gain knowledge, the future for cancer research looks brighter and a lot more fascinating. ■ Reference 1. Ansell SM, Lesokhin AM, Borrello I, et al.

PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J

Med. 2015;372(4):311-319.

A30 CANCER THERAPY ADVISOR | SEPTEMBER/OCTOBER 2015 | CancerTherapyAdvisor.com

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VIEWPOINT | BY JOHN SCHIESZER

Study Suggests Using Caution When Sharing Information of Adult Patients Over 75 Sharing health information about an older patient with their family may have unintended consequences.

O

ncologists may need to be careful when using patient portals w it h t heir older patients. Boston researchers reported that information sharing and control are complex issues in older adults, and clinicians may want to be cautious when sharing control of their personal health information with family members. The researchers conducted a study in which they looked at how patients older than 75 and family caregivers approach sharing health information.

Patient portals can be helpful when it comes to sharing information, but some older adults may be more concerned about their privacy and keeping autonomy. Researchers found that patients older than 75 in general do not want to feel “spied on” by their family members. In addition, the study showed that control of information sharing is f luid.1 The researchers found older patients wanted to retain control of decision making as long as possible and that transfer of control tends to occur gradually.

“We were surprised to see so many nuances in patients’ preferences for sharing information with their families.

We learned that some older patients would try to shield their families from knowing about health problems. This especially seemed true when family caregivers had many competing responsibilities, such as raising their own children and busy work lives,” said study investigator

Bradley Crotty, MD, MPH, who is the director of patient portals and associate program director for informatics training in the Division of Clinical Informatics at Beth Israel Deaconess Medical Center in Boston, MA. He and his colleagues studied 10 focus groups of people older than 75 and family members who care for people older than 75. The study was conducted between October 2013 and February 2014, and it included 30 people older than 75 and 23 individuals who assist an older family member. The cohort was drawn from the Information Sharing Across Generations (InfoSAGE) Living

Patient portals can be helpful, but some older adults are concerned about their privacy and autonomy.

Laboratory, an affiliated network of senior housing in metropolitan Boston. The researchers separated the caregivers from the patients, and a professional moderator led groups through a discussion guide.

The study showed that the patients a nd c a reg i ver s h ave d i f f ere nt perspectives on what is seen as “the burden” of informat ion. It also

suggested that access to medical information by families can have u n i ntended consequences. “ We found no one-size-fits-all approach to different older patient and family preferences,” Dr. Crotty told Cancer Therapy Advisor. “Decision making and control of information is dynamic depending on health functional status.

Checking in periodically with the elderly patient about their preferences and boundaries is important.”

Patient portals are secure websites that provide access to health data and communication with the clinical team.

Patient portals can be a hub for families, but they also can lead to a transfer of control from the patient to the family member. Currently, there are a record number of adults older than 75 who are cancer survivors. The risk of cancer increases with age, and the American Cancer Society estimates that 45% of cancer survivors are 70 or older and only 5% are under the age of 40.2 Dr. Crotty said some older patients don’t want the aggressive therapies their family member wants. Oncologists see this commonly in their practice.

“We learned that some older patients would not disclose biopsies or even some diagnoses with family. Patients were quite aware that sometimes families might want more aggressive approaches to care, and would try to keep information away from families to head that off,” said Dr. Crotty.

“Conversations about advanced care planning should include mention of information sharing preferences, such as access to patient portals, medical records, and communication with clinicians.”

In the study, 87% of the patients and 70% of the caregivers were women. The study showed that 60% of patients used the Internet daily or almost daily, and 96% of the caregivers reported similarly high Internet use.

CancerTherapyAdvisor.com | SEPTEMBER/OCTOBER 2015 | CANCER THERAPY ADVISOR A31

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Visit CancerTherapyAdvisor.com • Browse oncology news and resources • • Read in-depth articles and clinical commentary authored by experts • • Review full listings of cancer treatment regimens • • Gain easy access to an extensive range of current and concise drug information • • Stay up-to-date by registering to receive our e-newsletters •

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VIEWPOINT Jeremy L. Warner MD, MS, who is an assistant professor of medicine and biomedical informatics at Vanderbilt University Medical Center in Nashville, TN, said this study is somewhat skewed by the fact that the participants were predominantly women, white, and welleducated. “The sample size was also small but this type of qualitative research is very time-consuming, and given their careful methodologic approach, the sample seems reasonable for the time frame that they had. The finding that there is no one-size-fits-all [approach] to information sharing with the elderly is not too surprising to me. What was surprising is that the elder population was actually fairly tech-inclined,” Dr. Warner told Cancer Therapy Advisor.

Dr. Warner, who is also the chair of the American Society of Clinical Oncolog y ’s Healt h I nfor mat ion Technology Work Group, said the findings are important because there is little research so far in this field. Patient portals are growing in numbers, and oncologists must be keenly aware of how disclosures may have unintended consequences. Dr. Warner said when it comes to cancer, the problem of data liquidity is currently a bigger problem than information sharing.

He said patients with cancer often have multiple providers at multiple institutions as well as an extensive network of caregivers during different phases of their illness.

“Although it is very important for an autonomous older patient to be able to choose who has access to their information and when, it is just as important for patients with cancer that they have uninterrupted access to all of their data,” said Dr. Warner.

“Oncologists should be aware that patients are beginning to expect their data as part of their care. With movements such as Open Notes, Blue Button, and the Meaningful Use requirements to share data with patients, there is now the mechanism for patients to begin to share their information with loved ones and other caregivers.”

He said a discussion of a patient’s information sharing desires, especially patients who are older, should become an essential part of the oncologist’s

Patients want to be in control of decisions and of information, even if it means that filtration is limited. history and physical. Dr. Warner said oncologists should also be aware that there are an increasing number of thirdparty care coordination companies that are being established to enable teambased, patient-centered care.

Don Dizon, MD, who is the clinical co-director of gynecologic oncology at Massachusetts General Hospital Cancer Center, agrees with Dr. Warner. He said that information sharing is a dynamic process and that both elders and their caregivers can approach information in different ways.

“Particularly noteworthy are the potential unintended consequences of access, which include the potential of accidental disclosure of medical history that might have been unknown to the caregiver, or sharing of medical

knowledge with the patient’s providers heretofore unknown to them,” Dr. Dizon told Cancer Therapy Advisor. “I think the importance of these findings is to validate that control is important regardless of age.”

He said patients want to be in control of decisions and of information, even if it means that filtration is limited.

Dr. Dizon said it is important that oncolog ists reg ularly assess t he capacity of all patients over the age of 75. “A fit, older patient needs to be treated with respect. Still, it is important to understand that the preferences for shared decision making are also quite fluid. What may have been the case when we first meet a patient may change dramatically over the span of years that we are caring for them,” said Dr. Dizon.

Just as social histories are never static, neither are the preferences of caregiver involvement and shared decision making in patients, especially as they age. “Other factors are cultural and racial. We need to bear in mind that the social history is important and that it is dynamic. I also think it reminds us that our patient requires being treated with dignity and respect, and that extends to how, when, and to what degree we share their medical information,” said Dr. Dizon. ■ References 1. Crotty BH, Walker J, Dierks M, et al.

Information sharing preferences of older patients and their families. JAMA Intern

Med. July 6, 2015. [Epub ahead of print] doi: 10.1001/jamainternmed.2015.2903.

2. American Cancer Society. Cancer Facts &

Figures 2015. Atlanta, GA: American Cancer Society; 2015.

Looking for more expert opinions? Visit us at CancerTherapyAdvisor.com/viewpoint

CancerTherapyAdvisor.com | SEPTEMBER/OCTOBER 2015 | CANCER THERAPY ADVISOR A33

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REGIMEN & MONOGRAPH INDEX CANCER THERAPY REGIMENS & DRUG MONOGRAPHS

1

Bone Cancer  Bone Cancer

7

Brain Cancer

9

Breast Cancer

22

Endocrine Cancer

25

Gastrointestinal Cancer  Gastric Cancer

37

Genitourinary Cancer

45

Gynecologic Cancer

47

Head and Neck Cancer  Head and Neck Cancer

53

Hematologic Cancer  Acute Myeloid Leukemia (AML)

73

Lung Cancer

78

Sarcoma

79

Skin Cancer

83

Associated Hematological Disorders

To view the complete collection of cancer treatment regimens for all cancer types visit CancerTherapyAdvisor.com/TreatmentRegimens.

To view the complete collection of drug monographs visit CancerTherapyAdvisor.com/DrugMonographs.

IMPORTANT INFORMATION FOR ALL READERS CANCER THERAPY ADVISOR (CTA) is an up-to-date guide to commonly prescribed pharmaceuticals, as well as certain OTC products. It has been produced to provide an easily accessible reminder of basic information useful to review when prescribing medications, such as specific indications for use, dosage, and a checklist of precautions, interactions, and adverse drug reactions. Reference should always be made to each drug being coadmin­ is­tered. The information it contains is intended solely for use by the medical profession. IT IS NOT INTENDED FOR LAY READERS. This reference has been assembled and edited by an experienced staff of pharmacists uti­ liz­ing information available from FDA-approved labeling.

Distinctions have not necessarily been made between those reactions that are well-documented and/or clinically significant, and those that carry only a theoretical risk. A renowned board of consulting medical specialists has also independently reviewed the product references.

However, although every effort is made to assure accuracy, the information in CTA is not necessarily reviewed by the supplier of a particular drug. If any questions arise about information in CTA, the physician should verify it against labeling or by contacting the company marketing the drug. The publisher and editors do not warrant or guarantee any of the products described or the information describing them. THE PUBLISHER AND EDITORS DO NOT ASSUME, AND HEREBY EXPRESSLY DISCLAIM ANY LIABILITY WHATSOEVER FOR ANY ERRORS OR OMISSIONS IN SUCH INFORMATION OR FOR ANY USE OF ANY OF THE PRODUCTS LISTED. No prescription drug should be used except on the advice of, and as directed by, a physician. The training and experience of a physician are essential to forming any opinion on the appropriateness of a specific drug for a specific patient. The information in this publication is not by itself sufficient for a lay person—or even a physician—to evaluate the risks and benefits of taking any particular drug.

In reaching professional judgments on whether to prescribe a pharmaceutical, which to prescribe, and under what regimen, the physician should thoroughly understand the options available for any clinical application, the potential effectiveness of each product, and the associated risks and side effects. This knowledge should be considered in light of the special circumstances of the patient, for each patient is unique. No single reference can substitute for medical training and experience. The physician must be familiar with the full product labeling, provided by the manufacturer or distributor of the drug, of every product he or she prescribes, as well as the relevant medical literature.

Certain additional qualifications are important in using this book. First, CTA has been deliberately kept concise, with a standardized format, so that it could be a convenient reference tool. This means that lengthy and detailed explanations about certain aspects of drugs commonly found in labeling are omitted or condensed.

Second, by revising and reprinting quarterly, CTA should be one of the most up-to-date guides to prescription drugs now available in print. Only the current issue should be used.

The prescribing decision is ultimately the responsibility of the physician. CTA is offered to assist physicians in this area. © 2015 Haymarket Media, Inc.

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BONE CANCER Bone Cancer Treatment Regimens Clinical Trials: The NCCN recommends cancer patient participation in clinical trials as the gold standard for treatment.

Cancer therapy selection, dosing, administration, and the management of related adverse events can be a complex process that should be handled by an experienced healthcare team. Clinicians must choose and verify treatment options based on the individual patient; drug dose modifications and supportive care interventions should be administered accordingly. The cancer treatment regimens below may include both U.S. Food and Drug Administration-approved and unapproved indications/regimens. These regimens are only provided to supplement the latest treatment strategies.

These Guidelines are a work in progress that may be refined as often as new significant data becomes available. The NCCN Guidelines® are a consensus statement of its authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult any NCCN Guidelines® is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way.

General Treatment Notes1 • Chemotherapy for Ewing’s sarcoma and osteosarcoma should include growth factor support.

• Conventional chondrosarcoma (Grades 1–3) has no known standard chemotherapy options.

• Mesenchymal chondrosarcoma: follow Ewing’s sarcoma regimens (category 2B).

• High-grade undifferentiated pleomorphic sarcoma (UPS) of bone and dedifferentiated chondrosarcoma: follow osteosarcoma regimens (category 2B).

Chordoma1 Note: All recommendations are Category 2A unless otherwise indicated.

REGIMEN

DOSING

Imatinib2,3

Imatinib 800mg orally once daily.

Imatinib with cisplatin4

Imatinib 400mg orally once daily and cisplatin 25mg/m2/week.

Imatinib with sirolimus5

Imatinib 400mg orally once daily and sirolimus 2mg/day orally once daily.

Erlotinib6

Erlotinib 150mg orally once daily.

Sunitinib7

Sunitinib 37.5mg orally once daily.

Lapatinib for EGFR-positive chordomas (category 2B)8

Lapatinib 1,500mg orally once daily.

Ewing’s Sarcoma and Mesenchymal Chondrosarcoma1 First-Line Therapy (Primary/Neoadjuvant/Adjuvant) VAC/IE (vincristine + doxorubicin† + Alternating VAC and IE cycles cyclophosphamide alternating with VAC cycles ifosfamide + etoposide)9 Day 1: Vincristine 2mg/m2 (max 2mg) IV + doxorubicin 75mg/m2 IVP + cyclophosphamide 1,200mg/m2 IV. Dactinomycin 1.25mg/m2 IV can be substituted for doxorubicin when a total doxorubicin dose of 375mg/m2 is reached.

IE cycles Days 1–5: Ifosfamide 1,800mg/m2 IV + mesna + etoposide 100mg/m2 IV. Repeat each cycle every 3 weeks for 17 cycles.

VAI (vincristine + ifosfamide + dactinomycin + doxorubicin)10

Day 1: Vincristine 1.5mg/m2 IV Days 1–3: Ifosfamide 2,000mg/m2 IV + mesna Days 1, 3, and 5: Dactinomycin 0.5mg/m2 IV Days 2 and 4: Doxorubicin 30mg/m2 IV. Repeat cycle every 3 weeks.

VIDE (vincristine + ifosfamide + doxorubicin + etoposide)11

Day 1: Vincristine 1.4mg/m2 (max 2mg) Days 1–3: Doxorubicin 20mg/m2 IV + ifosfamide 3mg/m2 IV + mesna 3g/m2 continuous IV infusion + etoposide 150mg/m2 IV. Repeat cycle every 3 weeks for up to 6 cycles. continued

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BONE CANCER Bone Cancer Treatment Regimens Ewing’s Sarcoma and Mesenchymal Chondrosarcoma (continued) REGIMEN

DOSING

Primary Therapy for Metastatic Disease at Initial Presentation VAC/IE (vincristine + doxorubicin† + cyclophosphamide alternating with ifosfamide + etoposide)9

Alternating VAC and IE cycles VAC cycles Day 1: Vincristine 2mg/m2 (max 2mg) IV + doxorubicin 75mg/m2 IV bolus + cyclophosphamide 1,200mg/m2 IV. Dactinomycin 1.25mg/m2 IV can be substituted for doxorubicin when a total doxorubicin dose of 375mg/m2 is reached.

IE cycles Days 1–5: Ifosfamide 1,800mg/m2 IV + mesna + etoposide 100mg/m2 IV. Repeat each cycle every 3 weeks for 17 cycles.

VAI (vincristine + ifosfamide + dactinomycin [actinomycin D] + doxorubicin)10

Day 1: Vincristine 1.5mg/m2 IV Days 1–3: Ifosfamide 2,000mg/m2 IV + mesna Days 1, 3 and 5: Dactinomycin 0.5mg/m2 IV Days 2 and 4: Doxorubicin 30mg/m2 IV. Repeat cycle every 3 weeks.

VIDE (vincristine + ifosfamide + doxorubicin + etoposide)11

Day 1: Vincristine 1.4mg/m2 (max 2mg) Days 1–3: Doxorubicin 20mg/m2 IV + ifosfamide 3mg/m2 IV + mesna 3g/m2 continuous IV infusion + etoposide 150mg/m2 IV. Repeat cycle every 3 weeks for up to 6 cycles.

VAdriaC† (cyclophosphamide + vincristine + doxorubicin OR dactinomycin)12

Day 1: Vincristine 2mg/m2 IV + cyclophosphamide 1,200mg/m2 + doxorubicin 75mg/m2 (the first 5 cycles) OR dactinomycin 1.25mg/m2 IV (subsequent cycles).

Repeat cycle every 3 weeks for 17 cycles.

Second-Line Therapy (Relapsed/Refractory Disease or Metastatic Disease) Cyclophosphamide + topotecan13–16

Days 1–5: Cyclophosphamide 250mg/m2/day IV + topotecan 0.75mg/m2/day IV. Repeat cycle every 3 weeks for 12–14 cycles.

Irinotecan ± temozolomide17–23

Days 1–5: Temozolomide 100mg/m2/day orally, plus Days 1–5 and 8–12: Irinotecan 10–20mg/m2/day IV at least 1 hour after temozolomide.

Repeat cycle every 3 or 4 weeks.

Ifosfamide + etoposide24

Days 1–5: Ifosfamide 1,800mg/m2/day IV + mesna Days 1–5: Etoposide 100mg/m2/day IV. Repeat every 3 weeks for 12 cycles.

Ifosfamide + carboplatin + etoposide25

Days 1 and 2: Carboplatin 400mg/m2/day IV, plus Days 1–5: Ifosfamide 1,800mg/m2/day IV + mesna + etoposide 100mg/m2/day IV. Repeat cycle every 3 weeks for up to 12 cycles (median 1 cycle).

Docetaxel + gemcitabine26

Days 1 and 8: Gemcitabine 675mg/m2 IV, plus Day 8: Docetaxel 75–100mg/m2 IV. Repeat cycle every 3 weeks for up to 13 cycles (median 4 cycles).

Irinotecan, temozolomide + cefpodoxime23

Days 1–5 and Days 8–21: Irinotecan 20–30mg/m2 IV with continuous oral cefpodoxime 10mg/kg/day divided BID starting 2 days prior to irinotecan.

Cyclophosphamide + sirolimus27 (Category 2B)*

First cycle of treatment Days 1–7 and 15–21: Cyclophosphamide 100mg oral twice daily from first cycle of treatment Days 1–7: Sirolimus 1mg orally once daily Days 8–14: Sirolimus 1mg orally twice daily Days 15–21: Sirolimus 1mg orally three times daily.

Second cycle of treatment Days 1–7 and 15-21: Cyclophosphamide 100mg oral twice daily from first cycle of treatment Days 1–21: Sirolimus 1mg orally three times daily.

Repeat cycle every 4 weeks

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BONE CANCER Giant Cell Tumor of Bone1 REGIMEN

DOSING

Denosumab28,29

Denosumab 120mg subcutaneously every 4 weeks with additional doses on Days 8 and 15.

Interferon alfa30,31

Interferon alpha-2 or beta (3,000,000 units/m2) 48 to 72 hours postoperatively OR increasing dosage from 4 × 106 units 3 times a week to 9 × 106 units 3 times a week.

Osteosarcoma1 First-Line Therapy (Primary/Neoadjuvant/Adjuvant Therapy or Metastatic Disease) Cisplatin + doxorubicin32–34

Days 1–3: Doxorubicin 25mg/m2/day IV, plus Day 1: Cisplatin 100mg/m2 IV continuous IV infusion.

Repeat cycle every 3 weeks for 6 cycles.

MAP (high-dose methotrexate + cisplatin + doxorubicin)35,36

Day 1: Methotrexate 8g/m2 IV (with leucovorin rescue 15mg every 6 hours for 11 doses, starting 24 hours after beginning methotrexate), followed by Days 7–9: Cisplatin 120mg/m2/day intra-arterially, followed by Day 9: Doxorubicin 60mg/m2 IV (48 hours after start of cisplatin infusion).

Repeat cycle once after 4 weeks.

Doxorubicin + cisplatin + ifosfamide + high-dose methotrexate37

Days 0, 6, 18, 27, and 36: Methotrexate (MTX) 12g/m2 as a 4-hour infusion, increased by 2g/m2 if the hour-4 level of serum MTX in the previous course was <1000 µmol/L Days 1, 7, 19, 28, and 37: Cisplatin 60mg/m2/day as a 48-hour continuous IV infusion (total dose 120mg/m2) Days 1 and 7: Doxorubicin (ADM1) (preoperative): 75mg/m2 as a 24-hour continuous IV infusion Day 12: Surgery Days 13, 22, and 31: Doxorubicin (ADM2) (postoperative): 90mg/m2 as a 24-hour continuous IV infusion Days 4, 10, 16, 25, and 34: Ifosfamide: 3 g/m2/day as a 120-hour (5-day) continuous IV infusion (total dose 15 g/m2).

Ifosfamide + cisplatin + epirubicin38

Day 1: Epirubicin 90mg/m2, cisplatin 100mg/m2 Days 2–4: Ifosfamide 2.0 g/m2 with an equivalent dose of mesna, repeated every 21 days. Six cycles of this combination regimen were administered (3 cycles prior to surgery and 3 cycles postoperatively).

Second-Line Therapy (Relapsed/Refractory or Metastatic Disease) Carboplatin + ifosfamide + etoposide25

Days 1 and 2: Carboplatin 400mg/m2/day IV, plus Days 1–5: Ifosfamide 1,800mg/m2/day IV + mesna + etoposide 100mg/m2/day IV. Repeat cycle every 3 weeks for up to 12 cycles (median 1 cycles).

Gemcitabine + docetaxel26

Days 1 and 8: Gemcitabine 675mg/m2 IV, plus Day 8: Docetaxel 75–100mg/m2 IV. Repeat cycle every 3 weeks for up to 13 cycles (median 4 cycles).

Cyclophosphamide + topotecan16

Days 1–5: Cyclophosphamide 250mg/m2/dose followed by topotecan (0.75mg/m2/dose), each given as a 30-minute IV infusion once daily for 5 days.

Sorafenib39

Sorafenib 400mg orally twice daily.

Ifosfamide + etoposide24

Days 1–5: Ifosfamide 1,800mg/m2/day IV and etoposide 100mg/m2/day; 5-day cycles every 3 weeks for 12 cycles.

Cyclophosphamide + etoposide40

Day 1: Cyclophosphamide 4000mg/m2 3-hour IV infusion Days 2–4: Etoposide 100mg/m2 over 1 hour twice daily for 3 days on Days 2, 3, and 4 (total dose 600mg/m2).

Gemcitabine41

Days 1 and 8: Gemcitabine 1,200mg/m2 IV. Repeat cycle every 21 days.

High-dose methotrexate + etoposide + ifosfamide42

Weeks 1, 2, 3, 7, 8, 12, and 13: High-dose methotrexate IV Weeks 4 and 9: Etoposide 75mg/m2/day IV + ifosfamide 3g/m2/day + mesna 3.6mg/m2/day continuous IV infusion for 4 days.

* †

Indicated for high-grade chondrosarcoma for systemic recurrence.

Dactinomycin can be substituted for doxorubicin because of concerns regarding cardiotoxicity. continued

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BONE CANCER References 1.

Bone Cancer Treatment Regimens

Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology™. Breast Cancer. v1.2015. Available at: http://www.nccn.org/ professionals/ physician_gls/pdf/bone.pdf. Accessed March 3, 2015.

2. Casali PG, Messina A, Stacchiotti S, et al. Imatinib mesylate in chordoma. Cancer.

2004;101:2086–2097.

3. Stacchiotti S, Longhi A, Ferraresi V, et al. Phase II study of imatinib in advanced chordoma. J Clin Oncol. 2012;30:914–920.

4. Casali PG, Stacchiotti S, Sangalli C, et al. Chordoma. Current Opin Oncol. 2007;19:367–370.

5. Stacchiotti S, Marrari A, Tamborini E, et al. Response to imatinib plus sirolimus in advanced chordoma. Ann Oncol. 2009;20:1886–1894.

6. Singhal N, Kotasek D, Parnis FX. Response to erlotinib in a patient with treatment refractory chordoma. Anti Cancer Drugs. 2009;20:953–955 7.

George S, Merriam P, Maki RG, et al. Multicenter phase II trial of sunitinib in the treatment of nongastrointestinal stromal tumor sarcomas. J Clin Oncol. 2009;27:3154–3160.

8. Stacchiotti S, Tamborini E, LoVullo S, et al. A phase II study on lapatinib in advanced EGFR-positive chordoma. Ann Oncol. 2013;24(7):1931–1936.

9. Grier HE, Krailo MD, Tarbell NJ, et al. Addition of ifosfamide and etoposide to standard chemotherapy for Ewing’s sarcoma and primitive neuroectodermal tumor of bone. N Engl J Med. 2003;348:694–701.

10. Paulussen M, Craft AW, Lewis I, et al; European Intergroup Cooperative Ewing’s Sarcoma Study-92. Results of the EICESS-92 Study: two randomized trials of Ewing’s sarcoma treatment—cyclophosphamide compared with ifosfamide in standard-risk patients and assessment of benefit of etoposide added to standard treatment in high-risk patients. J Clin Oncol. 2008;26:4385–4393.

11. Juergens C, Weston C, Lewis I, et al. Safety assessment of intensive induction with vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) in the treatment of Ewing tumors in the EURO-E.W.I.N.G. 99 clinical trial. Pediatr Blood Cancer.

2006 Jul;47(1):22–29.

12. Miser JS, Krailo MD, Tarbell NJ, et al. Treatment of metastatic Ewing’s sarcoma or primitive neuroectodermal tumor of bone: evaluation of combination ifosfamide and etoposide—a Children’s Cancer Group and Pediatric Oncology Group study.

J Clin Oncol. 2004;22:2873–2876.

13. Bernstein ML, Devidas M, Lafreniere D, et al. Intensive therapy with growth factor support for patients with Ewing tumor metastatic at diagnosis: Pediatric Oncology Group/Children’s Cancer Group Phase II Study 9457—a report from the Children’s Oncology Group. J Clin Oncol. 2006;24(1):152–159.

14. Hunold A, Weddeling N, Paulussen M, Ranft A, Liebscher C, Jürgens H. Topotecan and cyclophosphamide in patients with refractory or relapsed Ewing tumors.

Pediatr Blood Cancer. 2006;47:795–800.

15. Kushner BH, Kramer K, Meyers PA, et al. Pilot study of topotecan and high-dose cyclophosphamide for resistant pediatric solid tumors. Med Pediatr Oncol.

2000;35(5):468–474.

16. Saylors RL 3rd, Stine KC, Sullivan J, et al; Pediatric Oncology Group. Cyclophosphamide plus topotecan in children with recurrent or refractory solid tumors: a Pediatric Oncology Group phase II study. J Clin Oncol. 2001;19:3463–3469.

17. Casey DA, Wexler LH, Merchant MS, et al. Irinotecan and temozolomide for Ewing sarcoma: the Memorial Sloan-Kettering Experience. Pediatr Blood Cancer.

2009 Dec;53(6): 1029–1034.

18. Wagner LM, McAllister N, Goldsby RE, Rausen AR, McNall- Knapp RY, McCarville MB, Albritton K. Temozolomide and intravenous irinotecan for treatment of advanced Ewing sarcoma. Pediatr Blood Cancer. 2007;48:132–139.

19. Wagner LM, Crews KR, Iacono LC, et al. Phase I trial of temozolomide and protracted irinotecan in pediatric patients with refractory solid tumors. Clin Cancer Res. 2004;10(3): 840–848.

20. McNall-Knapp RY, Williams CN, Reeves EN, et al. Extended phase I evaluation of vincristine, irinotecan, temozolomide, and antibiotic in children with refractory solid tumors. Pediatr Blood Cancer. 2010 Jul 1;54(7):909–915.

21. Blaney S, Berg SL, Pratt C, et al. A phase I study of irinotecan in pediatric patients: a pediatric oncology group study. Clin Cancer Res. 2001 Jan;7(1):32–37.

22. Furman WL, Stewart CF, Poquette CA, et al. Direct translation of a protracted irinotecan schedule from a xenograft model to a phase I trial in children.

J Clin Oncol. 1999 Jun;17(6): 1815–1824.

23. 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.

24. Miser JS, Kinsella TJ, Triche TJ, et al. Ifosfamide with mesna uroprotection and etoposide: an effective regimen in the treatment of recurrent sarcomas and other tumors of children and young adults. J Clin Oncol. 1987;5:1191–1198.

25. Van Winkle P, Angiolillo A, Krailo M, et al. Ifosfamide, carboplatin, and etoposide (ICE) reinduction chemotherapy in a large cohort of children and adolescents with recurrent/refractory sarcoma: the Children’s Cancer Group (CCG) experience.

Pediatr Blood Cancer. 2005;44:338–347.

26. Navid F, Willert JR, McCarville MB, Furman W, Watkins A, Roberts W, Daw NC. Combination of gemcitabine and docetaxel in the treatment of children and young adults with refractory bone sarcoma. Cancer. 2008;113:419–425.

27. Bernstein-Molho R, Kollender Y, Issakov J, et al. Clinical activity of mTOR inhibition in combination with cyclophosphamide in the treatment of recurrent unresectable chondrosarcomas. Cancer Chemother Pharmacol. 2012;70:855–860.

28. Branstetter DG, Nelson SD, Manivel JC, et al. Denosumab induces tumor reduction and bone formation in patients with giant-cell tumor of bone. Clin Cancer Res. 2012 Aug 15; 18(16):4415–4424.

29. Thomas D, Henshaw R, Skubitz K, et al. Denosumab in patients with giant-cell tumour of bone: an open-label, phase 2 study. Lancet Oncol. 2010 Mar;11(3):275–280.

30. Kaiser U, Neumann K, Havemann K.Generalised giant-cell tumour of bone: successful treatment of pulmonary metastases with interferon alpha, a case report. J Cancer Res Clin Oncol. 1993;119(5):301–303.

31. Kaban LB, Troulis MJ, Ebb DJ, et al. Antiangiogenic therapy with interferon alpha for giant cell lesions of the jaws. Oral Maxillofac Surg. 2002 Oct;60(10):1103–1111; discussion 1111–1113.

32. Bramwell VH, Burgers M, Sneath R, et al. A comparison of two short intensive adjuvant chemotherapy regimens in operable osteosarcoma of limbs in children and young adults: the first study of the European Osteosarcoma Intergroup.

J Clin Oncol. 1992;10(10):1579–1591 33. Lewis IJ, Nooij MA, Whelan J, et al; MRC BO06 and EORTC 80931 collaborators; European Osteosarcoma Intergroup. Improvement in histologic response but not survival in osteosarcoma patients treated with intensified chemotherapy: a randomized phase III trial of the European Osteosarcoma Intergroup.

J Natl Cancer Inst. 2007;99:112–128.

34. Souhami RL, Craft AW, Van der Eijken JW, et al. Randomised trial of two regimens of chemotherapy in operable osteosarcoma: a study of the European Osteosarcoma Intergroup. Lancet. 1997 Sep 27;350(9082):911–917.

35. Bacci G, Ferrari S, Bertoni F, et al. Long-term outcome for patients with nonmetastatic osteosarcoma of the extremity treated at the istituto ortopedico rizzoli according to the istituto ortopedico rizzoli/osteosarcoma-2 protocol: an updated report. J Clin Oncol. 2000;18:4016–4027.

36. Winkler K, Beron G, Delling G,Neoadjuvant chemotherapy of osteosarcoma: results of a randomized cooperative trial (COSS-82) with salvage chemotherapy based on histological tumor response. J Clin Oncol.

1988 Feb;6(2):329–337.

37. Bacci G, Briccoli A, Rocca M, et al. Neoadjuvant chemotherapy for osteosarcoma of the extremities with metastases at presentation: recent experience at the Rizzoli Institute in 57 patients treated with cisplatin, doxorubicin, and a high dose of methotrexate and ifosfamide. Ann Oncol. 2003 Jul;14(7): 1126–1134.

38. Basaran M, Bavbek ES, Saglam S, et al. A phase II study of cisplatin, ifosfamide and epirubicin combination chemotherapy in adults with nonmetastatic and extremity osteosarcomas. Oncology. 2007;72:255–260.

39. Grignani G, Palmerini E, Dileo P, et al. A phase II trial of sorafenib in relapsed and unresectable high-grade osteosarcoma after failure of standard multimodal therapy: an Italian Sarcoma Group study. Ann Oncol. 2012;23:508–516.

40. Berger M, Grignani G, Ferrari S, et al. Phase 2 trial of two courses of cyclophosphamide and etoposide for relapsed high-risk osteosarcoma patients. Cancer.

2009;115:2980–2987.

41. Maki RG, Wathen JK, Patel SR, et al. Randomized phase II study of gemcitabine and docetaxel compared with gemcitabine alone in patients with metastatic soft tissue sarcomas: results of sarcoma alliance for research through collaboration study 002. J Clin Oncol. 2007;25:2755–2763.

42. Le Deley MC, Guinebretiere JM, Gentet JC, et al. SFOP OS93: a randomised trial comparing preoperative high-dose methotrexate plus doxorubicin to high-dose methotrexate plus etoposide and ifosfamide in osteosarcoma patients.

Eur J Cancer. 2007; 43;752–761.

(Revised 3/2015) © 2015 by Haymarket Media, Inc.

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DRUG MONOGRAPHS

BONE CANCER Methotrexate injection

℞

Bedford

Folic acid antagonist. Methotrexate 25mg/mL; soln for IV, IM, intra-arterial, or intrathecal administration after dilution; preservative-free. ℞ Also: Methotrexate for injection Methotrexate 1g/vial; pwd for IV, IM, intra-arterial, or intrathecal administration after dilution; preservative-free.

Indications: Non-metastatic osteosarcoma in patients who have undergone surgical resection or amputation for the primary tumor (high-dose therapy with leucovorin rescue).

Adults: Initially 12g/m2 IV infusion over 4 hours; may be increased to 15g/m2; see literature for leucovorin rescue dosing with high-dose methotrexate.

Children: See literature.

Contraindications: Pregnancy (Cat.X). Nursing mothers.

Warnings/Precautions: Be fully familiar with this drug’s toxicity before use. Discontinue if malignant lymphomas occur. Obtain baseline and monitor CBCs with differential, platelet counts, chest X-ray, and hepatic, renal and pulmonary function. During therapy monitor hematology monthly, renal and hepatic function every 1–2 months, more often if increasing dose or predisposed to toxicity (eg, dehydration).

Discontinue immediately if blood counts drop significantly. Rule out pregnancy in women of childbearing potential; use effective contraception during therapy and for at least 1 ovulatory cycle afterwards for women and for at least 3 months afterwards for men. Interrupt therapy if vomiting, diarrhea, stomatitis, or pulmonary symptoms occur. Hepatic or renal impairment. Obesity. Diabetes. Peptic ulcer.

Ulcerative colitis. Infection. Dehydration. Folate deficiency. Ascites, pleural effusions: evacuate fluid, monitor for toxicity and reduce dose or discontinue if needed. Elderly (use low doses and monitor closely). Debilitated.

Interactions: Avoid live virus vaccines. Toxicity increased by NSAIDs, salicylates, phenytoin, sulfonylureas, sulfonamides, probenecid, folic acid antagonists. May be potentiated by penicillins (monitor), tetracyclines, chloramphenicol, non-absorbable broad spectrum antibiotics. May be antagonized by folic acid. May potentiate theophylline, mercaptopurine. Increased risk of soft tissue necrosis and osteonecrosis with radiotherapy.

Caution with other hepatotoxic drugs (eg, azathioprine, retinoids, sulfasalazine) and nephrotoxic agents (eg, cisplatin).

Adverse reactions: Ulcerative stomatitis, leukopenia, nausea, GI upset, malaise, fatigue, chills, fever, dizziness, infection, myelosuppression, hepatotoxicity, renal toxicity, CNS toxicity, seizures (esp in children); interstitial pneumonitis, tumor lysis syndrome, skin reactions (may be fatal; eg, toxic epidermal necrolysis, Stevens-Johnson syndrome).

How supplied: Soln (2mL, 4mL, 8mL, 10mL)—10 (single-use vials); pwd (1 gram)—1 (single-use vial)

VOTRIENT GlaxoSmithKline

℞

Tyrosine kinase inhibitor. Pazopanib 200mg; tabs.

Indications: Advanced soft tissue sarcoma in patients who have received prior chemotherapy.

Limitation of use: not for treating adipocytic soft tissue sarcoma or gastrointestinal stromal tumors.

Adults: Take on an empty stomach. Swallow whole. 800mg once daily. Dose adjustments: see full labeling. Hepatic impairment: moderate: 200mg once daily; severe: not recommended.

Concomitant strong CYP3A4 inhibitors (eg, ketoconazole, ritonavir, clarithromycin): avoid and consider alternate drug; if warranted, reduce dose of pazopanib to 400mg; may reduce further if toxicity occurs. Concomitant strong CYP3A4 inducers (eg, rifampin): avoid and consider alternate drug.

Children: Not established (increased toxicity in developing organs).

Warnings/Precautions: Not indicated for use in combination with other cancer agents. Risk of severe and fatal hepatotoxicity (esp. ≥65yrs old). Monitor liver tests before starting and at Weeks 3, 5, 7, and 9, thereafter at Months 3 and 4, then periodically. If ALT between 3×ULN and 8×ULN continue therapy with weekly monitoring until ALT returns to Grade 1 or baseline. If ALT >8×ULN interrupt therapy until ALT returns to Grade 1 or baseline; may consider reintroducing at a reduced dose, measure liver tests weekly for 8 weeks; if ALT>3×ULN recurs, permanently discontinue. Permanently discontinue if ALT>3×ULN and bilirubin >2×ULN. Gilbert’s syndrome (see full labeling). History of QT prolongation. Cardiac dysfunction risk: evaluate LVEF at baseline and periodically; monitor for CHF. Monitor ECG, electrolytes (eg, calcium, magnesium, potassium), thyroid function. History of hemoptysis, cerebral, or clinically significant GI hemorrhage in the past 6 months: not recommended. Risk of arterial thrombotic events (within previous 6 months: not recommended).

Monitor for VTE, PE, infection, proteinuria (reduce dose if 24-hour urine protein ≥3g), thrombotic

microangiopathy, GI perforation or fistula.

Monitor BP and manage hypertension promptly.

Discontinue if severe and persistent hypertension (despite antihypertensives and dose reduction), if repeat episodes of proteinuria (despite dose reductions), thrombotic microangiopathy, or serious infection occurs. Stop therapy at least 7 days before surgery; discontinue in patients with wound dehiscence. Pregnancy (Cat.D), nursing mothers: not recommended.

Interactions: See Adult dosing: Potentiated by strong CYP3A4 inhibitors, grapefruit juice. Avoid concomitant strong Pgp or BCRP inhibitors.

Antagonized by strong CYP3A4 inducers.

Concomitant drugs with narrow therapeutic windows metabolized by CYP3A4, CYP2D6, or CYP2C8: not recommended. Increased risk of ALT elevations with concomitant simvastatin; caution and monitor closely; follow dosing guidelines or consider alternatives to pazopanib, or discontinuing simvastatin if develops.

Separate antacids by several hours. Caution with concomitant drugs that prolong QT interval (eg, antiarrhythmics).

Adverse reactions: Diarrhea, hypertension, hair color changes, nausea, anorexia, vomiting, fatigue, decreased weight, decreased appetite, tumor pain, musculoskeletal pain, headache, dysgeusia, dyspnea, skin hypopigmentation; hepatoxicity, QT prolongation, hemorrhagic events, arterial thrombotic events (eg, MI, angina, ischemic stroke, TIA), venous thrombotic events (eg, VTE, PE), GI perforation or fistula, impaired wound healing, hypothyroidism, proteinuria, infection, reversible posterior leukoencephalopathy syndrome (discontinue if occurs).

How supplied: Tabs—120

XGEVA Amgen

℞

Osteoclast inhibitor (RANKL inhibitor).

Denosumab 120mg/vial (70mg/mL); soln for SC inj; preservative-free.

Indications: Treatment of adults and skeletallymature adolescents with giant cell tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity.

Adults: Give by SC inj into upper arm, upper thigh, or abdomen. 120mg once every 4 weeks with additional 120mg doses on Days 8 and 15 of the 1st month of therapy.

Children: Not established (interferes with bone growth and dentition).

Contraindications: Pre-existing hypocalcemia.

Warnings/Precautions: Correct hypocalcemia before starting; ensure adequate daily calcium, magnesium, and Vit.D intake, esp. in renal impairment (CrCl <30mL/min). Monitor calcium,

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DRUG MONOGRAPHS

BONE CANCER phosphorus, magnesium levels in susceptible patients (eg, severe renal impairment, receiving dialysis). Monitor for osteonecrosis of the jaw.

Perform oral exam and preventive dentistry before and regularly during therapy. Maintain good oral hygiene. Avoid invasive dental procedures during treatment. Evaluate for atypical fractures if thigh/groin pain develops; consider withholding therapy until risk/benefit

Adverse reactions: Fatigue, asthenia, hypophosphatemia, nausea, arthralgia, headache, back pain, pain in extremity, dyspnea, decreased appetite, peripheral edema, vomiting, anemia, constipation, diarrhea; osteonecrosis of jaw, severe hypocalcemia (may be fatal), anaphylactic reactions (discontinue if occurs).

How supplied: Single-use vial (1.7mL)—1

assessment. Pregnancy (Cat.D); use highly effective contraception during therapy, and for at least 5 months after last dose. Nursing mothers: avoid (may impair mammary gland development/ lactation).

Interactions: Concomitant other denosumabcontaining products (eg, Prolia): not recommended. Concomitant drugs that can lower calcium levels; monitor.

EMETOGENIC POTENTIAL OF ANTINEOPLASTIC AGENTS High Risk (>90% frequency without antiemetics) AC combination: Doxorubicin or Epirubicin (Ellence) + Cyclophosphamide (Cytoxan) IV Altretamine (HMM, Hexalen) oral Carmustine (BCNU, BiCNU) IV: >250mg/m2

Cisplatin (CDDP) IV Cyclophosphamide (CTX, Cytoxan) IV: >1,500mg/m2 Dacarbazine (DTIC, DTIC-Dome) IV Doxorubicin IV: >60mg/m2

Epirubicin (Ellence) IV: >90mg/m2 Ifosfamide (Ifex) IV: ≥2g/m2 per dose Mechlorethamine (Mustargen) IV Procarbazine (Matulane) oral Streptozocin (Zanosar) IV

Moderate Risk (30–90% frequency without antiemetics) Aldesleukin (IL-2, Proleukin) IV: >12–15 million IU/m2 Amifostine (Ethyol) IV: >300mg/m2 Arsenic trioxide (As2O3, Trisenox) IV Azacitidine (Vidaza) IV Bendamustine (Treanda) IV Busulfan (Busulfex) IV; oral: >4mg/day Carboplatin IV Carmustine (BCNU, BiCNU) IV: ≤250mg/m2 Clofarabine (Clolar) IV

Idarubicin (Idamycin) IV Cyclophosphamide (CTX, Cytoxan) IV: Ifosfamide (Ifex) IV: <2g/m2 ≤1,500mg/m2 Cyclophosphamide (CTX) oral ≥100mg/m2/day Interferon alpha (IFN-alfa, Intron A) IV: ≥10 Cytarabine (ARA-C) IV: >200mg/m2 million IU/m2 Dactinomycin (Cosmegen) IV Irinotecan (CPT-11, Camptosar) IV Daunorubicin (Cerubidine) IV Lomustine (CCNU, CeeNU) oral 2 Doxorubicin IV: ≤60mg/m Melphalan (L-PAM, Alkeran) IV 2 Methotrexate (MTX) IV: ≥250mg/m2 Epirubicin (Ellence) IV: ≤90mg/m Estramustine (Emcyt) oral Oxaliplatin (Eloxatin) IV Etoposide (VP-16) oral Temozolomide (Temodar) IV; oral >75mg/ m2/day

Low Risk (10–30% frequency without antiemetics) Aldesleukin (IL-2, Proleukin) IV: ≤12 million IU/m2 Amifostine (Ethyol) IV: ≤300mg Bexarotene (Targretin) oral Cabazitaxel (Jevtana) IV Capecitabine (Xeloda) oral Cyclophosphamide (CTX) oral <100mg/m2/day Cytarabine (ARA-C) IV: 100–200mg/m2 Docetaxel (Taxotere) IV Doxorubicin liposomal (Doxil) IV

Eribulin (Halaven) IV Etoposide (VP-16, Etopophos) IV Floxuridine IV Fludarabine (Fludara) oral Fluorouracil (5-FU) IV Gemcitabine (Gemzar) IV Interferon alpha (IFN-alfa, Intron A) IV: >5–<10 million IU/m2 Ixabepilone (Ixempra) IV Methotrexate (MTX) IV: >50mg/m2 to <250mg/m2

Mitomycin (MTC) IV Mitoxantrone (DHAD) IV Paclitaxel (Taxol) IV Paclitaxel albumin (Abraxane) IV Pemetrexed (Alimta) IV Pentostatin IV Pralatrexate (Folotyn) IV Romidepsin (Istodax) IV Thiotepa IV Topotecan (Hycamtin) IV, oral

Minimal Risk (<10% frequency without antiemetics) Alemtuzumab (Campath) IV Bevacizumab (Avastin) IV Bleomycin IV Bortezomib (Velcade) IV Busulfan (Busulfex) oral: <4mg/day Cetuximab (Erbitux) IV Chlorambucil (Leukeran) oral Cladribine (2-CdA) IV Cytarabine (ARA-C) IV: <100mg/m2 Dasatinib (Sprycel) oral Decitabine (Dacogen) IV Denileukin diftitox (Ontak) IV Dexrazoxane (Totect, Zinecard) IV Erlotinib (Tarceva) oral Everolimus (Afinitor, Zortress) oral Fludarabine (Fludara) IV

Hydroxyurea (Hydrea) oral Imatinib (Gleevec) oral Interferon alpha (IFN-alfa, Intron A) IV: ≤5 million IU/m2 Ipilimumab (Yervoy) IV Lapatinib (Tykerb) oral Lenalidomide (Revlimid) oral Melphalan (L-PAM, Alkeran) oral Mercaptopurine (Purinethol) oral Methotrexate (MTX) IV: ≤50mg/m2; oral Nelarabine (Arranon) IV Niltoinib (Tasigna) oral Ofatumumab (Arzerra) IV Panitumumab (Vectibix) IV Pazopanib (Votrient) oral Pegasparagase (Oncaspar) IV

Peginterferon IV Rituximab (Rituxan) IV Sorafenib (Nexavar) oral Sunitinib (Sutent) oral Temsirolimus (Torisel) IV Temozolamide (Temodar) oral: ≤75mg/m2/day Thalidomide (Thalomid) oral Thioguanine (6-TG, Tabloid) oral Trastuzumab (Herceptin) IV Tretinoin (Vesanoid) oral Valrubicin (Valstar) IV Vandetanib (Caprelsa) oral Vinblastine (VLB) IV Vincristine (VCR) IV Vinorelbine (Navelbine) IV Vorinostat (Zolinza) oral

Daily use of antiemetics is not recommended based on clinical experience.

References

Adapted from: 1. Kris MG, Hesketh PJ, Somerfield MR, et al. American Society of Clinical Oncology Guideline for Antiemetics in Oncology: Update 2006.

J Clin Oncol 2006;24:2932–2947. 2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology; v.1.2012: Antiemesis.

(Rev. 6/2014) Available at: http://www.nccn.org/professionals/physician_gls/PDF/antiemesis.pdf. Accessed August 8, 2012.

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DRUG MONOGRAPHS

BRAIN CANCER AFINITOR Novartis

℞

mTOR kinase inhibitor. Everolimus 2.5mg, 5mg, 7.5mg, 10mg; tabs. ℞ Also: AFINITOR DISPERZ Everolimus 2mg, 3mg, 5mg; tabs for oral susp.

Indications: Subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis complex (TSC) in adults and children who require therapeutic intervention but are not candidates for curative surgical resection.

Adults and Children: <1yr: not recommended.

Swallow tabs whole with water or use Disperz tabs administered as a suspension only. Take at the same time each day either consistently with or without food. Prepare suspension using 5mL of water in an oral syringe or 25mL of water in a drinking glass; max 10mg dose per syringe or glass. ≥1yrs: initially 4.5mg/m2 once daily.

Do not combine the 2 dosage forms to achieve the desired total dose. Use therapeutic drug monitoring to guide subsequent dosing. Adjust dose at 2 week intervals as needed to achieve and maintain trough concentrations of 5–15ng/mL (see full labeling). Severe hepatic impairment: initiate at 2.5mg/m2 once daily. Concomitant strong CYP3A4/PgP inhibitors: avoid; moderate CYP3A4/PgP inhibitors: initiate at 2.5mg/m2 once daily, if CYP3A4/PgP inhibitor discontinued, after 2–3 days, return to dose used prior to initiating moderate inhibitor. Concomitant strong CYP3A4 inducers: avoid, if required, then initiate at 9mg/m2 once daily; if discontinued, then return to dose used prior to initiating strong inducer.

Continue therapy until disease progression or unacceptable toxicity occurs. Dose modifications for adverse reactions, or others: see full labeling.

Contraindications: Allergy to other rapamycin derivatives.

Warnings/Precautions: Monitor for new or worsening respiratory symptoms. Increased risk of infections; some may be severe or fatal; monitor and treat promptly if occur. Pre-existing invasive fungal infections: treat before starting.

Monitor for signs of wound-related complications.

Peri-surgical period. Hepatic impairment (see Adult dose). Monitor CBCs, renal function, lipids, and blood glucose prior to starting and periodically thereafter. Avoid close contact with those who have received live vaccines.

Pediatrics: complete childhood vaccination series according to ACIP guidelines prior to initiation. Elderly. Women of childbearing potential should use effective method of contraception during and up to 8 weeks after treatment. Pregnancy (Cat.D), nursing mothers: not recommended.

Interactions: Avoid live vaccines. Potentiated by strong CYP3A4/PgP inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole), grapefruit or grapefruit juice; avoid. Caution with moderate CYP3A4/PgP inhibitors (eg, amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem); reduce everolimus dose if used. Antagonized by strong CYP3A4/PgP inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital), St. John’s Wort; avoid.

Adverse reactions: Pneumonitis (interrupt, reduce dose and/or manage with corticosteroids; if severe, discontinue; may reintroduce daily dose at approx. 50% lower than previously administered), infections (discontinue if invasive systemic fungal infection develops), stomatitis (treat with non-alcoholic, non-peroxide mouthwash), diarrhea, nausea, abdominal pain, rash, fatigue, edema, fever, asthenia, cough, headache, decreased appetite; increased serum creatinine, blood glucose, lipids; decreased hemoglobin, platelets, neutrophils, serum phosphate; proteinuria, renal failure, others (see full labeling).

How supplied: Tabs, Disperz—28 (4 blister cards × 7 tabs)

AVASTIN Genentech

℞

Angiogenesis inhibitor. Bevacizumab 100mg, 400mg; per vial; soln for IV infusion after dilution; preservative-free.

Indications: Glioblastoma, as a single agent for patients with progressive disease following prior therapy.

Adults: Give by IV infusion. Infuse 1st dose over 90 mins; if tolerated, infuse 2nd dose over 60 mins, and subsequent doses over 30 mins.

10mg/kg every 2 weeks.

Children: Not established.

Warnings/Precautions: Risk of GI perforations, surgery and wound healing complications, and hemorrhage. Do not start therapy before or for at least 28 days after surgery; allow surgical incisions to completely heal (see full labeling). Do not administer if recent history of hemoptysis of ≥ ½-teaspoon of red blood.

Permanently discontinue if GI perforation, tracheoesophageal fistula, any grade 4 fistula, or grade 4 venous thromboembolic event.

Discontinue if fistula involving internal organ, wound healing complications, hemorrhage, severe arterial thromboembolic event (ATE), hypertensive crisis or encephalopathy, posterior

reversible encephalopathy syndrome, or nephrotic syndrome occurs; suspend therapy if severe hypertension, moderate-to-severe proteinuria (resume when <2g/24hrs), or severe infusion reaction occurs. Avoid in ovarian cancer if evidence of recto-sigmoid involvement by pelvic exam, bowel involvement on CT scan, or symptoms of bowel obstruction. History of arterial thromboembolism. Diabetes. Monitor BP every 2–3 weeks. Monitor proteinuria by dipstick urine analysis; if ≥2+, do further assessment with a 24-hour urine collection.

Elderly. Increased risk of ovarian failure; inform females of reproductive potential prior to starting therapy. Pregnancy: may cause fetal harm; use effective contraception during and for 6 months after last dose. Nursing mothers: not recommended.

Adverse reactions: Epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain, exfoliative dermatitis; GI perforation and fistulae, wound dehiscence/impaired healing, necrotizing fasciitis (discontinue if occurs), hemorrhage, non-GI fistula formation, arterial or venous thromboembolic events, posterior reversible encephalopathy syndrome, infusion reactions, ovarian failure, neutropenia, and infection.

How supplied: Single-use vial—1

TEMODAR Merck

℞

Alkylating agent. Temozolomide 5mg, 20mg, 100mg, 140mg, 180mg, 250mg; caps. ℞ Also: TEMODAR INJECTION Temozolomide 100mg; per vial; lyophilized pwd for IV infusion after reconstitution; contains mannitol.

Indications: Newly diagnosed glioblastoma multiforme. Refractory anaplastic astrocytoma.

Adults: See full labeling for monitoring and dose adjustment guidelines. IV: Infuse over 90 mins.

Oral caps: Swallow whole with water; take on empty stomach at bedtime to reduce nausea, pretreat with antiemetics. Glioma: Concomitant phase, for newly diagnosed: 75mg/m2 daily for 42 days with focal radiotherapy; Maintenance phase, Cycle 1: 150mg/m2 once daily for 5 consecutive days, then 23 days off; for Cycles 2 through 6: increase to 200mg/m2 once daily for 5 consecutive days if tolerated, then 23 days off.

Anaplastic astrocytoma: 150mg/m2 once daily for 5 consecutive days per 28-day treatment cycle; increase dose in subsequent cycles to 200mg/m2 if tolerated; continue until disease progression, discontinue if minimum dose not tolerated.

Children: Not established.

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DRUG MONOGRAPHS

BRAIN CANCER Contraindications: Hypersensitivity to dacarbazine.

Warnings/Precautions: Myelosuppression (higher risk in women or elderly, esp. in 1st cycle).

Do not begin therapy unless hematology (ANC and platelets) is acceptable. Do CBC prior to treatment initiation and on Day 22 of each cycle or within 48 hours of that day; repeat weekly until recovery if ANC or platelets fall below acceptable limits. Perform LFTs at baseline, midway through Cycle 1, prior to each subsequent cycle, and 2–4wks after last dose. Screen for HBV infection prior to initiation. Monitor for signs of hepatitis or HBV reactivation during and several months after treatment; discontinue if occurs. Glioblastoma: monitor for and provide prophylaxis against P. carinii pneumonia (PCP). Severe renal or hepatic impairment. Avoid inhalation, and skin/ mucous membrane contact, of capsule contents.

Elderly. Pregnancy (Cat.D), nursing mothers: not recommended. See full labeling.

Interactions: Valproic acid may increase temozolomide levels. Concomitant carbamazepine, phenytoin, sulfamethoxazole/trimethoprim may complicate myelosuppression assessment.

Adverse reactions: Alopecia, fatigue, nausea, vomiting, anorexia, constipation, headache, convulsions, rash, hemiparesis, diarrhea, asthenia, fever, dizziness, abnormal coordination, viral infection, amnesia, insomnia, edema; myelosuppression (may be dose-limiting; see full labeling), hepatotoxicity; others.

How supplied: Caps 5mg, 20mg, 100mg, 140mg 180mg—5, 14; 250mg—5; Single-use vials—1

UNITUXIN United Therapeutics

℞

GD2-binding monoclonal antibody. Dinutuximab 3.5mg/mL; soln for IV infusion after dilution; preservative-free.

Indications: In combination with granulocytemacrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2) and 13-cis-retinoic acid (RA), for the treatment of children with highrisk neuroblastoma who achieve at least a partial response to prior first-line multiagent, multimodality therapy.

Adults: Not applicable.

Children: Confirm adequate hematologic, respiratory, hepatic, and renal function prior to each course. Hydrate and premedicate with antihistamines, analgesics (eg, IV opioids), and antipyretics prior to each dose: see full labeling. Give via IV infusion over 10–20 hours for 4 consecutive days; max 5 cycles. Initial rate: 0.875mg/m2/hr for 30mins; may gradually increase as tolerated up to max 1.75mg/m2/hr.

Cycles 1, 3, and 5 (24-day cycle): 17.5mg/m2/day on Days 4–7. Cycles 2 and 4 (32-day cycle): 17.5mg/m2/day on Days 8–11. Dose modifications: see full labeling.

Warnings/Precautions: Risk of serious infusion reactions; monitor during and at least 4 hours after completion of each infusion; interrupt or discontinue if severe or prolonged infusion reactions occur. Have resuscitative medications and equipment available. Risk of neuropathy. Permanently discontinue if lifethreatening infusion reactions, Grade 3 pain unresponsive to max supportive measures, Grade 4 sensory neuropathy or Grade 3 sensory neuropathy that interferes with daily activities for more than 2 weeks, Grade 2 peripheral motor neuropathy, recurrent signs of eye disorders or vision loss, signs of atypical hemolytic uremic syndrome occurs. Interrupt or discontinue if severe capillary leak syndrome, symptomatic hypotension, systolic BP less than lower limit of normal for age or decreased by

>15% compared to baseline develops.

Monitor for systemic infection; temporarily discontinue until resolves. Monitor BP, peripheral blood counts during therapy, and serum electrolytes daily. Renal or hepatic impairment. Pregnancy; avoid. Use effective contraception during therapy and for at least 2 months after last dose. Nursing mothers: not recommended.

Adverse reactions: Pain, pyrexia, infusion reactions, hypotension, hyponatremia, hypokalemia, hypocalcemia, hypoalbuminemia, increased ALT/AST, vomiting, diarrhea, capillary leak syndrome, urticaria, infections, bone marrow suppression (eg, thrombocytopenia, anemia, neutropenia, lymphopenia).

How supplied: Single-use vial (5mL)—1

SEE LITERATURE Consult the manufacturer’s labeling for full prescribing information.

ADVERSE REACTIONS Those adverse reactions listed within product monographs represent the potential for adverse effects based upon the active ingredient(s) and/or the drug class. It is not meant to be an inclusive list of responses.

DOSAGES FOR THE ELDERLY Special caution is advised when prescribing drugs for elderly patients. Keep the following points in mind when prescribing drugs for patients of approximately 60 years or older:

1. Renal Function: Glomerular filtration rate, renal tubular secretion and blood flow tend to decrease with advancing age, while the incidence of renal pathology increases.

2. Drug Sensitivity: Elderly patients may show unusual sensitivity or paradoxical reactions to a number of drugs. Refer to the complete prescribing information.

3. Drug Distribution: The ratio of fat to lean body weight may increase in the elderly, which affects the volume of distribution of fat-soluble drugs. Plasma albumin concentrations may be decreased in the elderly. This potentiates plasma-protein bound drugs and increases the potential for drug interactions caused by plasma-protein displacement.

4. Polypharmacy: It is important to determine the patient’s current medication use, including nonprescription products, before adding any medication to determine any possible interactions.

5. Hepatic Function: Reduced function of metabolic enzymes in the liver may occur in the elderly.

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DRUG MONOGRAPHS

BREAST CANCER ABRAXANE Celgene

℞

Taxane antimicrotubule. Paclitaxel [bound to albumin (human)] 100mg/vial; pwd for IV infusion after reconstitution; solvent-free.

Indications: Treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy (prior therapy should have included an anthracycline unless clinically contraindicated).

Adults: Do not treat if neutrophil count <1,500 cells/mm3 or platelets <100,000 cells/mm3.

260mg/m2 by IV infusion over 30 mins every 3 weeks. If severe neutropenia (neutrophil <500 cells/mm3 for ≥1week) or severe sensory neuropathy occurs: reduce subsequent doses to 220mg/m2; reduce to 180mg/m2 if severe neutropenia or sensory neuropathy recurs. If grade 3 sensory neuropathy occurs, suspend use until resolution to grade 1 or 2; reduce subsequent doses. Hepatic impairment: see full labeling. Avoid extravasation.

Children: Not evaluated.

Contraindications: Baseline neutrophil count <1,500 cells/mm3. Prior severe hypersensitivity reaction (do not rechallenge).

Warnings/Precautions: Do not substitute for, or with, other paclitaxel products (due to formulation differences). Do frequent complete blood cell counts. Hepatic impairment (total bilirubin >5 × ULN or AST >10 × ULN): not recommended. Monitor for sensory neuropathy, sepsis, or pneumonitis.

Renal dysfunction. Contains human albumin; remote risk of viral transmission. Use appropriate contraception (men and women). Pregnancy (Cat.D), nursing mothers: not recommended.

Interactions: May potentiate or be potentiated

by CYP2C8 and/or CYP3A4 inducers (eg, rifampin, carbamazepine, phenytoin, efavirenz, nevirapine) and/or inhibitors (eg, ketoconazole, other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir, nelfinavir).

Adverse reactions: Bone marrow suppression (eg, neutropenia, anemia), infections, alopecia, sensory neuropathy (may require dose reduction or interruption), peripheral neuropathy, GI upset, mucositis, fatigue/asthenia, myalgia/arthralgia, abnormal ECG; alkaline phosphatase or AST elevation; dyspnea, edema, hypotension, rash (may be serious); rare: thrombotic events.

How supplied: Single-use vial—1

AFINITOR Novartis mTOR kinase inhibitor. Everolimus 2.5mg, 5mg, 7.5mg, 10mg; tabs.

Indications: Postmenopausal women with advanced hormone receptor-positive, HER2-

℞

negative breast cancer (advanced HR+ BC) in combination with exemestane after failure of treatment with letrozole or anastrozole.

Adults: Swallow tabs whole with water. Take at the same time each day either consistently with or without food. 10mg once daily. Mild hepatic impairment (Child-Pugh class A): 7.5mg daily, may reduce to 5mg if not tolerated. Moderate hepatic impairment (Child-Pugh class B): 5mg daily, may be reduce to 2.5mg if not tolerated.

Severe hepatic impairment (Child-Pugh class C): max 2.5mg daily if benefits outweigh risk.

Concomitant moderate CYP3A4/PgP inhibitors: reduce to 2.5mg once daily; may consider increasing to 5mg if tolerated. If moderate inhibitor is discontinued, allow 2–3 days washout period before increasing everolimus dose; return to dose used prior to initiating the moderate inhibitor. Concomitant strong CYP3A4/PgP inducers: consider doubling the daily dose by increments of 5mg or less. If strong inducer is discontinued, consider washout period of 3–5 days before returning to the dose used prior to initiating the strong inducer. Continue therapy until disease progression or unacceptable toxicity occurs. Dose modifications for adverse reactions, or others: see full labeling.

Children: Not recommended.

Contraindications: Allergy to other rapamycin derivatives.

Warnings/Precautions: Monitor for new or worsening respiratory symptoms. Increased risk of infections; some may be severe or fatal; monitor and treat promptly if occur. Pre-existing invasive fungal infections: treat before starting.

Monitor for signs of wound-related complications.

Peri-surgical period. Hepatic impairment (see Adult dose). Monitor CBCs, renal function, lipids, and blood glucose prior to starting and periodically thereafter. Avoid close contact with those who have received live vaccines. Pediatrics: complete childhood vaccination series according to ACIP guidelines prior to initiation. Elderly.

Women of childbearing potential should use effective method of contraception during and up to 8 weeks after treatment. Pregnancy (Cat.D), nursing mothers: not recommended.

Interactions: Avoid live vaccines. Potentiated by strong CYP3A4/PgP inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole), grapefruit or grapefruit juice; avoid. Caution with moderate CYP3A4/PgP inhibitors (eg, amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem); reduce everolimus dose if used. Antagonized by

strong CYP3A4/PgP inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital), St. John’s Wort; avoid.

Adverse reactions: Pneumonitis (interrupt, reduce dose and/or manage with corticosteroids; if severe, discontinue; may reintroduce daily dose at approx. 50% lower than previously administered), infections (discontinue if invasive systemic fungal infection develops), stomatitis (treat with non-alcoholic, non-peroxide mouthwash), diarrhea, nausea, abdominal pain, rash, fatigue, edema, fever, asthenia, cough, headache, decreased appetite; increased serum creatinine, blood glucose, lipids; decreased hemoglobin, platelets, neutrophils, serum phosphate; proteinuria, renal failure, others (see full labeling).

How supplied: Tabs—28 (4 blister cards × 7 tabs)

ARIMIDEX AstraZeneca

℞

Aromatase inhibitor. Anastrozole 1mg; tabs.

Indications: In postmenopausal women: adjuvant treatment of hormone receptor-positive early breast cancer; first-line treatment of hormone receptor-positive or unknown locally advanced or metastatic breast cancer; advanced breast cancer with disease progression after tamoxifen therapy.

Adults: 1mg once daily. Advanced disease: continue until tumor progression.

Children: Not applicable.

Contraindications: Women who are or may become pregnant. Pregnancy (Cat.X).

Warnings/Precautions: Pre-existing ischemic heart disease. Severe hepatic impairment.

Monitor bone mineral density, cholesterol.

Nursing mothers: not recommended.

Interactions: Antagonized by tamoxifen, estrogens; do not give concomitantly.

Adverse reactions: Hot flashes, asthenia, arthritis, pain, arthralgia, pharyngitis, hypertension, depression, nausea, vomiting, rash, osteoporosis, fractures, back pain, insomnia, headache, peripheral edema, lymphedema, dyspnea, dizziness, paresthesia, vaginal bleeding, cough, hypercholesterolemia.

How supplied: Tabs—30

AROMASIN Pfizer

℞

Aromatase inactivator. Exemestane 25mg; tabs.

Indications: In postmenopausal women: adjuvant treatment of estrogen-receptor positive early breast cancer after 2–3yrs of tamoxifen therapy to complete a total of 5yrs of hormonal therapy; advanced breast cancer with disease progression after tamoxifen therapy.

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DRUG MONOGRAPHS

BREAST CANCER Adults: Give after a meal. 25mg once daily.

Concomitant strong CYP3A4 inducers (see Interactions): 50mg once daily.

Children: Not established.

Contraindications: Pregnancy (Cat.X).

Premenopausal women.

Warnings/Precautions: Hepatic or renal insufficiency. Osteoporosis; assess bone mineral density (BMD) at start of treatment. Monitor all patients for BMD loss and treat as appropriate.

Perform routine assessment of Vit. D levels prior to initiation; supplement if deficient. Nursing mothers: not recommended.

Interactions: Antagonized by strong CYP3A4 inducers (eg, rifampicin, phenytoin, carbamazepine, phenobarbital, St. John’s wort).

Adverse reactions: Hot flashes, fatigue, arthralgia, headache, insomnia, increased sweating, nausea, increased appetite; reductions in bone mineral density.

How supplied: Tabs—30

Adults: 10mg 3 times daily for at least 3 months.

Children: Not applicable.

Contraindications: Thrombophlebitis.

Thromboembolic disorders. Cerebrovascular disorders. Abnormal undiagnosed genital bleeding. Estrogen-depended neoplasias. Liver dysfunction or disease. Pregnancy (Cat.X).

Warnings/Precautions: Asthma (2mg tabs).

Hepatic dysfunction. Conditions aggravated by fluid retention. Cardiovascular disorders, arterial vascular disease, and risks factors (eg, hypertension, diabetes, obesity, SLE). Familial hyperlipoprotenemia. Monitor BP. Discontinue if jaundice occurs and before prolonged immobilization (eg, surgery). Nursing mothers.

Adverse reactions: See literature. GI upset, headache, hypertension, edema, hypercalcemia, gallbladder or thromboembolic disease, gynecomastia, impotence, impaired glucose tolerance.

How supplied: Tabs—100

DELATESTRYL Endo

EVISTA Lilly

CIII

Androgen. Testosterone enanthate 200mg/mL; IM inj; in sesame oil; contains chlorobutanol.

Indications: Inoperable metastatic mammary cancer in females who are 1–5 years postmenopausal.

Adults: Give by deep IM inj into gluteal muscle.

200–400mg once every 2–4 weeks. Max 400mg/month. Monitor closely.

Children: Not established.

Contraindications: Male breast or prostate cancer. Pregnancy (Cat.X).

Warnings/Precautions: Discontinue if jaundice, abnormal liver function, hypercalcemia, or edema occurs. Monitor liver function, hemoglobin, hematocrit, cholesterol, urine, serum calcium. Preexisting cardiac, hepatic, or renal dysfunction. History of MI or coronary artery disease. Monitor for venous thromboembolism; discontinue if suspected. Elderly. Nursing mothers: not recommended.

Interactions: May potentiate oral anticoagulants, oxyphenbutazone. May alter insulin requirements.

Increased risk of edema with ACTH, corticosteroids. May affect thyroid levels.

Adverse reactions: Amenorrhea, menstrual irregularities, inhibition of gonadotropin secretion, virilization; others: inj site reactions, peliosis hepatis, edema, hepatic carcinoma, nausea, jaundice, hirsutism, acne, polycythemia, headache, anxiety, depression, paresthesia, altered libido, fluid and electrolyte disturbances, suppression of clotting factors, increased serum cholesterol.

How supplied: Multidose vial (5mL)—1

ESTRACE Warner Chilcott Estrogen. Estradiol 0.5mg, 1mg, 2mg+; scored tabs; +contains tartrazine.

Indications: Palliative treatment of metastatic breast cancer in select patients (see literature).

℞

℞

Selective estrogen receptor modulator (SERM).

Raloxifene HCl 60mg; tabs.

Indications: Reduction in risk of invasive breast cancer in postmenopausal women: with osteoporosis and/or at high risk for invasive breast cancer.

Adults: 60mg once daily.

Children: Not recommended.

Contraindications: Active or history of venous thromboembolic events. Nursing mothers.

Pregnancy (Cat.X). Women who may become pregnant.

Warnings/Precautions: Not for use in premenopausal women. Concomitant systemic estrogen therapy: not recommended. Discontinue 72 hours before, and during prolonged immobilization; resume when fully ambulatory.

Coronary heart disease or risk of coronary event (increased risk of death due to stroke).

Hepatic dysfunction. Moderate to severe renal impairment.

Interactions: May antagonize warfarin; monitor.

Avoid concomitant cholestyramine, other anion exchange resins. Caution with other highly protein-bound drugs (eg, diazepam, diazoxide, lidocaine).

Adverse reactions: Hot flashes, leg cramps, peripheral edema, flu syndrome, arthralgia, sweating; rare: venous thromboembolic events.

How supplied: Tabs—30, 100, 2000

FASLODEX AstraZeneca

℞

Estrogen receptor antagonist. Fulvestrant 50mg/mL; soln for IM inj.

Indications: Hormone receptor positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy.

Adults: Give by IM inj slowly (1–2 mins/ injection). 500mg (as two 5mL injections, one

in each buttock) on days 1, 15, 29, then once per month thereafter. Moderate hepatic impairment: 250mg (as one 5mL injection) on days 1, 15, 29, then once per month thereafter.

Children: Not applicable.

Warnings/Precautions: Bleeding diatheses, thrombocytopenia, or anticoagulant use.

Moderate to severe hepatic impairment.

Pregnancy (Cat.D; avoid); exclude pregnancy before starting. Nursing mothers: not recommended.

Adverse reactions: Inj site pain, GI upset, bone pain, arthralgia, headache, back pain, fatigue, pain in extremity, hot flash, anorexia, asthenia, musculoskeletal pain, cough, dyspnea, constipation; increased hepatic enzymes, hypersensitivity reactions.

How supplied: Prefilled syringe kit (2 × 5mL)—1

FEMARA Novartis

℞

Aromatase inhibitor. Letrozole 2.5mg; tabs.

Indications: In postmenopausal women: Adjuvant treatment of hormone receptor positive early breast cancer; Extended adjuvant treatment of early breast cancer after 5 years of adjuvant tamoxifen therapy; First-line treatment of hormone receptor positive or unknown, locally advanced or metastatic breast cancer; Treatment of advanced breast cancer with disease progression following antiestrogen therapy.

Adults: 2.5mg once daily. Continue until tumor progression is evident. Adjuvant or extended adjuvant therapy: treat for at least 24 months (see literature). Severe hepatic impairment or cirrhosis: 2.5mg every other day.

Children: Not applicable.

Contraindications: Women of premenopausal endocrine status. Pregnancy (Cat.X).

Warnings/Precautions: Severe renal or hepatic impairment. Monitor bone mineral density, serum cholesterol. Nursing mothers.

Adverse reactions: Pain (bone, musculoskeletal, and others), hot flashes, arthralgia, flushing, asthenia, edema, headache, dizziness, hypercholesterolemia, sweating increased, GI upset, fatigue, dyspnea, cough, insomnia, hypertension, alopecia, anorexia, weight changes, hypercalcemia, pleural effusion, vertigo; thromboembolic or cardio- or cerebrovascular events (rare).

How supplied: Tabs—30

Fluorouracil (various)

℞

Antimetabolite. Fluorouracil 50mg/mL; soln for IV inj.

Indications: Palliative management of carcinoma of the breast.

Adults: Give by IV inj. 12mg/kg once daily for 4 successive days; max 800mg/day. If no toxicity is observed, 6mg/kg are given on the 6th, 8th, 10th, and 12th days unless toxicity occurs.

Maintenance therapy: repeat dosage of 1st course every 30 days after the last day of the previous

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DRUG MONOGRAPHS

BREAST CANCER course of treatment; or give a maintenance dose of 10–15mg/kg per week as a single dose; max: 1g/week. Poor risk patients: see literature for dose adjustments.

Children: Not recommended.

Contraindications: Poor nutritional state.

Depressed bone marrow function. Potentially serious infections.

Warnings/Precautions: Narrow margin of safety; monitor for toxicity. Consider hospitalization for 1st course. History of highdose pelvic irradiation. Previous use of alkylating agents. Widespread involvement of bone marrow by metastatic tumors. Renal or hepatic impairment. Discontinue if signs of toxicity appear (eg, stomatitis, esophagopharyngitis, leukopenia, intractable vomiting, diarrhea, GI ulceration or bleeding, thrombocytopenia, hemorrhage).

Monitor WBCs with differential before each dose.

Avoid extravasation. Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended.

Interactions: Potentiated by leucovorin.

Adverse reactions: Stomatitis, esophagopharyngitis, GI upset, anorexia, leukopenia, alopecia, dermatitis, hand-foot syndrome; others.

Testing considerations: TS (thymidylate synthase), MSI (microsatellite instability), DPD (dihydropyrimidine dehydrogenase).

How supplied: Contact supplier.

HALAVEN Eisai

℞

Non-taxane microtubule dynamics inhibitor.

Eribulin mesylate 0.5mg/mL, soln for IV inj.

Indications: Treatment of metastatic breast cancer in patients who have previously received at least two chemotherapeutic regimens for metastatic disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting.

Adults: Give by IV injection over 2–5mins.

1.4mg/m2 on Days 1 and 8 of a 21-day cycle. Mild hepatic impairment (Child-Pugh A) or moderate renal impairment (CrCl 30–50mL/min): 1.1mg/m2 on Days 1 and 8 of a 21-day cycle. Moderate hepatic impairment (Child-Pugh B): 0.7mg/m2 on Days 1 and 8 of a 21-day cycle. Hold dose for ANC <1000/mm3, platelets <75000/mm3, or grade 3 or 4 non-hematological toxicities. Delay or reduce dose according to toxicities; see full labeling. Do not re-escalate dose after it is reduced.

Children: <18yrs: not established.

Warnings/Precautions: Monitor CBCs; increase frequency of monitoring if grade 3 or 4 cytopenias develop, delay and reduce subsequent doses if febrile neutropenia or grade 4

neutropenia lasting >7 days develops. Monitor for peripheral neuropathy; withhold dose if grade 3 or 4 peripheral neuropathy develops until resolution to grade 2 or less. Congenital long QT syndrome: avoid. CHF, bradyarrhythmias, electrolyte abnormalities: monitor ECG for prolonged QT interval. Correct electrolyte abnormalities (K+, Mg+) before treatment; monitor. Severe hepatic impairment (Child-Pugh C) or severe renal impairment (CrCl<30mL/min): insufficient data. Pregnancy (Cat.D), nursing mothers: not recommended.

Interactions: Caution with other drugs that prolong QT interval (eg, Class IA and III antiarrhythmics); monitor.

Adverse reactions: Neutropenia, anemia, asthenia/fatigue, alopecia, peripheral neuropathy, nausea, constipation, febrile neutropenia; possible QT prolongation, elevated liver enzymes.

Note: Do not mix with dextrose-containing solutions. Do not administer in same line as other drugs or fluids.

How supplied: Single-use vial (2mL)—1

HERCEPTIN Genentech

℞

Human epidermal growth factor receptor (HER2) inhibitor. Trastuzumab 440mg/vial; lyophilized pwd for IV infusion after reconstitution and dilution; preservative-free.

Indications: HER2-overexpressing metastatic breast cancer as a single agent in patients who have received one or more chemotherapy regimens; or in combination with paclitaxel in patients who have not received chemotherapy.

Adjuvant treatment in HER2-overexpressing, node-positive or node-negative breast cancer (as a single agent following multi-modality anthracycline based therapy; in combination with doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel; or in combination with docetaxel and carboplatin).

Adults: Do not substitute for or with adotrastuzumab emtansine. Give as IV infusion.

Initially 4mg/kg over 90 mins, followed by 2mg/kg over 30 mins weekly; administer until tumor progression. Adjuvant treatment (administer trastuzumab weekly for 52 weeks; therapy >52 weeks: not recommended); In combination therapy: with doxorubicin and cyclophosphamide, followed by either paclitaxel or docetaxel; or with docetaxel/carboplatin: initially 4mg/kg over 90 mins, followed by 2mg/kg over 30 mins once weekly for the 1st 12 weeks (concurrently w. paclitaxel or docetaxel) or 1st 18 weeks (concurrently w. docetaxel/ carboplatin). One week after the last trastuzumab

weekly dose, give trastuzumab 6mg/kg over 30–90 mins every 3 weeks. Following multimodality anthracycline based therapy: initially 8mg/kg over 90 mins, then 6mg/kg over 30–90 mins every 3 weeks. Infusion reactions or cardiomyopathy: see full labeling.

Children: Not established.

Warnings/Precautions: Increased risk of cardiomyopathy. Conduct cardiac assessment (eg, history, physical exam, LVEF) at baseline, every 3 months during and after therapy or every 6 months for ≥2yrs after therapy (if adjuvant); repeat LVEF at 4 week intervals if dose is withheld due to significant left ventricular cardiac dysfunction. Interrupt therapy if dyspnea or significant hypotension occurs; consider discontinuing permanently if severe infusion reactions, CHF, pulmonary toxicity, or significant left ventricular myocardial dysfunction develops. Symptomatic intrinsic lung disease.

Extensive tumor involvement of the lungs. Test for HER2 protein overexpression and HER2 gene amplification using FDA-approved tests for specific tumor type (breast or gastric/ gastroesophageal adenocarcinoma). Elderly.

Pregnancy (Cat.D); use adequate contraception during and at least 7 months after therapy.

Nursing mothers: not recommended.

Interactions: Increased cardiomyopathy with anthracycline-containing chemotherapy.

Increased toxicity with other myelosuppressives.

Potentiated by paclitaxel.

Adverse reactions: Fever, diarrhea, nausea, chills, infections, increased cough, headache, CHF, insomnia, fatigue, dyspnea, rash, neutropenia, anemia, stomatitis, mucosal inflammation, nasopharyngitis, dysgeusia, myalgia, thrombosis/embolism; severe infusion reactions, febrile neutropenia/exacerbation of chemotherapy-induced neutropenia, pulmonary toxicity (eg, interstitial pneumonitis), cardiomyopathy (eg, left ventricular myocardial dysfunction); pregnant women: possible oligohydramnios (monitor).

Note: Enroll pregnant women with breast cancer who are using trastuzumab in the MotHER-the Herceptin Pregnancy Registry (800) 690-6720.

Testing considerations: HER2 protein overexpression How supplied: Vial—1 (w. diluent)

IBRANCE Pfizer

℞

Kinase inhibitor. Palbociclib 75mg, 100mg, 125mg; capsules.

Indications: In combination with letrozole, for the treatment of postmenopausal women

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BREAST CANCER with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)negative advanced breast cancer as initial endocrine-based therapy for metastatic disease.

Adults: Swallow whole. Take with food. 125mg once daily for 21 days followed by 7 days off to complete a 28-day cycle, in combination with letrozole 2.5mg once daily continuously throughout the 28-day cycle. Dose modification for adverse reactions: First reduction: 100mg/day; Second dose reduction: 75mg/day; discontinue if <75mg/day required. Dose modification for hematologic or non-hematologic toxicities: see full labeling. Concomitant strong CYP3A inhibitors: avoid and consider alternative drug; if use necessary, reduce palbociclib dose to 75mg.

Children: Not evaluated.

Warnings/Precautions: Monitor CBC prior to initiation and at start of each cycle, as well as Day 14 of first 2 cycles, and as clinically indicated. Interrupt, reduce dose, or delay starting treatment cycles if Grade 3 or 4 neutropenia develops. Monitor for signs/symptoms of infection and pulmonary embolism; treat appropriately if develop. Moderate or severe hepatic impairment. Severe renal impairment.

Pregnancy: avoid. Use effective contraception during therapy and for at least 2 weeks after last dose. Lactation: discontinue nursing.

Interactions: Avoid concomitant strong CYP3A inhibitors (eg, clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, verapamil, voriconazole), grapefruit or grapefruit juice; if unavoidable, reduce dose (see Adults). Avoid concomitant strong CYP3A inducers (eg, phenytoin, rifampin, carbamazepine, St. John’s wort) or moderate CYP3A inducers (eg, bosentan, efavirenz, etravirine, modafinil, nafcillin). May potentiate midazolam or other CYP3A substrates with narrow therapeutic index (eg, alfentanil, cyclosporine, dihydroergotamine, ergotamine, everolimus, fentanyl, pimozide, quinidine, sirolimus, tacrolimus); reduce dose of these drugs.

Adverse reactions: Neutropenia, leukopenia, fatigue, anemia, upper respiratory infection, nausea, stomatitis, alopecia, diarrhea, thrombocytopenia, decreased appetite, vomiting, asthenia, peripheral neuropathy, epistaxis.

How supplied: Caps—21

IXEMPRA Bristol-Myers Squibb

℞

Epothilone microtubule inhibitor. Ixabepilone 15mg/vial, 45mg/vial; pwd for IV infusion after constitution and dilution; diluent contains alcohol, polyoxyethylated castor oil.

Indications: Metastatic or locally advanced breast cancer: In combination with capecitabine after failure of an anthracycline and a taxane; and as monotherapy after failure of an anthracycline, a taxane, and capecitabine.

Adults: Pretreat with both H1 and H2 blockers 1hr before infusion; and with steroid if previous hypersensitivity reaction occurred. 40mg/m2

by IV infusion over 3hrs, once every 3wks. Use max body surface area (BSA) of 2.2m2 to calculate dose if BSA >2.2m2. Moderate hepatic impairment (as monotherapy): initially 20mg/m2 per dose; max 30mg/m2 per dose (see literature).

Neuropathy, myelosuppression, concomitant strong CYP3A4 inhibitors: reduce dose.

Concomitant strong CYP3A4 inducers: consider gradual dose increases. See literature.

Children: Not recommended.

Contraindications: Baseline neutrophils <1500cells/mm3 or platelets <100,000cells/mm3. AST or ALT >2.5×ULN or bilirubin >1×ULN (in combination with capecitabine).

Warnings/Precautions: Monitor CBC and liver function at baseline, then periodically. Hepatic impairment (ALT or AST >10×ULN or bilirubin >3×ULN: not recommended; ALT or AST >5×ULN: limited data, use caution). Diabetes. Neuropathy.

Cardiac disease (discontinue if cardiac ischemia or cardiac dysfunction occurs). Monitor for signs/ symptoms of neuropathy, neutropenia. Pregnancy (Cat.D), nursing mothers: not recommended.

Interactions: Potentiated by strong CYP3A4 inhibitors (eg, azole antifungals, protease inhibitors, certain macrolides, nefazodone, grapefruit juice); avoid. Caution with mild or moderate CYP3A4 inhibitors; consider alternative agents. Antagonized by strong CYP3A4 inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, dexamethasone, phenobarbital); avoid.

Avoid St. John’s wort.

Adverse reactions: Peripheral sensory neuropathy, fatigue, asthenia, myalgia, arthralgia, alopecia, GI upset, stomatitis, mucositis, musculoskeletal pain, palmarplantar erythrodysesthesia syndrome, anorexia, abdominal pain, nail disorder, constipation; myelosuppression (neutropenia, leukopenia, anemia, thrombocytopenia); hypersensitivity reactions; others.

How supplied: Kit—1 vial (w. diluent)

KADCYLA Genentech

℞

HER2-targeted antibody-drug conjugate. Adotrastuzumab emtansine 100mg, 160mg; per vial; powder; for IV infusion after reconstitution.

Indications: Treatment in patients with HER2positive (+), metastatic breast cancer (MBC) who previously received trastuzumab and a taxane, separately or in combination. Patients should have either: received prior therapy for metastatic disease or developed disease recurrence during or within 6 months of completing adjuvant therapy.

Adults: Give by IV infusion only over 90 minutes 3.6mg/kg max every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity.

Subsequent infusions may be given over 30 minutes if previously tolerated. Monitor closely

for possible SC infiltration during infusion. Dose modifications: see full labeling.

Children: Not established.

Warnings/Precautions: Do not substitute for or with trastuzumab. Hepatotoxicity; monitor serum transaminases and bilirubin prior to starting and to each dose; reduce dose or discontinue if occurs. Permanently discontinue if serum transaminases >3×ULN and with total bilirubin >2×ULN. Risk of left ventricular dysfunction. Assess LVEF prior to initiation and every 3 months during treatment; interrupt and discontinue as appropriate. Risk of embryo-fetal toxicity. Permanently discontinue if interstitial lung disease or pneumonitis occurs.

Monitor for signs/symptoms of extravasation, infusion-related or hypersensitivity reactions; if significant, slow or interrupt infusion; discontinue if life-threatening. Monitor platelets at baseline and prior to each dose; if platelets <50,000/mm3, delay dose until recovery to ≥75,000/mm3; if platelets <25,000/mm3, delay until recovery to ≥75,000/mm3 and reduce dose.

If thrombocytopenia occurs <100,000/mm3 and concomitant anticoagulants, monitor closely.

Monitor for neurotoxicity; withhold temporarily if Grade 3 or 4 peripheral neuropathy occurs.

Test for HER2 protein overexpression or gene amplification using FDA-approved tests by labs with demonstrated proficiency. Pregnancy (Cat.D); use adequate contraception during and for 7 months after last dose. Nursing mothers: not recommended.

Interactions: Avoid concomitant strong CYP3A4 inhibitors (eg, azole antifungals, clarithromycin, atazanavir, indinavir, ritonavir, nefazodone, nelfinavir, saquinavir, telithromycin); if unavoidable, consider delaying therapy. Caution with concomitant anticoagulation or antiplatelet therapy; monitor closely.

Adverse reactions: Fatigue, nausea, musculoskeletal pain, hemorrhage, thrombocytopenia, headache; increased transaminases, constipation, epistaxis.

Note: Enroll pregnant women who were exposed to Kadcyla in the MotHER Pregnancy Registry (800) 690-6720.

How supplied: Single-use vial—1

PERJETA Genentech

℞

Human epidermal growth factor receptor (HER2) dimerization inhibitor. Pertuzumab 420mg/14mL (30mg/mL); soln for IV infusion; preservative-free.

Indications: In combination with trastuzumab and docetaxel: to treat patients with HER2positive metastatic breast cancer (MBC) who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease; for the neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (either >2cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer.

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PERJETA® (pertuzumab) is a HER2/neu receptor antagonist indicated in combination with Herceptin® (trastuzumab) and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.

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Boxed WARNINGS: Left Ventricular Dysfunction and Embryo-Fetal Toxicity • PERJETA administration can result in subclinical and clinical cardiac failure. Evaluate left ventricular function in all patients prior to and during treatment with PERJETA. Discontinue PERJETA treatment for a confirmed clinically significant decrease in left ventricular function.

• Exposure to PERJETA can result in embryo-fetal death and birth defects. Studies in animals have resulted in oligohydramnios, delayed renal development, and death.

Advise patients of these risks and the need for effective contraception.

Please see additional select Important Safety Information throughout, and the Brief Summary of full Prescribing Information including Boxed WARNINGS on the following pages.

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NCCN®=National Comprehensive Cancer Network®; HER2=human epidermal growth factor receptor 2; ASCO®=American Society of Clinical Oncology®.

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• NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) recommend pertuzumab (PERJETA) + trastuzumab (Herceptin) + docetaxel as a (category 1) preferred option for the first-line treatment of patients with HER2+ MBC1

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Treatment guidelines recommend PERJETA-based therapy as the preferred first-line option

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STRENGTHEN • ASCO® Clinical Oncology Practice Guidelines recommend pertuzumab + trastuzumab + docetaxel as first-line therapy for advanced HER2+ breast cancer 2

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PERJETA + Herceptin (trastuzumab) + docetaxel

Significantly extended progression-free survival (PFS) in first-line HER2+ metastatic breast cancer Combining PERJETA with Herceptin + docetaxel added 6 months median PFS3

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• In Study 1, for patients with MBC, PERJETA in combination with Herceptin and docetaxel was not associated with increases in the incidence of symptomatic left ventricular systolic dysfunction (LVSD) or decreases in left ventricular ejection fraction (LVEF) compared with placebo in combination with Herceptin and docetaxel • Left ventricular dysfunction occurred in 4.4% of patients in the PERJETA-treated group and in 8.3% of patients in the placebo-treated group • Symptomatic LVSD (congestive heart failure) occurred in 1.0% of patients in the PERJETA-treated group and in 1.8% of patients in the placebo-treated group • Patients who have received prior anthracyclines or prior radiotherapy to the chest area may be at higher risk of decreased LVEF • Assess LVEF prior to initiation of PERJETA and at regular intervals (eg, every 3 months in the metastatic setting) during treatment to ensure that LVEF is within your institution’s normal limits • If LVEF is <45%, or is 45% to 49% with a 10% or greater absolute decrease below the pretreatment value, withhold PERJETA and Herceptin and repeat LVEF assessment within approximately 3 weeks. Discontinue PERJETA and Herceptin if LVEF has not improved or has declined further, unless benefits for the individual patient outweigh the risks

Infusion-Associated Reactions

• PERJETA has been associated with infusion reactions • In Study 1, for patients with MBC, on the first day, when only PERJETA was administered, the overall frequency of infusion reactions was 13.0% in the PERJETAtreated group and 9.8% in the placebo-treated group, with the majority being mild to moderate. The most common infusion reactions (≥1.0%) were pyrexia, chills, fatigue, headache, asthenia, hypersensitivity, and vomiting • During the second cycle, when all drugs were administered on the same day, the most common infusion reactions in the PERJETA-treated group (≥1.0%) were fatigue, dysgeusia, hypersensitivity, myalgia, and vomiting

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• PERJETA improved both PFS and OS when combined with Herceptin + docetaxel in patients, including the visceral metastasis subgroup4,5 — There was an inability to show an OS benefit with PERJETA in patients with nonvisceral metastases (n=178; HR=1.11 [95% CI: 0.66-1.85])3 • Observe patients closely for 60 minutes after the first infusion and for 30 minutes after subsequent infusions of PERJETA. If a significant infusion reaction occurs, slow or interrupt the infusion and administer appropriate medical therapies. Monitor patients carefully until complete resolution of signs and symptoms. Consider permanent discontinuation in patients with severe infusion reactions

Hypersensitivity Reactions/Anaphylaxis

• In Study 1, the overall frequency of hypersensitivity/anaphylaxis reactions was 10.8% in the PERJETA-treated group and 9.1% in the placebo-treated group. The incidence of Grades 3-4 hypersensitivity/anaphylaxis reactions was 2.0% in the PERJETA-treated group and 2.5% in the placebo-treated group according to NCI-CTCAE (version 3). Overall, 4 patients in PERJETA-treated group and 2 patients in the placebo-treated group experienced anaphylaxis • Patients should be observed closely for hypersensitivity reactions. Severe hypersensitivity, including anaphylaxis, has been observed in clinical trials with treatment of PERJETA. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use. PERJETA is contraindicated in patients with known hypersensitivity to pertuzumab or to any of its excipients

HER2 Testing

• Detection of HER2 protein overexpression is necessary for selection of patients appropriate for PERJETA therapy because these are the only patients studied and for whom benefit has been shown • Patients were required to have evidence of HER2 overexpression, defined as 3+ IHC or FISH amplification ratio ≥2.0 in the clinical studies. Only limited data were available for patients whose breast cancer was positive by FISH but did not demonstrate protein overexpression by IHC

© 2015 Genentech USA, Inc.

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• Assessment of HER2 status should be performed by laboratories using FDA-approved tests with demonstrated proficiency in the specific technology being utilized

Most Common Adverse Reactions • In MBC, the most common adverse reactions (>30%) seen with PERJETA in combination with Herceptin and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. The most common NCI-CTCAE (version 3) Grade 3-4 adverse reactions (>2%) were neutropenia, febrile neutropenia, leukopenia, diarrhea, peripheral neuropathy, anemia, asthenia, and fatigue.

You may report side effects to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

You may also report side effects to Genentech at 1-888-835-2555.

For more information about PERJETA, contact your local representative or visit www.PERJETA.com/hcp.

Please see additional select Important Safety Information throughout, and the Brief Summary of full Prescribing Information including Boxed WARNINGS on the following pages.

References: 1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer V.2.2015. © National Comprehensive Cancer Network, Inc. 2015. All rights reserved. Accessed April 23, 2015. To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 2. Giordano SH, Temin S, Kirshner JJ, et al. Systemic therapy for patients with advanced human epidermal growth factor receptor 2-positive breast cancer: American Society of Clinical Oncology Clinical Practice Guideline.

J Clin Oncol. 2014;32(19):2078-2099. 3. PERJETA Prescribing Information. Genentech, Inc. 2015.

4. Data on file. Genentech, Inc. 5. Baselga J, Cortés J, Kim S-B, et al; CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366:109-119.

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• PERJETA administration can result in subclinical and clinical cardiac failure. Evaluate left ventricular function in all patients prior to and during treatment with PERJETA. Discontinue PERJETA treatment for a confirmed clinically significant decrease in left ventricular function • Exposure to PERJETA can result in embryo-fetal death and birth defects.

Studies in animals have resulted in oligohydramnios, delayed renal development, and death. Advise patients of these risks and the need for effective contraception — Verify pregnancy status prior to the initiation of PERJETA. Advise patients of the risks of embryo-fetal death and birth defects and the need for contraception during and for 7 months after treatment. Advise patients to contact their healthcare provider immediately if they suspect they may be pregnant — If PERJETA is used during pregnancy or if a patient becomes pregnant while being treated with PERJETA or within 7 months following the last dose of PERJETA in combination with trastuzumab, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy or within 7 months prior to conception to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 — Monitor patients who become pregnant during PERJETA therapy for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with community standards of care. The efficacy of intravenous hydration in the management of oligohydramnios due to PERJETA exposure is not known

Left Ventricular Dysfunction (LVD)

PERJETA is contraindicated in patients with known hypersensitivity to pertuzumab or to any of its excipients.

HR=0.68 95% CI: 0.56-0.84 P=0.0002

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• The final OS analysis was performed when 221 patient deaths occurred in the placebo-treated group and 168 in the PERJETA-treated group3 • The most common adverse reactions (>30%) seen with the PERJETA-based regimen were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy 3

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Boxed WARNINGS: Left Ventricular Dysfunction and Embryo-Fetal Toxicity

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Withhold PERJETA and Herceptin and repeat left ventricular ejection fraction (LVEF) assessment within 3 weeks in patients with significant decrease in LVEF. Discontinue PERJETA and Herceptin if LVEF has not improved or has declined further. If a significant infusion reaction occurs, slow or interrupt the infusion and administer appropriate medical therapies.

Consider permanent discontinuation in patients with severe infusion reactions. PERJETA treatment should be withheld or discontinued if Herceptin treatment is withheld or discontinued. Advise nursing mothers receiving PERJETA to discontinue treatment, taking into account the importance of the drug to the mother.

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Select Important Safety Information: Discontinue/Interrupt/Withhold

HR=hazard ratio; CI=confidence interval.

Median PFS was reached at the first interim analysis.3 Results of the phase III, randomized, double-blind, placebo-controlled CLEOPATRA trial in patients (N=808) with HER2+ locally recurrent, unresectable, or metastatic breast cancer previously untreated with a biologic or chemotherapy for metastatic disease. Patients received PERJETA + Herceptin + docetaxel or placebo + Herceptin + docetaxel every 3 weeks until progression or unacceptable toxicity. Primary endpoint: PFS, assessed by independent review.3

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• At the first interim analysis, PFS events occurred in 191 (47.5%) patients treated with PERJETA + Herceptin + docetaxel and 242 (59.6%) patients treated with Herceptin + docetaxel3

OS (%)

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JOB#: 52783K CLIENT: Genentech DESC: Journal Ad 3-pg FILE NAME: GNH_HER_52783K_JA_D01.indd DATE: 6-19-2015 7:06 PM ROUND: 1 PG: WangJames/DilenaM AD: R Vetrano-Pyke x4077 PM: B Fu x4416 AE: K McGinty x3950 CW: L Gibbons Last Saved: 6-19-2015 7:06 PM TRIM: 15.5” x 10.5” BLEED: 17.5” x 11.5” SAFETY: 14.75” x 9.875” PROD: M Haight x4245 INK Spec: 4C PRINT SCALE: 75.88% FONTS: Myriad Pro (Regular, Bold, Condensed, Bold Condensed, Condensed Italic) IMAGES: 52783K_JA_2_fn.tif (CMYK; 300 ppi; 100%), Genentech_AMOTRG_4C.eps (96.6%), Perjeta_US_MBC_NEO_4C.eps (65%), 52783K_KMchart_v6.eps (100%), 52783K_oschartREV_v4.eps (100%) Cyan, Magenta, Yellow, Black INKS: DOC PATH: Macintosh HD:Users:wangjames:D...:52783K:GNH_HER_52783K_JA_D01.indd NOTES: None C

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PERJETA demonstrated an OS improvement when combined with Herceptin + docetaxel at the final analysis3

15.7-month improvement in median OS in the final analysis (secondary endpoint)3

6.1-month improvement in median PFS by independent review (primary endpoint)3

S&H

Overall survival (OS) data

B:17.5” T:15.5” S:6.875”

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Significantly extended progression-free survival (PFS) in first-line HER2+ metastatic breast cancer Combining PERJETA with Herceptin + docetaxel added 6 months median PFS3

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• PERJETA administration can result in subclinical and clinical cardiac failure. Evaluate left ventricular function in all patients prior to and during treatment with PERJETA. Discontinue PERJETA treatment for a confirmed clinically significant decrease in left ventricular function • Exposure to PERJETA can result in embryo-fetal death and birth defects.

Studies in animals have resulted in oligohydramnios, delayed renal development, and death. Advise patients of these risks and the need for effective contraception — Verify pregnancy status prior to the initiation of PERJETA. Advise patients of the risks of embryo-fetal death and birth defects and the need for contraception during and for 7 months after treatment. Advise patients to contact their healthcare provider immediately if they suspect they may be pregnant — If PERJETA is used during pregnancy or if a patient becomes pregnant while being treated with PERJETA or within 7 months following the last dose of PERJETA in combination with trastuzumab, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy or within 7 months prior to conception to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 — Monitor patients who become pregnant during PERJETA therapy for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with community standards of care. The efficacy of intravenous hydration in the management of oligohydramnios due to PERJETA exposure is not known

80

PERJETA is contraindicated in patients with known hypersensitivity to pertuzumab or to any of its excipients.

Left Ventricular Dysfunction (LVD)

• In Study 1, for patients with MBC, PERJETA in combination with Herceptin and docetaxel was not associated with increases in the incidence of symptomatic left ventricular systolic dysfunction (LVSD) or decreases in left ventricular ejection fraction (LVEF) compared with placebo in combination with Herceptin and docetaxel • Left ventricular dysfunction occurred in 4.4% of patients in the PERJETA-treated group and in 8.3% of patients in the placebo-treated group • Symptomatic LVSD (congestive heart failure) occurred in 1.0% of patients in the PERJETA-treated group and in 1.8% of patients in the placebo-treated group • Patients who have received prior anthracyclines or prior radiotherapy to the chest area may be at higher risk of decreased LVEF • Assess LVEF prior to initiation of PERJETA and at regular intervals (eg, every 3 months in the metastatic setting) during treatment to ensure that LVEF is within your institution’s normal limits • If LVEF is <45%, or is 45% to 49% with a 10% or greater absolute decrease below the pretreatment value, withhold PERJETA and Herceptin and repeat LVEF assessment within approximately 3 weeks. Discontinue PERJETA and Herceptin if LVEF has not improved or has declined further, unless benefits for the individual patient outweigh the risks

Infusion-Associated Reactions

• PERJETA has been associated with infusion reactions • In Study 1, for patients with MBC, on the first day, when only PERJETA was administered, the overall frequency of infusion reactions was 13.0% in the PERJETAtreated group and 9.8% in the placebo-treated group, with the majority being mild to moderate. The most common infusion reactions (≥1.0%) were pyrexia, chills, fatigue, headache, asthenia, hypersensitivity, and vomiting • During the second cycle, when all drugs were administered on the same day, the most common infusion reactions in the PERJETA-treated group (≥1.0%) were fatigue, dysgeusia, hypersensitivity, myalgia, and vomiting

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• PERJETA improved both PFS and OS when combined with Herceptin + docetaxel in patients, including the visceral metastasis subgroup4,5 — There was an inability to show an OS benefit with PERJETA in patients with nonvisceral metastases (n=178; HR=1.11 [95% CI: 0.66-1.85])3 • Observe patients closely for 60 minutes after the first infusion and for 30 minutes after subsequent infusions of PERJETA. If a significant infusion reaction occurs, slow or interrupt the infusion and administer appropriate medical therapies. Monitor patients carefully until complete resolution of signs and symptoms. Consider permanent discontinuation in patients with severe infusion reactions

Hypersensitivity Reactions/Anaphylaxis

• In Study 1, the overall frequency of hypersensitivity/anaphylaxis reactions was 10.8% in the PERJETA-treated group and 9.1% in the placebo-treated group. The incidence of Grades 3-4 hypersensitivity/anaphylaxis reactions was 2.0% in the PERJETA-treated group and 2.5% in the placebo-treated group according to NCI-CTCAE (version 3). Overall, 4 patients in PERJETA-treated group and 2 patients in the placebo-treated group experienced anaphylaxis • Patients should be observed closely for hypersensitivity reactions. Severe hypersensitivity, including anaphylaxis, has been observed in clinical trials with treatment of PERJETA. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use. PERJETA is contraindicated in patients with known hypersensitivity to pertuzumab or to any of its excipients

HER2 Testing

• Detection of HER2 protein overexpression is necessary for selection of patients appropriate for PERJETA therapy because these are the only patients studied and for whom benefit has been shown • Patients were required to have evidence of HER2 overexpression, defined as 3+ IHC or FISH amplification ratio ≥2.0 in the clinical studies. Only limited data were available for patients whose breast cancer was positive by FISH but did not demonstrate protein overexpression by IHC

© 2015 Genentech USA, Inc.

All rights reserved.

PER/100114/0010(2)

Printed in USA.

06/15

• Assessment of HER2 status should be performed by laboratories using FDA-approved tests with demonstrated proficiency in the specific technology being utilized

Most Common Adverse Reactions • In MBC, the most common adverse reactions (>30%) seen with PERJETA in combination with Herceptin and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. The most common NCI-CTCAE (version 3) Grade 3-4 adverse reactions (>2%) were neutropenia, febrile neutropenia, leukopenia, diarrhea, peripheral neuropathy, anemia, asthenia, and fatigue.

You may report side effects to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

You may also report side effects to Genentech at 1-888-835-2555.

For more information about PERJETA, contact your local representative or visit www.PERJETA.com/hcp.

Please see additional select Important Safety Information throughout, and the Brief Summary of full Prescribing Information including Boxed WARNINGS on the following pages.

References: 1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer V.2.2015. © National Comprehensive Cancer Network, Inc. 2015. All rights reserved. Accessed April 23, 2015. To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 2. Giordano SH, Temin S, Kirshner JJ, et al. Systemic therapy for patients with advanced human epidermal growth factor receptor 2-positive breast cancer: American Society of Clinical Oncology Clinical Practice Guideline.

J Clin Oncol. 2014;32(19):2078-2099. 3. PERJETA Prescribing Information. Genentech, Inc. 2015.

4. Data on file. Genentech, Inc. 5. Baselga J, Cortés J, Kim S-B, et al; CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366:109-119.

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Additional Important Safety Information

HR=0.68 95% CI: 0.56-0.84 P=0.0002

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• The final OS analysis was performed when 221 patient deaths occurred in the placebo-treated group and 168 in the PERJETA-treated group3 • The most common adverse reactions (>30%) seen with the PERJETA-based regimen were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy 3

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Withhold PERJETA and Herceptin and repeat left ventricular ejection fraction (LVEF) assessment within 3 weeks in patients with significant decrease in LVEF. Discontinue PERJETA and Herceptin if LVEF has not improved or has declined further. If a significant infusion reaction occurs, slow or interrupt the infusion and administer appropriate medical therapies.

Consider permanent discontinuation in patients with severe infusion reactions. PERJETA treatment should be withheld or discontinued if Herceptin treatment is withheld or discontinued. Advise nursing mothers receiving PERJETA to discontinue treatment, taking into account the importance of the drug to the mother.

PERJETA + Herceptin + docetaxel

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Select Important Safety Information: Discontinue/Interrupt/Withhold

HR=hazard ratio; CI=confidence interval.

Median PFS was reached at the first interim analysis.3 Results of the phase III, randomized, double-blind, placebo-controlled CLEOPATRA trial in patients (N=808) with HER2+ locally recurrent, unresectable, or metastatic breast cancer previously untreated with a biologic or chemotherapy for metastatic disease. Patients received PERJETA + Herceptin + docetaxel or placebo + Herceptin + docetaxel every 3 weeks until progression or unacceptable toxicity. Primary endpoint: PFS, assessed by independent review.3

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OS (%)

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GNH_HER_52783K_JA_D01.indd

JOB#: 52783K CLIENT: Genentech DESC: Journal Ad 3-pg FILE NAME: GNH_HER_52783K_JA_D01.indd DATE: 6-19-2015 7:06 PM ROUND: 1 PG: WangJames/DilenaM AD: R Vetrano-Pyke x4077 PM: B Fu x4416 AE: K McGinty x3950 CW: L Gibbons Last Saved: 6-19-2015 7:06 PM TRIM: 15.5” x 10.5” BLEED: 17.5” x 11.5” SAFETY: 14.75” x 9.875” PROD: M Haight x4245 INK Spec: 4C PRINT SCALE: 75.88% FONTS: Myriad Pro (Regular, Bold, Condensed, Bold Condensed, Condensed Italic) IMAGES: 52783K_JA_2_fn.tif (CMYK; 300 ppi; 100%), Genentech_AMOTRG_4C.eps (96.6%), Perjeta_US_MBC_NEO_4C.eps (65%), 52783K_KMchart_v6.eps (100%), 52783K_oschartREV_v4.eps (100%) Cyan, Magenta, Yellow, Black INKS: DOC PATH: Macintosh HD:Users:wangjames:D...:52783K:GNH_HER_52783K_JA_D01.indd NOTES: None C

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PERJETA demonstrated an OS improvement when combined with Herceptin + docetaxel at the final analysis3

15.7-month improvement in median OS in the final analysis (secondary endpoint)3

6.1-month improvement in median PFS by independent review (primary endpoint)3

S&H

Overall survival (OS) data

PERJETA® (pertuzumab) INJECTION, FOR INTRAVENOUS USE INITIAL U.S. APPROVAL: 2012

WARNING: LEFT VENTRICULAR DYSFUNCTION and EMBRYO-FETAL TOXICITY Left Ventricular Dysfunction PERJETA administration can result in subclinical and clinical cardiac failure. Evaluate left ventricular function in all patients prior to and during treatment with PERJETA. Discontinue PERJETA treatment for a confirmed clinically significant decrease in left ventricular function. (2.2, 5.1, 6.1) Embryo-Fetal Toxicity Exposure to PERJETA can result in embryo-fetal death and birth defects. Studies in animals have resulted in oligohydramnios, delayed renal development, and death. Advise patients of these risks and the need for effective contraception. (5.2, 8.1, 8.6)

1 INDICATIONS AND USAGE 1.1 Metastatic Breast Cancer (MBC) PERJETA is indicated for use in combination with trastuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.

1.2 Neoadjuvant Treatment of Breast Cancer PERJETA is indicated for use in combination with trastuzumab and docetaxel for the neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (either greater than 2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer. This indication is based on demonstration of an improvement in pathological complete response rate. No data are available demonstrating improvement in eventfree survival or overall survival [see Clinical Studies (14.2) and Dosage and Administration (2.1)].

Limitations of Use: • The safety of PERJETA as part of a doxorubicincontaining regimen has not been established.

• The safety of PERJETA administered for greater than 6 cycles for early breast cancer has not been established.

4 CONTRAINDICATIONS PERJETA is contraindicated in patients with known hypersensitivity to pertuzumab or to any of its excipients.

5 WARNINGS AND PRECAUTIONS 5.1 Left Ventricular Dysfunction Decreases in LVEF have been reported with drugs that block HER2 activity, including PERJETA. In Study 1, for patients with MBC, PERJETA in combination with trastuzumab and docetaxel was not associated with increases in the incidence of symptomatic left ventricular systolic dysfunction (LVSD) or decreases in LVEF compared with placebo in combination with trastuzumab and docetaxel [see Clinical Studies (14.1)].

Left ventricular dysfunction occurred in 4.4% of patients in the PERJETA-treated group and 8.3% of patients in the placebo-treated group. Symptomatic left ventricular systolic dysfunction (congestive heart failure) occurred in 1.0% of patients in the PERJETA-treated group and 1.8% of patients in the placebo-treated group [see Adverse Reactions (6.1)]. Patients who have received prior anthracyclines or prior radiotherapy to the chest area may be at higher risk of decreased LVEF. In patients receiving neoadjuvant treatment in Study 2, the incidence of LVSD was higher in the PERJETA-treated groups compared to the trastuzumab- and docetaxeltreated group. An increased incidence of LVEF declines was observed in patients treated with PERJETA in combination with trastuzumab and docetaxel. In the overall treatment period, LVEF decline > 10% and a drop to less than 50% occurred in 1.9% of patients treated with neoadjuvant trastuzumab and docetaxel as compared to 8.4% of patients treated with neoadjuvant PERJETA in combination with trastuzumab and docetaxel.

Symptomatic LVSD occurred in 0.9% of patients treated with neoadjuvant PERJETA in combination with

trastuzumab and no patients in the other 3 arms. LVEF recovered to ≥ 50% in all patients.

In patients receiving neoadjuvant PERJETA in Study 3, in the overall treatment period, LVEF decline > 10% and a drop to less than 50% occurred in 6.9% of patients treated with PERJETA plus trastuzumab and FEC followed

by PERJETA plus trastuzumab and docetaxel, 16.0% of patients treated with PERJETA plus trastuzumab and docetaxel following FEC, and 10.5% of patients treated with PERJETA in combination with TCH. Symptomatic LVSD occurred in 4.0% of patients treated with PERJETA plus trastuzumab and docetaxel following FEC, 1.3% of patients treated with PERJETA in combination with TCH, and none of the patients treated with PERJETA plus trastuzumab and FEC followed by PERJETA plus trastuzumab and docetaxel. LVEF recovered to ≥ 50% in all but one patient.

PERJETA has not been studied in patients with a pretreatment LVEF value of ≤ 50%, a prior history of CHF, decreases in LVEF to < 50% during prior trastuzumab therapy, or conditions that could impair left ventricular function such as uncontrolled hypertension, recent myocardial infarction, serious cardiac arrhythmia requiring treatment or a cumulative prior anthracycline exposure to > 360 mg/m 2 of doxorubicin or its equivalent.

Assess LVEF prior to initiation of PERJETA and at regular intervals (e.g., every three months in the metastatic setting and every six weeks in the neoadjuvant setting) during treatment to ensure that LVEF is within the institution’s normal limits. If LVEF is < 45%, or is 45% to 49% with a 10% or greater absolute decrease below the pretreatment value, withhold PERJETA and trastuzumab and repeat LVEF assessment within approximately 3 weeks. Discontinue PERJETA and trastuzumab if the LVEF has not improved or has declined further, unless the benefits for the individual patient outweigh the risks [see Dosage and Administration (2.2)].

5.2 Embryo-Fetal Toxicity PERJETA can cause fetal harm when administered to a pregnant woman. Treatment of pregnant cynomolgus monkeys with pertuzumab resulted in oligohydramnios, delayed fetal kidney development, and embryo-fetal death. If PERJETA is administered during pregnancy, or if the patient becomes pregnant while receiving this drug or within 7 months following the last dose of PERJETA in combination with trastuzumab, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)].

Verify pregnancy status prior to the initiation of PERJETA. Advise patients of the risks of embryo-fetal death and birth defects and the need for contraception during and after treatment. Advise patients to contact their healthcare provider immediately if they suspect they may be pregnant. If PERJETA is administered during pregnancy or if a patient becomes pregnant while receiving PERJETA or within 7 months following the last dose of PERJETA in combination with trastuzumab, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy or within 7 months for PERJETA in combination with trastuzumab prior to conception, to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see Patient Counseling Information (17)].

Monitor patients who become pregnant during PERJETA therapy for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with community standards of care.

The efficacy of intravenous hydration in the management of oligohydramnios due to PERJETA exposure is not known.

5.3 Infusion-Related Reactions PERJETA has been associated with infusion reactions [see Adverse Reactions (6.1)]. An infusion reaction was defined in Study 1 as any event described as hypersensitivity, anaphylactic reaction, acute infusion reaction, or cytokine release syndrome occurring during an infusion or on the same day as the infusion.

The initial dose of PERJETA was given the day before trastuzumab and docetaxel to allow for the examination of PERJETA-associated reactions. On the first day, when only PERJETA was administered, the overall frequency

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of infusion reactions was 13.0% in the PERJETA-treated group and 9.8% in the placebo-treated group. Less than 1% were Grade 3 or 4. The most common infusion reactions (≥ 1.0%) were pyrexia, chills, fatigue, headache, asthenia, hypersensitivity, and vomiting.

During the second cycle when all drugs were administered on the same day, the most common infusion reactions in the PERJETA-treated group (≥ 1.0%) were fatigue, dysgeusia, hypersensitivity, myalgia, and vomiting.

In Study 2 and Study 3, PERJETA was administered on the same day as the other study treatment drugs. Infusion reactions were consistent with those observed in Study 1, with a majority of reactions being National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI - CTCAE v3.0) Grade 1 – 2.

Observe patients closely for 60 minutes after the first infusion and for 30 minutes after subsequent infusions of PERJETA. If a significant infusion-related reaction occurs, slow or interrupt the infusion, and administer appropriate medical therapies. Monitor patients carefully until complete resolution of signs and symptoms. Consider permanent discontinuation in patients with severe infusion reactions [see Dosage and Administration (2.2)].

5.4 Hypersensitivity Reactions/Anaphylaxis In Study 1, the overall frequency of hypersensitivity/ anaphylaxis reactions was 10.8% in the PERJETA-treated group and 9.1% in the placebo-treated group. The incidence of Grade 3 – 4 hypersensitivity/anaphylaxis reactions was 2.0% in the PERJETA-treated group and 2.5% in the placebo-treated group according to NCI - CTCAE v3.0. Overall, 4 patients in PERJETA-treated group and 2 patients in the placebo-treated group experienced anaphylaxis.

In Study 2 and Study 3, hypersensitivity/anaphylaxis events were consistent with those observed in Study 1.

In Study 2, two patients in the PERJETA- and docetaxeltreated group experienced anaphylaxis. In Study 3, the overall frequency of hypersensitivity/anaphylaxis was highest in the PERJETA plus TCH treated group (13.2%), of which 2.6% were NCI-CTCAE (version 3) Grade 3 – 4.

Patients should be observed closely for hypersensitivity reactions. Severe hypersensitivity, including anaphylaxis, has been observed in clinical trials with treatment of PERJETA [see Clinical Trials Experience (6.1)].

Medications to treat such reactions, as well as emergency equipment, should be available for immediate use. PERJETA is contraindicated in patients with known hypersensitivity to pertuzumab or to any of its excipients [see Contraindications (4)].

5.5 HER2 Testing Detection of HER2 protein overexpression is necessary for selection of patients appropriate for PERJETA therapy because these are the only patients studied and for whom benefit has been shown [see Indications and Usage (1) and Clinical Studies (14)]. Patients with breast cancer were required to have evidence of HER2 overexpression defined as 3+ IHC or FISH amplification ratio ≥ 2.0 in the clinical studies. Only limited data were available for patients whose breast cancer was positive

by FISH, but did not demonstrate protein overexpression

by IHC. Assessment of HER2 status should be performed by laboratories using FDA-approved tests with demonstrated proficiency in the specific technology being utilized.

Improper assay performance, including use of suboptimally fixed tissue, failure to utilize specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results.

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Left Ventricular Dysfunction [see Warnings and Precautions (5.1)] • Embryo-Fetal Toxicity [see Warnings and Precautions (5.2)] • Infusion-Related Reactions [see Warnings and Precautions (5.3)] • Hypersensitivity Reactions/Anaphylaxis [see Warnings and Precautions (5.4)]

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Metastatic Breast Cancer (MBC) The adverse reactions described in Table 1 were identified in 804 patients with HER2-positive metastatic breast cancer treated in Study 1. Patients were randomized to receive either PERJETA in combination with trastuzumab and docetaxel or placebo in combination with trastuzumab and docetaxel. The median duration of study treatment was 18.1 months for patients in the PERJETA-treated group and 11.8 months for patients in the placebo-treated group. No dose adjustment was permitted for PERJETA or trastuzumab. The rates of adverse events resulting in permanent discontinuation of all study therapy were 6.1% for patients in the PERJETA-treated group and 5.3% for patients in the placebo-treated group. Adverse events led to discontinuation of docetaxel alone in 23.6% of patients in the PERJETA-treated group and 23.2% of patients in the placebo-treated group. Table 1 reports the adverse reactions that occurred in at least 10% of patients in the PERJETA-treated group. The safety profile of PERJETA remained unchanged with an additional 2.75 years of follow-up (median total follow-up of 50 months) in Study 1.

The most common adverse reactions (> 30%) seen with PERJETA in combination with trastuzumab and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. The most common NCI CTCAE v3.0 Grade 3 – 4 adverse reactions (> 2%) were neutropenia, febrile neutropenia, leukopenia, diarrhea, peripheral neuropathy, anemia, asthenia, and fatigue. An increased incidence of febrile neutropenia was observed for Asian patients in both treatment arms compared with patients of other races and from other geographic regions. Among Asian patients, the incidence of febrile neutropenia was higher in the pertuzumab-treated group (26%) compared with the placebo-treated group (12%).

Table 1 Summary of Adverse Reactions Occurring in ≥ 10% of Patients on the PERJETA Treatment Arm in Study 1 Placebo PERJETA + trastuzumab + trastuzumab + docetaxel + docetaxel n=407 n=397 Body System/ Adverse Reactions Frequency rate, % Frequency rate, % All Grades Grades, % 3–4, %

All Grades, %

Grades 3–4, %

General disorders and administration site conditions Fatigue 37.6 2.2 36.8 3.3 Asthenia 26.0 2.5 30.2 1.5 Edema peripheral 23.1 0.5 30.0 0.8 Mucosal inflammation 27.8 1.5 19.9 1.0 Pyrexia 18.7 1.2 17.9 0.5 Skin and subcutaneous tissue disorders Alopecia 60.9 0.0 60.5 0.3 Rash 33.7 0.7 24.2 0.8 Nail disorder 22.9 1.2 22.9 0.3 Pruritus 14.0 0.0 10.1 0.0 Dry skin 10.6 0.0 4.3 0.0 Gastrointestinal disorders Diarrhea 66.8 7.9 46.3 5.0 Nausea 42.3 1.2 41.6 0.5 Vomiting 24.1 1.5 23.9 1.5 Constipation 15.0 0.0 24.9 1.0 Stomatitis 18.9 0.5 15.4 0.3 Blood and lymphatic system disorders Neutropenia 52.8 48.9 49.6 45.8 Anemia 23.1 2.5 18.9 3.5 Leukopenia 18.2 12.3 20.4 14.6 Febrile neutropenia* 13.8 13.0 7.6 7.3 Nervous system disorders Neuropathy peripheral 32.4 3.2 33.8 2.0 Headache 20.9 1.2 16.9 0.5 Dysgeusia 18.4 0.0 15.6 0.0 Dizziness 12.5 0.5 12.1 0.0 Musculoskeletal and connective tissue disorders Myalgia 22.9 1.0 23.9 0.8 Arthralgia 15.5 0.2 16.1 0.8

Infections and infestations Upper respiratory tract infection 16.7 0.7 13.4 Nasopharyngitis 11.8 0.0 12.8 Respiratory, thoracic, and mediastinal disorders Dyspnea 14.0 1.0 15.6 Metabolism and nutrition disorders Decreased appetite 29.2 1.7 26.4 Eye disorders Lacrimation increased 14.0 0.0 13.9 Psychiatric disorders Insomnia 13.3 0.0 13.4

0.0 0.3 2.0 1.5 0.0 0.0

*In this table this denotes an adverse reaction that has been reported in association with a fatal outcome The following clinically relevant adverse reactions were reported in < 10% of patients in the PERJETA‑treated group in Study 1: Skin and subcutaneous tissue disorders: Paronychia (7.1% in the PERJETA-treated group vs. 3.5% in the placebo-treated group) Respiratory, thoracic and mediastinal disorders: Pleural effusion (5.2% in the PERJETA-treated group vs. 5.8% in the placebo-treated group) Cardiac disorders: Left ventricular dysfunction (4.4% in the PERJETA-treated group vs. 8.3% in the placebotreated group) including symptomatic left ventricular systolic dysfunction (CHF) (1.0% in the PERJETA-treated group vs. 1.8% in the placebo-treated group) Immune system disorders: Hypersensitivity (10.1% in the PERJETA-treated group vs. 8.6% in placebotreated group) Adverse Reactions Reported in Patients Receiving PERJETA and Trastuzumab after Discontinuation of Docetaxel In Study 1, adverse reactions were reported less frequently after discontinuation of docetaxel treatment.

All adverse reactions in the PERJETA and trastuzumab treatment group occurred in < 10% of patients with the exception of diarrhea (19.1%), upper respiratory tract infection (12.8%), rash (11.7%), headache (11.4%), and fatigue (11.1%).

Neoadjuvant Treatment of Breast Cancer (Study 2) In Study 2, the most common adverse reactions seen with PERJETA in combination with trastuzumab and docetaxel administered for 4 cycles were similar to those seen in the PERJETA-treated group in Study 1.

The most common adverse reactions (>30%) were alopecia, neutropenia, diarrhea, and nausea.

The most common NCI – CTCAE v3.0 Grade 3 – 4 adverse reactions (>2%) were neutropenia, febrile neutropenia, leukopenia, and diarrhea. In this group, one patient permanently discontinued neoadjuvant treatment due to an adverse event. Table 2 reports the adverse reactions that occurred in patients who received neoadjuvant treatment with PERJETA for breast cancer in Study 2.

Table 2 Summary of Adverse Reactions Occurring in ≥ 10% in the Neoadjuvant Setting for Patients Receiving PERJETA in Study 2

Body System/ Adverse Reactions

PERJETA PERJETA PERJETA + trastuzumab Trastuzumab + docetaxel + trastuzumab + docetaxel + docetaxel n=108 n=108 n=107 n=107 Frequency rate Frequency rate Frequency rate Frequency rate % % % % Grades All Grades All Grades All Grades All Grades 3–4 Grades 3–4 Grades 3–4 Grades 3–4 % % % % % % % %

General disorders and administration site conditions Fatigue Asthenia Edema peripheral Mucosal inflammation Pyrexia

27.1 0.0 26.2 0.9 12.0 17.8 0.0 20.6 1.9 2.8 10.3 0.0

2.8

0.0 25.5 1.1 0.0 16.0 2.1

0.0

0.9

0.0

21.5 0.0 26.2 1.9 10.3 0.0 16.8 0.0

2.8 8.3

0.0 25.5 0.0 0.0 8.5 0.0

5.3

0.0

66.4 0.0 65.4 0.0 2.8 21.5 1.9 26.2 0.9 11.1

0.0 67.0 0.0 0.0 28.7 1.1

Skin and subcutaneous tissue disorders Alopecia Rash

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Gastrointestinal disorders Diarrhea 33.6 3.7 45.8 5.6 27.8 0.0 Nausea 36.4 0.0 39.3 0.0 13.9 0.0 Vomiting 12.1 0.0 13.1 0.0 4.6 0.0 Stomatitis 7.5 0.0 17.8 0.0 4.6 0.0 Blood and lymphatic system disorders Neutropenia 63.6 58.9 50.5 44.9 0.9 0.9 Leukopenia 21.5 11.2 9.3 4.7 0.0 0.0 Nervous system disorders Headache 11.2 0.0 11.2 0.0 13.9 0.0 Dysgeusia 10.3 0.0 15.0 0.0 4.6 0.0 Peripheral Sensory Neuropathy 12.1 0.9 8.4 0.9 1.9 0.0 Musculoskeletal and connective tissue disorders Myalgia 22.4 0.0 22.4 0.0 9.3 0.0 Arthralgia 8.4 0.0 10.3 0.0 4.6 0.0 Metabolism and nutrition disorders Decreased appetite 6.5 0.0 14.0 0.0 1.9 0.0 Psychiatric disorders Insomnia 11.2 0.0 8.4 0.0 3.7 0.0

54.3 36.2 16.0 9.6

4.3 1.1 2.1 0.0

64.9 57.4 13.8 8.5 12.8 0.0 7.4 0.0 10.6 0.0 21.3 0.0 9.6 0.0 14.9 0.0 8.5

0.0

The following adverse reactions were reported in < 10% of patients receiving neoadjuvant treatment and occurred more frequently in PERJETA‑treated groups in Study 2: (Ptz=pertuzumab; T=trastuzumab; D=docetaxel) Blood and lymphatic system disorders: Anemia (6.5% in the T+D arm, 2.8% in the Ptz+T+D arm, 4.6% in the Ptz+T arm and 8.5% in the Ptz+D arm), Febrile neutropenia (6.5% in the T+D arm, 8.4% in the Ptz+T+D arm, 0.0% in the Ptz+T arm and 7.4% in the Ptz+D arm) Immune system disorders: Hypersensitivity (1.9% in the T +D arm, 5.6% in the Ptz+T+D arm, 5.6% in the Ptz+T arm and 5.3% in the Ptz+D arm) Nervous system disorders: Dizziness (3.7% in the T+D arm, 2.8% in the Ptz+T+D arm, 5.6% in the Ptz+T arm and 3.2% in the Ptz+D arm) Infections and infestations: Upper respiratory tract infection (2.8% in the T+D arm, 4.7% in the Ptz+T+D arm, 1.9% in the Ptz+T arm and 7.4% in the Ptz+D arm) Respiratory, thoracic and mediastinal disorders: Dyspnea (3.7% in the T+D arm, 4.7% in the Ptz+T+D arm, 2.8% in the Ptz+T arm and 2.1% in the Ptz+D arm) Cardiac disorders: Left ventricular dysfunction (0.9% in the T+D arm, 2.8% in the Ptz+T+D arm, 0.0% in the Ptz+ T arm, and 1.1% in the Ptz+D arm) including symptomatic left ventricular dysfunction (CHF) (0.9% in the Ptz+T arm and 0.0% in the T+D arm, Ptz+T+D arm, and Ptz+D arm) Eye disorders: Lacrimation increased (1.9% in the T+D arm, 3.7% in the Ptz+T+D arm, 0.9% in the Ptz+T arm, and 4.3% in the Ptz+D arm) Neoadjuvant Treatment of Breast Cancer (Study 3) In Study 3, when PERJETA was administered in combination with trastuzumab and docetaxel for 3 cycles following 3 cycles of FEC, the most common adverse reactions (>30%) were diarrhea, nausea, alopecia, neutropenia, vomiting, and fatigue. The most common NCI-CTCAE (version 3) Grade 3 – 4 adverse reactions (>2%) were neutropenia, leukopenia, febrile neutropenia, diarrhea, left ventricular dysfunction, anemia, dyspnea, nausea, and vomiting.

Similarly, when PERJETA was administered in combination with docetaxel, carboplatin, and trastuzumab (TCH) for 6 cycles, the most common adverse reactions (>30%) were diarrhea, alopecia, neutropenia, nausea, fatigue, vomiting, anemia, and thrombocytopenia. The most common NCI-CTCAE (version 3) Grade 3 – 4 adverse reactions (>2%) were neutropenia, febrile neutropenia, anemia, leukopenia, diarrhea, thrombocytopenia, vomiting, fatigue, ALT increased, hypokalemia, and hypersensitivity.

The rates of adverse events resulting in permanent discontinuation of any component of neoadjuvant treatment were 6.7% for patients receiving PERJETA in combination with trastuzumab and docetaxel following FEC and 7.9% for patients receiving PERJETA in combination with TCH. Table 3 reports the adverse reactions that occurred in patients who received neoadjuvant treatment with PERJETA for breast cancer in Study 3.

Table 3 Summary of Adverse Reactions Occurring in ≥ 10% of Patients Receiving Neoadjuvant Treatment with PERJETA in Study 3

Body System/ Adverse Reactions

PERJETA + trastuzumab PERJETA + FEC followed + trastuzumab

by PERJETA + trastuzumab + docetaxel following FEC PERJETA + TCH + docetaxel n=75 n=76 n=72 Frequency rate, % Frequency rate, % Frequency rate, % Grades All Grades Grades All All 3–4 Grades 3–4 Grades 3–4 Grades % % % % % %

General disorders and administration site conditions Fatigue 36.1 0.0 36.0 0.0 42.1 3.9 Asthenia 9.7 0.0 14.7 1.3 13.2 1.3 Edema peripheral 11.1 0.0 4.0 0.0 9.2 0.0 Mucosal 23.6 0.0 20.0 0.0 17.1 1.3 inflammation Pyrexia 16.7 0.0 9.3 0.0 15.8 0.0 Skin and subcutaneous tissue disorders Alopecia 48.6 0.0 52.0 0.0 55.3 0.0 Rash 19.4 0.0 10.7 0.0 21.1 1.3 Dry skin 5.6 0.0 9.3 0.0 10.5 0.0 Palmar-Plantar Erythrodysaesthesia 6.9 0.0 10.7 0.0 7.9 0.0 Syndrome Gastrointestinal disorders Diarrhea 61.1 4.2 61.3 5.3 72.4 11.8 Dyspepsia 25.0 1.4 8 0.0 22.4 0.0 Nausea 52.8 0.0 53.3 2.7 44.7 0.0 Vomiting 40.3 0.0 36.0 2.7 39.5 5.3 Constipation 18.1 0.0 22.7 0.0 15.8 0.0 Stomatitis 13.9 0.0 17.3 0.0 11.8 0.0 Blood and lymphatic system disorders Neutropenia 51.4 47.2 46.7 42.7 48.7 46.1 Anemia 19.4 1.4 9.3 4.0 38.2 17.1 Leukopenia 22.2 19.4 16.0 12.0 17.1 11.8 Febrile neutropenia 18.1 18.1 9.3 9.3 17.1 17.1 Thrombocytopenia 6.9 0.0 1.3 0.0 30.3 11.8 Immune system disorders Hypersensitivity 9.7 2.8 1.3 0.0 11.8 2.6 Nervous system disorders Neuropathy 5.6 0.0 1.3 0.0 10.5 0.0 peripheral Headache 22.2 0.0 14.7 0.0 17.1 0.0 Dysgeusia 11.1 0.0 13.3 0.0 21.1 0.0 Dizziness 8.3 0.0 8.0 1.3 15.8 0.0 Musculoskeletal and connective tissue disorders Myalgia 16.7 0.0 10.7 1.3 10.5 0.0 Arthralgia 11.1 0.0 12.0 0.0 6.6 0.0 Respiratory, thoracic, and mediastinal disorders Cough 9.7 0.0 5.3 0.0 11.8 0.0 Dyspnea 12.5 0.0 8.0 2.7 10.5 1.3 Epistaxis 11.1 0.0 10.7 0.0 15.8 1.3 Oropharyngeal pain 8.3 0.0 6.7 0.0 11.8 0.0 Metabolism and nutrition disorders Decreased appetite 20.8 0.0 10.7 0.0 21.1 0.0 Eye disorders Lacrimation 12.5 0.0 5.3 0.0 7.9 0.0 increased Psychiatric disorders Insomnia 11.1 Investigations ALT increased 6.9

0.0

13.3

0.0

21.1

0.0

0.0

2.7

0.0

10.5

3.9

FEC=5-fluorouracil, epirubicin, cyclophosphamide, TCH=docetaxel, carboplatin, trastuzumab The following selected adverse reactions were reported in < 10% of patients receiving neoadjuvant treatment in Study 3: (Ptz=pertuzumab; T=trastuzumab; D=docetaxel; FEC=fluorouracil, epirubicin, and cyclophosphamide; TCH=docetaxel, carboplatin, and trastuzumab) Skin and subcutaneous tissue disorders: Nail disorder (9.7% in the Ptz+T+FEC/Ptz+T+D arm, 6.7% in the FEC/ Ptz+T+D arm, and 9.2% in the Ptz+TCH arm), Paronychia (0% in the Ptz+T+FEC/Ptz+T+D and 1.3% in both the FEC/Ptz+T+D and Ptz+TCH arms), Pruritis (2.8% in the Ptz+T+FEC/Ptz+T+D arm, 4.0% in the FEC/Ptz+T+D arm, and 3.9% in the Ptz+TCH arm) Infections and infestations: Upper respiratory tract infection (8.3% in the Ptz+T+FEC/Ptz+T+D arm, 4.0% in the FEC/Ptz+T+D arm, and 2.6% in the Ptz+TCH arm), Nasopharyngitis (6.9% in the Ptz+T+FEC/Ptz+T+D arm, 6.7% in the FEC/Ptz+T+D arm, and 7.9% in the Ptz+TCH arm) Respiratory, thoracic, and mediastinal disorders: Pleural effusion (1.4% in the Ptz+T+FEC/Ptz+T+D arm and 0% in the FEC/Ptz+T+D and Ptz+TCH arm) Cardiac disorders: Left ventricular dysfunction (5.6% in the Ptz+T+FEC/PTZ+T+D arm, 4.0% in the FEC/Ptz+T+D arm, and 2.6% in the Ptz+TCH arm) including symptomatic left ventricular systolic dysfunction (CHF) (2.7% in the FEC/Ptz+T+D arm and 0% in the Ptz+T+FEC/Ptz+T+D and Ptz+TCH arms)

6.2 Immunogenicity As with all therapeutic proteins, there is the potential for an immune response to PERJETA.

8.4 Pediatric Use The safety and effectiveness of PERJETA have not been established in pediatric patients.

Patients in Study 1 were tested at multiple time-points for antibodies to PERJETA. Approximately 2.8% (11/386) of patients in the PERJETA-treated group and 6.2% (23/372) of patients in the placebo-treated group tested positive for anti-PERJETA antibodies. Of these 34 patients, none experienced anaphylactic/hypersensitivity reactions that were clearly related to the anti-therapeutic antibodies (ATA). The presence of pertuzumab in patient serum at the levels expected at the time of ATA sampling can interfere with the ability of this assay to detect anti-pertuzumab antibodies. In addition, the assay may be detecting antibodies to trastuzumab. As a result, data may not accurately reflect the true incidence of anti-pertuzumab antibody development.

8.5 Geriatric Use Of 402 patients who received PERJETA in Study 1, 60 patients (15%) were ≥ 65 years of age and 5 patients (1%) were ≥ 75 years of age. No overall differences in efficacy and safety of PERJETA were observed between these patients and younger patients.

Immunogenicity data are highly dependent on the sensitivity and specificity of the test methods used. Additionally, the observed incidence of a positive result in a test method may be influenced by several factors, including sample handling, timing of sample collection, drug interference, concomitant medication, and the underlying disease. For these reasons, comparison of the incidence of antibodies to PERJETA with the incidence of antibodies to other products may be misleading.

7 DRUG INTERACTIONS No drug-drug interactions were observed between pertuzumab and trastuzumab, or between pertuzumab and docetaxel.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D Risk Summary There are no adequate and well-controlled studies of PERJETA in pregnant women. Based on findings in animal studies, PERJETA can cause fetal harm when administered to a pregnant woman. The effects of PERJETA are likely to be present during all trimesters of pregnancy. Pertuzumab administered to pregnant cynomolgus monkeys resulted in oligohydramnios, delayed fetal kidney development, and embryo-fetal deaths at clinically relevant exposures of 2.5 to 20-fold greater than the recommended human dose, based on Cmax. If PERJETA is administered during pregnancy, or if a patient becomes pregnant while receiving PERJETA or within 7 months following the last dose of PERJETA in combination with trastuzumab, the patient should be apprised of the potential hazard to the fetus.

If PERJETA is administered during pregnancy or if a patient becomes pregnant while receiving PERJETA or within 7 months following the last dose of PERJETA in combination with trastuzumab, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy or within 7 months for PERJETA in combination with trastuzumab prior to conception, to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see Patient Counseling Information (17)].

Animal Data Reproductive toxicology studies have been conducted in cynomolgus monkeys. Pregnant monkeys were treated on Gestational Day (GD)19 with loading doses of 30 to 150 mg/kg pertuzumab, followed by bi-weekly doses of 10 to 100 mg/kg.

These dose levels resulted in clinically relevant exposures of 2.5 to 20-fold greater than the recommended human dose, based on Cmax. Intravenous administration of pertuzumab from GD19 through GD50 (period of organogenesis) was embryotoxic, with dose-dependent increases in embryofetal death between GD25 to GD70. The incidences of embryo-fetal loss were 33, 50, and 85% for dams treated with bi-weekly pertuzumab doses of 10, 30, and 100 mg/kg, respectively (2.5 to 20-fold greater than the recommended human dose, based on Cmax). At Caesarean section on GD100, oligohydramnios, decreased relative lung and kidney weights, and microscopic evidence of renal hypoplasia consistent with delayed renal development were identified in all pertuzumab dose groups. Pertuzumab exposure was reported in offspring from all treated groups, at levels of 29% to 40% of maternal serum levels at GD100.

8.3 Nursing Mothers It is not known whether PERJETA is excreted in human milk, but human IgG is excreted in human milk. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from PERJETA, a decision should be made whether to discontinue nursing, or discontinue drug, taking into account the elimination half-life of PERJETA and the importance of the drug to the mother [See Warnings and Precautions (5.2), Clinical Pharmacology (12.3)].

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Based on a population pharmacokinetic analysis, no significant difference was observed in the pharmacokinetics of pertuzumab between patients < 65 years (n=306) and patients ≥ 65 years (n=175).

8.6 Females of Reproductive Potential PERJETA can cause embryo-fetal harm when administered during pregnancy. Counsel patients regarding pregnancy prevention and planning. Advise females of reproductive potential to use effective contraception while receiving PERJETA and for 7 months following the last dose of PERJETA in combination with trastuzumab.

If PERJETA is administered during pregnancy or if a patient becomes pregnant while receiving PERJETA or within 7 months following the last dose of PERJETA in combination with trastuzumab, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy or within 7 months for PERJETA in combination with trastuzumab prior to conception, to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see Patient Counseling Information (17)].

8.7 Renal Impairment Dose adjustments of PERJETA are not needed in patients with mild (creatinine clearance [CLcr] 60 to 90 mL/min) or moderate (CLcr 30 to 60 mL/min) renal impairment. No dose adjustment can be recommended for patients with severe renal impairment (CLcr less than 30 mL/min) because of the limited pharmacokinetic data available [see Clinical Pharmacology (12.3)].

8.8 Hepatic Impairment No clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of pertuzumab.

10 OVERDOSAGE No drug overdoses have been reported with PERJETA to date.

17 PATIENT COUNSELING INFORMATION • Advise patients to contact a health care professional immediately for any of the following: new onset or worsening shortness of breath, cough, swelling of the ankles/legs, swelling of the face, palpitations, weight gain of more than 5 pounds in 24 hours, dizziness or loss of consciousness [see Warnings and Precautions (5.1)] • Advise pregnant women and females of reproductive potential that PERJETA exposure can result in fetal harm, including embryo-fetal death or birth defects [see Warnings and Precautions (5.2) and Use in Specific Populations (8.1)] • Advise females of reproductive potential to use effective contraception while receiving PERJETA and for 7 months following the last dose of PERJETA in combination with trastuzumab [see Warnings and Precautions (5.2) and Use in Special Populations (8.6)] • Advise nursing mothers treated with PERJETA to discontinue nursing or discontinue PERJETA, taking into account the importance of the drug to the mother [see Use in Specific Populations (8.3)] • If PERJETA is administered during pregnancy or if a patient becomes pregnant while receiving PERJETA or within 7 months following the last dose of PERJETA in combination with trastuzumab, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who are exposed to PERJETA during pregnancy or within 7 months for PERJETA in combination with trastuzumab prior to conception, to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see Warnings and Precautions (5.2) and Use in Specific Populations (8.1, 8.6)]

PERJETA® (pertuzumab) Manufactured by: Genentech, Inc. A Member of the Roche Group 1 DNA Way South San Francisco, CA 94080-4990 U.S. License No. 1048

PERJETA is a registered trademark of Genentech, Inc. 06/15 PER/041015/0031(2) © 2015 Genentech, Inc. 10139000

DRUG MONOGRAPHS

BREAST CANCER Limitations of use: not established as part of a doxorubicin-containing regimen. Not established in administration for >6 cycles for early breast cancer.

Adults: In combination with trastuzumab and docetaxel: initially 840mg IV over 60 minutes, followed every 3 weeks thereafter by a dose of 420mg IV over 30–60 minutes.

Pertuzumab should be withheld or discontinued if trastuzumab is withheld or discontinued.

If docetaxel is discontinued, treatment with pertuzumab and trastuzumab may continue.

Neoadjuvant treatment: give every 3 weeks for 3 to 6 cycles as part of one of the treatment regimens for early breast cancer: see full labeling.

Dose modification (missed dose, LVEF, or infusion reactions): see full labeling.

Children: Not established.

Warnings/Precautions: Risk of embryo-fetal toxicity. Pretreatment LVEF value of ≤50%, history of CHF, decreases in LVEF to <50% during prior trastuzumab therapy, uncontrolled hypertension, recent MI, serious cardiac arrythmia requiring treatment or a cumulative prior anthracycline exposure to >360mg/m2 of doxorubicin or its equivalent: not studied. Assess LVEF at baseline and at regular intervals (eg, every 3 months in metastatic setting, and every 6 weeks in the neoadjuvant setting) during treatment; if LVEF is <45%, or is 45% to 49% with a ≥10% absolute decrease below the pretreatment value, withhold (pertuzumab + trastuzumab) and repeat LVEF within 3 weeks; discontinue if LVEF has not improved. Monitor for signs/symptoms of infusion reactions; slow or interrupt infusion and treat if occurs; discontinue if severe. Test and confirm for HER2 protein overexpression using FDA-approved tests by labs with demonstrated proficiency. Pregnancy (Cat.D); use adequate contraception during and at least 6 months after therapy. Nursing mothers: not recommended.

Adverse reactions: Diarrhea, alopecia, neutropenia, nausea, fatigue, rash, peripheral neuropathy; hypersensitivity (monitor), decreases in LVEF; pregnant women: possible oligohydramnios (monitor).

Note: Encourage women who are exposed to Perjeta during pregnancy to enroll in the MotHER Pregnancy Registry: (800) 690-6720.

How supplied: Single-use vial—1

PREMARIN Pfizer

℞

Estrogen. Conjugated estrogens 0.3mg, 0.45mg, 0.625mg, 0.9mg, 1.25mg; tabs.

Indications: Treatment of breast cancer (for palliation only) in appropriately selected women and men with metastatic disease.

Adults: 10mg 3 times daily for at least 3 months.

Children: Not applicable.

Contraindications: Known, suspected, or history of breast cancer, except in appropriately selected patients being treated for metastatic disease. Known or suspected estrogen-dependent neoplasia. Undiagnosed abnormal genital bleeding. Pulmonary embolism/DVT (active or history of). Arterial thromboembolism (eg, stroke, MI; active or history of). Liver dysfunction or disease. Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders. Known or suspected pregnancy (Cat.X).

Warnings/Precautions: Not for prevention of cardiovascular disease. Use for shortest duration consistent with treatment goals and risks. Reevaluate periodically. Patients with an intact uterus should almost always receive a progestin with systemic estrogens to avoid endometrial hyperplasia. Discontinue if cardiovascular events occur or are suspected; if jaundice occurs; and during immobilization or at least 4–6 weeks before surgery associated with thromboembolism. Hepatic dysfunction.

Conditions aggravated by fluid retention.

Gallbladder disease. Bone disease associated with hypercalcemia. Hereditary angioedema.

Do initial complete physical and repeat annually (include BP, mammogram, PAP smear). Adolescents. Nursing mothers: not recommended.

Adverse reactions: See literature. Increased risk of cardiovascular events, estrogen-dependent carcinoma, gallbladder disease, thromboembolic disorders, hepatic tumors. GI upset, breakthrough bleeding, edema, weight changes, mastodynia, hypertension, depression, anaphylactic reactions, angioedema, intolerance to contact lenses.

How supplied: Tabs 0.3mg, 0.625mg, 1.25mg— 100, 1000; 0.45mg, 0.9mg—100

SOLTAMOX ORAL

SOLUTION DARA BioSciences

℞

Antiestrogen. Tamoxifen (as citrate) 10mg/5mL; licorice and aniseed flavors; sugar-free; contains alcohol.

Indications: Treatment of metastatic breast cancer in men and women. Axillary node-positive breast cancer in postmenopausal women after surgery + irradiation. Axillary node-negative breast cancer in women after surgery + irradiation. Reduction in risk of invasive breast cancer in women with ductal carcinoma in situ (DCIS) after surgery + radiation. Reduction in breast cancer incidence in high-risk women.

Adults: Treatment: 20–40mg/day; give doses >20mg in divided doses (AM and PM). Reduction of incidence in high-risk women or DCIS: 20mg once daily for 5 years.

Children: Not recommended.

Contraindications: For reduction in incidence in high-risk women and women with DCIS: concomitant coumarin anticoagulants, history of deep vein thrombosis or pulmonary embolism.

Warnings/Precautions: See literature. Do gynecological exam at least annually. DCIS and risk reduction: consider increased risk of uterine cancer (endometrial adenocarcinoma, uterine sarcoma), stroke and pulmonary embolism.

Women with advanced disease: discontinue if severe hypercalcemia occurs. Monitor blood, lipids, liver function, for thromboembolism symptoms (eg, leg swelling, unexplained shortness of breath), and for uterine changes/ cancer (eg, pelvic pain or pressure); promptly investigate any abnormal vaginal bleeding.

Breast cancer treatment: history of thromboembolic events. Pregnancy (Cat.D); avoid. Premenopausal: use effective nonhormonal contraception during and within 2 months of discontinuing therapy; begin therapy during menses or, if irregular menses, obtain (−) B-hCG pregnancy test first. Nursing mothers: not recommended.

Interactions: See Contraindications. May potentiate oral anticoagulants; if co-administered, monitor PT. Concomitant anastrozole: not recommended. Antagonizes letrozole. Plasma levels reduced by CYP3A4 inducers (eg, rifampin, aminoglutethimide). Cytotoxic drugs increase risk of thrombotic events. Potentiated by bromocriptine.

Adverse reactions: Hot flashes, vaginal discharge, altered menses, oligomenorrhea, nausea, cough, edema, fatigue, abdominal cramps, bone and tumor pain (in advanced disease), local disease flare, hypercalcemia, thrombotic events, ovarian cysts, uterine fibroids or cancer (endometrial adenocarcinoma, uterine sarcoma), endometrial or visual changes, liver abnormalities, hypertriglyceridemia, blood dyscrasias, hair loss.

How supplied: Soln—150mL

Tamoxifen (various)

℞

Antiestrogen. Tamoxifen (as citrate) 10mg, 20mg; tabs.

Indications: Treatment of metastatic breast cancer in men and women. Axillary node-positive breast cancer in postmenopausal women after surgery + irradiation. Axillary node-negative

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CancerTherapyAdvisor.com | SEPTEMBER/OCTOBER 2015 | CANCER THERAPY ADVISOR 19

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DRUG MONOGRAPHS

BREAST CANCER breast cancer in women after surgery + irradiation. Reduction in risk of invasive breast cancer in women with ductal carcinoma in situ (DCIS) after surgery + radiation. Reduction in breast cancer incidence in high-risk women.

Adults: Treatment: 20–40mg/day; give doses >20mg in divided doses (AM and PM). Reduction of incidence in high-risk women or DCIS: 20mg once daily for 5 years.

Children: McCune-Albright Syndrome, precocious puberty: see literature.

Contraindications: For risk reduction: concomitant coumarin anticoagulants, history of deep vein thrombosis or pulmonary embolism, planned pregnancy. Pregnancy (Cat.D). Nursing mothers.

Warnings/Precautions: See literature. Do gynecological exam at least annually. DCIS and risk reduction: consider increased risk of uterine cancer (endometrial adenocarcinoma, uterine sarcoma) and thrombotic events.

Women with advanced disease: discontinue if severe hypercalcemia occurs. Monitor blood, lipids, liver function, for thromboembolism symptoms (eg, leg swelling, unexplained shortness of breath), and for uterine changes/ cancer (eg, pelvic pain or pressure); promptly investigate any abnormal vaginal bleeding. Breast cancer treatment: history of thromboembolic events. Premenopausal: use effective nonhormonal contraception during and within 2 months of discontinuing therapy; begin therapy during menses or, if irregular menses, obtain (−) B-hCG pregnancy test first.

Interactions: May potentiate oral anticoagulants (see Contraindications). Antagonizes anastrozole (avoid concomitant use); letrozole. Plasma levels reduced by CYP3A4 inducers (eg, rifampin).

Cytotoxic drugs increase risk of thrombotic events. Potentiated by bromocriptine.

Adverse reactions: Hot flashes, vaginal discharge, altered menses, rash, headache, nausea, cough, edema, fatigue, abdominal cramps, bone and tumor pain (in advanced disease), local disease flare, hypercalcemia, thrombotic events, ovarian cysts, uterine fibroids or cancer (endometrial adenocarcinoma, uterine sarcoma), endometrial or visual changes, jaundice, hypertriglyceridemia, blood dyscrasias, hair loss.

How supplied: Contact supplier.

Adults: See literature.

Children: Not established.

Contraindications: Pregnancy (Cat.X). Nursing mothers.

Warnings/Precautions: Be fully familiar with this drug’s toxicity before use. Discontinue if malignant lymphomas occur. Obtain baseline and monitor CBCs with differential, platelet counts, chest X-ray, and hepatic, renal and pulmonary function. During therapy monitor hematology monthly, renal and hepatic function every 1–2 months, more often if increasing dose or predisposed to toxicity (eg, dehydration).

Discontinue immediately if blood counts drop significantly. Rule out pregnancy in women of childbearing potential; use effective contraception during therapy and for at least 1 ovulatory cycle afterwards for women and for at least 3 months afterwards for men. Interrupt therapy if vomiting, diarrhea, stomatitis, or pulmonary symptoms occur. Hepatic or renal impairment. Obesity. Diabetes. Peptic ulcer.

Ulcerative colitis. Infection. Dehydration. Folate deficiency. Ascites, pleural effusions: evacuate fluid, monitor for toxicity and reduce dose or discontinue if needed. Elderly (use low doses and monitor closely). Debilitated.

Interactions: Avoid live virus vaccines. Toxicity increased by NSAIDs, salicylates, phenytoin, sulfonylureas, sulfonamides, probenecid, folic acid antagonists. May be potentiated by penicillins (monitor), tetracyclines, chloramphenicol, non-absorbable broad spectrum antibiotics. May be antagonized by folic acid. May potentiate theophylline, mercaptopurine. Increased risk of soft tissue necrosis and osteonecrosis with radiotherapy.

Caution with other hepatotoxic drugs (eg, azathioprine, retinoids, sulfasalazine) and nephrotoxic agents (eg, cisplatin).

Adverse reactions: Ulcerative stomatitis, leukopenia, nausea, GI upset, malaise, fatigue, chills, fever, dizziness, infection, myelosuppression, hepatotoxicity, renal toxicity, CNS toxicity, seizures (esp in children); interstitial pneumonitis, tumor lysis syndrome, skin reactions (may be fatal; eg, toxic epidermal necrolysis, Stevens-Johnson syndrome).

How supplied: Tabs—30; soln (2mL, 4mL, 8mL, 10mL)—10 (single-use vials); pwd (1 gram)—1 (single-use vial)

TREXALL Teva

TYKERB GlaxoSmithKline

℞

Folic acid antagonist. Methotrexate sodium 5mg, 7.5mg, 10mg, 15mg; scored tabs. ℞ Also: Methotrexate injection Bedford Methotrexate 25mg/mL; soln for IV, IM, intraarterial, or intrathecal administration after dilution; preservative-free. ℞ Also: Methotrexate for injection Bedford Methotrexate 1g/vial; pwd for IV, IM, intra-arterial, or intrathecal administration after dilution; preservative-free.

Indications: Breast cancer.

℞

Tyrosine kinase inhibitor. Lapatinib 250mg; tabs.

Indications: In combination with capecitabine, for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 and who have received prior therapy including an anthracycline, a taxane, and trastuzumab. Limitation of use: patients should have disease progression on trastuzumab before initiating Tykerb in combination with capecitabine. In combination with letrozole for the treatment of postmenopausal women with

hormone receptor positive metastatic breast cancer that overexpresses HER2 for whom hormonal therapy is indicated.

Adults: Take 1hr before or 1hr after a meal (capecitabine should be taken with food or within 30mins after food). HER2 metastatic breast cancer: 1250mg (5 tabs) once daily on Days 1–21 continuously in combination with capecitabine 2000mg/m2/day (administered orally in 2 doses approx. 12hrs apart) on Days 1–14 in a repeating 21 day cycle; continue until disease progression or unacceptable toxicity occurs.

After recovery from left ventricular ejection fraction (LVEF) decrease: 1000mg/day. Severe hepatic dysfunction (Child-Pugh Class C): 750mg/day (no clinical data for this dose adjustment). Concomitant potent CYP3A4 inducers: may titrate up to 4500mg/day (no clinical data for this dose adjustment).

Hormone receptor positive, HER2 positive metastatic breast cancer: 1500mg (6 tabs) once daily continuously in combination with letrozole 2.5mg once daily. After recovery from LVEF decrease: 1250mg/day. Severe hepatic dysfunction: 1000mg/day (no clinical data for this dose adjustment). Concomitant potent CYP3A4 inducers: may titrate up to 5500mg/day (no clinical data for this dose adjustment). For both: Concomitant potent CYP3A4 inhibitors: 500mg/day (no clinical data for this dose adjustment). Interrupt if diarrhea is NCI CTC grade 3, or grade 1 or 2 with complicating features develop; may restart at lower dose (reduced from 1250mg/day to 1000mg/day or from 1500mg/day to 1250mg/day) when resolves ≤ grade 1; permanently discontinue if diarrhea is grade 4. Other toxicities: discontinue if ≥grade 2 NCI CTC toxicity occurs; may restart at 1250mg/day if toxicity improves to grade 1; if recurs, may restart at 1000mg/day (with capecitabine); 1250mg/day (w. letrozole).

Children: Not established.

Warnings/Precautions: Confirm normal LVEF before starting. Discontinue if ≥grade 2 decrease in LVEF occurs, or if LVEF falls below institution’s lower limit of normal; may restart after at least 2 weeks at reduced dose if asymptomatic and LVEF recovers. Conditions that impair left ventricular function, or risk factors for QT prolongation (eg, hypokalemia, hypomagnesemia, congenital long QT syndrome, concomitant antiarrhythmics, cumulative high dose anthracyclines); correct electrolyte disturbances before starting. Monitor for interstitial lung disease or pneumonitis; discontinue if pulmonary symptoms ≥grade 3 (NCI CTCAE). Monitor liver function tests before, every 4–6 weeks during therapy and as indicated; discontinue if hepatotoxicity occurs; do not retreat. Severe hepatic impairment: consider dose reduction. Diarrhea: promptly treat with anti-diarrheal agents; if severe, may require fluids, electrolytes, antibiotics and therapy interruption/discontinuation. Monitor ECG.

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DRUG MONOGRAPHS

BREAST CANCER Pregnancy (Cat.D); avoid. Nursing mothers: not recommended.

Interactions: Avoid potent CYP3A4 inhibitors (eg, ketoconazole), grapefruit; reduce dose if unavoidable. Avoid potent CYP3A4 inducers (eg, carbamazepine); slowly titrate dose up if unavoidable. May affect drugs that are affected by p-glycoprotein, CYP2C8, CYP3A4.

Adverse reactions: Diarrhea (may be severe), nausea, vomiting, hand/foot syndrome, rash, fatigue; decreased LVEF, QT prolongation, interstitial lung disease, pneumonitis, hepatotoxicity (may be fatal).

Testing considerations: HER2 protein overexpression How supplied: Tabs—150

XELODA Genentech

℞

Fluoropyrimidine. Capecitabine (prodrug of 5-fluorouracil) 150mg, 500mg; tabs.

Indications: Metastatic breast cancer resistant to both paclitaxel and an anthracyclinecontaining chemotherapy regimen or resistant to paclitaxel when further anthracycline therapy is not indicated (eg, prior cumulative doses of 400mg/m2 of doxorubicin or its equivalents).

With docetaxel for metastatic breast cancer after failure of prior anthracycline-containing regimen.

Adults: See full labeling. Give cyclically (2 weeks on, 1 week off). Swallow whole. Take with water within 30 minutes after AM & PM meals. ≥18yrs: 1250mg/m2 twice daily. Combination therapy: give with docetaxel 75mg/m2 IV infused over 1 hour every 3 weeks. Interrupt, adjust dose, and/or treat symptoms if toxicity occurs (eg, hyperbilirubinemia, diarrhea, nausea, vomiting, hand-and-foot syndrome, stomatitis) (see full labeling); do not increase dose afterwards.

Renal impairment (CrCl 51–80mL/min): monitor carefully; (CrCl 30–50mL/min): reduce capecitabine dose to 75% of starting dose (ie, 950mg/m2 twice daily).

Children: <18yrs: not established.

Contraindications: Severe renal impairment (CrCl <30mL/min).

Warnings/Precautions: Hepatic or renal dysfunction. Monitor and correct dehydration at initiation. Coronary artery disease. Interrupt therapy if severe diarrhea occurs; give antidiarrheals until resolves or reduces to Grade 1. Dihydropyrimidine dehydrogenase deficiency.

Elderly. Pregnancy (Cat.D), nursing mothers: not recommended.

Interactions: Increased anticoagulant effect with warfarin; monitor PT/INR frequently.

Potentiated by leucovorin. Monitor phenytoin and other CYP2C9 substrates.

Adverse reactions: Diarrhea, hand-andfoot syndrome, nausea, vomiting, abdominal pain, fatigue/weakness, hyperbilirubinemia; lymphopenia, necrotizing enterocolitis, stomatitis, dermatitis, anorexia, cardiotoxicity, blood dyscrasias, paresthesias, eye irritation, edema, myalgia, dehydration, alopecia; severe mucocutaneous reactions (eg, SJS, TEN); permanently discontinue if occurs.

Testing considerations: TS (thymidylate synthase), MSI (microsatellite instability), DPD (dihydropyrimidine dehydrogenase) How supplied: Tabs 150mg—60; 500mg—120

DOSAGE Recommended adult dosage and, where appropriate, the dosage for children. Doses are given for children <12 years of age unless stated otherwise.

Assume the adult dosage for children ≥12 years. Dosages for children are presented in ascending age order.

FDA PREGNANCY CATEGORIES When pregnancy appears as a contraindication or precaution to the use of a drug, it is usually qualified by a category as assigned by the FDA.

A: Adequate and well-controlled studies in pregnant women have failed to show a risk to the fetus in the first trimester of pregnancy and there is no evidence of risk in later trimesters.

B: Animal studies have failed to show a risk to the fetus and there are no adequate and wellcontrolled studies in pregnant women; or animal studies have shown an adverse effect but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus during the first trimester of pregnancy and there is no evidence of a risk in later trimesters.

C: Animal studies have shown an adverse effect on the fetus, there are no adequate and well-controlled studies in humans, and the potential benefits may outweigh the risks; or there are no animal studies and no adequate and well-controlled studies in humans.

D: Positive evidence of human fetal risk but the benefits may outweigh the risks.

X: Animal or human studies have shown fetal abnormalities or toxicity, or both, and the risks clearly outweigh any possible benefits.

Visit OncologyNurseAdvisor.com for practical clinical information geared toward oncology nurses and other cancer care professionals.

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DRUG MONOGRAPHS

ENDOCRINE CANCER ABRAXANE Celgene

℞

Taxane antimicrotubule. Paclitaxel [bound to albumin (human)] 100mg/vial; pwd for IV infusion after reconstitution; solvent-free.

Indications: First-line treatment of metastatic adenocarcinoma of the pancreas, in combination with gemcitabine.

Adults: Do not treat if neutrophil count <1,500 cells/mm3 or platelets <100,000 cells/mm3.

125mg/m2 IV over 30–40 mins on Days 1, 8, and 15 of each 28-day cycle. Moderate to severe hepatic impairment (total bilirubin >1.5): not recommended. Dose reductions for hematologic and neurologic adverse reactions: see full labeling. Avoid extravasation.

Children: Not evaluated.

Contraindications: Baseline neutrophil count <1,500 cells/mm3. Prior severe hypersensitivity reaction (do not rechallenge).

Warnings/Precautions: Do not substitute for, or with, other paclitaxel products (due to formulation differences). Do frequent complete blood cell counts. Hepatic impairment (total bilirubin >5 × ULN or AST >10 × ULN): not recommended. Monitor for sensory neuropathy, sepsis, or pneumonitis.

Renal dysfunction. Contains human albumin; remote risk of viral transmission. Use appropriate contraception (men and women). Pregnancy (Cat.D), nursing mothers: not recommended.

Interactions: May potentiate or be potentiated

by CYP2C8 and/or CYP3A4 inducers (eg, rifampin, carbamazepine, phenytoin, efavirenz, nevirapine) and/or inhibitors (eg, ketoconazole, other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir, nelfinavir).

Adverse reactions: Bone marrow suppression (eg, neutropenia, anemia), infections, alopecia, sensory neuropathy (may require dose reduction or interruption), peripheral neuropathy, GI upset, mucositis, fatigue/asthenia, myalgia/arthralgia, abnormal ECG; alkaline phosphatase or AST elevation; dyspnea, edema, hypotension, rash (may be serious); rare: thrombotic events.

How supplied: Single-use vial—1

AFINITOR Novartis

℞

mTOR kinase inhibitor. Everolimus 2.5mg, 5mg, 7.5mg, 10mg; tabs.

Indications: Progressive neuroendocrine tumors of pancreatic origin (PNET) in adults with unresectable, locally advanced or metastatic disease. Not for treating functional carcinoid tumors.

Adults: Swallow tabs whole with water. Take at the same time each day either consistently with or without food. 10mg once daily. Mild hepatic impairment (Child-Pugh class A): 7.5mg daily, may reduce to 5mg if not tolerated. Moderate hepatic impairment (Child-Pugh class B): 5mg daily, may be reduce to 2.5mg if not tolerated. Severe hepatic impairment (Child-Pugh class C): max 2.5mg daily if benefits outweigh risk. Concomitant moderate CYP3A4/PgP inhibitors: reduce to 2.5mg once daily; may consider increasing to 5mg if tolerated. If

moderate inhibitor is discontinued, allow 2–3 days washout period before increasing everolimus dose; return to dose used prior to initiating the moderate inhibitor. Concomitant strong CYP3A4/PgP inducers: consider doubling the daily dose by increments of 5mg or less. If strong inducer is discontinued, consider washout period of 3–5 days before returning to the dose used prior to initiating the strong inducer. Continue therapy until disease progression or unacceptable toxicity occurs. Dose modifications for adverse reactions, or others: see full labeling.

Children: Not recommended.

Contraindications: Allergy to other rapamycin derivatives.

Warnings/Precautions: Monitor for new or worsening respiratory symptoms. Increased risk of infections; some may be severe or fatal; monitor and treat promptly if occur. Pre-existing invasive fungal infections: treat before starting. Monitor for signs of wound-related complications. Peri-surgical period.

Hepatic impairment (see Adult dose). Monitor CBCs, renal function, lipids, and blood glucose prior to starting and periodically thereafter. Avoid close contact with those who have received live vaccines.

Pediatrics: complete childhood vaccination series according to ACIP guidelines prior to initiation.

Elderly. Women of childbearing potential should use effective method of contraception during and up to 8 weeks after treatment. Pregnancy (Cat.D), nursing mothers: not recommended.

Interactions: Avoid live vaccines. Potentiated by strong CYP3A4/PgP inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole), grapefruit or grapefruit juice; avoid. Caution with moderate CYP3A4/ PgP inhibitors (eg, amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem); reduce everolimus dose if used.

Antagonized by strong CYP3A4/PgP inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital), St. John’s Wort; avoid.

Adverse reactions: Pneumonitis (interrupt, reduce dose and/or manage with corticosteroids; if severe, discontinue; may reintroduce daily dose at approx.

50% lower than previously administered), infections (discontinue if invasive systemic fungal infection develops), stomatitis (treat with non-alcoholic, non-peroxide mouthwash), diarrhea, nausea, abdominal pain, rash, fatigue, edema, fever, asthenia, cough, headache, decreased appetite; increased serum creatinine, blood glucose, lipids; decreased hemoglobin, platelets, neutrophils, serum phosphate; proteinuria, renal failure, others (see full labeling).

How supplied: Tabs—28 (4 blister cards × 7 tabs)

CAPRELSA AstraZeneca

℞

Kinase inhibitor. Vandetanib 100mg, 300mg, tabs.

Indications: Symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease.

Adults: Do not crush tabs. May disperse tabs in 2oz noncarbonated water for oral or NGT administration; avoid contact of dispersion with skin, mucous membranes. 300mg once daily.

Renal impairment (CrCl<50mL/min): initially 200mg once daily. Dose adjustments for adverse reactions: see full labeling. Do not take a missed dose within 12hrs of the next dose.

Children: Not established.

Contraindications: Congenital long QT syndrome.

Warnings/Precautions: Hypocalcemia, hypokalemia, hypomagnesemia, QTcF interval >450msec, history of torsades de pointes, bradyarrhythmias, uncompensated heart failure, recent hemoptysis: not recommended. Ventricular arrhythmias. Recent MI. Monitor electrolytes (esp.

K+, Ca++, Mg++), TSH, and ECG for QT prolongation at baseline, 2–4 weeks and 8–12 weeks after starting, then every 3 months, and after dose reductions or dose interruptions >2 weeks; reduce dose as needed.

Correct electrolyte disturbances before starting.

Maintain serum K+ at least 4mEq/mL. Hepatic impairment (Child-Pugh B or C): not recommended.

Interrupt therapy and follow-up if acute or worsening pulmonary symptoms, QTcF >500msec, or CTCAE Grade ≥3 toxicity occurs. Monitor for heart failure; consider discontinuing if occurs. Discontinue if confirmed interstitial lung disease, severe ischemic cerebrovascular event, hemorrhage, uncontrolled hypertension, or posterior leukoencephalopathy symptoms (RPLS) occur. Avoid sun, UV light.

Elderly. Pregnancy (Cat.D) (may cause fetal harm; use appropriate effective contraception during and for 4 months after stopping therapy), nursing mothers: not recommended.

Interactions: Avoid strong CYP3A4 inducers (eg, rifampicin, St. John’s Wort). Avoid other drugs that can prolong QT interval (eg, amiodarone, disopyramide, procainamide, sotalol, dofetilide, chloroquine, clarithromycin, dolasetron, granisetron, haloperidol, pimozide, methadone, moxifloxacin). Potentiates OCT2 transporters (eg, metformin), digoxin; monitor.

Adverse reactions: Diarrhea/colitis (suspend if severe), rash, acneiform dermatitis, nausea, hypertension, headache, upper respiratory tract infections, decreased appetite, abdominal pain, hypocalcemia, hypoglycemia, increased ALT; QT prolongation, torsades de pointes, sudden death, severe skin reactions (eg, Stevens-Johnson syndrome; discontinue if occurs).

Note: Prescribers and pharmacies must enroll in the Caprelsa REMS program by calling (800) 2369933 or visit www.caprelsarems.com.

How supplied: Tabs—30

COMETRIQ Exelixis

℞

Kinase inhibitor. Cabozantinib 20mg, 80mg; caps.

Indications: Treatment of progressive, metastatic medullary thyroid cancer (MTC).

Adults: Swallow whole. 140mg daily. Do not eat at least 2 hours before or 1 hour after dose. Continue until disease progression or unacceptable toxicity.

Withhold for Grade 4 hematologic adverse reactions, ≥Grade 3 non-hematologic reactions or intolerable Grade 2 reactions. Upon improvement to Grade 1 or to baseline, reduce dose as follows: previously on 140mg daily, resume at 100mg daily; previously on 100mg daily, resume at 60mg daily; previously on

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DRUG MONOGRAPHS

ENDOCRINE CANCER 60mg daily, resume at 60mg if tolerated, otherwise discontinue. Concomitant strong CYP3A4 inhibitor: reduce daily dose by 40mg; resume dose used prior to starting inhibitor 2–3 days after discontinuation of inhibitor. Concomitant strong CYP3A4 inducers: increase daily dose by 40mg; resume dose used prior to starting inducer 2–3 days after discontinuation of inducer. Max daily dose: 180mg.

Children: Not studied.

Warnings/Precautions: Permanently discontinue if the following occurs: GI or non-GI perforation/fistula formation, severe hemorrhage, serious arterial thromboembolic events (eg, MI, cerebral infarction), nephrotic syndrome, malignant hypertension, hypertensive crisis, persistent uncontrolled hypertension despite optimal medical management, osteonecrosis of the jaw, reversible posterior leukoencephalopathy syndrome. Moderate to severe hepatic impairment: not recommended. Recent history of hemorrhage, hemoptysis: avoid. Stop treatment at least 28 days prior to scheduled surgery (including invasive dental procedures); withhold dose if dehiscence or wound healing complications require medical intervention. Monitor for bleeding, hypertension, proteinuria (measure urine protein regularly).

Use effective contraception during and up to 4 months after completion of therapy. Pregnancy (Cat.D). Nursing mothers: not recommended.

Interactions: Avoid concomitant strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole, grapefruit or grapefruit juice) and strong CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, St. John’s Wort): see Adult dose.

Adverse reactions: Diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome, decreased weight/appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, constipation, increased AST, ALT, alkaline phosphatase, lymphopenia, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, hyperbilirubinemia.

How supplied: 140mg daily-dose carton—4 blister cards (each: 7×80mg and 21×20mg caps); 100mg daily-dose carton—4 blister cards (each: 7×80mg and 7×20mg caps); 60mg daily-dose carton—4 blister cards (each: 21×20mg caps)

Fluorouracil (various)

℞

Antimetabolite. Fluorouracil 50mg/mL; soln for IV inj.

Indications: Palliative management of carcinoma of the pancreas.

Adults: Give by IV inj. 12mg/kg once daily for 4 successive days; max 800mg/day. If no toxicity is observed, 6mg/kg are given on the 6th, 8th, 10th,

and 12th days unless toxicity occurs. Maintenance therapy: repeat dosage of 1st course every 30 days after the last day of the previous course of treatment; or give a maintenance dose of 10–15mg/kg per week as a single dose; max: 1g/week. Poor risk patients: see literature for dose adjustments.

Children: Not recommended.

Contraindications: Poor nutritional state.

Depressed bone marrow function. Potentially serious infections.

Warnings/Precautions: Narrow margin of safety; monitor for toxicity. Consider hospitalization for 1st course. History of highdose pelvic irradiation. Previous use of alkylating agents. Widespread involvement of bone marrow by metastatic tumors. Renal or hepatic impairment. Discontinue if signs of toxicity appear (eg, stomatitis, esophagopharyngitis, leukopenia, intractable vomiting, diarrhea, GI ulceration or bleeding, thrombocytopenia, hemorrhage).

Monitor WBCs with differential before each dose.

Avoid extravasation. Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended.

Interactions: Potentiated by leucovorin.

Adverse reactions: Stomatitis, esophagopharyngitis, GI upset, anorexia, leukopenia, alopecia, dermatitis, hand-foot syndrome; others.

Testing considerations: TS (thymidylate synthase), MSI (microsatellite instability), DPD (dihydropyrimidine dehydrogenase).

How supplied: Contact supplier.

LENVIMA Eisai

℞

Kinase inhibitor. Lenvatinib 4mg, 10mg; capsules.

Indications: Treatment of locally recurrent or metastatic, progressive, radioactive iodinerefractory differentiated thyroid cancer.

Adults: 24mg once daily until disease progression or unacceptable toxicity occurs. Severe renal impairment (CrCl <30mL/min) or severe hepatic impairment (Child-Pugh C): 14mg once daily.

Dose modifications for adverse reactions or lab abnormalities: see full labeling.

Children: Not established.

Warnings/Precautions: Control blood pressure prior to treatment; monitor after 1 week, every 2 weeks for the first 2 months, and then at least monthly thereafter during therapy. Discontinue if life-threatening hypertension, Grade 4 cardiac dysfunction or hemorrhage, arterial thrombotic event, hepatic failure, nephrotic syndrome, GI perforation or life-threatening fistula, or severe and persistent neurologic symptoms occur. Withhold if Grade 3 hypertension persists despite therapy, Grade 3 cardiac dysfunction or hemorrhage, ≥Grade 3 liver impairment or QT prolongation, Grade 3 or 4 renal failure/impairment, ≥2g of proteinuria/24hrs, or reversible posterior leukoencephalopathy syndrome

(RPLS) occurs. Monitor for signs/symptoms of cardiac decompensation. Monitor liver function prior to treatment, every 2 weeks for the first 2 months, then at least monthly during treatment. Monitor for proteinuria prior to, and periodically during treatment. Dehydration. Hypovolemia. Congenital long QT syndrome, CHF, bradyarrhythmias, or those taking Class Ia or III antiarrhythmic drugs; monitor ECGs. Monitor and correct electrolyte abnormalities. Monitor blood calcium levels at least monthly; replace as needed during treatment.

Monitor thyroid stimulating hormone levels monthly; adjust replacement therapy as needed. Pregnancy: avoid. Use effective contraception during treatment and for at least 2 weeks after treatment completion. Lactation: discontinue nursing.

Adverse reactions: Hypertension, fatigue, diarrhea, arthralgia/myalgia, decreased appetite, weight decreased, nausea, stomatitis, headache, vomiting, proteinuria, palmar-plantar erythrodysesthesia syndrome, abdominal pain, dysphonia.

How supplied: Blister cards—6

NEXAVAR Bayer and Onyx

℞

Multikinase inhibitor. Sorafenib 200mg; tabs.

Indications: Locally recurrent or metastatic, progressive, differentiated thyroid carcinoma refractory to radioactive iodine treatment.

Adults: Take on an empty stomach. 400mg twice daily. If toxicity occurs, may reduce dose to 400mg and 200mg 12hrs apart (either dose can come first); if second reduction is required, may reduce dose to 200mg twice daily; if third reduction is required, may reduce to 200mg once daily (see full labeling). Concomitant strong CYP3A4 inducers: consider increasing dose, monitor for toxicity.

Children: Not established.

Contraindications: Concomitant carboplatin/ paclitaxel in patients with squamous cell lung cancer.

Warnings/Precautions: Avoid in congenital long QT syndrome. Monitor patients with CHF, bradyarrhythmias, drugs known to prolong the QT interval, electrolyte abnormalities. Discontinue if severe dermatologic toxicity, hypertension, GI perforation, hemorrhage, cardiac ischemia, MI occurs. Suspend therapy before major surgery.

Monitor BP weekly during the first 6 weeks and thereafter. Monitor hepatic function regularly; discontinue if transaminases significantly elevated.

Severe hepatic impairment (Child-Pugh C) or on dialysis. Monitor TSH levels monthly and adjust thyroid therapy. Use effective contraception during and for 2 weeks after stopping treatment. Pregnancy (Cat.D), nursing mothers: not recommended.

Interactions: See Contraindications. Avoid strong CYP3A4 inducers (eg, St. John’s Wort, dexamethasone, phenytoin, carbamazepine, rifabutin, rifampin, phenobarbital) and neomycin; may

Access Cancer Therapy Advisor treatment regimens in a user-friendly format.

CancerTherapyAdvisor.com/TreatmentRegimens.

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DRUG MONOGRAPHS

ENDOCRINE CANCER decrease sorafenib levels. May potentiate warfarin (monitor PT & INR), other drugs metabolized by UGT1A1 or UGT1A9 pathway, or substrates of CYP2B6, CYP2C8, CYP2C9, P-gp. Concomitant Class Ia and III antiarrhythmics; may prolong QT interval.

Adverse reactions: Dermatologic toxicity (eg, rash, hand-foot skin reaction, alopecia, pruritus, dry skin, Stevens-Johnson syndrome, toxic epidermal necrolysis), fatigue, weight loss, diarrhea, anorexia, abdominal pain, hypertension, hemorrhage, electrolyte abnormalities; druginduced hepatitis, QT prolongation.

How supplied: Tabs—120

SOMATULINE DEPOT Ipsen

℞

Somatostatin analogue. Lanreotide 60mg, 90mg, 120mg; prolonged-release soln for SC inj.

Indications: Treatment of unresectable, well- or moderately-differentiated, locally advanced or metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs) to improve progression-free survival.

Adults: Give by deep SC inj into the superior external quadrant of the buttock. Rotate inj site.

120mg every 4 weeks.

Children: Not established.

Warnings/Precautions: Diabetes.

Hypothyroidism. Cardiovascular disease. Hepatic or severe renal impairment. Monitor thyroid function, gallbladder, glucose. Pregnancy (Cat.C).

Nursing mothers: not recommended.

Interactions: Potentiates bromocriptine, CYP450 substrates (eg, quinidine, terfenadine), bradycardia-inducing drugs (eg, β-blockers); adjust doses. Antagonizes cyclosporine; adjust dose. May need to adjust antidiabetic agents.

Adverse reactions: Diarrhea, cholelithiasis, abdominal pain, nausea, inj site reactions; gallbladder sludge, gallstones, hyperglycemia, hypoglycemia, sinus bradycardia, hypertension, anemia; rare: hypothyroidism.

How supplied: Single-use pre-filled syringe—1

SUTENT Pfizer

℞

Multikinase inhibitor. Sunitinib (as malate) 12.5mg, 25mg, 37.5mg, 50mg; gelatin caps.

Indications: Progressive, well-differentiated pancreatic neuroendocrine tumors (pNET) in patients with unresectable locally advanced or metastatic disease.

Adults: 37.5mg once daily continuously without a scheduled off-treatment period. May adjust dose in increments or decrements of 12.5mg.

Concomitant strong CYP3A4 inhibitors (see Interactions): may reduce dose to 25mg daily.

Concomitant strong CYP3A4 inducers (see Interactions): may increase to max 62.5mg daily.

Children: Not established.

Warnings/Precautions: Hepatotoxicity; may be severe or fatal. Monitor liver function tests before starting, during each cycle of treatment and as clinically needed; interrupt if Grade 3 or 4 hepatic adverse events occur and discontinue if no resolution; if severe liver function changes or signs/

symptoms of failure, do not restart. Cardiovascular events: monitor for CHF during therapy, and LVEF at baseline and periodically; interrupt or reduce dose if LVEF <50% and >20% below baseline; discontinue if CHF occurs. History of QT prolongation or proarrythmic conditions (eg, bradycardia, electrolyte disturbances); perform periodic ECG, monitor electrolytes. Monitor BP. Suspend therapy if severe hypertension, seizures, or pancreatitis develops. Obtain CBCs, platelets, serum chemistries at start of each cycle. Concomitant exposure to risk factors (eg, IV bisphosphonates therapy or dental disease) may increase the risk of osteonecrosis of the jaw; avoid or consider preventive dentistry prior to treatment. Risk of tumor lysis syndrome: monitor closely in RCC and GIST patients with high tumor burden. Monitor for thyroid dysfunction; obtain baseline levels prior to treatment. Monitor blood glucose levels during and after treatment discontinuation. Monitor for proteinuria; perform baseline and periodic urinalyses; interrupt and reduce dose if 24-hr urine protein ≥3g; discontinue if nephrotic syndrome or repeat urine protein ≥3g persists. Undergoing major surgery. Stress (monitor for adrenal insufficiency).

Discontinue if severe cutaneous reactions (eg, erythema multiforme, SJS, TEN) develop; do not restart if diagnosis suspected. ESRD on dialysis.

Severe hepatic impairment. Pregnancy (Cat.D; avoid). Nursing mothers: not recommended.

Interactions: May be potentiated by strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole), grapefruit; consider reducing dose or use alternate drug. May be antagonized by CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital); consider increasing dose or use alternate drug. Concomitant St. John’s wort: not recommended. Caution with concomitant antiarrhythmics.

Adverse reactions: Fatigue, asthenia, fever, diarrhea, nausea, vomiting, mucositis/stomatitis, dyspepsia, abdominal pain, constipation, hypertension, peripheral edema, rash, handfoot syndrome, skin discoloration, dry skin, hair color changes, altered taste, headache, back pain, arthralgia, extremity pain, cough, dyspnea, anorexia, bleeding; hepatotoxicity, left ventricular dysfunction, QT prolongation, osteonecrosis of the jaw, tumor lysis syndrome, thyroid dysfunction, impaired wound healing, hypoglycemia, thrombotic microangiopathy (discontinue if develops), proteinuria, necrotizing fasciitis (discontinue if occurs), others (see full labeling).

How supplied: Caps—28

TARCEVA Astellas and Genentech

℞

Kinase inhibitor. Erlotinib (as HCl) 25mg, 100mg, 150mg; tabs.

Indications: In combination with gemcitabine: first-line treatment of locally advanced, unresectable or metastatic pancreatic cancer.

Adults: Take on empty stomach. 100mg once daily + gemcitabine (see full labeling). Use until disease progression or unacceptable toxicity occurs. Diarrhea unresponsive to loperamide, severe skin reactions, strong CYP3A4 inhibitors (see Interactions), hepatic impairment: reduce in 50mg decrements.

Concomitant CYP3A4 inducers (see Interactions): increase in 50mg increments at 2-week intervals; max 450mg (see full labeling). Concurrent cigarette smoking: increase in 50mg increments at 2-week intervals; max 300mg (see full labeling); upon cessation, reduce to 150mg or 100mg daily.

Children: Not established.

Warnings/Precautions: Discontinue if interstitial lung disease, severe hepatic toxicity, GI perforation, severe bullous, blistering or exfoliating skin conditions, or corneal perforation or severe ulceration occurs. Withhold or consider discontinuing therapy if severe renal failure due to dehydration, or acute/worsening ocular disorders occur. Monitor LFTs periodically; withhold in patients without history of hepatic impairment for total bilirubin >3×ULN or transaminases >5×ULN, or in patients with history of hepatic impairment or biliary obstruction for doubling of bilirubin or tripling of transaminases over baseline. Discontinue if abnormal LFTs do not improve or resolve within 3 weeks. Withhold for persistent severe diarrhea unresponsive to loperamide, severe rash, or grade 3–4 keratitis. Monitor renal function, serum electrolytes, pulmonary function, INR, prothrombin time. History of peptic ulcers or diverticular disease.

Pregnancy (Cat.D); use effective contraception during therapy and at least 2 weeks after the last dose. Nursing mothers: not recommended.

Interactions: Potentiated by CYP3A4 inhibitors (eg, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, voriconazole, grapefruit) and CYP1A2 inhibitors (eg, ciprofloxacin); avoid if possible. Plasma levels decreased by CYP3A4 inducers (eg, rifampin, rifabutin, rifapentine, phenytoin, carbamazepine, phenobarbital, St. John’s wort), proton pump inhibitors or H2 blockers (take erlotinib 10hrs after and at least 2hrs before next dose), and smoking; avoid if possible. Increased risk of GI perforation with concomitant anti-angiogenic agents, steroids, NSAIDs, taxane-based chemotherapy. Monitor for bleeding with oral anticoagulants, NSAIDs. Adverse reactions: Rash, diarrhea, nausea, vomiting, anorexia, fatigue, elevated LFTs, unexplained pulmonary symptoms (eg, dyspnea, cough, fever; discontinue and follow-up if occurs), stomatitis, infection; rare: GI perforation (may be fatal), ocular disorders (eg, conjunctivitis, keratitis, corneal ulceration/perforation), MI/ischemia, hemolytic anemia, cerebrovascular accidents, interstitial lung disease; hepatic or renal failure and hepatorenal syndrome (may be fatal); bullous, blistering and exfoliative skin conditions (eg, StevensJohnson syndrome, toxic epidermal necrolysis).

Testing considerations: K-RAS mutation analysis, EGFR amplification analysis How supplied: Tabs—30

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GASTROINTESTINAL CANCER Gastric Cancer Treatment Regimens Clinical Trials: The NCCN recommends cancer patient participation in clinical trials as the gold standard for treatment.

Cancer therapy selection, dosing, administration, and the management of related adverse events can be a complex process that should be handled by an experienced healthcare team. Clinicians must choose and verify treatment options based on the individual patient; drug dose modifications and supportive care interventions should be administered accordingly. The cancer treatment regimens below may include both U.S. Food and Drug Administration-approved and unapproved indications/regimens. These regimens are only provided to supplement the latest treatment strategies.

These Guidelines are a work in progress that may be refined as often as new significant data becomes available. The NCCN Guidelines® are a consensus statement of its authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult any NCCN Guidelines® is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way.

Principles of Systemic Therapy1 Chemotherapy regimens should be chosen in the context of performance status, medical comorbidities, toxicity profile, and HER2-neu expression (for adenocarcinoma only). Two-drug cytotoxic regimens are preferred for patients with advanced disease because of lower toxicity. Three-drug cytotoxic regimens should be reserved for medically fit patients with good performance status and access to frequent toxicity evaluation. Doses and schedules for any regimen that is not derived from category 1 evidence is a suggestion, and subject to appropriate modifications depending on the circumstances. Infusional fluorouracil and capecitabine may be used interchangeably (except as indicated). Cisplatin and oxaliplatin may be used interchangeably depending on toxicity profile.

Preoperative Chemoradiation (esophagogastric junction and gastric cardia)1 Note: All recommendations are Category 2A unless otherwise indicated.

REGIMEN

DOSING

Preferred Regimens Paclitaxel + carboplatin (Category 1)2

Day 1: Paclitaxel 50mg/m2 IV + carboplatin AUC 2mg/mL × min IV. Repeat weekly for 5 weeks.

Cisplatin + 5-fluorouracil (5-FU) (Category 1)3,4

Days 1 and 29: Cisplatin 75–100mg/m2 IV. Days 1–4 and 29–32: 5-FU 750–1000mg/m2 IV continuous infusion over 24 hours.

OR Days 1–5: Cisplatin 15mg/m2 IV once daily plus 5-FU 800mg/m2 IV continuous infusion over 24 hours daily.

Repeat cycle every 21 days for 2 cycles.

Oxaliplatin + 5-FU (Category 1)5,6

Days 1, 15, and 29: Oxaliplatin 85mg/m2 IV. Days 1–33: 5-FU 180mg/m2 IV. OR Day 1: Oxaliplatin 85mg/m2 and leucovorin 400mg/m2 followed by 5-FU 400mg/m2 bolus, then 800mg/m2 24-hour continuous infusion over days 1 and 2; the first 3 cycles were delivered during radiotherapy (RT), the other 3 after RT; 6 bimonthly (14 days) cycles.

Cisplatin + capecitabine7

Day 1: Cisplatin 30mg/m2 IV. Days 1–5: Capecitabine 800mg/m2 orally twice daily.

Repeat cycle weekly for 5 weeks.

Oxaliplatin + capecitabine8

Days 1, 15, and 29: Oxaliplatin 85mg/m2 IV. Days 1–5: Capecitabine 625mg/m2 orally twice daily for 5 weeks.

Other Regimens Irinotecan + cisplatin (Category 2B)9 Paclitaxel + 5-FU (Category 2B)10

Paclitaxel + capecitabine (Category 2B)10

Days 1, 8, 22, 29: Irinotecan 65mg/m2 IV plus cisplatin 30mg/m2 IV. Day 1: Paclitaxel 45–50mg/m2 IV weekly.

Days 1–5: 5-FU 300mg/m2 IV continuous infusion.

Weekly for 5 weeks.

Day 1: Paclitaxel 45–50mg/m2 IV. Days 1–5: Capecitabine 625-825mg/m2 orally BID. Weekly for 5 weeks. continued

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GASTROINTESTINAL CANCER Gastric Cancer Treatment Regimens Perioperative Chemotherapy (including esophagogastric junction)1 REGIMEN

DOSING

Epirubicin + cisplatin + 5-FU (ECF) (Category 1)11

Day 1: Epirubicin 50mg/m2 IV bolus + cisplatin 60mg/m2 IV. Days 1–21: 5-FU 200mg/m2 IV continuous infusion over 24 hours daily.

Repeat cycle every 21 days for 3 cycles preoperatively and 3 cycles postoperatively.

ECF modification: epirubicin + oxaliplatin + 5-FU12

Day 1: Epirubicin 50mg/m2 IV; oxaliplatin 130mg/m2 IV. Days 1–21: 5-FU 200mg/m2 IV continuous infusion over 24 hours.

Repeat cycle every 21 days for 3 cycles preoperatively and 3 cycles postoperatively.

ECF modification: epirubicin + cisplatin + capecitabine12

Day 1: Epirubicin 50mg/m2 IV; cisplatin 60mg/m2 IV. Days 1–21: Capecitabine 625mg/m2 orally twice daily.

Repeat cycle every 21 days for 3 cycles preoperatively and 3 cycles postoperatively.

ECF modification: epirubicin + oxaliplatin + capecitabine12

Day 1: Epirubicin 50mg/m2 IV; oxaliplatin 130mg/m2 IV. Days 1–21: Capecitabine 625mg/m2 orally twice daily.

Repeat cycle every 21 days for 3 cycles preoperatively and 3 cycles postoperatively.

5-FU + cisplatin (Category 1)13

Day 1: Cisplatin 75–80mg/m2 IV. Days 1–5: 5-FU 800mg/m2 IV continuous infusion over 24 hours daily.

Repeat cycle every 28 days for 2–3 cycles preoperatively and 3–4 cyclespostoperatively for a total of 6 cycles.

Postoperative Chemoradiation (including esophagogastric junction)1 5-FU + leucovorin14

Cycles 1, 3, and 4 (before and after radiation) Days 1–5: Leucovorin 20mg/m2 IVP plus 5-FU 425mg/m2/day IVP. Repeat cycle every 28 days.

Cycle 2 (with radiation) Days 1–4 and 31–33: Leucovorin 20mg/m2 IVP. Days 1–4: 5-FU 400mg/m2/day IVP. Repeat cycle every 35 days.

The NCCN panel acknowledges that the Intergroup 0116 Trial formed the basis for postoperative adjuvant chemoradiation strategy. However, the panel does not recommend the above specified doses or schedule of cytotoxic agents because of concerns regarding toxicity. The panel recommends one of the following modifications instead.

Capecitabine15

Days 1–14: Capecitabine 750–1000mg/m2 orally twice daily.

Repeat cycle every 28 days; 1 cycle before and 2 cycles after chemoradiation.

5-FU + leucovorin16

Days 1, 2, 15, and 16: Leucovorin 400mg/m2 IV followed by 5-FU 400mg/m2 IVP and a 24-hour infusion of 5-FU 1200mg/m2; 1 cycle before and 2 cycles after chemoradiation.

Repeat cycle every 28 days.

5-FU with radiation17

Days 1–5 OR Days 1–7: 5-FU 200–250mg/m2 IV continuous infusion over 24 hours once daily; weekly for 5 weeks.

Capecitabine with radiation18

Days 1–5 OR Days 1–7: Capecitabine 625–825mg/m2 orally twice daily; weekly for 5 weeks.

Postoperative Chemotherapy Capecitabine + oxaliplatin19

Days 1–14: Capecitabine 1000mg/m2 orally twice daily.

Day 1: Oxaliplatin 130mg/m2 IV. Repeat cycle every 21 days for 8 cycles.

Capecitabine + cisplatin20

Days 1–14: Capecitabine 1000mg/m2 orally twice daily.

Day 1: Cisplatin 60mg/m2 IV. Repeat cycle every 21 days for 6 cycles.

Metastatic or Locally Advanced Cancer (where local therapy is not indicated)1 First-line Therapy Trastuzumab + chemotherapy (NOTE: for HER2-neu overexpressing adenocarcinoma)21

Day 1: Trastuzumab 8mg/kg IV loading dose (Cycle 1 only); followed by trastuzumab 6mg/kg IV every 3 weeks, plus chemotherapy.

OR Day 1 of Cycle 1: Trastuzumab 6mg/kg IV loading dose, then 4mg/kg IV every 14 days.

Chemotherapy: Day 1: Cisplatin 80mg/m2 IV, plus Days 1–14: Capecitabine 1000mg/m2 orally twice daily. (Category 1).

OR Days 1–5: 5-FU 800mg/m2 continuous IV infusion.

Repeat cycle every 21 days for 6 cycles.

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GASTROINTESTINAL CANCER Metastatic or Locally Advanced Cancer (where local therapy is not indicated)1 (continued) REGIMEN

DOSING

First-line Therapy (continued) Docetaxel + cisplatin + 5-FU (DCF) (Category 1)22

Day 1: Docetaxel 75mg/m2 IV + cisplatin 75mg/m2 IV. Days 1–5: 5-FU 1,000mg/m2 IV continuous infusion over 24 hours, daily.

Repeat cycle every 28 days.

The panel does not recommend the above specified doses or schedule of cytotoxic agents because of concerns regarding toxicity.

Modified DCF (docetaxel + cisplatin + leucovorin + 5-FU)23

Day 1: Docetaxel 40mg/m2 IV plus leucovorin 400mg/m2 IV plus 5-FU 400mg/m2.

Days 1 and 2: 5-FU 1000mg/m2 IV continuous infusion over 24 hours.

Day 3: Cisplatin 40mg/m2 IV. Repeat cycle every 14 days.

Modified DCF (docetaxel + oxaliplatin + 5-FU)24

Day 1: Docetaxel 50mg/m2 IV plus oxaliplatin 85mg/m2.

Days 1 and 2: 5-FU 1,200mg/m2 IV continuous infusion over 24 hours.

Repeat cycle every 14 days.

Modified DCF (docetaxel + carboplatin + 5-FU) (Category 2B)25

Day 1: Docetaxel 75mg/m2.

Day 2: Carboplatin AUC 6mg/mL × min.

Days 1–3: 5-FU 1,200mg/m2 IV continuous infusion over 24 hours daily.

Repeat cycle every 21 days.

ECF (Category 1)26

Day 1: Epirubicin 50mg/m2 IV bolus + cisplatin 60mg/m2 IV. Days 1–21: 5-FU 200mg/m2 IV continuous infusion over 24 hours daily.

Repeat cycle every 21 days.

ECF modifications (epirubicin + oxaliplatin + 5-FU) (Category 1)27

Days 1: Epirubicin 50mg/m2 IV plus oxaliplatin 130mg/m2 IV. Days 1–21: 5-FU 200mg/m2 IV continuous infusion over 24 hours.

Repeat cycle every 21 days.

ECF modifications (epirubicin + cisplatin + capecitabine) (Category 1)27

Day 1: Epirubicin 50mg/m2 IV plus cisplatin 60mg/m2 IV. Days 1–21: Capecitabine 625mg/m2 orally twice daily.

Repeat cycle every 21 days.

ECF modifications (epirubicin + oxaliplatin + capecitabine) (Category 1)27

Day 1: Epirubicin 50mg/m2 IV plus oxaliplatin 130mg/m2 IV. Days 1–21: capecitabine 625mg/m2 IV orally twice daily.

Repeat cycle every 21 days.

Fluoropyrimidine and cisplatin (5-FU + cisplatin) (Category 1)33

Day 1: Cisplatin 75−100mg/m2 IV. Days 1–4: 5-FU 1,000mg/m2 IV continuous infusion over 24 hours daily.

Fluoropyrimidine and cisplatin (5-FU + cisplatin + leucovorin) (Category 1)28–31

Day 1: Cisplatin 50mg/m2 IV plus leucovorin 200mg/m2 IV plus 5-FU 2,000mg/m2 IV continuous infusion over 24 hours.

Repeat cycle every 14 days.

Fluoropyrimidine and cisplatin (capecitabine + cisplatin) (Category 1)28–31

Day 1: Cisplatin 80mg/m2 IV. Day 1–14: Capecitabine 1000mg/m2 orally twice daily.

Repeat cycle every 3 weeks.

Fluoropyrimidine and oxaliplatin (oxaliplatin + capecitabine)29,32,33

Day 1: Oxaliplatin 130mg/m2 IV. Days 1–14: Capecitabine 1000mg/m2 orally twice daily.

Repeat cycle every 21 days.

Fluoropyrimidine and oxaliplatin Day 1: Oxaliplatin 85mg/m2 IV plus leucovorin 400mg/m2 IV plus 5-FU 400mg/m2 IVP. (oxaliplatin + leucovorin + 5-FU)29,32,33 Days 1 and 2: 5-FU 1200mg/m2 IV continuous infusion over 24 hours daily.

Repeat cycle every 14 days.

OR Day 1: Oxaliplatin 85mg/m2 IV plus leucovorin 200mg/m2 IV plus 5-FU 2,600mg/m2 IV continuous infusion over 24 hours.

Repeat cycle every 14 days. continued

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GASTROINTESTINAL CANCER Gastric Cancer Treatment Regimens Metastatic or Locally Advanced Cancer (where local therapy is not indicated)1 (continued) REGIMEN

DOSING

Other Regimens Fluorouracil and irinotecan (irinotecan + leucovorin + 5-FU) (Category 1)34-36

Day 1: Irinotecan 80mg/m2 IV plus leucovorin 500mg/m2 IV plus 5-FU 2000mg/m2 IV continuous infusion over 24 hours.

Weekly for 6 weeks followed by 1 week off treatment Or weekly for 6 weeks followed by 2 weeks off treatment.

OR Day 1: Irinotecan 150mg/m2 IV plus leucovorin 20mg/m2 IV. Days 1–2: 5-FU 1000mg/m2 IV continuous infusion over 24 hours daily.

Repeat cycle every 14 days.

Paclitaxel + cisplatin or carboplatin37–39

Day 1: Paclitaxel 135–200mg/m2 IV. Day 2: Cisplatin 75mg/m2 IV. Repeat cycle every 21 days.

OR Day 1: Paclitaxel 90mg/m2 IV plus cisplatin 50mg/m2 IV. Repeat cycle every 14 days.

OR Day 1: Paclitaxel 200mg/m2 IV plus carboplatin AUC 5mg/mL × min.

Repeat cycle every 21 days.

Docetaxel + cisplatin40,41

Day 1: Docetaxel 70–85mg/m2 IV plus cisplatin 70–75mg/m2 IV. Repeat cycle every 21 days.

Docetaxel + irinotecan (Category 2B)42

Days 1 and 8: Docetaxel 35mg/m2 IV plus irinotecan 50mg/m2 IV. Repeat cycle every 21 days.

Fluoropyridimine32,43,44

Day 1: Leucovorin 400mg/m2 IV plus 5-FU 400mg/m2 IVP. Days 1 and 2: 5-FU 1200mg/m2 IV continuous infusion over 24 hours daily.

Repeat cycle every 14 days.

OR Days 1–5: 5-FU 800mg/m2 IV continuous infusion over 24 hours daily.

Repeat cycle every 28 days.

OR Days 1–14: Capecitabine 1000–1250mg/m2 orally twice daily.

Repeat cycle every 21 days.

Taxane45–48

Day 1: Docetaxel 75–100mg/m2 IV. Repeat cycle every 21 days.

OR Day 1: Paclitaxel 135–250mg/m2 IV. Repeat cycle every 21 days.

OR Days 1, 8, 15 and 22: Paclitaxel 80mg/m2 IV once weekly.

Repeat cycle every 28 days.

Second-line Therapy (preferred regimens) Ramucirumab (Category 1)49

Day 1: Ramucirumab 8mg/kg IV. Repeat cycle every 14 days.

Ramucirumab + paclitaxel (Category 1)50

Day 1 and 15: Ramucirumab 8mg/kg IV. Day 1, 8, and 15: Paclitaxel 80mg/m2.

Repeat cycle every 28 days.

Docetaxel (Category 1)49

Day 1: Docetaxel 75–100mg/m2 IV. Repeat cycle every 21 days.

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CANCER TREATMENT REGIMEN

GASTROINTESTINAL CANCER Metastatic or Locally Advanced Cancer (where local therapy is not indicated)1 (continued) REGIMEN

DOSING

Second-line Therapy (preferred regimens) (continued) Paclitaxel (Category 1)50-52

Day 1: Paclitaxel 135–250mg/m2 IV. Repeat cycle every 21 days.

OR Day 1: Paclitaxel 80mg/m2 IV once weekly.

Repeat cycle every 28 days.

OR Days 1, 8, and 15: Paclitaxel 80mg/m2 IV. Repeat cycle every 28 days.

Irinotecan (Category 1)35,51–53

Day 1: Irinotecan 250–350mg/m2 IV. Repeat cycle every 21 days.

OR Day 1: Irinotecan 150–180mg/m2 IV. Repeat cycle every 14 days.

OR Days 1 and 8: Irinotecan 125mg/m2 IV. Repeat cycle every 21 days.

Other Regimens Irinotecan + cisplatin32,54

Days 1 and 8: Irinotecan 65mg/m2 IV plus cisplatin 25–30mg/m2 IV. Repeat cycle every 21 days.

Irinotecan + fluoropyridimine (Category 2B)56,57

Day 1: Irinotecan 250mg/m2 IV. Days 1–14: Capecitabine 1000mg/m2 PO BID daily.

Repeat cycle every 21 days.

Irinotecan + fluoropyridimine (Category 2B)56,57

Day 1: Irinotecan 180mg/m2 IV plus leucovorin 400mg/m2 IV plus 5-FU 400mg/m2 IVP. Days 1 and 2: 5-FU 600–1200mg/m2/day IV continuous infusion on Days 1 and 2.

Repeat cycle every 14 days.

Docetaxel + irinotecan (Category 2B)42

Days 1 and 8: Docetaxel 35mg/m2 IV plus irinotecan 50mg/m2 IV. Repeat cycle every 21 days.

Alternative Regimens for Consideration Mitomycin + irinotecan57–59

Day 1: Mitomycin 6mg/m2 IV. Days 2 and 9: Irinotecan 125mg/m2.

Repeat cycle every 28 days.

OR Days 1 and 15: Irinotecan 150mg/m2 IV. Day 1: Mitomycin 8mg/m2 IV. Repeat cycle every 28 days.

OR Day 1: Irinotecan 125mg/m2 IV plus mitomycin 5mg/m2 IV. Repeat cycle every 14 days.

Mitomycin + leucovorin + 5-FU60

Days 1 and 22: Mitomycin 10mg/m2 IV. Day 1: Leucovorin 500mg/m2 IV plus 5-FU 2600mg/m2/day IV continuous infusion.

Weekly for 6 weeks, followed by 2 weeks off treatment.

References 1.

2.

3.

4.

Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology™. Gastric Cancer. v 3.2015. Available at: http://www.nccn.org/professionals/physician_gls/pdf/gastric.pdf. Accessed May 6, 2015. van Hagen P, Hulshof MC, van Lanschot JJ, et al. CROSS Group. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med. 2012;366:2074–2084.

Tepper J, Krasna MJ, Niedzwiecki D, et al. Phase III trial of trimodality therapy with cisplatin, fluorouracil, radiotherapy, and surgery compared with surgery alone for esophageal cancer: CALGB 9781. J Clin Oncol. 2008;26:1086–1092.

Bedenne L, Michel P, Bouché O, et al. Chemoradiation followed by surgery com-

5.

6.

pared with chemoradiation alone in squamous cancer of the esophagus: FFCD 9102. J Clin Oncol. 2007;25: 1160–1168.

Conroy T, Galais M-P, Raoul JL, et al. UNICANCER-GI/FFCD PRODIGE Intergroup.

Phase III randomized trial of definitive chemoradiotherapy (CRT) with FOLFOX or cisplatin and fluorouracil in esophageal cancer (EC): Final results of the PRODIGE 5/ACCORD 17 trial [abstract]. J Clin Oncol. 2012;30 (Suppl 18): LBA4003.

Khushalani NI, Leichman CG, Proulx G, et al. Oxaliplatin in combination with protracted-infusion fluorouracil and radiation: report of a clinical trial for patients with esophageal cancer. J Clin Oncol. 2002;20:2844–2850.

continued

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GASTROINTESTINAL CANCER Gastric Cancer Treatment Regimens References (continued) 7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19 .

20.

21.

22.

23.

24.

25.

Lee SS, Kim SB, Park SI, et al. Capecitabine and cisplatin chemotherapy (XP) alone or sequentially combined chemoradiotherapy containing XP regiment in patients with three different settings of stage IV esophageal cancer. Jpn J Clin Oncol.

2007;37:829–835.

Javle MM, Yang G, Nwogu CE, et al. Capecitabine, oxaliplatin and radiotherapy: a phase 1B neoadjuvant study for esophageal cancer with gene expression analysis.

Cancer Invest. 2009;27:193–200.

Sharma R, Yang GY, Nwogu CE at al. A single institution experience with neoadjuvant chemoradiation (CRT) with irinotecan (I) and cisplatin ( C ) in locally advanced esophageal carcinoma (LAEC) [abstract]. J Clin Oncol. 2009;27(Suppl 15): Abstract e15619.

Ajani JA, Winter K, Okawara GS, et al. Phase II trial of preoperative chemoradiation in patients with localized gastric adenocarcinoma (RTOG 9904): quality of combined modality therapy and pathologic response. J Clin Oncol. 2006;24:3953–3958.

Cunningham D, Allum WH, Stenning SP, et al. MAGIC Trial Participants.

Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006;355:11–20.

Sumpter K, Harper-Wynne C, et al. Report of two protocol planned interim analyses in a randomised multicentre phase III study comparing capecitabine with fluorouracil and oxaliplatin with cisplatin in patients with advanced oesophagogastric cancer receiving ECF. Br J Cancer. 2005;92:1976–1983.

Ychou M, Boige V, Pignon JP, et al. Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial. J Clin Oncol. 2011;29:1715–1721.

Macdonald JS, Smalley SR, Benedetti J, et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med. 2001;345:725–730.

Jansen EP, Boot H, Saunders MP, et al. A phase I-II study of postoperative capecitabine-based chemoradiotherapy in gastric cancer. Int J Radiat Oncol Biol Phys. 2007;69:1424–1428.

André T, Quinaux E, Louvet C, et al. Phase III study comparing a semimonthly with a monthly regimen of fluorouracil and leucovorin as adjuvant treatment for stage II and III colon cancer patients: final results of GERCOR C96.1. J Clin Oncol.

2007;25:3732–3738.

Leong T, Joon DL, Willis D, et al. Adjuvant chemoradiation for gastric cancer using epirubicin, cisplatin, and 5-fluorouracil before and after three-dimensional conformal radiotherapy with concurrent infusional 5-fluorouracil: a multicenter study of the Trans-Tasman Radiation Oncology Group. Int J Radiat Oncol Biol Phys.

2011;79:690–695.

Lee HS, Choi Y, Hur WJ, et al. Pilot study of postoperative adjuvant chemoradiation for advanced gastric cancer: adjuvant 5-FU/cisplatin and chemoradiation with capecitabine. World J Gastroenterol. 2006;12:603–607.

Bang YJ, Kim YW, Yang HK, et al. CLASSIC trial investigators. Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 openlabel, randomised controlled trial. Lancet. 2012;379:315-321.

Lee J, Lim do H, Kim S, et al. Phase III trial comparing capecitabine plus cisplatin versus capecitabine plus cisplatin with concurrent capecitabine radiotherapy in completely resected gastric cancer with D2 lymph node dissection: the ARTIST trial. J Clin Oncol. 2012;30:268–273.

Bang YJ, Van Cutsem E, Feyereislova A, et al. ToGA Trial Investigators. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376(9742):687–697.

Van Cutsem E, Moiseyenko VM, Tjulandin S, et al. V325 Study Group. Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group. J Clin Oncol. 2006;24:4991–4997.

Shah MA, Shibata S, Stoller RG, et al. MSKCC Gastric Cancer Consortium. Random assignment multicenter phase II study of modified docetaxel, cisplatin, fluorouracil (mDCF) versus DCF with growth factor support (GCSF) in metastatic gastroesophageal adenocarcinoma (GE). J Clin Oncol. 2010;28 (Suppl 15): 4010.

Shankaran V, Mulcahy MF, Hochster HS, et al. Docetaxel, oxaliplatin, and 5-fluorouracil for the treatment of metastatic or unresectable gastric or gastroesophageal junction (GEJ) adenocarcinomas: Preliminary results of a phase II study [abstract 47]. Presented at the 2009 Gastrointestinal Cancers Symposium.

Elkerm YM, Elsaid A, Al-Batran SE, et al. Final results of a phase II trial of docetaxelcarboplatin-FU in locally advanced gastric carcinoma. Presented at the Gastrointestinal Cancers Symposium, January 25–27, 2008, Orlando, FL.

26. Ross P, Nicolson M, Cunningham D, et al. Prospective randomized trial comparing mitomycin, cisplatin, and protracted venous-infusion fluorouracil (PVI 5-FU) with epirubicin, cisplatin, and PVI 5-FU in advanced esophagogastric cancer.

J Clin Oncol. 2002;20:1996–2004.

27. Cunningham D, Starling N, Rao S, et al. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008;358:36–46.

28. Lorenzen S, Schuster T, Porschen R, et al. Cetuximab plus cisplatin-5-fluorouracil versus cisplatin-5-fluorouracil alone in first-line metastatic squamous cell carcinoma of the esophagus: a randomized phase II study of the Arbeitsgemeinschaft Internistische Onkologie. Ann Oncol. 2009;20:1667–1673.

29. Al-Batran SE, Hartmann JT, Probst S, et al. Phase III trial in metastatic gastroesophageal adenocarcinoma with fluorouracil, leucovorin plus either oxaliplatin or cisplatin: a study of the Arbeitsgemeinschaft Internistische Onkologie. J Clin Oncol. 2008;26:1435–1442.

30. Kang YK, Kang WK, Shin DB, et al. Capecitabine/cisplatin versus 5-fluorouracil/ cisplatin as first-line therapy in patients with advanced gastric cancer: a randomised phase III non-inferiority trial. Ann Oncol. 2009;20:666–673.

31. Bouché O, Raoul JL, Bonnetain F, et al. Fédération Francophone de Cancérologie Digestive Group. Randomized multicenter phase II trial of a biweekly regimen of fluorouracil and leucovorin (LV5FU2), LV5FU2 plus cisplatin, or LV5FU2 plus irinotecan in patients with previously untreated metastatic gastric cancer: a Federation Francophone de Cancerologie Digestive Group Study—FFCD 9803.

J Clin Oncol. 2004;22:4319–4328.

32. Enzinger PC, Burtness B, Hollis D, et al. CALGB 80403/ECOG 1206: A randomized phase II study of three standard chemotherapy regimens (ECF, IC, FOLFOX) plus cetuximab in metastatic esophageal and GE junction cancer [abstract 4006].

J Clin Oncol. 2010; 28 (suppl 15):4007.

33. Kim GM, Jeung HC, Rha SY, et al. A randomized phase II trial of S-1-oxaliplatin versus capecitabine-oxaliplatin in advanced gastric cancer. Eur J Cancer.

2012;48:518–526.

34. Dank M, Zaluski J, Barone C, et al. Randomized phase III study comparing irinotecan combined with 5-fluorouracil and folinic acid to cisplatin combined with 5-fluorouracil in chemotherapy naive patients with advanced adenocarcinoma of the stomach or esophagogastric junction. Ann Oncol. 2008;19: 1450–1457.

35. Sym SJ, Hong J, Park J, et al. A randomized phase II study of biweekly irinotecan plus 5-fluorouracil/leucovorin (mFOLFIRI) in patients with metastatic gastric adenocarcinoma refractory to or progressive after first-line chemotherapy.

Cancer Chemother Pharmacol. 2013;71:481–488.

36. Wolff K, Wein A, Reulbach U, et al. Weekly high-dose 5-fluorouracil as a 24-h infusion and sodium folinic acid (AIO regimen) plus irinotecan in patients with locally advanced nonresectable and metastatic adenocarcinoma or squamous cell carcinoma of the oesophagus: a phase II trial. Anticancer Drugs. 2009;20:165–173.

37. Ilson DH, Forastiere A, Arquette M, et al. A phase II trial of paclitaxel and cisplatin in patients with advanced carcinoma of the esophagus. Cancer J. 2000;6:316–323.

38. Petrasch S, Welt A, Reinacher A, et al. Chemotherapy with cisplatin and paclitaxel in patients with locally advanced, recurrent or metastatic oesophageal cancer.

Br J Cancer. 1998;78:511–514.

39. Gadgeel SM, Shields AF, Heilbrun LK, et al. Phase II study of paclitaxel and carboplatin in patients with advanced gastric cancer. Am J Clin Oncol. 2003;26:37–41.

40. Ajani JA, Fodor MB, Tjulandin SA, et al. Phase II multi-institutional randomized trial of docetaxel plus cisplatin with or without fluorouracil in patients with untreated, advanced gastric, or gastroesophageal adenocarcinoma. J Clin Oncol. 2005;23:5660–5667.

41. Kim JY, Do YR, Park KU, et al. A multi-center phase II study of docetaxel plus cisplatin as first-line therapy in patients with metastatic squamous cell esophageal cancer. Cancer Chemother Pharmacol. 2010;66:31–36.

42. Burtness B, Gibson M, Egleston B, et al. Phase II trial of docetaxel-irinotecan combination in advanced esophageal cancer. Ann Oncol. 2009;20:1242–1248.

43. Ohtsu A, Shimada Y, Shirao K, et al. Randomized phase III trial of fluorouracil alone versus fluorouracil plus cisplatin versus uracil and tegafur plus mitomycin in patients with unresectable, advanced gastric cancer: The Japan Clinical Oncology Group Study (JCOG9205). J Clin Oncol. 2003;21:54–59.

44. Hong YS, Song SY, Lee SI, et al. A phase II trial of capecitabine in previously untreated patients with advanced and/or metastatic gastric cancer. Ann Oncol.

2004;15:1344–1347.

45. Albertsson M, Johansson B, Friesland S, et al. Phase II studies on docetaxel alone every third week, or weekly in combination with gemcitabine in patients with primarily locally advanced, metastatic, or recurrent esophageal cancer. Med Oncol.

2007; 24:407–412.

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CANCER TREATMENT REGIMEN

GASTROINTESTINAL CANCER References (continued) 46. Ford HE, Marshall A, Bridgewater JA, et al. Docetaxel versus active symptom control for refractory oesophagogastric adenocarcinoma (COUGAR-02): an openlabel, phase 3 randomised controlled trial. Lancet Oncol. 2014;15:78–86.

47. Ajani JA, Ilson DH, Daugherty K, et al. Activity of taxol in patients with squamous cell carcinoma and adenocarcinoma of the esophague. J Natl Cancer Inst.

1994;86:1086–1091.

48. Ilson DH, Wadleigh RG, Leichman LP, Kelsen DP. Paclitaxel given by a weekly 1-h infusion in advanced esophageal cancer. Ann Oncol. 2007;18:898–902.

49. Fuchs CS, Tomasek J, Yong CJ, et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomized, multicentre, placebo-controlled, phase 3 trial. Lancet. 2014;383:31–39.

50. Wilke H, Van Cutsem E, Oh SC, et al. RAINBOW: A global, phase III, randomized, double-blind study of ramucirumab plus paclitaxel versus placebo plus paclitaxel in the treatment of metastatic gastroesophageal junction (GEJ) and gastric adenocarcinoma following disease progression on first-line platinum- and fluoropyrimidine-containing combination therapy rainbow IMCL COP12-0922 (I4TIE-JVBE). J Clin Oncol. 2014;32 (3_suppl):Abstract LBA7.

51. Hironaka S, Ueda S, Yasui H, et al. Randomized, Open-Label, Phase III Study Comparing Irinotecan With Paclitaxel in Patients With Advanced Gastric Cancer Without Severe Peritoneal Metastasis After Failure of Prior Combination Using Fluoropyrimidine Plus Platinum: WJOG 4007 Trial. J Clin Oncol.

2013;31:4438–4444.

52. Thuss-Patience PC, Kretzschmar A, Bichev D, et al. Survival advantage for irinotecan versus best supportive care as second-line chemotherapy in gastric cancer—a randomized phase III study of the Arbeitsgemeinschaft Internistische Onkologie (AIO). Eur J Cancer. 2011;47:2306–2314.

53. Fuchs CS, Moore MR, Harker G, et al. Phase III comparison of two irinotecan dosing regimens in second-line therapy of metastatic colorectal cancer. J Clin Oncol. 2003;21:807–814.

54. Ilson DH. Phase II trial of weekly irinotecan/cisplatin in advanced esophageal cancer. Oncology (Williston Park). 2004;18:22–25.

55. Leary A, Assersohn L, Cunningham D, et al. A phase II trial evaluating capecitabine and irinotecan as second line treatment in patients with oesophago-gastric cancer who have progressed on, or within 3 months of platinum-based chemotherapy.

Cancer Chemother Pharmacol. 2009;64: 455–462.

56. Maugeri-Sacca M, Pizzuti L, Sergi D, et al. FOLFIRI as a second-line therapy in patients with docetaxel-pretreated gastric cancer: a historic cohort. J Exp Clin Cancer Res. 2013;32:67.

57. Lustberg MB, Bekali-Saab T, Young D, et al. Phase II randomized study of two regimens of sequentially administered mitomycin C and irinotecan in patients with unresectable esophageal and gastroesophageal adenocarcinoma. J Thorac Oncol.

2010;5:713–718.

58. Giuliani F, Molica S, Maiello E, et al. Irinotecan (CPT-11) and mitomycin-C (MMC) as second-line therapy in advanced gastric cancer: a phase II study of the Gruppo Oncologico dell’ Italia Meridonale (prot. 2106). Am J Clin Oncol.

2005; 28:581–585.

59. Barnias A, Papamichael D, Syrigos K, Pavlidis N. Phase II study of irinotecan and mitomycin C in 5-fluorouracil-pretreated patients with advanced colorectal and gastric cancer. J Chemother. 2003;15:275–281.

60. Hofheinz RD, Hartung G, Samel S, et al. High-dose 5-fluorouracil/folinic acid in combination with three-weekly mitomycin C in the treatment of advanced gastric cancer: A phase II study. Onkologie. 2002;25:255–260.

(Revised 5/2015) © 2015 by Haymarket Media, Inc.

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DRUG MONOGRAPHS

GASTROINTESTINAL CANCER AVASTIN Genentech

℞

Angiogenesis inhibitor. Bevacizumab 100mg, 400mg; per vial; soln for IV infusion after dilution; preservative-free.

Indications: Metastatic colorectal carcinoma, in combination with 5-FU-based chemotherapy for first- or second-line treatment; or in combination with fluoropyrimidine-irinotecanor fluoropyrimidine-oxaliplatin-based therapy for second-line treatment in patients who have progressed on a first-line Avastin-containing regimen. Limitation of use: not for adjuvant treatment of colon cancer.

Adults: Give by IV infusion. Infuse 1st dose over 90 mins; if tolerated, infuse 2nd dose over 60 mins, and subsequent doses over 30 mins.

5mg/kg (when used with bolus-IFL) or 10mg/kg (when used with FOLFOX-4) once every 2 weeks until disease progression detected; 5mg/kg every 2 weeks or 7.5mg/kg every 3 weeks (when used with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based therapy).

Children: Not established.

Warnings/Precautions: Risk of GI perforations, surgery and wound healing complications, and hemorrhage. Do not start therapy before or for at least 28 days after surgery; allow surgical incisions to completely heal (see full labeling).

Do not administer if recent history of hemoptysis of ≥ ½-teaspoon of red blood. Permanently discontinue if GI perforation, tracheoesophageal fistula, any grade 4 fistula, or grade 4 venous thromboembolic event. Discontinue if fistula involving internal organ, wound healing complications, hemorrhage, severe arterial thromboembolic event (ATE), hypertensive crisis or encephalopathy, posterior reversible encephalopathy syndrome, or nephrotic syndrome occurs; suspend therapy if severe hypertension, moderate-to-severe proteinuria (resume when <2g/24hrs), or severe infusion reaction occurs.

Avoid in ovarian cancer if evidence of recto-sigmoid involvement by pelvic exam, bowel involvement on CT scan, or symptoms of bowel obstruction.

History of arterial thromboembolism. Diabetes.

Monitor BP every 2–3 weeks. Monitor proteinuria by dipstick urine analysis; if ≥2+, do further assessment with a 24-hour urine collection. Elderly.

Increased risk of ovarian failure; inform females of reproductive potential prior to starting therapy.

Pregnancy: may cause fetal harm; use effective contraception during and for 6 months after last dose. Nursing mothers: not recommended.

Adverse reactions: Epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain, exfoliative dermatitis; GI perforation and fistulae, wound dehiscence/impaired healing, necrotizing fasciitis (discontinue if occurs), hemorrhage, non-GI fistula formation, arterial or venous thromboembolic events, posterior reversible encephalopathy syndrome, infusion reactions, ovarian failure, neutropenia, and infection.

How supplied: Single-use vial—1

CYRAMZA Lilly

℞

Human IgG1 monoclonal antibody. Ramucirumab 10mg/mL; per vial; soln for IV infusion after dilution; preservative-free.

Indications: As a single agent, or in combination with paclitaxel, for treatment of advanced or metastatic, gastric or gastro-esophageal junction adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy. In combination with FOLFIRI (irinotecan, folinic acid, and 5-fluorouracil), for the treatment of metastatic colorectal cancer (mCRC) with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine.

Adults: Give by IV infusion over 60 mins.

Premedicate with IV histamine H1-antagonist (eg, diphenhydramine) prior to each infusion; or with dexamethasone and acetaminophen in those who have experienced Grade 1 or 2 infusion reaction.

Gastric cancer: 8mg/kg every 2 weeks. When given in combination: administer prior to paclitaxel. mCRC: 8mg/kg every 2 weeks prior to FOLFIRI. Continue until disease progression or unacceptable toxicity. Dose modifications: see full labeling.

Children: Not established.

Warnings/Precautions: Increased risk of hemorrhage; permanently discontinue if severe bleeding occurs. Control hypertension prior to initiating. Monitor blood pressure every 2 weeks or more frequently as indicated; if severe hypertension develops, temporarily suspend until medically controlled. Monitor for infusionrelated reactions during therapy. Have emergency resuscitative equipment available. Permanently discontinue if severe arterial thromboembolic events, severe uncontrolled hypertension (despite antihypertensives), hypertensive crisis or encephalopathy, Grade 3 or 4 infusion-related reactions, urine protein >3g/24hrs, nephrotic syndrome, or GI perforation occurs. Impaired wound healing: withhold Cyramza prior to surgery. Clinical deterioration in patients with Child-Pugh B or C cirrhosis (eg, new or worsening encephalopathy, ascites, hepatorenal syndrome). Discontinue if reversible posterior leukoencephalopathy syndrome develops. Monitor proteinuria by urine dipstick and/or urinary protein creatinine ratio.

Monitor thyroid function. Pregnancy: avoid. Use effective contraception during therapy and for ≥3 months after last ramucirumab dose. Nursing mothers: not recommended.

Adverse reactions: Hypertension, diarrhea, headache, fatigue, asthenia, hyponatremia, anemia, intestinal obstruction, neutropenia, epistaxis, stomatitis/mucosal inflammation, rash, decreased appetite; arterial thromboembolic events, proteinuria, GI perforation, infusion-related reactions.

How supplied: Single-dose vial (10mL, 50mL)—1

ELOXATIN Sanofi Aventis

℞

Alkylating agent (organoplatinum complex).

Oxaliplatin 5mg/mL; soln for IV infusion after dilution; preservative-free.

Indications: Adjuvant treatment for Stage III colon cancer in patients who have undergone complete resection of the primary tumor (in combination with infusional 5-FU/LV). Treatment of advanced colorectal cancer (in combination with infusional 5-FU/LV).

Adults: See literature. Premedicate with antiemetics. Give by IV infusion every two weeks for a total of 6 months (eg, 12 cycles).

Day 1: 85mg/m2 + leucovorin, followed by 5-FU. Day 2: Leucovorin followed by 5-FU. Severe renal impairment: initially 65mg/m2. Neuropathy, other toxicities: see literature for dose adjustments.

Children: Not recommended.

Warnings/Precautions: Have epinephrine, corticosteroids, antihistamines available during infusion. Discontinue if interstitial lung disease or pulmonary fibrosis suspected. Monitor for neuropathy; reduce dose or discontinue if needed.

Renal impairment. Monitor WBCs with differential, hemogloblin, platelets, blood chemistries (including ALT, AST, bilirubin, creatinine) before each treatment. Avoid extravasation. Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended.

Interactions: Caution with concomitant nephrotoxic agents. Monitor oral anticoagulants.

Adverse reactions: Peripheral sensory neuropathy, neutropenia, thrombocytopenia, anemia, GI upset, increased liver enzymes, emesis, fatigue, stomatitis; hypersensitivity reactions (monitor), pulmonary fibrosis (may be fatal), hepatotoxicity.

Testing considerations: ERCC1 overexpression How supplied: Single-use vials (50mg, 100mg, 200mg)—1

ERBITUX Bristol-Myers Squibb

℞

Epidermal growth factor receptor blocker.

Cetuximab 100mg/vial, 200mg/vial; soln for IV infusion; preservative-free.

Indications: K-Ras (wild-type), EGFR-expressing metastatic colorectal cancer: for use in combination with FOLFIRI (irinotecan, 5-fluorouracil, leucovorin) for first-line treatment, or in combination with irinotecan (if refractory to irinotecan-based chemotherapy), or as a single agent (after failure of both irinotecan- and oxaliplatin-based regimens or if irinotecan-intolerant). Limitation of use: not indicated for Ras mutant colorectal cancer that harbor somatic mutations in exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146) or when Ras mutation test results are unknown.

Adults: Pretreat with H1 blocker. Give by IV infusion (use filter); max rate: 10mg/min. Initial dose: 400mg/m2 once over 2hrs; then 250mg/m2 once weekly over 1 hour until disease progression or unacceptable toxicity. Complete administration 1hr prior to FOLFIRI. Permanently reduce infusion rate by 50% if Grade 1 or 2 and non-serious Grade 3 infusion reaction occurs; permanently discontinue if Grade 3 or 4 serious reaction occurs. Monitor patient during and for 1hr postinfusion. Skin toxicity: see full labeling.

Children: Not established.

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DRUG MONOGRAPHS

GASTROINTESTINAL CANCER Warnings/Precautions: Confirm EGFR expression status and absence of Ras mutation for colorectal cancer prior to initiation.

Discontinue if severe infusion reactions or interstitial lung disease occur. Monitor for infusion reactions, cardiopulmonary arrest, pulmonary toxicity, dermatologic toxicities/infection; avoid sun, UV light. Additive cutaneous reactions with irradiation. Cardiovascular diseases (w. irradiation or platinum-based therapy with 5-FU). Monitor electrolytes (eg, magnesium, potassium, calcium) during and after cetuximab therapy. Pregnancy (Cat.C). Nursing mothers: not recommended.

Interactions: Increased mucositis (Grade 3–4), radiation recall syndrome, acneiform rash, cardiac events, and electrolyte disturbances with radiation and cisplatin.

Adverse reactions: Cutaneous reactions (pruritus, nail changes), acneform rash, headache, diarrhea, infection, asthenia, mucositis, weight loss, xerostomia, dehydration, electrolyte abnormalities; infusion reactions (may be severe: eg, bronchospasm, dyspnea), interstitial lung disease, cardiopulmonary arrest, hypomagnesemia, fever, sepsis, kidney failure, pulmonary embolus; others (see full labeling).

Testing considerations: EGFR amplification analysis, K-RAS mutation analysis, B-RAF mutation analysis.

How supplied: Single-use vials—1

Fluorouracil (various)

℞

Antimetabolite. Fluorouracil 50mg/mL; soln for IV inj.

Indications: Palliative management of carcinoma of the colon, rectum, and stomach.

Adults: Give by IV inj. 12mg/kg once daily for 4 successive days; max 800mg/day. If no toxicity is observed, 6mg/kg are given on the 6th, 8th, 10th, and 12th days unless toxicity occurs. Maintenance therapy: repeat dosage of 1st course every 30 days after the last day of the previous course of treatment; or give a maintenance dose of 10–15mg/kg per week as a single dose; max: 1g/week. Poor risk patients: see literature for dose adjustments.

Children: Not recommended.

Contraindications: Poor nutritional state.

Depressed bone marrow function. Potentially serious infections.

Warnings/Precautions: Narrow margin of safety; monitor for toxicity. Consider hospitalization for 1st course. History of highdose pelvic irradiation. Previous use of alkylating agents. Widespread involvement of bone marrow by metastatic tumors. Renal or hepatic impairment. Discontinue if signs of toxicity appear (eg, stomatitis, esophagopharyngitis, leukopenia, intractable vomiting, diarrhea, GI ulceration

or bleeding, thrombocytopenia, hemorrhage).

Monitor WBCs with differential before each dose.

Avoid extravasation. Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended.

Interactions: Potentiated by leucovorin.

Adverse reactions: Stomatitis, esophagopharyngitis, GI upset, anorexia, leukopenia, alopecia, dermatitis, hand-foot syndrome; others.

Testing considerations: TS (thymidylate synthase), MSI (microsatellite instability), DPD (dihydropyrimidine dehydrogenase).

How supplied: Contact supplier.

FUSILEV Spectrum

℞

Folate analogue. Levoleucovorin (as calcium pentahydrate) 50mg/vial; pwd for IV inj after reconstitution; contains mannitol 50mg/vial; 175mg/17.5mL; soln for IV inj; preservative-free.

Indications: Palliative treatment of advanced metastatic colorectal cancer in combination with 5-fluorouracil (5-FU).

Adults: Administer levoleucovorin and 5-FU separately to avoid precipitate formation. Regimen 1: give levoleucovorin at 100mg/m2 by slow IV inj over a minimum of 3 minutes, followed by 5-FU at 370mg/m2 by IV inj. Regimen 2: give levoleucovorin at 10mg/m2 by IV inj, followed by 5-FU at 425mg/m2

by IV inj. Both: Treat daily for 5 days. Five-day treatment course may be repeated at 4 week (28 days) intervals for 2 courses, and then repeated at 4–5 week (28–35 days) intervals provided that patient recovered completely from toxic effects from prior treatment course. Dose adjustments for subsequent treatment course: see literature.

Children: Not recommended.

Warnings/Precautions: Not for treating pernicious anemia and megaloblastic anemia.

Elderly. Debilitated. Pregnancy (Cat.C). Nursing mothers.

Interactions: Potentiates 5-fluorouracil toxicity.

Antagonizes TMP/SMZ. Antagonizes anticonvulsants (eg, phenobarbital, primidone, phenytoin). May be affected by drugs that affect MTX elimination.

Adverse reactions: Stomatitis, nausea, diarrhea.

How supplied: Single-use vial (pwd, soln)—1

GLEEVEC Novartis

℞

Kinase inhibitor. Imatinib (as mesylate) 100mg, 400mg; scored tabs.

Indications: Kit (CD117) (+) unresectable and/or metastatic malignant GI stromal tumors (GIST).

Adjuvant treatment of adults following complete gross resection of Kit (CD117) (+) GIST. Adults: Take with food and water. May disperse tab in water or apple juice and take promptly. ≥18yrs: GIST: 400mg once daily; up to 800mg daily (given

as 400mg twice daily) may be considered if clinically indicated. Adjuvant GIST treatment: 400mg once daily; 36 months of treatment recommended (see full labeling). If severe non-hematologic reactions develop: interrupt dose; resume at a lower dose in hepatic dysfunction. Severe hepatic impairment: reduce dose by 25%. Renal or hematologic reactions: see full labeling. Avoid concomitant strong CYP3A4 inducers (eg, rifampin): if needed, increase imatinib dose by at least 50%.

Children: Not recommended.

Warnings/Precautions: Hepatic or renal impairment. Monitor weight and for fluid retention regularly; CBCs weekly for 1st month, bi-weekly for 2nd month, then periodically (eg, every 2–3 months); liver function at baseline then monthly or as needed; GI symptoms at baseline.

Cardiovascular disease or risk factors; monitor.

Immunosuppression and potential toxicities (liver, kidney, cardiac) from long-term use. Monitor for tumor lysis syndrome; correct clinically significant dehydration and treat high uric acid levels before initiating therapy. Monitor growth in children.

Possible cardiogenic shock/LV dysfunction in conditions with high eosinophil levels (eg, HES/ CEL, MDS/MPD, ASM); consider concomitant systemic steroid prophylaxis (1–2mg/kg) for 1 or 2 wks if abnormal ECG or serum troponin. Monitor TSH levels in thyroidectomy patients undergoing levothyroxine replacement. Pregnancy (Cat.D); avoid. Use highly effective contraception during treatment. Nursing mothers: not recommended.

Interactions: Avoid grapefruit juice. Potentiated

by CYP3A4 inhibitors (eg, azole antifungals, protease inhibitors, nefazodone, clarithromycin, telithromycin). Antagonized by strong CYP3A4 inducers (eg, dexamethasone, fosphenytoin, phenytoin, phenobarbital, carbamazepine, oxcarbamazepine, primidone, St. John’s wort, rifampin, rifabutin, rifampicin); consider alternatives. May potentiate drugs metabolized

by CYP3A4 (eg, benzodiazepines, dihydropyridine calcium channel blockers, cyclosporine, ergots, alfentanil, fentanyl, pimozide, quinidine, certain statins, sirolimus, tacrolimus), CYP2D6, or CYP2C9 (use heparin instead of warfarin).

Adverse reactions: Edema (may be severe), nausea, vomiting, musculoskeletal pain, diarrhea, muscle cramps, rash (may be severe; eg, erythema multiforme, Stevens-Johnson syndrome), fatigue, abdominal pain, dizziness, blurred vision, somnolence, fever, headache, cough, arthralgia/myalgia, dyspnea, hypokalemia, night sweats, anorexia, pruritus, hemorrhage, anemia, neutropenia, thrombocytopenia, weight gain, renal or hepatotoxicity, immunosuppression, hypothyroidism; rare: severe CHF, LV dysfunction.

How supplied: 100mg—90; 400mg—30

Take advantage of our free online medical calculators at CancerTherapyAdvisor.com/MedicalCalculators.

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DRUG MONOGRAPHS

GASTROINTESTINAL CANCER HERCEPTIN Genentech

℞

Human epidermal growth factor receptor (HER2) inhibitor. Trastuzumab 440mg/vial; lyophilized pwd for IV infusion after reconstitution and dilution; preservative-free.

Indications: HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma, in combination with cisplatin and capecitabine or 5-fluorouracil, in patients who have not received prior treatment.

Adults: Do not substitute for or with adotrastuzumab emtasine. Give as IV infusion.

Initially 8mg/kg over 90 mins, followed by 6mg/kg over 30–90 mins every 3 weeks until disease progression. Infusion reactions or cardiomyopathy: see full labeling.

Children: Not established.

Warnings/Precautions: Increased risk of cardiomyopathy. Conduct cardiac assessment (eg, history, physical exam, LVEF) at baseline, every 3 months during and after therapy or every 6 months for ≥2yrs after therapy (if adjuvant); repeat LVEF at 4 week intervals if dose is withheld due to significant left ventricular cardiac dysfunction. Interrupt therapy if dyspnea or significant hypotension occurs; consider discontinuing permanently if severe infusion reactions, CHF, pulmonary toxicity, or significant left ventricular myocardial dysfunction develops. Symptomatic intrinsic lung disease. Extensive tumor involvement of the lungs.

Test for HER2 protein overexpression and HER2 gene amplification using FDA-approved tests for specific tumor type (breast or gastric/gastroesophageal adenocarcinoma). Elderly. Pregnancy (Cat.D); use adequate contraception during and at least 7 months after therapy. Nursing mothers: not recommended.

Interactions: Increased cardiomyopathy with anthracycline-containing chemotherapy.

Increased toxicity with other myelosuppressives.

Potentiated by paclitaxel.

Adverse reactions: Diarrhea, fatigue, anemia, stomatitis, weight loss, upper respiratory tract infections, fever, thrombocytopenia, mucosal inflammation, nasopharyngitis, dysgeusia, infections; severe infusion reactions, febrile neutropenia/exacerbation of chemotherapyinduced neutropenia, pulmonary toxicity (eg, interstitial pneumonitis), cardiomyopathy (eg, left ventricular myocardial dysfunction); pregnant women: possible oligohydramnios (monitor).

Testing considerations: HER2 protein overexpression How supplied: Vial—1 (w. diluent)

Leucovorin Teva

℞

Folic acid derivative. Leucovorin calcium 100mg/vial, 350mg/vial; lyophilized pwd for IV or IM inj after reconstitution; preservative-free.

Indications: Palliative treatment of advanced colorectal cancer in combination with 5-fluorouracil.

Adults: Max IV infusion rate: 160mg/min.

200mg/m2 by slow IV inj over a minimum of 3 minutes, followed by 5-fluorouracil (370mg/m2); or

20mg/m2 IV followed by 5-fluorouracil (425mg/m2); both regimens: daily for 5 days, may be repeated at 4-week intervals for 2 courses and then repeated at 4–5 week intervals (if completely recovered from toxic effects of previous course).

Children: See literature.

Contraindications: Pernicious anemia and other megaloblastic anemias due to Vit. B12 deficiency.

Warnings/Precautions: Do not administer intrathecally. CNS metastases. Monitor CBCs with differential, platelets, electrolytes, liver function tests prior to each treatment, then periodically. Elderly.

Debilitated. Pregnancy (Cat.C). Nursing mothers.

Interactions: Potentiates toxicity of 5-fluorouracil; use lower 5-fluorouracil dose. May antagonize phenobarbital, phenytoin, and primidone. Caution with trimethoprim-sulfamethoxazole.

Adverse reactions: Leukopenia, thrombocytopenia, infection, GI upset, stomatitis, constipation, lethargy, malaise, fatigue, alopecia, dermatitis, anorexia; seizures, syncope.

How supplied: Single-use vials—1

NEXAVAR Bayer and Onyx

℞

Multikinase inhibitor. Sorafenib 200mg; tabs.

Indications: Unresectable hepatocellular carcinoma.

Adults: Take on an empty stomach. 400mg twice daily. If toxicity occurs, may reduce dose to 400mg once daily; if further dose reduction required, may reduce dose to 400mg every other day (see full labeling). Concomitant strong CYP3A4 inducers: consider increasing dose, monitor for toxicity.

Children: Not established.

Contraindications: Concomitant carboplatin/ paclitaxel in patients with squamous cell lung cancer.

Warnings/Precautions: Avoid in congenital long QT syndrome. Monitor patients with CHF, bradyarrhythmias, drugs known to prolong the QT interval, electrolyte abnormalities. Discontinue if severe dermatologic toxicity, hypertension, GI perforation, hemorrhage, cardiac ischemia, MI occurs. Suspend therapy before major surgery.

Monitor BP weekly during the first 6 weeks and thereafter. Monitor hepatic function regularly; discontinue if transaminases significantly elevated.

Severe hepatic impairment (Child-Pugh C) or on dialysis. Use effective contraception during and for 2 weeks after stopping treatment. Pregnancy (Cat.D), nursing mothers: not recommended.

Interactions: See Contraindications. Avoid strong CYP3A4 inducers (eg, St. John’s Wort, dexamethasone, phenytoin, carbamazepine, rifabutin, rifampin, phenobarbital) and neomycin; may decrease sorafenib levels. May potentiate warfarin (monitor PT & INR), other drugs metabolized by UGT1A1 or UGT1A9 pathway, or substrates of CYP2B6, CYP2C8, CYP2C9, P-gp.

Concomitant Class Ia and III antiarrhythmics; may prolong QT interval.

Adverse reactions: Dermatologic toxicity (eg, rash, hand-foot skin reaction, alopecia,

pruritus, dry skin, Stevens-Johnson syndrome, toxic epidermal necrolysis), fatigue, weight loss, diarrhea, anorexia, abdominal pain, hypertension, hemorrhage, electrolyte abnormalities; druginduced hepatitis, QT prolongation.

How supplied: Tabs—120

STIVARGA Bayer

℞

Kinase inhibitor. Regorafenib 40mg; tabs.

Indications: Treatment of patients with metastatic colorectal cancer who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecanbased chemotherapy, an anti-VEGF therapy, and, if KRAS wild type, an anti-EGFR therapy. Treatment of patients with locally advanced, unresectable or metastatic gastrointestinal stromal tumor (GIST) who have been previously treated with imatinib mesylate or sunitinib malate.

Adults: Swallow whole with water after a lowfat meal (contains <600 calories and <30% fat). 160mg once daily for the first 21 days of each 28-day cycle; until disease progression or unacceptable toxicity. Dose modifications: see full prescribing information.

Children: <18yrs: not established.

Warnings/Precautions: Risk of severe hepatotoxicity (may be fatal). Monitor hepatic function before starting and at least every 2 weeks during first 2 months of treatment; interrupt and reduce or discontinue if hepatotoxicity or hepatocellular necrosis occurs. Severe hepatic impairment: not recommended. Increased risk of hemorrhage; permanently discontinue if severe or life-threatening. Interrupt and reduce or permanently discontinue if dermatological toxicity occurs (eg, hand-foot skin reaction [a.k.a. palmar-plantar erythrodysesthesia], rash). Ensure BP is controlled before starting; monitor weekly for the first 6 weeks then every cycle or as clinically indicated; withhold if severe or uncontrolled. Myocardial ischemia/ infarction: withhold if new or acute onset develops; resume when resolved. Discontinue if reversible posterior leukoencephalopathy syndrome (RPLS) or GI perforation/fistula develops. Wound healing complications: stop treatment at least 2 weeks before surgery; discontinue if wound dehiscence occurs. Fetal toxicity. Pregnancy (Cat.D); use effective contraception during treatment and up to 2 months after completion. Nursing mothers: not recommended.

Interactions: Avoid concomitant strong CYP3A4 inducers (eg, rifampin, phenytoin, carbamazepine, phenobarbital, St. John’s Wort). Avoid concomitant strong CYP3A4 inhibitors (eg, clarithromycin, grapefruit juice, itraconazole, ketoconazole, posaconazole, telithromycin, voriconazole).

Monitor INR levels with concomitant warfarin.

Adverse reactions: Asthenia/fatigue, decreased appetite and food intake, hand-foot skin reaction, diarrhea, mucositis, weight loss, infection, hypertension, dysphonia, GI and abdominal pain, rash, fever, nausea; hepatotoxicity, hemorrhage, GI perforation, cardiac ischemia/infarction, RPLS. How supplied: Tabs—84 (3 × 28)

34 CANCER THERAPY ADVISOR | SEPTEMBER/OCTOBER 2015 | CancerTherapyAdvisor.com

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DRUG MONOGRAPHS

GASTROINTESTINAL CANCER SUTENT Pfizer

℞

Multikinase inhibitor. Sunitinib (as malate) 12.5mg, 25mg, 37.5mg, 50mg; gelatin caps.

Indications: Gastrointestinal stromal tumor (GIST) after disease progression on or intolerance to imatinib mesylate.

Adults: 50mg once daily for 4 weeks, then 2 weeks off (see full labeling). May adjust dose in increments or decrements of 12.5mg.

Concomitant strong CYP3A4 inhibitors (see Interactions): may reduce dose to 37.5mg daily.

Concomitant strong CYP3A4 inducers (see Interactions): may increase to max 87.5mg daily.

Children: Not established.

Warnings/Precautions: Hepatotoxicity; may be severe or fatal. Monitor liver function tests before starting, during each cycle of treatment and as clinically needed; interrupt if Grade 3 or 4 hepatic adverse events occur and discontinue if no resolution; if severe liver function changes or signs/ symptoms of failure, do not restart. Cardiovascular events: monitor for CHF during therapy, and LVEF at baseline and periodically; interrupt or reduce dose if LVEF <50% and >20% below baseline; discontinue if CHF occurs. History of QT prolongation or proarrythmic conditions (eg, bradycardia, electrolyte disturbances); perform periodic ECG, monitor electrolytes. Monitor BP. Suspend therapy if severe hypertension, seizures, or pancreatitis develops. Obtain CBCs, platelets, serum chemistries at start of each cycle. Concomitant exposure to risk factors (eg, IV bisphosphonates therapy or dental disease) may increase the risk of osteonecrosis of the jaw; avoid or consider preventive dentistry prior to treatment. Risk of tumor lysis syndrome: monitor closely in RCC and GIST patients with high tumor burden. Monitor for thyroid dysfunction; obtain baseline levels prior to treatment. Monitor blood glucose levels during and after treatment discontinuation. Monitor for proteinuria; perform baseline and periodic urinalyses; interrupt and reduce dose if 24-hr urine protein ≥3g; discontinue if nephrotic syndrome or repeat urine protein ≥3g persists. Undergoing major surgery. Stress (monitor for adrenal insufficiency).

Discontinue if severe cutaneous reactions (eg, erythema multiforme, SJS, TEN) develop; do not restart if diagnosis suspected. ESRD on dialysis.

Severe hepatic impairment. Pregnancy (Cat.D; avoid). Nursing mothers: not recommended.

Interactions: May be potentiated by strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole), grapefruit; consider reducing dose or use alternate drug. May be antagonized by CYP3A4 inducers (eg, dexamethasone, phenytoin,

carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital); consider increasing dose or use alternate drug. Concomitant St. John’s wort: not recommended. Caution with concomitant antiarrhythmics.

Adverse reactions: Fatigue, asthenia, fever, diarrhea, nausea, vomiting, mucositis/stomatitis, dyspepsia, abdominal pain, constipation, hypertension, peripheral edema, rash, hand-foot syndrome, skin discoloration, dry skin, hair color changes, altered taste, headache, back pain, arthralgia, extremity pain, cough, dyspnea, anorexia, bleeding; hepatotoxicity, left ventricular dysfunction, QT prolongation, osteonecrosis of the jaw, tumor lysis syndrome, thyroid dysfunction, impaired wound healing, hypoglycemia, thrombotic microangiopathy (discontinue if develops), proteinuria, necrotizing fasciitis (discontinue if occurs), others (see full labeling).

How supplied: Caps—28

VECTIBIX Amgen

℞

Human epidermal growth factor receptor (EGFR) inhibitor. Panitumumab 20mg/mL; soln for IV infusion after dilution; preservative-free.

Indications: First-line treatment of wild-type KRAS metastatic colorectal carcinoma (mCRC) in combination with FOLFOX, or as monotherapy following disease progression after prior fluoropyrimidine-, oxaliplatin-, and irinotecancontaining chemotherapy as determined by an FDA-approved test. Limitation of use: not for treating KRAS-mutant mCRC or for whom KRAS mutation status is unknown.

Adults: 6mg/kg by IV infusion over 60 mins once every 14 days. If 1st infusion is tolerated, give subsequent infusions over 30–60 mins.

Doses >1000mg: infuse over 90 mins. Dose modifications: see full labeling.

Children: Not established.

Warnings/Precautions: Confirm absence of a KRAS mutation using an FDA-approved test prior to initiation. Withhold or discontinue therapy for dermatologic or soft tissue toxicity associated with severe inflammatory or infectious complications; monitor. Discontinue if severe infusion reactions develop. Interrupt therapy if acute onset or worsening of pulmonary symptoms; discontinue if interstitial lung disease (ILD) is confirmed. Limit sun exposure. Monitor electrolytes (eg, magnesium, calcium) prior to initiation, during, and for 8 weeks after completing therapy. Monitor for ocular toxicities (eg, keratitis); interrupt or discontinue if occur. May impair fertility in women; use effective contraception during treatment and for 6 months following last dose. Pregnancy (Cat.C). Nursing mothers: not recommended; discontinue during therapy and for 2 months after last dose.

Interactions: Concomitant bevacizumab and chemotherapy: increased mortality and toxicity may occur.

Adverse reactions: Skin rash, paronychia, fatigue, nausea, diarrhea; hypomagnesemia, hypocalcemia, hypokalemia, dermatologic toxicities with possible infection (may be fatal), infusion reactions, immunogenicity, ILD, pulmonary fibrosis, keratitis, photosensitivity, possible acute renal failure w. chemotherapy.

Testing considerations: EGFR amplification analysis, K-RAS mutation analysis.

How supplied: Single-use vial (5mL, 10mL, 20mL)—1

XELODA Genentech

℞

Fluoropyrimidine. Capecitabine (prodrug of 5-fluorouracil) 150mg, 500mg; tabs.

Indications: First-line treatment of metastatic colorectal carcinoma when fluoropyrimidine therapy alone is preferred. Adjuvant treatment of Dukes’ C colon cancer after complete resection of the primary tumor when fluoropyrimidine therapy alone is preferred.

Adults: See full labeling. Give cyclically (2 weeks on, 1 week off). Swallow whole. Take with water within 30 minutes after AM & PM meals. ≥18yrs: 1250mg/m2 twice daily. Continue for a total of 8 cycles. Interrupt, adjust dose, and/or treat symptoms if toxicity occurs (eg, hyperbilirubinemia, diarrhea, nausea, vomiting, hand-and-foot syndrome, stomatitis) (see full labeling); do not increase dose afterwards. Renal impairment (CrCl 51–80mL/min): monitor carefully; (CrCl 30–50mL/min): reduce capecitabine dose to 75% of starting dose (ie, 950mg/m2 twice daily).

Children: <18yrs: not established.

Contraindications: Severe renal impairment (CrCl <30mL/min).

Warnings/Precautions: Hepatic or renal dysfunction. Monitor and correct dehydration at initiation. Coronary artery disease. Interrupt therapy if severe diarrhea occurs; give antidiarrheals until resolves or reduces to Grade 1. Dihydropyrimidine dehydrogenase deficiency. Elderly. Pregnancy (Cat.D), nursing mothers: not recommended.

Interactions: Increased anticoagulant effect with warfarin; monitor PT/INR frequently.

Potentiated by leucovorin. Monitor phenytoin and other CYP2C9 substrates.

Adverse reactions: Diarrhea, hand-andfoot syndrome, nausea, vomiting, abdominal pain, fatigue/weakness, hyperbilirubinemia; lymphopenia, necrotizing enterocolitis, stomatitis, dermatitis, anorexia, cardiotoxicity, blood dyscrasias, paresthesias, eye irritation, edema, myalgia, dehydration, alopecia; severe

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DRUG MONOGRAPHS

GASTROINTESTINAL CANCER mucocutaneous reactions (eg, SJS, TEN); permanently discontinue if occurs.

Testing considerations: TS (thymidylate synthase), MSI (microsatellite instability), DPD (dihydropyrimidine dehydrogenase) How supplied: Tabs 150mg—60; 500mg—120

ZALTRAP

℞

Regeneron and Sanofi Aventis

Fusion protein. Ziv-aflibercept 25mg/mL; soln for IV infusion after dilution; preservative-free.

Indications: In combination with 5-fluorouracil, leucovorin, irinotecan (FOLFIRI) for patients with metastatic colorectal cancer (mCRC) that is resistant to or has progressed following an oxaliplatin-containing regimen.

Adults: Start ziv-aflibercept prior to any component of the FOLFIRI regimen on treatment day. Give 4mg/kg as an IV infusion over 1hr every

2 weeks; continue until disease progression or unacceptable toxicity. For recurrent or severe hypertension, suspend until controlled. Upon resumption, permanently reduce to 2mg/kg. For recurrent proteinuria, suspend until proteinuria <2g per 24hrs, then permanently reduce to 2mg/kg.

Children: Not established.

Warnings/Precautions: Increased risk of hemorrhage; monitor for signs/symptoms. Do not start in patients with severe hemorrhage; discontinue if develops. Monitor for GI perforation, fistula formation, compromised wound healing; discontinue if occurs. Suspend therapy at least 4 weeks prior to elective surgery; do not resume for at least 4 weeks following major surgery and until wound is fully healed. Monitor BP every 2 weeks and treat appropriately if hypertension occurs; temporarily suspend until controlled; discontinue if hypertensive crisis/encephalopathy occurs.

Discontinue if arterial thromboembolic events (eg,

transient ischemic attack, cerebrovascular accident, angina pectoris) occur. Monitor for proteinuria; suspend if proteinuria ≥2g per 24hrs; discontinue if nephrotic syndrome or thrombotic microangiopathy occurs. Monitor CBC with differential at baseline and prior to start of each cycle; delay until neutrophils ≥1.5×109/L. Risk of severe diarrhea and dehydration esp. in elderly (monitor). Discontinue if reversible posterior leukoencephalopathy syndrome occurs.

Pregnancy (Cat.C). Use effective contraception during and up to 3 months after the last dose.

Nursing mothers: not recommended.

Adverse reactions: Leukopenia, diarrhea, neutropenia, proteinuria, AST/ALT increased, stomatitis, fatigue, thrombocytopenia, hypertension, weight decreased, decreased appetite, epistaxis, abdominal pain, dysphonia, serum creatinine increased, headache.

How supplied: Single-use vials (100mg/4mL)—1, 3; (200mg/8mL)—1

FDA-APPROVED COLORECTAL CANCER TREATMENTS Generic Brand ALKYLATING AGENTS

Strength

Form

oxaliplatin

5mg/mL

soln for IV infusion Day 1: 85mg/m2 + leucovorin, followed by 5–FU. after dilution Day 2: Leucovorin followed by 5–FU. Give by IV infusion every 2wks for a total of 6mos (eg, 12 cycles).

Eloxatin

Usual Dose

ANTIMETABOLITES capecitabine

Xeloda

150mg, 500mg tabs

1250mg/m2 twice daily for 2wks on and 1wk off, for a total of 8 cycles

fluorouracil

—

50mg/mL

12mg/kg once daily for 4 successive days; max 800mg/day. If no toxicity, then 6mg/kg on days 6, 8, 10, 12; stop after day 12. Discontinue if toxicity occurs.

soln for IV inj

FOLIC ACID DERIVATIVE leucovorin

—

levoleucovorin Fusilev

100mg, 350mg lyophilized pwd for IV or IM inj reconstitution

200mg/m2 by slow IV inj over a minimum of 3min followed by 5-fluorouracil (370mg/m2); or 20mg/m2 IV followed by 5-fluorouracil (425mg/m2); both regimens: daily for 5 days, may be repeated at 4-week intervals for 2 courses and then repeated at 4–5-week intervals

lyophilized powder 100mg/m2 by slow IV inj over a minimum of 3min, followed by 5-FU at for IV inj after 370mg/m2 by IV inj; or 10mg/m2 by IV inj followed by 5-FU at 425mg/m2 reconstitution

by IV inj. Administer 5-FU separately to avoid precipitate formation. Treat daily for 5wks; may repeat at 4-week intervals for 2 courses, then at 4–5175mg/17.5mL, soln for IV inj week intervals.

250mg/25mL 50mg/vial

FUSION PROTEIN ziv-aflibercept Zaltrap

25mg/mL

soln for IV infusion 4mg/kg as an IV infusion over 1hr every 2wks; continue until disease after dilution progression or unacceptable toxicity.

MONOCLONAL ANTIBODIES bevacizumab

Avastin

100mg, 400mg soln for IV infusion 5mg/kg (with bolus–IFL) or 10mg/kg (with FOLFOX–4) once every 14 days after dilution until disease progression detected; 5mg/kg every 2wks or 7.5mg/kg every 3wks (when used with fluoropyrimidine-irinotecan- or fluoropyrimidineoxaliplatin-based therapy). 1st infusion over 90min, 2nd infusion over 60min, subsequent infusion over 30min.

cetuximab

Erbitux

100mg, 200mg soln for IV infusion Loading dose: 400mg/m2 once over 2hrs; then 250mg/m2 once weekly over 1hr

panitumumab Vectibix

20mg/mL

soln for IV infusion 6mg/kg as IV inf over 60min once every 14 days. Doses >1000mg: infuse after dilution over 90min.

TOPOISOMERASE INHIBITORS irinotecan

Camptosar 20mg/mL

soln for IV infusion Combination therapy (with 5-FU and leucovorin): 125mg/m2 on days 1, 8, 15, after dilution 22; or, 180mg/m2 on days 1, 15, 29; both: give every 6wks.

Monotherapy: 125mg/m2 on days 1, 8, 15, 22, then 2-week rest; or, 350mg/m2 once every 3wks.

Notes

Not an inclusive list of medications, official indications and/or dosing details. Please see drug monograph at www.eMPR.com and/or contact company for full (Rev. 1/2015) drug labeling.

36 CANCER THERAPY ADVISOR | SEPTEMBER/OCTOBER 2015 | CancerTherapyAdvisor.com

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DRUG MONOGRAPHS

GENITOURINARY CANCER AFINITOR Novartis

℞

mTOR kinase inhibitor. Everolimus 2.5mg, 5mg, 7.5mg, 10mg; tabs.

Indications: In adults with advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib. In adults with renal angiomyolipoma and tuberous sclerosis complex (TSC), not requiring immediate surgery.

Adults: Swallow tabs whole with water. Take at the same time each day either consistently with or without food. 10mg once daily. Mild hepatic impairment (Child-Pugh class A): 7.5mg daily, may reduce to 5mg if not tolerated. Moderate hepatic impairment (Child-Pugh class B): 5mg daily, may be reduce to 2.5mg if not tolerated.

Severe hepatic impairment (Child-Pugh class C): max 2.5mg daily if benefits outweigh risk.

Concomitant moderate CYP3A4/PgP inhibitors: reduce to 2.5mg once daily; may consider increasing to 5mg if tolerated. If moderate inhibitor is discontinued, allow 2–3 days washout period before increasing everolimus dose; return to dose used prior to initiating the moderate inhibitor. Concomitant strong CYP3A4/PgP inducers: consider doubling the daily dose by increments of 5mg or less. If strong inducer is discontinued, consider washout period of 3–5 days before returning to the dose used prior to initiating the strong inducer. Continue therapy until disease progression or unacceptable toxicity occurs. Dose modifications for adverse reactions, or others: see full labeling.

Children: Not recommended.

Contraindications: Allergy to other rapamycin derivatives.

Warnings/Precautions: Monitor for new or worsening respiratory symptoms. Increased risk of infections; some may be severe or fatal; monitor and treat promptly if occur. Pre-existing invasive fungal infections: treat before starting.

Monitor for signs of wound-related complications. Peri-surgical period. Hepatic impairment (see Adult dose). Monitor CBCs, renal function, lipids, and blood glucose prior to starting and periodically thereafter. Avoid close contact with those who have received live vaccines. Pediatrics: complete childhood vaccination series according to ACIP guidelines prior to initiation. Elderly. Women of childbearing potential should use effective method of contraception during and up to 8 weeks after treatment. Pregnancy (Cat.D), nursing mothers: not recommended.

Interactions: Avoid live vaccines. Potentiated by strong CYP3A4/PgP inhibitors (eg, ketoconazole, itraconazole, clarithromycin,

atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole), grapefruit or grapefruit juice; avoid. Caution with moderate CYP3A4/PgP inhibitors (eg, amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem); reduce everolimus dose if used. Antagonized by strong CYP3A4/PgP inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital), St. John’s Wort; avoid.

Adverse reactions: Pneumonitis (interrupt, reduce dose and/or manage with corticosteroids; if severe, discontinue; may reintroduce daily dose at approx. 50% lower than previously administered), infections (discontinue if invasive systemic fungal infection develops), stomatitis (treat with non-alcoholic, non-peroxide mouthwash), diarrhea, nausea, abdominal pain, rash, fatigue, edema, fever, asthenia, cough, headache, decreased appetite; increased serum creatinine, blood glucose, lipids; decreased hemoglobin, platelets, neutrophils, serum phosphate; proteinuria, renal failure, others (see full labeling).

How supplied: Tabs—28 (4 blister cards × 7 tabs)

AVASTIN Genentech

℞

Angiogenesis inhibitor. Bevacizumab 100mg, 400mg; per vial; soln for IV infusion after dilution; preservative-free.

Indications: Metastatic renal cell carcinoma (mRCC) in combination with interferon alfa.

Adults: Give by IV infusion. Infuse 1st dose over 90 mins; if tolerated, infuse 2nd dose over 60 mins, and subsequent doses over 30 mins.

10mg/kg every 2 weeks with interferon alfa.

Children: Not established.

Warnings/Precautions: Do not start therapy before or for at least 28 days after surgery; allow surgical incisions to completely heal (see full labeling). History of hemoptysis of ≥ ½-teaspoon of red blood: do not administer.

Discontinue if GI perforation, non-GI fistula formation, wound healing complications, serious hemorrhage, severe arterial or Grade 4 venous thromboembolic events, hypertensive crisis, nephrotic syndrome, or posterior reversible encephalopathy syndrome occurs; suspend therapy if severe hypertension, moderate to severe proteinuria (resume when <2g/24hrs), or severe infusion reaction occurs. Cardiovascular disease. Diabetes. Monitor BP every 2–3 weeks.

Monitor proteinuria by dipstick urine analysis.

Elderly. Increased risk of ovarian failure; inform females of reproductive potential prior to starting

therapy. Pregnancy (Cat.C). Nursing mothers: not recommended.

Adverse reactions: Epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain, exfoliative dermatitis; GI perforation, wound dehiscence/ impaired healing, necrotizing fasciitis (discontinue if occurs), hemorrhage, nonGI fistula formation, arterial or venous thromboembolic events, posterior reversible encephalopathy syndrome, infusion reactions, ovarian failure.

How supplied: Single-use vial—1

CASODEX AstraZeneca

℞

Antiandrogen. Bicalutamide 50mg; tabs.

Indications: In combination with luteinizing hormone-releasing hormone (LHRH) analogue in stage D2 metastatic prostate carcinoma.

Adults: Take at the same time each day. 50mg daily. Start treatment at same time as starting LHRH analogue.

Children: Not applicable.

Contraindications: Women of childbearing potential. Pregnancy (Cat.X).

Warnings/Precautions: Moderate to severe hepatic impairment. Monitor prostate specific antigen and hepatic function (discontinue if ALT >2×ULN or if jaundice occurs). Nursing mothers.

Interactions: Monitor oral anticoagulants.

Adverse reactions: Hot flashes, gynecomastia, breast pain, diarrhea, pain, asthenia, infection, dyspnea, impotence, loss of libido, others (see literature); rare: hepatitis.

How supplied: Tabs—30, 100

DELESTROGEN JHP

℞

Estrogen. Estradiol valerate 10mg/mL (in a vehicle containing chlorobutanol 5mg and sesame oil), 20mg/mL (in a vehicle containing benzyl benzoate 224mg, benzyl alcohol 20mg, and castor oil), 40mg/mL (in a vehicle containing benzyl benzoate 447mg, benzyl alcohol 20mg, and castor oil); soln for IM inj.

Indications: Advanced androgen-dependent carcinoma of the prostate (for palliation only).

Adults: Give by deep IM inj into upper, outer quadrant of gluteal muscle. 30mg or more every 1 or 2 weeks.

Children: Not applicable.

Contraindications: Thrombophlebitis.

Thromboembolic disorders. Cerebrovascular disorders. Abnormal undiagnosed genital bleeding. Estrogen-depended neoplasias. Liver dysfunction or disease. Pregnancy (Cat.X).

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DRUG MONOGRAPHS

GENITOURINARY CANCER Warnings/Precautions: Hepatic dysfunction. Conditions aggravated by fluid retention. Cardiovascular disorders, arterial vascular disease, and risks factors (eg, hypertension, diabetes, obesity, SLE). Familial hyperlipoprotenemia. Monitor BP. Discontinue if jaundice occurs and before prolonged immobilization (eg, surgery).

Adverse reactions: See literature. GI upset, headache, hypertension, edema, hypercalcemia, gallbladder or thromboembolic disease, gynecomastia, impotence, impaired glucose tolerance.

How supplied: Multi-dose vials (5mL)—1

ELIGARD 7.5mg 1-MONTH

℞

Tolmar

GnRH analogue. Leuprolide acetate 7.5mg per inj; ext-rel susp; for SC inj.

Also: ELIGARD 22.5mg 3-MONTH ℞ Sanofi Aventis Leuprolide acetate 22.5mg per inj; ext-rel susp; for SC inj.

Also: ELIGARD 30mg 4-MONTH ℞ Sanofi Aventis Leuprolide acetate 30mg per inj; ext-rel susp; for SC inj.

Also: ELIGARD 45mg 6-MONTH ℞ Sanofi Aventis Leuprolide acetate 45mg per inj; ext-rel susp; for SC inj.

Indications: Palliative treatment of advanced prostate cancer.

Adults: Allow product to reach room temperature before using; inject within 30 minutes of mixing. Use correct formulation.

7.5mg SC once per month; or 22.5mg SC once every 3 months; or 30mg SC once every 4 months; or 45mg SC once every 6 months.

Rotate inj site.

Children: Not established.

Contraindications: Women. Pregnancy (Cat.X).

Warnings/Precautions: May worsen metastatic vertebral lesions and/or urinary tract obstruction; monitor closely during first few weeks. Increased risk of diabetes, MI, sudden cardiac death, stroke; monitor blood glucose, HbA1c, and for signs/symptoms of CVD during therapy. Risk of QT prolongation in patients with congenital long QT syndrome, CHF, or frequent electrolyte abnormalities. Correct and monitor electrolyte abnormalities; consider monitoring ECGs. Monitor serum testosterone, PSA periodically. Nursing mothers: not recommended.

Interactions: Caution with concomitant drugs known to prolong the QT interval. May interfere with pituitary-gonadal diagnostic tests.

Adverse reactions: Malaise, fatigue, hot flashes/sweats, testicular atrophy, gynecomastia, local reactions, pain, spinal cord compression, decreased bone density; transient worsening of signs/symptoms (eg, bone pain, neuropathy,

hematuria, bladder outlet obstruction); rare: pituitary apoplexy.

How supplied: Single-use kit—1 (with sterile or sterile safety needle)

EMCYT Pfizer

FIRMAGON Ferring

℞

Estramustine phosphate sodium (prodrug of estradiol) 140mg; caps.

Indications: Palliative of metastatic, progressive prostate cancer.

Adults: Take 1 hour before or 2 hours after meals.

14mg/kg in 3 or 4 divided doses; reevaluate after 30 to 90 days. Continue as long as favorable response maintained.

Children: Not applicable.

Contraindications: Active thrombophlebitis or thromboembolic disorders (except when tumor mass caused by thromboembolic phenomenon).

Allergy to estradiol, nitrogen mustard.

Warnings/Precautions: History of thrombophlebitis, thrombosis, thromboembolic disorders. Cerebro- or cardiovascular disease.

Diabetes. Hypertension. Conditions aggravated by fluid retention. Renal or hepatic dysfunction.

Monitor bilirubin and hepatic enzymes during and for 2 months after treatment is discontinued.

Metabolic bone diseases associated with hypercalcemia. Use effective contraception.

Interactions: Absorption impaired by calcium.

Adverse reactions: Edema, dyspnea, leg cramps; nausea, diarrhea, GI upset; pruritus, dry skin, easy bruising; breast tenderness and enlargement; lethargy, emotional lability, insomnia; leucopenia; abnormal bilirubin, LDH, SGOT. Thrombosis, MI. How supplied: Caps—100

ESTRACE Warner Chilcott

℞

Estrogen. Estradiol 0.5mg, 1mg, 2mg+; scored tabs; +contains tartrazine.

Indications: Palliative treatment of androgendependent advanced prostate cancer.

Adults: 1–2mg 3 times daily.

Children: Not applicable.

Contraindications: Thrombophlebitis.

Thromboembolic disorders. Cerebrovascular disorders. Abnormal undiagnosed genital bleeding. Estrogen-depended neoplasias. Liver dysfunction or disease. Pregnancy (Cat.X).

Warnings/Precautions: Asthma (2mg tabs).

Hepatic dysfunction. Conditions aggravated by fluid retention. Cardiovascular disorders, arterial vascular disease, and risks factors (eg, hypertension, diabetes, obesity, SLE). Familial hyperlipoprotenemia. Monitor BP. Discontinue if jaundice occurs and before prolonged immobilization (eg, surgery). Nursing mothers.

Adverse reactions: See literature. GI upset, headache, hypertension, edema, hypercalcemia, gallbladder or thromboembolic disease, gynecomastia, impotence, impaired glucose tolerance.

How supplied: Tabs—100

℞

GnRH receptor antagonist. Degarelix 80mg/vial, 120mg/vial; pwd for SC inj after reconstitution.

Indications: Advanced prostate cancer.

Adults: Give by SC inj in abdomen once every 28 days; avoid waist and rib areas. Two 120mg injections once, then one 80mg inj once every 28 days.

Children: Not established.

Contraindications: Pregnancy (Cat.X).

Warnings/Precautions: Congenital long QT syndrome. CHF. Correct electrolyte abnormalities. Monitor electrolytes and ECG periodically. Monitor serum PSA. Discontinue if serious hypersensitivity reaction occurs; do not rechallenge. Moderate or severe renal impairment (CrCl <50mL/min). Severe hepatic impairment. Nursing mothers: not recommended.

Interactions: Caution with concomitant drugs known to prolong the QT interval.

Adverse reactions: Inj site reactions (eg, pain, erythema, swelling, induration), hot flashes, increased weight, fatigue, increased transaminases, increased gammaglutamyltransferase; QT prolongation.

How supplied: Treatment Initiation pack (120mg/vial)—2 (w. supplies); Treatment Maintenance pack (80mg/vial)—1 (w. supplies)

Flutamide (various)

℞

Antiandrogen. Flutamide 125mg; caps.

Indications: In combination with LHRH agonists (GnRH analogues) in locally confined stage B2–C and stage D2 metastatic prostate carcinoma.

Adults: 250mg every 8 hrs.

Children: Not applicable.

Contraindications: Severe hepatic impairment.

ALT ≥2×ULN: not recommended.

Warnings/Precautions: Monitor liver function at baseline, monthly for first 4 months, then periodically, and if liver dysfunction occurs; if ALT >2×ULN or jaundice occurs, discontinue and monitor closely until resolution. Monitor prostate specific antigen (PSA). Consider monitoring methemoglobin levels in patients susceptible to aniline toxicity (eg, G6PD deficiency, smokers, hemoglobin M disease). Pregnancy (Cat.D); not for use in women.

Interactions: Monitor warfarin.

Adverse reactions: Diarrhea, hot flashes, loss of libido, impotence, GI disturbances, gynecomastia, rash, edema, hypertension, CNS effects, blood dyscrasias, urine discoloration, liver failure.

How supplied: Contact supplier.

IFEX Baxter

℞

Alkylating agent. Ifosfamide 1g, 3g; per vial; pwd for IV infusion after reconstitution.

Indications: Third-line adjunctive treatment of germ cell testicular cancer.

38 CANCER THERAPY ADVISOR | SEPTEMBER/OCTOBER 2015 | CancerTherapyAdvisor.com

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DRUG MONOGRAPHS

GENITOURINARY CANCER Adults: Give by slow IV infusion over at least 30 mins. 1.2g/m2 per day for 5 consecutive days; repeat every 3 weeks or after hematological recovery (platelets ≥100000/µL, WBC ≥4000/µL).

Children: Not recommended.

Contraindications: Severe bone marrow depression.

Warnings/Precautions: Discontinue if neurologic effects (eg, somnolence, confusion, hallucinations) occur. Do urinalysis before each dose, postpone dose if hematuria occurs. Give mesna and at least 2L fluids daily. Do hematologic profile before each dose; discontinue if WBCs <2000/µL or platelets <50000/µL. May interfere with wound healing. Impaired hepatic, renal, or hematopoetic function. Prior radiation therapy or other cytotoxic agents. Ensure adequate hydration. Pregnancy (Cat.D). Nursing mothers: not recommended.

Interactions: Increased risk of myelosuppression with other chemotherapy agents.

Adverse reactions: Alopecia, GI upset, hematuria, CNS toxicity, infection, renal or liver dysfunction, phlebitis, fever, urotoxicity (eg, hemorrhagic cystitis), leukopenia, thrombocytopenia.

How supplied: Single-dose vials—1

INLYTA Pfizer

℞

Kinase inhibitor. Axitinib 1mg, 5mg; tabs.

Indications: Treatment of advanced renal cell carcinoma (RCC) after failure of one prior systemic therapy.

Adults: Take 12hrs apart. Swallow whole with a glass of water. Initially 5mg twice daily. If tolerated for at least two consecutive weeks with no adverse reactions >Grade 2, normotensive, and not receiving antihypertensives, may increase dose to 7mg twice daily, then 10mg twice daily.

May reduce dose from 5mg twice daily to 3mg twice daily, then 2mg twice daily if additional dose reduction required. Concomitant strong CYP3A4/5 inhibitors: avoid; if warranted, decrease Inlyta dose by approximately ½. If strong CYP3A4/5 inhibitor discontinued, return Inlyta dose (after 3–5 half-lives of the inhibitor) to that used prior to CYP3A4/5 inhibitor initiation.

Moderate hepatic impairment: decrease dose by approximately ½.

Children: Not studied.

Warnings/Precautions: Control and monitor BP prior to and during therapy; discontinue if severe and persistent hypertension (despite antihypertensive therapy and dose reduction).

Risk of thromboembolic events. Untreated

brain metastasis, recent active GI bleed: not recommended. Interrupt therapy if bleeding requires medical intervention. Monitor for signs/symptoms of cardiac failure during therapy; permanently discontinue if occurs.

GI perforation and fistula formation; monitor.

Monitor thyroid, liver function (ALT, AST, bilirubin), and for proteinuria before starting therapy, then periodically. Reduce dose or temporarily interrupt for moderate-to-severe proteinuria.

Risk of reversible posterior leukoencephalopathy syndrome (discontinue if occurs). Stop treatment at least 24hrs prior to scheduled surgery.

Severe hepatic impairment. End-stage renal disease. Pregnancy (Cat.D); avoid. Use adequate contraception during therapy. Nursing mothers: not recommended.

Interactions: See Adult dose. Avoid strong CYP3A4/5 inhibitors (eg, grapefruit juice, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole), CYP3A4/5 inducers (eg, rifampin, dexamethasone, phenytoin, carbamazepine, rifabutin, rifapentin, phenobarbital, St. John’s wort), moderate CYP3A4/5 inducers (eg, bosentan, efavirenz, etravirine, modafinil, nafcillin).

Adverse reactions: Diarrhea, nausea, vomiting, hypertension, fatigue, decreased appetite, dysphonia, palmar-plantar erythrodysesthesia (hand-foot) syndrome, weight decreased, asthenia, constipation.

How supplied: Tabs 1mg—180; 5mg—60

JEVTANA Sanofi Aventis

℞

Antimicrotubule agent. Cabazitaxel 60mg/1.5mL; soln for IV infusion after dilution; contains polysorbate 80, diluent contains ethanol.

Indications: In combination with prednisone, hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing regimen.

Adults: Pretreat with IV antihistamine, corticosteroid, and H2 blocker 30 mins before each dose (see full labeling) and with antiemetic (IV or oral as needed). 25mg/m2 by IV infusion over 1hr every 3 weeks, with oral prednisone 10mg/day during treatment. Do not treat if neutrophil count ≤1,500 cells/mm3. Prolonged grade ≥3 neutropenia (>1 week), febrile neutropenia, grade ≥3 diarrhea: delay treatment and/or reduce dose to 20mg/m2 (see full labeling). Discontinue if reactions persist after dosing at 20mg/m2.

Children: Not established.

Contraindications: Baseline neutrophil count ≤1,500cells/mm3. Allergy to polysorbate 80.

Warnings/Precautions: Do CBC weekly in 1st cycle and before each subsequent cycle. Increased risk of neutropenia complications; consider G-CSF prophylaxis. Discontinue if hypersensitivity reactions occur. Increased risk of GI disorders in patients with neutropenia, age, or history of pelvic radiotherapy, adhesions, ulceration, and GI bleeding. Evaluate and treat if serious GI toxicity occurs; treatment delay or discontinuation may be needed. Hepatic impairment: not recommended.

Severe renal impairment (CrCl <30mL/min) or ESRD. Elderly (increased susceptibility to adverse reactions); monitor closely. Pregnancy (Cat.D); avoid. Nursing mothers: not recommended.

Interactions: Avoid concomitant strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) (may potentiate cabazitaxel); caution with moderate CYP3A4 inhibitors. Avoid concomitant strong CYP3A4 inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital) (may antagonize cabazitaxel). Avoid St. John’s Wort. Increased GI toxicity with concomitant steroids, NSAIDs, antiplatelets, anticoagulants.

Adverse reactions: Bone marrow suppression (esp. neutropenia, anemia, leukopenia, thrombocytopenia), febrile neutropenia, diarrhea (may be fatal), nausea, vomiting, constipation, fatigue, asthenia, abdominal pain, hematuria, back pain, anorexia, peripheral neuropathy, pyrexia, dyspnea, dysgeusia, cough, arthralgia, alopecia; renal failure, hypersensitivity reactions (eg, rash, hypotension, bronchospasm).

How supplied: Kit (single-use vial + diluent)—1

LUPRON DEPOT 7.5mg AbbVie ℞ GnRH analogue. Leuprolide acetate 7.5mg; depot susp for IM inj.

Indications: Palliative treatment of advanced prostatic carcinoma.

Adults: 7.5mg IM once a month. Rotate inj site.

Children: Not applicable. ℞ Also: LUPRON DEPOT-6 MONTH 45mg Leuprolide acetate 45mg; depot susp for IM inj.

Adults: 45mg as single IM inj every 6 months (24 weeks). Do not split doses.

Children: Not applicable. ℞ Also: LUPRON DEPOT-3 MONTH 22.5mg Leuprolide acetate 22.5mg; depot susp for IM inj.

Adults: 22.5mg IM inj every 3 months (84 days).

Do not split doses.

Children: Not applicable.

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CancerTherapyAdvisor.com | SEPTEMBER/OCTOBER 2015 | CANCER THERAPY ADVISOR 39

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DRUG MONOGRAPHS

GENITOURINARY CANCER ℞ Also: LUPRON DEPOT-4 MONTH 30mg Leuprolide acetate 30mg; depot susp for IM inj; preservative-free.

Adults: 30mg as single IM inj every 4 months (16 weeks). Do not split doses.

Children: Not applicable.

Contraindications: Pregnancy (Cat.X).

Warnings/Precautions: Metastatic vertebral lesions. Urinary obstruction. Monitor serum testosterone, PSA, acid phosphatase. Increased risk of diabetes, MI, sudden cardiac death, stroke; monitor blood glucose, HbA1c, and for signs/ symptoms of CVD during therapy. History of seizures. Risk of QT prolongation: long-term androgen deprivation therapy, congenital long QT syndrome, electrolyte abnormalities, or CHF. Correct and monitor electrolyte abnormalities; consider monitoring ECGs. Instruct patient on correct self administration. Nursing mothers: not recommended.

Interactions: Concomitant antiarrhythmics may prolong the QT interval.

Adverse reactions: Hot flashes/sweats, inj site reaction, initial worsening of signs/ symptoms (eg, bone pain, urinary tract obstruction, hematuria), edema, GI disorders, pain, cardiovascular events, CNS and antiandrogenic effects, asthenia, testicular atrophy, urinary disorders, spinal cord compression; hyperglycemia, anaphylactoid, photosensitivity.

How supplied: Depot kit—1 (prefilled dualchamber syringe w. supplies)

MENEST Pfizer

℞

Estrogen. Esterified estrogens 0.3mg, 0.625mg, 1.25mg, 2.5mg; tabs.

Indications: Palliative treatment of androgendependent advanced prostate cancer.

Adults: 1.25–2.5mg 3 times daily.

Children: Not applicable.

Contraindications: Thrombophlebitis.

Thromboembolic disorders. Cerebrovascular or coronary artery disease. Pregnancy (Cat.X).

Warnings/Precautions: Hepatic dysfunction.

Gallbladder disease. Conditions aggravated by fluid retention. Familial hyperlipoproteinemia.

Discontinue if jaundice occurs. Nursing mothers.

Adverse reactions: See literature. Migraine, depression, edema, weight changes, hypertension, GI upset, gynecomastia, impotence.

How supplied: Tabs 2.5mg—50 0.3mg, 0.625mg, 1.25mg—100

NEXAVAR Bayer and Onyx

℞

Multikinase inhibitor. Sorafenib 200mg; tabs.

Indications: Advanced renal cell carcinoma.

Adults: Take on an empty stomach. 400mg twice daily. If toxicity occurs, may reduce dose to 400mg once daily; if further dose reduction required, may reduce dose to 400mg every other day (see full labeling). Concomitant strong

CYP3A4 inducers: consider increasing dose, monitor for toxicity.

Children: Not established.

Contraindications: Concomitant carboplatin/ paclitaxel in patients with squamous cell lung cancer.

Warnings/Precautions: Avoid in congenital long QT syndrome. Monitor patients with CHF, bradyarrhythmias, drugs known to prolong the QT interval, electrolyte abnormalities. Discontinue if severe dermatologic toxicity, hypertension, GI perforation, hemorrhage, cardiac ischemia, MI occurs. Suspend therapy before major surgery.

Monitor BP weekly during the first 6 weeks and thereafter. Monitor hepatic function regularly; discontinue if transaminases significantly elevated. Severe hepatic impairment (Child-Pugh C) or on dialysis. Use effective contraception during and for 2 weeks after stopping treatment.

Pregnancy (Cat.D), nursing mothers: not recommended.

Interactions: See Contraindications. Avoid strong CYP3A4 inducers (eg, St. John’s Wort, dexamethasone, phenytoin, carbamazepine, rifabutin, rifampin, phenobarbital) and neomycin; may decrease sorafenib levels. May potentiate warfarin (monitor PT & INR), other drugs metabolized by UGT1A1 or UGT1A9 pathway, or substrates of CYP2B6, CYP2C8, CYP2C9, P-gp.

Concomitant Class Ia and III antiarrhythmics; may prolong QT interval.

Adverse reactions: Dermatologic toxicity (eg, rash, hand-foot skin reaction, alopecia, pruritus, dry skin, Stevens-Johnson syndrome, toxic epidermal necrolysis), fatigue, weight loss, diarrhea, anorexia, abdominal pain, hypertension, hemorrhage, electrolyte abnormalities; drug-induced hepatitis, QT prolongation.

How supplied: Tabs—120

PREMARIN Pfizer

℞

Estrogen. Conjugated estrogens 0.3mg, 0.45mg, 0.625mg, 0.9mg, 1.25mg; tabs.

Indications: Treatment of advanced androgendependent carcinoma of the prostate (for palliation only).

Adults: 1.25mg–2.5mg 3 times daily.

Children: Not applicable.

Contraindications: Known, suspected, or history of breast cancer, except in appropriately selected patients being treated for metastatic disease. Known or suspected estrogen-dependent neoplasia. Undiagnosed abnormal genital bleeding. Pulmonary embolism/DVT (active or history of). Arterial thromboembolism (eg, stroke, MI; active or history of). Liver dysfunction or disease. Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders. Known or suspected pregnancy (Cat.X).

Warnings/Precautions: Not for prevention of cardiovascular disease. Use for shortest duration consistent with treatment goals

and risks. Reevaluate periodically. Patients with an intact uterus should almost always receive a progestin with systemic estrogens to avoid endometrial hyperplasia. Discontinue if cardiovascular events occur or are suspected; if jaundice occurs; and during immobilization or at least 4–6 weeks before surgery associated with thromboembolism. Hepatic dysfunction.

Conditions aggravated by fluid retention.

Gallbladder disease. Bone disease associated with hypercalcemia. Hereditary angioedema.

Do initial complete physical and repeat annually (include BP, mammogram, PAP smear). Adolescents. Nursing mothers: not recommended.

Adverse reactions: See literature. Increased risk of cardiovascular events, estrogendependent carcinoma, gallbladder disease, thromboembolic disorders, hepatic tumors. GI upset, breakthrough bleeding, edema, weight changes, mastodynia, hypertension, depression, anaphylactic reactions, angioedema, intolerance to contact lenses.

How supplied: Tabs 0.3mg, 0.625mg, 1.25mg— 100, 1000; 0.45mg, 0.9mg—100

PROLEUKIN Prometheus

℞

Interleukin-2, recombinant. Aldesleukin 22 million IU/vial; pwd for IV infusion after reconstitution and dilution; contains mannitol; preservative-free.

Indications: Metastatic renal cell carcinoma.

Adults: ≥18yrs: 600,000 IU/kg (0.037mg/kg) every 8 hours by IV infusion over 15 minutes for a max of 14 doses, followed by 9 days rest, then repeat for another 14 doses (max 28 doses/ course), as tolerated. Retreatment and dose adjustments: see literature.

Children: <18yrs: not established.

Contraindications: Abnormal thallium stress test or pulmonary function tests. Organ allografts.

Previous drug related toxicity (eg, sustained ventricular tachycardia [≥5 beats], uncontrolled or unresponsive arrhythmias, chest pain with ECG changes consistent with angina, or MI, cardiac tamponade, intubation >72hrs, renal failure requiring dialysis >72hrs, coma or toxic psychosis >48hrs, repetitive or difficult seizures, bowel ischemia or perforation, GI bleeding requiring surgery).

Warnings/Precautions: See literature.

History of cardiac or pulmonary disease. Renal, hepatic, or CNS impairment. Seizure disorder.

Bacterial infections (treat prior to starting therapy; esp. patients with indwelling central lines). Withhold dose if organ perfusion is not maintained, urine output is reduced, systolic BP <90mmHg, CHF, cardiac ischemia or arrhythmias occur; or if moderate-to-severe lethargy or somnolence (continuing may result in coma) develops. Evaluate and treat CNS metastases; obtain negative scan before starting treatment.

Do thallium stress test; monitor vital signs, weight, fluid intake and output daily. Correct hypovolemia or fluid accumulations if occur.

40 CANCER THERAPY ADVISOR | SEPTEMBER/OCTOBER 2015 | CancerTherapyAdvisor.com

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DRUG MONOGRAPHS

GENITOURINARY CANCER Obtain CBCs, differential and platelets, blood chemistries (electrolytes, renal and hepatic function tests), chest X-rays, serum creatinine (should be ≤1.5mg/dL before starting therapy), pulmonary function tests, arterial blood gases.

Monitor for capillary leak syndrome, mental status changes, thyroid changes, diabetes onset.

Elderly. Pregnancy (Cat.C). Nursing mothers: not recommended.

Interactions: Psychotropics may increase CNS toxicity. Increased toxicity with other nephrotoxic, hepatotoxic, myelotoxic, or cardiotoxic drugs. Hypersensitivity reactions with other antineoplastics. Myocardial injury and rhabdomyolysis risk increased with interferonalfa. Antagonized by glucocorticoids (avoid). β-blockers and other antihypertensives may potentiate hypotension. Delayed reactions to iodinated contrast media. May increase risk of allograft rejection.

Adverse reactions: Hypotension, GI upset, oliguria, flu-like syndrome, respiratory disorders (eg, dyspnea), CNS effects (eg, confusion, somnolence), rash, metabolic and nutritional disorders (eg, bilirubinemia, increased creatinine), hyperglycemia, thyroid disorder, thrombocytopenia, anemia, impaired neutrophil function, capillary leak syndrome, cardiotoxicity, exacerbation of autoimmune and inflammatory disease, eosinophilia, possible antibody formation; others.

How supplied: Single-use vials—1

PROVENGE Dendreon

℞

Autologous cellular immunotherapy. Sipuleucel-T (autologous CD54+ cells activated with PAP-GMCSF); minimum 50 million cells/dose; suspension for IV infusion.

Indications: Asymptomatic or minimally symptomatic metastatic castrate-resistant (hormone-refractory) prostate cancer.

Adults: Autologous use only. Obtain product release from manufacturer, match patient identity on product and Cell Product Disposition form, check expiration date and time on product before infusing. Premedicate 30 minutes before infusion with acetaminophen and antihistamine. Give three doses at 2-week intervals. For each dose: give entire contents of bag by IV infusion over 60 minutes; do not use filter; do not use if clumps do not disperse with gentle mixing. Observe patient for at least 30 minutes after infusion. May interrupt or slow infusion if acute transfusion reaction occurs; do not restart if product at room temp for >3 hours.

Children: Not applicable.

Warnings/Precautions: Cardiac or pulmonary conditions. Each dose requires a standard leukapheresis procedure about 3 days before infusion. If scheduled infusion is missed, do an additional leukapheresis procedure if treatment course is to be continued. Risk of disease transmission. Pregnancy, lactation: not applicable.

Interactions: May be antagonized by concomitant chemotherapy or immunosuppressive therapy.

Adverse reactions: Infusion reactions (eg, chills, fever, respiratory events, GI upset, hypertension, tachycardia), fatigue, back pain, joint ache, headache.

Note: If product sterility tests indicate microbial contamination, manufacturer will contact physician (tests are incomplete at time of infusion).

How supplied: Patient-specific bag (250mL)—1

SUTENT Pfizer

℞

Multikinase inhibitor. Sunitinib (as malate) 12.5mg, 25mg, 37.5mg, 50mg; gelatin caps.

Indications: Advanced renal cell carcinoma (RCC).

Adults: 50mg once daily for 4 weeks, then 2 weeks off (see full labeling). May adjust dose in increments or decrements of 12.5mg.

Concomitant strong CYP3A4 inhibitors (see Interactions): may reduce dose to 37.5mg daily.

Concomitant strong CYP3A4 inducers (see Interactions): may increase to max 87.5mg daily.

Children: Not established.

Warnings/Precautions: Hepatotoxicity; may be severe or fatal. Monitor liver function tests before starting, during each cycle of treatment and as clinically needed; interrupt if Grade 3 or 4 hepatic adverse events occur and discontinue if no resolution; if severe liver function changes or signs/symptoms of failure, do not restart.

Cardiovascular events: monitor for CHF during therapy, and LVEF at baseline and periodically; interrupt or reduce dose if LVEF <50% and >20% below baseline; discontinue if CHF occurs.

History of QT prolongation or proarrythmic conditions (eg, bradycardia, electrolyte disturbances); perform periodic ECG, monitor electrolytes. Monitor BP. Suspend therapy if severe hypertension, seizures, or pancreatitis develops. Obtain CBCs, platelets, serum chemistries at start of each cycle. Concomitant exposure to risk factors (eg, IV bisphosphonates therapy or dental disease) may increase the risk of osteonecrosis of the jaw; avoid or consider preventive dentistry prior to treatment. Risk of

tumor lysis syndrome: monitor closely in RCC and GIST patients with high tumor burden. Monitor for thyroid dysfunction; obtain baseline levels prior to treatment. Monitor blood glucose levels during and after treatment discontinuation.

Monitor for proteinuria; perform baseline and periodic urinalyses; interrupt and reduce dose if 24-hr urine protein ≥3g; discontinue if nephrotic syndrome or repeat urine protein ≥3g persists.

Undergoing major surgery. Stress (monitor for adrenal insufficiency). Discontinue if severe cutaneous reactions (eg, erythema multiforme, SJS, TEN) develop; do not restart if diagnosis suspected. ESRD on dialysis. Severe hepatic impairment. Pregnancy (Cat.D; avoid). Nursing mothers: not recommended.

Interactions: May be potentiated by strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole), grapefruit; consider reducing dose or use alternate drug. May be antagonized by CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital); consider increasing dose or use alternate drug. Concomitant St. John’s wort: not recommended. Caution with concomitant antiarrhythmics.

Adverse reactions: Fatigue, asthenia, fever, diarrhea, nausea, vomiting, mucositis/stomatitis, dyspepsia, abdominal pain, constipation, hypertension, peripheral edema, rash, handfoot syndrome, skin discoloration, dry skin, hair color changes, altered taste, headache, back pain, arthralgia, extremity pain, cough, dyspnea, anorexia, bleeding; hepatotoxicity, left ventricular dysfunction, QT prolongation, osteonecrosis of the jaw, tumor lysis syndrome, thyroid dysfunction, impaired wound healing, hypoglycemia, thrombotic microangiopathy (discontinue if develops), proteinuria, necrotizing fasciitis (discontinue if occurs), others (see full labeling).

How supplied: Caps—28

THERACYS Sanofi Pasteur

℞

BCG Live. Live Bacillus Calmette and Guerin (BCG) strain of attenuated Mycobacterium bovis; 81mg per vial; pwd for intravesical administration after reconstitution and dilution; preservativefree.

Indications: Treatment and prophylaxis of carcinoma in situ (CIS) of the urinary bladder.

Prophylaxis of stage Ta and/or T1 papillary tumors following transurethral resection (TUR).

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CancerTherapyAdvisor.com | SEPTEMBER/OCTOBER 2015 | CANCER THERAPY ADVISOR 41

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DRUG MONOGRAPHS

GENITOURINARY CANCER Adults: Drain bladder via urethral catheter prior to instillation. Induction: Instill 1 dose intravesically once per week for 6 weeks.

Maintenance: one dose at 3, 6, 12, 18, and 24 months after initial dose. Retain in bladder for up to 2 hours, then void seated. Increase fluid intake to flush bladder.

Children: Not recommended.

Contraindications: Immunosuppressed. Active TB. Febrile illness. UTI (withhold until complete resolution). Gross hematuria. Do not give within 7–14 days after biopsy, TUR, or traumatic catheterization.

Warnings/Precautions: Not for the prevention of cancer or TB. Determine PPD status prior to therapy; rule out active TB if (+). Not for stage TaG1 papillary tumors unless high tumor recurrence risk. Not for IV, IM, or SC injection.

Monitor for systemic BCG reaction; may occur as a hypersensitivity reaction (eg, malaise, fever, chills) or active infection (eg, fever ≥101.3°F, or acute localized inflammation such as epididymitis, prostatitis, or orchitis persisting ≥2 days); if persistent fever or acute febrile illness consistent with BCG infection occurs, discontinue BCG permanently and treat with ≥2 antimycobacterial drugs (except pyrazinamide). Local irritative effects: do not use antimycobacterial drugs prophylactically. Preexisting arterial aneurysm or prosthetic devices: risk of ectopic BCG infection. High-risk for HIV. Latex allergy. Small bladder. PPD seroconversion may occur with treatment. Pregnancy (Cat.C).

Nursing mothers: not recommended.

Interactions: See contraindications.

Immunosuppressants, myelosuppressants, radiation, antimicrobial therapy may reduce efficacy.

Adverse reactions: Bladder irritation, inflammation (begins after 4 hrs and last up to 72 hrs), dysuria, urinary frequency, malaise, hematuria, fever, chills, cystitis, anemia, UTI, GI upset, renal toxicity, genital pain, arthralgia, incontinence, cramps, flu-like syndrome, systemic BCG infection.

How supplied: Vial—1 (w. diluent)

TORISEL Pfizer

℞

mTOR kinase inhibitor. Temsirolimus 25mg/mL; ethanolic soln for IV infusion after two dilutions (first w. supplied diluent); contains alcohol, polysorbate 80.

Indications: Advanced renal cell carcinoma.

Adults: 25mg once weekly. Infuse IV over 30–60min, using an infusion pump. Continue until disease progression or unacceptable toxicity occurs. Premedicate with IV antihistamine (eg, diphenydramine). Hold dose if ANC <1000/mm3, platelets <75000/mm3, or NCI CTCAE ≥Grade 3 adverse reaction occurs; may restart at a dose reduced by 5mg/week (no lower than 15mg/week) if adverse reactions resolve to ≤Grade 2. Hepatic impairment: bilirubin >1–1.5×ULN or AST > ULN but bilirubin

≤ ULN: reduce to 15mg/week; >1.5×ULN: contraindicated. See Interactions.

Children: Not recommended.

Contraindications: Bilirubin >1.5×ULN. Warnings/Precautions: Sirolimus or related allergy. Hemodialysis. Perioperative period (may interfere with wound healing). CNS tumors.

Monitor for opportunistic infections; consider prophylaxis for pneumocystis jiroveci pneumonia (PJP) when concomitant corticosteroids, other immunosuppresives required. Monitor for interstitial lung disease (ILD); discontinue if suspected. Monitor CBCs weekly and chemistry panels every 2 weeks, blood glucose, lipids, renal function, and for worsening respiratory or GI symptoms (eg, acute abdomen, blood in stool). Elderly. Pregnancy (Cat.D) (avoid pregnancy during and for 3 months after therapy, male patients should use appropriate contraception), nursing mothers: not recommended.

Interactions: Avoid strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole, grapefruit juice); if used, consider reducing temsirolimus dose to 12.5mg/week (allow 1 week after discontinuing CYP3A4 inhibitor before readjusting temsirolimus dose). Avoid strong CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifampicin, phenobarbital, St. John’s Wort); if used, consider increasing temsirolimus dose to 50mg/week. Avoid live vaccines, close contact with vaccinees. Additive toxicity with sunitinib (rash, gout/cellulitis), anticoagulants (intracerebral bleeding).

Adverse reactions: Rash, asthenia, mucositis, nausea, edema, anorexia, infection, pain, anemia, hyperglycemia, hyperlipemia, hypertriglyceridemia, elevated alkaline phosphatase, elevated serum creatinine, lymphopenia, hypophosphatemia, thrombocytopenia, elevated AST, leukopenia; hypersensitivity/infusion reactions (anaphylaxis, dyspnea, flushing, chest pain), immunosuppression, PJP, ILD, bowel perforation, acute renal failure, abnormal wound healing; others (see full labeling).

How supplied: Kit (vial + diluent)—1

TRELSTAR Actavis

℞

GnRH analogue. Triptorelin pamoate 3.75mg, 11.25mg, 22.5mg; pwd for IM inj after reconstitution; contains mannitol.

Indications: Palliative treatment of advanced prostate cancer.

Adults: Give by IM inj in buttock. 3.75mg every 4 weeks, or 11.25mg every 12 weeks, or 22.5mg every 24 weeks.

Children: Not established.

Contraindications: Women. Pregnancy (Cat.X).

Warnings/Precautions: Must administer under physician supervision. Discontinue if

hypersensitivity occurs. Initial transient increase in serum testosterone may result in worsening of symptoms. Spinal cord compression. Renal or hepatic impairment. Metastatic vertebral lesions. Upper or lower urinary tract obstruction.

Increased risk of diabetes, MI, sudden cardiac death, stroke; monitor blood glucose and for signs/symptoms of CVD during therapy.

Interactions: Avoid hyperprolactinemic drugs.

Adverse reactions: Inj site reactions, hot flushes, skeletal pain, fatigue, hypertension, headache, dizziness, diarrhea, vomiting, leg edema, insomnia, impotence, emotional lability, anemia, pruritus, urinary retention, UTI, erectile dysfunction, testicular atrophy; hyperglycemia.

How supplied: Single-dose vial—1 MixJect system—1 (vial + vial adapter + prefilled syringe)

VALSTAR Endo

℞

Anthracycline. Valrubicin 40mg/mL; soln for intravesical instillation after dilution; contains 50% polyoxyl castor oil/50% dehydrated alcohol; preservative-free.

Indications: Intravesical therapy of BCGrefractory carcinoma in situ (CIS) of the urinary bladder in patients for whom immediate cystectomy would be associated with unacceptable morbidity or mortality.

Adults: Drain bladder before instilliation. 800mg given intravesically via urethral catheter once weekly for 6 weeks. Retain drug for 2 hours before voiding, then void.

Children: Not recommended.

Contraindications: Concurrent UTI. Small bladder capacity (eg, unable to tolerate a 75mL instillation).

Warnings/Precautions: Monitor for disease recurrence or progression with cystoscopy, biopsy, and urine cytology every 3 months; if there is not a complete response of CIS to treatment after 3 months or if CIS recurs, cystectomy must be reconsidered. Severe irritable bladder symptoms. Perforated bladder. Bladder mucosa compromised.

Delay administration for at least 2 weeks after transurethral resection and/or fulguration.

Maintain adequate hydration. Pregnancy (Cat.C); avoid, both males and females should use effective birth control. Nursing mothers: not recommended.

Adverse reactions: Bladder symptoms (eg, urinary frequency, dysuria, urinary urgency, spasm, hematuria, pain, incontinence, cystitis, nocturia, local burning, urethral pain, pelvic pain, UTI).

How supplied: Single-use vials—4, 24

VANTAS Endo

℞

GnRH analogue. Histrelin acetate 50mg; SC implant.

Indications: Palliative treatment of advanced prostate cancer.

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DRUG MONOGRAPHS

GENITOURINARY CANCER Adults: Insert 1 implant SC in the inner aspect of the upper arm. Remove after 12 months; may replace.

Children: Not applicable.

Contraindications: Pregnancy (Cat.X).

Nursing mothers. Not for use in women or children.

Warnings/Precautions: Initial transient increase in serum testosterone may result in worsening signs/symptoms (eg, bone pain, neuropathy, hematuria). Metastatic vertebral lesions, urinary tract obstruction (monitor closely in 1st few weeks). Avoid wetting inserted arm for 24hrs and heavy lifting or strenuous exertion for 1st week. Increased risk of developing diabetes; monitor blood glucose and HbA1c periodically; treat if occurs.

Increased risk of developing MI, sudden cardiac death, stroke; monitor for signs/symptoms of cardiovascular disease. May prolong QT/ QTc interval in patients with congenital long QT syndrome, CHF, electrolyte abnormalities; monitor ECGs. If electrolyte abnormalities occur, correct and monitor. Measure serum testosterone, PSA levels periodically. Implant not visible on X-ray.

Interactions: May interfere with pituitary gonadotropic and gonadal function tests. Caution with concomitant drugs known to prolong the QT interval.

Adverse reactions: Hot flashes, fatigue, implant site reactions, testicular atrophy, renal impairment; hyperglycemia, diabetes, cardiovascular disease.

How supplied: Kit—1 (w. implant and supplies)

VOTRIENT GlaxoSmithKline

℞

Tyrosine kinase inhibitor. Pazopanib 200mg; tabs.

Indications: Advanced renal cell carcinoma.

Limitation of use: not for treating adipocytic soft tissue sarcoma or gastrointestinal stromal tumors.

Adults: Take on an empty stomach. Swallow whole. 800mg once daily. Dose adjustments: see full labeling. Hepatic impairment: moderate: 200mg once daily; severe: not recommended.

Concomitant strong CYP3A4 inhibitors (eg, ketoconazole, ritonavir, clarithromycin): avoid and consider alternate drug; if warranted, reduce dose of pazopanib to 400mg; may reduce further if toxicity occurs. Concomitant strong CYP3A4 inducers (eg, rifampin): avoid and consider alternate drug.

Children: Not established (increased toxicity in developing organs).

Warnings/Precautions: Not indicated for use in combination with other cancer agents. Risk of severe and fatal hepatotoxicity (esp. ≥65yrs old). Monitor liver tests before starting and at Weeks 3, 5, 7, and 9, thereafter at Months 3 and 4, then periodically. If ALT between 3×ULN and 8×ULN continue therapy with weekly monitoring until ALT returns to Grade 1 or baseline. If ALT >8×ULN interrupt therapy until ALT returns to Grade 1 or baseline; may consider reintroducing at a reduced dose, measure liver tests weekly for 8 weeks; if ALT>3×ULN recurs, permanently discontinue. Permanently discontinue if ALT>3×ULN and bilirubin >2×ULN. Gilbert’s syndrome (see full labeling). History of QT prolongation. Cardiac dysfunction risk: evaluate LVEF at baseline and periodically; monitor for CHF. Monitor ECG, electrolytes (eg, calcium, magnesium, potassium), thyroid function. History of hemoptysis, cerebral, or clinically significant GI hemorrhage in the past 6 months: not recommended. Risk of arterial thrombotic events (within previous 6 months: not recommended).

Monitor for VTE, PE, infection, proteinuria (reduce dose if 24-hour urine protein ≥3g), thrombotic microangiopathy, GI perforation or fistula.

Monitor BP and manage hypertension promptly.

Discontinue if severe and persistent hypertension (despite antihypertensives and dose reduction), if repeat episodes of proteinuria (despite dose reductions), thrombotic microangiopathy, or serious infection occurs. Stop therapy at least 7 days before surgery; discontinue in patients with wound dehiscence. Pregnancy (Cat.D), nursing mothers: not recommended.

Interactions: See Adult dosing: Potentiated by strong CYP3A4 inhibitors, grapefruit juice. Avoid concomitant strong Pgp or BCRP inhibitors.

Antagonized by strong CYP3A4 inducers.

Concomitant drugs with narrow therapeutic windows metabolized by CYP3A4, CYP2D6, or CYP2C8: not recommended. Increased risk of ALT elevations with concomitant simvastatin; caution and monitor closely; follow dosing guidelines or consider alternatives to pazopanib, or discontinuing simvastatin if develops.

Separate antacids by several hours. Caution with concomitant drugs that prolong QT interval (eg, antiarrhythmics).

Adverse reactions: Diarrhea, hypertension, hair color changes, nausea, anorexia, vomiting, fatigue, decreased weight, decreased appetite, tumor pain, musculoskeletal pain, headache, dysgeusia, dyspnea, skin hypopigmentation; hepatoxicity, QT prolongation, hemorrhagic events, arterial thrombotic events (eg, MI, angina, ischemic stroke, TIA), venous thrombotic events (eg, VTE,

PE), GI perforation or fistula, impaired wound healing, hypothyroidism, proteinuria, infection, reversible posterior leukoencephalopathy syndrome (discontinue if occurs).

How supplied: Tabs—120

XOFIGO Bayer

℞

Alpha particle-emitting radioactive therapeutic agent. Radium Ra 223 dichloride 1000 kBq/mL (27 microcurie/mL) with a total radioactivity of 6000 kBq/vial (162 microcurie/vial) at the reference date; IV injection.

Indications: Treatment of patients with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastatic disease.

Adults: See full labeling. Administer by slow IV over 1 min. 50kBq (1.35 microcurie) per kg given at 4 week intervals for 6 injections.

Children: <18yrs: not established.

Contraindications: Women who are or may become pregnant. Pregnancy (Cat.X).

Warnings/Precautions: Not for use in women.

Bone marrow suppression. Perform hematologic evaluation at baseline and prior to every dose.

Before 1st dose, the ANC should be ≥1.5 ×109/L, platelets ≥100 ×109/L and hemoglobin ≥10g/dL. Before subsequent doses, the ANC should be ≥1 ×109/L and platelets ≥50 ×109/L; discontinue if no recovery within 6–8 weeks after last dose despite receiving supportive care. Monitor closely if evidence of compromised bone marrow reserve.

Discontinue if life-threatening complications occur despite supportive care for bone marrow failure. Monitor oral intake and fluid status carefully. Males (use condoms) and female partners of reproductive potential should use highly effective contraceptive method during and 6 months after completion. Nursing mothers: not recommended.

Interactions: Concomitant chemotherapy: not established. Discontinue if concomitant with chemotherapy, other systemic radioisotopes or hemibody external radiotherapy.

Adverse reactions: Nausea, diarrhea, vomiting, peripheral edema, anemia, lymphocytopenia, leukopenia, thrombocytopenia, neutropenia.

How supplied: Single-use vials (6mL)—1

XTANDI Astellas

℞

Androgen receptor inhibitor. Enzalutamide 40mg; soft gelatin caps.

Indications: Treatment of metastatic castrationresistant prostate cancer.

Adults: Swallow whole. 160mg once daily. Dose modifications: ≥Grade 3 toxicity or intolerable

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CancerTherapyAdvisor.com | SEPTEMBER/OCTOBER 2015 | CANCER THERAPY ADVISOR 43

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DRUG MONOGRAPHS

GENITOURINARY CANCER side effect: withhold dosing for 1 week or until symptoms improve to ≤Grade 2, then resume at same or reduced dose (120mg or 80mg), if warranted. Concomitant strong CYP2C8 inhibitors: avoid if possible. If co-administration necessary, reduce enzalutamide dose to 80mg once daily; if inhibitor is discontinued, return enzalutamide dose to the dose used prior to initiation of inhibitor.

Children: Not established.

Contraindications: Pregnancy (Cat.X).

Warnings/Precautions: Risk of seizure; permanently discontinue if develops during treatment. Severe renal or hepatic impairment.

Nursing mothers: not recommended.

Interactions: Avoid concomitant strong CYP2C8 inhibitors (eg, gemfibrozil) if possible; reduce enzalutamide dose if cannot be avoided.

Avoid concomitant CYP2C8 inducers (eg, rifampin), CYP3A4 inducers (eg, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, bosentan, efavirenz, etravirine, modafinil, nafcillin), and St. John’s Wort if possible. Potentiated by CYP3A4 inhibitors (itraconazole). Antagonizes midazolam (CYP3A4 substrate), warfarin (CYP2C9 substrate), and omeprazole (CYP2C19 substrate). Avoid concomitant drugs with narrow therapeutic indexes metabolized by CYP3A4 (eg, alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus), CYP2C9 (eg, phenytoin, warfarin), CYP2C19 (eg, S-mephenytoin); enzalutamide may decrease their exposure. Caution with concomitant drugs that may lower the seizure threshold. Conduct more INR monitoring if concomitant warfarin cannot be avoided.

Adverse reactions: Asthenia/fatigue, back pain, decreased appetite, constipation,

arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight decreased, headache, hypertension, dizziness/vertigo.

How supplied: Caps—120

ZYTIGA Janssen Biotech

℞

CYP17 inhibitor. Abiraterone acetate 250mg; tablets.

Indications: In combination with prednisone for the treatment of metastatic castration-resistant prostate cancer.

Adults: Take on empty stomach (no food 2 hours before or 1 hour after administration). Swallow whole with water. 1g once daily (in combination with prednisone 5mg twice daily). Moderate hepatic impairment (Child-Pugh Class B): 250mg once daily. If hepatotoxicity occurs: interrupt, then restart at reduced dose; discontinue if severe (see full labeling). If concomitant strong CYP3A4 inducer necessary, increase abiraterone dose frequency to twice daily during co-administration period (eg, from 1g once daily to 1g twice daily); reduce back to previous dose/frequency when CYP3A4 inducer is discontinued.

Children: Not established.

Contraindications: Pregnancy (Cat.X). Women who are or may become pregnant.

Warnings/Precautions: Risk of mineralocorticoid excess: patients with history of cardiovascular disease, LVEF <50%, Class III or IV heart failure, recent MI, ventricular arrhythmias.

Monitor BP, serum potassium, and for fluid retention monthly. Control hypertension and correct hypokalemia before and during treatment. Monitor for adrenocortical insufficiency. Stress (may need higher corticosteroid dose). Baseline severe hepatic

impairment (Child-Pugh Class C); avoid. Monitor liver function (ALT/AST, bilirubin) prior to starting treatment, every 2 weeks for the first 3 months, and monthly thereafter; interrupt, reduce dose, or discontinue if hepatic dysfunction occurs.

Nursing mothers: not recommended.

Interactions: Avoid concomitant CYP2D6 substrates with narrow therapeutic index (eg, thioridazine); if no alternatives, use caution and consider dose reduction of substrate. Potentiates dextromethorphan. May affect, or be affected by, strong inhibitors or inducers of CYP3A4; avoid or use caution. Concomitant CYP2C8 substrates: monitor closely for signs of toxicity.

Adverse reactions: Joint swelling or discomfort, fatigue, hypokalemia, edema, myalgia, hot flush, diarrhea, vomiting, UTI, cough, hypertension, dyspnea, arrhythmias, urinary frequency, nocturia, URI, adrenocortical insufficiency, hepatotoxicity.

Note: Pregnant women and those of childbearing potential should not handle Zytiga tablets without protection (eg, gloves). Partners must use appropriate barrier contraception.

How supplied: Tabs—120

ADVERSE REACTIONS Those adverse reactions listed within product monographs represent the potential for adverse effects based upon the active ingredient(s) and/or the drug class. It is not meant to be an inclusive list of responses.

LIVER FUNCTION ASSESSMENT Child-Pugh Score is used to assess residual liver function and injury severity in cirrhosis patients.

CHILD-PUGH SCORES Criteria

1 point

2 points

3 points

Total serum bilirubin (mg/dL)

<2

2–3

>3

Serum albumin (g/dL)

>3.5

2.8–3.5

<2.8

INR

<1.70

1.71–2.20

>2.20

Ascites

No ascites

Ascites controlled

Ascites not controlled

Encephalopathy

No encephalopathy

Encephalopathy controlled

Encephalopathy not controlled

Class A

Class B

Class C

Points

5–6

7–9

10–15

Life expectancy

15–20 years

Candidate for liver transplant

1–3 years

Perioperative mortality

10%

30%

82%

INTERPRETATION OF CHILD-PUGH SCORES

44 CANCER THERAPY ADVISOR | SEPTEMBER/OCTOBER 2015 | CancerTherapyAdvisor.com

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DRUG MONOGRAPHS

GYNECOLOGIC CANCER AVASTIN Genentech

℞

Angiogenesis inhibitor. Bevacizumab 100mg, 400mg; per vial; soln for IV infusion after dilution; preservative-free.

Indications: Persistent, recurrent, or metastatic cervical cancer in combination with paclitaxel and cisplatin, or paclitaxel and topotecan. Platinumresistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer in patients who received no more than 2 prior chemotherapy regimens, in combination with paclitaxel, pegylated liposomal doxorubicin or topotecan.

Adults: Give by IV infusion. Infuse 1st dose over 90 mins; if tolerated, infuse 2nd dose over 60 mins, and subsequent doses over 30 mins.

Cervical cancer: 15mg/kg every 3 weeks with either paclitaxel/cisplatin, or paclitaxel/topotecan.

Epithelial ovarian, fallopian tube or primary peritoneal cancer: 10mg/kg every 2 weeks with either paclitaxel, pegylated liposomal doxorubicin, or topotecan (weekly); 15mg/kg every 3 weeks with topotecan (every 3 weeks).

Children: Not established.

Warnings/Precautions: Risk of GI perforations, surgery and wound healing complications, and hemorrhage. Do not start therapy before or for at least 28 days after surgery; allow surgical incisions to completely heal (see full labeling). Do not administer if recent history of hemoptysis of ≥ ½-teaspoon of red blood.

Permanently discontinue if GI perforation, tracheoesophageal fistula, any grade 4 fistula, or grade 4 venous thromboembolic event.

Discontinue if fistula involving internal organ, wound healing complications, hemorrhage, severe arterial thromboembolic event (ATE), hypertensive crisis or encephalopathy, posterior reversible encephalopathy syndrome, or nephrotic syndrome occurs; suspend therapy if severe hypertension, moderate-to-severe proteinuria (resume when <2g/24hrs), or severe infusion reaction occurs. Avoid in ovarian cancer if evidence of recto-sigmoid involvement by pelvic exam, bowel involvement on CT scan, or symptoms of bowel obstruction. History of arterial thromboembolism. Diabetes. Monitor BP every 2–3 weeks. Monitor proteinuria by dipstick urine analysis; if ≥2+, do further assessment with a 24-hour urine collection. Elderly. Increased risk of ovarian failure; inform females of reproductive potential prior to starting therapy. Pregnancy: may cause fetal harm; use effective contraception during and for 6 months after last dose. Nursing mothers: not recommended.

Adverse reactions: Epistaxis, headache, hypertension, rhinitis, proteinuria, taste

alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain, exfoliative dermatitis; GI perforation and fistulae, wound dehiscence/impaired healing, necrotizing fasciitis (discontinue if occurs), hemorrhage, non-GI fistula formation, arterial or venous thromboembolic events, posterior reversible encephalopathy syndrome, infusion reactions, ovarian failure, neutropenia, and infection.

How supplied: Single-use vial—1

DOXIL Janssen Biotech

HEXALEN Eisai

℞

Anthracycline. Doxorubicin HCl (liposomal) 2mg/mL; dispersion for IV infusion after dilution; preservative-free.

Indications: Ovarian cancer refractory to platinum-based chemotherapy.

Adults: Give by IV infusion at initial rate of 1mg/min; may increase rate to complete infusion over 1hr if no infusion reactions occur; may premedicate with antiemetics. 50mg/m2 once every 4 weeks; continue for at least 4 cycles as tolerated. Hepatic dysfunction (serum bilirubin ≥1.2mg/dL), hand-foot syndrome, hematologic toxicity (esp. ANC, platelets), or stomatitis: reduce dose. Consider total anthracycline and anthracenedione doses and irradiation when calculating total cumulative dose. See full labeling.

Children: Not established.

Warnings/Precautions: Not substitutable on a mg/mg basis with other doxorubicin products.

Cardiotoxicity, acute infusion-related reactions, myelosuppression may occur. Have resuscitative/ antiallergic equipment and expertise available.

Hepatic impairment. Monitor blood (esp. CBC + platelets), hepatic (esp. SGOT/SGPT, alkaline phosphatase), and cardiac function (esp. myocardial biopsy). Monitor periodically for secondary oral cancers with long-term use. Avoid extravasation. Pregnancy (Cat.D); avoid. Nursing mothers: not recommended.

Interactions: Caution with cyclosporine, phenobarbital, phenytoin, streptozocin, digoxin, myelosuppressants, others. Previous mediastinal irradiation, cyclophosphamide, other cardiotoxic drugs: monitor for cardiotoxicity and hepatotoxicity.

Adverse reactions: Asthenia, fatigue, fever, anorexia, nausea, vomiting, stomatitis, diarrhea, constipation, hand and foot syndrome, rash, neutropenia, thrombocytopenia, anemia; infusion reactions, cardiovascular events (eg, cardiomyopathy, CHF, acute LV failure), recall of skin reaction from prior radiation therapy, toxoplasmosis, urine discoloration (red/orange).

How supplied: Single-use vials (10mL, 25mL)—1

℞

S-triazine derivative. Altretamine 50mg; caps.

Indications: Palliative treatment of persistent or recurrent ovarian cancer following first-line therapy with a cisplatin and/or alkylating agentbased combination.

Adults: 260mg/m2 daily in four divided doses (after meals and at bedtime), for either 14 or 21 consecutive days in a 28-day cycle. Discontinue for >14 days if GI intolerance is unresponsive to treatment, WBC count <2000/mm3 or granulocyte count <1000/mm3, platelet count <75000/mm3, or progressive neurotoxicity occurs. Restart at 200mg/m2 daily. Discontinue indefinitely if neurologic symptoms fail to stabilize.

Children: Not recommended.

Contraindications: Severe myelosuppression or neurologic toxicity, except cisplatin-related neuropathy.

Warnings/Precautions: Monitor for myelosuppression (do monthly CBCs) and neurotoxicity. Pregnancy (Cat.D). Nursing mothers: not recommended.

Interactions: Avoid pyridoxine. Severe orthostatic hypotension with MAOIs. Adverse reactions: Nausea, vomiting, peripheral neuropathy, CNS symptoms (eg, mood disorders, ataxia, dizziness), myelosuppression, renal dysfunction, increased alkaline phosphatase.

How supplied: Caps—100

HYCAMTIN GlaxoSmithKline

℞

Topoisomerase inhibitor. Topotecan (as HCl) 4mg/vial; pwd for IV infusion after reconstitution and dilution; contains mannitol; preservative-free.

Indications: Metastatic carcinoma of the ovary after failure of initial or subsequent chemotherapy.

Stage IV-B, recurrent or persistent carcinoma of the cervix in combination with cisplatin.

Adults: Verify dose using BSA. Usual max dose 4mg IV. Confirm baseline neutrophils >1,500cells/mm3 and platelets >100,000cells/mm3 prior to 1st course of therapy. Give by IV infusion over 30 mins. Ovarian cancer: 1.5mg/m2 daily for 5 consecutive days starting on Day 1 of a 21-day cycle. Cervical cancer: 0.75mg/m2 on Days 1 (with cisplatin), 2, and 3, repeated every 21 days. Dose adjustments, renal impairment: see full labeling.

Children: Not established.

Warnings/Precautions: Monitor peripheral blood cell counts during therapy; hold subsequent doses until neutrophils >1,000cells/mm3, platelets >100,000cells/mm3, and hemoglobin ≥9g/dL. History of interstitial lung disease, pulmonary fibrosis, lung cancer, thoracic exposure to radiation, use of pneumotoxic drugs

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DRUG MONOGRAPHS

GYNECOLOGIC CANCER and/or colony stimulating factors: increased risk of interstitial lung disease; monitor, discontinue if occurs. Moderate to severe renal impairment.

Avoid extravasation. Elderly. Use effective contraception during and for ≥1 month after last dose (in females), or during and for ≥3 months (in males with female partners). Pregnancy (Cat.D).

Nursing mothers: not recommended.

Interactions: Myelosuppression potentiated with platinum agents. Neutropenia potentiated by G-CSF; administer ≥24hrs after last topotecan dose.

Adverse reactions: See full labeling. Neutropenia, leukopenia, thrombocytopenia, anemia, nausea, vomiting, diarrhea, anorexia, abdominal pain, stomatitis, headache, dyspnea, cough, pyrexia, alopecia, fatigue; infection, sepsis, interstitial lung disease, neutropenic colitis (may be fatal).

How supplied: Single-use vials—1

HYDREA Bristol-Myers Squibb

℞

Substituted urea. Hydroxyurea 500mg; caps.

Indications: Recurrent metastatic or inoperable ovarian carcinoma.

Adults: See literature. Intermittant therapy for solid tumors: 80mg/kg as single dose every 3rd day. Continuous therapy for solid tumors: 20–30mg/kg/day as single dose. Renal impairment: reduce dose.

Children: Not recommended.

Contraindications: Marked bone marrow depression.

Warnings/Precautions: Previous irradiation therapy or chemotherapy. Correct anemia before starting. Monitor hematologic, renal, hepatic function before and during treatment. Marked renal dysfunction. Myeloproliferative disorders; discontinue if cutaneous vasculitic ulcerations develop and use alternative agents. Elderly.

Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended.

Interactions: Avoid concomitant didanosine, with or without stavudine, or other antiretrovirals (may cause pancreatitis [monitor], fatal hepatotoxicity, peripheral neuropathy).

Myelosuppressives potentiate antineoplastic effect. May antagonize antigout agents. Increased risk of vasculitic toxicities with interferon therapy.

May cause falsely elevated urease, uricase, lactate dehydrogenase.

Adverse reactions: Leukopenia, anemia, erythrocytic abnormalities, thrombocytopenia, GI upset, rash, erythema, fever, CNS effects, temporary renal impairment, acute pulmonary reactions, secondary leukemias, skin cancer.

Note: Wear disposable gloves when handling caps or bottle.

How supplied: Caps—100

LYNPARZA AstraZeneca Poly (ADP-ribose) polymerase (PARP) inhibitor.

Olaparib 50mg; caps.

Indications: Monotherapy in patients with deleterious or suspected deleterious germline

℞

BRCA-mutated (as detected by an FDA-approved test) advanced ovarian cancer who have been treated with ≥3 prior lines of chemotherapy.

Adults: Swallow whole. 400mg twice daily; max 800mg daily. Continue until disease progression or unacceptable toxicity. Dose adjustments for adverse reactions: reduce to 200mg twice daily; may further reduce to 100mg twice daily. If concomitant strong CYP3A inhibitor unavoidable: reduce to 150mg twice daily; or if concomitant moderate CYP3A inhibitor unavoidable: reduce to 200mg twice daily.

Children: Not established.

Warnings/Precautions: Monitor CBC at baseline and monthly thereafter; do not start therapy until recovery from hematological toxicity due to previous chemotherapy (CTCAE Grade ≤1). Discontinue if myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) is confirmed. Interrupt therapy and evaluate if new or worsening respiratory symptoms occur; discontinue if pneumonitis is confirmed. Hepatic and moderate-to-severe renal impairment: not studied. Pregnancy (Cat.D); avoid. Use effective contraception during therapy and for at least 1 month after last dose. Nursing mothers: not recommended.

Interactions: Increased myelosuppressive toxicity with concomitant other myelosuppressive anticancer agents, including DNA damaging agents. Avoid concomitant strong CYP3A inhibitors (eg, itraconazole, telithromycin, clarithromycin, ketoconazole, voriconazole, nefazodone, posaconazole, ritonavir, lopinavir/ ritonavir, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) and moderate CYP3A inhibitors (eg, amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, darunavir/ ritonavir, diltiazem, erythromycin, fluconazole, fosamprenavir, imatinib, verapamil); if unavoidable, reduce dose (see Adults). Avoid grapefruit and Seville oranges. Avoid concomitant strong CYP3A inducers (eg, phenytoin, rifampicin, carbamazepine, St. John’s Wort) and moderate CYP3A inducers (eg, bosentan, efavirenz, etravirine, modafinil, nafcillin); if unavoidable, be aware of potential for decreased efficacy.

Adverse reactions: Anemia, nausea, fatigue, asthenia, vomiting, diarrhea, dysgeusia, dyspepsia, headache, decreased appetite, nasopharyngitis/pharyngitis/URI, cough, arthralgia/musculoskeletal pain, myalgia, back pain, dermatitis/rash, abdominal pain/ discomfort; lab abnormalities (see full labeling), MDS/AML, pneumonitis.

How supplied: Caps—112

TREXALL Teva

℞

Folic acid antagonist. Methotrexate sodium 5mg, 7.5mg, 10mg, 15mg; scored tabs. ℞ Also: Methotrexate injection Bedford Methotrexate 25mg/mL; soln for IV, IM, intraarterial, or intrathecal administration after dilution; preservative-free.

℞ Also: Methotrexate for injection Bedford Methotrexate 1g/vial; pwd for IV, IM, intra-arterial, or intrathecal administration after dilution; preservative-free.

Indications: Gestational choriocarcinoma.

Chorioadenoma destruens. Hydatidiform mole.

Adults: See literature. Tablet form is often preferred when low doses are being administered. Choriocarcinoma and similar trophoblastic diseases: 15–30mg orally or by IM inj daily for 5 days; usually repeated 3–5 times as required with a rest period of ≥1 week between courses.

Children: Not applicable.

Contraindications: Pregnancy (Cat.X). Nursing mothers.

Warnings/Precautions: Be fully familiar with this drug’s toxicity before use.

Discontinue if malignant lymphomas occur.

Obtain baseline and monitor CBCs with differential, platelet counts, chest X-ray, and hepatic, renal and pulmonary function. During therapy monitor hematology monthly, renal and hepatic function every 1–2 months, more often if increasing dose or predisposed to toxicity (eg, dehydration). Discontinue immediately if blood counts drop significantly.

Rule out pregnancy in women of childbearing potential; use effective contraception during therapy and for at least 1 ovulatory cycle afterwards for women and for at least 3 months afterwards for men. Interrupt therapy if vomiting, diarrhea, stomatitis, or pulmonary symptoms occur. Hepatic or renal impairment.

Obesity. Diabetes. Peptic ulcer. Ulcerative colitis.

Infection. Dehydration. Folate deficiency. Ascites, pleural effusions: evacuate fluid, monitor for toxicity and reduce dose or discontinue if needed.

Elderly (use low doses and monitor closely).

Debilitated.

Interactions: Avoid live virus vaccines. Toxicity increased by NSAIDs, salicylates, phenytoin, sulfonylureas, sulfonamides, probenecid, folic acid antagonists. May be potentiated by penicillins (monitor), tetracyclines, chloramphenicol, non-absorbable broad spectrum antibiotics. May be antagonized by folic acid. May potentiate theophylline, mercaptopurine. Increased risk of soft tissue necrosis and osteonecrosis with radiotherapy.

Caution with other hepatotoxic drugs (eg, azathioprine, retinoids, sulfasalazine) and nephrotoxic agents (eg, cisplatin).

Adverse reactions: Ulcerative stomatitis, leukopenia, nausea, GI upset, malaise, fatigue, chills, fever, dizziness, infection, myelosuppression, hepatotoxicity, renal toxicity, CNS toxicity, seizures (esp in children); interstitial pneumonitis, tumor lysis syndrome, skin reactions (may be fatal; eg, toxic epidermal necrolysis, Stevens-Johnson syndrome).

How supplied: Tabs—30; soln (2mL, 4mL, 8mL, 10mL)—10 (single-use vials); pwd (1 gram)—1 (single-use vial)

46 CANCER THERAPY ADVISOR | SEPTEMBER/OCTOBER 2015 | CancerTherapyAdvisor.com

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CANCER TREATMENT REGIMEN

HEAD AND NECK CANCER Head And Neck Cancer Treatment Regimens Clinical Trials: The NCCN recommends cancer patient participation in clinical trials as the gold standard for treatment.

Cancer therapy selection, dosing, administration, and the management of related adverse events can be a complex process that should be handled by an experienced healthcare team. Clinicians must choose and verify treatment options based on the individual patient; drug dose modifications and supportive care interventions should be administered accordingly. The cancer treatment regimens below may include both U.S. Food and Drug Administration-approved and unapproved indications/regimens. These regimens are only provided to supplement the latest treatment strategies.

These Guidelines are a work in progress that may be refined as often as new significant data becomes available. The NCCN Guidelines® are a consensus statement of its authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult any NCCN Guidelines® is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way.

Squamous Cell Cancers* REGIMEN

DOSING

Primary Systemic Therapy + Concurrent Radiotherapy1 Cisplatin (preferred)2,3

Days 1, 22 and 43: Cisplatin 100mg/m2 IV + concurrent radiotherapy 2Gy/day to a total of 70Gy.

Cetuximab (Category 1)4

Day 1: Cetuximab 400mg/m2 loading dose over 2 hours, 1 week before radiotherapy, plus Day 7: Begin radiotherapy with 7 weekly infusions of cetuximab 250mg/m2.

Carboplatin + infusional 5-FU (Category 1)5,6

Days 1–4: 5-FU 600mg/m2/day as continuous IV infusion + carboplatin 70mg/m2/day IV bolus.

Repeat every 3 weeks for 3 cycles (given concurrently with radiotherapy).

5-FU + hydroxyurea7

Day 1: Hydroxyurea 1,000mg PO every 12 hours (11 doses/cycle) and 5-FU 400mg/m2/day continuous IV infusion, plus radiotherapy: 70Gy, delivered in 35 fractions; 1 fraction delivered daily Monday–Friday.

Concurrent radiotherapy and chemotherapy every other week for total treatment duration of 13 weeks.

Cisplatin + paclitaxel7

Day 1: Paclitaxel 30mg/m2 IV (begin on Monday), plus Day 2: Cisplatin 20mg/m2 IV (every Tuesday).

Repeat cycle every week for 7 cycles, plus radiotherapy: 70Gy, delivered in 35 fractions; 1 fraction delivered daily Monday–Friday.

Cisplatin + infusional 5-FU8

Day 1: Cisplatin 60mg/m2 over 15 minutes; plus Days 1–5: 5-FU 800mg/m2 by continuous infusion; plus Days 1–5: Radiotherapy: 2Gy repeated every other week for 7 cycles.

Carboplatin/paclitaxel (Category 2B)9

Day 1: Paclitaxel 40–45mg/m2/week and carboplatin 100mg/m2/week; prior to radiotherapy: 70.2Gy at 1.8Gy/fraction/day for 5 days/week.

Weekly cisplatin (Category 2B)10,11

Day 1–28: Cisplatin 40mg/mg2 IV over 30 minutes weekly; plus Days 1–38: Radiotherapy (5 fractions/week): 1.8Gy single dose (up to total dose of 50.4Gy); plus Days 22–38: Boost radiotherapy: 1.5Gy/day (up to 19.5Gy) in addition to regular dose. Booster doses to be given at least 6-hours after regular dose (total tumor dose of 69.9Gy.) OR Day 1–28: Cisplatin 40mg/mg2 IV weekly; plus Days 1–40: Radiotherapy: five fractions of 1.8Gy/week (up to total dose of 54Gy); plus Days 25–40: Boost radiotherapy: 1.5Gy/day (up to 19.5Gy) in addition to regular dose. Booster doses to be given at least 6-hours after regular dose.

Primary Chemotherapy With Postoperative Chemoradiation1 Cisplatin (Category 1 for high-risk)12–15

Days 1, 22 and 43: Cisplatin 100mg/m2 IV + radiotherapy.

Induction Chemotherapy†/Sequential chemotherapy1‡ Docetaxel + cisplatin + 5-FU (Category 1 if induction is chosen)16-18

Day 1: Docetaxel 75mg/m2 IV + cisplatin 75mg/m2 IV, plus Days 1–5: 5-FU 750mg/m2 continuous IV infusion.

Repeat every 3 weeks for 4 cycles.

Paclitaxel + cisplatin+ infusional 5-FU19§

Day 1: Paclitaxel 175mg/m2 over 3 hours Day 2: Cisplatin 100mg/m2; plus Day 2–6: 5-FU 500mg/m2 continuous infusion Repeat every 3 weeks for 3 cycles. continued

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HEAD AND NECK CANCER Head And Neck Cancer Treatment Regimens Nasopharynx Cancer REGIMEN

DOSING

Chemoradiation Followed by Adjuvant Chemotherapy1 Cisplatin + radiotherapy + cisplatin + 5-FU20-22

Cycles 1–3 Day 1: Cisplatin 100mg/m2 IV; plus radiotherapy.

Repeat cycle every 3 weeks; followed by Cycles 4–6 Days 1–4: Cisplatin 80mg/m2/day + 5-FU 1,000mg/m2/day IV over 96 hours.

Repeat cycle every 4 weeks for 3 cycles.

Carboplatin + radiotherapy + carboplatin + 5-FU (Category 2B)23

Cycles 1–3 Day 1: Carboplatin AUC 6 IV; plus radiotherapy: 200cGy/fraction w/ five daily fractions/week (to a total dose of 6600–7000cGy).

Repeat every 3 weeks for 3 cycles; followed by Cycles 4–6 Days 1–4: Carboplatin AUC 5 IV + 5-FU 1,000mg/m2/day IV over 96 hours. Repeat cycle every 3 weeks.

Induction Chemotherapy†/Sequential Chemotherapy1|| Docetaxel + cisplatin + 5-FU24

Day 1: Docetaxel 70mg/m2 IV over 1 hour and cisplatin 75mg/m2 IV over 3 hours; followed by Days 1–4: 5-FU 1,000mg/m2 IV over 96 hours.

Repeat every week for 3 cycles; followed by Cisplatin 100mg/m2; plus radiotherapy: 5 daily fractions of 1.8 or 2Gy/day (total dose of 68.4Gy) Repeat every 3 weeks.

Docetaxel + cisplatin (Category 2B)25

Day 1: Docetaxel 75mg/m2 IV + cisplatin 75mg/m2 IV every 3 weeks for two cycles, followed by Cisplatin 40mg/m2 IV weekly concurrent with radiotherapy.

Cisplatin + 5-FU17,26

Day 1: Cisplatin 100mg/m2/day IV. Days 1–4: 5-FU 1,000mg/m2/day continuous IV infusion.

Repeat cycle every 3 weeks for a minimum of 6 cycles.

Cisplatin + epirubicin + paclitaxel

This regimen was included in the NCCN guidelines but no reference was provided to indicate appropriate dosage.

Principles of Systemic Therapy1 • The choice of chemotherapy should be individualized based on patient characteristics (performance status, goals of therapy).

• Unless otherwise specified, regimens listed below can be used for either nasopharyngeal or non-nasopharyngeal cancer.

Combination Therapy for Recurrent, Unresectable, or Metastatic Disease (incurable)1 Cisplatin or carboplatin + 5-FU + cetuximab (Category 1)27 (non-nasopharyngeal)

Day 1: Cisplatin 100mg/m2 IV or carboplatin AUC=5mg/mL/min 1 hour IV infusion, plus Day 1: Cetuximab 400mg/m2 IV over 2 hours (initial dose), followed by 250mg/m2 IV over 1 hour once weekly.

Days 1–4: 5-FU 1,000mg/m2/day.

Repeat cycle every 3 weeks for a maximum of 6 cycles.

Carboplatin + docetaxel28

Day 1: Docetaxel 65mg/m2 IV over 1 hour; followed immediately by carboplatin AUC=6 IV. Repeat cycle every 3 weeks.

Cisplatin + paclitaxel26

Day 1: Cisplatin 75mg/m2/day IV + paclitaxel 175mg/m2 IV over 3 hours.

Repeat cycle every 3 weeks for a minimum of 6 cycles.

Cisplatin + cetuximab29 (non-nasopharyngeal)

Day 1: Cetuximab 400mg/m2 IV for one cycle, then cetuximab 250mg/m2 IV for subsequent cycles.

Repeat once weekly, plus Day 1: Cisplatin 100mg/m2 IV. Repeat every 4 weeks

Cisplatin + 5-FU26,30

Day 1: Cisplatin 100mg/m2/day IV. Days 1–4: 5-FU 1,000mg/m2/day continuous IV infusion.

Repeat cycle every 3 weeks for a minimum of 6 cycles.

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HEAD AND NECK CANCER Nasopharynx Cancer (continued) REGIMEN

DOSING

Combination Therapy for Recurrent, Unresectable, or Metastatic Disease (incurable)1 (continued) Cisplatin + docetaxel + cetuximab31 (non-nasopharyngeal)

Day 1: Docetaxel 75mg/m2 IV + cisplatin 75mg/m2 IV + cetuximab (400mg/m2 on day of cycle 1, then 250mg/m2 weekly).

Repeat cycle every 21 days for 4 cycles, followed by cetuximab 500mg/m2 IV every 2 weeks as maintenance therapy until disease progression or unacceptable toxicity.

Cisplatin + paclitaxel + cetuximab32 (non-nasopharyngeal)

Day 1: Cisplatin 75mg/m2 IV + paclitaxel 75mg/m2 IV every 3 weeks for 2 cycles, followed by Day 1: Cisplatin 75–100mg/m2 IV every 3 weeks + cetuximab (400mg/m2 IV on day 1, then 250mg/m2 weekly) for 4 cycles.

Carboplatin + cetuximab33

Day 1: Cetuximab initial dose of 400mg/m2 IV over 2 hours; followed by weekly doses of cetuximab 250mg/m2 IV over 1 hour; followed by carboplatin AUC=5 IV. Repeat every 3 weeks for a maximum of 8 cycles.

Cisplatin + gemcitabine34 (nasopharyngeal)

Days 1 and 8: Gemcitabine 1,000mg/m2 IV Days 1–3: Cisplatin 80mg/m2 IV in divided doses.

Repeat cycle every 3 weeks.

Gemcitabine + vinorelbine35 (non-nasopharyngeal)

Day 1 and 8: Vinorelbine 25mg/m2 IV; followed by gemcitabine 1,000mg/m2 IV over 30 minutes.

Repeat every 3 weeks.

Single Agents for Recurrent, Unresectable, or Metastatic Disease (incurable)1 Cisplatin29,36

Day 1: Cisplatin 100mg/m2 IV over 15–20 minutes.

Repeat every 3–4 weeks.

Carboplatin37

Day 1: 25mg/m2 daily followed by radiotherapy: 5 daily fractions of 1.8 or 2Gy.

Paclitaxel38

Day 1: Paclitaxel 80mg/m2 IV over 1 hour.

Repeat every 6 weeks.

Docetaxel39,40

Day 1: Docetaxel 40–100mg/m2 IV over 1 hour.

Repeat every 3 weeks.

5-FU36

Days 1–4: 5-FU 1,000mg/m2 IV over 24 hours.

Repeat every 3 weeks.

Methotrexate30,41

Day 1: Methotrexate 40mg/m2 IV weekly.

Cetuximab42 (non-nasopharyngeal)

Day 1: Cetuximab 400mg/m2 over 2 hours as a loading dose (including a 20mg test dose); followed by cetuximab 250mg/m2 IV over 1 hour weekly.

Repeat at least every 6 weeks.

Ifosfamide (Category 2B)43

Days 1–3: Ifosfamide 3g/m2 IV daily; plus mesna 600mg/m2 PO daily.

Repeat every 3 weeks.

Bleomycin (Category 2B)44,45

Days 1–21: Bleomycin 10mg IV bolus twice weekly on Tuesday and Thursday (60mg/six fractions); followed by radiotherapy: 25Gy split into two courses, with each course given in 10 fractions over 2 weeks, with a 2 week split (total dose of 50Gy/20 fractions).

OR Days 1–35: Bleomycin 15mg IM twice a week (total dose 150mg); followed by radiotherapy: 70Gy

Gemcitabine46 (nasopharyngeal)

Days 1, 8, 15: Gemcitabine 1,000mg/m2 IV over 30 minutes.

Repeat every 4 weeks.

Capecitabine47

Days 1–14: Capecitabine 1,250mg/m2 PO; followed by a 1-week rest period.

Repeat every 3 weeks for at least two cycles.

Vinorelbine48,49 (non-nasopharyngeal)

Day 1: Vinorelbine 30mg/m2/week IV (over a short duration, on an out-patient basis)

Includes lip, oral cavity, oropharynx, hypopharynx, glottic larynx, supraglottic larynx, ethmoid sinus, maxillary sinus, occult primary.

Induction chemotherapy should only be done in a tertiary setting. ‡ Following induction, agents to be used with concurrent chemoradiation typically include weekly carboplatin or cetuximab.50-52 § Patients with complete partial response of greater than 80% in primary tumor received additional chemoradiation therapy (i.e., cisplatin 100mg/m2 on days 1, 22, and 43 plus 70Gy). Radiotherapy was administered in 35 fractions of 2Gy each over a 7-week period. || Following induction, agents to be used with concurrent chemoradiation typically include weekly cisplatin21 or carboplatin.50 *

†

continued

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HEAD AND NECK CANCER Head And Neck Cancer Treatment Regimens References 1.

Referenced with permission from NCCN Clinical Practice Guidelines in Oncology™.

Bladder Cancer. v 2.2014. Available at: http://www.nccn.org/professionals/ physician_gls/pdf/head-and-neck.pdf. Accessed April 10, 2015.

2. Adelstein DJ, Li Y, Adams GL, et al. An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. J Clin Oncol. 2003;21(1):92–98.

3. Forastiere AA, Zhang Q, Weber RS, et al. Long-term results of RTOG 91–11: a comparison of three nonsurgical treatment strategies to preserve the larynx in patients with locally advanced larynx cancer. J Clin Oncol. 2013;31:845–852.

4. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomized trial, and relation between cetuximab-induced rash and survival.

Lancet Oncol. 2010;11:21–28.

5. Denis F, Garaud P, Bardet E, et al. Final results of the 94-01 French Head and Neck Oncology and Radiotherapy Group randomized trial comparing radiotherapy alone with concomitant radiochemotherapy in advanced-stage oropharynx carcinoma.

J Clin Oncol. 2004;22:69–76.

6. Bourhis J, Sire C, Graff P, et al. Concomitant chemoradiotherapy versus acceleration of radiotherapy with or without concomitant chemotherapy in locally advanced head and neck carcinoma (GORTEC 99-02): an open-label phase 3 randomised trial. Lancet Oncol. 2012;13:145–153.

7. Garden AS, Harris J, Vokes EE, et al. Preliminary results of Radiation Therapy Oncology Group 97-03: A randomized phase II trial of concurrent radiation and chemotherapy for advanced squamous cell carcinomas of the head and neck.

J Clin Oncol. 2004;22(14):2856–2864.

8. Taylor 5, Murthy A, Vannetzel J, et al. Randomized comparison of neoadjuvant cisplatin and fluorouracil infusion followed by radiation versus concomitant treatment in advanced head and neck cancer. J Clin Oncol. 1994;12:385–395.

9. Suntharalingam M, Haas ML, Conley BA, et al. The use of carboplatin and paclitaxel with daily radiotherapy in patients with locally advanced squamous cell carcinomas of the head and neck. Int J Radiat Oncol Biol Phys. 2000;47:49–56.

10. Beckmann GK, Hoppe F, Pfreundner L, et al. Hyperfractionated accelerated radiotherapy in combination with weekly cisplatin for locally advanced head and neck cancer. Head Neck. 2005;27:36–43.

11. Medina JA, Rueda A, de Pasos AS, et al. A phase II study of concomitant boost radiation plus concurrent weekly cisplatin for locally advanced unresectable head and neck carcinomas. Radiother Oncol. 2006;79:34–38.

12. Cooper JS, Pajak TF, Forastiere AA, et al. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck.

N EngI J Med. 2004; 350:1937–1944.

13. Bernier J, Domenge C, Ozsahin M, et al. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer.

N EngI J Med. 2004;350: 1945–1952.

14. Bernier J, Cooper JS, Pajak TF, et al. Defining risk levels in locally advanced head and neck cancers: A comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (# 9501). Head Neck.

2005;27:843–850.

15. Bachaud JM, Cohen-Jonathan E, Alzieu C, et al. Combined postoperative radiotherapy and weekly cisplatin infusion for locally advanced head and neck carcinoma: final report of a randomized trial. Int J Radiat Oncol Biol Phys. 1996 Dec 1;36:999–1004.

16. Vermorken JB, Remenar E, van Herpen C, et al; EORTC 24971/TAX 323 Study Group. Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer.

N EngI J Med. 2007;357(17):1695–1704.

17. Posner MR, Hershock DM, Blajman CR, et al. Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N EngI J Med. 2007;357(17):1705–1715.

18. Pointreau Y, Garaud P, Chapet S, et al. Randomized trial of induction chemotherapy with cisplatin and 5-fluorouracil with or without docetaxel for larynx preservation.

J NatI Cancer Inst. 2009;101:498–506.

19. Hiff R, LOpez-Pousa A, Martinez-Trufero J, et al. Phase III study comparing cisplatin plus fluorouracil to paclitaxel, cisplatin, and fluorouracil induction chemotherapy followed by chemoradiotherapy in locally advanced head and neck cancer.

J Clin Oncol. 2005;23:8636–8645.

20. Al-Sarraf M, LeBlanc M, Gin PG, et al. Chemoradiotherapy versus radiotherapy in patients with advanced nasophanyngeal cancer: phase III randomized Intergroup study 0099. J Clin Oncol 1998;16:1310–1317.

21. Chan AT, Leung SF, Ngan RK, et al. Overall survival after concurrent cisplatinradiotherapy compared with radiotherapy alone in locoregionally advanced nasopharyngeal carcinoma. J NatI Cancer Inst. 2005;97:536–539.

22. Lee AW, Tung SY, Chua DT, et al. Randomized trial of radiotherapy plus concurrentadjuvant chemotherapy vs radiotherapy alone for regionally advanced nasopharyngeal carcinoma. J Natl Cancer Inst. 2010;102:1188–1198.

23. Dechaphunkul T, Pruegsanusak K, Sangthawan D, et al. Concurrent chemoradiotherapy with carboplatin followed by carboplatin and 5- fluorouracil in locally advanced nasopharyngeal carcinoma. Head Neck Oncol. 2011;3:30.

24. Bae WK, Hwang JE, Shim HJ, et al. Phase II study of docetaxel, cisplatin, and 5-FU induction chemotherapy followed by chemoradiotherapy in locoregionally advanced nasopharyngeal cancer. Cancer Chemother Pharmacol. 2010;65(3): 589–595.

25. Hui EP, Ma BB, Leung SF, et al. Randomized phase II trial of concurrent cisplatinradiotherapy with or without neoadjuvant docetaxel and cisplatin in advanced nasopharyngeal carcinoma. J Clin Oncol. 2009;27:242–249.

26. Gibson MK, Li Y, Murphy B, Hussain MH, DeConti RC, Ensley J, Forastiere AA; Eastern Cooperative Oncology Group. Random- ized phase III evaluation of cisplatin plus fluorouracil versus cisplatin plus paclitaxel in advanced head and neck cancer (E1395): an intergroup trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 2005; 23:3562–3567.

27. Vermorken JB, Mesia R, Rivera F, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med. 2008;359:1116–1127.

28. Samlowski WE, Moon J, Kuebler JP, et al. Evaluation of the combination of docetaxel/carboplatin in patients with meta- static or recurrent squamous cell carcinoma of the head and neck (SCCHN): a Southwest Oncology Group Phase II study. Cancer Invest. 2007;25:182–188.

29. Burtness B, Goldwasser MA, Flood W, Mattar B, Forastiere AA; Eastern Cooperative Oncology Group. Phase III randomized trial of cisplatin plus placebo compared with cisplatin plus cetuximab in metastatic/recurrent head and neck cancer: an Eastern Cooperative Oncology Group study. J Clin Oncol.

2005;23(34):8646–8654.

30. Forastiere AA, Metch B, Schuller DE, et al. Randomized comparison of cisplatin plus flurouracil and carboplatin plus fluorouracil versus methotrexate in advanced squamous cell carcinoma of the head and neck: A Southwest Oncology Group Study. J Clin Oncol. 1992;10:1245–1251.

31. Guigay J, Fayette J, Dillies A-F, et al. Cetuximab, docetaxel, and cisplatin (TPEx) as first-line treatment in patients with recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN): Final results of phase II trial GORTEC 2008-03 [abstract]. J Clin Oncol. 2012;30(Suppl 15):Abstract 5505.

32. Herbst RS, Arquette M, Shin DM, et al. Phase II multicenter study of the epidermal growth factor receptor antibody cetuximab and cisplatin for recurrent and refractory squamous cell carcinoma of the head and neck. J Clin Oncol.

2005;23:5578–5587.

33. Chan AT, Hsu MM, Goh BC, et al. Multicenter, phase II study of cetuximab in combination with carboplatin in patients with recurrent or metastatic nasopharyngeal carcinoma. J Clin Oncol. 2005;23:3568–3576.

34. Jin Y, Cai XY, Shi YX, et al. Comparison of five cisplatin-based regimens frequently used as the first-line protocols in metastatic nasopharyngeal carcinoma. J Cancer Res Clin Oncol. 2012;138(10):1717–25.

35. Chen C, Wang FH, Wang ZQ, et al. Salvage gemcitabine-vinorelbine chemotherapy in patients with metastatic nasopharyngeal carcinoma pretreated with platinumbased chemotherapy. Oral Oncol. 2012;48:1146–1151.

36. Jacobs C, Lyman G, Velez-GarcIa E, et al. A phase III randomized study comparing cisplatin and fluorouracil as single agents and in combination for advanced squamous cell carcinoma of the head and neck. J Clin Oncol.

1992;1O:257–263.

37. Jeremic B1, Shibamoto Y, Stanisavljevic B, et al. Radiation therapy alone or with concurrent low-dose daily either cisplatin or carboplatin in locally advanced unresectable squamous cell carcinoma of the head and neck: a prospective randomized trial. Radiother Oncol. 1997 Apr;43(1):29–37.

38. Grau JJ, Caballero M, Verger E, et al. Weekly paclitaxel for platin-resistant stage IV head and neck cancer patients. Acta Otolaryngol. 2009;129:1294–1299.

39. Catimel G, Verweij J, Mattijssen V, et al. Docetaxel (Taxotere): an active drug for the treatment of patients with advanced squamous cell carcinoma of the head and neck. EORTC Early Clinical Trials Group. Ann Oncol. 1994;5:533–537.

40. Guardiola E, Peyrade F, Chaigneau L, et al. Results of a randomised phase II study comparing docetaxel with methotrexate in patients with recurrent head and neck cancer. Eur J Cancer. 2004;40:2071–2076.

41. Stewart JS, Cohen EE, Licitra L, et al. Phase III study of gefitinib compared with intravenous methotrexate for recurrent squamous cell carcinoma of the head and neck [corrected]. J Clin Oncol. 2009:27:1864–1 871.

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HEAD AND NECK CANCER References (continued) 42. Vermorken JB, Trigo J, Hitt R, et al. Open-label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who failed to respond to platinum-based therapy. J Clin Oncol.

2007;25:2171–2177.

43. Martin M, Diaz-Rubio E, Gonzalez Larriba JL, et al. Ifosfamide in advanced epidermoid head and neck cancer. Cancer Chemother Pharmacol.

1993;31:340–342 44. Eschwege F, Sancho-Gamier H, Gerard JP, et al. Ten-year results of randomized trial comparing radiotherapy and concomitant bleomycin to radiotherapy alone in epidermoid carcinomas of the oropharynx: experience of the European Organization for Research and Treatment of Cancer. NCI Monogr. 1988;(6):275–278.

45. Minatel E, Gigante M, Franchin G, et al. Combined radiotherapy and bleomycin in patients with inoperable head and neck cancer with unfavourable prognostic factors and severe symptoms. Oral Oncol. 1998;34:119–122.

46. Zhang L, Zhang Y, Huang PY, et al. Phase II clinical study of gemcitabine in the treatment of patients with advanced nasopharyngeal carcinoma after the failure of platinum-based chemotherapy. Cancer Chemother Pharmacol. 2008; 61:33–38.

Epub 2007 Mar 20.

47.

48.

49.

50.

51.

52.

Martinez-Trufero J, Isla D, Adansa JC, et al. Phase II study of capecitabine as palliative treatment for patients with recurrent and metastatic squamous head and neck cancer after previous platinum-based treatment. Br J Cancer. 2010; 102:1687–1691.

Degardin M, Oliveira J, Geoffrois L, et al. An EORTC-ECSG phase II study of vinorelbine in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck. Ann Oncol. 1998;9:1103–1107.

Saxman 5, Mann B, Canfield V, et al. A phase II trial of vinorelbine in patients with recurrent or metastatic squamous cell carcinoma of the head and neck. Am J Clin Oncol. 1998;21: 398–400.

Chitapanarux I, Lorvidhaya V, Kamnerdsupaphon P, et al. Chemoradiation comparing cisplatin versus carboplatin in locally advanced nasopharyngeal cancer: Randomised, non-inferiority, open trial. Eur J Cancer. 2007;43:1399–1406.

Haddad R, O’Neill A, Rabinowits G, et al. Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM): a randomised phase 3 trial. Lancet Oncol. 2013;14:257–264.

Lefebvre JL, Pointreau Y, Rolland F, et al. Induction chemotherapy followed by either chemoradiotherapy or bioradiotherapy for larynx preservation: the TREMPLIN randomized phase II study. J Clin Oncol. 2013;31:853–859.

(Revised 5/2015) © 2015 by Haymarket Media, Inc.

Cancer Therapy Advisor’s Publishers Alliance Cancer Therapy Advisor has partnered with leading medical publishers, including Dove Press, Libertas Academica, and Moffit Cancer Center, to present Publishers Alliance, a selection of oncology-focused articles from a number of clinically relevant research journals.

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DRUG MONOGRAPHS

HEAD AND NECK CANCER ERBITUX Bristol-Myers Squibb

℞

Epidermal growth factor receptor blocker.

Cetuximab 100mg/vial, 200mg/vial; soln for IV infusion; preservative-free.

Indications: In combination with radiation therapy for treating locally or regionally advanced squamous cell carcinoma of the head and neck (SCCHN). In combination with platinum-based therapy with 5-fluorouracil (5-FU) for first-line treatment of recurrent locoregional disease or metastatic SCCHN. As a single agent for recurrent or metastatic SCCHN after failure of prior platinum-based therapy.

Adults: Pretreat with H1 blocker. Give by IV infusion (use filter); max rate: 10mg/min. Initial dose: 400mg/m2 once over 2hrs; then 250mg/m2 once weekly over 1 hour. Combination therapy: Give initial dose 1 week prior to initiation of radiation therapy. Complete administration 1 hour prior to platinum-based therapy with 5-FU. Give subsequent weekly dose for duration of radiation therapy (6–7 weeks) or until disease progression or unacceptable toxicity.

Permanently reduce infusion rate by 50% if Grade 1 or 2 and non-serious Grade 3 infusion reaction occurs; permanently discontinue if Grade 3 or 4 serious reaction occurs. Monitor patient during and for 1hr post-infusion. Skin toxicity: see full labeling.

Children: Not established.

Warnings/Precautions: Discontinue if severe infusion reactions or interstitial lung disease occur. Monitor for infusion reactions, cardiopulmonary arrest, pulmonary toxicity, dermatologic toxicities/infection; avoid sun, UV light. Additive cutaneous reactions with irradiation. Cardiovascular diseases (w. irradiation or platinum-based therapy with 5-FU). Monitor electrolytes (eg, magnesium, potassium, calcium) during and after cetuximab therapy.

Pregnancy (Cat.C). Nursing mothers: not recommended.

Interactions: Increased mucositis (Grade 3–4), radiation recall syndrome, acneiform rash, cardiac events, and electrolyte disturbances with radiation and cisplatin.

Adverse reactions: Cutaneous reactions (pruritus, nail changes), acneform rash, headache, diarrhea, infection, asthenia, mucositis, weight loss, xerostomia, dehydration, electrolyte abnormalities; infusion reactions (may be severe: eg, bronchospasm, dyspnea), interstitial lung disease, cardiopulmonary arrest, hypomagnesemia, fever, sepsis, kidney failure, pulmonary embolus; others (see full labeling).

How supplied: Single-use vials—1

HYDREA Bristol-Myers Squibb

℞

Substituted urea. Hydroxyurea 500mg; caps.

Indications: Adjunct with irradiation therapy in primary squamous cell (epidermoid) carcinomas of the head and neck, excluding the lip.

Adults: See literature. 80mg/kg as single dose every 3rd day. Renal impairment: reduce dose.

Children: Not recommended.

Contraindications: Marked bone marrow depression.

Warnings/Precautions: Previous irradiation therapy or chemotherapy. Correct anemia before starting. Monitor hematologic, renal, hepatic function before and during treatment. Marked renal dysfunction. Myeloproliferative disorders; discontinue if cutaneous vasculitic ulcerations develop and use alternative agents. Elderly.

Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended.

Interactions: Avoid concomitant didanosine, with or without stavudine, or other antiretrovirals (may cause pancreatitis [monitor], fatal hepatotoxicity, peripheral neuropathy).

Myelosuppressives potentiate antineoplastic effect. May antagonize antigout agents. Increased risk of vasculitic toxicities with interferon therapy.

May cause falsely elevated urease, uricase, lactate dehydrogenase.

Adverse reactions: Leukopenia, anemia, erythrocytic abnormalities, thrombocytopenia, GI upset, rash, erythema, fever, CNS effects, temporary renal impairment, acute pulmonary reactions, secondary leukemias, skin cancer.

Note: Wear disposable gloves when handling caps or bottle.

How supplied: Caps—100

TREXALL Teva

℞

Folic acid antagonist. Methotrexate sodium 5mg, 7.5mg, 10mg, 15mg; scored tabs. ℞ Also: Methotrexate injection Bedford Methotrexate 25mg/mL; soln for IV, IM, intraarterial, or intrathecal administration after dilution; preservative-free. ℞ Also: Methotrexate for injection Bedford Methotrexate 1g/vial; pwd for IV, IM, intra-arterial, or intrathecal administration after dilution; preservative-free.

Indications: Epidermoid cancers of the head and neck.

Adults: See literature.

Children: Not established.

Contraindications: Pregnancy (Cat.X). Nursing mothers.

Warnings/Precautions: Be fully familiar with this drug’s toxicity before use. Discontinue if malignant lymphomas occur. Obtain baseline and monitor CBCs with differential, platelet counts, chest X-ray, and hepatic, renal and pulmonary function. During therapy monitor hematology monthly, renal and hepatic function every 1–2 months, more often if increasing dose or predisposed to toxicity (eg, dehydration). Discontinue immediately if blood counts drop significantly. Rule out pregnancy in women of childbearing potential; use effective contraception during therapy and for at least 1 ovulatory cycle afterwards for women and for at least 3 months afterwards

for men. Interrupt therapy if vomiting, diarrhea, stomatitis, or pulmonary symptoms occur.

Hepatic or renal impairment. Obesity. Diabetes.

Peptic ulcer. Ulcerative colitis. Infection.

Dehydration. Folate deficiency. Ascites, pleural effusions: evacuate fluid, monitor for toxicity and reduce dose or discontinue if needed.

Elderly (use low doses and monitor closely).

Debilitated.

Interactions: Avoid live virus vaccines. Toxicity increased by NSAIDs, salicylates, phenytoin, sulfonylureas, sulfonamides, probenecid, folic acid antagonists. May be potentiated by penicillins (monitor), tetracyclines, chloramphenicol, non-absorbable broad spectrum antibiotics. May be antagonized by folic acid. May potentiate theophylline, mercaptopurine. Increased risk of soft tissue necrosis and osteonecrosis with radiotherapy.

Caution with other hepatotoxic drugs (eg, azathioprine, retinoids, sulfasalazine) and nephrotoxic agents (eg, cisplatin).

Adverse reactions: Ulcerative stomatitis, leukopenia, nausea, GI upset, malaise, fatigue, chills, fever, dizziness, infection, myelosuppression, hepatotoxicity, renal toxicity, CNS toxicity, seizures (esp in children); interstitial pneumonitis, tumor lysis syndrome, skin reactions (may be fatal; eg, toxic epidermal necrolysis, Stevens-Johnson syndrome).

How supplied: Tabs—30; soln (2mL, 4mL, 8mL, 10mL)—10 (single-use vials); pwd (1 gram)—1 (single-use vial)

HYPERSENSITIVITY to

a drug or its class is assumed to be a contraindication in all product monographs, although not explicitly stated.

SEE LITERATURE Consult the manufacturer’s labeling for full prescribing information.

DOSAGE Recommended adult dosage and, where appropriate, the dosage for children. Doses are given for children <12 years of age unless stated otherwise.

Assume the adult dosage for children ≥12 years. Dosages for children are presented in ascending age order.

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CANCER TREATMENT REGIMEN

HEMATOLOGIC CANCER Leukemia Treatment Regimens: Acute Myeloid Leukemia (AML) Clinical Trials: The NCCN recommends cancer patient participation in clinical trials as the gold standard for treatment.

Cancer therapy selection, dosing, administration, and the management of related adverse events can be a complex process that should be handled by an experienced healthcare team. Clinicians must choose and verify treatment options based on the individual patient; drug dose modifications and supportive care interventions should be administered accordingly. The cancer treatment regimens below may include both U.S. Food and Drug Administration-approved and unapproved indications/regimens. These regimens are only provided to supplement the latest treatment strategies.

These Guidelines are a work in progress that may be refined as often as new significant data becomes available. The NCCN Guidelines® are a consensus statement of its authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult any NCCN Guidelines® is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way.

Induction Therapy1 Note: All recommendations are Category 2A unless otherwise indicated.

REGIMEN Age <60 years

DOSING 2-5

Days 1–3: An anthracycline (daunorubicin 90mg/m2 continuous IV, OR idarubicin 12mg/m2), Days 1–7: Cytarabine 100–200mg/m2 continuous IV (Category 1).

OR Days 1–3: Daunorubicin 60mg/m2 continuous IV, Days 1–7: Cytarabine 200mg/m2 continuous IV, Days 1–5: Cladribine 5 mg/m2 (Category 1).

OR Days 1–3: An anthracycline (daunorubicin 60mg/m2 continuous IV, OR idarubicin 12mg/m2), Days 1–6: High-dose cytarabine 2g/m2 IV every 12 hours, OR Days 1–4: High-dose cytarabine 3g/m2 IV every 12 hours (Category 1 for patients ≤45 years, category 2B for other age groups).

Age ≥60 years6-10 Performance Status 0–2 Favorable cytogenetic markers without prior MDS/Therapy- related AML

Days 1–3: An anthracycline (daunorubicin 45–90mg/m2 continuous IV, OR idarubicin 12mg/m2 IV (preferred), OR mitoxantrone 12mg/m2 IV), Days 1–7: Cytarabine 100–200mg/m2 continuous IV. OR Low-intensity therapy Days 1–10: Cytarabine 20mg SC twice daily, OR Days 1–7: 5-azacytidine 75mg/m2 IV every 28 days, OR Days 1–5: Decitabine 20mg/m2 IV for a 4-week cycle.

Age ≥60 years6,7,9,10 Performance Status 0–2 Unfavorable cytogenetic markers with prior MDS/Therapy-related AML

Low-intensity therapy Days 1–7: 5-azacytidine 75mg/m2 IV every 28 days, OR Days 1–5: Decitabine 20mg/m2 IV for a 4-week cycle.

OR Days 1–3: An anthracycline (daunorubicin 45–60mg/m2 continuous IV,OR idarubicin 12mg/m2 IV (preferred), OR mitoxantrone 12mg/m2 IV), Days 1–7: Cytarabine 100–200mg/m2 continuous IV.

Age ≥60 years8-11 Performance Status >2 or 0–3 with significant comorbidities or age ≥75 years

Low-intensity therapy Days 1–10: Cytarabine 20mg SC twice daily, OR Days 1–7: 5-azacytidine 75mg/m2 IV every 28 days, OR Days 1–5: Decitabine 20mg/m2 IV every 28 days.

OR Hydroxyurea 10–70mg/kg/day orally in divided doses.

Post-Remission Therapy1 Age <60 years12,13 Better-risk cytogenetics or molecular abnormalities

Days 1, 3, and 5: High-dose cytarabine 3g/m2 IV every 12 hours for 3–4 cycles (Category 1).

OR 1–2 cycles of high-dose cytarabine-based consolidation followed by autologous hematopoietic stem cell transplant (HSCT) (Category 2B).

Age <60 years12,13 Intermediate-risk cytogenetics or molecular abnormalities

Days 1, 3, and 5: High-dose cytarabine 1.5–3g/m2 IV every 12 hours for 3–4 cycles.

OR Matched sibling or unrelated donor HSCT.

Matched sibling or unrelated donor HSCT. Age <60 years Treatment-related disease or poor-risk cytogenetics or molecular abnormalities continued

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CANCER TREATMENT REGIMEN

HEMATOLOGIC CANCER Leukemia Treatment Regimens: Acute Myeloid Leukemia (AML) Post-Remission Therapy1 (continued) REGIMEN

DOSING

Age ≥60 years Complete Response

Cytarabine 100–200mg/m2 IV for 5–7 days for 1–2 cycles, ± anthracycline (idarubicin or daunorubicin).

OR Cytarabine 1–1.5g/m2 IV for 4–6 doses for 1–2 cycles for patients.

OR Continue low-intensity regimens (5-azacytidine, decitabine) every 4–6 weeks until progression.

OR Reduced intensity HSCT.

Age ≥60 years Induction Failure

Reduced-intensity HSCT in context of clinical trial OR Best supportive care

Salvage Therapy1 Age <60 years Early Relapse (<12 months)

Salvage chemotherapy* followed by matched sibling or alternative donor HSCT.

Age <60 years Late Relapse (>12 months)

Salvage chemotherapy* followed by matched sibling or alternative donor HSCT. OR Repeat initial successful induction regimen.

Age ≥60 years Early Relapse (<12 months)

Salvage chemotherapy* followed by matched sibling or alternative donor HSCT. OR Best supportive care

Age ≥60 years Late Relapse (>12 months)

Repeat initial successful regimen.

OR Salvage chemotherapy* followed by matched sibling or alternative donor HSCT. OR Best supportive care

*Salvage Chemotherapy Options8-10, 14-19

Aggressive therapy for appropriate patients: Days 1–5: Cladribine 5mg/m2 IV, Days 1–5: Cytarabine 2g/m2 IV, Days 0–5: Granulocyte-colony stimulating factor (G-CSF) 300mcg SC Days 1–3: Mitoxantrone 10mg/m2 IV, OR idarubicin 10mg/m2 IV. OR High-dose cytarabine (if not previously used in treatment) ± anthracycline.

OR Days 1–5: Fludarabine 30mg/m2 IV over 0.5 hours, Days 1–5: Cytarabine 2g/m2 IV over 4 hours, Days 0 to polymorphonuclear recovery (>0.5 x 109/L): G-CSF 5mcg/kg or 300mcg/m2.

(G-CSF may also start on Day +6 until engraftment.) ± Days 1–3: Idarubicin 10mg/m2 IV. OR Days 1–6: Etoposide 80mg/m2 IV over 1 hour, Days 1–6: Cytarabine 1g/m2 IV over 6 hours. ± Days 1–6: Mitoxantrone 6mg/m2 IV bolus.

OR Days 1–5: Clofarabine 25mg/m2 IV, Days 2–6: Cytarabine 2g/m2 IV, Days 0 to neutrophil recovery: G-CSF 5mcg/kg/day.

Less aggressive therapy: Days 1–10: Cytarabine 20mg SC twice daily OR Days 1–7: 5-azacytidine 75mg/m2 IV every 28 days, OR Days 1–5: Decitabine 20mg/m2 IV every 28 days.

OR Days 1–7: 5-azacytidine 75mg/m2 IV every 28 days, OR Days 1–5: Decitabine 20mg/m2 IV every 28 days, plus sorafenib for FLT3-ITD mutations

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CANCER TREATMENT REGIMEN

HEMATOLOGIC CANCER References 1.

2.

3.

4.

5.

6.

7.

8.

9.

NCCN Clinical Practice Guidelines in Oncology™. Acute Myeloid Leukemia. v1.2015.

Available at: http://www.nccn.org/professionals/physician_gls/pdf/aml.pdf.

Accessed June 24, 2015.

Fernandez HF, Sun Z, Yao X, et al. Anthracycline dose intensification in acute myeloid leukemia. N Engl J Med. 2009;361: 1249–1259.

Kern W, Estey EH. High-dose cytarabine arabinoside in the treatment of acute myeloid leukemia review of three randomized trials. Cancer. 2006;107:116–124.

Weick JK, Kopecky KJ, Appelbaum FR, et al. A randomized investigation of highdose versus standard-dose cytosine arabinoside with daunorubicin in patients with previously untreated acute myeloid leukemia: a Southwest Oncology Group study. Blood. 1996:88:2841–2851.

Bishop JF, Matthews JP, Young GA, et al. A randomized study of high-dose cytarabine in induction in acute myeloid leukemia. Blood. 1996;87:1710–1717.

Krug U, Röllig C, Koschmieder A, et al. Complete remission and early death after intensive chemotherapy in patients aged 60 years or older with acute myeloid leukaemia: a web-based application for prediction of outcomes. Lancet. 2010;376: 2000–2008.

Löwenberg B, Ossenkoppele GJ, van Putten W, et al. High-dose daunorubicin in older patients with acute myeloid leukemia. N Engl J Med. 2009;361:1235–1248.

Burnett AK, Milligan D, Prentice AG, et al. A comparison of low-dose cytarabine and hydroxyurea with or without all-trans retinoic acid for acute myeloid leukemia and high-risk myelodysplastic syndrome in patients not considered fit for intensive treatment. Cancer. 2007;109:1114–1124.

Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol. 2009; 10:223–232.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

Cashen AF, Schiller GJ, O’Donnell MR, DiPersio JF. Multicenter, phase II study of decitabine for the first-line treatment of older patients with acute myeloid leukemia. J Clin Oncol. 2010;28:556–561.

Kantarjian HM, Erba HP, Claxton D, et al. Phase II study of clofarabine monotherapy in previously untreated older adults with acute myeloid leukemia and unfavorable prognostic factors. J Clin Oncol. 2010;28:549–555.

Mayer RJ, Davis RB, Schiffer CA, et al. Intensive postremission chemotherapy in adults with acute myeloid leukemia. N Engl J Med. 1994;331:896–903.

Löwenberg B, Pabst T, Vellenga E, et al. Cytarabine dose for acute myeloid leukemia. N Engl J Med. 2011;364: 1027–1036.

Martin MG, Welch JS, Augustin K, et al. Cladribine in the treatment of acute myeloid leukemia: a single-institution experience. Clin Lymphoma Myeloma.

2009;9:298–301.

Montillo M, Mirto S, Petti MC, et al. Fludarabine, cytarabine, and G-CSF (FLAG) for the treatment of poor risk acute myeloid leukemia. Am J Hematol. 1998;58:105–109.

Parker JE, Pagliuca A, Mijovic A, et al. Fludarabine, cytarabine, G-CSF and idarubicin (FLAG-IDA) for the treatment of poor-risk myelodysplastic syndromes and acute myeloid leukaemia. Br J Haematol. 1997;99:939–944.

Amadori S, Arcese W, Isacchi G, et al. Mitoxantrone, etoposide, and intermediatedose cytarabine: an effective and tolerable regimen for the treatment of refractory acute myeloid leukemia. J Clin Oncol. 1991;9:1210–1214.

Becker PS, Kantarjian HM, Appelbaum FR, et al. Clofarabine with high dose cytarabine and granulocyte colony-stimulating factor (G-CSF) priming for relapse and refractory acute myeloid leukaemia. Br J Haematol. 2011;155:182–189.

Ravandi F, Alattar ML, Grunwald, MR, et al. Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation. Blood. 2013:121:4655–4662.

(Revised 6/2015) © 2015 by Haymarket Media, Inc.

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER ADCETRIS Seattle Genetics

℞

CD30-directed antibody-drug conjugate.

Brentuximab vedotin 50mg/vial; lyophilized pwd for IV infusion after reconstitution; preservative-free.

Indications: Treatment of Hodgkin lymphoma (HL) after failure of autologous stem cell transplant (ASCT) or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates. Treatment of systemic anaplastic large cell lymphoma (sALCL) after failure of at least one prior multiagent chemotherapy regimen.

Adults: Give by IV infusion over 30 mins. Initially 1.8mg/kg up to 180mg every 3 weeks until disease progression or unacceptable toxicity. Mild hepatic impairment: initially 1.2mg/kg up to 120mg every 3 weeks. Peripheral neuropathy: if Grade 2/3: withhold until resolve to ≤Grade 1, then restart with 1.2mg/kg; if Grade 4: discontinue therapy.

Neutropenia: Grade 3/4: withhold until resolve to ≤Grade 2; may consider growth factor support; recurrent Grade 4: discontinue or consider reducing dose to 1.2mg/kg.

Children: Not established.

Contraindications: Concomitant bleomycin.

Warnings/Precautions: Risk of JC virus infection. Monitor for progressive multifocal leukoencephalopathy (PML); withhold dose if suspected and discontinue if confirmed. Monitor for neuropathy and delay, change, or discontinue dose accordingly. Monitor for infusion-related reactions; permanently discontinue and treat if anaphylaxis occurs. Monitor CBCs prior to each dose and frequently for Grade 3 or 4 neutropenia; delay, reduce or discontinue dose if develops.

Increased risk of tumor lysis syndrome in rapidly proliferating tumor/high tumor burden patients; monitor closely. Monitor for emergence of bacterial, fungal, or viral infections. Monitor liver enzymes and bilirubin; delay, change dose, or discontinue if hepatotoxicity occurs. Severe renal impairment or moderate or severe hepatic impairment: avoid. Discontinue if serious skin reactions occur. Elderly. Pregnancy (Cat.D); avoid.

Nursing mothers: not recommended.

Interactions: See Contraindications. Potentiated by strong CYP3A4 inhibitors (eg, ketoconazole) or P-gp inhibitors; monitor closely. Antagonized by potent CYP3A4 inducers (eg, rifampin).

Adverse reactions: Neutropenia, peripheral sensory neuropathy, fatigue, nausea, anemia, upper respiratory tract infection, diarrhea, pyrexia, rash, thrombocytopenia, cough, vomiting; infusion reactions, PML (may be fatal), hepatotoxicity, serious skin reactions (eg, Stevens-Johnson syndrome, TEN).

How supplied: Single-use vial—1

ARRANON GlaxoSmithKline

℞

Nucleoside analogue. Nelarabine 250mg/vial; soln for IV infusion.

Indications: T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma

(T-LBL) that is unresponsive or has relapsed after ≥2 chemotherapy regimens.

Adults and Children: Contact manufacturer.

From the pediatric trial: Patients ≤21 yrs: 650mg/m2 by IV infusion over 1 hour daily for 5 consecutive days; repeat every 21 days. From the adult trial: Patients 16–65yrs: 1500mg/m2

by IV infusion over 2 hours on days 1, 3, and 5; repeat every 21 days. The recommended duration of treatment has not been clearly established.

Treatment was generally continued until there was evidence of disease progression, the patient experienced unacceptable toxicity, the patient became a candidate for bone marrow transplant, or the patient no longer continued to benefit from treatment. See literature.

Warnings/Precautions: Discontinue if ≥ Grade 2 neurotoxicity occurs; may delay dosing if other toxicities occur (eg, hematologic toxicity).

Prior or concurrent intrathecal chemotherapy or craniospinal irradiation (increased risk of neurotoxicity). Renal or hepatic impairment.

Obtain CBCs, platelet counts. Monitor for signs/ symptoms of infection, tumor lysis syndrome.

Ensure adequate hydration. Elderly. Pregnancy (Cat.D); use effective contraception. Nursing mothers: not recommended.

Interactions: Avoid live vaccines. Concomitant adenosine deaminase inhibitors (eg, pentostatin): not recommended.

Adverse reactions: Hematologic disorders (eg, anemia, neutropenia, thrombocytopenia), headache, GI upset, constipation, fatigue, somnolence, dizziness, peripheral neuropathy, seizures, respiratory disorders, pyrexia; increased transaminase levels, bilirubin; decreased potassium, albumin.

How supplied: Vials—6

ARZERRA GlaxoSmithKline

℞

CD20-directed cytolytic monoclonal antibody.

Ofatumumab 20mg/mL; soln for IV infusion after dilution; preservative-free.

Indications: In combination with chlorambucil in previously untreated patients with chronic lymphocytic leukemia (CLL), for whom fludarabinebased therapy is considered inappropriate. CLL refractory to fludarabine and alemtuzumab.

Adults: See full labeling. Premedicate with acetaminophen (oral), antihistamine (oral or IV), corticosteroid (IV). Give by IV infusion (use in-line filter; rate varies with dose and during infusion).

Previously untreated: initially 300mg on Day 1, then 1 week later by 1000mg on Day 8 (Cycle 1), follow by 1000mg on Day 1 of subsequent 28-day cycles for at least 3 cycles until best response or max 12 cycles. Refractory: initially 300mg once, then 1 week later by 2000mg weekly for 7 doses, followed 4 weeks later by 2000mg every 4 weeks for 4 doses.

Children: Not established.

Warnings/Precautions: Increased risk of HBV reactivation. Test/treat HBV infection prior to initiating therapy. Monitor for signs of hepatitis or

HBV reactivation during and for several months after therapy; discontinue if HBV reactivation occurs. Monitor CBCs at regular intervals during and after therapy, increase frequency if Grade 3/4 cytopenias develop. Monitor for new onset of or changes in neurological signs/symptoms.

Increased risk of tumor lysis syndrome (TLS) in high tumor burden and/or high circulating lymphocytes; consider prophylaxis with anti-hyperuricemics and hydration beginning 12–24hrs prior to infusion. Pregnancy (Cat.C).

Nursing mothers.

Interactions: Avoid vaccination with live viral vaccines.

Adverse reactions: Neutropenia, thrombocytopenia, anemia, pneumonia, pyrexia, cough, fatigue, dyspnea, rash, nausea, diarrhea, bronchitis, upper respiratory tract infections; infusion reactions (eg, bronchospasm; laryngeal, pulmonary, or angioedema; flushing, hyper- or hypotension, syncope, cardiac ischemia, back or abdominal pain, fever, urticaria) (interrupt, adjust infusion rate and monitor; permanently discontinue if anaphylaxis occurs), progressive multifocal leukoencephalopathy (discontinue if suspected and evaluate), infections (eg, sepsis), hepatotoxicity, TLS. How supplied: Single-use vial (5mL)—3; (50mL)—1

BELEODAQ Spectrum

℞

Histone deacetylase inhibitor. Belinostat 500mg; per vial; lyophilized pwd for IV inj after reconstitution and dilution.

Indications: Relapsed or refractory peripheral T-cell lymphoma.

Adults: Give 1000mg/m2 once daily by IV infusion over 30 mins on Days 1–5 of a 21-day cycle; can repeat cycles every 21 days until disease progression or unacceptable toxicity. Dose modifications: Hematologic toxicities: if ANC nadir <0.5×109/L or platelet count <25×109/L: decrease dose by 25% (750mg/m2); discontinue if recurrent ANC <0.5×109/L or platelet count <25×109/L nadirs after 2 dose reductions; Nonhematologic toxicities: if any CTCAE Grade 3/4 reaction: decrease dose by 25% (750mg/m2); discontinue if recurrent CTCAE Grade 3/4 reaction after 2 dose reductions. Patients with homozygous UGT1A1*28 allele: initially 750mg/m2.

Children: Not established.

Warnings/Precautions: Risk of hematologic toxicity; monitor blood counts with differential at baseline and weekly during therapy; adjust dose as necessary. Active infection: do not administer.

History of extensive or intensive chemotherapy: may be at higher risk of life-threatening infections. Renal or hepatic impairment. Monitor serum chemistry, renal and hepatic function before treatment and the start of each cycle; interrupt, adjust, or discontinue dose based on severity of hepatotoxicity. Tumor lysis syndrome; monitor patients with advanced stage disease and/or high tumor syndrome. GI toxicity; may

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER require use of antiemetics and antidiarrheals.

Embryo-fetal toxicity. Pregnancy (Cat.D), nursing mothers: not recommended.

Interactions: Avoid concomitant use of strong UGT1A1 inhibitors.

Adverse reactions: Nausea, fatigue, pyrexia, anemia, vomiting; hematologic toxicity, infection, hepatotoxicity, tumor lysis syndrome, GI toxicity.

How supplied: Single-use vial (30mL)—1

BEXXAR GlaxoSmithKline

℞

Radionuclide (B-lymphocyte-restricted differentiation antigen [CD20] inhibitor).

Tositumomab 35mg/vial, 225mg/vial; soln; Iodine I131 tositumomab 0.61mCi/mL, 5.6mCi/mL soln; both for IV infusion after dilution; preservative-free.

Indications: Non-Hodgkin’s lymphoma (CD20 antigen-expressing relapsed or refractory, low grade, follicular, transformed, or rituximab-refractory).

Adults: See literature. Pretreat with acetaminophen 650mg and oral diphenhydramine 50mg and thyroid blockers; continue thyroid blockers 2 weeks after therapeutic dose. Give

by IV infusion. Dosimetric step: Tositumomab 450mg over 1hr, then Iodine I131 tositumomab (containing 5mCi I131 and 35mg tositumomab) over 20 minutes. Therapeutic step (7–14 days after dosimetric step if biodistribution acceptable): tositumomab 450mg over 1hr, then calculated therapeutic dose of Iodine I131 tositumomab over 20 minutes. Reduce infusion rate by 50% if infusional toxicity occurs; stop if severe; may continue at 50% rate if severe symptoms resolve.

Children: Not recommended.

Contraindications: Hypersensitivity to murine proteins. Pregnancy (Cat.X).

Warnings/Precautions: Use only by physicians trained in radionuclide therapy. Handle and dispose of properly. See literature on patient contact restrictions. Not for initial treatment. >25% lymphoma marrow involvement and/or impaired bone marrow reserve, platelet count <100000cells/mm3, neutrophil count <1500cells/mm3, or intolerant to thyroid blockers: not recommended. High tumor burden.

Splenomegaly. Renal impairment. Screen for human anti-mouse antibodies (increases anaphylaxis risk). Obtain CBCs and platelet counts before and for up to 12 weeks after therapy.

Monitor TSH (before and annually), serum creatinine (before). Use adequate contraception during and for 12 months after therapy. Elderly.

Nursing mothers: not recommended.

Interactions: Concomitant other forms of irradiation or chemotherapy: not recommended.

Caution with live viral vaccines, anticoagulants, platelet aggregation inhibitors.

Adverse reactions: Thrombocytopenia, neutropenia, anemia, headache, asthenia, fever, chills, pain, GI upset, cough, pneumonia, pleural effusion, dehydration, rash, infection, hemorrhage, hypersensitivity reactions (may be fatal), myelodysplastic syndrome, secondary malignancies, antibody formation.

Note: For technical questions call (877) 423-9927.

How supplied: Dosimetric pack (tositumomab 2 × 225mg/vial + 1 × 35mg/vial and Iodine I131 tositumomab 1 × 20mL single-use vial)—1; Therapeutic pack (tositumomab 2 × 225mg/vial + 1 × 35mg/vial and Iodine I131 tositumomab 1 or 2 × 20mL single-use vial)—1

BLINCYTO Amgen

℞

Bispecific CD19-directed CD3 T-cell engager.

Blinatumomab 35mcg; per vial; lyophilized pwd for IV infusion after reconstitution; preservative-free.

Indications: Philadelphia chromosome-negative relapsed or refractory B-cell precursor acute lymphoblastic leukemia.

Adults: Strictly follow preparation and administration instructions. Pre-medicate with IV dexamethasone 20mg 1 hour prior to 1st dose of each cycle, prior to a step dose, or when restarting infusion after interruption (≥4 hours).

Hospitalization recommended for first 9 days of Cycle 1 and first 2 days of Cycle 2. One single cycle = 4 weeks of continuous IV infusion followed by a 2-week treatment-free interval. ≥18yrs (≥45kg): Give by continuous IV infusion at a rate of 10mL/hr for 24 hours or 5mL/hr for 48 hours.

Cycle 1: 9mcg/day on Days 1–7 and 28mcg/day on Days 8–28. Subsequent cycles: 28mcg/day on Days 1–28. Treat up to a total of 5 cycles. Dose adjustments: see full labeling.

Children: <18yrs: not established.

Warnings/Precautions: Monitor for signs/ symptoms of cytokine release syndrome or neurological toxicities; interrupt or discontinue as recommended (see full labeling). Monitor for infections; give antibiotic prophylaxis as appropriate. Monitor for tumor lysis syndrome; interrupt or discontinue as needed. Obtain lab tests (including WBC, ANC) during infusion; interrupt if prolonged neutropenia occurs.

Monitor ALT, AST, GGT, and total bilirubin prior to and during treatment; interrupt if transaminases rise >5×ULN or if bilirubin rises >3×ULN. Risk of leukoencephalopathy, esp. in those with prior treatment with cranial irradiation and antileukemic chemotherapy (including high-dose methotrexate or intrathecal cytarabine). Renal impairment (CrCl <30mL/min) or hemodialysis.

Elderly. Pregnancy (Cat.C). Nursing mothers: not recommended.

Interactions: Caution with concomitant CYP450 substrates (esp. drugs with narrow therapeutic index); adjust dose as needed. Monitor for toxicity with warfarin. Monitor cyclosporine.

Adverse reactions: Pyrexia, headache, peripheral edema, febrile neutropenia, nausea, hypokalemia, tremor, rash, constipation; pneumonia, sepsis, neutropenia, device-related infection, tremor, encephalopathy, confusion, overdose, possible immunogenicity.

How supplied: Pack—1 (single-use vial + IV solution stabilizer)

BOSULIF Pfizer

℞

Tyrosine kinase inhibitor. Bosutinib 100mg, 500mg; tabs.

Indications: Treatment of chronic, accelerated, or blast phase Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) with resistance or intolerance to prior therapy.

Adults: Initially 500mg once daily with food.

Continue until disease progression or patient intolerance. Consider dose escalation to 600mg once daily in patients who do not reach complete hematological response (CHR) by Week 8 or a complete cytogenetic response (CCyR) by Week 12, who did not have Grade 3 or higher adverse reactions. Adjust dose for hematologic and non-hematologic toxicity: see full labeling.

Hepatic impairment: initially 200mg daily. Renal impairment (CrCl 30–50mL/min): initially 400mg daily; (CrCl <30mL/min): initially 300mg daily.

Children: <18yrs: not established.

Warnings/Precautions: Monitor and manage GI toxicity, fluid retention; withhold, reduce dose, or discontinue as necessary. Perform CBC weekly for first month, then monthly; hepatic enzyme tests monthly for first three months (more frequently if transaminase elevations occur); withhold, reduce dose, or discontinue as necessary. Monitor renal function at baseline and during therapy; consider adjusting dose if renal impairment occurs. Pregnancy (Cat.D); avoid.

Nursing mothers: not recommended.

Interactions: Potentiated by concomitant strong or moderate CYP3A and/or P-gp inhibitors (eg, ritonavir, indinavir, nelfinavir, saquinavir, ketoconazole, boceprevir, telaprevir, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin, nefazodone, conivaptan, fluconazole, darunavir, erythromycin, diltiazem, atazanavir, aprepitant, amprenavir, fosamprenavir, crizotinib, imatinib, verapamil, grapefruit products, ciprofloxacin); avoid. Antagonized by concomitant strong or moderate CYP3A inducers (eg, rifampin, phenytoin, carbamazepine, St. John’s Wort, rifabutin, phenobarbital,

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER bosentan, nafcillin, efavirenz, modafinil, etravirine); avoid. Antagonized by proton pump inhibitors (eg, lansoprazole); consider shortacting antacids or H2 blockers instead; separate dosing by more than 2hrs. May potentiate drugs that are P-gp substrates (eg, digoxin).

Adverse reactions: Diarrhea, nausea, thrombocytopenia, vomiting, abdominal pain, rash, anemia, pyrexia, fatigue; fluid retention (monitor), hepatic toxicity.

How supplied: Tabs 100mg—120; 500mg—30

BUSULFEX Otsuka

℞

Alkylating agent. Busulfan 6mg/mL; soln for IV administration after dilution.

Indications: In combination with cyclophosphamide, as a conditioning regimen prior to allogeneic hematopoietic progenitor cell transplantation for chronic myelogenous leukemia.

Adults: See full labeling. Premedicate with anticonvulsants and antiemetics. Give by IV infusion over 2 hours. 0.8mg/kg of ideal body weight or actual body weight, whichever is lower, every 6 hours for 4 days (total of 16 doses). Give cyclophosphamide after the 16th dose of busulfan (Days -3 and -2). Give hematopoietic progenitor cells on Day 0. Obese: base dose on adjusted ideal body weight.

Children: See full labeling.

Warnings/Precautions: Risk of severe and prolonged myelosuppression; requires hematopoietic progenitor cell transplantation.

Seizure disorder. Head trauma. Renal or hepatic impairment. Monitor CBCs with differential, platelet counts, liver enzymes, bilirubin during treatment and until recovery. Monitor for infection and bleeding. Use effective contraception during and after treatment. Pregnancy; avoid use.

Nursing mothers: not recommended.

Interactions: Potentiated by itraconazole and acetaminophen. May be antagonized by phenytoin.

Caution with potentially epileptogenic drugs.

Adverse reactions: Myelosuppression (eg, granulocytopenia, thrombocytopenia, anemia), GI upset, stomatitis, anorexia, abdominal pain, dyspepsia, fever, headache, asthenia, chills, pain, tachycardia, hypertension, edema, dyspnea, dizziness, depression, elevated creatinine, hypomagnesemia, hyperglycemia, hypokalemia, hypocalcemia, hyperbilirubinemia, insomnia, anxiety, rhinitis, rash; seizures (with higher doses), hepatic veno-occlusive disease (with high AUC), cardiac tamponade (in pediatric patients with thalassemia), cellular dysplasia; rare: bronchopulmonary dysplasia with pulmonary fibrosis.

How supplied: Single-use vials (10mL)—8

CAMPATH Genzyme

℞

Monoclonal antibody, CD52 (recombinant, humanized). Alemtuzumab 30mg/mL; soln; for IV infusion after dilution; preservative-free.

Indications: B-cell chronic lymphocytic leukemia (B-CLL).

Adults: Premedicate with antihistamine and acetaminophen before 1st dose, and at dose escalations. Give by IV infusion over 2 hrs. Initially 3mg per day until infusion reactions are ≤ grade 2, then increase to 10mg per day until infusion reactions are ≤ grade 2, then to maintenance 30mg/day three times per week (on alternate days); duration of therapy (including escalation): 12 weeks.

Do not exceed max single dose 30mg/dose or 90mg/week. Give prophylactic antibiotics and antivirals during treatment and for at least 2 months after completion or until CD4+ counts resolve (whichever occurs later). Dose adjustments for neutropenia and thrombocytopenia: see literature.

Retitrate if therapy interrupted for ≥7 days.

Children: Not recommended.

Warnings/Precautions: Discontinue dose for autoimmune or recurrent/persistent severe cytopenias (except lymphopenia). Withhold dose for severe cytopenias (except lymphopenia), grade 3 or 4 infusion reactions, serious infections, or during antiviral treatment for cytomegalovirus (CMV) infection or confirmed CMV viremia. Obtain CBCs, platelet counts weekly, assess CD4+ counts after treatment until recovery to ≥200cells/µL. Monitor for infusion reactions; CMV infection (continue for 2 months after therapy ends). Pregnancy (Cat.C).

Nursing mothers: not recommended.

Interactions: Avoid live virus vaccines (after recent therapy). May interfere with tests using antibodies. Irradiate any blood products given (GVHD may occur).

Adverse reactions: See literature; may be fatal.

Infusion reactions, cytopenias (eg, neutropenia, lymphopenia, thrombocytopenia, anemia), infections (eg, CMV), GI upset, insomnia, anxiety; others.

How supplied: Single-use vials—1, 3

CERUBIDINE Bedford

℞

Anthracycline. Daunorubicin HCl 20mg/vial; lyophilized pwd for IV infusion after reconstitution; contains mannitol.

Indications: In combination with other chemotherapy for remission induction in acute nonlymphocytic leukemia (myelogenous, monocytic, erythroid) of adults and for remission induction in acute lymphocytic leukemia of children and adults.

Adults: Give by IV infusion. Acute nonlymphocytic leukemia (in combination with cytosine arabinoside): <60yrs: 45mg/m2 daily on days 1, 2 and 3 of the first course and on days 1, 2 of subsequent courses; ≥60yrs: 30mg/m2 daily on days 1, 2 and 3 of the first course and on days 1, 2 of subsequent courses. Acute lymphocytic leukemia (in combination with vincristine, prednisone, L-asparaginase): 45mg/m2 daily on days 1, 2 and 3. Hepatic or renal impairment: reduce dose (see literature).

Children: Give by IV infusion. <2yrs or BSA<0.5m2: use weight (mg/kg) to calculate dose. 25mg/m2 on day 1 every week (in combination with vincristine and prednisone).

Warnings/Precautions: Treat if any systemic infections 1st. Pre-existing drug-induced bone marrow suppression. Cardiovascular disease, thoracic irradiation, previous doxorubicin therapy (cumulative doses >550mg/m2): increased risk of cardiotoxicity. Monitor blood counts, cardiac, hepatic and renal function prior to each treatment.

Renal or hepatic impairment. Hyperuricemia; monitor blood uric acid levels and give allopurinol prophylatically. Avoid extravasation. Children.

Elderly. Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended.

Interactions: Do not use if previously received max cumulative doxorubicin dose; or if concomitant with cyclophosphamide: increased cardiotoxicity.

Concomitant myelosuppressives: consider dose reduction. Increased risk of liver toxicity with hepatotoxic agents (eg, high-dose methotrexate).

Adverse reactions: Myelosuppression, cardiotoxicity, alopecia, rash, inj site reactions, GI upset, mucositis, abdominal pain, hyperuricemia; rare: anaphylaxis.

How supplied: Single-dose vials—10

CLOLAR Genzyme

℞

Purine nucleoside antimetabolite. Clofarabine 1mg/mL; soln for IV infusion after dilution; preservative-free.

Indications: Acute lymphoblastic leukemia (ALL) in patients 1–21 years of age after relapses from, and/or refractoriness to, at least two prior regimens.

Adults: Not established.

Children: Monitor blood pressure, cardiac, renal, and hepatic function before and during therapy. Give by IV infusion over 2 hours.

1–21yrs: 52mg/m2 daily for 5 consecutive days; repeat approximately every 2–6 weeks following recovery or return to baseline organ function. Provide supportive care (eg, IV fluids, antihyperuricemics, alkalinize urine, steroids, antiemetics, diuretics, albumin) throughout treatment. Renal impairment (CrCl 30–60mL/min): reduce dose by 50%. Dose modifications: see full labeling.

Warnings/Precautions: Obtain CBCs and platelets daily during the 5 days of therapy, then 1–2 times weekly or as needed. Monitor for signs/symptoms of infection, tumor lysis syndrome, cytokine release (eg, tachypnea, hypotension); if cytokine release progresses to systemic inflammatory response syndrome (SIRS)/capillary leak syndrome and/or if organ dysfunction (grade 3 or 4 hepatic or renal toxicity) occurs, discontinue and treat; may restart at lower dose if organ function recovers and patient is stable. Ensure adequate hydration. Monitor for venous occlusive disease of the liver in patients who previously received hematopoietic stem cell transplant; discontinue if suspected. Pregnancy (Cat.D); use effective contraception. Nursing mothers: not recommended.

Interactions: Minimize exposure to drugs with known renal toxicity during treatment. Consider avoiding concomitant drugs known to induce

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER hepatic toxicity. Caution with drugs that affect BP or cardiac function; monitor.

Adverse reactions: Nausea, vomiting, diarrhea, headache, rash, pruritus, pyrexia, fatigue, palmarplantar erythrodysesthesia syndrome, anxiety, flushing, mucosal inflammation; bone marrow suppression (eg, febrile neutropenia, anemia, leukopenia, thrombocytopenia), infections, hyperuricemia, hypotension, cardiac events, SIRS/capillary leak syndrome, hemorrhage (may be fatal), enterocolitis (monitor), serious skin reactions (discontinue for exfoliative or bullous rash or if Stevens-Johnson syndrome or toxic epidermal necrolysis suspected).

How supplied: Single-use vial (20mL)—1, 4

DACOGEN Otsuka

℞

Nucleoside analogue. Decitabine 50mg/vial; lyophilized pwd for IV infusion after reconstitution and dilution.

Indications: Myelodysplastic syndromes (MDS) including previously treated and untreated, de novo and secondary MDS of all FrenchAmerican-British subtypes and Intermediate-1, Intermediate-2, and High-risk International Prognostic Scoring System groups.

Adults: May premedicate with antiemetics. Treat for a minimum of 4 cycles; may take longer for a complete or partial response. Regimen 1: Give by continuous IV infusion over 3 hours. 15mg/m2 every 8 hours for 3 days; repeat every 6 weeks.

Regimen 2: Give by continuous IV infusion over 1 hour. 20mg/m2 once daily for 5 days; repeat every 4 weeks. Both: dose adjustment based on hematology values: see literature. Non-hematologic toxicities (eg, serum creatinine ≥2mg/dL; SGPT, total bilirubin ≥ 2 × ULN; active or uncontrolled infection): do not restart until toxicity resolved.

Children: Not recommended.

Warnings/Precautions: Renal or hepatic impairment. Obtain CBC and platelet counts before each dosing cycle and as needed. Monitor hepatic function (do baseline liver chemistries and serum creatinine). Pregnancy (Cat.D); use appropriate contraception (both men and women). Nursing mothers: not recommended.

Adverse reactions: Neutropenia, thrombocytopenia, anemia, leukopenia, fatigue, pyrexia, nausea, cough, petechiae, constipation, diarrhea, hyperglycemia.

How supplied: Single-use vial—1

DEPOCYT Sigma-Tau

℞

Antimetabolite. Cytarabine 50mg/vial; liposomal suspension for intrathecal administration; preservative-free.

Indications: Intrathecal treatment of lymphomatous meningitis.

Adults: See literature. Give intrathecally over 1–5 minutes. Administer dexamethasone 4mg twice daily for 5 days with each cycle of treatment.

Induction: 50mg every 14 days for 2 doses (weeks 1 and 3). Consolidation: 50mg every 14 days for 3 doses (weeks 5, 7 and 9) followed by 1 additional dose at week 13. Maintenance: 50mg every 28 days for 4 doses (weeks 17, 21, 25 and 29).

Reduce dose to 25mg if neurotoxicity develops and discontinue if it persists.

Children: Not recommended.

Contraindications: Active meningeal infection.

Warnings/Precautions: Chemical arachnoiditis; reduce symptoms with dexamethasone. Previous irradiation, cytotoxic chemotherapy. Monitor blood counts and for development of neurotoxicity. Renal and hepatic impairment. Pregnancy (Cat.D); avoid use.

Nursing mothers: not recommended.

Interactions: Increased risk of neurotoxicity with concomitant cranial/spinal irradiation or other intrathecal antineoplastics.

Adverse reactions: See literature. Arachnoiditis, GI upset, headache, fever, neurological toxicity (myelopathy), hydrocephalus, elevated CSF protein and WBC, weakness, back pain, insomnia, blurred vision, anaphylactic reactions; others.

How supplied: Single-use vials (5mL)—1

DOXIL Janssen Biotech

℞

Anthracycline. Doxorubicin HCl (liposomal) 2mg/mL; dispersion for IV infusion after dilution; preservative-free.

Indications: Multiple myeloma, in combination with bortezomib, in patients not previously treated with bortezomib and who have received at least one prior therapy.

Adults: Give by IV infusion at initial rate of 1mg/min; may increase rate to complete infusion over 1hr if no infusion reactions occur; may premedicate with antiemetics. 30mg/m2 on day 4 of each cycle following bortezomib (see full labeling for bortezomib dose); may treat for up to 8 cycles. Hepatic dysfunction (serum bilirubin ≥1.2mg/dL), hand-foot syndrome, hematologic toxicity (esp. ANC, platelets), or stomatitis: reduce dose. Consider total anthracycline and anthracenedione doses and irradiation when calculating total cumulative dose. See full labeling.

Children: Not established.

Warnings/Precautions: Not substitutable on a mg/mg basis with other doxorubicin products.

Cardiotoxicity, acute infusion-related reactions, myelosuppression may occur. Have resuscitative/ antiallergic equipment and expertise available.

Hepatic impairment. Monitor blood (esp. CBC + platelets), hepatic (esp. SGOT/SGPT, alkaline phosphatase), and cardiac function (esp. myocardial biopsy). Monitor periodically for secondary oral cancers with long-term use. Avoid extravasation. Pregnancy (Cat.D); avoid. Nursing mothers: not recommended.

Interactions: Caution with cyclosporine, phenobarbital, phenytoin, streptozocin, digoxin, myelosuppressants, others. Previous mediastinal irradiation, cyclophosphamide, other cardiotoxic drugs: monitor for cardiotoxicity and hepatotoxicity.

Adverse reactions: Asthenia, fatigue, fever, anorexia, nausea, vomiting, stomatitis, diarrhea, constipation, hand and foot syndrome, rash, neutropenia, thrombocytopenia, anemia; infusion reactions, cardiovascular events (eg, cardiomyopathy, CHF, acute LV failure), recall of skin reaction from prior radiation therapy, toxoplasmosis, urine discoloration (red/orange).

How supplied: Single-use vials (10mL, 25mL)—1

ERWINAZE Jazz

℞

Asparagine-specific enzyme. Asparaginase Erwinia chrysanthemi 10,000 IU; per vial; lyophilized pwd for IM or IV inj after reconstitution.

Indications: As a component of a multi-agent chemotherapeutic regimen for the treatment of patients with acute lymphoblastic leukemia (ALL) who have developed hypersensitivity to E. coliderived asparaginase.

Adults and Children: Give by IM inj (max 2mL/inj site) or IV (infuse over 1hr). To substitute for a pegaspargase dose: 25,000 IU/m2 three times weekly (M/W/F) for 6 doses for each planned pegaspargase dose. To substitute for a native E. coli asparaginase dose: 25,000 IU/m2 for each scheduled native E. coli asparaginase dose within a treatment. When IV use: consider monitoring nadir serum asparaginase activity (NSAA) levels; switch to IM inj if levels are inadequate.

Contraindications: History of serious pancreatitis, thrombosis, hemorrhagic events with prior L-asparaginase therapy.

Warnings/Precautions: Have resuscitation equipment available and other agents necessary to treat anaphylaxis. Discontinue if serious hypersensitivity reactions occur. Monitor for pancreatitis; discontinue if severe or hemorrhagic pancreatitis manifested by abdominal pain >72hrs and amylase elevation ≥2×ULN occurs.

Withhold therapy if mild pancreatitis; may resume after resolution. Monitor glucose levels at baseline and during therapy. Discontinue if thrombotic or hemorrhagic event occurs; may resume after

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER resolution. Pregnancy (Cat.C). Nursing mothers: not recommended.

Adverse reactions: Systemic hypersensitivity, hyperglycemia, abnormal transaminases, fever, pancreatitis, local reactions, vomiting, nausea, thrombosis, hyperbilirubinemia, abdominal pain/ discomfort, diarrhea.

How supplied: Vials (3mL)—5

FARYDAK Novartis

℞

Histone deacetylase inhibitor. Panobinostat 10mg, 15mg, 20mg; caps.

Indications: Multiple myeloma, in patients who have received at least two prior therapies (including bortezomib and an immunomodulatory agent), in combination with bortezomib and dexamethasone.

Adults: Swallow whole with water. Take at same time on scheduled days. Initially 20mg once every other day for 3 doses/wk in Weeks 1 and 2 of each 21-day cycle for up to 8 cycles. Consider 8 more cycles for patients with clinical benefit if no severe or significant toxicity; max 16 cycles (48 wks).

Give with bortezomib inj and oral dexamethasone per scheduled day. Hepatic impairment: mild: initially 15mg; moderate: initially 10mg; severe: avoid. Concomitant strong CYP3A inhibitors: initially 10mg. Dose adjustments and modifications for toxicity: see full labeling.

Children: Not established.

Warnings/Precautions: Risk of severe diarrhea and cardiac toxicities. Monitor hydration and electrolytes at baseline, weekly during therapy, or more as indicated. Initiate antidiarrheals at onset of diarrhea; interrupt dose if 4–6 stools/day.

Do not initiate if history of recent MI or unstable angina, QTcF >450msec, significant baseline ST-segment or T-wave abnormalities, active infections. Perform ECG prior to initiation and repeat during treatment as indicated. Correct electrolyte abnormalities prior to initiation and monitor; interrupt if QTcF ≥480msec; discontinue if QT prolongation does not resolve.

Serious hemorrhage. Obtain CBC prior to initiation; monitor weekly during therapy or more as indicated. Monitor for infections; treat and consider interruption or discontinuation if diagnosed. Monitor liver function prior to and during treatment; consider dose adjustments if abnormal tests observed. ESRD or dialysis: not studied. Elderly: monitor for toxicity more frequently (esp. GI, myelosuppression, cardiac).

Pregnancy: avoid. Obtain pregnancy test prior to and during treatment. Use effective contraception during and for ≥1 month after last dose; males: use condoms during and for ≥3 months after last dose. Nursing mothers: not recommended.

Interactions: Potentiated by strong CYP3A inhibitors (eg, boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, others); see Adults. Avoid star fruit, pomegranate or grapefruit juice. Avoid concomitant strong CYP3A inducers. Avoid concomitant sensitive CYP2D6 substrates (eg,

atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, tolterodine, venlafaxine) or substrates with narrow therapeutic index (eg, thioridazine, pimozide); if unavoidable, monitor frequently. Concomitant antiarrhythmics or QT prolonging drugs: not recommended. Antiemetics that prolong QT interval (eg, dolasetron, ondansetron, tropisetron): monitor ECG frequently.

Adverse reactions: Diarrhea, fatigue, nausea, peripheral edema, decreased appetite, pyrexia, vomiting, electrolyte imbalance, increased creatinine, thrombocytopenia, lymphopenia, leukopenia, neutropenia, anemia.

How supplied: Blister packs—6

FLUDARA Genzyme

℞

Antimetabolite. Fludarabine phosphate 50mg/vial; lyophilized pwd for IV infusion after reconstitution and dilution; preservative-free; contains mannitol.

Indications: B-cell chronic lymphocytic leukemia (CLL) in patients who have not responded to or whose disease progressed during treatment with at least 1 alkylating-agent containing regimen.

Adults: Give by IV infusion over 30 minutes.

25mg/m2 daily for 5 days every 28 days. Renal dysfunction (CrCl 30–70mL/min): reduce dose by 20%; CrCl <30mL/min: not recommended. Give for 3 cycles after the max response. Reduce or delay dose if toxicity occurs.

Children: Not recommended.

Warnings/Precautions: Myelosuppression.

Evaluate and monitor for hemolysis. Monitor blood (esp CBC, platelets). Use irradiated blood products if transfusions are required. May need to prophylax for tumor lysis syndrome with large tumors. Renal insufficiency. Delay or stop therapy if neurotoxicity occurs. Elderly.

Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended.

Interactions: Severe pulmonary toxicity with pentostatin (not recommended).

Adverse reactions: Myelosuppression (severe/ cumulative), bone marrow hypoplasia, autoimmune hemolytic anemia (fatal/severe), infection, fever, chills, GI upset, malaise, fatigue, CNS effects (eg, weakness, agitation, confusion, visual disturbances, coma, peripheral neuropathy), pneumonia, pulmonary hypersensitivity (eg, dyspnea, interstitial pulmonary infiltrate), stomatitis, GI bleeding, edema, tumor lysis syndrome, rash, hemorrhagic cystitis (rare); others.

How supplied: Single-dose vials—5

GAZYVA Genentech

℞

Cytolytic monoclonal antibody (CD20-directed).

Obinutuzumab 25mg/mL; soln for IV infusion after dilution; preservative-free.

Indications: Treatment of patients with previously untreated chronic lymphocytic leukemia (CLL), in combination with chlorambucil.

Adults: Premedicate (eg, glucocorticoid, APAP, antihistamine) before each infusion.

Give by IV infusion for 6 treatment cycles (28 days duration). Cycle 1: 100mg on Day 1 at 25mg/hr over 4 hours; 900mg on Day 2 at 50mg/hr, may increase at 50mg/hr every 30mins (max 400mg/hr); 1000mg on Days 8 and 15 at 100mg/hr, may increase by 100mg/hr increments every 30mins (max 400mg/hr); Cycles 2–6: 1000mg on Day 1 at 100mg/hr, may increase by 100mg/hr increments every 30mins (max 400mg/hr). Infusion rate and premedication adjustments: see full labeling.

Children: Not established.

Warnings/Precautions: Risk of hepatitis B virus (HBV) reactivation; immediately discontinue and any concomitant chemotherapy if occurs. Screen for HBV infection prior to initiation; if positive evidence, monitor and consider antiviral therapy. Discontinue treatment and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressives if PML develops.

Monitor closely for infusion reactions; if Grade 4: discontinue permanently; if Grade 3: interrupt until resolved; if Grade 1 or 2: interrupt or reduce the infusion rate and manage symptoms.

Preexisting cardiac or pulmonary conditions: monitor more frequently during and postinfusion period for severe reactions. Risk of TLS in high tumor burden and/or high circulating lymphocyte count (>25 × 109/L): prophylaxis with antihyperuricemics and hydration. Active infection: do not administer. Monitor for bleeding; obtain blood and platelet counts frequently. Risk of neutropenia; give antimicrobial prophylaxis; consider antiviral and antifungal prophylaxis.

Hepatic or renal impairment (CrCl <30mL/min).

Pregnancy (Cat.C). Nursing mothers: not recommended.

Interactions: Concomitant live viral vaccines: not recommended. Consider withholding antihypertensives for 12hrs prior to, during, and for 1hr after infusion until BP is stable. Consider withholding drugs that may increase bleeding risk (eg, platelet inhibitors, anticoagulants) esp. during 1st cycle.

Adverse reactions: Infusion reactions, neutropenia, thrombocytopenia, anemia, pyrexia, cough, musculoskeletal disorders.

How supplied: Single-use vial (40mL)—1

GLEEVEC Novartis

℞

Kinase inhibitor. Imatinib (as mesylate) 100mg, 400mg; scored tabs.

Indications: Philadelphia-chromosome (+) chronic myeloid leukemia (CML): in newlydiagnosed adults and children in chronic phase; in patients in blast crisis, accelerated phase, or chronic phase after failure of interferon-alpha therapy. Adults with relapsed or refractory Ph (+) acute lymphoblastic leukemia (ALL). Children with newly diagnosed Ph+ ALL in combination with chemotherapy. Adults with myelodysplastic/

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER myeloproliferative diseases (MDS/MPD) associated with PDGFR (platelet-derived growth factor receptor) gene rearrangements. Adults with hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL) who have the FIP1L1-PDGFRα fusion kinase and for patients with HES and/or CEL who are FIP1L1-PDGFRα fusion kinase negative or unknown.

Adults: Take with food and water. May disperse tab in water or apple juice and take promptly. ≥18yrs: Chronic phase CML: 400mg once daily; may increase to 600mg if clinically indicated.

Accelerated phase or blast crisis: 600mg once daily; may increase to 800mg (given as 400mg twice daily) if clinically indicated. Relapsed/ refractory Ph+ ALL: 600mg once daily.

MDS/MPD: 400mg once daily. HES/CEL: 400mg once daily. HES/CEL w. FIP1L1-PDGFRα fusion kinase: initially 100mg once daily; may increase to 400mg once daily if insufficient response.

If severe non-hematologic reactions develop: interrupt dose; resume at a lower dose in hepatic dysfunction. Severe hepatic impairment: reduce dose by 25%. Renal or hematologic reactions: see full labeling. Avoid concomitant strong CYP3A4 inducers (eg, rifampin): if needed, increase imatinib dose by at least 50%.

Children: Take with food and water in 1 or 2 divided doses; may disperse tab in water or apple juice and take promptly. <1yrs: not recommended. ≥1yrs: Newly diagnosed Ph+CML: 340mg/m2 per day (max 600mg). Newly diagnosed Ph+ALL: 340mg/m2 per day (max 600mg); give with chemotherapy. If severe nonhematologic reactions develop: interrupt dose; resume at a lower dose in hepatic dysfunction.

Renal or hematologic reactions: see full labeling.

Avoid concomitant strong CYP3A4 inducers (eg, phenytoin): if needed, increase imatinib dose by at least 50%; monitor closely.

Warnings/Precautions: Hepatic or renal impairment. Monitor weight and for fluid retention regularly; CBCs weekly for 1st month, bi-weekly for 2nd month, then periodically (eg, every 2–3 months); liver function at baseline then monthly or as needed; GI symptoms at baseline. Cardiovascular disease or risk factors; monitor. Immunosuppression and potential toxicities (liver, kidney, cardiac) from long-term use. Monitor for tumor lysis syndrome; correct clinically significant dehydration and treat high uric acid levels before initiating therapy.

Monitor growth in children. Possible cardiogenic shock/LV dysfunction in conditions with high eosinophil levels (eg, HES/CEL, MDS/MPD, ASM); consider concomitant systemic steroid prophylaxis (1–2mg/kg) for 1 or 2 wks if abnormal

ECG or serum troponin. Monitor TSH levels in thyroidectomy patients undergoing levothyroxine replacement. Pregnancy (Cat.D); avoid. Use highly effective contraception during treatment.

Nursing mothers: not recommended.

Interactions: Avoid grapefruit juice. Potentiated

by CYP3A4 inhibitors (eg, azole antifungals, protease inhibitors, nefazodone, clarithromycin, telithromycin). Antagonized by strong CYP3A4 inducers (eg, dexamethasone, fosphenytoin, phenytoin, phenobarbital, carbamazepine, oxcarbamazepine, primidone, St. John’s wort, rifampin, rifabutin, rifampicin); consider alternatives. May potentiate drugs metabolized

by CYP3A4 (eg, benzodiazepines, dihydropyridine calcium channel blockers, cyclosporine, ergots, alfentanil, fentanyl, pimozide, quinidine, certain statins, sirolimus, tacrolimus), CYP2D6, or CYP2C9 (use heparin instead of warfarin).

Adverse reactions: Edema (may be severe), nausea, vomiting, musculoskeletal pain, diarrhea, muscle cramps, rash (may be severe; eg, erythema multiforme, Stevens-Johnson syndrome), fatigue, abdominal pain, dizziness, blurred vision, somnolence, fever, headache, cough, arthralgia/myalgia, dyspnea, hypokalemia, night sweats, anorexia, pruritus, hemorrhage, anemia, neutropenia, thrombocytopenia, weight gain, renal or hepatotoxicity, immunosuppression, hypothyroidism; rare: severe CHF, LV dysfunction.

Testing considerations: BCR-Abl t(9;22) in Ph+CML patients How supplied: 100mg—90; 400mg—30

HYDREA Bristol-Myers Squibb

℞

Substituted urea. Hydroxyurea 500mg; caps.

Indications: Resistant chronic myelocytic leukemia.

Adults: See literature. 20–30mg/kg/day as single dose. Renal impairment: reduce dose.

Children: Not recommended.

Contraindications: Marked bone marrow depression.

Warnings/Precautions: Previous irradiation therapy or chemotherapy. Correct anemia before starting. Monitor hematologic, renal, hepatic function before and during treatment. Marked renal dysfunction. Myeloproliferative disorders; discontinue if cutaneous vasculitic ulcerations develop and use alternative agents. Elderly.

Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended.

Interactions: Avoid concomitant didanosine, with or without stavudine, or other antiretrovirals (may cause pancreatitis [monitor], fatal hepatotoxicity, peripheral neuropathy).

Myelosuppressives potentiate antineoplastic

effect. May antagonize antigout agents. Increased risk of vasculitic toxicities with interferon therapy.

May cause falsely elevated urease, uricase, lactate dehydrogenase.

Adverse reactions: Leukopenia, anemia, erythrocytic abnormalities, thrombocytopenia, GI upset, rash, erythema, fever, CNS effects, temporary renal impairment, acute pulmonary reactions, secondary leukemias, skin cancer.

Note: Wear disposable gloves when handling caps or bottle.

How supplied: Caps—100

ICLUSIG ARIAD

℞

Kinase inhibitor. Ponatinib 15mg, 45mg; tabs; contains lactose.

Indications: Treatment of adults with T315Ipositive chronic, accelerated, or blast phase chronic myeloid leukemia (CML) or T315I-positive Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). Treatment of adults with chronic, accelerated, or blast phase CML or Ph+ ALL for whom no other tyrosine kinase inhibitor (TKI) therapy is indicated.

Adults: Swallow whole. ≥18yrs: initially 45mg once daily; consider reducing dose in chronic and accelerated phase CML if major cytogenic response achieved. Consider discontinuing if no response occurred by 3 months. Concomitant strong CYP3A inhibitors: reduce to 30mg once daily. Dose modification for hematologic and nonhematologic toxicity: see full labeling.

Children: <18yrs: not established.

Warnings/Precautions: Risk of vascular occlusion (eg, arterial and venous thrombosis, fatal MI, stroke, stenosis of arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures) in patients with or without CV risk factors (including ≤50yrs old, or increasing age, history of ischemia, HTN, diabetes, hyperlipidemia); monitor and interrupt or discontinue if occurs. Monitor for signs/symptoms of heart failure; interrupt or consider discontinuing if develops or worsens.

Monitor hepatic function at baseline, then at least monthly or as needed; interrupt, reduce or discontinue as clinically indicated. Moderate-tosevere hepatic impairment: not recommended.

Monitor and manage BP elevations; interrupt, reduce dose or discontinue if not controlled. Risk of pancreatitis; check serum lipase every 2 weeks for the first 2 months and then monthly thereafter or as clinically indicated; do not restart until complete resolution and lipase levels <1.5×ULN. Monitor for neuropathy; consider interrupting and evaluate if suspected. Conduct eye exams at baseline and periodically during treatment.

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER Interrupt therapy and evaluate for serious/severe hemorrhage or cardiac arrhythmias. Monitor for fluid retention; interrupt, reduce, or discontinue as indicated. Obtain CBCs every 2 weeks for the first 3 months, then monthly or as indicated.

Tumor lysis syndrome; ensure adequate hydration and treat uric levels prior to therapy.

Compromised wound healing (withhold for 1 week prior to major surgery) and GI perforation. Elderly.

Pregnancy (Cat.D); avoid. Nursing mothers: not recommended.

Interactions: Potentiated by strong CYP3A inhibitors (eg, boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole); see Adult dose. Avoid concomitant strong CYP3A inducers (eg, carbamazepine, rifampin, phenytoin, St. John’s Wort), or drugs that elevate gastric pH (eg, PPIs, H2 blockers, antacids). Caution with concomitant P-gp and ABCG2 substrates.

Adverse reactions: Hypertension, rash, abdominal pain, fatigue, headache, dry skin, constipation, arthralgia, nausea, pyrexia, anemia, thrombocytopenia, leukopenia, neutropenia, lymphopenia; vascular occlusion, heart failure, hepatotoxicity, ocular toxicities, hemorrhage, myelosuppression.

How supplied: Tabs 15mg—60, 180; 45mg— 30, 90

IDAMYCIN Pfizer

℞

Anthracycline. Idarubicin HCl 20mg/vial; lyophilized pwd for IV infusion after reconstitution. ℞ Also: IDAMYCIN PFS Idarubicin 1mg/mL; soln for IV infusion; preservative-free.

Indications: Acute myeloid leukemia.

Adults: Give by slow IV infusion (over 10–15 mins). 12mg/m2 daily for 3 days (in combination with cytarabine). May give 2nd course if needed; if toxicity develops after 1st course, delay until resolved; reduce dose by 25%. Hepatic and renal impairment: consider reduce dose.

Children: Not established.

Warnings/Precautions: Pre-existing bone marrow suppression. Cardiovascular disease.

Thoracic irradiation. Previous anthracycline therapy at high cumulative doses. Renal or hepatic impairment. Monitor CBCs, cardiac, renal and hepatic function prior to and during treatment. Avoid extravasation. Elderly.

Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended.

Interactions: Concomitant drugs that suppress cardiac contractility or cardiotoxic drugs (eg, trastuzumab, cyclophosphamide, paclitaxel): not recommended; avoid use for 5 half-lives after discontinuing cardiotoxic drug.

Adverse reactions: Myelosuppression, GI upset, mucositis, abdominal pain, alopecia, rash, inj site reactions, hepatotoxicity, renal toxicity, cardiotoxicity (eg, CHF, arrhythmias,

chest pain, MI, asymptomatic declines in LVEF), hyperuricemia.

How supplied: Single-dose vials—1; PFS: Singledose vials (5mL, 10mL, 20mL)—1

IMBRUVICA

℞

Pharmacyclics and Janssen Biotech

Bruton’s tyrosine kinase (BTK) inhibitor. Ibrutinib 140mg; caps.

Indications: Mantle cell lymphoma (MCL) in patients who have received at least one prior therapy. Chronic lymphocytic leukemia (CLL) in patients who have received at least one prior therapy. CLL in patients with 17p deletion.

Waldenstrom’s macroglobulinemia (WM).

Adults: Swallow whole with water. MCL: 560mg once daily. CLL and WM: 420mg once daily.

Concomitant moderate CYP3A inhibitors: 140mg once daily. Mild hepatic impairment (Child-Pugh Class A): 140mg once daily. Dose modifications for toxicities: see full labeling.

Children: Not established.

Warnings/Precautions: Risk of hemorrhage; consider the benefit/risk of withholding treatment for 3–7 days pre-and post-surgery.

Monitor for fever and infections; evaluate promptly if occurs. Monitor for myelosuppression; obtain CBCs monthly. Periodically monitor for atrial fibrillation (esp. in those with cardiac risk factors, acute infections, history of atrial fibrillation); do ECG if arrhythmic symptoms or new onset dyspnea develop. Risk of second primary malignancies (eg, skin cancer or other carcinomas). Monitor for tumor lysis syndrome in patients at risk (eg, high tumor burden). Moderate or severe hepatic impairment: not recommended.

Maintain adequate hydration. Pregnancy (Cat.D); avoid. Nursing mothers: not recommended.

Interactions: Concomitant strong CYP3A inhibitors taken chronically (eg, ritonavir, indinavir, nelfinavir, saquinavir, boceprevir, telaprevir, nefazodone): not recommended; for shortterm (≤7days) use of strong CYP3A inhibitors (eg, ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin); consider interrupting ibrutinib therapy. If concomitant moderate CYP3A inhibitors must be used (eg, fluconazole, darunavir, erythromycin, diltiazem, atazanavir, aprepitant, amprenavir, fosamprevir, crizotinib, imatinib, verapamil, ciprofloxacin): reduce ibrutinib dose (see Adults). Avoid grapefruit and Seville oranges during treatment. Avoid concomitant strong CYP3A inducers (eg, carbamazepine, rifampin, phenytoin, St. John’s Wort); consider alternatives.

Increased risk of hemorrhage with concomitant antiplatelets or anticoagulants.

Adverse reactions: Thrombocytopenia, diarrhea, neutropenia, anemia, fatigue, musculoskeletal pain, peripheral edema, upper respiratory tract infection, nausea, bruising, dyspnea, constipation, rash, abdominal pain, vomiting, decreased appetite, pyrexia.

How supplied: Caps—90, 120

INTRON A Merck

℞

Interferon alfa-2b, recombinant; 10 million, 18 million, or 50 million IU per vial; pwd; for inj after reconstitution/dilution; preservative-free.

Also: INTRON A SOLN ℞ Interferon alfa-2b, recombinant; 10 million IU, 18 million IU, 25 million IU; per vial; for inj; contains m-cresol.

Indications: Hairy cell leukemia. Initial treatment of clinically aggressive follicular Non-Hodgkin’s lymphoma in conjunction with anthracyclinecontaining combination chemotherapy.

Adults: Use SC route if platelets <50,000/mm3.

Hairy cell leukemia: 2 million IU/m2 IM or SC 3 times a week for up to 6 months. Follicular lymphoma: 5 million IU SC 3 times a week for up to 18 months in conjunction with anthracyclinecontaining chemotherapy regimen and following completion of the chemotherapy regimen. See literature for appropriate preparation and route and for dose adjustments.

Children: Not recommended.

Contraindications: Hepatitis: decompensated liver disease. Autoimmune disorders.

Warnings/Precautions: May cause or exacerbate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, or infectious disorders: monitor closely, discontinue if they worsen. Severe psychiatric disorders (esp. depression). Cardiovascular or pulmonary disease.

Severe myelosuppression. Uncontrolled thyroid abnormalities. Diabetes. Coagulation disorders.

Maintain adequate hydration. Monitor blood, thyroid, visual and liver function before and during therapy; EKG in cardiovascular disease and cancer patients. Psoriasis. Renal dysfunction. Transplant recipients. Elderly. Debilitated. Pregnancy (Cat.C).

Nursing mothers: not recommended.

Interactions: Caution with myelosuppressives, and drugs that can exacerbate depression. May potentiate theophylline (may double its levels).

Adverse reactions: Flu-like symptoms (fever, headache, myalgia, fatigue); hepatic, hematologic, respiratory, skin, genitourinary system, CNS, cardiovascular, endocrine (esp thyroid), GI, or visual disorders; colitis, hypertriglyceridemia, pancreatitis, infections, injection site reactions; others (see literature).

How supplied: Pwd (w. diluent): 10million, 18million, 50million IU/vial—1; Soln (vials): 10million IU/vial—6 (kit w. supplies); Soln (multidose vials): 18million, 25million IU/vial—1

ISTODAX Celgene

℞

Histone deacetylase inhibitor. Romidepsin 10mg/vial; pwd for IV infusion after reconstitution and dilution; contains povidone.

Indications: Cutaneous T-cell lymphoma in patients who have received at least one prior systemic therapy. Peripheral T-cell lymphoma in patients who have received at least one prior therapy.

Adults: ≥18yrs: Give by IV infusion over 4hrs.

14mg/m2 on days 1, 8, and 15 of a 28-day cycle;

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER repeat cycle every 28 days; continue as tolerated and as beneficial. May interrupt, reduce dose to 10mg/m2, or discontinue based on toxicities (see full labeling).

Children: <18yrs: not established.

Warnings/Precautions: Increased risk of serious infections (eg, pneumonia, sepsis, Epstein Barr, HBV). Prior history of hep B infection; consider monitoring for reactivation and give antiviral prophylaxis. Correct electrolyte imbalances (esp. K+, Mg++) before starting.

Monitor ECG and electrolytes in congenital long QT syndrome, significant cardiovascular disease. Advanced stage disease and/or high tumor syndrome: monitor closely for tumor lysis syndrome. Moderate-to-severe hepatic impairment. End-stage renal disease. Monitor CBC with differential. Pregnancy (Cat.D; may cause fetal harm). Nursing mothers: not recommended.

Interactions: Caution with other drugs that can cause QT prolongation (monitor). Monitor PT/INR with warfarin. Potentiated by drugs that inhibit P-gp and CYP3A4; avoid concomitant strong CYP3A4 inhibitors (eg, azole antifungals, protease inhibitors, clarithromycin, telithromycin, nefazodone). Caution with moderate CYP3A4 inhibitors. Avoid concomitant rifampin. May be antagonized by other strong CYP3A4 inducers (eg, dexamethasone, carbamazepine, phenytoin, phenobarbital, rifabutin, rifapentine, St. John’s Wort); avoid when possible.

Adverse reactions: Neutropenia, lymphopenia, thrombocytopenia, anemia, nausea, vomiting, fatigue, infections, anorexia, ECG T-wave changes; tumor lysis syndrome.

How supplied: Kit—1 (single-use vial + diluent and supplies)

JAKAFI Incyte

℞

Kinase inhibitor. Ruxolitinib 5mg, 10mg, 15mg, 20mg, 25mg; tabs.

Indications: Treatment of intermediate or highrisk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis.

Treatment of polycythemia vera (PV) in patients with inadequate response to, or intolerant of, hydroxyurea.

Adults: Doses may be given by NG tube if unable to swallow tabs. Myelofibrosis: Platelets >200×109/L: initially 20mg twice daily. Platelets 100–200×109/L: initially 15mg twice daily.

Platelets 50–<100×109/L: initially 5mg twice daily.

May increase doses by 5mg twice daily to a max of 25mg twice daily; do not increase during the first 4 weeks of therapy and not more frequently than every 2 weeks. Discontinue treatment after 6

months if no reduction in spleen size or symptom improvement. Interrupt treatment if platelets <50×109/L or ANC <0.5×109/L. May restart after recovery of platelets or ANC (see full labeling for max allowable restarting doses). Consider dose reductions if platelets decrease but remain ≥50×109/L (see full labeling). Dose modifications for patients starting treatment with platelets 50–<100×109/L: see full labeling. PV: initially 10mg twice daily. May increase doses by 5mg twice daily to a max of 25mg twice daily; do not increase during the first 4 weeks of therapy and not more frequently than every 2 weeks. Consider dose reductions for Hgb and/or platelet decreases (see full labeling). Interrupt treatment if Hgb <8g/dL, platelets <50×109/L, or ANC <1.0×109/L. May restart after recovery of hematologic parameters (see full labeling for max allowable restarting doses). Concomitant strong CYP3A4 inhibitors (see Interactions) or fluconazole ≤200mg (Myelofibrosis): initially 10mg twice daily if platelets ≥100×109/L; if platelets 50–<100×109/L: initially 5mg once daily; (PV): initially 5mg twice daily. Other reductions, hepatic or renal impairment, ESRD: see full labeling.

Children: Not established.

Warnings/Precautions: Monitor for thrombocytopenia, anemia, neutropenia; manage by reducing dose, interrupt, or transfusion if occur. Obtain CBC and platelets before initiating therapy, every 2–4 weeks until doses are stabilized, and then as clinically indicated.

Risk of serious bacterial, mycobacterial, fungal, and viral infections; evaluate and treat if signs/ symptoms occur. Confirm resolution of active infections before starting. May exacerbate myelofibrosis following treatment interruption or discontinuation. Risk of non-melanoma skin cancer; perform periodic skin exams. Avoid abrupt cessation. Renal or hepatic impairment. Pregnancy (Cat.C). Nursing mothers: not recommended.

Interactions: Avoid concomitant fluconazole doses >200mg daily. Potentiated by strong CYP3A4 inhibitors (eg, boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole) and mild or moderate CYP3A4 inhibitors (eg, erythromycin). Antagonized by strong CYP3A4 inducers (eg, rifampin).

Adverse reactions: Thrombocytopenia, anemia, bruising, dizziness, headache; herpes zoster, tuberculosis (monitor promptly and test for latent infection), progressive multifocal leukoencephalopathy (discontinue if occurs).

How supplied: Tabs—60

KYPROLIS Onyx

℞

Proteasome inhibitor. Carfilzomib 60mg/vial; lyophilized pwd for IV inj after reconstitution; preservative-free.

Indications: As monotherapy for treatment of patients with multiple myeloma who have received at least two prior therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of the last therapy. In combination with lenalidomide and dexamethasone for treatment of patients with relapsed multiple myeloma who have received 1–3 prior therapies.

Adults: See full labeling. Premedicate with dexamethasone for monotherapy prior to all Cycle 1 doses, during subsequent cycles, and if infusion reactions occur. Give by IV over 10 mins, on two consecutive days each week for 3 weeks (Days 1, 2, 8, 9, 15, and 16), followed by a 12-day rest period (Days 17–28). In Cycle 1: 20mg/m2 per each dose on Days 1 and 2, if tolerated increase to 27mg/m2 on Day 8 and subsequent cycles. From Cycle 13, omit the Day 8 and 9 doses. In combination therapy: discontinue after Cycle 18; see full labeling for lenalidomide and dexamethasone dosing. Both therapies: continue until disease progression or unacceptable toxicity occurs. On dialysis: give dose after session.

Toxicity dose modification: see full labeling.

Children: Not established.

Warnings/Precautions: Risk of cardiac complications (eg, CHF, MI, pulmonary edema); monitor and manage promptly if occurs.

Pulmonary hypertension; if suspected, withold therapy until resolved; may consider restarting after reevaluate. Discontinue if pulmonary toxicity occurs. Monitor for dyspnea or tumor lysis syndrome, and manage promptly if occurs; interrupt therapy until resolved. Maintain adequate hydration. Monitor for volume overload.

Monitor platelets frequently during therapy.

Monitor for thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/ HUS); discontinue and evaluate if suspected.

Discontinue and evaluate if posterior reversible encephalopathy syndrome (PRES) is suspected. Monitor BP, renal function regularly; reduce or withhold dose as needed. Hepatic impairment (monitor enzymes). Consider thromboprophylaxis for combination therapy.

Consider antiviral prophylaxis for monotherapy.

Elderly (≥75yrs). Pregnancy; avoid. Use effective contraception during and for ≥2 weeks after therapy completion. Nursing mothers.

Adverse reactions: Fatigue, anemia, nausea, thrombocytopenia, dyspnea, diarrhea, pyrexia,

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER decreased platelets, headache, decreased hemoglobin, cough, edema peripheral; cardiac events, pulmonary HTN, acute kidney injury, infusion reactions, tumor lysis syndrome, hepatic toxicity/failure, TTP/HUS, PRES. How supplied: Single-use vial—1

LEUKERAN GlaxoSmithKline

℞

Alkylating agent. Chlorambucil 2mg; tabs.

Indications: Palliative treatment of chronic lymphatic (lymphocytic) leukemia and malignant lymphomas (including lymphosarcoma, giant follicular lymphoma, and Hodgkin’s disease).

Adults: See literature. 0.1–0.2mg/kg per day for 3–6 weeks. Reduce dose if leukocyte or platelet counts fall below normal values and discontinue if more severe depression occurs. Do not give full dose within 4 weeks of radio- or chemotherapy.

Children: Not recommended.

Warnings/Precautions: Compromised bone marrow function. History of seizure disorder or head trauma. Monitor blood weekly (during first 3–6 weeks, do WBC count 3–4 days after each weekly CBC). Discontinue if skin reactions occur.

Elderly. Pregnancy (Cat.D), nursing mothers: not recommended.

Interactions: Avoid live vaccines.

Myelosuppressives, radiotherapy potentiate antineoplastic effect. Caution with drugs that lower seizure threshold.

Adverse reactions: Bone marrow suppression, seizures, fever, rash, hypersensitivity, urticaria, azoospermia, amenorrhea, sterility, hepato- and pulmonary toxicity, secondary malignancies, GI upset.

How supplied: Tabs—50

MARQIBO Spectrum

℞

Vinca alkaloid. Vincristine sulfate liposome injection; after preparation, each vial contains 0.16mg/mL; for IV infusion.

Indications: Philadelphia chromosome-negative (Ph–) acute lymphoblastic leukemia (ALL) in second or greater relapse or has progressed following ≥2 anti-leukemia therapies.

Adults: 2.25mg/m2 IV over 1hr once every 7 days.

Dose modifications for peripheral neuropathy: see full labeling.

Children: Not established.

Contraindications: Demyelinating conditions, including Charcot-Marie-Tooth syndrome.

Intrathecal administration (death has occurred).

Warnings/Precautions: For IV use only; fatal if given by other routes. Discontinue and treat if extravasation is suspected. Preexisting neuromuscular disorders. Monitor for symptoms of neuropathy before and during therapy; if occurs or worsens, delay, reduce or discontinue dose. Monitor CBCs prior to each dose; if Grade 3 or 4 myelosuppression develops, consider dose modification or reduction. Monitor for tumor lysis syndrome; manage if occurs. Institute a prophylactic bowel regimen to mitigate potential

constipation, bowel obstruction, and/or paralytic ileus; consider dietary fiber intake, hydration, stool softeners. Monitor liver function tests; if hepatotoxicity occurs, reduce or interrupt dosing. Elderly. Pregnancy (Cat.D); avoid. Nursing mothers: not recommended.

Interactions: Drugs known to interact with non-liposomal vincristine sulfate (eg, phenytoin: increased seizure risk). Avoid concomitant strong CYP3A inhibitors (eg, ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin) or strong CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, St. John’s Wort).

Avoid concomitant potent P-gp inhibitors or inducers.

Adverse reactions: Constipation, nausea, pyrexia, fatigue (may be severe; adjust dose or discontinue), peripheral neuropathy, febrile neutropenia, diarrhea, anemia, decreased appetite, insomnia.

How supplied: Kit—1, 3 (vials + supplies)

MUSTARGEN Recordati

℞

Nitrogen mustard. Mechlorethamine HCl 10mg/vial; pwd for IV or intracavitary inj after reconstitution.

Indications: Palliative treatment of Hodgkin’s disease (stages III and IV), lymphosarcoma, chronic myelocytic or chronic lymphocytic leukemia, polycythemia vera, mycosis fungoides.

Palliative treatment of metastatic carcinoma resulting in effusion.

Adults: By IV infusion, per therapeutic course: 0.4mg/kg (lean body weight) as single dose or in divided doses of 0.1–0.2mg/kg per day.

See literature for intracavitary (eg, intrapleural) administration. Do not exceed recommended dose. Repeat course only after hematological recovery (eg, every 3 weeks).

Children: See literature.

Contraindications: Infectious diseases.

Warnings/Precautions: Drug is highly toxic; verify potential benefits outweigh risks; avoid inadvertent contact with powder or vapor. Do not use if foci of acute and chronic suppurative inflammation are present. Ensure adequate hydration. Avoid extravasation. Chronic lymphatic leukemia. Bone marrow suppression. Previous X-ray, cytotoxic chemotherapy. Infection.

Hemorrhagic tendency. Monitor renal, hepatic and bone marrow function. Elderly. Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended.

Adverse reactions: Bone marrow suppression, hyperheparinemia, GI upset (may be severe), anorexia, weakness, thrombosis, thrombophlebitis, hypersensitivity, jaundice, alopecia, vertigo, auditory disturbances, hemolytic anemia, skin reactions, infection, amyloidosis, hyperuricemia, gonad damage.

How supplied: Vials—4

MYLERAN GlaxoSmithKline

℞

Alkylating agent. Busulfan 2mg; tabs.

Indications: Palliative treatment of chronic myelogenous leukemia.

Adults: Remission induction: 4–8mg/day or 60micrograms/kg or 1.8mg/m2, daily. Reserve doses >4mg/day for severe cases. Reduce dose or discontinue at first sign of reduced bone marrow reserve. Discontinue before leukocyte count normalizes; see literature. Normal leukocyte counts usually achieved in 12–20 weeks. If remission <3 months, maintenance therapy of 1–3mg/day may be advisable.

Children: Remission induction: 60micrograms/kg or 1.8mg/m2, daily. Reduce dose or discontinue at first sign of reduced bone marrow reserve. Discontinue before leukocyte count normalizes. Normal leukocyte counts usually achieved in 12–20 weeks. See literature.

Warnings/Precautions: Confirm diagnosis.

Monitor hepatic and bone marrow function.

Obtain CBCs and differential weekly; monitor for anemia. Previously compromised bone marrow (irradiation, chemotherapy). Seizure disorder or risk. Head trauma. Elderly. Pregnancy (Cat.D), nursing mothers: not recommended.

Interactions: Myelosuppression increased with other myelosuppressives. Increased pulmonary toxicity with other cytotoxic drugs. Potentiated by itraconazole, cyclophosphamide (see literature).

May be antagonized by phenytoin. Hepatotoxicity possible with long-term continuous thioguanine therapy. Caution with drugs that lower seizure threshold.

Adverse reactions: See literature. Bone marrow suppression (eg, pancytopenia, anemia, leukopenia, thrombocytopenia, aplastic anemia), pulmonary toxicity, cellular dysplasia, malignant tumors, acute leukemias, cardiac tamponade (esp. in thalassemia), hyperpigmentation, adrenal insufficiency, seizures, hepatic veno-occlusive disease, infection (eg, pneumonia, sepsis), mucositis, myasthenia gravis, gonadal suppression, rash; rare: cataracts, bronchopulmonary dysplasia (discontinue if occurs).

How supplied: Tabs—25

ONCASPAR Sigma-Tau

℞

Enzyme. Pegaspargase 750 IU/mL; soln for IV or IM inj; preservative-free.

Indications: First-line acute lymphoblastic leukemia (including patients with asparaginase hypersensitivity).

Adults and Children: Give by IV inj over 1–2hrs or by IM inj (max 2mL/inj site). 2500 IU/m2 no more frequently than every 14 days.

Contraindications: History of pancreatitis, serious hemorrhage, or thrombosis with prior L-asparaginase therapy.

Warnings/Precautions: Have resuscitation equipment available and observe patient for 1hr post-dose. Monitor coagulation parameters.

Discontinue if serious allergic reactions,

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER thrombotic events, or pancreatitis occurs.

Monitor for hepatotoxicity and abnormal liver function. Pregnancy (Cat.C). Nursing mothers: not recommended.

Adverse reactions: Allergic reactions (including anaphylaxis), hyperglycemia, pancreatitis, CNS thrombosis, coagulopathy, hyperbilirubinemia, hepatotoxicity, elevated transaminases, hyperlipidemia.

How supplied: Single-use vial (5mL)—1

ONTAK Eisai

℞

Interleukin 2-diphtheria toxin fusion protein.

Denileukin diftitox 150mcg/mL; soln for IV infusion after thawing and dilution.

Indications: Persistent or recurrent cutaneous T-cell lymphoma in which malignant cells express the CD25 component of the IL-2 receptor.

Adults: Premedicate with an antihistamine or acetaminophen prior to each infusion. Give by IV infusion over 30–60 minutes. 9 or 18mcg/kg per day for 5 consecutive days every 21 days for 8 cycles.

Children: Not recommended.

Warnings/Precautions: Ensure CD25 expression before starting therapy. Have resuscitative equipment available during administration. Permanently discontinue if serious infusion reactions occur. Monitor for signs/symptoms of capillary leak syndrome (hypotension, edema, hypoalbuminemia) and weight gain. Monitor serum albumin levels prior to each treatment course; withhold treatment if serum albumin <3g/dL. Pregnancy (Cat.C).

Nursing mothers: not recommended.

Adverse reactions: Fever, fatigue, rigors, GI upset, headache, edema, cough, dyspnea, pruritus, rash, hypotension, back pain, myalgia, chest pain, tachycardia, hypoalbuminemia, asthenia, elevated transaminases; capillary leak syndrome (may be fatal), serious infusion reactions, visual impairment (monitor).

Testing considerations: CD25 expression How supplied: Single-use vials (2mL)—6

POMALYST Celgene

℞

Immunomodulator. Pomalidomide 1mg, 2mg, 3mg, 4mg; caps.

Indications: In combination with dexamethasone for multiple myeloma, in patients who have received at least two prior therapies (including lenalidomide and a proteasome inhibitor), and have shown disease progression on or within 60 days of completion of the last therapy.

Adults: Swallow whole; may be taken with water.

Take without food. 4mg once daily on Days 1–21 of

repeated 28-day cycles until disease progression; give with dexamethasone. Concomitant strong CYP1A2 inhibitors in presence of strong CYP3A4 and P-gp inhibitors: reduce Pomalyst dose by 50%. Dose modification for hematologic and other Grade 3/4 toxicities: see full labeling.

Children: <18yrs: not established.

Contraindications: Pregnancy (Cat.X): avoid during and for at least 4 weeks after completing therapy.

Warnings/Precautions: Females of reproductive potential must commit either to abstain from heterosexual sex or to use two methods of reliable contraception, beginning 4 weeks prior to initiating, during therapy, dose interruptions and for 4 weeks after discontinuation. Obtain two negative pregnancy tests prior to initiating therapy: perform first test within 10–14 days, and second test within 24hrs prior to prescribing, and then weekly during first month, then monthly thereafter in women with regular menstrual cycles or every 2 weeks if irregular cycles. Males: must use latex or synthetic condom during therapy and up to 28 days after discontinuing, even after successful vasectomy; do not donate sperm. Patients must not donate blood during therapy and for 1 month after discontinuation. Venous and arterial thromboembolism; consider anticoagulation prophylaxis. Monitor for hematologic toxicities (esp. neutropenia); obtain CBCs weekly for first 8 weeks and monthly thereafter; may need dose interruption and/or modification. Renal impairment (serum creatinine >3mg/dL) or hepatic impairment (serum bilirubin >2mg/dL and AST/ALT >3x ULN): avoid. Monitor LFTs monthly; discontinue and evaluate if elevated liver enzymes occur; consider using lower dose when restarting. Risk of second primary malignancies.

High tumor burden (monitor). Discontinue if angioedema, skin exfoliation, bullae, or other severe dermatologic reactions occur; do not restart. Nursing mothers: not recommended.

Interactions: May be potentiated by strong CYP1A2, CYP3A (eg, ketoconazole), or P-gp inhibitors; avoid. May be antagonized by strong CYP1A2, CYP3A (eg, rifampin), or P-gp inducers; avoid. Smoking may reduce efficacy.

Adverse reactions: Fatigue, asthenia, neutropenia, anemia, constipation, nausea, diarrhea, dyspnea, upper-respiratory tract infections, back pain, pyrexia; thromboembolism, dizziness, confusion, neuropathy, pneumonia, thrombocytopenia, tumor lysis syndrome.

Note: Available only through Pomalyst REMS program.

How supplied: Caps—21, 100

PURINETHOL Teva

℞

Antimetabolite. Mercaptopurine (6-MP) 50mg; scored tabs.

Indications: Maintenance therapy of acute lymphatic leukemia as part of a combination regimen.

Adults and Children: 1.5–2.5mg/kg per day as a single dose. Concomitant allopurinol: reduce dose of mercaptopurine to 1/3–1/4 of the usual dose. TPMT-deficient, renal or hepatic impairment: reduce dose, see literature.

Contraindications: Prior resistance to mercaptopurine.

Warnings/Precautions: Not effective in CNS leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, the lymphomas (including Hodgkin’s disease), or solid tumors. Renal impairment. Monitor liver function tests weekly at start of therapy, then monthly thereafter; discontinue if hepatotoxicity occurs. Preexisting liver disease (monitor more frequently).

Obtain CBCs with differential, hemoglobin, hematocrit, platelets; discontinue if severe bone marrow suppression occurs. Thiopurine-Smethyltransferase (TPMT) deficient: increased risk of myelosuppression, consider genotypic/ phenotypic testing. Pregnancy (Cat.D); esp. 1st trimester, nursing mothers: not recommended.

Interactions: Increased risk of bone marrow suppression with allopurinol, aminosalicylate derivatives (eg, olsalazine, mesalazine, sulphasalazine), trimethoprim-sulfamethoxazole.

Antagonizes warfarin. Caution with concomitant hepatotoxic agents.

Adverse reactions: Myelosuppression, hyperuricemia/hyperuricosuria, GI upset, intestinal ulceration, rash, hyperpigmentation, alopecia, oligospermia; hepatotoxicity, infection, immunosuppression.

How supplied: Tabs—60

PURIXAN Rare Disease

℞

Antimetabolite. Mercaptopurine (6-MP) 20mg/mL; oral susp; contains fruit extract, aspartame.

Indications: Maintenance therapy of acute lymphoblastic leukemia as part of a combination regimen.

Adults and Children: Shake bottle vigorously for at least 30 secs. Initially 1.5–2.5mg/kg (50–75mg/m2) per day as a single dose. Monitor subsequent doses to maintain desirable ANC level and adjust for excessive hematological toxicity. Thiopurine-S-methyltransferase (TPMT)deficient: if homozygous, may require up to a 90% dose reduction; if heterozygous, some may require dose reduction based on toxicities. Renal

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER or hepatic impairment: use lower starting doses; monitor for toxicity. See full labeling.

Warnings/Precautions: Myelosuppression; monitor CBCs and adjust dose for severe neutropenia and thrombocytopenia. Consider testing for TPMT gene polymorphism in patients who experience repeated severe bone marrow toxicities. Monitor serum transaminase, alkaline phosphatase, and bilirubin levels at weekly intervals when starting therapy, then monthly thereafter; interrupt treatment if evidence of hepatotoxicity occurs. Concomitant other hepatotoxic drugs or with pre-existing liver disease; monitor LFTs more frequently. Immunosuppression. Increased risk of secondary malignancies. Renal or hepatic impairment. Elderly. Pregnancy (Cat.D); esp. 1st trimester, nursing mothers: not recommended.

Interactions: Avoid concomitant allopurinol.

Increased risk of bone marrow suppression with allopurinol, aminosalicylate derivatives (eg, olsalazine, mesalamine, sulfasalazine), trimethoprim-sulfamethoxazole. Possibly decreased effectiveness with concomitant warfarin; monitor PT or INR; may need warfarin dose adjustments. Concomitant live virus vaccines: may get suboptimal response and risk of infection.

Adverse reactions: Myelosuppression, nausea, vomiting, anorexia, diarrhea, malaise, rashes, oral lesions, elevated transaminases and bilirubin, intestinal ulceration; hepatotoxicity.

How supplied: Susp—100mL

REVLIMID Celgene

℞

Immunomodulator. Lenalidomide 2.5mg, 5mg, 10mg, 15mg, 20mg, 25mg; caps; contains lactose.

Indications: In combination with dexamethasone for treatment of patients with multiple myeloma (MM). Treatment of patients with mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib. Limitations of use: not for treating patients with chronic lymphocytic leukemia (CLL) outside of controlled clinical trials.

Adults: Swallow whole with water. ≥18yrs: initially 25mg once daily on Days 1–21 of each 28-day cycle until disease progression or unacceptable toxicity. >75yrs: may reduce dexamethasone initial dose. Renal impairment: MCL: Moderate (CrCl 30–60mL/min): 10mg per day; MM: Moderate (CrCl 30–50mL/min): 10mg per day; consider increasing to 15mg after 2 cycles, if tolerant. Severe (CrCl <30mL/min without dialysis): 15mg every 48hrs. ESRD (CrCl <30mL/min with dialysis): 5mg once daily; administer after dialysis (on dialysis days). Autologous stem cell transplantation (ASCT) eligible: refer for hematopoietic cell mobilization within 4 cycles; if non-eligible, continue therapy until disease progression or unacceptable toxicity.

Dose adjustments if thrombocytopenia or neutropenia develops: see full labeling.

Children: <18yrs: not established.

Contraindications: Pregnancy (Cat.X).

Warnings/Precautions: Must register patient in Revlimid REMS program; patient must understand

toxicity with fetal exposure. Counsel patient on need for contraception; females: use 2 forms of contraception 1 month before, during therapy, during dose interruptions, and 1 month after therapy; males: use condom during and 1 month after therapy; obtain 2 negative pregnancy tests (one within 10–14 days, and then another within 24hrs prior to starting therapy), repeat at least weekly for 1st month then every 4 weeks (regular menstrual cycles) or every 2 weeks (irregular cycles); get informed consent. Do not donate blood during and for 1 month after therapy. Monitor for signs/symptoms of thromboembolic events; base thromboprophylaxis on patient’s risks. For MM: obtain CBCs weekly for the first 2 cycles, on Days 1 and 15 of Cycle 3, and every 28 days thereafter; for MCL: obtain CBCs weekly for the first cycle, every 2 weeks during Cycles 2–4, and then monthly thereafter; both: dose interruption and/or reduction may be needed. May require blood product support and/or growth factors.

Renal impairment (monitor). Monitor for tumor lysis syndrome in those with high tumor burden.

Monitor liver enzymes; discontinue if elevation occurs. Monitor for second primary malignancies.

Lactose intolerance. Maximum 1 month per ℞.

Nursing mothers: not recommended.

Interactions: Monitor digoxin. Concomitant warfarin; monitor PT, INR. May increase risk of thrombosis with dexamethasone, erythropoietic agents, or estrogen containing therapies.

Adverse reactions: Birth defects, thrombocytopenia, neutropenia, anemia, leukopenia, constipation, diarrhea, nausea, vomiting, pruritus, rash, fatigue, arthralgia, pyrexia, back pain, cough, dizziness, headache, dyspnea, nasopharyngitis, epistaxis, upper respiratory tract infection, tremor, blurred vision, muscle cramp, decreased appetite, peripheral edema; thrombosis/ embolism, allergic reactions (discontinue if occurs; do not resume), tumor flare reaction (monitor; esp. in treating MCL), hepatotoxicity.

Note: Available only through Revlimid REMS program. Report any suspected fetal exposure to the FDA at (800) FDA-1088 and Celgene at (888) 423-5436.

How supplied: Caps 2.5mg, 5mg, 10mg—28, 100; 15mg, 20mg, 25mg—21, 100

RITUXAN Genentech

℞

CD20-directed cytolytic monoclonal antibody.

Rituximab 10mg/mL; soln for IV infusion; preservative-free.

Indications: Relapsed or refractory, low-grade or follicular, CD20(+), B-cell non-Hodgkin’s lymphoma (NHL). Previously untreated follcular, CD20(+), B-cell NHL in combination with first line chemotherapy and, in patients achieving a complete or partial response to Rituxan in combination with chemotherapy, as singleagent maintenance therapy. Non-progressing (including stable disease), low-grade, CD20(+), B-cell NHL as a single agent after first-line CVP chemotherapy. Previously untreated diffuse large

B-cell, CD20(+) NHL (DLBCL) in combination with CHOP or other anthracycline-based chemotherapy regimens. CD20(+) chronic lymphocytic leukemia (CLL) in combination with fludarabine and cyclophosphamide. Limitation of use: not recommended for use in patients with severe, active infections.

Adults: Give by IV infusion. Premedicate with an antihistamine and acetaminophen prior to each infusion. First infusion: initially at a rate of 50mg/hr; may increase infusion rate in 50mg/hr increments every 30 mins. Subsequent infusions: initially at a rate of 100mg/hr; may increase infusion rate in 100mg/hr increments every 30 mins. Both: max 400mg/hr if infusion reactions do not occur. Previously untreated follicular NHL and DLBCL patients: if no Grade 3 or 4 infusion related adverse events during Cycle 1, a 90-minute infusion may be given in Cycle 2 with a glucocorticoid-containing chemotherapy regimen (see full labeling). NHL: 375mg/m2 once weekly for 4 or 8 doses. Retreatment therapy: 375mg/m2 once weekly for 4 doses. Previously untreated, follicular, CD20(+), B-cell NHL: 375mg/m2 on day 1 of each cycle of CVP chemotherapy for up to 8 doses. In patients with complete or partial response, initiate Rituxan maintenance 8 weeks following completion of Rituxan in combination with chemotherapy. Administer Rituxan as a single-agent every 8 weeks for 12 doses. Low-grade, CD20(+), B-cell NHL after CVP chemotherapy: 375mg/m2 once weekly for 4 doses every 6 months for up to 16 doses. Diffuse large B-cell NHL: 375mg/m2 on day 1 of each cycle for up to 8 infusions. CLL: 375mg/m2 the day prior to FC chemotherapy, then 500mg/m2 on day 1 of cycles 2–6 (every 28 days). Give PCP and antiherpetic viral prophylaxis during and up to 12 months after CLL therapy. As a component of Zevalin regimen: see full labeling.

Children: Not established.

Warnings/Precautions: Discontinue if severe infusion or mucocutaneous reactions occur (eg, urticaria, hypotension, angioedema, hypoxia, pulmonary infiltrates, acute respiratory distress syndrome, MI, ventricular fibrillation, cardiogenic shock, paraneoplastic pemphigus, StevensJohnson syndrome, lichenoid or vesiculobullous dermatitis, toxic epidermal necrolysis). Increased risk of HBV reactivation. Test/treat HBV infection prior to initiating therapy. Monitor for signs of hepatitis or HBV reactivation during and for several months after therapy; discontinue if HBV reactivation occurs. Tumor lysis syndrome (esp. with high tumor burden); monitor for renal toxicity, fluid balance, electrolyte abnormalities (correct if occurs); discontinue if SCr rises or oliguria occurs. Monitor for new-onset neurologic manifestations; discontinue if progressive multifocal leukoencephalopathy (PML) develops.

Discontinue and treat if serious infections (eg, bacterial, fungal, viral) occur. Pre-existing cardiovascular disease; monitor during and after treatment. Monitor CBCs, platelet counts during

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER treatment, then periodically. Elderly. Pregnancy (Cat.C). Nursing mothers: not recommended.

Interactions: Live virus vaccines: not recommended. Renal toxicity with cisplatin.

Adverse reactions: Fever, chills, rigors, nausea, vomiting, diarrhea, asthenia, fatigue, headache, throat irritation, flushing, rash, pruritus, urticaria, angioedema, cough, rhinitis, bronchospasm, dizziness, myalgia, arthralgia, hypotension, hypertension, chest tightness; myelosuppression (eg, lymphopenia, neutropenia, leukopenia, anemia, thrombocytopenia), infusion reactions (may be fatal), mucocutaneous reactions (may be fatal), PML, serious infections, tumor lysis syndrome, renal toxicity, bowel obstruction/perforation, HBV reactivation with fulminant hepatitis, cardiac arrhythmias (discontinue if serious).

Testing considerations: FCGR3A genotype testing How supplied: Single-use vial (10mL, 50mL)—1

SPRYCEL Bristol-Myers Squibb

℞

Tyrosine kinase inhibitor. Dasatinib 20mg, 50mg, 70mg, 80mg, 100mg, 140mg; tabs.

Indications: Newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase. Chronic, accelerated, or myeloid or lymphoid blast phase Ph+ CML with resistance or intolerance to prior therapy including imatinib. Philadelphia chromosomepositive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy.

Adults: Swallow whole. ≥18yrs: Chronic phase CML: 100mg once daily. Doses of up to 140mg once daily have been used. Accelerated phase CML, myeloid or lymphoid blast CML, Ph+ ALL: 140mg once daily. Doses of up to 180mg once daily have been used. Concomitant CYP3A4 inhibitors (see Interactions): consider reducing dose. Concomitant CYP3A4 inducers (see Interactions): consider increasing dose. See full labeling for dose adjustments with toxicity.

Children: <18yrs: not established.

Warnings/Precautions: History of QT prolongation. Proarrhythmic conditions.

Cumulative high-dose anthracycline therapy.

Monitor for signs/symptoms of cardiac dysfunction; treat appropriately if occur.

Hypokalemia, hypomagnesemia; correct electrolyte imbalances before starting therapy.

Monitor for pleural effusions. Increased risk of pulmonary arterial hypertension (PAH); evaluate for signs/symptoms of underlying cardiopulmonary disease before and during treatment; permanently discontinue if occurs.

Obtain CBCs weekly for the first 2 months, then monthly thereafter. Hepatic impairment. Elderly.

Pregnancy (Cat.D; use adequate contraception); nursing mothers: not recommended.

Interactions: Avoid potent CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, ritonavir, atazanavir, indinavir, nefazodone, nelfinavir, saquinavir, telithromycin, voriconazole), grapefruit juice. May be antagonized by strong CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital), St. John’s wort: not recommended. Separate dosing of antacids by at least 2hrs; H2 blockers, proton pump inhibitors: not recommended. May potentiate drugs metabolized by CYP3A4 (eg, cyclosporine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, ergot alkaloids). Caution with concomitant anticoagulants or drugs that inhibit platelet function. Caution with antiarrhythmics or other drugs that may lead to QT prolongation.

Adverse reactions: Myelosuppression (eg, severe thrombocytopenia, neutropenia, anemia), fluid retention (eg, ascites, edema, pleural and pericardial effusions), diarrhea, headache, dyspnea, musculoskeletal pain, rash, fatigue, nausea, severe hemorrhage (eg, CNS, GI); QT prolongation, cardiac events (eg, cardiomyopathy, CHF, fatal MI, left ventricular dysfunction), PAH. How supplied: Tabs 20mg, 50mg, 70mg—60; 80mg, 100mg, 140mg—30

SYNRIBO Teva

℞

Protein synthesis inhibitor. Omacetaxine mepesuccinate 3.5mg/vial; lyophilized powder for SC injection after reconstitution; contains mannitol; preservative-free.

Indications: Treatment of adult patients with chronic or accelerated phase chronic myeloid leukemia (CML) with resistance and/or intolerance to two or more tyrosine kinase inhibitors (TKI).

Adults: Induction: 1.25mg/m2 by SC injection twice daily for 14 consecutive days every 28 days, over a 28-day cycle. Repeat cycles every 28 days until hematologic response achieved.

Maintenance: 1.25mg/m2 by SC injection twice daily for 7 consecutive days every 28 days, over a 28-day cycle, as long as clinically beneficial. Dose adjustments and modifications: see full labeling.

Children: Not established.

Warnings/Precautions: Risk of myelosuppression (thrombocytopenia, neutropenia, anemia), hemorrhage (cerebral, GI). Monitor CBCs with platelets weekly during induction, initial maintenance cycles, and every 2 weeks during later cycles. Monitor glucose levels (esp. in diabetics).

Avoid in poorly controlled diabetes until glycemic control is established. Elderly. Pregnancy (Cat.D); avoid. Nursing mothers: not recommended.

Interactions: Avoid concomitant anticoagulants, aspirin, NSAIDs if platelets <50,000/microliters; may increase risk of bleeding.

Adverse reactions: Thrombocytopenia, anemia, neutropenia, diarrhea, nausea, fatigue, asthenia, injection site reaction, pyrexia, infection, lymphopenia; bleeding, hyperglycemia.

How supplied: Single-use vial—1

TABLOID GlaxoSmithKline

℞

Antimetabolite. Thioguanine 40mg; tabs; scored.

Indications: Remission induction and remission consolidation treatment of acute nonlymphocytic leukemias. Treatment of the chronic phase of chronic myelogenous leukemia (see literature).

Adults and Children: See literature. Initially, 2mg/kg per day. If, after 4 weeks, with no improvement, no leukocyte or platelet depression, may increase to 3mg/kg per day. Total daily dose may be given at one time.

Contraindications: Allergy to mercaptopurine.

Warnings/Precautions: Not recommended for maintenance therapy or long-term continuous treatments; increased risk of liver toxicity (discontinue if occurs). Pre-existing liver disease.

Monitor liver function tests weekly at start of therapy, then monthly thereafter. Thiopurine methyltransferase (TPMT) enzyme deficiency (may need to reduce dose to avoid severe bone marrow suppression); consider testing for TPMT deficiency. Obtain hemoglobin, hematocrit, WBCs with differential, platelets frequently during therapy. Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended.

Interactions: Avoid live vaccines (if immunocompromised). Caution with drugs that inhibit TPMT (eg, olsalazine, mesalazine, or sulphasalazine).

Adverse reactions: Myelosuppression, hyperuricemia, GI upset, anorexia, stomatitis, hepatotoxicity, elevated liver enzymes, jaundice (discontinue if occurs).

How supplied: Tabs—25

TARGRETIN Valeant

℞

Retinoid. Bexarotene 75mg; caps.

Indications: Cutaneous manifestations of cutaneous T-cell lymphoma in patients who are refractory to at least one prior systemic therapy.

Adults: Take with food. Initially 300mg/m2 once daily; may increase after 8 weeks to 400mg/m2 once daily if no tumor response and if well tolerated; monitor carefully. If toxicity occurs, reduce to 200mg/m2 then 100mg/m2 once daily, or suspend therapy.

Children: Not recommended.

Access Cancer Therapy Advisor treatment regimens in a user-friendly format.

CancerTherapyAdvisor.com/TreatmentRegimens.

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HEMATOLOGIC CANCER Contraindications: Pregnancy (Cat.X).

Warnings/Precautions: Be fully familiar with this drug’s toxicity before use. Pancreatitis or risk of pancreatitis (eg, history of pancreatitis, uncontrolled hyperlipidemia, excess alcohol consumption, uncontrolled diabetes, biliary tract disease, drugs that can cause pancreatitis).

Counsel patients monthly about need for contraception. Women of childbearing potential: obtain reliable negative pregnancy test within 1 week of start; repeat monthly. Start therapy on 2nd or 3rd day of normal menstrual period. Use two effective forms of contraception 1 month prior to, during, and for 1 month after therapy. Max 1 month/℞. Men with partners who are or may become pregnant: use condoms during and for at least 1 month after therapy. Monitor lipids before treatment, weekly until stable, then every 8 weeks; try to keep triglycerides <400mg/dL; treat hyperlipidemia, or reduce or suspend bexarotene if needed. Hepatic or renal insufficiency. Monitor liver function at baseline, 1, 2, and 4 weeks after start, then (if stable) at least every 8 weeks during therapy; consider suspending or discontinuing treatment if SGOT/AST, SGPT/ALT, or bilirubin >3×ULN occurs. Monitor WBC with differential and thyroid function at baseline and during treatment; treat hypothyroidism if needed. Avoid sun and UV light. Nursing mothers: not recommended.

Interactions: Concomitant gemfibrozil: not recommended. Levels may be increased by CYP3A4 inhibitors (eg, ketoconazole, itraconazole, erythromycin, grapefruit juice). Levels may be reduced by CYP3A4 inducers (eg, rifampin, phenobarbital, phenytoin). May potentiate antihyperglycemics (eg, insulin, sulfonylureas, thiazolidinediones); monitor. May potentiate or be potentiated by protein-bound drugs. May antagonize tamoxifen, hormonal contraceptives, other CYP3A4 substrates. Limit Vit. A supplements to avoid toxicity. May increase CA125 assay values.

Adverse reactions: Lipid abnormalities, headache, hypothyroidism, asthenia, leukopenia, anemia, rash, GI disturbances, peripheral edema, dry skin, exfoliative dermatitis, alopecia, insomnia, fatigue, abnormal liver function tests, pancreatitis, pruritus, photosensitivity.

How supplied: Caps—100

TARGRETIN GEL Valeant

℞

Retinoid. Bexarotene 1%; gel.

Indications: Cutaneous lesions in patients with CTCL (Stage IA and IB) who have refractory or persistent disease after other therapies or who have not tolerated other therapies.

Adults: Apply once every other day for the 1st week; then increase frequency at weekly intervals to once daily, then twice daily, then 3 times daily, then 4 times daily based on lesion tolerance.

Usual dosing frequency: 2–4 times daily; may reduce if application site toxicity occurs. Allow gel to dry. Do not occlude.

Children: Not recommended.

Contraindications: Pregnancy (Cat.X).

Warnings/Precautions: Be fully familiar with this drug’s toxicity before use. Counsel patients monthly about need for contraception. Women of childbearing potential: obtain reliable negative pregnancy test within 1 week of start; repeat monthly. Start therapy on 2nd or 3rd day of normal menstrual period. Use two effective forms of contraception 1 month prior to, during, and for 1 month after therapy. Max 1 month/℞. Men with partners who are or may become pregnant: use condoms during and for at least 1 month after therapy. Hepatic or renal insufficiency.

Discontinue temporarily if severe irritation occurs.

Avoid sun, UV light, and mucosal membranes.

Nursing mothers: not recommended.

Interactions: Avoid concomitant products that contain DEET. May be potentiated by CYP3A4 inhibitors (eg, ketoconazole, itraconazole, erythromycin, grapefruit juice). Caution with gemfibrozil. Limit Vit. A supplements to avoid toxicity.

Adverse reactions: Application site reactions (eg, rash, pruritus, skin disorders, pain, contact dermatitis).

How supplied: Gel—60g

TASIGNA Novartis

℞

Kinase inhibitor. Nilotinib (as HCl monohydrate) 150mg, 200mg; caps; contains lactose.

Indications: Newly diagnosed adults with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase.

Chronic and accelerated phase Ph+ CML in adults resistant or intolerant to imatinib.

Adults: Take on an empty stomach. Swallow whole with water; if unable, may disperse capsule contents in 1 tsp of applesauce, then take immediately (within 15 mins). Newly diagnosed Ph+ CML: 300mg every 12hrs. Hepatic impairment (mild, moderate, severe): initially 200mg twice daily, followed by dose increase to 300mg twice daily if tolerated. Resistant or intolerant Ph+ CML: 400mg every 12hrs. Hepatic impairment (mild or moderate): initially 300mg twice daily, followed by dose increase to 400mg twice daily if tolerated; severe: initially 200mg twice daily, followed by sequential dose increase to 300mg twice daily, and then 400mg twice daily if tolerated. May give concomitant hematopoietic growth factors, hydroxyurea, or anagrelide if clinically indicated. See full labeling for dose adjustments in QT prolongation, hematological and non-hematological toxicities, concomitant strong CYP3A4 inhibitors and inducers.

Children: Not established.

Contraindications: Hypokalemia.

Hypomagnesemia. Long QT syndrome.

Warnings/Precautions: Prolongs QT interval, sudden deaths have been reported; correct electrolyte abnormalities before starting; monitor. Monitor ECG at baseline, after 7 days, then periodically and after dose changes.

Cardiovascular status should be evaluated; monitor cardiovascular risk factors and actively

manage during therapy. Hereditary galactose intolerance, severe lactase deficiency, glucosegalactose malabsorption: not recommended.

Hepatic impairment. History of pancreatitis.

Monitor for myelosuppression; withhold or reduce dose if occurs; perform CBCs every 2 weeks for 1st 2 months then once monthly. Monitor serum lipase, liver function monthly. Monitor lipids and glucose periodically during first year, then yearly.

Total gastrectomy (monitor frequently); consider dose increase or alternative therapy. Tumor lysis syndrome possible; maintain adequate hydration, correct uric acid levels prior to initiating therapy.

Pregnancy (Cat.D) (use adequate contraception), nursing mothers: not recommended.

Interactions: Avoid concomitant food (for at least 2hrs before and 1hr after dose), antiarrhythmics (eg, amiodarone, disopyramide, procainamide, quinidine, sotalol), or other drugs that may prolong QT interval (eg, chloroquine, haloperidol, methadone, moxifloxacin, pimozide). Avoid strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole), grapefruit; if necessary, interrupt therapy or consider dose reduction of nilotinib; if unavoidable, monitor closely for QT prolongation. Avoid strong CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital), St. John’s wort. May affect, or be affected by, other drugs metabolized by CYP3A4, 2B6, 2C8, 2C9, 2D6, UGT1A1, P-glycoprotein. Concomitant proton pump inhibitors: not recommended. Administer H2-blockers at least 10hrs before or 2hrs after nilotinib dose. Separate dosing of antacids by at least 2hrs of nilotinib dose.

Adverse reactions: Rash, pruritus, nausea, fatigue, headache, myalgia, nasopharyngitis, constipation, diarrhea, abdominal pain, vomiting, arthralgia, pyrexia, upper respiratory tract infection, back pain, cough, asthenia, pneumonia, febrile neutropenia, leukopenia, intracranial hemorrhage, reversible myelosuppression (thrombocytopenia, neutropenia, anemia); QT prolongation, elevated serum lipase, electrolyte disturbances (hypophosphatemia, hypo- and hyperkalemia, hypocalcemia, hyponatremia), sudden death, hepatotoxicity, cardiac and arterial vascular occlusive events, severe fluid retention (monitor).

Testing considerations: BCR-Abl t(9;22) How supplied: Blister pack (28 caps)—1, 4

THALOMID Celgene

℞

Immunomodulator. Thalidomide 50mg, 100mg, 150mg, 200mg; caps.

Indications: Newly diagnosed multiple myeloma in combination with dexamethasone. Treatment, suppression and prevention of cutaneous manifestations of erythema nodosum leprosum (ENL).

Adults: Take at bedtime, at least 1 hour after evening meal. Multiple myeloma: 200mg once daily in combination with dexamethasone in 28-day

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER treatment cycles. ENL: initially 100–300mg/day; <50kg: start with lower dose; continue until signs/symptoms of active reaction have subsided (usually at least 2 weeks), then taper off in 50mg decrements every 2–4 weeks. Severe ENL: may start at higher doses; max 400mg/day.

Moderate to severe neuritis with severe ENL: give concomitant corticosteroids (see full labeling).

Children: Not established.

Contraindications: Pregnancy (Cat.X). Nursing mothers. Women who may become pregnant.

Warnings/Precautions: Must register patient in STEPS program; patient must understand toxicity with fetal exposure. Counsel patient on need for contraception; female: use 2 forms of contraception 1 month before, during, and 1 month after therapy; male: use condom during and 1 month after therapy; obtain negative pregnancy test within 24 hours prior to starting treatment; repeat at least weekly for 1st month then every 4 weeks; get informed consent. Monitor for neuropathy monthly for first 3 months; discontinue if symptoms develop. Monitor for signs/symptoms of thromboembolic events, neutropenia, bradycardia, syncope, orthostatic hypotension, tumor lysis syndrome. Reevaluate if ANC <750/mm2; consider withholding if neutropenia persists.

Measure HIV viral load after 1st and 3rd months, and every 3 months thereafter. Discontinue if pregnancy or severe skin rash occurs. History of seizure. Avoid contact with non-intact capsule or powder content. Maximum 1 month per ℞.

Interactions: Increased sedative effect with barbiturates, alcohol, chlorpromazine, reserpine. Caution with drugs associated with peripheral neuropathy. Avoid drugs (eg, rifampin, carbamazepine, St. John’s wort) that decrease effectiveness of hormonal contraceptives.

Increased risk of thromboembolism with concomitant erythropoietic agents, or estrogencontaining therapies in those receiving thalidomide with dexamethasone.

Adverse reactions: Fatigue, birth defects, somnolence, skin rash (eg, Stevens-Johnson Syndrome, toxic epidermal necrolysis), headache, bradycardia, peripheral neuropathy, seizures, drowsiness, dizziness, orthostatic hypotension, leukopenia, anorexia, nausea, anxiety, asthenia, tremor, fever, weight loss, dry skin, neutropenia, increased HIV viral load, constipation, confusion, hypocalcemia, edema, dyspnea, thrombosis/ embolism.

Note: Available only through STEPS program.

Suspected fetal exposure must be reported to the FDA at (800) FDA-1088 and Celgene at (888) 423-5436.

How supplied: Blister packs (50mg)—1, 28; (100mg, 150mg, 200mg)—28

TREANDA Teva

℞

Alkylating agent. Bendamustine HCl 90mg/mL; soln for IV infusion after dilution; preservativefree.

Indications: Chronic lymphocytic leukemia (CLL). Indolent B-cell non-Hodgkin’s lymphoma (NHL) that has progressed during or within 6 months of treatment with rituximab or a rituximab–containing regimen.

Adults: CLL: Give by IV infusion over 30 minutes.

100mg/m2 on Days 1 and 2 of a 28-day cycle, up to 6 cycles. Hematologic toxicity (≥Grade 3): reduce dose to 50mg/m2 on Days 1 and 2 of each cycle; if toxicity recurs, reduce dose to 25mg/m2 on Days 1 and 2. Non-hematologic toxicity (clinically significant ≥Grade 3): reduce dose to 50mg/m2 on Days 1 and 2 of each cycle. Subsequent cycles: may consider dose re-escalation. NHL: Give by IV infusion over 60 minutes. 120mg/m2 on Days 1 and 2 of a 21-day cycle, up to 8 cycles. Hematologic toxicity (Grade 4) or non-hematologic toxicity (≥Grade 3): reduce dose to 90mg/m2 on Days 1 and 2 of each cycle; if toxicity recurs, reduce dose to 60mg/m2 on Days 1 and 2. Delay treatment for Grade 4 hematologic toxicity or clinically significant ≥Grade 2 non-hematologic toxicity.

Severe renal impairment (CrCl <40mL/min) or moderate to severe hepatic impairment: not recommended.

Children: Not established.

Warnings/Precautions: Myelosuppression; monitor leukocytes, platelets, hemoglobin, neutrophils closely; restart treatment based on ANC and platelet count recovery. Renal or hepatic impairment. Monitor for infection, infusion or skin reactions, tumor lysis syndrome. Avoid extravasation. Pregnancy (Cat.D); avoid use.

Nursing mothers: not recommended.

Interactions: May be potentiated or antagonized

by CYP1A2 inhibitors, inducers; consider alternatives.

Adverse reactions: Lymphopenia, anemia, leukopenia, thrombocytopenia, neutropenia, pyrexia, nausea, vomiting, diarrhea, asthenia, fatigue, malaise, dry mouth, somnolence, cough, constipation, headache, mucosal inflammation, stomatitis, increased bilirubin, increased AST or ALT; infection, infusion reactions (discontinue if severe), tumor lysis syndrome, skin reactions (if severe or progressive, withhold dose or discontinue), other malignancies (eg, myelodysplastic syndrome, acute myeloid leukemia, bronchial carcinoma).

How supplied: Single-use vial (45mg/0.5mL, 180mg/2mL)—1

TREXALL Teva

℞

Folic acid antagonist. Methotrexate sodium 5mg, 7.5mg, 10mg, 15mg; scored tabs. ℞ Also: Methotrexate injection Bedford Methotrexate 25mg/mL; soln for IV, IM, intraarterial, or intrathecal administration after dilution; preservative-free. ℞ Also: Methotrexate for injection Bedford Methotrexate 1g/vial; pwd for IV, IM, intra-arterial, or intrathecal administration after dilution; preservative-free.

Indications: Prophylaxis and treatment of meningeal leukemia. Advanced mycosis fungoids (cutaneous T cell lymphoma). Advanced nonHodgkin’s lymphomas.

Adults: See literature. Tablet form is often preferred when low doses are being administered.

Leukemia: Induction: 3.3mg/m2 + prednisone, given daily; maintenance: give twice weekly either orally or by IM inj for a total weekly dose of 30mg/m2; or 2.5mg/kg IV every 14 days. Meningeal leukemia (treatment): 12mg/m2 intrathecally (max 15mg) at intervals of 2–5 days; see literature for prophylaxis treatment. Burkitt’s tumor (stage I–II): 10–25mg per day orally for 4–8 days. Lymphosarcomas (stage III): 0.625–2.5mg/kg daily. Mycosis fungoides (cutaneous T cell lymphoma): 5–50mg once weekly.

Children: See literature.

Contraindications: Pregnancy (Cat.X). Nursing mothers.

Warnings/Precautions: Be fully familiar with this drug’s toxicity before use. Discontinue if malignant lymphomas occur. Obtain baseline and monitor CBCs with differential, platelet counts, chest X-ray, and hepatic, renal and pulmonary function. During therapy monitor hematology monthly, renal and hepatic function every 1–2 months, more often if increasing dose or predisposed to toxicity (eg, dehydration).

Discontinue immediately if blood counts drop significantly. Rule out pregnancy in women of childbearing potential; use effective contraception during therapy and for at least 1 ovulatory cycle afterwards for women and for at least 3 months afterwards for men. Interrupt therapy if vomiting, diarrhea, stomatitis, or pulmonary symptoms occur. Hepatic or renal impairment. Obesity.

Diabetes. Peptic ulcer. Ulcerative colitis. Infection.

Dehydration. Folate deficiency. Ascites, pleural effusions: evacuate fluid, monitor for toxicity and reduce dose or discontinue if needed. Elderly (use low doses and monitor closely). Debilitated.

Interactions: Avoid live virus vaccines. Toxicity increased by NSAIDs, salicylates, phenytoin, sulfonylureas, sulfonamides, probenecid, folic acid

Take advantage of our free online medical calculators at CancerTherapyAdvisor.com/MedicalCalculators.

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER antagonists. May be potentiated by penicillins (monitor), tetracyclines, chloramphenicol, nonabsorbable broad spectrum antibiotics. May be antagonized by folic acid. May potentiate theophylline, mercaptopurine. Increased risk of soft tissue necrosis and osteonecrosis with radiotherapy. Caution with other hepatotoxic drugs (eg, azathioprine, retinoids, sulfasalazine) and nephrotoxic agents (eg, cisplatin).

Adverse reactions: Ulcerative stomatitis, leukopenia, nausea, GI upset, malaise, fatigue, chills, fever, dizziness, infection, myelosuppression, hepatotoxicity, renal toxicity, CNS toxicity, seizures (esp in children); interstitial pneumonitis, tumor lysis syndrome, skin reactions (may be fatal; eg, toxic epidermal necrolysis, Stevens-Johnson syndrome).

How supplied: Tabs—30; soln (2mL, 4mL, 8mL, 10mL)—10 (single-use vials); pwd (1 gram)—1 (single-use vial)

TRISENOX Teva

℞

Antineoplastic. Arsenic trioxide 1mg/mL; soln for IV inj after dilution; preservative-free.

Indications: Induction of remission and consolidation in acute promyelocytic leukemia (APL) refractory to or relapsed from retinoid and anthracycline chemotherapy, and whose APL has the t(15;17) translocation or PML/RAR-alpha gene expression.

Adults: Give by IV infusion over 1–2 hours; may extend infusion up to 4 hours if acute vasomotor symptoms occur. Induction: 0.15mg/kg per day until bone marrow remission; max 60 doses.

Consolidation treatment (begin 3–6 weeks after completion of induction therapy): 0.15mg/kg per day for 25 doses for up to 5 weeks.

Children: See literature. <5yrs: not recommended.

5–16yrs: doses of 0.15mg/kg per day have been used.

Warnings/Precautions: Renal or hepatic dysfunction. History of torsades de pointes.

Preexisting QT interval prolongation. CHF. Monitor hematology, renal function, and electrolytes at least twice weekly, perform ECG at baseline then weekly (hospitalize if cardiac irregularities develop); unstable patients: monitor more frequently. Correct electrolyte imbalances before starting therapy (maintain K+ above 4mEq/dL and Mg++ above 1.8mg/dL). Pregnancy: (Cat.D), nursing mothers: not recommended.

Interactions: Caution with drugs that can cause QT prolongation (discontinue these before starting therapy, if possible) or electrolyte imbalances.

Adverse reactions: Leukocytosis, GI upset, fatigue, edema, hyperglycemia, cough, rash, headache, dizziness, paresthesia, arthralgia, renal failure, electrolyte disorders (eg,hypokalemia, hypomagnesemia), abnormal LFTs; APL differentiation syndrome (eg, fever, dyspnea, weight gain, pulmonary infiltrates, pericardial effusion; give high-dose IV steroids at 1st sign), hyperleukocytosis, QT interval prolongation/heart block, atrial dysrhythmias, tachycardia, others (see literature).

How supplied: Single-use amps (10mL)—10

UVADEX Therakos

℞

Photoactive agent. Methoxsalen 20mcg/mL; sterile soln.

Indications: Extracorporeal administration with the UVAR Photopheresis System in the palliative treatment of skin manifestations of cutaneous T-cell lymphoma that is unresponsive to other forms of treatment.

Adults: Consult UVAR Photopheresis System Operator’s Manual before administering. Give on two consecutive days every 4 weeks for minimum of 7 treatment cycles (6 months). 200mcg per photopheresis treatment. Accelerated treatment schedule: see literature.

Children: Not recommended.

Contraindications: Idiosyncratic reactions to psoralen compounds. History of light sensitive disease. Lupus erythematosus. Porphyria cutanea tarda. Erythropoietic protoporphyria. Variegate porphyria. Xeroderma pigmentosum. Albinism.

Aphakia.

Warnings/Precautions: Exposure to sun or UV light may cause actinic degeneration, skin burning, cataracts; wear UVA-absorbing, wrap-around sunglasses and cover exposed skin (or use sunblock: SPF ≥15) for 24hrs after treatment. Basal cell carcinomas (monitor and treat if occur). Pregnancy (Cat.D); nursing mothers: not recommended.

Interactions: Increased photosensitivity with anthralin, coal tar, griseofulvin, phenothiazines, nalidixic acid, halogenated salicylanilides, sulfonamides, tetracyclines, thiazides, organic staining dyes.

Adverse reactions: Hypotension secondary to changes in extracorporeal volume.

How supplied: Vials (10mL)—12

VALCHLOR Actelion

℞

Nitrogen mustard. Mechlorethamine 0.016%; topical gel; contains propylene glycol, isopropyl alcohol.

Indications: Treatment of Stage IA and IB mycosis fungoides-type cutaneous T-cell lymphoma in patients who have received prior skin-directed therapy.

Adults: Apply a thin film once daily to affected areas of the skin. Apply to completely dry skin ≥4 hours before or 30 minutes after showering or washing. Allow treated areas to completely dry for 5–10 minutes after applying. Wash hands thoroughly after application. Discontinue if any grade of skin ulceration, blistering, or moderatelyto-severe, or severe dermatitis occur; restart at reduced frequency of once every 3 days upon improvement; if reintroduction is tolerated for at least 1 week, can increase to every other day for 1 week and then once daily if tolerated.

Children: Not established.

Warnings/Precautions: Mucosal (oral, nasal) or eye exposure; blindness and severe irreversible anterior eye injury may occur; immediately irrigate for ≥15 minutes with copious amounts of water.

Secondary exposure; avoid direct skin contact

with patient. Risk of dermatitis (eg, face, genitalia, anus, and intertriginous skin); monitor for redness, swelling, inflammation, itchiness, blisters, ulceration, and secondary skin infections. Monitor for nonmelanoma skin cancer during and after treatment. Flammable (avoid fire and flame until gel has dried). Pregnancy (Category D); may cause fetal harm. Nursing mothers: not recommended.

Adverse reactions: Dermatitis, pruritus, bacterial skin infection, skin ulceration or blistering, hyperpigmentation.

How supplied: Gel—60g

VELCADE Millennium

℞

Proteasome inhibitor. Bortezomib 3.5mg/vial; lyophilized pwd for IV or SC inj after reconstitution; contains mannitol.

Indications: Multiple myeloma. Mantle cell lymphoma.

Adults: Give as a 3–5 second IV bolus inj or as SC inj into thigh or abdomen (rotate sites).

Previously untreated multiple myeloma: Treat for nine 6-week cycles in combination with oral melphalan and oral prednisone. Cycles 1–4: 1.3mg/m2 twice weekly (Days 1, 4, 8, 11, 22, 25, 29, 32); Cycles 5–9: 1.3mg/m2 once weekly (Days 1, 8, 22, 29). Previously untreated mantle cell lymphoma: Treat for six 3-week cycles in combination with IV rituximab, cyclophosphamide, doxorubicin, and oral prednisone. 1.3mg/m2 twice weekly for 2 weeks (Days 1, 4, 8, 11) then 10 day rest period (Days 12–21); if response first documented at Cycle 6, two more cycles are recommended.

Relapsed multiple myeloma or mantle cell lymphoma: Standard schedule: 1.3mg/m2 twice weekly for 2 weeks (Days 1, 4, 8, 11) then 10 day rest period (Days 12–21); Extended therapy (if using >8 cycles): may use standard schedule, or maintenance schedule: 1.3mg/m2 once weekly for 4 weeks (Days 1, 8, 15, 22) then 13-day rest period (Days 23–35). Multiple myeloma patients who have previously responded to bortezomib (alone or in combination) and have relapsed at least 6 months after completing prior bortezomib therapy: may retreat starting at last tolerated dose, given twice weekly every 3 weeks (Days 1, 4, 8, 11); max 8 cycles. Allow at least 72hrs between consecutive doses. May be given as a single agent or in combination with dexamethasone.

Dose modifications: see full labeling. SC inj may be considered for patients with pre-existing or at high-risk of peripheral neuropathy. Moderate-tosevere hepatic impairment: reduce to 0.7mg/m2 in 1st cycle; may consider dose increase to 1mg/m2 or further decrease to 0.5mg/m2 in subsequent cycles based on tolerance.

Children: Not established.

Contraindications: Boron or mannitol sensitivity. Intrathecal administration.

Warnings/Precautions: Hepatic impairment.

Pre-existing severe neuropathy; treat only after careful risk-benefit assessment. Monitor for development or worsening of peripheral neuropathy; consider dose and/or schedule

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HEMATOLOGIC CANCER adjustment. Diabetes (closely monitor blood glucose). History of syncope. Avoid dehydration; give fluids and electrolytes. Heart disease (monitor for CHF). Interrupt therapy and evaluate if new or worsening cardiopulmonary symptoms develop. Monitor CBC frequently during therapy and platelets prior to each dose; adjust dose/ schedule for thrombocytopenia (see full labeling).

Monitor for toxicities. High tumor burden (monitor for tumor lysis syndrome). Pregnancy (Cat.D); avoid. Nursing mothers: not recommended.

Interactions: Concomitant strong CYP3A4 inducers (eg, rifampin): not recommended; efficacy may be reduced. Avoid St. John’s Wort. Potentiated by strong CYP3A4 inhibitors (eg, ketoconazole, ritonavir); consider reducing bortezomib dose.

Caution with hypotensives and hypoglycemics.

Adverse reactions: GI toxicity (eg, nausea, diarrhea, constipation, vomiting; interrupt therapy if severe), thrombocytopenia, neutropenia, anemia, leukopenia, lymphopenia, peripheral neuropathy, fatigue, neuralgia, rash, pyrexia, anorexia, asthenia, herpes reactivation, insomnia, dyspnea, paresthesia, headache, decreased appetite, dizziness, blurred vision, edema, arthralgia, pain, dysesthesia, psychiatric disorders, cough, pruritus, orthostatic hypotension, CHF, decreased LVEF, hepatotoxicity; rare: posterior reversible encephalopathy syndrome (discontinue if occurs).

How supplied: Single-dose vial—1

VESANOID Roche

℞

Retinoid. Tretinoin 10mg; soft gelatin caps; contain parabens.

Indications: Induction of remission in patients with acute promyelocytic leukemia (APL), FrenchAmerican-British (FAB) classification M3 (including the M3 variant), characterized by the presence of the t(15;17) translocation and/or the presence of the PML/RARα gene who are refractory to, or who have relapsed from, anthracycline chemotherapy, or for whom anthracycline-based chemotherapy is contraindicated.

Adults: Use only for induction of remission.

45mg/m2 per day in two divided doses until complete remission is documented. Discontinue 30 days after complete remission or after 90 days of treatment, whichever occurs first.

Children: See literature.

Warnings/Precautions: Confirm APL diagnosis. Monitor for Retinoic Acid-APL (RA-APL) syndrome, leukocytosis, pseudotumor cerebri, or respiratory compromise. Consider temporarily interrupting therapy if moderate to severe RA-APL syndrome develops. Monitor blood counts, coagulation profile, lipids, liver function; consider temporary withdrawal if tests >5×ULN. Pregnancy

(Cat.D); obtain negative pregnancy test 1 week before starting treatment, counsel patient about need to use 2 effective methods of contraception during, and 1 month after therapy. Nursing mothers: not recommended.

Interactions: Do not administer with Vitamin A. May be potentiated or antagonized by CYP450 enzyme inducers or inhibitors. Caution with anti-fibrinolytic agents; and other agents known to cause pseudotumor cerebri/intracranial hypertension.

Adverse reactions: Headache, fever, skin/ mucous membrane dryness, bone pain, GI upset, rash, mucositis, pruritus, increased sweating, visual disturbances, alopecia; RA-APL syndrome, leukocytosis, pseudotumor cerebri, hypercholesterolemia/hypertriglyceridemia, others.

How supplied: Caps—100

VIDAZA Celgene

℞

Cytidine analogue. Azacitidine 100mg/vial; lyophilized pwd for SC inj after reconstitution or IV inj after reconstitution and dilution; contains mannitol; preservative-free.

Indications: Myelodysplastic syndromes (refractory anemias, chronic myelomonocytic leukemia).

Adults: Premedicate for nausea & vomiting.

Initially 75mg/m2 SC (doses >4mL divide equally into 2 syringes and inject into 2 separate sites) or IV (infuse over 10–40 mins, must complete within 1hr of reconstitution) daily for 7 days; repeat cycle every 4 weeks. May increase to 100mg/m2 after 2 cycles if no response and no toxicity. Treat for at least 4–6 cycles. Adjust subsequent doses on blood counts and toxicities (eg, neutropenia, thrombocytopenia, decreased serum bicarbonate).

Children: Not established.

Contraindications: Advanced malignant hepatic tumors.

Warnings/Precautions: Renal or hepatic impairment. High tumor burden. Obtain CBC counts before each dosing cycle and as needed.

Monitor serum bicarbonate and renal and hepatic function (do baseline liver chemistries and serum creatinine). Elderly. Pregnancy (Cat.D); use appropriate contraception (both men and women). Nursing mothers: not recommended.

Adverse reactions: Nausea, vomiting, diarrhea, blood dyscrasias (esp. anemia, thrombocytopenia, neutropenia, leukopenia), fever, fatigue, inj site reactions, constipation, ecchymosis, petechiae, rigors, dyspnea, arthralgia, headache, anorexia, renal failure/ tubular acidosis, hypokalemia, hepatic coma, others (see full labeling).

How supplied: Single-use vial—1

VUMON Bristol-Myers Squibb

℞

Topoisomerase inhibitor. Teniposide 10mg/mL; soln for IV infusion after dilution; contains benzyl alcohol, Cremophor EL (polyoxyethylated castor oil), dehydrated alcohol.

Indications: Refractory childhood acute lymphoblastic leukemia.

Adults and Children: See literature. Give as slow IV infusion (at least 30–60 minutes).

Patients failing induction therapy with a cytarabine-containing regimen: 165mg/m2 + cytarabine twice weekly for 8 to 9 doses.

Refractory to vincristine/prednisone-containing regimen: 250mg/m2 + vincristine weekly for 4 to 8 weeks + oral prednisone for 28 days.

Warnings/Precautions: Severe myelosuppression. Monitor for hypersensitivity reactions following infusion; have epinephrine available. Risk of hypotension with rapid IV administration. Hepatic dysfunction. Monitor and obtain CBCs with differential, hemoglobin, platelets, renal and hepatic functions before, during, and after therapy. Down syndrome (use reduced dose). Monitor children with hypoalbuminemia. Avoid extravasation.

Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended.

Interactions: Potentiated by tolbutamide, sodium salicylate, and sulfamethizole.

Concomitant vincristine sulfate may cause neuropathy. Concomitant antiemetics in patients given high doses of teniposide may increase risk of CNS depression, hypotension.

Adverse reactions: Myelosuppression (leukopenia, neutropenia, thrombocytopenia, anemia), mucositis, GI upset, infection, alopecia, bleeding, rash, fever, hypotension, CNS depression, hypersensitivity reactions (may be fatal).

How supplied: Ampules (5mL)—1

ZEVALIN Spectrum

℞

Radionuclide (B-lymphocyte-restricted differentiation antigen [CD20] inhibitor).

Ibritumomab tiuxetan 3.2mg/2mL; soln for IV inj; contains albumin; preservative-free.

Indications: B-cell non-Hodgkin’s lymphoma (relapsed or refractory, low grade or follicular).

Previously untreated follicular non-Hodgkin’s lymphoma in patients who achieve a partial or complete response to first-line chemotherapy.

Adults: See literature. Prepare In-111 Zevalin and Y-90 Zevalin as directed. Initiate Zevalin therapy after recovery of platelets to ≥150,000/mm3 at least 6 weeks, but no more than 12 weeks, after the last dose of first-line chemotherapy.

Download the Oncology Nurse Advisor app for convenient access to clinical information and updates relevant to the oncology nursing community.

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER Administered in two steps. Step 1: Single infusion of rituximab followed by a fixed dose of 5mCi (1.6mg total antibody dose) of In-111 Zevalin given as a 10-minute IV push. Step 2 (7–9 days after Step 1): Second rituximab infusion followed by 0.4mCi/kg of Y-90 Zevalin given as a 10-minute IV push; if platelet count 100,000–149,000cells/mm3, reduce dose to 0.3 mCi/kg. Do not treat if platelets <100,000cells/mm3. Max Y-90 Zevalin dose: 32mCi. Children: Not recommended.

Contraindications: Hypersensitivity to murine proteins.

Warnings/Precautions: See literature. Use only if trained in radionuclide therapy. Do not treat patients with altered biodistribution. ≥25% lymphoma marrow involvement and/or impaired bone marrow reserve (eg, prior myeloablative therapies, platelet count <100,000cells/mm3, neutrophil count <1,500cells/mm3), or history of failed stem cell collection: not recommended.

Monitor for cytopenias and complications (eg, febrile neutropenia, hemorrhage) for up to 3 months after treatment. Obtain CBCs, platelets weekly until levels recover. Avoid extravasation.

Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended.

Interactions: Caution with anticoagulants, platelet aggregation inhibitors, or live viral vaccines. Separate growth factor treatment by 2 weeks before and after Zevalin therapy.

Adverse reactions: Neutropenia, leukopenia, thrombocytopenia, anemia, infections, asthenia, musculoskeletal symptoms, GI upset, abdominal pain, fatigue, nasopharyngitis, cough, dizziness, hemorrhage, altered biodistribution; infusion reactions, severe cutaneous/mucocutaneous reactions: both may be fatal, discontinue if occurs; leukemia and myelodysplastic syndrome.

Note: Indium-11 chloride sterile solution must be ordered separately at the time the In-11 Zevalin kit is ordered. Yttrium-90 chloride sterile solution will be shipped directly upon placement of order for Y-90 Zevalin kit.

How supplied: In-111 Zevalin kit (ibritumomab tiuxetan 3.2mg/2mL vial + sodium acetate vial + formulation buffer vial + empty reaction vial)—1 Y-90 Zevalin kit (ibritumomab tiuxetan 3.2mg/2mL vial + sodium acetate vial + formulation buffer vial + empty reaction vial)—1

ZOLINZA Merck

℞

Histone deacetylase inhibitor. Vorinostat 100mg; caps.

Indications: Refractory cutaneous T-cell lymphoma.

Adults: Take with food. Swallow whole. 400mg once daily. If not tolerated, may reduce to 300mg once daily, then to 300mg once daily 5 days/week if needed. Continue until disease progression or not tolerated.

Children: <18yrs: not recommended.

Warnings/Precautions: Renal or hepatic impairment. Monitor for DVT, pulmonary embolism. Correct electrolyte disturbances before starting therapy. Maintain adequate hydration. Diabetes. Monitor CBC, platelets, blood glucose, serum creatinine, electrolytes (esp. potassium, calcium, magnesium) every 2 weeks for 1st 2 months, then monthly. Pregnancy (Cat.D).

Nursing mothers: not recommended.

Interactions: Increased risk of thrombocytopenia and GI bleed with other HDAC inhibitors (eg, valproic acid). Concomitant warfarin: monitor PT, INR. Adverse reactions: GI upset, fatigue, chills; thrombocytopenia, anemia (may need to modify dose or discontinue); anorexia, dysgeusia, pulmonary embolism, DVT, hyperglycemia.

How supplied: Caps—120

ZOMETA Novartis

℞

Bisphosphonate. Zoledronic acid 4mg/5mL concentrated soln for IV infusion after dilution; 4mg/100mL ready-to-use soln for IV infusion.

Indications: Adjunct in multiple myeloma and bone metastases of solid tumors.

Limitation of use: not established for use in hyperparathyroidism or nontumor-related hypercalcemia.

Adults: Give by IV infusion over at least 15 minutes. CrCl >60mL/min: 4mg; CrCl 50–60mL/min: 3.5mg; CrCl 40–49mL/min: 3.3mg; CrCl 30–39mL/min: 3mg; CrCl <30mL/min: see full labeling; all: every 3–4 weeks (give oral multivitamin supplement with calcium 500mg + Vit. D 400 IU daily).

Children: Not recommended.

Warnings/Precautions: Not recommended for use in patients with bone metastases with severe renal impairment. Renal or hepatic insufficiency. Check serum creatinine before each dose: withhold until serum creatinine is within 10% of baseline if serum creatinine increases by 0.5 mg/dL from a normal pre-treatment level, or by 1 mg/dL from an abnormal pre-treatment level, within 2 weeks of next dose. Assure adequate hydration when treating hypercalcemia of malignancy. Correct hypocalcemia before initiating treatment; supplement with calcium and vitamin D. Closely monitor electrolytes (esp. calcium, magnesium, phosphate), CBC/ differential, hematocrit, hemoglobin. Evaluate if thigh or groin pain develops and consider discontinuing if atypical femur fracture is suspected. Aspirin-sensitive asthma. Avoid dental surgery (do preventative dental work before therapy). Elderly. Pregnancy (Cat.D). Nursing mothers: not recommended.

Interactions: Avoid concomitant other bisphosphonates. Additive hypocalcemic effect with aminoglycosides, loop diuretics. Caution with other nephrotoxic drugs (eg, thalidomide).

Adverse reactions: Nausea, fatigue, anemia, musculoskeletal pain (discontinue if severe), constipation, fever, vomiting, dyspnea, flu-like

syndrome, electrolyte disturbances, hypotension, CNS effects, rigors, headache, paresthesia, renal toxicity; jaw osteonecrosis, atypical subtrochanteric, diaphyseal femoral fractures, severe hypocalcemia.

How supplied: Single-use vial, ready-to-use bottle—1

ZYDELIG Gilead

℞

Phosphatidylinositol 3-kinase inhibitor. Idelalisib 100mg, 150mg; tabs.

Indications: Relapsed chronic lymphocytic leukemia (CLL), in combination with rituximab, in patients for whom rituximab alone would be considered appropriate due to other co-morbidities. Relapsed follicular B-cell nonHodgkin lymphoma (FL) in patients who have received at least 2 prior systemic therapies.

Relapsed small lymphocytic lymphoma (SLL) in patients who have received at least 2 prior systemic therapies.

Adults: Swallow whole. ≥18yrs: initially 150mg twice daily; continue until disease progression or unacceptable toxicity. Dose modifications: see full labeling.

Children: <18yrs: not established.

Contraindications: History of serious allergic reactions including anaphylaxis and toxic epidermal necrolysis.

Warnings/Precautions: Risk of fatal/ serious hepatotoxicity: monitor ALT/AST every 2 weeks for the first 3 months, every 4 weeks for the next 3 months, then every 1–3 months thereafter; if ALT/AST >3×ULN, monitor weekly until resolved; if ALT/AST >5×ULN, withhold and continue monitoring weekly until resolved.

Monitor for diarrhea or colitis; withhold if severe and discontinue if life-threatening. Risk of fatal/ serious pneumonitis; monitor for pulmonary symptoms, interstitial infiltrates, or a decline by >5% in oxygen saturation; if suspected, interrupt or discontinue as indicated. Risk of fatal/serious intestinal perforation; discontinue permanently if occurs. Monitor for severe cutaneous or serious allergic reactions; discontinue if occur.

Monitor CBCs at least every 2 weeks for the first 3 months, and at least weekly if neutrophils <1.0Gi/L. Pregnancy (Cat.D); avoid. Use effective contraception during treatment and for at least 1 month after last dose. Nursing mothers: not recommended.

Interactions: Avoid concomitant drugs that may cause hepatotoxicity or diarrhea. Avoid concomitant strong CYP3A inducers (eg, rifampin, phenytoin, St. John’s wort, carbamazepine) or CYP3A substrates (eg, oral midazolam). Concomitant strong CYP3A inhibitors (eg, ketoconazole); monitor for idelalisib toxicity.

Adverse reactions: Diarrhea, pyrexia, fatigue, nausea, cough, pneumonia, abdominal pain, chills, rash, neutropenia, hypertriglyceridemia, hyperglycemia, ALT/AST elevations.

How supplied: Tabs—60

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DRUG MONOGRAPHS

LUNG CANCER ABRAXANE Celgene

℞

Taxane antimicrotubule. Paclitaxel [bound to albumin (human)] 100mg/vial; pwd for IV infusion after reconstitution; solvent-free.

Indications: First-line treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC), in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy.

Adults: Do not treat if neutrophil count <1,500 cells/mm3 or platelets <100,000 cells/mm3. In combination with carboplatin: 100mg/m2 IV over 30 mins on Days 1, 8, and 15 of each 21-day cycle.

Dose reductions for hematologic and neurologic adverse reactions, hepatic impairment: see full labeling. Avoid extravasation.

Children: Not evaluated.

Contraindications: Baseline neutrophil count <1,500 cells/mm3. Prior severe hypersensitivity reaction (do not rechallenge).

Warnings/Precautions: Do not substitute for, or with, other paclitaxel products (due to formulation differences). Do frequent complete blood cell counts. Hepatic impairment (total bilirubin >5 × ULN or AST >10 × ULN): not recommended. Monitor for sensory neuropathy, sepsis, or pneumonitis.

Renal dysfunction. Contains human albumin; remote risk of viral transmission. Use appropriate contraception (men and women). Pregnancy (Cat.D), nursing mothers: not recommended.

Interactions: May potentiate or be potentiated

by CYP2C8 and/or CYP3A4 inducers (eg, rifampin, carbamazepine, phenytoin, efavirenz, nevirapine) and/or inhibitors (eg, ketoconazole, other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir, nelfinavir).

Adverse reactions: Bone marrow suppression (eg, neutropenia, anemia), infections, alopecia, sensory neuropathy (may require dose reduction or interruption), peripheral neuropathy, GI upset, mucositis, fatigue/asthenia, myalgia/arthralgia, abnormal ECG; alkaline phosphatase or AST elevation; dyspnea, edema, hypotension, rash (may be serious); rare: thrombotic events.

How supplied: Single-use vial—1

ALIMTA Lilly

℞

Antifolate. Pemetrexed 100mg/vial, 500mg/vial; pwd for IV inj after reconstitution and dilution; preservative-free.

Indications: Locally advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC): in combination with cisplatin as initial treatment, or as maintenance in patients whose disease has not progressed after 4 cycles of

platinum-based 1st-line chemotherapy; or as a single agent after prior chemotherapy. Malignant pleural mesothelioma (MPM): in combination with cisplatin in patients whose disease is either unresectable or who are otherwise not candidates for curative surgery. Limitations of use: not for the treatment of squamous cell NSCLC. Adults: See full labeling. 500mg/m2 by IV infusion over 10 mins on Day 1 of each 21-day cycle. Adjust dose if toxicity (esp. myelosuppression) develops.

Combination therapy: Give cisplatin beginning 30 mins after pemetrexed infusion. Supplement with oral folic acid and intramuscular vitamin B12 prior to initiating pemetrexed and continue during treatment. Pretreat with corticosteroid the day before, the day of, and day after pemetrexed.

Children: Not recommended.

Warnings/Precautions: See full labeling. Renal impairment (CrCl <45mL/min): not recommended.

Discontinue if Grade 3 or 4 neurotoxicity occurs, or if any Grade 3 or 4 toxicity occurs after two dose reductions. Do not start a treatment cycle unless ANC is ≥1500cells/mm3, platelets ≥100,000cells/mm3 and CrCl ≥45mL/min. Hepatic impairment. Monitor CBCs, platelets, renal and hepatic function. Clinically significant third space fluid: consider draining effusion first. Pregnancy (Cat.D); avoid, use effective contraception.

Nursing mothers: not recommended.

Interactions: May be potentiated by nephrotoxic agents, drugs eliminated by renal tubular secretion (eg, probenecid). Concomitant NSAIDs: use caution in patients with mild to moderate renal insufficiency (esp. ibuprofen).

Adverse reactions: Fatigue, nausea, anorexia, vomiting, stomatitis, pharyngitis, constipation, fever, infection with neutropenia, rash, desquamation, neutropenia, leukopenia, anemia, thrombocytopenia, elevated creatinine, chest pain, neuropathy; rare: renal failure.

Testing considerations: TS (thymidylate synthase) expression for response and toxicity How supplied: Single-use vial—1

AVASTIN Genentech

Warnings/Precautions: Risk of GI perforations, surgery and wound healing complications, and hemorrhage. Do not start therapy before or for at least 28 days after surgery; allow surgical incisions to completely heal (see full labeling). Do not administer if recent history of hemoptysis of ≥ ½-teaspoon of red blood.

Permanently discontinue if GI perforation, tracheoesophageal fistula, any grade 4 fistula, or grade 4 venous thromboembolic event.

Discontinue if fistula involving internal organ, wound healing complications, hemorrhage, severe arterial thromboembolic event (ATE), hypertensive crisis or encephalopathy, posterior reversible encephalopathy syndrome, or nephrotic syndrome occurs; suspend therapy if severe hypertension, moderate-to-severe proteinuria (resume when <2g/24hrs), or severe infusion reaction occurs. Avoid in ovarian cancer if evidence of recto-sigmoid involvement by pelvic exam, bowel involvement on CT scan, or symptoms of bowel obstruction. History of arterial thromboembolism. Diabetes. Monitor BP every 2–3 weeks. Monitor proteinuria by dipstick urine analysis; if ≥2+, do further assessment with a 24-hour urine collection. Elderly. Increased risk of ovarian failure; inform females of reproductive potential prior to starting therapy. Pregnancy: may cause fetal harm; use effective contraception during and for 6 months after last dose. Nursing mothers: not recommended.

Adverse reactions: Epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain, exfoliative dermatitis; GI perforation and fistulae, wound dehiscence/impaired healing, necrotizing fasciitis (discontinue if occurs), hemorrhage, non-GI fistula formation, arterial or venous thromboembolic events, posterior reversible encephalopathy syndrome, infusion reactions, ovarian failure, neutropenia, and infection.

How supplied: Single-use vial—1

CYRAMZA Lilly ℞

Angiogenesis inhibitor. Bevacizumab 100mg, 400mg; per vial; soln for IV infusion after dilution; preservative-free.

Indications: First-line treatment of unresectable, locally advanced, recurrent or metastatic nonsquamous, non-small cell lung cancer (NSCLC), in combination with carboplatin and paclitaxel.

Adults: Give by IV infusion. Infuse 1st dose over 90 mins; if tolerated, infuse 2nd dose over 60 mins, and subsequent doses over 30 mins. 15mg/kg every 3 weeks with carboplatin/paclitaxel.

Children: Not established.

℞

Human IgG1 monoclonal antibody. Ramucirumab 10mg/mL; per vial; soln for IV infusion after dilution; preservative-free.

Indications: In combination with docetaxel, for treatment of metastatic non-small cell lung cancer (NSCLC) with disease progression on or after platinum-based chemotherapy; patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to initiation.

Adults: Give by IV infusion over 60 mins.

Premedicate with IV histamine H1-antagonist (eg, diphenhydramine) prior to each infusion;

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DRUG MONOGRAPHS

LUNG CANCER or with dexamethasone and acetaminophen in those who have experienced Grade 1 or 2 infusion reaction. 10mg/kg on Day 1 of a 21-day cycle prior to docetaxel; continue until disease progression or unacceptable toxicity. Dose modifications: see full labeling.

Children: Not established.

Warnings/Precautions: Increased risk of hemorrhage; permanently discontinue if severe bleeding occurs. Control hypertension prior to initiating. Monitor blood pressure every 2 weeks or more frequently as indicated; if severe hypertension develops, temporarily suspend until medically controlled. Monitor for infusionrelated reactions during therapy. Have emergency resuscitative equipment available. Permanently discontinue if severe arterial thromboembolic events, severe uncontrolled hypertension (despite antihypertensives), hypertensive crisis or encephalopathy, Grade 3 or 4 infusion-related reactions, urine protein >3g/24hrs, nephrotic syndrome, or GI perforation occurs. Impaired wound healing: withhold Cyramza prior to surgery. Clinical deterioration in patients with Child-Pugh B or C cirrhosis (eg, new or worsening encephalopathy, ascites, hepatorenal syndrome). Discontinue if reversible posterior leukoencephalopathy syndrome develops. Monitor proteinuria by urine dipstick and/or urinary protein creatinine ratio.

Monitor thyroid function. Pregnancy: avoid. Use effective contraception during therapy and for ≥3 months after last ramucirumab dose. Nursing mothers: not recommended.

Adverse reactions: Hypertension, diarrhea, headache, fatigue, asthenia, hyponatremia, anemia, intestinal obstruction, neutropenia, epistaxis, stomatitis/mucosal inflammation, rash, decreased appetite; arterial thromboembolic events, proteinuria, GI perforation, infusionrelated reactions.

How supplied: Single-dose vial (10mL, 50mL)—1

GILOTRIF Boehringer Ingelheim

℞

Tyrosine kinase inhibitor. Afatinib 20mg, 30mg, 40mg; tabs.

Indications: First-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitutions as detected by an FDAapproved test. Limitations of use: safety and efficacy of Gilotrif have not been established in patients whose tumors have other EGFR mutations.

Adults: Take on an empty stomach at least 1 hour before or 2 hours after a meal. 40mg once daily until disease progression or not tolerated.

Concomitant P-gp inhibitors: reduce afatinib daily dose by 10mg if not tolerated; resume previous dose after discontinuing the P-gp inhibitor.

Concomitant P-gp inducers: increase afatinib by 10mg as tolerated; resume previous dose 2–3 days after discontinuing the P-gp inducer.

Dose modification: see full labeling.

Children: Not established.

Warnings/Precautions: Permanently discontinue for life-threatening bullous, blistering, or exfoliative skin lesions, confirmed interstitial lung disease, severe drug-induced hepatic impairment, persistent ulcerative keratitis, symptomatic left ventricular dysfunction, or severe/intolerable adverse reactions (at dose 20mg/day). Withhold for severe or prolonged diarrhea Grade ≥2 lasting for ≥2 consecutive days while taking antidiarrheal, prolonged cutaneous reaction Grade ≥2 (lasting >7 days) or intolerable, renal dysfunction Grade ≥2, or worsening liver function. History of keratitis, ulcerative keratitis, or severe dry eye. Monitor closely in moderate-to-severe renal impairment or severe hepatic impairment; adjust dose if not tolerated. Embryofetal toxicity: females of reproductive potential should use highly effective contraception during treatment and for at least 2 weeks after last afatinib dose. Pregnancy (Cat.D). Nursing mothers: not recommended.

Interactions: Potentiated by P-gp inhibitors (eg, ritonavir, cyclosporine A, ketoconazole, itraconazole, erythromycin, verapamil, quinidine, tacrolimus, nelfinavir, saquinavir, amiodarone).

Antagonized by P-gp inducer (eg, rifampicin, carbamazepine, phenytoin, phenobarbital, St. John’s wort).

Adverse reactions: Diarrhea, rash/dermatitis acneiform, stomatitis, paronychia, dry skin, decreased appetite, pruritus.

How supplied: Tabs—30

HYCAMTIN GlaxoSmithKline

℞

Topoisomerase inhibitor. Topotecan (as HCl) 4mg/vial; pwd for IV infusion after reconstitution and dilution; contains mannitol; preservative-free.

Indications: Small cell lung cancer sensitive disease after failure of 1st line chemotherapy.

Adults: Verify dose using BSA. Usual max dose 4mg IV. Confirm baseline neutrophils >1,500cells/mm3 and platelets >100,000cells/mm3 prior to 1st course of therapy. Give by IV infusion over 30 mins.

1.5mg/m2 daily for 5 consecutive days starting on Day 1 of a 21-day cycle. Dose adjustments, renal impairment: see full labeling.

Children: Not established. ℞ Also: HYCAMTIN CAPSULES Topotecan (as HCl) 0.25mg, 1mg; caps.

Indications: Relapsed small cell lung cancer with prior complete or partial response and at least 45 days from the end of 1st line chemotherapy.

Adults: Confirm baseline neutrophils ≥1,500cells/mm3 and platelets ≥100,000cells/mm3 prior to 1st course of therapy.

Swallow whole. 2.3mg/m2/day once daily for 5 consecutive days; repeat every 21 days. Dose adjustments, renal impairment: see full labeling.

Children: Not established.

Warnings/Precautions: Monitor peripheral blood cell counts during therapy; hold subsequent doses until neutrophils >1,000cells/mm3, platelets >100,000cells/mm3, and hemoglobin ≥9g/dL. History of interstitial lung disease,

pulmonary fibrosis, lung cancer, thoracic exposure to radiation, use of pneumotoxic drugs and/or colony stimulating factors: increased risk of interstitial lung disease; monitor, discontinue if occurs. Moderate to severe renal impairment.

Caps: severe diarrhea; may need to reduce dose.

IV: avoid extravasation. Elderly. Use effective contraception during and for ≥1 month after last dose (in females), or during and for ≥3 months (in males with female partners). Pregnancy (Cat.D).

Nursing mothers: not recommended.

Interactions: IV: Myelosuppression potentiated with platinum agents. Neutropenia potentiated

by G-CSF; administer ≥24hrs after last topotecan dose. Caps: Avoid concomitant P-glycoprotein inhibitors (eg, amiodarone, azithromycin, captopril, carvedilol, clarithromycin, conivaptan, cyclosporine, diltiazem, dronedarone, erythromycin, felodipine, itraconazole, ketoconazole, lopinavir, ritonavir, quercetin, quinidine, ranolazine, ticagrelor, verapamil) and BCRP inhibitors (eg, cyclosporine, eltrombopag).

Adverse reactions: See full labeling.

Neutropenia, leukopenia, thrombocytopenia, anemia, nausea, vomiting, diarrhea, anorexia, abdominal pain, stomatitis, headache, dyspnea, cough, pyrexia, alopecia, fatigue; infection, sepsis, interstitial lung disease, neutropenic colitis (may be fatal).

How supplied: Single-use vials—1; Caps—10

MUSTARGEN Recordati

℞

Nitrogen mustard. Mechlorethamine HCl 10mg/vial; pwd for IV or intracavitary inj after reconstitution.

Indications: Palliative treatment of bronchogenic carcinoma.

Adults: By IV infusion, per therapeutic course: 0.4mg/kg (lean body weight) as single dose or in divided doses of 0.1–0.2mg/kg per day.

See literature for intracavitary (eg, intrapleural) administration. Do not exceed recommended dose. Repeat course only after hematological recovery (eg, every 3 weeks).

Children: See literature.

Contraindications: Infectious diseases.

Warnings/Precautions: Drug is highly toxic; verify potential benefits outweigh risks; avoid inadvertent contact with powder or vapor. Do not use if foci of acute and chronic suppurative inflammation are present. Ensure adequate hydration. Avoid extravasation. Chronic lymphatic leukemia. Bone marrow suppression. Previous X-ray, cytotoxic chemotherapy. Infection.

Hemorrhagic tendency. Monitor renal, hepatic and bone marrow function. Elderly. Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended.

Adverse reactions: Bone marrow suppression, hyperheparinemia, GI upset (may be severe), anorexia, weakness, thrombosis, thrombophlebitis, hypersensitivity, jaundice, alopecia, vertigo, auditory disturbances, hemolytic anemia, skin reactions, infection, amyloidosis, hyperuricemia, gonad damage.

How supplied: Vials—4

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In EGFRm+ advanced NSCLC,

NEARLY 2 OUT OF 3 cases of progression with firstgeneration EGFR TKIs are related to the T790M mutation1,2

NEARLY 2 OUT OF 3

CASES ARE RELATED TO T790M

T790M is an acquired mutation and has been identified as the most common mechanism of acquired resistance in nearly 2 out of 3 patients with advanced NSCLC.1,2 When patients with EGFRm+ status progress, prior to changing therapy, a biopsy is reasonable to identify mechanisms of acquired resistance, as stated in NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®).3 Find out how the T790M mutation could affect the future of NSCLC at: EGFRevolution.com.

AstraZeneca is conducting ongoing research to understand the science of the T790M mutation

as a driver of resistance.

References: 1. Yu HA, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res. 2013;19: 2240-2247. 2. Arcila ME, et al. Rebiopsy of lung cancer patients with acquired resistance to EGFR inhibitors and enhanced detection of the T790M mutation using a locked nucleic acid-based assay.

Clin Cancer Res. 2011;17:1169-1180. 3. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.7.2015. ©National Comprehensive Cancer Network, Inc. 2015. All rights reserved. Accessed June 12, 2015. To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. ©2015 AstraZeneca. All rights reserved. 3140405 6/15

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DRUG MONOGRAPHS

LUNG CANCER NAVELBINE Pierre Fabre

℞

Antimicrotubule agent. Vinorelbine (as tartrate) 10mg/mL; soln for IV inj after dilution; preservative-free.

Indications: First-line treatment of ambulatory patients with unresectable, advanced non-small cell lung cancer (NSCLC), as a single agent or in combination with cisplatin. In Stage III NSCLC, use in combination with cisplatin.

Adults: See literature. Give by IV inj over 6–10 minutes. Monotherapy: 30mg/m2 once weekly.

Combination therapy: 25mg/m2 once weekly with cisplatin given every 4 weeks; or 30mg/m2 once weekly with cisplatin given on Days 1 and 29, then every 6 weeks. Dose adjustment for toxicities, hepatic impairment: see literature.

Children: Not recommended.

Contraindications: Pretreatment granulocyte counts <1000 cells/mm3.

Warnings/Precautions: IV use only; fatal if given intrathecally. Discontinue if neurotoxicity ≥grade 2.

Pre-existing pulmonary dysfunction or neuropathy.

Prior irradiation or chemotherapy. Cardiovascular disease. Monitor for myelosuppression, infection, and/or fever; obtain CBCs with differentials prior to each dose. Avoid contamination of the eyes or injecting into an extremity with poor circulation (thrombosis possible). Hepatic injury or impairment. Avoid extravasation. Pregnancy (Cat.D), nursing mothers: not recommended.

Interactions: May be potentiated by CYP3A inhibitors. Acute pulmonary reactions possible with mitomycin. Increased risk of granulocytopenia with cisplatin. May increase risk of neurotoxicity with paclitaxel. Prior or concomitant radiation therapy; may result in radiosensitizing effects.

Adverse reactions: Myelosuppression (esp. granulocytopenia), inj site reactions, elevated liver enzymes, chest pain, fatigue, GI upset, alopecia, jaw pain, myalgia, arthralgia, rash, severe constipation, paralytic ileus, intestinal obstruction, necrosis, and/or perforation; dyspnea, severe bronchospasm.

How supplied: Single-use vial (1mL, 5mL)—1

OPDIVO Bristol-Myers Squibb

℞

Human programmed death receptor-1 (PD-1)blocking antibody. Nivolumab 10mg/mL; per vial; soln for IV infusion after dilution; preservativefree; contains mannitol.

Indications: Metastatic squamous non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy.

Adults: Give as IV infusion over 60 minutes.

3mg/kg every 2 weeks until disease progression or unacceptable toxicity. Dose modifications: see full labeling.

Children: Not established.

Warnings/Precautions: See full labeling.

Monitor for any immune-mediated adverse reactions; withhold dose and give corticosteroids (at 1–2mg/kg/day prednisone equivalents) based on severity of event. Permanently discontinue for

any life-threatening or Grade 4 adverse reaction, Grade 3 or 4 pneumonitis, Grade 4 colitis, AST/ALT >5×ULN or total bilirubin >3×ULN, SCr >6×ULN, recurring severe or Grade 3 adverse reaction, inability to reduce prednisone dose to ≤10mg/day (or equivalent) within 12 weeks, or failure to recover to Grade 0–1 within 12 weeks after last dose. Grade 2 pneumonitis, Grade 2 or 3 colitis, AST/ALT >3–5×ULN or total bilirubin >1.5–3×ULN, SCr >1.5–6×ULN or >1.5X baseline, other severe or Grade 3 adverse reactions; withhold dose, give corticosteroids, and when recovered to Grade 0–1 or resolved, consider re-initiation.

Monitor for abnormal liver tests, elevated serum creatinine, and thyroid function prior to and during treatment; give replacement therapy for hypothyroidism. Pregnancy: avoid. Use effective contraception during and for ≥5 months after last dose. Lactation: discontinue nursing.

Adverse reactions: Fatigue, dyspnea, musculoskeletal pain, decreased appetite, cough, nausea, constipation; any immune-mediated reactions.

How supplied: Single-use vial (4mL, 10mL)—1

TARCEVA Astellas and Genentech

℞

Kinase inhibitor. Erlotinib (as HCl) 25mg, 100mg, 150mg; tabs.

Indications: First-line treatment in patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test. Maintenance treatment of patients with locally advanced or metastatic NSCLC whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. Treatment of locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen. Limitations of use: Do not use in combination with platinumbased chemotherapy. Not evaluated as first-line treatment in patients with metastatic NSCLC whose tumors have EGFR mutations other than exon 19 deletions or exon 21 (L858R) substitution.

Adults: Take on empty stomach. 150mg once daily. Use until disease progression or unacceptable toxicity occurs. Diarrhea unresponsive to loperamide, severe skin reactions, strong CYP3A4 inhibitors (see Interactions), hepatic impairment: reduce in 50mg decrements.

Concomitant CYP3A4 inducers (see Interactions): increase in 50mg increments at 2-week intervals; max 450mg (see full labeling). Concurrent cigarette smoking: increase in 50mg increments at 2-week intervals; max 300mg (see full labeling); upon cessation, reduce to 150mg or 100mg daily.

Children: Not established.

Warnings/Precautions: Discontinue if interstitial lung disease, severe hepatic toxicity, GI perforation, severe bullous, blistering or exfoliating skin conditions, or corneal perforation or severe ulceration occurs. Withhold or consider discontinuing therapy if severe renal failure due to dehydration, or acute/worsening ocular disorders

occur. Monitor LFTs periodically; withhold in patients without history of hepatic impairment for total bilirubin >3×ULN or transaminases >5×ULN, or in patients with history of hepatic impairment or biliary obstruction for doubling of bilirubin or tripling of transaminases over baseline. Discontinue if abnormal LFTs do not improve or resolve within 3 weeks. Withhold for persistent severe diarrhea unresponsive to loperamide, severe rash, or grade 3–4 keratitis. Monitor renal function, serum electrolytes, pulmonary function, INR, prothrombin time. History of peptic ulcers or diverticular disease.

Pregnancy (Cat.D); use effective contraception during therapy and at least 2 weeks after the last dose. Nursing mothers: not recommended.

Interactions: Potentiated by CYP3A4 inhibitors (eg, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, voriconazole, grapefruit) and CYP1A2 inhibitors (eg, ciprofloxacin); avoid if possible. Plasma levels decreased by CYP3A4 inducers (eg, rifampin, rifabutin, rifapentine, phenytoin, carbamazepine, phenobarbital, St. John’s wort), proton pump inhibitors or H2 blockers (take erlotinib 10hrs after and at least 2hrs before next dose), and smoking; avoid if possible. Increased risk of GI perforation with concomitant anti-angiogenic agents, steroids, NSAIDs, taxane-based chemotherapy. Monitor for bleeding with oral anticoagulants, NSAIDs. Adverse reactions: Rash, diarrhea, nausea, vomiting, anorexia, fatigue, elevated LFTs, unexplained pulmonary symptoms (eg, dyspnea, cough, fever; discontinue and follow-up if occurs), stomatitis, infection; rare: GI perforation (may be fatal), ocular disorders (eg, conjunctivitis, keratitis, corneal ulceration/perforation), MI/ ischemia, hemolytic anemia, cerebrovascular accidents, interstitial lung disease; hepatic or renal failure and hepatorenal syndrome (may be fatal); bullous, blistering and exfoliative skin conditions (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis).

Testing considerations: K-RAS mutation analysis, EGFR amplification analysis How supplied: Tabs—30

TREXALL Teva

℞

Folic acid antagonist. Methotrexate sodium 5mg, 7.5mg, 10mg, 15mg; scored tabs. ℞ Also: Methotrexate injection Bedford Methotrexate 25mg/mL; soln for IV, IM, intraarterial, or intrathecal administration after dilution; preservative-free. ℞ Also: Methotrexate for injection Bedford Methotrexate 1g/vial; pwd for IV, IM, intra-arterial, or intrathecal administration after dilution; preservative-free.

Indications: Lung cancer (squamous cell and small cell types).

Adults: See literature.

Children: Not established.

Contraindications: Pregnancy (Cat.X). Nursing mothers.

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DRUG MONOGRAPHS

LUNG CANCER Warnings/Precautions: Be fully familiar with this drug’s toxicity before use. Discontinue if malignant lymphomas occur. Obtain baseline and monitor CBCs with differential, platelet counts, chest X-ray, and hepatic, renal and pulmonary function. During therapy monitor hematology monthly, renal and hepatic function every 1–2 months, more often if increasing dose or predisposed to toxicity (eg, dehydration).

Discontinue immediately if blood counts drop significantly. Rule out pregnancy in women of childbearing potential; use effective contraception during therapy and for at least 1 ovulatory cycle afterwards for women and for at least 3 months afterwards for men. Interrupt therapy if vomiting, diarrhea, stomatitis, or pulmonary symptoms occur. Hepatic or renal impairment. Obesity.

Diabetes. Peptic ulcer. Ulcerative colitis. Infection.

Dehydration. Folate deficiency. Ascites, pleural effusions: evacuate fluid, monitor for toxicity and reduce dose or discontinue if needed. Elderly (use low doses and monitor closely). Debilitated.

Interactions: Avoid live virus vaccines. Toxicity increased by NSAIDs, salicylates, phenytoin, sulfonylureas, sulfonamides, probenecid, folic acid antagonists. May be potentiated by penicillins (monitor), tetracyclines, chloramphenicol, nonabsorbable broad spectrum antibiotics. May be antagonized by folic acid. May potentiate theophylline, mercaptopurine. Increased risk of soft tissue necrosis and osteonecrosis with radiotherapy. Caution with other hepatotoxic drugs (eg, azathioprine, retinoids, sulfasalazine) and nephrotoxic agents (eg, cisplatin).

Adverse reactions: Ulcerative stomatitis, leukopenia, nausea, GI upset, malaise, fatigue, chills, fever, dizziness, infection, myelosuppression, hepatotoxicity, renal toxicity, CNS toxicity, seizures (esp in children); interstitial pneumonitis, tumor lysis syndrome, skin reactions (may be fatal; eg, toxic epidermal necrolysis, Stevens-Johnson syndrome).

How supplied: Tabs—30; soln (2mL, 4mL, 8mL, 10mL)—10 (single-use vials); pwd (1 gram)—1 (single-use vial)

XALKORI Pfizer

℞

Tyrosine kinase inhibitor. Crizotinib 200mg, 250mg; hard gel caps.

Indications: Treatment of metastatic non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test.

Adults: Swallow whole. 250mg twice daily until disease progression or intolerance. Dose modification and/or dose reduction to 200mg twice daily may be required based on Grade 3 or 4 severity, then to 250mg once daily, or

permanently discontinue if intolerable. Severe renal impairment (CrCl <30mL/min) not requiring dialysis: 250mg once daily. Dose reduction for hematologic and non-hematologic toxicities: see full labeling.

Children: Not established.

Warnings/Precautions: Confirm ALK-positive NSCLC with an FDA-approved test before treating. Monitor ALT and total bilirubin every 2 weeks during first 2 months, then monthly, and more frequently for elevated transaminases; temporarily suspend, reduce dose, or permanently discontinue as clinically indicated.

Monitor CBCs with differential monthly and more frequently if Grade 3 or 4 abnormalities, fever or infection occurs. Risk of severe pneumonitis: monitor for pulmonary symptoms; permanently discontinue if occurs. Congenital long QT syndrome; avoid. History of or predisposition for QTc prolongation (eg, CHF, bradyarrhythmias, electrolyte abnormalities, concomitant drugs that prolong QT interval): consider monitoring ECG, electrolytes periodically. Torsade de pointes, ventricular tachycardia, serious arrhythmia: permanently discontinue if QTc >500ms or ≥60ms change from baseline. Monitor HR and BP regularly; discontinue if life-threatening bradycardia occurs. Hepatic impairment. Severe renal impairment. Pregnancy (Cat.D); avoid. Use adequate contraception during therapy and at least 90 days after completion. Nursing mothers: not recommended.

Interactions: Avoid concomitant strong CYP3A inhibitors (eg, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, voriconazole), grapefruit juice, or strong CYP3A inducers (eg, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, St. John’s Wort). Avoid concomitant CYP3A substrates with narrow therapeutic indices (eg, alfentanil, cyclosporine, ergots, fentanyl, pimozide, quinidine, sirolimus, tacrolimus); if needed, reduce doses. Avoid concomitant agents known to cause bradycardia (eg, beta-blockers, non-dihydropyridine calcium channel blockers, clonidine, digoxin); adjust dose or discontinue.

Caution with moderate CYP3A inhibitors. Dose reduction may be needed with coadministered drugs metabolized by CYP3A. Adverse reactions: Vision disorder, nausea, diarrhea, vomiting, constipation, edema, fatigue, Grade 3–4 events: ALT increased, neutropenia; elevated total bilirubin, pneumonitis (may be fatal), QT prolongation, bradycardia, hepatotoxicity (may be fatal).

How supplied: Caps—60

ZYKADIA Novartis

℞

Tyrosine kinase inhibitor. Ceritinib 150mg; hard gel caps.

Indications: Treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib. Not established for improvement in survival or disease-related symptoms.

Adults: Take on an empty stomach (at least 2 hours before or after a meal). 750mg once daily until disease progression or unacceptable toxicity.

Discontinue if 300mg once daily not tolerated.

Moderate-to-severe hepatic impairment: not established. Dose modifications: see full labeling.

Children: Not established.

Warnings/Precautions: Monitor for severe or persistent GI toxicity; if occurs, withhold until improved; resume at reduced dose. Monitor ALT/AST and total bilirubin once monthly, and more frequently if elevated transaminases develop; withhold then reduce dose, or permanently discontinue as clinically indicated. Congenital long QT syndrome; avoid. CHF, bradyarrhythmias, electrolyte abnormalities; monitor ECG, electrolytes periodically. Permanently discontinue if QTc prolongation in combination with Torsade de pointes or polymorphic ventricular tachycardia or serious arrhythmia develop. Monitor HR and BP regularly; serum glucose and pulmonary symptoms as clinically indicated. Permanently discontinue if treatment-related interstitial lung disease (ILD)/pneumonitis, uncontrolled hyperglycemia, or life-threatening bradycardia occur. Pregnancy (Cat.D). Females of reproductive potential should use effective contraception during treatment and for at least 2 weeks after completion. Nursing mothers: not recommended.

Interactions: Avoid concomitant strong CYP3A4 inhibitors (eg, ritonavir, macrolides, ketoconazole, nefazodone), grapefruit juice; if unavoidable, reduce ceritinib dose by 1/3. Avoid concomitant strong CYP3A4 inducers (eg, carbamazepine, phenytoin, rifampin, St. John’s Wort). Avoid concomitant CYP3A substrates (eg, alfentanil, cyclosporine, ergots, fentanyl, pimozide, quinidine, sirolimus, tacrolimus) or CYP2C9 substrates (eg, phenytoin, warfarin) with narrow therapeutic indices; if unavoidable, reduce doses of these drugs. Avoid concomitant agents known to cause bradycardia (eg, beta-blockers, non-dihydropyridine CCBs, clonidine, digoxin).

Adverse reactions: Diarrhea, nausea, vomiting, abdominal pain, constipation, elevated transaminases, fatigue, decreased appetite; bradycardia, hepatotoxicity, ILD/pneumonitis, QTc prolongation, hyperglycemia.

How supplied: Caps—70

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DRUG MONOGRAPHS

SARCOMA DOXIL Janssen Biotech

℞

Anthracycline. Doxorubicin HCl (liposomal) 2mg/mL; dispersion for IV infusion after dilution; preservative-free.

Indications: AIDS-related Kaposi’s sarcoma refractory to combination chemotherapy.

Adults: Give by IV infusion at initial rate of 1mg/min; may increase rate to complete infusion over 1hr if no infusion reactions occur; may premedicate with antiemetics. 20mg/m2 once every 3 weeks. Hepatic dysfunction (serum bilirubin ≥1.2mg/dL), hand-foot syndrome, hematologic toxicity (esp. ANC, platelets), or stomatitis: reduce dose. Consider total anthracycline and anthracenedione doses and irradiation when calculating total cumulative dose. See full labeling.

Children: Not established.

Warnings/Precautions: Not substitutable on a mg/mg basis with other doxorubicin products.

Cardiotoxicity, acute infusion-related reactions, myelosuppression may occur. Have resuscitative/ antiallergic equipment and expertise available.

Hepatic impairment. Monitor blood (esp. CBC + platelets), hepatic (esp. SGOT/SGPT, alkaline phosphatase), and cardiac function (esp. myocardial biopsy). Monitor periodically for secondary oral cancers with long-term use. Avoid extravasation. Pregnancy (Cat.D); avoid. Nursing mothers: not recommended.

Interactions: Caution with cyclosporine, phenobarbital, phenytoin, streptozocin, digoxin, myelosuppressants, others. Previous mediastinal irradiation, cyclophosphamide, other cardiotoxic drugs: monitor for cardiotoxicity and hepatotoxicity.

Adverse reactions: Asthenia, fatigue, fever, anorexia, nausea, vomiting, stomatitis, diarrhea,

constipation, hand and foot syndrome, rash, neutropenia, thrombocytopenia, anemia; infusion reactions, cardiovascular events (eg, cardiomyopathy, CHF, acute LV failure), recall of skin reaction from prior radiation therapy, toxoplasmosis, urine discoloration (red/orange).

How supplied: Single-use vials (10mL, 25mL)—1

INTRON A Merck

℞

Interferon alfa-2b, recombinant; 10 million, 18 million, or 50 million IU per vial; pwd; for inj after reconstitution/dilution; preservative-free. ℞ Also: INTRON A SOLN Interferon alfa-2b, recombinant; 10 million IU, 18 million IU, 25 million IU; per vial; for inj; contains m-cresol.

Indications: AIDS-related Kaposi’s sarcoma.

Adults: Use appropriate preparation and route: see literature. Use SC route if platelets <50,000/mm3. 30 million IU/m2 IM or SC three times weekly; continue until rapid disease progression or maximal response achieved after 16 weeks; reduce dose by ½ or suspend therapy if severe adverse reactions occur; discontinue if persists.

Children: Not recommended.

Contraindications: Hepatitis: decompensated liver disease. Autoimmune disorders.

Warnings/Precautions: May cause or exacerbate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, or infectious disorders: monitor closely, discontinue if they worsen. Severe psychiatric disorders (esp. depression). Cardiovascular or pulmonary disease.

Severe myelosuppression. Uncontrolled thyroid abnormalities. Diabetes. Coagulation disorders.

Maintain adequate hydration. Monitor blood, thyroid, visual and liver function before and during

therapy; EKG in cardiovascular disease and cancer patients. Psoriasis. Renal dysfunction. Transplant recipients. Elderly. Debilitated. Pregnancy (Cat.C).

Nursing mothers: not recommended.

Interactions: Caution with myelosuppressives, and drugs that can exacerbate depression. May potentiate theophylline (may double its levels).

Adverse reactions: Flu-like symptoms (fever, headache, myalgia, fatigue); hepatic, hematologic, respiratory, skin, genitourinary system, CNS, cardiovascular, endocrine (esp thyroid), GI, or visual disorders; colitis, hypertriglyceridemia, pancreatitis, infections, injection site reactions; others (see literature).

How supplied: Pwd (w. diluent): 10million, 18million, 50million IU/vial—1; Soln (vials): 10million IU/vial—6 (kit w. supplies); Soln (multidose vials): 18million, 25million IU/vial—1

PANRETIN Eisai

℞

Retinoid. Alitretinoin 0.1%; gel.

Indications: Cutaneous lesions of AIDS-related Kaposi’s sarcoma (KS).

Adults: Apply twice daily to lesions (avoid mucous membranes and normal skin); do not occlude; may increase to 3-4 times daily as tolerated. Reduce frequency or suspend treatment if local toxicity occurs.

Children: Not recommended.

Warnings/Precautions: Not for use when systemic KS therapy required. Avoid sun, UV light.

Flammable. Pregnancy (Cat.D), nursing mothers: not recommended.

Interactions: Increases DEET toxicity (avoid).

Adverse reactions: Photosensitivity, rash, pruritus, pain, exfoliative dermatitis, paresthesia, edema.

How supplied: Gel—60g

FDA PREGNANCY CATEGORIES When pregnancy appears as a contraindication or precaution to the use of a drug, it is usually qualified by a category as assigned by the FDA.

A: Adequate and well-controlled studies in pregnant women have failed to show a risk to the fetus in the first trimester of pregnancy and there is no evidence of risk in later trimesters.

B: Animal studies have failed to show a risk to the fetus and there are no adequate and well-controlled studies in pregnant women; or animal studies have shown an adverse effect but adequate and wellcontrolled studies in pregnant women have failed to demonstrate a risk to the fetus during the first trimester of pregnancy and there is no evidence of a risk in later trimesters.

C: Animal studies have shown an adverse effect on the fetus, there are no adequate and well-controlled studies in humans, and the potential benefits may outweigh the risks; or there are no animal studies and no adequate and well-controlled studies in humans.

D: Positive evidence of human fetal risk but the benefits may outweigh the risks.

X: Animal or human studies have shown fetal abnormalities or toxicity, or both, and the risks clearly outweigh any possible benefits.

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DRUG MONOGRAPHS

SKIN CANCER EFUDEX Valeant

℞

Antimetabolite. Fluorouracil 2%, 5%; soln. ℞ Also: EFUDEX CREAM Fluorouracil 5%.

Indications: Multiple actinic or solar keratoses.

Superficial basal cell carcinoma when conventional therapy is impractical (5% only); see literature.

Adults: Keratoses: Apply twice daily until erosion occurs (usually 2–4 wks). Basal cell carcinoma (5% only): Apply twice daily, usually for 3–6 weeks (obliteration may take 10–12 weeks).

Children: Not recommended.

Contraindications: Dihydropyrimidine dehydrogenase (DPD) deficiency. Pregnancy (Cat.X).

Warnings/Precautions: Apply cautiously near eyes, nose, mouth. Avoid mucous membranes, occlusion, ulcerated/inflamed skin, exposure to UV light. Wash hands after application if fingers were used. Notify patients of expected skin reaction. Biopsy unresponsive lesions. Nursing mothers: not recommended.

Adverse reactions: Pain or burning at application site, pruritus, irritation, hyperpigmentation.

How supplied: Soln—10mL (w. drop dispenser); Crm—25g

ERIVEDGE Genentech

℞

Hedgehog pathway inhibitor. Vismodegib 150mg; caps.

Indications: Treatment of adults with metastatic basal cell carcinoma, or locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation.

Adults: Swallow whole. 150mg once daily, until disease progression or unacceptable toxicity.

Children: Not established.

Warnings/Precautions: Risk of embryo-fetal death and severe birth defects in pregnant women. Verify pregnancy status within 7 days prior to initiation of therapy. Counsel patients (males and females) on the need for contraception during and after treatment. Advise patients not to donate blood or blood products while on therapy and for 7 months after last dose. Advise male patients not to donate semen during and for 3 months after final dose. Nursing mothers: not recommended during and for 7 months after final dose.

Interactions: May be potentiated by P-gp inhibitors (eg, clarithromycin, erythromycin,

azithromycin). May be antagonized by drugs that affect gastric pH (eg, proton pump inhibitors, H2-receptor antagonists, antacids).

Adverse reactions: Muscle spasms, alopecia, dysgeusia, weight loss, fatigue, GI upset, decreased appetite, constipation, arthralgias, ageusia; amenorrhea.

Note: Report immediately exposure to Erivedge during pregnancy by contacting the Genentech Adverse Event Line at (888) 835-2555.

How supplied: Caps—28

GLEEVEC Novartis

℞

Kinase inhibitor. Imatinib (as mesylate) 100mg, 400mg; scored tabs.

Indications: Adults with aggressive systemic mastocytosis (ASM) without the D816V c-Kit mutation or with c-Kit mutational status unknown. Adults with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans (DFSP).

Adults: Take with food and water. May disperse tab in water or apple juice and take promptly. ≥18yrs: ASM without D816V c-Kit mutation or status unknown: 400mg once daily. ASM associated with eosinophilia: initially 100mg once daily; may increase to 400mg once daily if insufficient response. If severe non-hematologic reactions develop: interrupt dose; resume at a lower dose in hepatic dysfunction. Severe hepatic impairment: reduce dose by 25%. Renal or hematologic reactions: see full labeling.

Avoid concomitant strong CYP3A4 inducers (eg, rifampin): if needed, increase imatinib dose by at least 50%.

Children: Not recommended.

Warnings/Precautions: Hepatic or renal impairment. Monitor weight and for fluid retention regularly; CBCs weekly for 1st month, bi-weekly for 2nd month, then periodically (eg, every 2–3 months); liver function at baseline then monthly or as needed; GI symptoms at baseline. Cardiovascular disease or risk factors; monitor. Immunosuppression and potential toxicities (liver, kidney, cardiac) from long-term use. Monitor for tumor lysis syndrome; correct clinically significant dehydration and treat high uric acid levels before initiating therapy.

Monitor growth in children. Possible cardiogenic shock/LV dysfunction in conditions with high eosinophil levels (eg, HES/CEL, MDS/MPD, ASM); consider concomitant systemic steroid prophylaxis (1–2mg/kg) for 1 or 2 wks if abnormal ECG or serum troponin. Monitor TSH levels in thyroidectomy patients undergoing levothyroxine replacement. Pregnancy (Cat.D);

avoid. Use highly effective contraception during treatment. Nursing mothers: not recommended.

Interactions: Avoid grapefruit juice.

Potentiated by CYP3A4 inhibitors (eg, azole antifungals, protease inhibitors, nefazodone, clarithromycin, telithromycin). Antagonized by strong CYP3A4 inducers (eg, dexamethasone, fosphenytoin, phenytoin, phenobarbital, carbamazepine, oxcarbamazepine, primidone, St. John’s wort, rifampin, rifabutin, rifampicin); consider alternatives. May potentiate drugs metabolized by CYP3A4 (eg, benzodiazepines, dihydropyridine calcium channel blockers, cyclosporine, ergots, alfentanil, fentanyl, pimozide, quinidine, certain statins, sirolimus, tacrolimus), CYP2D6, or CYP2C9 (use heparin instead of warfarin).

Adverse reactions: Edema (may be severe), nausea, vomiting, musculoskeletal pain, diarrhea, muscle cramps, rash (may be severe; eg, erythema multiforme, Stevens-Johnson syndrome), fatigue, abdominal pain, dizziness, blurred vision, somnolence, fever, headache, cough, arthralgia/myalgia, dyspnea, hypokalemia, night sweats, anorexia, pruritus, hemorrhage, anemia, neutropenia, thrombocytopenia, weight gain, renal or hepatotoxicity, immunosuppression, hypothyroidism; rare: severe CHF, LV dysfunction.

How supplied: 100mg—90; 400mg—30

HYDREA Bristol-Myers Squibb

℞

Substituted urea. Hydroxyurea 500mg; caps.

Indications: Melanoma.

Adults: See literature. Intermittant therapy for solid tumors: 80mg/kg as single dose every 3rd day. Continuous therapy for solid tumors: 20–30mg/kg/day as single dose. Renal impairment: reduce dose.

Children: Not recommended.

Contraindications: Marked bone marrow depression.

Warnings/Precautions: Previous irradiation therapy or chemotherapy. Correct anemia before starting. Monitor hematologic, renal, hepatic function before and during treatment. Marked renal dysfunction. Myeloproliferative disorders; discontinue if cutaneous vasculitic ulcerations develop and use alternative agents. Elderly.

Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended.

Interactions: Avoid concomitant didanosine, with or without stavudine, or other antiretrovirals (may cause pancreatitis [monitor], fatal

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DRUG MONOGRAPHS

SKIN CANCER hepatotoxicity, peripheral neuropathy).

Myelosuppressives potentiate antineoplastic effect. May antagonize antigout agents. Increased risk of vasculitic toxicities with interferon therapy.

May cause falsely elevated urease, uricase, lactate dehydrogenase.

Adverse reactions: Leukopenia, anemia, erythrocytic abnormalities, thrombocytopenia, GI upset, rash, erythema, fever, CNS effects, temporary renal impairment, acute pulmonary reactions, secondary leukemias, skin cancer.

Note: Wear disposable gloves when handling caps or bottle.

How supplied: Caps—100

INTRON A Merck

℞

Interferon alfa-2b, recombinant; 10 million, 18 million, or 50 million IU per vial; pwd; for inj after reconstitution/dilution; preservative-free. ℞ Also: INTRON A SOLN Interferon alfa-2b, recombinant; 10 million IU, 18 million IU, 25 million IU; per vial; for inj; contains m-cresol.

Indications: Malignant melanoma.

Adults: Induction: 20million IU/m2 IV over 20 mins, 5 consecutive days per week, for 4 weeks. Maintenance: 10 million IU/m2 SC 3 times per week for 48 weeks. See literature for appropriate preparation and route and for dose adjustments.

Children: Not recommended.

Contraindications: Hepatitis: decompensated liver disease. Autoimmune disorders.

Warnings/Precautions: May cause or exacerbate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, or infectious disorders: monitor closely, discontinue if they worsen. Severe psychiatric disorders (esp. depression). Cardiovascular or pulmonary disease. Severe myelosuppression. Uncontrolled thyroid abnormalities. Diabetes. Coagulation disorders. Maintain adequate hydration. Monitor blood, thyroid, visual and liver function before and during therapy; EKG in cardiovascular disease and cancer patients. Psoriasis. Renal dysfunction. Transplant recipients. Elderly.

Debilitated. Pregnancy (Cat.C). Nursing mothers: not recommended.

Interactions: Caution with myelosuppressives, and drugs that can exacerbate depression.

May potentiate theophylline (may double its levels).

Adverse reactions: Flu-like symptoms (fever, headache, myalgia, fatigue); hepatic, hematologic, respiratory, skin, genitourinary system, CNS, cardiovascular, endocrine (esp thyroid), GI, or visual disorders; colitis, hypertriglyceridemia, pancreatitis, infections, injection site reactions; others (see literature).

How supplied: Pwd (w. diluent): 10million, 18million, 50million IU/vial—1; Soln (vials): 10million IU/vial—6 (kit w. supplies); Soln (multidose vials): 18million, 25million IU/vial—1

KEYTRUDA Merck

℞

Human programmed death receptor-1 (PD-1)blocking antibody. Pembrolizumab 50mg; per vial; lyophilized pwd for IV infusion after reconstitution; preservative-free.

Indications: Treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor.

Adults: Give as IV infusion over 30mins.

2mg/kg every 3 weeks until disease progression or unacceptable toxicity. Dose modifications: see full labeling. Administer corticosteroids for most Grade ≥2 related immune-mediated reactions.

Children: Not established.

Warnings/Precautions: Monitor for signs/ symptoms of pneumonitis; withhold dose if Grade 2 pneumonitis; permanently discontinue if Grade 3 or 4 develops. Monitor for signs/ symptoms of colitis; withhold dose if Grade 2 or 3 colitis; permanently discontinue if Grade 4 develops. Monitor for changes in liver function; withhold dose or discontinue based on severity of elevated liver enzymes. Monitor for hypophysitis; withhold dose if Grade 2 hypophysitis; withhold or discontinue if Grade 3; permanently discontinue if Grade 4 develops. Monitor for changes in renal function; withhold dose if Grade 2 nephritis; permanently discontinue if Grade 3 or 4 develops. Monitor thyroid function at treatment initiation, during, and as clinically indicated; withhold if Grade 3 hyperthyroidism; permanently discontinue if Grade 4 develops. Permanently discontinue if any severe or Grade 3 immune-mediated adverse reaction that recurs and for any lifethreatening immune-mediated adverse reaction.

Use highly effective contraception during treatment and for at least 4 months after the last dose. Pregnancy (Cat.D), nursing mothers: not recommended.

Adverse reactions: Fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, arthralgia, diarrhea, sepsis; renal failure, dyspnea, pneumonia, cellulitis.

How supplied: Single-use vial—1

MEKINIST GlaxoSmithKline

℞

Kinase inhibitor. Trametinib 0.5mg, 1mg, 2mg; tabs.

Indications: As monotherapy or in combination with dabrafenib for the treatment of unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDAapproved test. Limitation of use: as a single agent is not indicated for the treatment of patients who have received prior BRAF-inhibitor therapy.

Adults: Confirm presence of BRAF V600E or V600K mutation prior to initiation. Take at least 1hr before or 2hrs after a meal. Monotherapy or in combination with dabrafenib: 2mg once daily; continue until disease progression or

unacceptable toxicity occurs. In combination therapy: take at same time each day either with the AM or PM dose of dabrafenib. Dose modifications: see full labeling.

Children: Not established.

Warnings/Precautions: See full labeling for dabrafenib prior to starting combination therapy. Risk of cardiomyopathy; assess LVEF prior to initiation, after one month, and then at every 2–3 month intervals during treatment; withhold if absolute LVEF decreases by 10% from pre-treatment values and is less than the lower limit of normal; permanently discontinue if symptomatic cardiomyopathy or persistent asymptomatic LVEF dysfunction is unresolved within 4 weeks. Perform eye exam at any time for visual disturbances and compare to baseline.

Retinal pigment epithelial detachment; withhold if diagnosed; if resolved within 3 weeks, may resume at reduced dose. Withhold if new or progressive pulmonary symptoms or findings develop. Permanently discontinue if retinal vein occlusion, interstitial lung disease, or pneumonitis occurs. Monitor for skin toxicities and secondary infections. Embryo-fetal toxicity. Females of reproductive potential should use highly effective contraception during and for 4 months after treatment. Pregnancy (Cat.D). Nursing mothers: not recommended.

Adverse reactions: Rash, diarrhea, lymphedema; combination with dabrafenib: pyrexia, chills, fatigue, rash, nausea, vomiting, constipation, abdominal pain, peripheral edema, cough, headache, arthralgia, night sweats, decreased appetite, myalgia; hemorrhage, thromboembolic events.

How supplied: Tabs—30

OPDIVO Bristol-Myers Squibb

℞

Human programmed death receptor-1 (PD-1)blocking antibody. Nivolumab 10mg/mL; per vial; soln for IV infusion after dilution; preservativefree; contains mannitol.

Indications: Unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor.

Adults: Give as IV infusion over 60 minutes.

3mg/kg every 2 weeks until disease progression or unacceptable toxicity. Dose modifications: see full labeling.

Children: Not established.

Warnings/Precautions: See full labeling.

Monitor for any immune-mediated adverse reactions; withhold dose and give corticosteroids (at 1–2mg/kg/day prednisone equivalents) based on severity of event. Permanently discontinue for any life-threatening or Grade 4 adverse reaction, Grade 3 or 4 pneumonitis, Grade 4 colitis, AST/ALT >5×ULN or total bilirubin >3×ULN, SCr >6×ULN, recurring severe or Grade 3 adverse reaction, inability to reduce prednisone dose to ≤10mg/day (or equivalent) within 12 weeks, or failure to recover to Grade 0–1 within 12 weeks

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DRUG MONOGRAPHS

SKIN CANCER after last dose. Grade 2 pneumonitis, Grade 2 or 3 colitis, AST/ALT >3–5×ULN or total bilirubin >1.5–3×ULN, SCr >1.5–6×ULN or >1.5X baseline, other severe or Grade 3 adverse reactions; withhold dose, give corticosteroids, and when recovered to Grade 0–1 or resolved, consider re-initiation. Monitor for abnormal liver tests, elevated serum creatinine, and thyroid function prior to and during treatment; give replacement therapy for hypothyroidism. Pregnancy: avoid.

Use effective contraception during and for ≥5 months after last dose. Lactation: discontinue nursing.

Adverse reactions: Rash, pruritus; any immunemediated reactions.

How supplied: Single-use vial (4mL, 10mL)—1

PROLEUKIN Prometheus

℞

Interleukin-2, recombinant. Aldesleukin 22 million IU/vial; pwd for IV infusion after reconstitution and dilution; contains mannitol; preservative-free.

Indications: Metastatic melanoma.

Adults: ≥18yrs: 600,000 IU/kg (0.037mg/kg) every 8 hours by IV infusion over 15 minutes for a max of 14 doses, followed by 9 days rest, then repeat for another 14 doses (max 28 doses/ course), as tolerated. Retreatment and dose adjustments: see literature.

Children: <18yrs: not established.

Contraindications: Abnormal thallium stress test or pulmonary function tests. Organ allografts.

Previous drug related toxicity (eg, sustained ventricular tachycardia [≥5 beats], uncontrolled or unresponsive arrhythmias, chest pain with ECG changes consistent with angina, or MI, cardiac tamponade, intubation >72hrs, renal failure requiring dialysis >72hrs, coma or toxic psychosis >48hrs, repetitive or difficult seizures, bowel ischemia or perforation, GI bleeding requiring surgery).

Warnings/Precautions: See literature.

History of cardiac or pulmonary disease. Renal, hepatic, or CNS impairment. Seizure disorder.

Bacterial infections (treat prior to starting therapy; esp. patients with indwelling central lines). Withhold dose if organ perfusion is not maintained, urine output is reduced, systolic BP <90mmHg, CHF, cardiac ischemia or arrhythmias occur; or if moderate-to-severe lethargy or somnolence (continuing may result in coma) develops. Evaluate and treat CNS metastases; obtain negative scan before starting treatment.

Do thallium stress test; monitor vital signs, weight, fluid intake and output daily. Correct hypovolemia or fluid accumulations if occur.

Obtain CBCs, differential and platelets, blood

chemistries (electrolytes, renal and hepatic function tests), chest X-rays, serum creatinine (should be ≤1.5mg/dL before starting therapy), pulmonary function tests, arterial blood gases.

Monitor for capillary leak syndrome, mental status changes, thyroid changes, diabetes onset.

Elderly. Pregnancy (Cat.C). Nursing mothers: not recommended.

Interactions: Psychotropics may increase CNS toxicity. Increased toxicity with other nephrotoxic, hepatotoxic, myelotoxic, or cardiotoxic drugs. Hypersensitivity reactions with other antineoplastics. Myocardial injury and rhabdomyolysis risk increased with interferonalfa. Antagonized by glucocorticoids (avoid). β-blockers and other antihypertensives may potentiate hypotension. Delayed reactions to iodinated contrast media. May increase risk of allograft rejection.

Adverse reactions: Hypotension, GI upset, oliguria, flu-like syndrome, respiratory disorders (eg, dyspnea), CNS effects (eg, confusion, somnolence), rash, metabolic and nutritional disorders (eg, bilirubinemia, increased creatinine), hyperglycemia, thyroid disorder, thrombocytopenia, anemia, impaired neutrophil function, capillary leak syndrome, cardiotoxicity, exacerbation of autoimmune and inflammatory disease, eosinophilia, possible antibody formation; others.

How supplied: Single-use vials—1

SYLATRON Merck

℞

Alpha interferon. Peginterferon alfa-2b 296mcg, 444mcg, 888mcg; per vial; lyophilized pwd for SC inj after reconstitution.

Indications: Adjuvant treatment of melanoma with microscopic or gross nodal involvement within 84 days of definitive surgical resection including complete lymphadenectomy.

Adults: Give by SC inj. Rotate inj sites.

Premedicate with acetaminophen. ≥18yrs: 6mcg/kg/week for 8 doses, followed by 3mcg/kg/week for up to 5yrs. Renal impairment (moderate): initially 4.5mcg/kg/week for 8 doses, followed by 2.25mcg/kg/week for up to 5yrs; (severe or ESRD on dialysis): initially 3mcg/kg/ week for 8 doses, followed by 1.5mcg/kg/week for up to 5yrs. Withhold dose if ANC <0.5×109/L, platelets <50×109/L, ECOG PS ≥2, or for nonhematologic toxicity ≥ Grade 3. Resume at reduced dose (see full labeling) when: ANC ≥0.5×109/L, platelets ≥50×109/L, ECOG PS 0–1, and non-hematologic toxicity has completely resolved or improved to Grade 1.

Children: <18yrs: not established.

Contraindications: Anaphylaxis to peginterferon alfa-2b or interferon alfa-2b.

Autoimmune hepatitis. Hepatic decompensation (Child-Pugh score >6 [Class B and C]).

Warnings/Precautions: Increased risk of serious depression, suicidal ideation, and other neuropsychiatric disorders. Permanently discontinue for: persistent severe or worsening neuropsychiatric disorders (eg, depression, psychosis, encephalopathy); new onset ventricular arrhythmia or cardiovascular decompensation; new or worsening retinopathy; Grade 4 non-hematologic toxicity; severe (Grade 3) hepatic injury or hepatic decompensation; hypothyroidism, hyperthyroidism, or diabetes mellitus that cannot be effectively managed; or if unable to tolerate a dose of 1mcg/kg/week.

Monitor for signs/symptoms of depression/ psychosis every 3 weeks during first 8 weeks, then every 6 months, continue for at least 6 months after last dose. Perform eye exam in patients with retinopathy and those with vision changes during therapy. Monitor hepatic function with serum bilirubin, ALT/AST, alkaline phosphate, and LDH at 2 and 8 weeks, and 2 and 3 months following initiation, then every 6 months. Obtain TSH levels within 4 weeks prior to initiation, at 3 and 6 months following initiation, then every 6 months. Moderate-to-severe renal impairment (monitor). Pregnancy (Cat.C). Nursing mothers: not recommended.

Interactions: Potentiates CYP1A2 (eg, caffeine) or CYP2D6 (eg, desipramine) substrates.

Concomitant drugs with narrow therapeutic range metabolized by CYP1A2 or CYP2D6; monitor for increased toxicities.

Adverse reactions: Fatigue, increased ALT/AST, pyrexia, headache, anorexia, myalgia, nausea, chills, inj site reactions; neuropsychiatric disorders.

How supplied: Single-use vial—1 (w. diluent)

TAFINLAR GlaxoSmithKline

℞

Kinase inhibitor. Dabrafenib 50mg, 75mg; caps.

Indications: As monotherapy for the treatment of unresectable or metastatic melanoma with BRAF V600E mutation, as detected by an FDAapproved test. In combination with trametinib for the treatment of unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test.

Limitation of use: not indicated for the treatment of wild-type BRAF melanoma.

Adults: Confirm presence of BRAF V600E or V600K mutation prior to initiation. Swallow whole.

Take at least 1hr before or 2hrs after a meal.

Visit the CTA Resource Centers at CancerTherapyAdvisor.com/Topics to view news, treatment regimens,patient fact sheets, and slideshows about a variety of cancer types.

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DRUG MONOGRAPHS

SKIN CANCER Monotherapy or in combination with trametinib: 150mg twice daily (about 12hrs apart); continue until disease progression or unacceptable toxicity occurs. Dose modifications or reductions: see full labeling.

Children: Not established.

Warnings/Precautions: See full labeling for trametinib prior to starting combination therapy.

Increased incidence of new primary cutaneous malignancies; perform skin evaluation prior to initiation, every 2 months during therapy, and up to 6 months after discontinuation. Withhold if fever ≥101.3°F or any serious febrile drug reaction occurs and evaluate for infection; prophylaxis with antipyretics may be needed when resuming.

Pre-existing diabetes or hyperglycemia; monitor serum glucose levels. Monitor for visual signs/ symptoms of uveitis. Closely monitor patients with G6PD deficiency for signs of hemolytic anemia. Males (risk of infertility). Embryo-fetal toxicity. Females of reproductive potential should use highly effective non-hormonal contraception during and for 4 weeks after treatment. Pregnancy (Cat.D). Nursing mothers: not recommended.

Interactions: Concomitant strong inhibitors (eg, ketoconazole, nefazodone, clarithromycin, gemfibrozil) or inducers (eg, rifampin, phenytoin, carbamazepine, phenobarbital, St John’s wort) of CYP3A4 or CYP2C8: not recommended; if unavoidable, monitor closely. Drugs that affect gastric pH (eg, PPIs, H2-blockers, antacids) may decrease dabrafenib exposure. May antagonize effects of CYP3A4, CYP2B6, CYP2C8, CYP2C9, CYP2C19, UGT, transporters, or other substrates (eg, midazolam, warfarin, dexamethasone, hormonal contraceptives).

Adverse reactions: Hyperkeratosis, headache, pyrexia, arthralgia, papilloma, alopecia, palmar-plantar erythrodysesthesia syndrome; combination with trametinib: chills, fatigue, rash, nausea, vomiting, diarrhea, constipation, abdominal pain, peripheral edema, cough, night sweats, decreased appetite, myalgia; hemorrhage, thromboembolic events.

How supplied: Caps—120

YERVOY Bristol-Myers Squibb

℞

Cytotoxic T-lymphocyte antigen 4 (CTLA-4)blocking antibody. Ipilimumab 5mg/mL; soln for IV infusion; preservative-free.

Indications: Treatment of unresectable or metastatic melanoma.

Adults: Give by IV infusion over 90 mins.

3mg/kg every 3 weeks for a total of 4 doses.

Withhold dose for moderate immune-mediated reactions or symptomatic endocrinopathy.

Complete/partial resolution of adverse reaction and receiving <7.5mg prednisone or equivalent per day: may resume treatment.

Permanently discontinue and initiate systemic high-dose corticosteroids for severe adverse reactions.

Children: Not established.

Warnings/Precautions: Permanently discontinue if: persistent moderate adverse reactions or inability to reduce corticosteroid dose to 7.5mg prednisone or equivalent per day; failure to complete full treatment course within 16 weeks from first dose; severe or lifethreatening reactions, including: 1) colitis with abdominal pain, fever, ileus, or peritoneal signs; increase in stool frequency and incontinence, need for IV hydration for >24hrs, GI hemorrhage/ perforation; 2) AST or ALT >5X ULN or total bilirubin >3X ULN; 3) Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; 4) severe motor or sensory neuropathy, GuillainBarre syndrome, or myasthenia gravis; 5) severe immune-mediated reactions involving any organ system; 6) immune-mediated ocular disease that is unresponsive to topical immunosuppressive therapy. Monitor for enterocolitis, dermatitis, neuropathy, endocrinopathy; perform LFTs and thyroid tests at baseline and before each dose. Moderate or severe hepatic impairment.

Pregnancy (Cat.C). Nursing mothers: not recommended.

Adverse reactions: Fatigue, diarrhea, pruritus, rash, colitis; immune-mediated adverse reactions (may be severe and fatal).

How supplied: Single-use vial (50mg, 200mg)—1

ZELBORAF Genentech

℞

Kinase inhibitor. Vemurafenib 240mg; tabs.

Indications: Treatment of unresectable or metastatic melanoma with BRAFV600E mutation as detected by an FDA-approved test. Limitation of use: not for treatment of wild-type BRAF melanoma.

Adults: Swallow whole. ≥18yrs: 960mg every 12hrs; until disease progression or unacceptable toxicity occurs. Dose modifications for adverse reactions or QTc prolongation: see full labeling.

Dose reductions <480mg twice daily: not recommended.

Children: <18yrs: not established.

Warnings/Precautions: Confirm BRAFV600E mutation-positive melanoma with FDA-approved test before initiating. Risk of cutaneous squamous cell carcinoma (cuSCC): ≥65yrs, prior skin cancer, chronic sun exposure; if occurs, do excision and evaluate. Perform dermatologic evaluation before therapy, every 2 months during, and consider monitoring 6 months after discontinuation. Monitor for signs/symptoms of new non-cutaneous SCC and other malignancies.

Long QT syndrome or QTc >500ms, uncorrectable electrolyte abnormalities, or concomitant drugs that prolong the QT interval: not recommended.

Prior to and following initiation or after dose adjustment for QTc prolongation, evaluate ECG and electrolytes after 15 days, monthly during the 1st 3 months, then every 3 months thereafter, or more as clinically indicated. Severe hepatic or

renal impairment. Monitor liver enzymes, bilirubin before initiating and monthly during treatment, or as needed. Monitor for ophthalmologic reactions routinely. Avoid sun exposure. Pregnancy (Cat.D); avoid. Use adequate contraception during therapy and for at least 2 months after discontinuation.

Nursing mothers: not recommended.

Interactions: Avoid concomitant strong CYP3A4 inhibitors (eg, azole antifungals, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir) or strong CYP3A4 inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital); consider alternatives. Concomitant CYP1A2 substrates with narrow therapeutic indices: not recommended; if unavoidable, consider dose reduction of substrates and monitor. Increased transaminase and bilirubin with concomitant ipilimumab.

Adverse reactions: Arthralgia, rash, alopecia, fatigue, photosensitivity, nausea, pruritus, skin papilloma; severe hypersensitivity or dermatologic reactions (permanently discontinue if occurs), hepatotoxicity, uveitis, blurry vision, photophobia, other malignancies.

How supplied: Tabs—120

GENERIC NAME The active ingredients and strengths are listed under the name of each dosage form. If the product contains tartrazine, alcohol, flavors, or is alcohol-, sugar-, or dye-free, it is noted.

Abbreviations are used to describe the dosage form and its formulation, e.g.: tabs = tablets caps = capsules e-c = enteric coated sust rel = sustained-release ext rel = extended-release

BRAND NAME The main name under which the product and all other dosage forms in the monograph are marketed.

LEGAL CATEGORY Federal schedule. The laws governing the prescribing/ dispensing of products vary from state to state.

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DRUG MONOGRAPHS

ASSOCIATED HEMATOLOGICAL DISORDERS Anemias

ANADROL-50 Meda

CIII

Androgen. Oxymetholone 50mg; scored tabs.

Indications: Anemia caused by deficient red cell production. Acquired aplastic anemia, congenital anemia, myelofibrosis, and hypoplastic anemias due to myelotoxic drugs.

Adults and Children: Individualized. 1–5mg/kg per day for at least 3–6 months; may attempt to lower dose or discontinue after remission.

Congenital aplastic anemia: may need continued maintenance dose.

Contraindications: Male breast or prostate carcinoma. Breast cancer in females with hypercalcemia. Nephrosis or the nephrotic phase of nephritis. Severe hepatic dysfunction.

Pregnancy (Cat.X).

Warnings/Precautions: Not a replacement for other supportive treatments (eg, transfusion; iron, folic acid, Vit. B12, Vit. B6 replacement).

Discontinue if jaundice, abnormal liver function, hypercalcemia, or edema occurs. Cardiac, hepatic, or renal dysfunction. Monitor hepatic function, blood, and bone age. Elderly. Young children. Nursing mothers: not recommended.

Interactions: May potentiate oral anticoagulants. May alter insulin needs.

Adverse reactions: Peliosis hepatis, premature epiphyseal closure in adolescents, edema, hepatic carcinoma, prostatic hypertrophy or carcinoma, gynecomastia, priapism, oligospermia, nausea, jaundice, hirsutism, virilization, male pattern baldness, acne, polycythemia, headache, CNS excitation, insomnia, altered libido, fluid and electrolyte disturbances, suppression of clotting factors, increased serum cholesterol.

How supplied: Tabs—100

ARANESP Amgen

℞

Erythropoiesis stimulating protein. Darbepoetin alfa 25mcg/mL, 40mcg/mL, 60mcg/mL, 100mcg/mL, 150mcg/0.75mL, 200mcg/mL, 300mcg/mL, 500mcg/mL; for IV or SC inj; preservative-free; contains albumin (human) or polysorbate 80.

Also: ARANESP SINGLEJECT ℞ Darbepoetin alfa 25mcg/0.42mL, 40mcg/0.4mL, 60mcg/0.3mL, 100mcg/0.5mL, 150mcg/0.3mL, 200mcg/0.4mL, 300mcg/0.6mL, 500mcg/mL; per prefilled syringe; for IV or SC inj; preservative-free; contains albumin (human) or polysorbate 80.

Indications: Anemia of chronic renal failure (CRF), including patients on and not on dialysis.

Chemotherapy-induced anemia in patients with non-myeloid malignancies.

Adults: CRF (not currently on epoetin alfa): initially 0.45mcg/kg SC or IV once weekly; alternatively for CRF (not on dialysis): 0.75mcg/kg SC once every 2 weeks. Cancer: initially 2.25mcg/kg SC once weekly or 500mcg SC once every 3 weeks.

Discontinue after completion of chemotherapy course. Adjust dose to maintain hemoglobin level (target 10–12g/dL; max 12g/dL) sufficient to avoid red blood cell transfusion; see literature.

Converting from epoetin alfa, and for dose adjustment: see literature.

Children: Not recommended.

Contraindications: Uncontrolled hypertension.

Do not use in patients with pure red cell aplasia due to erythropoietin antibodies.

Warnings/Precautions: See literature.

Evaluate serum iron, ferritin, transferrin saturation before and during therapy; most patients will need iron supplementation.

Monitor hemoglobin weekly for 4 weeks after start and dose changes, until stabilized, then periodically; reduce dose if hemoglobin increases >1g/dL in any 2-week period; withhold dose if hemoglobin exceeds 12g/dL. Monitor BP (reduce or withhold dose if hypertension occurs), folate, Vit. B12, renal function, electrolytes, fluid balance, and for premonitory neurological symptoms. Seizure, cardiovascular, or hematologic disorders. Infection, inflammation, malignancy, occult blood loss, severe albumin toxicity, bone marrow fibrosis may reduce effectiveness; consider other etiologies in treatment failures. Adjust dialysis ℞ as needed.

Latex allergy. Pregnancy (Cat.C). Nursing mothers.

Adverse reactions: Infection, hyper- or hypotension, myalgia, headache, GI upset, dyspnea, edema, arthralgia, limb or back pain, arrhythmia/cardiac arrest, cough, fatigue, chest pain, dizziness, pruritus, clotted vascular access, CHF, flu-like symptoms, local reactions, asthenia, seizure, iron deficiency. Increased risk of death, cardiovascular or thrombotic events if hemoglobin >12g/dL. May stimulate tumor growth, shorten time to tumor progression or overall survival if hemoglobin ≥12g/dL. Cancer patients also: pneumonia, dehydration.

How supplied: Single-dose vials (25, 40, 60, 100, 150mcg)—4; Single-dose vial (200, 300mcg)—1; Single-dose prefilled syringes (25, 40, 60, 100, 150mcg)—4; Single-dose prefilled syringes (200, 300, 500mcg)—1

ATGAM Pfizer

℞

Immune globulin. Lymphocyte immune globulin, anti-thymocyte globulin [equine] 50mg/mL; soln for IV infusion after dilution.

Indications: Treatment of moderate to severe aplastic anemia in patients who are unsuitable for bone marrow transplantation.

Adults: Perform intradermal test dose before initiating therapy (see literature). Do not dilute in dextrose injection or highly acidic infusion solutions. Give by IV infusion over >4hrs.

10–20mg/kg daily for 8–14 days. Additional alternate-day therapy up to a total of 21 doses can be administered. May need prophylactic platelet transfusions to maintain platelets.

Children: Limited experience (see literature).

Warnings/Precautions: To be administered by physicians with experience in immunosuppressive therapy and in facilities equipped with adequate lab and supportive medical resources.

Discontinue if symptoms of anaphylaxis develop.

Contains human plasma; monitor for possible infection transmission. Monitor for leukopenia, thrombocytopenia, or infection esp. with concomitant corticosteroids and antimetabolites.

Pregnancy (Cat.C): not recommended. Nursing mothers.

Interactions: Previously masked reactions may occur when corticosteroids and other immunosuppressant doses are reduced.

Adverse reactions: Fever, skin reactions, chills, arthralgia, headache, myalgia, GI upset, chest pain, phlebitis, diaphoresis, joint stiffness, edema, muscle ache, vomiting, agitation/ lethargy, listlessness, light-headedness, seizures, bradycardia, myocarditis, cardiac irregularity, hepatosplenomegaly, possible encephalitis or post viral encephalopathy, hypotension, CHF, hypertension, burning soles/palms, foot sole pain, lymphadenopathy, post-cervical lymphadenopathy, tender lymph nodes, bilateral pleural effusion, respiratory distress, anaphylactic reaction, proteinuria, abnormal LFTs and renal function, serum sickness.

How supplied: Ampules (5mL)—5

BIFERA Meda

OTC

Iron (as polysaccharide iron complex [PIC] 22mg + heme iron polypeptide [HIP] as Proferrin bovine source 6mg) 28mg; gluten-free tabs.

Indications: Iron supplement. Iron deficiency.

Adults: 1 tab once daily.

Children: Not recommended.

Contraindications: Hemochromatosis.

Hemosiderosis.

Warnings/Precautions: May mask pernicious anemia. Monitor hemoglobin, hematocrit, ferritin levels periodically. Pregnancy. Nursing mothers.

Adverse reactions: Allergic sensitization.

How supplied: Tabs—30

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DRUG MONOGRAPHS

ASSOCIATED HEMATOLOGICAL DISORDERS BIFERARx Meda

℞

Iron (as polysaccharide iron complex [PIC] 22mg + heme iron polypeptide [HIP] as Proferrin bovine source 6mg) 28mg, folic acid 1mg, Vit. B12 25mcg; tabs.

Indications: Iron supplement. Iron deficiency.

Adults: 1 tab once daily.

Children: Not recommended.

Contraindications: Hemochromatosis.

Hemosiderosis.

Warnings/Precautions: May mask pernicious anemia. Monitor hemoglobin, hematocrit, ferritin levels periodically. Pregnancy. Nursing mothers.

Adverse reactions: Allergic sensitization.

How supplied: Tabs—90

DEXFERRUM American Regent

℞

Hematinic. Iron (as dextran complex) 50mg/mL; soln for IV inj.

Indications: Iron deficiency where oral therapy is unsatisfactory or impossible.

Adults and Children: <4months: not recommended. Give by IV inj. Administer 0.5mL test dose first; if no signs/symptoms of anaphylactic-type reactions, may give full therapeutic dose. ≥4months: Iron deficiency anemia: determine total dose based on hemoglobin and body weight (see literature). Iron replacement for blood loss: Replacement iron (in mg) = blood loss (in mL) × hematocrit. Max daily doses: <5kg: 0.5mL (25mg), <10kg: 1mL (50mg), ≥10kg: 2mL (100mg).

Contraindications: Anemia not associated with iron deficiency.

Warnings/Precautions: Monitor for signs/ symptoms of anaphylactic-type reactions, esp. in patients with history of allergies, asthma; have epinephrine available. Hepatic impairment.

Avoid during acute phase of infectious kidney disease. Cardiovascular disease. Avoid large IV doses: higher incidence of adverse events.

Iron overload more likely with hemoglobinopathies or refractory anemias.

Rheumatoid arthritis. Neonates. Pregnancy (Cat.C). Nursing mothers.

Interactions: Concomitant ACE inhibitors may increase the risk for anaphylactic-type reactions.

May falsely elevate serum bilirubin and decrease serum calcium.

Adverse reactions: See literature. Anaphylactic reactions (may be fatal, even in patients who tolerated test dose), cardiovascular events, pruritus, GI upset, arthralgia, arthritis, inj site reactions, others.

How supplied: Single-dose vials (1mL, 2mL)—10

DROXIA Bristol-Myers Squibb Substituted urea. Hydroxyurea 200mg, 300mg, 400mg; caps.

Indications: To reduce the frequency of painful crises and to reduce the need for blood

℞

transfusions in adults with sickle cell anemia with recurrent moderate-to-severe painful crises.

Adults: Base dose on ideal or actual weight, whichever is less. Initially 15mg/kg/day as a single dose. May increase dose by 5mg/kg/day every 12 weeks to maximum tolerated dose or 35mg/kg/day achieved; do not increase dose if blood counts are between acceptable range and toxic. If blood counts toxic, discontinue until hematologic recovery, see literature for dosage adjustments. Renal impairment (CrCl <60mL/min or ESRD): initially 7.5mg/kg per day; give dose following dialysis.

Children: Not recommended.

Warnings/Precautions: Markedly depressed bone marrow function: not recommended.

Monitor hematologic, renal, and liver function before and during therapy. Renal dysfunction.

Macrocytosis may mask folic acid deficiency; prophylactic folic acid is recommended.

Myeloproliferative disorders; discontinue if cutaneous vasculitic ulcerations develop.

Pregnancy (Cat.D); avoid use. Nursing mother: not recommended.

Interactions: Avoid concomitant didanosine, with or without stavudine, or other antiretrovirals (may cause pancreatitis [monitor], fatal hepatotoxicity, peripheral neuropathy). May antagonize antigout agents. Increased risk of vasculitic toxicities with interferon therapy. May cause falsely elevated urease, uricase, lactate dehydrogenase.

Adverse reactions: Neutropenia, thrombocytopenia, anemia, low reticulocyte count, hair loss, rash, fever, GI upset, weight gain, bleeding, parvovirus B-19 infection, melanonychia, erythema, CNS effects, temporary renal impairment, acute pulmonary reactions, secondary leukemias, skin cancer.

Note: Wear disposable gloves when handling caps or bottle.

How supplied: Caps—60

EPOGEN Amgen

℞

Erythropoietin (human, recombinant). Epoetin alfa 2000 Units, 3000 Units, 4000 Units, 10000 Units, 40000 Units; per mL; soln for IV or SC inj; contains albumin (human); preservativefree. ℞ Also: EPOGEN MULTIDOSE Epoetin alfa 10000 Units, 20000 Units; per mL; soln for IV or SC inj; contains albumin (human) and benzyl alcohol.

Indications: Anemia in chronic renal failure (CRF). Anemia related to zidovudine in HIVinfected patients. Chemotherapy-induced anemia in patients with non-myeloid malignancies (serum erythropoietin ≤200 mUnits/mL). To reduce need for allogeneic blood transfusions in anemic (hemoglobin >10 to ≤13g/dL) patients scheduled for elective, noncardiac, nonvascular surgery.

Adults: Individualize (see literature for titration).

CRF: initially 50–100 Units/kg 3 times per week

IV (dialysis or non dialysis) or SC (non dialysis); usual max (non dialysis) 150 Units/kg 3 times per week; (dialysis) 200 Units/kg 3 times per week; target hemoglobin 10–12g/dL. Zidovudinetreated HIV patients: if serum erythropoietin ≤500 mUnits/mL and zidovudine dose ≤4.2 g/wk: initially 100 Units/kg IV or SC 3 times per week for 8 weeks; usual max 300 Units/kg 3 times per week. Chemotherapy-induced: initially 150 Units/kg SC 3 times per week; may increase to 300 Units/kg 3 times per week after 8 weeks.

Or, initially 40000 Units SC once weekly; may increase to 60000 Units once weekly after 4 weeks. Discontinue after completion of chemotherapy course. Surgery: If ≥21 days until surgery: 600 Units/kg once weekly SC at 21, 14 and 7 days before surgery, and a 4th dose on day of surgery. If <21 days until surgery: 300 Units/kg per day SC for 10 days before, on day of, and for 4 days after surgery. All: adjust dose to maintain the lowest hemoglobin level (target max 12g/dL) sufficient to avoid red blood cell transfusion; see literature.

Children: Individualize (see literature for monitoring). CRF (dialysis): <1 month: not recommended. ≥1 month of age: initially 50 Units/kg three times per week IV or SC. Target hemoglobin: 10–12g/dL. Chemotherapy-induced: ≥5yrs: 600 Units/kg IV weekly (max 40,000 Units); may increase to 900 Units/kg IV weekly (max 60,000 Units) after 4 weeks. Discontinue after completion of chemotherapy course. Other uses: see literature.

Contraindications: Uncontrolled hypertension.

Warnings/Precautions: See literature. Evaluate serum iron, ferritin, transferrin saturation before therapy; all patients will need iron supplementation. Monitor hemoglobin (measure twice weekly for 2–6 weeks after any dosage adjustment; reduce dose if hemoglobin increases >1g/dL in any 2-week period; withhold dose if hemoglobin exceeds 12g/dL), blood pressure, renal function, iron levels, clotting times, serum chemistry, CBC, and for premonitory neurological symptoms. Seizure disorders. Cardiovascular or hematologic disorders. Hypertension (esp. in renal failure). Porphyria. Concurrent infection, inflammation, increased zidovudine dose, or other factors may reduce effectiveness.

Perisurgery: consider DVT prophylaxis. Consider other etiologies in treatment failures. Adjust anticoagulant dose in dialysis patients. Menses may resume. Pregnancy (Cat.C). Nursing mothers.

Adverse reactions: Iron deficiency, hypertension, headache, arthralgia, GI disturbances, edema, local reaction, rash, paresthesia, dizziness, clotted vascular access (A-V shunt), pyrexia, respiratory congestion, seizures. Increased risk of death, cardiovascular or thrombotic events if hemoglobin >12g/dL. May stimulate tumor growth, shorten time to tumor progression or overall survival if hemoglobin ≥12g/dL. Children: also abdominal pain, upper

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DRUG MONOGRAPHS

ASSOCIATED HEMATOLOGICAL DISORDERS respiratory infection, cough, pharyngitis, constipation.

How supplied: Single-use 1mL vials (all)—10; Multidose 2mL vials (10000 Units/mL)—10; Multidose 1mL vials (20000 Units/mL)—10

FERAHEME AMAG

℞

Hematinic. Elemental iron 30mg/mL (as ferumoxytol 510mg/17mL); colloidal iron for IV infusion after dilution; contains mannitol 44mg/mL; preservative-free.

Indications: Iron deficiency anemia in adult patients with chronic kidney disease.

Adults: Give by IV infusion over at least 15 mins.

Initially 510mg, followed by a second 510mg dose 3–8 days later. May repeat in persistent or recurrent iron deficiency anemia. Hemodialysis: give at least 1 hour after starting hemodialysis and after BP is stable.

Children: <18yrs: not established.

Contraindications: History of any IV iron product allergy.

Warnings/Precautions: Iron overload: do not administer. Monitor for severe hypotension, and for hypersensitivity for at least 30 minutes after each infusion. Evaluate hemoglobin, ferritin, iron, transferrin saturation at least 1 month after 2nd infusion. Have equipment/personnel available to treat hypersensitivity reactions. Elderly. Pregnancy (Cat.C). Nursing mothers: not recommended.

Interactions: May reduce absorption of concomitantly administered oral iron preparations. May transiently (up to 3 months) affect diagnostic ability of MRI (see full labeling).

Concomitant chemotherapy or monoclonal antibodies: separate dosing by at least 30 mins.

Adverse reactions: Diarrhea, nausea, hypotension (may be significant), dizziness, constipation, peripheral edema; infusion reactions, anaphylactic reactions (may be fatal), other hypersensitivity reactions (eg, rash, pruritus, urticaria, wheeze).

How supplied: Single-use vials (17mL)—1, 10

FERRALET 90 Mission

℞

Iron (as carbonyl) 90mg, folic acid 1mg, Vit.B12 12mcg, Vit.C 120mg, docusate sodium 50mg; tabs; contains tartrazine.

Indications: Iron deficiency anemia.

Adults: Swallow whole. Take 2hrs after meals.

1 tab once daily.

Children: Not recommended.

Contraindications: Hemolytic anemia.

Hemochromatosis. Hemosiderosis.

Warnings/Precautions: May mask pernicious anemia. Monitor hemoglobin, hematocrit, reticulocyte count periodically. Elderly.

Interactions: Inhibits tetracycline, fluoroquinolone absorption. Aluminum- or magnesium-containing antacids inhibit iron absorption.

Adverse reactions: GI upset or irritation, constipation, dark stools, allergic sensitization.

How supplied: Tabs—90

FERRLECIT Sanofi Aventis

treatment. May obscure diagnosis of pernicious anemia. Pregnancy (Cat.A).

Interactions: May antagonize phenytoin. False low serum and red cell folate levels may occur with antibiotics (eg, tetracycline).

Adverse reactions: Allergic sensitization.

How supplied: Contact supplier. ℞

Hematinic. Iron (as sodium ferric gluconate complex in sucrose) 12.5mg/mL; soln for IV inj or infusion; contains benzyl alcohol.

Indications: Iron deficiency anemia in patients on chronic hemodialysis receiving epoetin therapy.

Adults: Give by IV infusion (diluted) or slow IV inj (undiluted). 125mg infused over 1 hour or by slow IV inj (at a rate of up to 12.5mg/min). Minimum cumulative dose: 1g given over 8 sequential dialysis sessions; usual max: 125mg/dose.

Children: <6 yrs: not recommended. Give by IV infusion (diluted) over 1 hour. ≥6yrs: 1.5mg/kg per dose at 8 sequential dialysis sessions; max: 125mg/dose.

Contraindications: Anemias not caused by iron deficiency. Iron overload. Neonates.

Warnings/Precautions: Hemoglobinopathies.

Refractory anemias. Pregnancy (Cat.B). Nursing mothers.

Interactions: May reduce absorption of concomitant oral iron preparations.

Adverse reactions: Hypotension, hypertension, GI upset, chest pain, back pain, abdominal pain, pruritus, inj site reaction, headache, dizziness, syncope, fatigue, fever, cramps, dyspnea, tachycardia; rare: hypersensitivity reactions.

How supplied: Ampules (5mL)—10

Folic acid (various)

℞

Hematinic. Folic acid 1mg; tabs. ℞ Also: Folic acid injection Folic acid 5mg/mL; soln for IV, IM or SC inj; contains benzyl alcohol and aluminum.

Indications: Megaloblastic anemias of folic acid deficiency. Anemias of nutritional origin, pregnancy, infancy or childhood.

Adults and Children: Usual dose: up to 1mg daily; may need higher dose if resistant disease.

Maintenance: infants: 0.1mg/day; <4yrs: 0.3mg/day; ≥4yrs: 0.4mg/day. Pregnant or lactating: 0.8mg/day. Alcoholism, hemolytic anemia, anticonvulsant therapy or chronic infection: may require higher dose.

Warnings/Precautions: Use injectable form if disease is severe or GI absorption impaired.

Rule out or treat vitamin B12 deficiency prior to

INFED Actavis

℞

Hematinic. Iron (as dextran complex) 50mg/mL; soln for IV or IM inj.

Indications: Iron deficiency where oral therapy is unsatisfactory or impossible.

Adults and Children: Give by IV or by deep IM (into upper outer quadrant of buttock only) inj.

Administer 0.5mL test dose first; if no signs/ symptoms of anaphylactic-type reactions, may give full therapeutic dose. Iron deficiency anemia: determine total dose based on hemoglobin and body weight (see literature). Iron replacement for blood loss: Replacement iron (in mg) = blood loss (in mL) × hematocrit. Max daily doses: <5kg: 0.5mL (25mg), <10kg: 1mL (50mg), ≥10kg: 2mL (100mg).

Contraindications: Anemias not associated with iron deficiency.

Warnings/Precautions: Monitor for signs/ symptoms of anaphylactic-type reactions, esp. in patients with history of drug allergies, asthma; have epinephrine available. Avoid large IV doses: higher incidence of adverse events. Severe hepatic impairment. Avoid during acute phase of infectious kidney disease. Dialysis. Cardiovascular disease. May reactivate quiescent rheumatoid arthritis. Neonates (avoid during first 4 months).

Pregnancy (Cat.C). Nursing mothers.

Interactions: Concomitant ACE inhibitors may increase the risk for anaphylactic-type reactions.

May falsely elevate serum bilirubin or decrease serum calcium levels.

Adverse reactions: See literature. Anaphylactic reactions (may be fatal; even if test dose was tolerated), cardiovascular events, pruritus, GI upset, arthralgia, arthritis, inj site reactions, others; possible IM inj site tumors, sepsis in neonates.

How supplied: Vials (2mL)—10

INJECTAFER American Regent

℞

Hematinic. Iron (as ferric carboxymaltose) 50mg/mL; soln for IV inj or infusion; preservativefree.

Indications: Iron deficiency anemia in adults who have intolerance or insufficient response to oral iron; or have non-dialysis-dependent chronic kidney disease.

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ASSOCIATED HEMATOLOGICAL DISORDERS Adults: Give by slow IV push (undiluted) at rate of approx. 100mg (2mL)/min; or by IV infusion (diluted) administered over at least 15 mins. When giving via IV infusion, dilute to concentration not less than 2mg iron/mL. Give in 2 doses separated by ≥7 days. <50kg: 15mg/kg/dose. ≥50kg: 750mg/dose. Total cumulative dose per course: max 1500mg. May repeat treatment if condition reoccurs.

Children: Not established.

Warnings/Precautions: Have epinephrine inj (1:1000) available. Monitor for serious hypersensitivity reactions during and after administration for ≥30 mins and until clinically stable. Monitor for signs/symptoms of hypertension after each administration. Avoid extravasation. Pregnancy (Cat.C). Nursing mothers.

Interactions: Lab assays may result in overestimating serum iron and transferrin bound iron within 24hrs after administration.

Adverse reactions: Nausea, hypertension, flushing, hypophosphatemia, dizziness; rare: hypersensitivity reactions.

How supplied: Single-use vial (15mL)—1, 2

Leucovorin Teva

℞

Folic acid derivative. Leucovorin calcium 100mg/vial, 350mg/vial; lyophilized pwd for IV or IM inj after reconstitution; preservative-free.

Indications: Megalobastic anemia due to folic acid deficiency when oral therapy is not feasible.

Adults: Up to 1mg daily.

Children: See literature.

Contraindications: Pernicious anemia and other megaloblastic anemias due to Vit. B12 deficiency.

Warnings/Precautions: Do not administer intrathecally. CNS metastases. Monitor CBCs with differential, platelets, electrolytes, liver function tests prior to each treatment, then periodically.

Elderly. Debilitated. Pregnancy (Cat.C). Nursing mothers.

Interactions: Potentiates toxicity of 5-fluorouracil; use lower 5-fluorouracil dose.

May antagonize phenobarbital, phenytoin, and primidone. Caution with trimethoprimsulfamethoxazole.

Adverse reactions: Leukopenia, thrombocytopenia, infection, GI upset, stomatitis, constipation, lethargy, malaise, fatigue, alopecia, dermatitis, anorexia; seizures, syncope.

How supplied: Single-use vials—1

LUPRON DEPOT 3.75mg AbbVie

GnRH analogue. Leuprolide acetate 3.75mg; depot susp for IM inj; preservative-free.

Indications: Presurgical treatment of patients with anemia due to uterine leiomyomata (fibroids), with iron therapy if iron therapy alone is inadequate.

℞

Adults: ≥18 years: 3.75mg IM once per month for up to 3 months.

Children: <18 years: not applicable.

Also: LUPRON DEPOT-3 MONTH 11.25mg ℞ Leuprolide acetate 11.25mg; depot susp for IM inj; preservative-free.

Adults: ≥18 years: 11.25mg IM once every 3 months (1 injection). Do not split doses.

Children: <18 years: not applicable.

Contraindications: Undiagnosed abnormal vaginal bleeding. Pregnancy (Cat.X). Nursing mothers.

Warnings/Precautions: Exclude pregnancy before starting; use nonhormonal contraception during therapy; discontinue if pregnancy occurs.

Risk factors for decreased bone mineral density (eg, chronic alcohol, tobacco, anticonvulsants, corticosteroids). Missing successive doses may cause breakthrough bleeding or ovulation. Elderly.

Adverse reactions: Hot flashes, headache, vaginitis, depression, emotional lability, pain, decreased libido, breast changes, amenorrhea, mastodynia, joint disorder, asthenia, GI upset, edema, bone density loss, local reactions, acne, memory disorders, others; rarely: anaphylaxis, asthma, increased serum transaminases or lipids.

How supplied: Kit—1 (single-dose syringe w. diluent, supplies)

NASCOBAL Strativa

℞

Cyanocobalamin 500mcg/spray; soln for nasal spray; contains benzalkonium chloride.

Indications: Maintenance of normal hematologic status in pernicious anemia patients who are in remission after intramuscular Vit. B12 therapy and who have no nervous system involvement. Supplementation for other Vit. B12 deficiencies.

Adults: Hematological parameters must be within normal range before beginning therapy.

Allow at least 1hr before or after hot foods or liquids. Initial dose: One spray (500mcg) in one nostril once weekly. Monitor response, may increase dose if serum B12 levels decline.

Children: Not recommended.

Warnings/Precautions: Confirm diagnosis.

May need supplemental folate. Risk of hypokalemia or sudden death in severe megablastic anemia. Leber’s disease. Defer dose if nasal congestion, rhinitis, or upper respiratory infections occur. Reevaluate if low levels of Vit. B12 persist despite treatment.

Do not use for Schilling Test. Infection, uremia, and iron or folic acid deficiency may reduce response. Increased risk of stomach carcinoma in those with pernicious anemia; perform tests when indicated. May unmask polycythemia vera. Monitor B12 blood levels 1 month after starting therapy, 1 month after any dose increase, and regularly at 3–6 month intervals. Monitor serum potassium, platelet counts. Pregnancy (Cat.C).

Interactions: Antibiotics, methotrexate, pyrimethamine may interfere with lab tests.

Colchicine, chronic heavy alcohol use may impair Vit. B12 absorption. Reduced response with bone marrow suppressants (eg, chloramphenicol).

Adverse reactions: Headache, nausea, rhinitis.

How supplied: Single-use nasal spray (0.125mL)—4

NULECIT Actavis

℞

Hematinic. Iron (as sodium ferric gluconate complex in sucrose) 12.5mg/mL; soln for IV inj or infusion; contains benzyl alcohol.

Indications: Iron deficiency anemia in patients on chronic hemodialysis receiving epoetin therapy.

Adults: Give by IV infusion (diluted) or slow IV inj (undiluted). 125mg infused over 1 hour or by slow IV inj (at a rate of up to 12.5mg/min). Minimum cumulative dose: 1g given over 8 sequential dialysis sessions; usual max: 125mg/dose.

Children: <6yrs: not recommended. Give by IV infusion (diluted) over 1 hour. ≥6yrs: 1.5mg/kg per dose at 8 sequential dialysis sessions; max: 125mg/dose.

Contraindications: Anemias not caused by iron deficiency. Iron overload.

Warnings/Precautions: Hemoglobinopathies.

Refractory anemias. Avoid in neonates. Pregnancy (Cat.B). Nursing mothers.

Interactions: May reduce absorption of concomitant oral iron preparations.

Adverse reactions: Hypotension, hypertension, GI upset, chest pain, back pain, abdominal pain, pruritus, inj site reaction, cramps, headache, dizziness, syncope, fatigue, fever, dyspnea, tachycardia; rare: hypersensitivity reactions.

How supplied: Vials (5mL)—10

PROCRIT Janssen Biotech

℞

Erythropoietin (human, recombinant). Epoetin alfa 2000 Units, 3000 Units, 4000 Units, 10000 Units, 40000 Units; per mL; soln for IV or SC inj; contains albumin (human); preservativefree. ℞ Also: PROCRIT MULTIDOSE Epoetin alfa 10000 Units, 20000 Units; per mL; soln for IV or SC inj; contains albumin (human) and benzyl alcohol.

Indications: Anemia in chronic renal failure (CRF). Anemia related to zidovudine in HIVinfected patients. Chemotherapy-induced anemia in patients with non-myeloid malignancies (serum erythropoietin ≤200 mUnits/mL). To reduce need for allogeneic blood transfusions in anemic (hemoglobin >10 to ≤13g/dL) patients scheduled for elective, noncardiac, nonvascular surgery.

Adults: Individualize (see literature for titration).

CRF: initially 50–100 Units/kg 3 times per week IV (dialysis or non dialysis) or SC (non dialysis); usual max (non dialysis) 150 Units/kg 3 times per week; (dialysis) 200 Units/kg 3 times per week; target hemoglobin: 10–12g/dL. Zidovudinetreated HIV patients: if serum erythropoietin

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ASSOCIATED HEMATOLOGICAL DISORDERS ≤500 mUnits/mL and zidovudine dose ≤4.2g/wk: initially 100 Units/kg IV or SC 3 times per week for 8 weeks; usual max 300 Units/kg 3 times per week. Chemotherapy-induced: initially 150 Units/kg SC 3 times per week; may increase to 300 Units/kg 3 times per week after 8 weeks.

Or, initially 40000 Units SC once weekly; may increase to 60000 Units once weekly after 4 weeks. Discontinue after completion of chemotherapy course. Surgery: If ≥21 days until surgery: 600 Units/kg once weekly SC at 21, 14 and 7 days before surgery, and a 4th dose on day of surgery. If <21 days until surgery: 300 Units/kg per day SC for 10 days before, on day of, and for 4 days after surgery. All: adjust dose to maintain the lowest hemoglobin level (target max 12g/dL) sufficient to avoid red blood cell transfusion; see literature.

Children: Individualize (see literature for monitoring). CRF (dialysis): <1 month: not recommended. ≥1 month of age: initially 50 Units/kg three times per week IV or SC. Target hemoglobin: 10–12g/dL. Chemotherapy-induced: ≥5yrs: 600 Units/kg IV weekly (max 40,000 Units); may increase to 900 Units/kg IV weekly (max 60,000 Units) after 4 weeks. Discontinue after completion of chemotherapy course. Other uses: see literature.

Contraindications: Uncontrolled hypertension.

Warnings/Precautions: See literature. Evaluate serum iron, ferritin, transferrin saturation before therapy; all patients will need iron supplementation. Monitor hemoglobin (measure twice weekly for 2–6 weeks after any dosage adjustment; reduce dose if hemoglobin increases >1g/dL in any 2-week period; withhold dose if hemoglobin exceeds 12g/dL), blood pressure, renal function, iron levels, clotting times, serum chemistry, CBC, and for premonitory neurological symptoms. Seizure disorders. Cardiovascular or hematologic disorders. Hypertension (esp. in renal failure). Porphyria. Concurrent infection, inflammation, increased zidovudine dose, or other factors may reduce effectiveness.

Perisurgery: consider DVT prophylaxis. Consider other etiologies in treatment failures. Adjust anticoagulant dose in dialysis patients. Menses may resume. Pregnancy (Cat.C). Nursing mothers.

Adverse reactions: Iron deficiency, hypertension, headache, arthralgia, GI disturbances, edema, local reaction, rash, paresthesia, dizziness, clotted vascular access (A-V shunt), pyrexia, respiratory congestion, seizures. Increased risk of death, cardiovascular or thrombotic events if hemoglobin >12g/dL. May stimulate tumor growth, shorten time to tumor

progression or overall survival if hemoglobin ≥12g/dL. Children: also abdominal pain, upper respiratory infection, cough, pharyngitis, constipation.

How supplied: Single-use 1mL vials (2000 Units/mL, 3000 Units/mL, 4000 Units/mL, 10000 Units/mL)—6, 25; Single-use 1mL vials (40000 Units/mL)—4; Multidose 2mL vials (10000 Units/mL)—4, 6; Multidose 1mL vials (20000 Units/mL)—4, 6

PROMACTA GlaxoSmithKline

hepatic enzymes, hepatotoxicity, hemorrhage, thrombotic complications from excessive increases in platelet counts, cataracts.

How supplied: Tabs—30

REVLIMID Celgene

℞

Thrombopoietin receptor agonist. Eltrombopag (as olamine) 12.5mg, 25mg, 50mg, 75mg; tabs.

Indications: Severe aplastic anemia in adults who have had insufficient response to immunosuppressive therapy.

Adults: Take on empty stomach. Initially 50mg once daily. Hepatic impairment or East Asian ancestry: initially 25mg once daily.

Titrate dose by 50mg every 2 weeks as needed to maintain platelet count ≥50×109/L; max 150mg daily. Monitoring, dose adjustment, and discontinuation: see full labeling.

Children: Not established.

Warnings/Precautions: Increased risk of hepatic decompensation in chronic hepatitis C, when concomitant with interferon and ribavirin; discontinue Promacta if antiviral therapy is discontinued. Monitor liver function prior to initiation, every 2 weeks during dose adjustments, and monthly after stabilized (see full labeling); discontinue if ALT ≥3×ULN and is progressive or persistent for ≥4 weeks, or if occurs with increased bilirubin, or evidence of hepatic injury/ decompensation; reinitiate therapy if benefit outweighs risk; if restarted, monitor carefully.

Increased risk of thromboembolism; do not use to normalize platelet counts. Do baseline eye exam; monitor for cataracts. Renal impairment.

Pregnancy (Cat.C). Nursing mothers: not recommended.

Interactions: Do not take within 4hrs of food/ drugs containing polyvalent cations (eg, Fe+2, Ca+2, Al+3, Mg+2, Se+2, Zn+2). Potentiate substrates of OATP1B1 (eg, most statins, bosentan, ezetimibe, glyburide, olmesartan, valsartan, repaglinide, rifampin) or BCRP (eg, imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone, sulfasalazine, topotecan); monitor and consider reducing their doses. Antagonized by lopinavir/ ritonavir.

Adverse reactions: Nausea, diarrhea, fatigue, cough, headache, pain, dyspnea, pyrexia, dizziness, febrile neutropenia, ecchymosis, muscle spasms, arthralgia, rhinorrhea; elevated

℞

Immunomodulator. Lenalidomide 2.5mg, 5mg, 10mg, 15mg, 20mg, 25mg; caps; contains lactose.

Indications: Transfusion-dependent anemia due to Low- or Intermediate-1-risk myelodysplastic syndromes (MDS) associated with a deletion 5q cytogenetic abnormality.

Adults: Swallow whole with water. ≥18yrs: initially 10mg per day; adjust dose based on response. Renal impairment: Moderate (CrCL 30–60mL/min): 5mg per day. Severe (CrCL <30mL/min without dialysis): 2.5mg per day.

ESRD (CrCL <30mL/min with dialysis): 2.5mg once daily; administer after dialysis (on dialysis days). Dose adjustments if thrombocytopenia or neutropenia develops: see full labeling.

Children: <18yrs: not established.

Contraindications: Pregnancy (Cat.X).

Warnings/Precautions: Must register patient in Revlimid REMS program; patient must understand toxicity with fetal exposure. Counsel patient on need for contraception; females: use 2 forms of contraception 1 month before, during therapy, during dose interruptions, and 1 month after therapy; males: use condom during and 1 month after therapy; obtain 2 negative pregnancy tests (one within 10–14 days, and then another within 24hrs prior to starting therapy), repeat at least weekly for 1st month then every 4 weeks (regular menstrual cycles) or every 2 weeks (irregular cycles); get informed consent. Do not donate blood during and for 1 month after therapy. Monitor for signs/ symptoms of thromboembolic events; base thromboprophylaxis on patient’s risks. Obtain CBCs weekly for first 8 weeks, then monthly; dose interruption and/or reduction may be needed.

May require blood product support and/or growth factors. Renal impairment (monitor). Monitor for tumor lysis syndrome in those with high tumor burden. Monitor liver enzymes; discontinue if elevation occurs. Lactose intolerance.

Maximum 1 month per ℞. Nursing mothers: not recommended.

Interactions: Monitor digoxin. Concomitant warfarin; monitor PT, INR. May increase risk of thrombosis with dexamethasone, erythropoietic agents, or estrogen containing therapies.

Adverse reactions: Birth defects, thrombocytopenia, neutropenia, anemia, leukopenia, constipation, diarrhea, nausea,

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ASSOCIATED HEMATOLOGICAL DISORDERS vomiting, pruritus, rash, fatigue, arthralgia, pyrexia, back pain, cough, dizziness, headache, dyspnea, nasopharyngitis, epistaxis, upper respiratory tract infection, tremor, blurred vision, muscle cramp, decreased appetite, peripheral edema; thrombosis/embolism, allergic reactions (discontinue if occurs; do not resume), tumor flare reaction (monitor; esp. in treating MCL), hepatotoxicity.

Note: Available only through Revlimid REMS program. Report any suspected fetal exposure to the FDA at (800) FDA-1088 and Celgene at (888) 423-5436.

How supplied: Caps 2.5mg, 5mg, 10mg—28, 100; 15mg, 20mg, 25mg—21, 100

SOLIRIS Alexion

℞

Complement inhibitor. Eculizumab 10mg/mL; soln for IV infusion after dilution; preservativefree.

Indications: Treatment of paroxysmal nocturnal hemoglobinuria (PNH) to reduce hemolysis.

Treatment of atypical hemolytic uremic syndrome (aHUS) to inhibit complementmediated thrombotic microangiopathy.

Limitation of use: not for treating Shiga toxin E. coli-related HUS. Adults: Give by IV infusion over 35 mins; monitor for ≥1hr after completion. ≥18yrs: PNH: initially 600mg weekly for the first 4 weeks, followed by 900mg for the fifth dose 1 week later, then 900mg every 2 weeks thereafter. aHUS: initially 900mg weekly for the first 4 weeks, followed by 1200mg for the fifth dose 1 week later, then 1200mg every 2 weeks thereafter.

Supplemental dosing after PE/PI: see full labeling.

Children: <18yrs: PNH: not established. aHUS: Give by IV infusion over 1–4hrs via gravity feed, syringe-type pump, or infusion pump; monitor for ≥1hr after completion. 5–<10kg: induction: 300mg weekly for 1 dose; maintenance: 300mg at Week 2, then 300mg every 3 weeks; 10–<20kg: induction: 600mg weekly for 1 dose; maintenance: 300mg at Week 2, then 300mg every 2 weeks; 20–<30kg: induction: 600mg weekly for 2 doses; maintenance: 600mg at Week 3, then 600mg every 2 weeks; 30–<40kg: induction: 600mg weekly for 2 doses; maintenance: 900mg at Week 3, then 900mg every 2 weeks; ≥40kg: induction: 900mg weekly for 4 doses; maintenance: 1200mg at Week 5, then 1200mg every 2 weeks.

Supplemental dosing after PE/PI: see full labeling.

Contraindications: Unresolved serious Neisseria meningitidis infection. Individuals not vaccinated against Neisseria meningitidis.

Warnings/Precautions: Increased risk of meningococcal infection. Give meningococcal vaccine at least 2 weeks prior to treatment.

Monitor for early signs of meningococcal infection; evaluate and treat if an infection develops. Discontinue eculizumab if undergoing

treatment for meningococcal infections.

Administering eculizumab treatment with any other systemic infection (eg, S. pneumoniae, H. influenza). PNH: risk of hemolysis after treatment discontinuation; monitor for at least 8 weeks. aHUS: risk of thrombotic microangiopathy (TMA) after treatment discontinuation; monitor for at least 12 weeks; if TMA occurs, consider reinitiating eculizumab, plasma therapy [plasmapheresis, plasma exchange, or fresh frozen plasma infusion (PE/ PI)], or appropriate organ-specific supportive measures. Monitor platelets, serum LDH, and creatinine during and after therapy. Pregnancy (Cat.C). Nursing mothers.

Adverse reactions: Headache, nasopharyngitis, back pain, nausea, diarrhea, vomiting, abdominal pain, hypertension, upper respiratory tract infection, anemia, cough, peripheral edema, UTI, pyrexia; meningococcal infection (may be fatal), hypersensitivity reactions.

How supplied: Single-use vials (30mL)—1

TRINSICON UCB

Bleeding disorders ℞

Iron (as fumarate) 110mg, Vit. B12 15micrograms, folic acid 0.5mg, Vit. C 75mg, liver-stomach concentrate 240mg; caps.

Indications: Megaloblastic anemias. Iron deficiency anemia.

Adults: 1 cap twice daily.

Children: <10yrs: not recommended.

Contraindications: Hemochromatosis.

Hemosiderosis.

Warnings/Precautions: For pernicious anemia, parenteral cyanocobalamin is preferred. Resistance to exogenous intrinsic factor may develop. Folic acid may mask pernicious anemia. Monitor blood parameters.

Hepatitis. Pancreatitis. Peptic ulcer or GI inflammation. Achlorhydria. Repeated blood transfusions. Pregnancy (Cat.C). Nursing mothers. Elderly.

Interactions: Inhibits tetracycline absorption.

Adverse reactions: Nausea, abdominal discomfort and pain, constipation, diarrhea, masks occult bleeding, black stools, rash.

How supplied: Caps—60, 100

VENOFER American Regent

of 300mg over 1.5hrs 14 days apart, then one 400mg infusion over 2.5hrs 14 days later.

Children: Not recommended.

Contraindications: Anemia not caused by iron deficiency. Iron overload.

Warnings/Precautions: Withhold therapy if tissue iron overload suspected. Monitor hemoglobin, hematocrit, serum ferritin, transferrin saturation; obtain serum iron values 48 hours after dosing. Pregnancy (Cat.B). Nursing mothers.

Interactions: May reduce absorption of concomitant oral iron preparations.

Adverse reactions: Hypotension (esp. by IV infusion), hypertension, muscle cramps, GI upset, headache, dizziness, chest pain, graft complications, dysgeusia, pruritus, edema, constipation; rare: hypersensitivity reactions (may be severe).

How supplied: Single-dose vials (100mg/5mL)—1, 10, 25; 200mg/10mL—1, 5,10

℞

Hematinic. Iron (as sucrose) 20mg/mL; soln for IV inj or infusion; preservative-free.

Indications: Iron deficiency anemia in chronic kidney disease.

Adults: Give by slow IV inj (undiluted) or infusion (diluted). Usual total cumulative dose: 1000mg.

Hemodialysis dependent: 100mg slow IV inj over 2–5 mins or infuse 100mg over at least 15 mins per consecutive session. Non-dialysis dependent: 200mg slow IV inj over 2–5 mins on 5 different occasions within a 14-day period; limited experience with IV infusion (see full labeling).

Peritoneal dialysis dependent: Two infusions

AMICAR TABLETS Clover

℞

Hemostatic (plasmin and plasminogen activator inhibitor). Aminocaproic acid 500mg, 1000mg; scored tabs. ℞ Also: AMICAR ORAL SOLUTION Aminocaproic acid 250mg/mL; raspberry-flavor.

Indications: Bleeding associated with fibrinolysis.

Adults: Initially 5g during 1st hour, then 1g/hour for 8 hours or until bleeding is controlled.

Children: Not recommended.

Also: Aminocaproic Acid Injection (various) ℞ Aminocaproic acid 250mg/mL; soln for IV infusion after dilution; contains benzyl alcohol.

Adults: 4–5g (in 250mL of diluent) by IV infusion during the 1st hour, then 1g/hour (in 50mL of diluent) for 8 hours or until bleeding is controlled.

Children: Not recommended.

Contraindications: Active intravascular clotting process. Disseminated intravascular coagulation without concomitant heparin.

Warnings/Precautions: Upper urinary tract bleeding: not recommended. Cardiac, hepatic or renal disease. Risk of myopathy with longterm use; monitor creatine phosphokinase (CPK); discontinue if CPK rises. Avoid rapid IV administration. Neonates. Pregnancy (Cat.C).

Nursing mothers.

Interactions: Avoid concomitant Factor IX complex or Anti-inhibitor Coagulant concentrates; may increase thrombosis risk.

Adverse reactions: Inj site reactions, bradycardia, hypotension, GI upset, edema, headache, malaise, CNS effects, thrombosis, others; rare: myopathy.

How supplied: Tabs—100; Oral soln—473mL; Inj—contact supplier

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ASSOCIATED HEMATOLOGICAL DISORDERS CARIMUNE NF CSL Behring

℞

Immune globulin. Immune globulin (human) 3g, 6g, 12g; per vial; pwd for IV infusion after reconstitution; contains sucrose and NaCl; preservative-free.

Indications: Immune thrombocytopenic purpura (ITP).

Adults and Children: Induction: give by IV infusion at a rate of 0.5mg/kg/min for first 30mins, if tolerated may increase to 1mg/kg/min up to max 3mg/kg/min in a stepwise manner.

0.4g/kg on 2–5 consecutive days. Use of 6% immunoglobulin solution is recommended. Acute childhood ITP: discontinue therapy after second day of 5 day course if platelet count response to first two doses is 30–50000/μL. Maintenance: If platelet count falls to <30000/μL and/or clinically significant bleed: give 0.4g/kg as a single infusion, may increase to 0.8–1g/kg as single infusion if inadequate response. Risk of renal dysfunction/failure or thrombosis: max infusion rate <2mg/kg/min.

Contraindications: IgA-deficiency with antibodies against IgA. Previous severe reaction to human immune globulin.

Warnings/Precautions: Advanced age, prolonged immobilization, hypercoagulable conditions, history of venous or arterial thrombosis, use of estrogens, indwelling central vascular catheters, hyperviscosity, cardiovascular risk factors: increased risk of thrombosis. Monitor for signs/symptoms of thrombosis and assess blood viscosity in patients at risk for hyperviscosity.

Pre-existing renal insufficiency, diabetes, >65yrs, hypovolemia, sepsis, paraproteinemia: increased risk of renal dysfunction or acute renal failure.

Correct volume depletion; assess renal function, BUN, serum creatinine, urine output before and during therapy; discontinue if renal function deteriorates. Monitor for aseptic meningitis, hemolysis and delayed hemolytic anemia.

Monitor for pulmonary dysfunction; perform test for anti-neutrophil antibodies if transfusionrelated acute lung injury (TRALI) suspected.

Contains human plasma; monitor for possible infection transmission. Have epinephrine inj available. Elderly. Pregnancy (Cat.C).

Interactions: Concomitant nephrotoxic drugs: increased risk of renal toxicity. May affect response to live virus vaccines.

Adverse reactions: Headache, arthralgia, myalgia, transient skin reactions, infusion reactions (eg, flushing, chills, fever), renal toxicities; aseptic meningitis syndrome (esp. high dose 2g/kg), TRALI, thrombosis.

How supplied: Single-use vial—1

CORIFACT CSL Behring

℞

Clotting factor. Factor XIII concentrate (human); 1000–1600 units; per vial; powder for IV injection after reconstitution; preservative-free.

Indications: Routine prophylactic treatment and peri-operative management of surgical bleeding in patients with congenital Factor XIII (FXIII) deficiency.

Adults and Children: Give by slow IV injection at a rate of ≤4mL/min. Initially 40units/kg. Adjust ±5units/kg to maintain 5–20% trough FXIII activity levels using Berichrom Activity Assay: One trough level of <5%: increase by 5units/kg; trough level of 5–20%: no change; two trough levels of >20%: decrease by 5units/kg; one trough level of >25%: decrease by 5units/kg.

Routine prophylaxis: give every 28 days. Perioperative management: individualized based on patient’s FXIII activity level, surgery type, and clinical response; dose adjustment: see full labeling.

Warnings/Precautions: Contains human plasma; monitor for possible infection transmission. Long-term therapy: consider appropriate vaccination (hepatitis A and B virus).

Monitor FXIII activity levels during and after surgery. Monitor for development of inhibitory antibodies, thromboembolic events. Pregnancy (Cat.C). Nursing mothers.

Adverse reactions: Joint inflammation, hypersensitivity, rash, pruritus, erythema, hematoma, arthralgia, headache, elevated thrombin-antithrombin levels, increased blood lactate dehydrogenase; acute ischemia, neutralizing antibodies.

How supplied: Single-use vial—1

CYKLOKAPRON Pfizer

℞

Plasminogen activation inhibitor. Tranexamic acid 100mg/mL; soln for IV inj.

Indications: Short-term use in hemophilia to reduce or prevent hemorrhage, and reduce the need for replacement therapy during and following tooth extraction.

Adults and Children: Give by IV inj. Max injection rate: 1mL/min. Pre-extraction: 10mg/kg; Post-op: 10mg/kg 3–4 times daily for 2–8 days. Renal impairment: serum creatinine 1.36–2.83mg/dL: 10mg/kg twice daily; 2.83–5.66mg/dL: 10mg/kg once daily; >5.66mg/dL: 10mg/kg every 48hrs or 5mg/kg every 24 hours.

Contraindications: Acquired defective color vision. Subarachnoid hemorrhage. Active intravascular clotting.

Warnings/Precautions: Therapy longer than several days: do ophthalmologic exam (before and during); discontinue if visual changes occur. Renal insufficiency; reduce dose. History of thromboembolic disease. Disseminated intravascular coagulation. Upper urinary tract bleeding. Pregnancy (Cat.B). Nursing mothers.

Interactions: Avoid concomitant Factor IX complex concentrates or Anti-inhibitor Coagulant concentrates; increased risk of thrombosis. Do not mix with solutions containing penicillin.

Adverse reactions: GI upset, giddiness, hypotension, visual abnormalities; rare: thromboembolic events.

How supplied: Amps (10mL)—10

ETHAMOLIN QOL Medical

℞

Sclerosing agent. Ethanolamine oleate 50mg/mL; soln for IV inj; contains benzyl alcohol 2%.

Indications: For the treatment of esophageal varices that have recently bled, to prevent rebleeding.

Adults: Usual IV dose: 1.5–5mL per varix. Max dose per treatment session: 20mL. Child Class C or concomitant cardiopulmonary disease: give less than the recommended max dose. To obliterate the varix, may give injections at the time of the acute bleeding episode and then after one week, six weeks, three months, and six months as indicated.

Children: Not recommended.

Warnings/Precautions: Should be performed by physician familiar with technique. Submucosal inj: not recommended. Cardiorespiratory disease; monitor. Child Class C (more likely to develop esophageal ulceration). Elderly, critically ill (increased risk of fatal aspiration pneumonia).

Pregnancy (Cat.C). Nursing mothers.

Adverse reactions: Pleural effusion/ infiltration, esophageal ulcer, pyrexia, retrosternal pain, esophageal stricture, pneumonia, rare: anaphylactic reaction (may be fatal), acute renal failure.

How supplied: Ampules (2mL)—10

FEIBA Baxter

℞

Clotting factor. Anti-inhibitor Coagulant Complex (AICC) 500 units, 1000 units, 2500 units; per vial; lyophilized pwd for IV infusion after reconstitution; contains Factors II, IX, X (non-activated); Factor VII (activated); Factor VIII inhibitor bypassing activity; Prothrombin Complex Factors; heparin-free.

Indications: To control and prevent bleeding episodes, perioperative management, or as routine prophylaxis to prevent or reduce the

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DRUG MONOGRAPHS

ASSOCIATED HEMATOLOGICAL DISORDERS frequency of bleeding episodes in Hemophilia A and B with inhibitors (see full labeling). Not for treating bleeding episodes due to coagulation factor deficiencies in the absence of inhibitors to factor VIII or IX. Adults and Children: Infusion rate: ≤2units/kg/ min. Joint hemorrhage: 50–100units/kg every 12hrs until improved. Mucous membrane bleeding: 50–100units/kg every 6hrs for at least 1 day or until resolved. Soft tissue hemorrhage: 100units/kg every 12hrs until resolved.

Other severe hemorrhage (eg, CNS bleeds): 100units/kg every 6–12hrs until resolved.

Preoperative: 50–100units/kg once immediately prior to surgery. Postoperative: 50–100units/kg every 6–12hrs until resolved and healed. Routine prophylaxis: 85units/kg every other day. All: Max 200units/kg per day (100units/kg per dose).

Contraindications: Hypersensitivity to factors of the kinin generating system. Disseminated intravascular coagulation (DIC). Acute thrombosis or embolism (including myocardial infarction).

Warnings/Precautions: Increased risk of thromboembolic events esp. after high-doses (>200units/kg/day) and/or in patients with thrombotic risk factors (eg, DIC, atherosclerosis, crush injury, septicemia, concomitant recombinant factor VIIa). Monitor patients receiving doses >100units/kg for DIC development, acute coronary ischemia, and signs/symptoms of other thromboembolic events; discontinue if occurs and treat.

Discontinue if hypersensitivity reactions occur.

Contains human plasma; monitor for possible infection transmission. Elderly. Neonates.

Pregnancy (Cat.C). Nursing mothers.

Interactions: Separate systemic antifibrinolytics by 12hrs.

Adverse reactions: Anemia, diarrhea, hemarthrosis, hep B surface antibody positive, nausea, vomiting; hypersensitivity, thromboembolic events (eg, stroke, DVT, PE).

Note: Report all infections suspected to be transmitted by Feiba to (800) 423-2862.

How supplied: Single-dose vials—1 (w. diluent, transfer device)

GAMUNEX-C Grifols Biologicals

℞

Immune globulin. Immune Globulin (human) 1g/10mL, 2.5g/25mL, 5g/50mL, 10g/100mL, 20g/200mL; soln for IV or SC infusion; preservative- and sucrose-free.

Indications: Idiopathic thrombocytopenic purpura (ITP).

Adults and Children: Give by IV infusion at a rate of 1mg/kg/min for first 30mins, if tolerated may increase to max 8mg/kg/min. 1g/kg once daily given on 2 consecutive days or 0.4g/kg once daily given on 5 consecutive days. If adequate response after first 1g/kg dose, may withhold second dose. Risk of renal dysfunction or thrombosis: give at minimum practicable infusion rate (<8mg/kg/min). Expanded fluid volumes: high dose regimen not recommended.

Contraindications: IgA deficiency with antibodies against IgA. Previous severe reaction to human immune globulin.

Warnings/Precautions: Advanced age, prolonged immobilization, hypercoagulable conditions, history of venous or arterial thrombosis, use of estrogens, indwelling central vascular catheters, hyperviscosity, cardiovascular risk factors: increased risk of thrombosis. Monitor for signs/symptoms of thrombosis and assess blood viscosity in patients at risk for hyperviscosity. Pre-existing renal insufficiency, diabetes, >65yrs, hypovolemia, sepsis, paraproteinemia: increased risk of renal dysfunction or acute renal failure. Correct volume depletion; assess renal function, BUN, serum creatinine, urine output before and during therapy; discontinue if renal function deteriorates.

Monitor for aseptic meningitis, hemolysis, hemolytic anemia. Monitor for pulmonary dysfunction; perform test for anti-neutrophil antibodies if transfusion-related acute lung injury (TRALI) suspected. Contains human plasma; monitor for possible infection transmission. Have epinephrine inj available. Pregnancy (Cat.C).

Nursing mothers: not evaluated.

Interactions: May affect response to live virus vaccines. Concomitant nephrotoxic drugs: increased risk of acute renal failure. May cause false positive direct or indirect Coombs’ test.

Adverse reactions: Headache, vomiting, fever, nausea, back pain, rash; renal dysfunction (may be fatal), hypersensitivity reactions; rare: hemolytic anemia, aseptic meningitis syndrome (esp. high dose of 2g/kg and/or rapid infusion), TRALI, thrombosis, hyperproteinemia.

Note: Report all infections suspected to be transmitted by Gamunex-C to (800) 520-2807.

How supplied: Vials—1

HELIXATE FS CSL Behring

℞

Clotting factor. Antihemophilic Factor VIII (recombinant) 250 IU, 500 IU, 1000 IU; per bottle; dried concentrate for IV infusion after reconstitution; contains sucrose; preservativefree.

Indications: Prevention and control of hemorrhagic episodes or in order to perform emergency or elective surgery in Hemophilia A patients.

Adults and Children: Dosage Required (IU) = Body Weight (kg) × Desired % Factor VIII Increase × 0.5. Individualize. Infuse over 5–10minutes if tolerated. Minor hemorrhage: 10–20 IU/kg; may repeat dose if needed.

Moderate/major hemorrhage or minor surgery: 15–30 IU/kg; may repeat 1 dose at 12–24hrs if needed. Major/life-threatening hemorrhage, fractures or head trauma: initially 40–50 IU/kg, then 20–25 IU/kg every 8–12hrs. Major surgery: pre-op dose: 50 IU/kg (verify ∼100% activity prior to surgery); may repeat after 6–12hrs initially, and for 10–14 days until completely healed.

Contraindications: Mouse or hamster protein sensitivity.

Warnings/Precautions: Not for treating von Willebrand’s disease. Confirm Factor VIII deficiency prior to treatment. Monitor for development of Factor VIII inhibitors. Pregnancy (Cat.C). Nursing mothers.

Adverse reactions: Inj site reactions, dizziness, rash, dysgeusia, increased BP, pruritus, depersonalization, GI upset, rhinitis; antibody formation, hypersensitivity reactions.

How supplied: Single-use bottle—1 (w. diluent)

HUMATE-P CSL Behring

℞

Clotting factors. Antihemophilic Factor VIII/Von Willebrand Factor Complex (human) 250 IU FVIII + 600 IU VWF, 500 IU FVIII + 1200 IU VWF, 1000 IU FVIII + 2400 IU VWF; per vial; lyophilized pwd for IV infusion after reconstitution; contains albumin.

Indications: Treatment and prevention of bleeding in adults with Hemophilia A. Treatment of spontaneous and trauma-induced bleeding, and prevention of excessive bleeding during and after surgery in adults and children with von Willebrand disease (VWD).

Adults: Max injection rate: 4mL/min. Hemophilia A: Minor bleed: 15 IU FVIII/kg (obtain 30% FVIII increase) once; if needed, may give ½ dose once or twice daily for 1–2 days. Moderate bleed: initially 25 IU FVIII/kg (obtain 50% FVIII increase), then 15 IU FVIII/kg (maintain 30% FVIII increase) every 8–12hrs for 1–2 days, then repeat dose for 1–2 times daily for a total of 7 days or until healed. Severe bleed: initially 40–50 IU FVIII/kg, then 20–25 IU FVIII/kg every 8hrs (maintain 80–100% FVIII increase) for 7 days, then repeat dose for 1–2 times daily for additional 7 days (maintain 30–50% FVIII increase). VWD: Type 1 (Mild): major bleed: initially 40–60 IU/kg, then 40–50 IU/kg every 8–12hrs for 3 days, then once daily for a total of 7 days. Type 1 (Moderate or severe): minor bleed: 40–50 IU/kg for 1–2 doses; major bleed: initially 50–75 IU/kg, then 40–60 IU/kg every 8–12hrs for 3 days, then once daily for a total of 7 days.

Types 2 and 3: minor bleed: 40–50 IU/kg for 1–2 doses; major bleed: initially 60–80 IU/kg, then 40–60 IU/kg every 8–12hrs for 3 days, then once daily for a total of 7 days. For dosing in surgery: see literature.

Children: Max injection rate: 4mL/min. VWD: Type 1 (Mild): major bleed: initially 40–60 IU/kg, then 40–50 IU/kg every 8–12hrs for 3 days, then once daily for a total of 7 days. Type 1 (Moderate or severe): minor bleed: 40–50 IU/kg for 1–2 doses; major bleed: initially 50–75 IU/kg, then 40–60 IU/kg every 8–12hrs for 3 days, then once daily for a total of 7 days. Types 2 and 3: minor bleed: 40–50 IU/kg for 1–2 doses; major bleed: initially 60–80 IU/kg, then 40–60 IU/kg every 8–12hrs for 3 days, then once daily for a total of 7 days. For dosing in surgery: see literature.

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ASSOCIATED HEMATOLOGICAL DISORDERS Contraindications: Previous anaphylactic or severe systemic response to antihemophilic factor or von Willebrand factor preparations.

Warnings/Precautions: Confirm Factor VIII or von Willebrand factor deficiency prior to treatment. Increased risk of thromboembolic events in VWD. Contains human plasma; monitor for possible infection transmission. Large or frequent doses: monitor hematocrit for signs of hemolytic anemia. Monitor for development of inhibitors. Pregnancy (Cat.C).

Adverse reactions: Allergic reaction, GI upset, inj site reactions, mild vasodilation, pruritus, paresthesia, peripheral edema, antibody formation; anaphylaxis, thrombosis.

Note: Report all infections suspected to be transmitted by Humate-P to (800) 504–5434.

How supplied: Single-use vials—1 (w. diluent, supplies)

KCENTRA CSL Behring

℞

Clotting factor. Prothrombin complex concentrate (human) 500 units, 1000 units; per vial; lyophilized pwd for IV infusion after reconstitution; contains non-activated coagulation Factors II, VII, IX, X, antithrombotic Proteins C and S; also, heparin, human albumin, antithrombin III; preservative-free; latex-free.

Indications: Urgent reversal of acquired coagulation factor deficiency induced by Vitamin K antagonist (VKA) therapy in adults with acute major bleeding or need for an urgent surgery/ invasive procedure.

Adults: See full labeling. Administer concomitant Vitamin K. Individualize dosing based on patient’s baseline INR and weight. Potency (units) is defined by Factor IX content. Give by IV Infusion at a rate of 0.12mL/kg/min (∼3 units/kg/min); max rate of 8.4mL/min (∼210 units/min). ≤100kg: Pre-treatment INR: (2–<4): 25 units of Factor IX/kg; max 2500 units; (4–6): 35 units of Factor IX/kg; max 3500 units; (>6): 50 units of Factor IX/kg; max 5000 units. >100kg: do not exceed max dose. Repeat dosing: not recommended.

Children: Not established.

Contraindications: Severe hypersensitivity to heparin, Factors II, VII, IX, X, Proteins C and S, antithrombin III, human albumin. Disseminated intravascular coagulation (DIC). Known heparininduced thrombocytopenia (HIT).

Warnings/Precautions: Risk of arterial and venous thromboembolic complications (may be fatal). History of thromboembolic events within the previous 3 months. Monitor for signs/ symptoms of thromboembolic events during

and after infusion. Discontinue immediately if hypersensitivity reactions occur. Measure INR before, during, and after each treatment. Contains human plasma; monitor for possible infection transmission. Pregnancy (Cat.C). Nursing mothers.

Adverse reactions: Headache, nausea, vomiting, hypotension, anemia; hypersensitivity, thromboembolic events (eg, stroke, PE, DVT).

Note: Report all infections suspected to be transmitted by Kcentra to (866) 915-6958.

How supplied: Kit (500 units, 1000 units)—1 (single-use vial + diluent, supplies)

NEUMEGA Pfizer

℞

Thrombopoietic growth factor (Interleukin-11).

Oprelvekin 5mg/vial; lyophilized pwd for SC inj after reconstitution; preservative-free.

Indications: Prevention of severe thrombocytopenia. To reduce platelet transfusions following myelosuppressive chemotherapy in adults with non-myeloid malignancies who are at high risk of severe thrombocytopenia.

Adults: Initiate 6–24hrs after chemotherapy completion. Give by SC inj into abdomen, thigh, or hip; also upper arm if not self-injecting.

50micrograms/kg once daily until post-nadir platelet count is ≥50,000/microliter; max 21 days.

Discontinue ≥2days prior to next chemotherapy cycle. Severe renal impairment: CrCl <30mL/min: 25micrograms/kg. May give for ≤6 cycles following chemotherapy.

Children: Not recommended.

Warnings/Precautions: Not for use after myeloablative chemotherapy. Monitor fluid balance and electrolytes; increased risk of serious fluid retention with CHF, renal impairment, chronic diuretic or aggressive hydration therapy. Consider draining pre-existing fluid collections (eg, pericardial effusion, ascites).

Obtain CBCs before and during therapy; monitor platelet counts. Pre-existing papilledema or tumors involving the CNS. History of stroke, transient ischemic attack, or atrial arrhythmias.

Effectiveness unknown with chemotherapy regimens >5 days duration or with regimens associated with delayed myelosuppression (eg, nitrosoureas, mitomycin-C). Pregnancy (Cat.C).

Nursing mothers: not recommended.

Adverse reactions: Edema, dyspnea, tachycardia, conjunctival injection, palpitations, atrial arrhythmias, pleural effusions, neutropenic fever, syncope, atrial fibrillation, fever, pneumonia, CHF, pulmonary edema, dilutional anemia, blurred vision, paresthesia, dehydration,

skin discoloration, exfoliative dermatitis, eye hemorrhage, stroke, papilledema, hypersensitivity reactions (permanently discontinue if occur).

How supplied: Single-use vials—7 (w. diluent)

NITROPRESS Hospira

℞

Vasodilator. Sodium nitroprusside 25mg/mL; soln for IV infusion after dilution.

Indications: To produce controlled hypotension to reduce surgical bleeding.

Adults and Children: Use infusion pump only.

Monitor BP closely. Initially 0.3microgram/kg/ min; may increase infusion rate every few minutes until desired effect; max 10microgram/kg/min and no more than 10 minutes. Titrate infusion rate (see literature).

Contraindications: Compensatory hypertension due to aortic coarctation or arteriovenous shunting. Inadequate cerebral circulation or moribund patients requiring emergency surgery. Congenital (Lebers) optic atrophy. Tobacco amblyopia. Acute CHF associated with reduced peripheral vascular resistance.

Warnings/Precautions: Use only when available equipment and personnel allow BP to be continuously monitored. Cyanide toxicity possible (esp. at infusion rates >2micrograms/kg/min); monitor acid-base disturbances and venous oxygen concentration. Elevated intracranial pressure. Correct pre-existing anemia and hypovolemia, esp. during anesthesia. Poor surigical risk. Hepatic impairment. Elderly.

Pregnancy (Cat.C). Nursing mothers: not recommended.

Interactions: Hypotensive effect potentiated by ganglionic blocking agents, negative inotropic agents, and inhaled anesthetics.

Adverse reactions: Excessive hypotension, cyanide toxicity, methemoglobinemia, abdominal pain, apprehension, diaphoresis, dizziness, headache, muscle twitch, nausea, palpitations, restlessness, rash, hypothyroidism, ileus, flushing, infusion site reactions.

How supplied: Single-dose vials (2mL)—100

NOVOSEVEN RT Novo Nordisk

℞

Clotting factors. Recombinant Coagulation Factor VIIa (rFVIIa) Room Temperature Stable 1mg, 2mg, 5mg, 8mg; per vial; lyophilized pwd for IV inj after reconstitution; preservative-free.

Indications: Treatment of bleeding and peri-operative management in adults and children with Hemophilia A and B with inhibitors, congenital Factor VII deficiency, and Glanzmann’s thrombasthenia refractory to

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ASSOCIATED HEMATOLOGICAL DISORDERS platelet transfusions, with or without antibodies to platelets. Treatment of bleeding and perioperative management in adults with acquired hemophilia.

Adults and Children: See full labeling. Give by IV bolus only. Individualize; base treatment schedule modification on hemostasis evaluation. Hemophilia A or B with inhibitors: Bleeding: 90mcg/kg every 2hrs, adjust until hemostasis is achieved; posthemostatic dosing: continue at 3–6hrs intervals for severe bleeds. Peri-operative: initially 90mcg/kg prior to surgery, repeat at 2hr intervals during surgery; minor (post-surgical dosing): every 2hrs for 48hrs, then every 2–6hrs until healed; major (post-surgical dosing): every 2hrs for 5 days, then every 4hrs until healed. Congenital Factor VII deficiency: Bleeding: 15–30mcg/kg every 4–6hrs until hemostasis is achieved; Perioperative: 15–30mcg/kg prior to surgery, repeat every 4–6hrs during surgery and until hemostasis is achieved. Glanzmann’s thrombasthenia: Bleeding: 90mcg/kg every 2–6hrs until hemostasis is achieved; Peri-operative: initially 90mcg/kg prior to surgery, repeat every 2hrs during surgery, then every 2–6hrs post-surgical.

Acquired hemophilia: Bleeding: 70–90mcg/kg every 2–3hrs until hemostasis is achieved; Perioperative: 70–90mcg/kg prior to surgery, repeat every 2–3hrs during surgery and until hemostasis is achieved.

Warnings/Precautions: Risk of serious arterial and venous thromboembolic events.

Disseminated intravascular coagulation (DIC), advanced atherosclerotic disease, crush injury, septicemia, uncontrolled post-partum hemorrhage, history of coronary heart disease, hepatic disease, post-op immobilization, elderly, neonates; increased risk of developing thrombotic events. Monitor for signs/symptoms of coagulation activation or thrombosis; discontinue or reduce dose if occur. Monitor prothrombin time and FVII coagulant activity before and after dosing in FVII deficiency. Perform analysis for antibodies if factor VIIa activity fails to reach expected level. Mouse, hamster, or bovine protein hypersensitivity. Pregnancy (Cat.C). Nursing mothers: not recommended.

Interactions: Avoid concomitant activated or non-activated prothrombin complex concentrates; may increase risk of thrombotic events. Do not mix with infusion solutions.

Concomitant Coagulation Factor XIII may cause thrombosis.

Adverse reactions: Thrombotic events, fever, fibrinogen plasma decreased, hypertension, headache, nausea, dyspnea; pain, thrombophlebitis, pulmonary embolism, decreased therapeutic response, cerebrovascular disorder, angina pectoris, abnormal hepatic function, DIC, hypersensitivity reactions (discontinue and treat if occur).

How supplied: Single-use vial—1 (w. diluent); MixPro—1 (single-use vial + pre-filled diluent syringe + vial adapter)

NPLATE Amgen

℞

Thrombopoietin receptor agonist. Romiplostim (recombinant) 250mcg, 500mcg; per vial; lyophilized pwd for SC inj after reconstitution; contains sucrose and mannitol; preservative-free.

Indications: Thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic purpura (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.

Adults: Give by SC inj. To reduce risk of bleeding: use lowest effective dose to achieve and maintain platelets ≥50×109/L. ≥18yrs: initially: 1mcg/kg weekly; may increase by 1mcg/kg if platelets <50×109/L; max: 10mcg/kg weekly. May reduce by 1mcg/kg if platelets >200×109/L for 2 consecutive weeks. Do not dose if platelets >400×109/L; resume Nplate at a dose reduced by 1mcg/kg when platelets fall to <200×109/L. Discontinue if platelets have not increased after 4 weeks at max dose.

Children: <18yrs: not recommended.

Warnings/Precautions: Not for normalization of platelet counts or to treat thrombocytopenia due to MDS or any cause of thrombocytopenia other than chronic ITP. Risk of bone marrow fibrosis with cytopenias. Worsened thrombocytopenia after discontinuation. Monitor CBCs, platelets, and peripheral blood smears before and weekly during dose adjustments then monthly after achieving stable dose; and weekly for 2 weeks after discontinuation of therapy.

Monitor after initial response for formation of neutralizing antibodies. Risk of hematologic malignancies (esp. myelodysplastic syndrome).

Renal or hepatic impairment. Elderly. Pregnancy (Cat.C). Nursing mothers.

Interactions: May increase bleeding risk with anticoagulants or antiplatelet agents.

Adverse reactions: Arthralgia, dizziness, insomnia, myalgia, pain in extremity, abdominal pain, shoulder pain, dyspepsia, paresthesia, headaches; bone marrow reticulin deposition, worsening thrombocytopenia, risk of bleeding, thrombotic/thromboembolic complications, antibody formation.

How supplied: Single-use vial—1

PRIVIGEN CSL Behring

℞

Immune globulin. Immune globulin (human) 0.1g/mL; soln for IV infusion; contains L-proline; sucrose-, preservative-, and latex-free.

Indications: Chronic immune thrombocytopenic purpura (ITP).

Adults and Children: <15yrs: not established. ≥15yrs: Give by IV infusion at an initial rate of 0.5mg/kg/min, if tolerated may increase to 4mg/kg/min. Renal dysfunction, thrombosis risk: give at the minimum infusion rate practicable.

Usual dose: 1g/kg once daily for 2 consecutive days for a total dose of 2g/kg. Increased risk of thrombosis, hemolysis, acute renal injury, or volume overload: consider carefully the relative

risks and benefits before prescribing high dose regimen (2g/kg).

Contraindications: IgA-deficiency with antibodies against IgA and history of hypersensitivity. Hyperprolinemia. Previous severe reaction to human immune globulin.

Warnings/Precautions: Advanced age, prolonged immobilization, hypercoagulable conditions, history of venous or arterial thrombosis, use of estrogens, indwelling central vascular catheters, hyperviscosity, cardiovascular risk factors: increased risk of thrombosis.

Monitor for signs/symptoms of thrombosis and assess blood viscosity in patients at risk for hyperviscosity. Pre-existing renal insufficiency, diabetes, >65yrs, obese, hypovolemia: increased risk of renal dysfunction and acute renal failure. Correct volume depletion; assess renal function, BUN, serum creatinine, urine output before and during therapy; discontinue if renal function deteriorates. Monitor for aseptic meningitis, hemolysis, delayed hemolytic anemia, transfusion-related acute lung injury (eg, respiratory distress, pulmonary edema, hypoxemia). Antibody formation. Risk of transmission of viral diseases. Have epinephrine inj available. Elderly. Pregnancy (Cat.C). Nursing mothers.

Interactions: Concomitant nephrotoxic drugs: increased risk of renal toxicity. May affect response to live virus vaccines. May interfere with serological test interpretation.

Adverse reactions: Headache, elevated body temperature, positive direct antiglobulin test, anemia, nausea, epistaxis, vomiting, hematocrit decreased, increase in blood bilirubin, blood total bilirubin and blood lactate dehydrogenase; hyperproteinemia, increased serum viscosity, hyponatremia; rare: aseptic meningitis syndrome (esp. high dose of 2g/kg), hemolysis, TRALI, thrombosis.

How supplied: Single-use vial (50mL, 100mL, 200mL, 400mL)—1

PROMACTA GlaxoSmithKline

℞

Thrombopoietin receptor agonist. Eltrombopag (as olamine) 12.5mg, 25mg, 50mg, 75mg; tabs.

Indications: Thrombocytopenia in adults with chronic immune (idiopathic) thrombocytopenic purpura (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Thrombocytopenia in adults with chronic hepatitis C to allow initiation and maintenance of interferon-based therapy.

Limitations of use: should be used only in ITP whose degree of thrombocytopenia and clinical condition increase the risk of bleeding; or, in chronic hepatitis C whose degree of thrombocytopenia prevents starting or limiting ability to maintain interferon-based therapy. Safety and efficacy not established in combination with direct-acting antiviral agents without interferon for chronic hepatitis C infection.

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ASSOCIATED HEMATOLOGICAL DISORDERS Adults: Take on empty stomach. ITP: initially 50mg once daily. Hepatic impairment or East Asian ancestry: initially 25mg once daily. East Asian ancestry with hepatic impairment: consider initiating at 12.5mg once daily. Titrate to maintain platelet count ≥50×109/L; max 75mg once daily. Chronic hepatitis C-associated thrombocytopenia: initially 25mg once daily. Titrate dose by 25mg every 2 weeks as needed to achieve target platelet counts; max 100mg/day. Monitoring, dose adjustment, and discontinuation: see full labeling.

Children: Not established.

Warnings/Precautions: Increased risk of hepatic decompensation in chronic hepatitis C, when concomitant with interferon and ribavirin; discontinue Promacta if antiviral therapy is discontinued. Monitor liver function prior to initiation, every 2 weeks during dose adjustments, and monthly after stabilized (see full labeling); discontinue if ALT ≥3×ULN and is progressive or persistent for ≥4 weeks, or if occurs with increased bilirubin, or evidence of hepatic injury/ decompensation; reinitiate therapy if benefit outweighs risk; if restarted, monitor carefully.

Increased risk of thromboembolism; do not use to normalize platelet counts. Do baseline eye exam; monitor for cataracts. Renal impairment.

Pregnancy (Cat.C). Nursing mothers: not recommended.

Interactions: Do not take within 4hrs of food/ drugs containing polyvalent cations (eg, Fe+2, Ca+2, Al+3, Mg+2, Se+2, Zn+2). Potentiate substrates of OATP1B1 (eg, most statins, bosentan, ezetimibe, glyburide, olmesartan, valsartan, repaglinide, rifampin) or BCRP (eg, imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone, sulfasalazine, topotecan); monitor and consider reducing their doses. Antagonized by lopinavir/ ritonavir.

Adverse reactions: Nausea, diarrhea, vomiting, infections, increased ALT/AST, myalgia, pain, pharyngitis, paresthesia, rash, anemia, pyrexia, fatigue, headache, decreased appetite, asthenia, insomnia, cough, pruritus, chills, alopecia, peripheral edema; hepatotoxicity, hemorrhage, thrombotic complications from excessive increases in platelet counts, cataracts.

How supplied: Tabs—30

RECOTHROM ZymoGenetics Topical hemostatic. Thrombin [recombinant] 5000 IU, 20000 IU; per vial; pwd for topical use after reconstitution; preservative-free.

Indications: Aid to hemostasis for minor bleeding/oozing from capillaries and venules

℞

when standard surgical techniques are inadequate or ineffective. May use with absorbable gelatin sponge.

Adults: Apply directly to bleeding area, or soak into absorbable gelatin sponge and apply in a single layer.

Children: Not recommended.

Contraindications: Not for direct injection into circulatory system. Not for treatment of massive or brisk arterial bleeding. Hypersensitivity to hamster proteins.

Warnings/Precautions: Avoid systemic absorption (thrombosis may occur).

Hypersensitivity to snake proteins. Pregnancy (Cat.C).

Adverse reactions: Incision site complication, infection, pain, bleeding, nausea/vomiting, cardiac events, thromboembolic events.

How supplied: Single-use vial (5000 IU, 20000 IU)—1 (w. diluent, supplies) 20000 IU Recothrom kit (co-packaged with ZymoGenetics Spray Applicator Kit)—1

REFACTO Pfizer

℞

Clotting factor. Antihemophilic Factor VIII (recombinant) 250 IU, 500 IU, 1000 IU, 2000 IU; per vial; lyophilized pwd for IV infusion after reconstitution; preservative-free.

Indications: Prevention and control of hemorrhagic episodes and for surgical prophylaxis in Hemophilia A. Short-term routine prophylaxis to reduce frequency of spontaneous bleeding episodes.

Adults and Children: Dosage Required (IU) = Body Weight (kg) × Desired % Factor VIII Increase × 0.5. Individualize. Infuse at rate comfortable to patient. Minor hemorrhage: obtain 20–40% FVIII increase; give every 12–24hrs for at least 1 day until resolved. Moderate hemorrhage and tooth extraction: obtain 30–60% FVIII increase; give every 12–24hrs for 3–4 days until adequate hemostasis; for tooth extraction: a single infusion plus oral antifibrinolytic therapy within 1hr may be sufficient. Major hemorrhage: obtain 60–100% FVIII increase; give every 8–24hrs until resolved; or, for surgery, until local hemostasis achieved. Prophylaxis: give ≥2 times weekly; children may need shorter dosage intervals or higher doses.

Contraindications: Mouse or hamster protein sensitivity.

Warnings/Precautions: Not for von Willebrand’s disease. Confirm Factor VIII deficiency prior to treatment. Monitor for development of Factor VIII inhibitors. Pregnancy (Cat.C). Nursing mothers.

Adverse reactions: Allergic reactions, headache, fever, chills, flushing, nausea, vomiting, lethargy, pruritus, antibody formation.

How supplied: Single-use vial—1 (w. diluent, supplies)

RHOPHYLAC CSL Behring

℞

Rho (D) immune globulin human 1500 IU (300mcg)/2mL; syringe; for IV or IM inj; preservative- and latex-free; contains albumin (human); solvent/detergent treated.

Indications: Raising platelet counts in Rho (D) positive non-splenectomized patients with chronic immune thrombocytopenic purpura (ITP).

Adults: See full labeling. 250 IU (50mcg) per kg

by IV only at rate of 2mL per 15–60 secs.

Children: Not recommended.

Contraindications: Rho (D) positive patients.

IgA deficiency.

Warnings/Precautions: Monitor patients 20 mins after administration. Pregnancy (Cat.C).

Interactions: Do not give live vaccines within 3 months.

Adverse reactions: Local or infusion reactions, fever, chills, headache; see full labeling.

How supplied: Single-dose prefilled syringes—1, 10

RIASTAP CSL Behring

℞

Hemostatic. Fibrinogen concentrate (human) 900–1300mg; per vial; lyophilized pwd for IV inj after reconstitution; contains albumin; preservative-free.

Indications: Acute bleeding episodes in patients with congenital fibrinogen deficiency, including afibrinogenemia and hypofibrinogenemia.

Adults and Children: See literature. Give by slow IV inj at rate not exceeding 5mL/min.

Individualize. Calculate dose when baseline fibrinogen level is known: Dose (mg/kg body wt) = [Target level (mg/dL)–measured level (mg/dL)]/1.7 (mg/dL per mg/kg body wt).

When baseline fibrinogen level is not known: 70mg/kg. Monitor fibrinogen level during therapy.

Maintain target fibrinogen level of 100mg/dL until hemostatis is obtained.

Warnings/Precautions: Not for use in dysfibrinogenemia. Monitor for allergic or hypersensitivity reactions; discontinue if occur. Risk of thrombosis (monitor). Contains human plasma; monitor for possible infection transmission. Labor & delivery. Pregnancy (Cat.C). Nursing mothers.

Adverse reactions: Fever, headache, chills, nausea, vomiting; thrombotic episodes (eg, pulmonary embolism, MI, DVT), anaphylactic reactions.

How supplied: Single-use vial—1

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ASSOCIATED HEMATOLOGICAL DISORDERS THROMBIN-JMI Pfizer

℞

Topical hemostatic. Thrombin [bovine origin] 5000 IU, 20000 IU; per vial; pwd for topical use after reconstitution; preservative-free.

Indications: Aid to hemostasis for oozing blood and minor bleeding from accessible capillaries and small venules. Adjunct for surgical hemostasis with absorbable gelatin sponge.

Adults: For topical use only. See literature.

Profuse bleeding (eg, abraided surfaces of liver or spleen): 1000 IU/mL. General use (eg, plastic surgery, dental extractions, skin grafting): 100 IU/mL. May dilute to prepare intermediate strengths, if needed. Oozing surfaces: may use dry form.

Children: Not recommended.

Warnings/Precautions: Not for injection or use in large blood vessels. Antibody formation: do not re-expose, abnormalities in hemostasis (eg, severe bleeding or thrombosis) more likely with repeated use. Pregnancy (Cat.C). Nursing mothers.

Adverse reactions: Hypersensitivity reactions, antibody formation.

How supplied: Vials—1 (w. diluent) Pump Spray Kit (20000 IU)—1 (w. diluent) Syringe Spray Kit (20000 IU)—1 (w. diluent) Epistaxis Kit (5000 IU)—1 (w. diluent)

WILATE Octapharma

℞

Coagulation factor complex. Von Willebrand Factor/Factor VIII Complex (human); 450 IU VWF:RCo and 450 IU FVIII activities per 5mL; 900 IU VWF:RCo and 900 IU FVIII activities per 10mL; pwd; for IV injection after reconstitution; preservative-free; solvent-detergent treated.

Indications: Bleeding episodes (spontaneous and trauma induced) in patients with severe von Willebrand disease, and patients with mild to moderate von Willebrand disease for whom desmopressin is ineffective or contraindicated.

Adults and Children: <5yrs: contact manufacturer. Give by IV injection at 2–4mL/min. ≥5yrs: Minor bleed: 20–40 IU/kg once, then 20–30 IU/kg every 12–24 hours. Major bleed: 40–60 IU/kg once, then 20–40 IU/kg every 12–24 hours. Monitor and adjust according to VWF:RCo and FVIII activity, and location of bleed; usual treatment duration is 3 days (minor hemorrhage) and 5–7 days (major hemorrhage).

See literature for activity level goals.

Warnings/Precautions: Not for prophylaxis of spontaneous bleeding, prevention of surgical bleeding, or hemophilia A. Treatment should be supervised by physician trained in coagulopathies. Risk of thrombotic events with sustained excessive FVIII levels; monitor.

Ineffectiveness may indicate antibody formation; discontinue if confirmed. Risk of transmission of blood-borne diseases; consider vaccination against hepatitis A and B. Monitor pulse during

injection; slow or stop infusion if marked increase in heart rate occurs. Pregnancy (Cat.C). Nursing mothers.

Adverse reactions: Urticaria, dizziness, hypersensitivity reactions, antibody formation.

How supplied: Kit—1 (w. diluent, supplies)

WINRHO SDF

℞

Emergent BioSolutions Rho(D) immune globulin intravenous human 600IU (120mcg), 1500IU (300mcg), 2500IU (500mcg), 5000IU (1000mcg), 15000IU (3000mcg); per vial; lyophilized pwd or soln; for IV or IM inj after reconstitution; preservativefree.

Indications: Treatment of non-splenectomized, Rho(D) positive children with acute immune thrombocytopenic purpura (ITP); adults and children with chronic ITP and ITP secondary to HIV infection; in clinical situations requiring an increase in platelet count to prevent excessive hemorrhage.

Adults and Children: Give by IV inj only. Confirm Rho(D) positive prior to treatment. Initially: 250 IU/kg as single dose or 2 divided doses on separate days; if Hgb <10g/dL, reduce to 125–200 IU/kg. Maintenance: 125–300 IU/kg; Hbg >10g/dL: 250–300 IU/kg; Hgb 8–10g/dL: 125–200 IU/kg; Hgb <8g/dL: use with caution.

Base frequency and dose on clinical response.

Contraindications: IgA deficiency. Allergy to blood products. Treatment of immune globulin deficiency syndromes.

Warnings/Precautions: Not for use in Rho(D) negative or splenectomized patients; monitor for intravascular hemolysis, anemia, renal insufficiency; hemoglobin <10g/dL decrease dose, if <8g/dL use extreme caution. Pregnancy (Cat.C).

Interactions: Do not give live vaccines within 3 months.

Adverse reactions: Headache, chills, fever, local or infusion reactions; see literature.

Note: Report all infections suspected to be transmitted by WinRho SDF to (800) 423-2090.

How supplied: Single-dose vials (pwd) 600IU, 1500IU, 5000IU—1 (w. diluent); Single-dose vials (soln) 600IU, 1500IU, 2500IU, 5000IU, 15000IU—1

XYNTHA Pfizer

℞

Clotting factor. Antihemophilic Factor (recombinant): nominally 250 IU, 500 IU, 1000 IU, or 2000 IU per vial; pwd for IV infusion after reconstitution; plasma/albumin-free; preservative-free; contains polysorbate 80. Actual factor VIII activity noted on each vial.

Indications: In Hemophilia A: to control bleeding episodes, and for surgical prophylaxis.

Adults: Individualize and titrate. Give by IV infusion over several minutes. One IU of factor VIII per kg raises the plasma factor VIII activity

by about 2 IU/dL. Minor bleeds: factor VIII level required is 20–40 IU/dL or % of normal, repeat infusion every 12–24 hours as needed for at least 1 day, until resolution. Moderate bleeds: 30–60 IU/dL or % of normal; repeat infusion every 12–24 hours for 3–4 days or until hemostasis.

Major bleeds: 60–100 IU/dL or % of normal, repeat infusion every 8–24 hours until resolution.

Minor surgical procedures: 30–60 IU/dL or % of normal, repeat infusion every 12–24 hours for 3–4 days or until hemostasis. Major surgery: 60–100 IU/dL or % of normal; repeat infusion every 8–24 hours until hemostasis and wound healing occurs.

Children: Consult manufacturer (limited pharmacokinetic data available; studies are ongoing).

Warnings/Precautions: Monitor for development of Factor VIII inhibitors; may need dose adjustment. Pregnancy (Cat.C). Labor & delivery. Nursing mothers.

Adverse reactions: Hypersensitivity reactions/ anaphylaxis, pyrexia, headache, GI upset, asthenia.

How supplied: Kit—1 (w. diluent, supplies)

White blood cell disorders

GRANIX Teva

℞

Granulocyte colony stimulating factor. Tbofilgrastim 300mcg/0.5mL, 480mcg/0.8mL; soln for SC inj; preservative-free.

Indications: To reduce the duration of severe neutropenia in patients with non-myeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia.

Adults: Administer the 1st dose no earlier than 24hrs following myelosuppressive chemotherapy. Do not administer within 24hrs prior to chemotherapy. Inject 5mcg/kg SC once daily until expected neutrophil nadir is passed and neutrophil count has recovered to normal range. Monitor CBC prior to chemotherapy and twice per week until recovery. Recommended inj sites: the abdomen (except for the 2-inch area around navel), the front of the middle thighs, the upper outer area of the buttocks, or the upper back portion of the upper arms; rotate inj site daily. Avoid injecting into an area that is tender, red, bruised or hard, or that has scars or stretch marks.

Children: <18yrs: not established.

Warnings/Precautions: Risk of splenic rupture; discontinue and evaluate if symptoms of enlarged spleen or rupture occur. Evaluate for acute respiratory distress syndrome if fever and lung infiltrates or respiratory distress develop after treatment; discontinue if acute respiratory distress syndrome is diagnosed. Permanently discontinue if serious allergic reactions occur.

Sickle cell disease: consider potential risks and

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ASSOCIATED HEMATOLOGICAL DISORDERS benefits prior to treatment and discontinue if sickle cell crisis develops. Hepatic or moderateto-severe renal impairment. Pregnancy (Cat.C).

Nursing mothers.

Interactions: Caution with drugs that may potentiate release of neutrophils (eg, lithium).

May cause transient positive changes in boneimaging test results.

Adverse reactions: Bone pain; splenic rupture (may be fatal), acute respiratory distress syndrome, serious allergic reactions, sickle cell crisis, potential for tumor growth stimulatory effects on malignant cells.

How supplied: Single-use prefilled syringe (0.5mL, 0.8mL)—1, 10 (w. safety needle guard)

LEUKINE Genzyme

℞

Granulocyte-macrophage colony stimulating factor (recombinant). Sargramostim (recombinant human granulocyte-macrophage colony stimulating factor, or rhu GM-CSF) 250mcg; per vial; pwd for SC inj or IV infusion after reconstitution; preservative-free.

Indications: To speed neutrophil recovery and reduce infections after induction chemotherapy in treatment of acute myelogenous leukemia (AML) in patients >55 years of age. To mobilize hematopoietic progenitor cells into peripheral blood for collection by leukapheresis. To speed myeloid recovery in non-Hodgkin’s lymphoma, acute lymphoblastic leukemia (ALL), and Hodgkin’s disease in autologous bone marrow transplantation (BMT). To speed myeloid recovery in allogeneic BMT. Patients with BMT failure or engraftment delay.

Adults: See literature for timing and duration of dosing, and for repeat courses of therapy.

Individualize. Neutrophil recovery: 250mcg/ m2 per day IV over 4 hrs. Mobilization or post peripheral blood progenitor cell transplantation: 250mcg/m2 per day IV over 24 hrs or SC once daily. Myeloid recovery after BMT: 250mcg/m2 per day IV over 2 hrs. BMT failure or engraftment delay: 250mcg/m2 per day IV over 2 hrs for 14 days.

Children: See literature.

Contraindications: Excessive leukemic myeloid blasts in bone marrow or peripheral blood (≥10%). Allergy to GM-CMF or yeastderived products. Concomitant (within 24 hrs) chemotherapy or radiotherapy.

Warnings/Precautions: Fluid retention, pleural or pericardial effusions. Pulmonary infiltrates. Respiratory disease or symptoms.

Hypoxia. Reduce infusion rate by ½ if dyspnea occurs; discontinue if dyspnea worsens. Cardiac

disease. CHF. Renal or hepatic dysfunction (monitor before and every other week during therapy). Monitor CBC and differential twice weekly. Reduce dose by ½ or discontinue if absolute neutrophil count exceeds 20,000cells/mm3 or if platelet count exceeds 500,000cells/mm3. Myeloid malignancies.

Monitor body weight and hydration. Pregnancy (Cat.C). Nursing mothers.

Interactions: Caution with lithium, corticosteroids, others that may enhance myeloproliferative effects. May be antagonized by radiotherapy, myelotoxic drugs.

Adverse reactions: Flu-like symptoms, GI disturbances, edema, dyspnea, pharyngitis, rash, joint or bone or chest pain, eye hemorrhage, hypomagnesemia, anxiety, headache, pleural +/or pericardial effusion, arthralgia, myalgia, others.

How supplied: Vials—5

NEULASTA Amgen

℞

Granulocyte colony stimulating factor.

Pegfilgrastim (polyethylene glycol/filgrastim conjugate) 6mg/0.6mL soln; SC inj; preservativefree.

Indications: To decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anticancer drugs associated with clinically significant incidence of febrile neutropenia.

Adults: Do not give between 14 days before and 24 hours after chemotherapy. Adolescents <45 kg: not recommended. ≥45 kg: 6mg SC once per chemotherapy cycle.

Children: Not recommended.

Contraindications: Do not use for peripheral blood progenitor cell (PBPC) mobilization.

Hypersensitivity to E. coli-derived products.

Warnings/Precautions: Monitor CBC and platelets before and during therapy. Monitor for splenomegaly/splenic rupture and for adult respiratory distress syndrome (ARDS); suspend until ARDS resolves if fever or lung infiltrates occur. Sickle cell disease (may cause sickle cell crisis). Myeloid malignancies. Myelodysplasia.

Pregnancy (Cat.C). Nursing mothers.

Interactions: Caution with drugs that cause delayed myelosuppression (eg, nitrosoureas, mitomycin C), or increase release of neutrophils (eg, lithium), antimetabolites (eg, 5-FU), and radiation therapy.

Adverse reactions: Bone pain, anaphylaxis, ARDS; splenic rupture (rare).

How supplied: Prefilled syringe—1

NEUPOGEN Amgen

℞

Granulocyte colony stimulating factor. Filgrastim 600mcg/mL prefilled syringe; for SC or IV infusion; preservative-free.

Also: NEUPOGEN VIALS ℞ Filgrastim 300mcg/mL; for SC or IV infusion; preservative-free.

Indications: See full labeling. To decrease incidence of infection in patients with nonmyeloid malignancies receiving certain myelosuppressive anti-cancer drugs. To reduce time to neutrophil recovery and fever duration after induction and consolidation chemotherapy treatment of adults with AML. To reduce duration of neutropenia and related sequelae in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by bone-marrow transplantation (BMT). To mobilize hematopoietic progenitor cells (PBPC) into peripheral blood for collection by leukapheresis. To reduce the incidence and duration of neutropenia sequelae in severe chronic neutropenia (SCN).

Adults: See full labeling. Do not give for at least 24hrs before or after cytotoxic chemotherapy dose. BMT: Give 1st dose at least 24hrs after bone marrow infusion. SCN: Give on a daily basis.

Children: See full labeling.

Contraindications: Hypersensitivity to E. coliderived products.

Warnings/Precautions: Monitor blood, including CBC and differential and platelets, before and during therapy (myelosuppressive chemotherapy: monitor twice weekly; BMT: at least 3 times weekly; SCN: twice per week during initial 4 weeks of therapy and during 2 weeks after dose adjustment).

Discontinue if post nadir absolute neutrophil count (ANC) reaches 10,000/mm3 for patients receiving myelosuppressive chemotherapy; other indications: see full labeling. Monitor for splenomegaly/splenic rupture and for adult respiratory distress syndrome (ARDS); suspend until ARDS resolves if fever or lung infiltrates occur. Confirm diagnosis and do appropriate pretreatment hematological workup in SCN. Preexisting cardiac or hyperplastic skin conditions. Sickle cell disease (may cause sickle cell crisis). Avoid simultaneous chemo- and radiation therapy. Pregnancy (Cat.C). Nursing mothers.

Interactions: Caution with mitomycin C, and with concomitant (same day) drugs that decrease platelets, or increase release of neutrophils (eg, lithium), or cause delayed myelosuppression, or with myelosuppressive doses of antimetabolites (eg, nitrosoureas, 5-FU).

Adverse reactions: Bone pain, cutaneous vasculitis, splenomegaly, others (see literature).

How supplied: Prefilled syringes (0.5mL, 0.8mL)—10; Vials (1mL, 1.6mL)—10

Access Cancer Therapy Advisor treatment regimens in a user-friendly format.

CancerTherapyAdvisor.com/TreatmentRegimens.

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DRUG MONOGRAPHS

ASSOCIATED HEMATOLOGICAL DISORDERS Miscellaneous hematological agents

CINRYZE ViroPharma

℞

C1 inhibitor. C1 inhibitor (human) 500 Units/vial; lyophilized pwd for IV infusion after reconstitution; preservative-free.

Indications: Routine prophylaxis against angioedema attacks in adolescent and adult patients with hereditary angioedema.

Adults: Give by IV infusion at a rate of 1mL/min (10mins). 1000 Units every 3–4 days.

Children: Not recommended.

Warnings/Precautions: Contains human plasma; monitor for possible infection transmission. Have epinephrine available to treat hypersensitivity reactions. Monitor patients with known risk factors for thrombotic events. Labor & delivery. Pregnancy (Cat.C). Nursing mothers.

Adverse reactions: Upper respiratory tract infection, sinusitis, rash, headache; thrombotic events, hypersensitivity reactions (may be severe); discontinue if occurs.

Note: To report infections that may have been transmitted by Cinryze, call CinryzeSolutions at (877) 945-1000.

How supplied: Single-use vial—1

EXJADE Novartis

℞

Iron chelating agent. Deferasirox 125mg, 250mg, 500mg; tabs for oral susp.

Indications: Chronic iron overload due to blood transfusions in patients ≥2yrs of age. Chronic iron overload in patients ≥10yrs of age with non-transfusion dependent thalassemia (NTDT) syndromes and with a liver iron concentration (LIC) of at least 5mg Fe per gram of dry weight and a serum ferritin >300 mcg/L. Adults and Children: Calculate dose to nearest whole tab. Take on empty stomach at least 30 mins before food. Do not chew or swallow tabs; disperse completely in water, orange juice or apple juice; drink immediately; resuspend remainder and drink.

Transfusional iron overload: <2yrs: not established. ≥2yrs: initially 20mg/kg once daily; may adjust dose by 5 or 10mg/kg every 3–6 months based on serum ferritin levels or response. If inadequate control at 30mg/kg, may consider increasing up to max 40mg/kg. Adjust dose if severe skin rashes occur; consider suspending therapy if serum ferritin <500mcg/L. NTDT syndromes: <10yrs: not established. ≥10yrs: initially 10mg/kg once daily; if baseline LIC>15mg Fe/g dw, consider increasing dose to 20mg/kg after 4 weeks. Suspend therapy if serum ferritin <300mcg/L and obtain LIC to determine whether it has fallen to <3mg Fe/g dw. After 6 months, if LIC remains >7mg Fe/g dw, increase dose to max 20mg/kg/day. If after

6 months, LIC is 3–7mg Fe/g dw, continue with max 10mg/kg/day. When LIC is <3mg Fe/g dw, interrupt treatment and continue to monitor LIC. Restart when LIC rises again to >5mg Fe/g dw.

Adjustments based on serum creatinine: see full labeling. Hepatic impairment: moderate: reduce dose by 50%; severe: avoid.

Contraindications: CrCl <40mL/min or serum creatinine >2x age-appropriate ULN. Poor performance status. High risk myelodysplastic syndromes.

Advanced malignancies. Platelets <50×109/L. Warnings/Precautions: May cause renal or hepatic failure, GI hemorrhage; may be fatal (monitor). Hepatic or renal impairment. Advanced disease or co-morbid conditions. Obtain baseline serum ferritin level, monitor monthly and adjust dose accordingly. Measure serum creatinine and CrCl in duplicate before starting therapy; monitor weekly during 1st month then at least monthly thereafter; more frequently if creatinine levels increase. Monitor for proteinuria monthly. Measure serum transaminases, bilirubin before initiating therapy then every 2 weeks during 1st month, then monthly. Monitor blood counts; interrupt therapy if cytopenias develop. For NTDT syndromes: obtain LIC by liver biopsy prior to starting therapy, monitor LIC every 6 months. Do baseline auditory and ocular exams, then every 12 months; if disturbances occur, adjust dose or suspend therapy. Elderly. Pregnancy (Cat.C). Nursing mothers: not recommended.

Interactions: Avoid aluminum-containing antacids, bile acid sequestrants (eg, cholestyramine, colesevelam, colestipol), or UGT inducers (eg, rifampicin, phenytoin, phenobarbital, ritonavir); if co-administration necessary consider increasing initial Exjade dose by 50% and monitor serum ferritin levels and clinical responses. Caution with drugs that have ulcerogenic or hemorrhagic potential (eg, NSAIDs, corticosteroids, oral bisphosphonates, anticoagulants) or drugs metabolized by CYP3A4 (eg, cyclosporine, simvastatin, hormonal contraceptives). Potentiates repaglinide (consider reducing repaglinide dose); monitor blood glucose levels. Caution with other CYP2C8 substrates (eg, paclitaxel). Avoid concomitant theophylline or other CYP1A2 substrates with narrow therapeutic index. Concomitant other iron chelation therapy: not recommended.

Adverse reactions: Diarrhea, vomiting, nausea, abdominal pain, elevated serum creatinine, rash; renal or hepatic impairment/failure (may be fatal), GI hemorrhage, cytopenias (eg, agranulocytosis, neutropenia, thrombocytopenia, anemia), hypersensitivity reactions, severe skin reactions (eg, Stevens-Johnson syndrome, erythema multiforme); discontinue if occurs.

How supplied: Tabs—30

FERRIPROX ApoPharma

℞

Iron chelating agent. Deferiprone 500mg; scored tabs.

Indications: Treatment of transfusional iron overload due to thalassemia syndromes when current chelation therapy is inadequate. Limitations of use: not for use in treating other chronic anemias.

Adults: Individualize. Initially 25mg/kg three times daily (total dose 75mg/kg/day). Max: 33mg/kg three times daily (total dose 99mg/kg/day). Round dose to the nearest 250mg (half-tablet). Adjust dose to individual response and therapeutic goals.

Consider temporary dose interruption if serum ferritin falls consistently <500mcg/L. Children: Not established.

Warnings/Precautions: Risk of neutropenia or fatal agranulocytosis. Measure ANC before starting therapy and monitor weekly during. Interrupt therapy if infection or neutropenia develops (ANC <1.5×109/L). If neutropenia occurs, obtain CBCs, WBCs, ANC, and platelets daily until recovery (ANC ≥1.5×109/L). Monitor serum ALT monthly; consider interruption if persistent increase in transaminase levels. Monitor serum ferritin every 2–3 months.

Monitor plasma zinc, supplement if deficient. Severe hepatic impairment. Elderly. Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended.

Interactions: Avoid concomitant use with other drugs associated with neutropenia or agranulocytosis. Allow at least 4-hour interval with antacids or mineral supplements containing polyvalent cations (eg, iron, aluminum, zinc).

Concomitant UGT 1A6 inhibitors: closely monitor and may need dose adjustments or interruptions.

Adverse reactions: Chromaturia, GI upset, abdominal pain, increased ALT, arthralgia, neutropenia; agranulocytosis.

Note: This product is available from Centric Health Resources (CHR). CHR is a specialty pharmacy specializing in orphan drugs and is the sole distributor of Ferriprox in the U.S. For more information, contact Ferriprox Total Care at (866) 758-7071.

How supplied: Tabs—100

FIRAZYR Shire

℞

Bradykinin B2 receptor antagonist. Icatibant 10mg/mL; soln for SC inj; preservative-free.

Indications: Treatment of acute attacks of hereditary angioedema.

Adults: ≥18yrs: 30mg SC in abdominal area; may give additional doses at intervals of at least 6 hours if response inadequate or symptoms recur. Max 3 doses/24hrs.

Children: <18yrs: not recommended.

Warnings/Precautions: Advise patients to seek medical attention after treating laryngeal attack

Take advantage of our free online medical calculators at CancerTherapyAdvisor.com/MedicalCalculators.

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DRUG MONOGRAPHS

ASSOCIATED HEMATOLOGICAL DISORDERS given the potential for airway obstruction. Elderly.

Labor & delivery. Pregnancy (Cat.C). Nursing mothers.

Interactions: May attenuate the antihypertensive effect of ACE inhibitors.

Adverse reactions: Inj site reactions, pyrexia, transaminase increase, dizziness, rash.

How supplied: Single-use prefilled syringe (3mL)—1, 3

KALBITOR Dyax

℞

Plasma kallikrein inhibitor. Ecallantide 10mg/mL; soln for SC inj; preservative-free.

Indications: Treatment of acute attacks of hereditary angioedema.

Adults: Give 30mg SC in three 10mg (1mL) inj into abdomen, thigh, or upper arm. May give additional 30mg within 24hrs if attack persists.

Children: <12yrs: not established.

Warnings/Precautions: Have medical support available to manage anaphylaxis and hereditary angioedema. Monitor closely for hypersensitivity reactions. Labor & delivery. Pregnancy (Cat.C).

Nursing mothers.

Adverse reactions: Headache, nausea, diarrhea, pyrexia, inj site reactions, nasopharyngitis, fatigue, upper respiratory tract infection, pruritus, upper abdominal pain; anaphylaxis, antibody formation.

How supplied: Single-use vials—3

MOZOBIL Genzyme

℞

Hematopoietic stem cell mobilizer. Plerixafor 20mg/mL; soln for SC inj; preservative-free.

Indications: In combination with granulocyte colony stimulating factor (G-CSF): To mobilize hematopoietic stem cells to the peripheral blood for collection and autologous transplantation in patients with non-Hodgkin’s lymphoma or multiple myeloma.

Adults: Start after 4 days’ treatment with G-CSF. Give approximately 11hrs before starting apheresis. Repeat up to 4 consecutive days. Base dose on actual body weight. 0.24mg/kg SC; max 40mg/day. Renal impairment (CrCl≤50mL/min): 0.16mg/kg; max 27mg/day.

Children: Not established.

Warnings/Precautions: Not for use in leukemia.

May cause mobilization of tumor cells. Monitor blood and platelet counts (esp. neutrophils).

Monitor for splenic rupture (eg, left upper quadrant/scapular or shoulder pain). Monitor for signs/symptoms of hypersensitivity during and after administration for at least 30mins. Pregnancy (Cat.D); avoid. Nursing mothers: not recommended.

Interactions: May be potentiated by drugs that reduce renal function or compete for active tubular secretion.

Adverse reactions: Diarrhea, nausea, fatigue, injection site reactions, headache, arthralgia, dizziness, vomiting; anaphylactic shock, hypersensitivity reactions (may be serious), tumor cell mobilization, increased circulating neutrophils, decreased platelet counts, enlarged spleen, vasovagal reaction may occur.

How supplied: Single-use vials (1.2mL)—1

HEMATOLOGICAL REFERENCE VALUES Analyte

Reference value Conventional units SI units

Antithrombin III • Antigenic • Functional

22–39mg/dL 80–130%

220–390mg/L 0.8–1.30 U/L

Bleeding time

2.0–9.5min

2.0–9.5min

Erythrocyte count • Male • Female

4.50–5.90 × 106/mm3 4.00–5.20 × 106/mm3

4.50–5.90 × 1012/L 4.00–5.20 × 1012/L

Erythrocyte sedimentation rate • Male • Female

0–17mm/hr 1–25mm/hr

0–17mm/hr 1–25mm/hr

Ferritin • Male • Female

30–300ng/mL 10–200ng/mL

30–300μg/L 10–200μg/L

Fibrinogen

150–400mg/dL

1.50–4.00g/L

Folate (folic acid) • Normal • Borderline deficient • Deficient • Excess

3.1–17.5ng/mL 2.2–3.0ng/mL <2.2ng/mL >17.5ng/mL

7.0–39.7nmol/L 5.0–6.8nmol/L <5.0nmol/L >39.7nmol/L

Folic acid

150–450ng/mL/cells

340–1020nmol/L/cells

Hematocrit • Male • Female

41.0–53.0% 36.0–46.0%

0.41–0.53 0.36–0.46

Hemoglobin • Plasma • Whole blood, male • Whole blood, female

1–5mg/dL 13.5–17.5g/dL 12.0–16.0g/dL

0.01–0.05g/L 8.4–10.9mmol/L 7.4–9.9mmol/L

Hemoglobin electrophoresis • Hemoglobin A • Hemoglobin A1c • Hemoglobin A2 • Hemoglobin F • Hemoglobins other than A, A2, or F

95–98% 3.8–6.4% 1.5–3.5% 0–2.0% Absent

0.95–0.98 0.038–0.064Hg fraction 0.015–0.035 0–0.02 Absent

Iron (hematology and coagulation values)

30–160μg/dL

5.4–28.7μmol/L

Iron-binding capacity (hematology and coagulation values)

228–428μg/dL

40.8–76.7μmol/L

Iron (clinical chemistry values)

50–150μg/dL

9–27μmol/L

Iron-binding capacity (clinical chemistry values)

250–370μg/dL

45–66μmol/L

Leukocyte count (WBC)

4.5–11.0 × 103/mm3

4.5–11 × 109/L

Mean corpuscular hemoglobin (MCH)

26.0–34.0pg/cell

26.0–34.0pg/cell

Mean corpuscular hemoglobin concentration (MCHC)

31.0–37.0g/dL

310–370g/L

Mean corpuscular volume (MCV)

80–100μm3

80–100fl

Partial-thromboplastin time (activated)

22.1–35.1sec

22.1–35.1sec

Platelet count

150–350 × 103/mm3

150–350 × 109/L

Prothrombin time

11.1–13.1sec

11.1–13.1sec

Reticulocyte count

0.5–2.5% red cells

0.005–0.025 red cells

Transferrin

230–390mg/dL

2.3–3.9g/L

Vitamin B12 • Normal • Borderline • Deficient

>250pg/mL 125–250pg/mL <125pg/mL

>185pmol/L 92–185pmol/L <92pmol/L

References National Institutes of Health. Third report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). September 2002. Available at: www.nhlbi.

(Rev. 8/2012) nih.gov/guidelines/cholesterol/index.htm. Accessed August 2012.

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DRUG MONOGRAPHS

ASSOCIATED HEMATOLOGICAL DISORDERS ANTICOAGULANT DOSING CONVERSIONS Conversion of DABIGATRAN ETEXILATE Switching from DABIGATRAN to WARFARIN • Adjust starting time of warfarin based on CrCl as follows: ° CrCl >50mL/min: Start warfarin 3 days before discontinuing dabigatran ° CrCl 30–50mL/min: Start warfarin 2 days before discontinuing dabigatran ° CrCl 15–30mL/min: Start warfarin 1 day before discontinuing dabigatran ° CrCl <15mL/min: No recommendations can be made • Since dabigatran can increase INR, the INR will better reflect warfarin’s effect only after dabigatran has been stopped for at least 2 days Switching from DABIGATRAN to PARENTERAL ANTICOAGULANT • Currently receiving dabigatran: ° Wait 12hrs (CrCl ≥30mL/min) or 24hrs (CrCl <30mL/min) after the last dose of dabigatran before initiating treatment with a parenteral anticoagulant

Conversion of APIXABAN Switching from APIXABAN to WARFARIN • Apixiban affects INR levels, so the INR measurement during co-administration with warfarin may not be useful for determing the appropriate dose of warfarin ° Discontinue apixaban and start both a parenteral anticoagulant and warfarin at the time the next dose of apixaban would have been taken, then discontinue the parenteral anticoagulant when INR reaches an acceptable range Switching between APIXABAN and ANTICOAGULANTS other than WARFARIN • Discontinue one being taken and begin the other at the next scheduled dose

Conversion of RIVAROXABAN Switching from RIVAROXABAN to WARFARIN • Rivaroxaban affects INR levels, so INR measurements during co-administration with warfarin may not be useful for determining the appropriate dose of warfarin ° Discontinue rivaroxaban and start both a parenteral anticoagulant and warfarin at the time the next dose of rivaroxaban would have been taken Switching from RIVAROXABAN to ANTICOAGULANTS other than WARFARIN • Currently taking rivaroxaban and transitioning to an anticoagulant with rapid onset: ° Discontinue rivaroxaban and give 1st dose of the other anticoagulant (oral or parenteral) at the time the next dose of rivaroxaban would have been taken Switching from ANTICOAGULANTS other than WARFARIN to RIVAROXABAN • Currently receiving an anticoagulant other than warfarin: ° Start rivaroxaban 0–2hrs prior to the next scheduled evening dose of the drug (eg, low molecular weight heparin or non-warfarin oral anticoagulant and omit administration of the other anticoagulant ° Start rivaroxaban at the same time a continuous infusion of unfractionated heparin is discontinued

Conversion of HEPARIN Switching from HEPARIN to WARFARIN • Dose warfarin with the usual initial amount (eg, 2–5mg PO or IV daily) and determine PT/INR at the usual intervals • Overlap warfarin with full dose heparin therapy for 4–5 days until warfarin has produced the desired therapeutic response as determined by PT/INR. Heparin may be discontinued at that time without tapering.

• The interference with heparin anticoagulation is of minimal clinical significance during initial therapy with warfarin • Patients receiving both heparin and warfarin should have blood for PT/INR determination drawn at least: ° 5hrs after the last IV bolus dose of heparin, or ° 4hrs after cessation of a continuous IV infusion of heparin, or ° 24hrs after the last subcutaneous heparin injection Switching from HEPARIN/PARENTERAL ANTICOAGULANT to DABIGATRAN • Currently receiving a parenteral anticoagulant: ° Start dabigatran 0–2hrs before the next scheduled dose of the parenteral drug would have been given, or ° Start dabigatran at the time of discontinuation of a continuously administered parenteral drug (eg, IV unfractionated heparin)

Conversion of WARFARIN Switching from WARFARIN to DABIGATRAN • Discontinue warfarin and start dabigatran when INR is <2.0 Switching from WARFARIN to APIXABAN • Discontinue warfarin and start apixaban when INR is <2.0 Switching from WARFARIN to RIVAROXABAN • Discontinue warfarin and start rivaroxaban as soon as INR is <3.0 to avoid periods of inadequate anticoagulation

Notes

Please see drug monograph at www.eMPR.com and/or contact company for full drug labeling.

(Rev. 11/2013)

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ALPHABETICAL INDEX A Abiraterone Zytiga 44 Abraxane (inj) cancer, breast 9 cancer, pancreatic 22 non-small cell lung cancer 73 Actinic keratoses 79 Adcetris (inj) 56 Ado-trastuzumab Kadcyla 12 Afatinib Gilotrif 74 Afinitor cancer, breast 7, 9, 22, 37 cancer, pancreatic 7, 9, 22, 37 cancer, renal 7, 9, 22, 37 progressive neuroendocrine tumors of pancreatic origin (pNET) 7, 9, 22, 37 subependymal giant cell astrocytoma (SEGA) 7, 9, 22, 37 Aldesleukin Proleukin (inj) 40, 81 Alemtuzumab Campath (inj) 58 Alimta (inj) 73 Alitretinoin Panretin (ext) 78 Altretamine Hexalen 45 Amicar 88 Aminocaproic acid Amicar 88 Anadrol-50 83 Anaplastic astrocytoma 7 Anastrozole Arimidex 9 Anemia 83–88 Angioedema, hereditary 99–100 Anti-inhibitor Coagulant Complex Feiba (inj) 89 Anti-thymocyte globulin Atgam (inj)* 83 Antihemophilic Factor VIII Helixate FS (inj) 90 Humate-P (inj)* 90 ReFacto (inj) 93 Xyntha (inj) 94 Aplastic anemia 83 Aranesp (inj) 83 Arimidex 9

Brand name–bold type Generic name–light type

Aromasin 9 Arranon 56 Arsenic trioxide Trisenox (inj) 70 Arzerra (inj) 56 Asparaginase Erwinia chrysanthemi Erwinaze (inj) 59 Atgam (inj) 83 Atypical hemolytic uremic syndrome 88 Avastin (inj) cancer, cervical 7, 32, 37, 45, 73 cancer, colorectal 7, 32, 37, 45, 73 cancer, ovarian 7, 32, 45, 73 cancer, renal 7, 32, 37, 45, 73 glioblastoma 7, 32, 37, 45, 73 non-small cell lung cancer 7, 32, 37, 45, 73 Axitinib Inlyta 39 Azacitidine Vidaza (inj) 71

B Basal cell carcinoma 79 BCG, live TheraCys (inj) 41 Beleodaq (inj) 56 Belinostat Beleodaq (inj) 56 Bendamustine Treanda (inj) 69 Bevacizumab Avastin (inj) 7, 32, 37, 45, 73 Bexarotene Targretin 67 Targretin (ext) 68 Bexxar 57 Bicalutamide Casodex 37 Bifera 83 BiferaRx 84 Bleeding 88–89, 91, 93–94 Blinatumomab Blincyto (inj) 57 Blincyto (inj) 57 Bone metastases 5, 72 Bortezomib Velcade (inj) 70 Bosulif 57

Medical condition–red type

Bosutinib Bosulif Brentuximab vedotin Adcetris (inj) Busulfan Busulfex (inj) Myleran Busulfex (inj)

57 56 58 64 58

C C1 inhibitor Cinryze (inj) Cabazitaxel Jevtana (inj) Cabozantinib Cometriq Campath (inj) Cancer, bladder Cancer, breast

99 39

22 58 41–42 5, 7, 9–23, 33–35, 37–38, 46, 52, 69, 76 Cancer, cervical 7, 32, 37, 45, 73–74 Cancer, colorectal 7, 10, 21, 23, 32–37, 45, 52, 73 Cancer, GI 11, 25–32, 34 Cancer, head and neck 5, 8, 20, 32, 46–52, 61, 69, 76, 79 Cancer, liver 34, 40 Cancer, lung 5, 20, 45–46, 52, 64, 69, 73–76 Cancer, ovarian 7, 32, 45–46, 52, 59, 61, 73–74, 78–79 Cancer, pancreatic 7, 9–10, 22–24, 33, 35, 37, 41, 76 Cancer, prostate 10, 37–44 Cancer, renal 7, 9, 22, 32, 34, 37, 39–40, 42–43, 45, 73, 81 Cancer, sarcoma 5 Cancer, stomach 10, 23, 33 Cancer, testicular 38 Cancer, thyroid 22–23, 34, 40 Capecitabine Xeloda 21, 35 Caprelsa 22 Carfilzomib Kyprolis (inj) 63 Carimune NF (inj) 89 Casodex 37 Ceritinib Zykadia 77 Cerubidine (inj) 58

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ALPHABETICAL INDEX

Brand name–bold type Generic name–light type

Medical condition–red type

Cetuximab Erbitux (inj) 32, 52 Chlorambucil Leukeran 64 Chorioadenoma destruens 5, 20, 46, 52, 69, 76 Choriocarcinoma, gestational 5, 20, 46, 52, 69, 76 Chronic kidney disease 85 Cinryze (inj) 99 Clofarabine Clolar (inj) 58 Clolar (inj) 58 Coagulation Factor VIIa NovoSeven RT (inj) 91 Colorectal cancer 33 Cometriq 22 Congenital Factor VII deficiency 91 Congenital Factor VIII deficiency 93 Congenital Factor XIII deficiency 89 Congenital fibrinogen deficiency 93 Corifact (inj) 89 Crizotinib Xalkori 77 Cyanocobalamin Nascobal (nasal) 86 Cyklokapron (inj) 89 Cyramza (inj) cancer, GI 32 cancer, lung 73 Cytarabine DepoCyt (inj) 59

Deferasirox Exjade 99 Deferiprone Ferriprox 99 Degarelix Firmagon (inj) 38 Delatestryl 10 Delestrogen (inj) 37 Denileukin diftitox Ontak (inj) 65 Denosumab Xgeva (inj) 5 DepoCyt (inj) 59 Dermatofibrosarcoma protuberans 33, 60, 79 DexFerrum (inj) 84 Dinutuximab Unituxin (inj) 8 Docusate sodium Ferralet 90* 85 Doxil (inj) cancer, ovarian 45, 59, 78 Kaposi’s sarcoma 45, 59, 78 multiple myeloma 45, 59, 78 Doxorubicin, liposomal Doxil (inj) 45, 59, 78 Droxia 84

D Dabrafenib Tafinlar Dacogen (inj) Darbepoetin alfa Aranesp (inj) Dasatinib Sprycel Daunorubicin Cerubidine (inj) Decitabine Dacogen (inj)

81 59 83 67 58 59

E Ecallantide Kalbitor (inj) Eculizumab Soliris (inj) Efudex (ext) Eligard Eloxatin (inj) Eltrombopag Promacta Emcyt Enzalutamide Xtandi Epoetin alfa Epogen (inj) Procrit (inj) Epogen (inj)

100 88 79 38 32 87, 92 38 43 84 86 84

Erbitux (inj) cancer, colorectal 32, 52 cancer, head and neck 32, 52 Eribulin Halaven 11 Erivedge 79 Erlotinib Tarceva 24, 76 Erwinaze (inj) 59 Erythema nodosum leprosum 68 Esophageal varices 89 Estrace cancer, breast 10, 38 cancer, prostate 10, 38 Estradiol Estrace 10, 38 Estradiol valerate Delestrogen (inj) 37 Estramustine Emcyt 38 Estrogens, conjugated Premarin 19, 40 Estrogens, esterified Menest 40 Ethamolin (inj) 89 Ethanolamine Ethamolin (inj) 89 Everolimus Afinitor 7, 9, 22, 37 Evista 10 Exemestane Aromasin 9 Exjade 99

F Factor VIII complex Wilate (inj)* Factor XIII Corifact (inj) Farydak Faslodex (inj) Feiba (inj) Femara Feraheme (inj) Ferralet 90

94 89 60 10 89 10 85 85

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ALPHABETICAL INDEX Ferric carboxymaltose Injectafer Ferriprox Ferrlecit (inj) Fibrinogen RiaSTAP (inj) Filgrastim Neupogen (inj) Firazyr (inj) Firmagon (inj) Fludara (inj) Fludarabine Fludara (inj) Fluorouracil cancer, breast cancer, colorectal cancer, pancreatic cancer, stomach Fluorouracil Efudex (ext) Fluorouracil Flutamide Folic acid BiferaRx* Ferralet 90* Folic acid Trinsicon* Fulvestrant Faslodex (inj) Fusilev (inj)

85 99 85 93 95 99 38 60 60 10, 23, 33 10, 23, 33 10, 23, 33 10, 23, 33 79 10, 23, 33 38 84 85 85 88 10 33

G Gamunex-C (inj) 90 Gazyva (inj) 60 GI stromal tumors 24–31, 33, 35, 41, 60, 79 Gilotrif 74 Glanzmann’s thrombasthenia 91 Gleevec dermatofibrosarcoma protuberans 33, 60, 79 GI stromal tumors 33, 60, 79 hypereosinophilic syndrome 33, 60, 79 leukemia, acute myeloid 33, 60, 79 leukemia, chronic eosinophilic 33, 60, 79 leukemia, chronic myelogenous 33, 60, 79 mastocytosis 33, 60, 79 myelodysplastic syndromes 33, 60, 79

Glioblastoma Granix (inj)

Brand name–bold type Generic name–light type

7, 32, 37, 45, 73 94

H Halaven 11 Helixate FS (inj) 90 Hematopoietic stem cell mobilizer 100 Hemophilia 89 Hemophilia A 90–91, 93–94 Hemophilia B 91 Herceptin (inj) cancer, breast 11, 34 cancer, GI 11, 34 Hexalen 45 Histrelin Vantas 42 Hodgkin lymphoma 56 Hodgkin’s disease 64, 74 Humate-P (inj) 90 Hycamtin cancer, cervical 45, 74 cancer, lung 45, 74 cancer, ovarian 45, 74 Hydatidiform mole 5, 20, 46, 52, 69, 76 Hydrea cancer, head and neck 46, 52, 61, 79 cancer, ovarian 46, 52, 61, 79 leukemia, chronic myelocytic 46, 52, 61, 79 melanoma 46, 52, 61, 79 Hydroxyurea Droxia 84 Hydrea 46, 52, 61, 79 Hypercalcemia 72 Hypereosinophilic syndrome 33, 60, 79 Hypogonadism 10

I Ibrance Ibritumomab Zevalin (inj) Ibrutinib Imbruvica Icatibant Firazyr (inj) Iclusig Idamycin (inj)

11 71 62 99 61 62

Medical condition–red type

Idarubicin Idamycin (inj) 62 Idelalisib Zydelig 72 Idiopathic thrombocytopenic purpura 89–90, 92–94 Ifex (inj) 38 Ifosfamide Ifex (inj) 38 Imatinib Gleevec 33, 60, 79 Imbruvica 62 Immune globulin Carimune NF (inj) 89 Gamunex-C (inj) 90 Privigen (inj) 92 Immunomodulators 95 INFeD (inj) 85 Injectafer 85 Inlyta 39 Interferon alfa-2b Intron A (inj) 62, 78, 80 Intron A (inj) Kaposi’s sarcoma 62, 78, 80 leukemia, hairy cell 62, 78, 80 lymphoma, follicular 62, 78, 80 melanoma 62, 78, 80 Iodine I 131 Tositumomab Bexxar* 57 Ipilimumab Yervoy (inj) 82 Iron deficiency anemia 85 Iron fumarate Trinsicon* 88 Iron gluconate Ferrlecit (inj) 85 Nulecit (inj) 86 Iron (as carbonyl) Ferralet 90* 85 Iron (as dextran complex) DexFerrum (inj) 84 INFeD (inj) 85 Iron (as ferumoxytol) Feraheme (inj) 85 Iron (as polysaccharide iron complex + heme iron polypeptide) Bifera 83 BiferaRx* 84 Iron (as sucrose) Venofer (inj) 88 Istodax 62 Ixabepilone Ixempra (inj) 12

104 CANCER THERAPY ADVISOR | SEPTEMBER/OCTOBER 2015 | CancerTherapyAdvisor.com

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ALPHABETICAL INDEX

Brand name–bold type Generic name–light type

Medical condition–red type

Ixempra (inj)

Leukemia, chronic myelocytic 46, 52, 61, 79 Leukemia, chronic myelogenous 33, 57–58, 60, 64, 67–68, 79 Leukemia, chronic myeloid 61 Leukemia, hairy cell 62, 78, 80 Leukemia, T-cell acute lymphoblastic 56 Leukeran 64 Leukine (inj) 95 Leuprolide Eligard 38 Lupron Depot 3.75mg (inj) 86 Lupron Depot 7.5mg (inj) 39 Levoleucovorin Fusilev (inj) 33 Lupron Depot 3.75mg (inj) 86 Lupron Depot 7.5mg (inj) 39 Lymphocyte immune globulin Atgam (inj)* 83 Lymphoma, cutaneous T-cell 62, 65, 67–68, 70, 72 Lymphoma, follicular 62, 72, 78, 80 Lymphoma, malignant 64 Lymphoma, mantle cell 62, 70 Lymphoma, peripheral T-cell 56, 62 Lymphoma, small lymphocytic 72 Lymphoma, T-cell lymphoblastic 56 Lymphomatous meningitis 59 Lymphosarcoma 64, 74 LYNPARZA 46

12

J Jakafi Jevtana (inj)

63 39

K Kadcyla Kalbitor (inj) Kaposi’s sarcoma KCentra (inj) Keytruda (inj) Kyprolis (inj)

12 100 45, 59, 62, 78, 80 91 80 63

L Lanreotide Somatuline Depot (inj) 24 Lapatinib Tykerb 20 Lenalidomide Revlimid 66, 87 Lenvatinib Lenvima 23 Lenvima 23 Letrozole Femara 10 Leucovorin anemia 86 cancer, colorectal 34 Leukemia 64, 74 Leukemia, acute lymphoblastic 57–59, 61, 64–65, 67, 71 Leukemia, acute lymphocytic 58, 65 Leukemia, acute myeloid 33, 53–55, 60, 62, 79 Leukemia, acute nonlymphocytic 58, 67 Leukemia, acute promyelocytic 70–71 Leukemia, B-cell chronic lymphocytic 58, 60 Leukemia, chronic eosinophilic 33, 60, 79 Leukemia, chronic lymphocytic 56, 60, 62, 66, 69, 72

M Malignant pleural mesothelioma 73 Mantle cell lymphoma 66 Marqibo (inj) 64 Mastocytosis 33, 60, 79 Mechlorethamine Mustargen (inj) 64, 74 Valchlor (ext) 70 Mekinist 80 Melanoma 46, 52, 61–62, 78–82 Melanoma, metastatic 40, 81 Menest 40

Mercaptopurine Purinethol Purixan Methotrexate Trexall Methoxsalen Uvadex Mozobil (inj) Multiple myeloma

65 65 5, 20, 46, 52, 69, 76 70 100 45, 59–60, 63, 65–66, 68, 70, 72, 78

Mustargen (inj) cancer, lung 64, 74 Hodgkin’s disease 64, 74 leukemia 64, 74 lymphosarcoma 64, 74 mycosis fungoides 64, 74 polycythemia vera 64, 74 Mycosis fungoides 5, 20, 46, 52, 64, 69, 74, 76 Mycosis fungoides-type cutaneous T-cell lymphoma 70 Myelodysplastic syndromes 33, 59–60, 71, 79 Myleran 64

N Nascobal (nasal) Navelbine (inj) Nelarabine Arranon Neoplasms Neulasta (inj) Neumega (inj) Neupogen (inj) Neuroblastoma Neuroendocrine tumors Neutropenia Nexavar cancer, liver cancer, renal cancer, thyroid Nilotinib Tasigna Nitropress (inj) Nivolumab Opdivo (inj)

86 76 56 38, 41–42 95 91 95 8 24, 35, 41 94–98 34, 40 34, 40 23, 34, 40 68 91 76, 80

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ALPHABETICAL INDEX Non-Hodgkin’s lymphoma 5, 20, 46, 52, 57, 66, 69, 71, 76 Non-small cell lung cancer 7, 24, 32, 37, 45, 73–74, 76–77 NovoSeven RT (inj) 91 Nplate (inj) 92 Nulecit (inj) 86

O Obinutuzumab Gazyva (inj) Ofatumumab Arzerra (inj) Olaparib LYNPARZA Omacetaxine mepesuccinate Synribo (inj) Oncaspar (inj) Ontak (inj) Opdivo (inj) cancer, lung melanoma Oprelvekin Neumega (inj) Oxaliplatin Eloxatin (inj) Oxymetholone Anadrol-50

60 56 46 67 64 65 76 80 91 32 83

P Paclitaxel, protein-bound Abraxane (inj) 9, 22, 73 Palbociclib Ibrance 11 Panitumumab Vectibix (inj) 35 Panobinostat Farydak 60 Panretin (ext) 78 Paroxysmal nocturnal hemoglobinuria 88 Pazopanib Votrient 5, 43 Pegaspargase Oncaspar (inj) 64 Pegfilgrastim Neulasta (inj) 95 Peginterferon alfa-2b Sylatron (inj) 81 Pembrolizumab Keytruda (inj) 80

Brand name–bold type Generic name–light type

Pemetrexed Alimta (inj) 73 Perjeta (inj) 12 Pertuzumab Perjeta (inj) 12 Plerixafor Mozobil (inj) 100 Poisoning/overdose 99 Polycythemia vera 63–64, 74 Pomalidomide Pomalyst 65 Pomalyst 65 Ponatinib Iclusig 61 Premarin cancer, breast 19 cancer, prostate 40 Privigen (inj) 92 Procrit (inj) 86 Progressive neuroendocrine tumors of pancreatic origin (pNET) 7, 9, 22, 37 Proleukin (inj) cancer, renal 40, 81 melanoma, metastatic 40, 81 Promacta anemia 87 thrombocytopenia 92 Prothrombin complex concentrate (human) KCentra (inj) 91 Provenge (inj) 41 Purinethol 65 Purixan 65

R Radium Ra 223 dichloride Xofigo (inj) Raloxifene Evista Ramucirumab Cyramza (inj) Recothrom ReFacto (inj) Regorafenib Stivarga Revlimid anemia mantle cell lymphoma multiple myeloma Rhophylac (inj)

43 10 32, 73 93 93

Medical condition–red type

Rho(D) immune globulin Rhophylac (inj) WinRho SDF (inj) RiaSTAP (inj) Rituxan (inj) Rituximab Rituxan (inj) Romidepsin Istodax Romiplostim Nplate (inj) Ruxolitinib Jakafi

93 94 93 66 66 62 92 63

S Sargramostim Leukine (inj) 95 Sickle cell anemia 84 Sipuleucel-T Provenge (inj) 41 Skeletal-related events 5 Sodium nitroprusside Nitropress (inj) 91 Soliris (inj) 88 Soltamox 19 Somatuline Depot (inj) 24 Sorafenib Nexavar 23, 34, 40 Sprycel 67 Stivarga 34 Subependymal giant cell astrocytoma (SEGA) 7, 9, 22, 37 Sunitinib Sutent 24, 35, 41 Superficial basal cell carcinoma 79 Surgical bleed 91 Sutent cancer, pancreatic 24, 35, 41 GI stromal tumors 24, 35, 41 neuroendocrine tumors 24, 35, 41 Sylatron (inj) 81 Synribo (inj) 67 Systemic anaplastic large cell lymphoma 56

34

T

87 66 66 93

Tabloid Tafinlar Tamoxifen Soltamox Tamoxifen

67 81 19 19

106 CANCER THERAPY ADVISOR | SEPTEMBER/OCTOBER 2015 | CancerTherapyAdvisor.com

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ALPHABETICAL INDEX

Brand name–bold type Generic name–light type

Medical condition–red type

Tarceva cancer, pancreatic 24, 76 non-small cell lung cancer 24, 76 Targretin 67 Targretin (ext) 68 Tasigna 68 Tbo-filgrastim Granix (inj) 94 Temodar 7 Temozolomide Temodar 7 Temsirolimus Torisel (inj) 42 Teniposide Vumon (inj) 71 Testosterone enanthate Delatestryl 10 Thalidomide Thalomid 68 Thalomid 68 TheraCys (inj) 41 Thioguanine Tabloid 67 Thrombin Recothrom 93 Thrombin-JMI 94 Thrombin-JMI 94 Thrombocytopenia 91–92 Topotecan Hycamtin 45, 74 Torisel (inj) 42 Tositumomab Bexxar* 57 Trametinib Mekinist 80 Tranexamic acid Cyklokapron (inj) 89 Trastuzumab Herceptin (inj) 11, 34 Treanda (inj) 69 Trelstar (inj) 42 Tretinoin Vesanoid 71 Trexall cancer, breast 5, 20, 46, 52, 69, 76 cancer, head and neck 5, 20, 46, 52, 69, 76

cancer, lung 5, 20, 46, 52, 69, 76 chorioadenoma destruens 5, 20, 46, 52, 69, 76 choriocarcinoma, gestational 5, 20, 46, 52, 69, 76 hydatidiform mole 5, 20, 46, 52, 69, 76 mycosis fungoides 5, 20, 46, 52, 69, 76 non-Hodgkin’s lymphoma 5, 20, 46, 52, 69, 76 Trinsicon 88 Triptorelin Trelstar (inj) 42 Trisenox (inj) 70 Tykerb 20

8 70

V Valchlor (ext) Valrubicin Valstar Valstar Vandetanib Caprelsa Vantas Vectibix (inj) Velcade (inj) Vemurafenib Zelboraf Venofer (inj) Vesanoid Vidaza (inj) Vincristine sulfate liposome Marqibo (inj) Vinorelbine Navelbine (inj) Vismodegib Erivedge VKA reversal Von Willebrand disease

90 94 72 43 5 71

W Wilate (inj) WinRho SDF (inj)

94 94

X

U Unituxin (inj) Uvadex

Von Willebrand Factor Humate-P (inj)* Wilate (inj)* Vorinostat Zolinza Votrient cancer, renal cancer, sarcoma Vumon (inj)

70 42 42 22 42 35 70 82 88 71 71 64 76 79 91 90, 94

Xalkori Xeloda cancer, breast cancer, colorectal Xgeva (inj) Xofigo (inj) Xtandi Xyntha (inj)

77 21, 35 21, 35 5 43 43 94

Y Yervoy (inj)

82

Z Zaltrap (inj) Zelboraf Zevalin (inj) Ziv-aflibercept Zaltrap (inj) Zoledronic acid Zometa Zolinza Zometa Zydelig Zykadia Zytiga

36 82 71 36 72 72 72 72 77 44

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MANUFACTURERS INDEX AbbVie (800) 633-9110 Actavis (800) 432-8534 (732) 465-3600 Actelion Pharmaceuticals (866) 228-3546 Alexion Pharmaceuticals, Inc. (203) 272-2596 AMAG Pharmaceuticals (617) 498-3300 American Regent, Inc. (800) 645-1706 (631) 924-4000 Amgen, Inc. (800) 772-6436 (805) 447-1000 ApoPharma USA Inc. (877) 427-6839 ARIAD Pharmaceuticals, Inc. (855) 552-7423 Astellas Pharma US, Inc. (800) 727-7003 (800) 888-7704 Astellas Pharma US, Inc. and Genentech, Inc. (888) 827-2382 AstraZeneca Pharmaceuticals (800) 237-8898 (800) 236-9933 Baxter (800) 422-9837 Bayer and Onyx (866) 639-2827 Bayer Healthcare Pharmaceuticals Inc. (800) 288-8371 (800) 468-0894 Bedford Laboratories (800) 521-5169 (800) 562-4797 Boehringer Ingelheim Pharmaceuticals (800) 542-6257 (800) 236-4248 Bristol-Myers Squibb (800) 321-1335 Celgene Corp (908) 673-9000 Clover Pharmaceuticals Corp.

(770) 499-8100 CSL Behring, LLC (800) 504-5434 (800) 683-1288 DARA BioSciences, Inc. (919) 872-5578 Dendreon (877) 256-4545 Dyax Corp.

(888) 452-5248 Eisai Pharmaceuticals (888) 422-4743 (201) 692-1100

Emergent BioSolutions Inc. (800) 768-2304 Endo Pharmaceuticals (800) 462-3636 (610) 558-9800 Exelixis, Inc. (650) 837-7000 Ferring Pharmaceuticals, Inc. (888) 337-7464 Genentech, Inc. (800) 821-8590 (650) 225-1000 Genzyme Corporation (800) 745-4447 (617) 252-7500 Gilead Sciences, Inc. (800) 445-3235 (650) 574-3000 GlaxoSmithKline (888) 825-5249 Grifols Biologicals, Inc. (888) 474-3657 Hospira (800) 615-0187 Incyte Corporation (855) 463-3463 Ipsen Biopharmaceuticals, Inc. (866) 837-2422 Janssen Biotech, Inc. (800) 526-7736 Jazz Pharmaceuticals plc (650) 496-3777 JHP Pharmaceuticals (866) 923-2547 Lilly, Eli and Company (800) 545-5979 (317) 276-2000 Meda Pharmaceuticals (888) 455-8383 Merck & Co., Inc. (800) 672-6372 (800) 609-4618 Millennium Pharmaceuticals, Inc. (866) 835-2233 Mission Pharmacal Company (210) 696-8400 (800) 292-7364 Novartis Pharmaceuticals Corp (800) 693-9993 (973) 503-8300 Novo Nordisk (800) 727-6500 (609) 987-5800 Octapharma (888) 429-4535 Onyx Pharmaceuticals (650) 266-0000 Otsuka America Pharmaceutical, Inc. (800) 441-6763 (301) 990-0030

Pfizer Inc. (800) 438-1985 (212) 573-2323 Pharmacyclics and Janssen Biotech (877) 877-3536 Pierre Fabre Pharmaceuticals, Inc. (973) 355-8000 Prometheus Labs, Inc. (888) 423-5227 QOL Medical, LLC (866) 469-3773 Rare Disease Therapeutics, Inc. (615) 399-0700 Recordati Rare Diseases, Inc. (908) 236-0888 Regeneron and Sanofi Aventis (800) 981-2491 Roche Laboratories (800) 526-6367 (973) 235-5000 Sanofi Aventis (800) 446-6267 (800) 633-1610 Sanofi Pasteur, Inc. (800) 822-2463 Seattle Genetics, Inc. (855) 473-2436 Shire US, Inc. (800) 536-7878 (859) 282-2100 Sigma-Tau Pharmaceuticals, Inc. (800) 447- 0169 Spectrum Pharmaceuticals, Inc. (877) 387-4538 Strativa Pharmaceuticals (201) 802-4000 Teva Pharmaceuticals (215) 591-3000 Therakos, Inc. (877) 865-6850 (610) 280-1000 Tolmar Inc. (877) 986-5627 UCB Inc. (800) 234-5535 (585) 475-9000 United Therapeutics Corp.

(877) 864-8437 Valeant Pharmaceuticals, Inc (877) 361-2719 ViroPharma (610) 458-7300 Warner Chilcott Laboratories (800) 521-8813 (973) 442-3200 ZymoGenetics, Inc. (800) 775-6686 (206) 442-6600

108 CANCER THERAPY ADVISOR | SEPTEMBER/OCTOBER 2015 | CancerTherapyAdvisor.com

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