Cancer Therapy Advisor July/August 2016 Issue by Haymarket Media

JULY/AUGUST 2016 | VOL 2, ISSUE 6

CancerTherapyAdvisor.com

CancerTherapyAdvisor

A24 FEATURE

Pipeline Series: Research Advances in Non-small Cell Lung Cancer Treatment An overview of drugs that may become influential in the treatment of patients with non-small cell lung cancer.

FEATURING Cancer Therapy Regimens and Oncology Drug Monographs from

1 Bone Cancer 3 Brain Cancer

5 Breast Cancer 20 Endocrine Cancer

A9 LATEST NEWS

26 Gastrointestinal Cancer

Headlines in Oncology Research, Including Immunotherapy and Cancer Prevention

44 Genitourinary Cancer 54 Gynecologic Cancer 60 Head and Neck Cancer

A22 IN THE CLINIC

NCCN Patient-focused Educational Materials for Non-Hodgkin Lymphoma

61 Hematologic Cancer 83 Lung Cancer 91 Sarcoma

JULY/AUGUST 2016 | VOL 2, ISSUE 6

92 Skin Cancer

A32 VIEWPOINT

Mental Disorder Risk High During Cancer Treatment and Before Diagnosis

97 Associated Hematological

Disorders

Regimen included

A23 EXPERT PERSPECTIVE Immunotherapy Q&A Session With Aude G. Chapuis, MD

CTA_Cover_0716.indd 1

7/6/16 2:48 PM

RAMUCIRUMAB + PACLITAXEL

THE FIRST AND ONLY FDA-APPROVED combination regimen included in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) with a CATEGORY 1 recommendation for the treatment of locally advanced or metastatic gastric or GEJ adenocarcinoma in the second-line setting1-3 CYRAMZA as a single agent, or in combination with paclitaxel, is indicated for the treatment of patients with advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinumcontaining chemotherapy.

RAMUCIRUMAB—A PREFERRED OPTION2,3 CATEGORY 1 NCCN Guidelines® Recommendations: Locally Advanced or Metastatic Gastric Adenocarcinoma*2

Locally Advanced or Metastatic Esophagogastric Junction Adenocarcinoma†3

 Single-agent ramucirumab  Ramucirumab with paclitaxel

CATEGORY 1: Based upon high-level evidence, there is uniform National Comprehensive Cancer Network® (NCCN®) consensus that the intervention is appropriate.

Review the results of the RAINBOW (combination therapy) and REGARD (monotherapy) trials

*NCCN Guidelines for Gastric Cancer V.3.2015 recommend single-agent ramucirumab (CYRAMZA) and ramucirumab (CYRAMZA) in combination with paclitaxel as preferred second-line treatment options for locally advanced or metastatic gastric adenocarcinoma. † NCCN Guidelines for Esophageal and Esophagogastric Junction (EGJ) Cancers V.3.2015 recommend single-agent ramucirumab (CYRAMZA) and ramucirumab (CYRAMZA) in combination with paclitaxel as preferred second-line treatment options for locally advanced or metastatic EGJ adenocarcinoma.

IMPORTANT SAFETY INFORMATION FOR CYRAMZA 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. Withhold CYRAMZA prior to surgery and discontinue CYRAMZA if a patient develops wound healing complications.

Warnings and Precautions Hemorrhage • CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. In study 1, which evaluated CYRAMZA as a single agent in advanced gastric cancer, the incidence of severe bleeding was 3.4% for CYRAMZA and 2.6% for placebo. In study 2, which evaluated CYRAMZA plus paclitaxel, 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. 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 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%). 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. 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. 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 who received CYRAMZA plus paclitaxel (1.2%) as compared to patients who received placebo plus paclitaxel (0.3%). 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, an antiangiogenic therapy, has the potential to adversely affect wound healing. Discontinue CYRAMZA therapy in patients with impaired 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.

LEARN MORE AT

WWW.CYRAMZAHCP.COM

Thyroid Dysfunction • Monitor thyroid function during treatment with CYRAMZA. 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 least 3 months after the last dose of CYRAMZA.

Most Common Adverse Reactions—Single Agent • The most commonly reported adverse reactions (all grades; grade 3/4) occurring in ≥5% of patients receiving CYRAMZA and ≥2% higher than placebo in study 1 were hypertension (16% vs 8%; 8% vs 3%), diarrhea (14% vs 9%; 1% vs 2%), headache (9% vs 3%; 0% vs 0%), and hyponatremia (6% vs 2%; 3% vs 1%). • The most common serious adverse events with CYRAMZA in study 1 were anemia (3.8%) and intestinal obstruction (2.1%). Red blood cell transfusions were given to 11% of CYRAMZA-treated patients vs 8.7% of patients who received placebo. • Clinically relevant adverse reactions reported in ≥1% and <5% of CYRAMZA-treated patients in study 1 were: neutropenia (4.7% vs 0.9%), epistaxis (4.7% vs 0.9%), rash (4.2% vs 1.7%), intestinal obstruction (2.1% vs 0%), and arterial thromboembolic events (1.7% vs 0%). • Across clinical trials of CYRAMZA administered as a single agent, clinically relevant adverse reactions (including grade ≥3) reported in CYRAMZA-treated patients included proteinuria, gastrointestinal perforation, and infusion-related reactions. In study 1, according to laboratory assessment, 8% of CYRAMZA-treated patients developed proteinuria vs 3% of placebo-treated patients. Two patients discontinued CYRAMZA due to proteinuria. The rate of gastrointestinal perforation in study 1 was 0.8% and the rate of infusion-related reactions was 0.4%.

Most Common Adverse Reactions—Combination With Paclitaxel • The most commonly reported adverse reactions (all grades; grade 3/4) occurring in ≥5% of patients receiving CYRAMZA plus paclitaxel and ≥2% higher than placebo plus paclitaxel in study 2 were fatigue/asthenia (57% vs 44%; 12% vs 6%), neutropenia (54% vs 31%; 41% vs 19%), diarrhea (32% vs 23%; 4% vs 2%), epistaxis (31% vs 7%; 0% vs 0%), hypertension (25% vs 6%; 15% vs 3%), peripheral edema (25% vs 14%; 2% vs 1%), stomatitis (20% vs 7%; 1% vs 1%), proteinuria (17% vs 6%; 1% vs 0%), thrombocytopenia (13% vs 6%; 2% vs 2%), hypoalbuminemia (11% vs 5%; 1% vs 1%), and gastrointestinal hemorrhage events (10% vs 6%; 4% vs 2%). • The most common serious adverse events with CYRAMZA plus paclitaxel in study 2 were neutropenia (3.7%) and febrile neutropenia (2.4%); 19% of patients treated with CYRAMZA plus paclitaxel received granulocyte colony-stimulating factors. • Adverse reactions resulting in discontinuation of any component of the CYRAMZA plus paclitaxel combination in 2% or more patients in study 2 were neutropenia (4%) and thrombocytopenia (3%).

R|O|U|T|I|N|G| |S|T|A|G|E

M02

• Clinically relevant adverse reactions reported in ≥1% and <5% of the CYRAMZA plus paclitaxel-treated patients in study 2 were sepsis (3.1% for CYRAMZA plus paclitaxel vs 1.8% for placebo plus paclitaxel) and gastrointestinal perforations (1.2% for CYRAMZA plus paclitaxel vs 0.3% for placebo plus paclitaxel).

Drug Interactions • No pharmacokinetic interactions were observed between ramucirumab (CYRAMZA) and paclitaxel.

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-G HCP ISI 17SEP2015 VEGF=vascular endothelial growth factor. References: 1. CYRAMZA (ramucirumab) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2015. 2. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Gastric Cancer V.3.2015. © National Comprehensive Cancer Network, Inc. 2015. All rights reserved. Accessed February 11, 2016. To view the most recent and complete version of the guidelines, go online to http://www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN content are trademarks owned by the National Comprehensive Cancer Network, Inc. 3. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Esophageal and Esophagogastric Junction Cancers V.3.2015. © National Comprehensive Cancer Network, Inc. 2015. All rights reserved. Accessed February 11, 2016. To view the most recent and complete version of the guidelines, go online to http://www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN content are trademarks owned by the National Comprehensive Cancer Network, Inc. PP-RB-US-0545

04/2016 PRINTED IN USA

PUB: A

ARTIST: MC

CLIENT: Lilly

BLEED: 17.5” x 11.25”

COLLECT DATE:

JOB#: ELRAMC 39635-17

TRIM: 17” x 10.875”

Production:

LOCATION: Mechanicals

SAFETY: 14” x 9.625”

CPM

ACD

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

Deborah R AE

RAMUCIRUMAB + PACLITAXEL

RAMUCIRUMAB—A PREFERRED OPTION2,3 CATEGORY 1 NCCN Guidelines® Recommendations: Locally Advanced or Metastatic Gastric Adenocarcinoma*2

Locally Advanced or Metastatic Esophagogastric Junction Adenocarcinoma†3

 Single-agent ramucirumab  Ramucirumab with paclitaxel

CATEGORY 1: Based upon high-level evidence, there is uniform National Comprehensive Cancer Network® (NCCN®) consensus that the intervention is appropriate.

Review the results of the RAINBOW (combination therapy) and REGARD (monotherapy) trials

LEARN MORE AT

WWW.CYRAMZAHCP.COM

R|O|U|T|I|N|G| |S|T|A|G|E

M02

Drug Interactions • No pharmacokinetic interactions were observed between ramucirumab (CYRAMZA) and paclitaxel.

04/2016 PRINTED IN USA

PUB: A

ARTIST: MC

CLIENT: Lilly

BLEED: 17.5” x 11.25”

COLLECT DATE:

JOB#: ELRAMC 39635-17

TRIM: 17” x 10.875”

Production:

LOCATION: Mechanicals

SAFETY: 14” x 9.625”

CPM

ACD

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

Deborah R AE

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. Withhold CYRAMZA prior to surgery and discontinue CYRAMZA if a patient develops wound healing complications. INDICATIONS AND USAGE Gastric Cancer CYRAMZA as a single agent, or in combination with paclitaxel, is indicated for the treatment of patients with advanced or metastatic, gastric or gastro-esophageal junction adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy. 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. CYRAMZA® (ramucirumab) injection RB-G HCP BS 29APR2015

CYRAMZA RB-G HCP BS 29APR2015 - 7 x 10

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 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, 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 Reversible Posterior Leukoencephalopathy Syndrome (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. Safety data are presented from two randomized, placebo controlled clinical trials in which patients received CYRAMZA: Study 1, a randomized (2:1), double-blind, clinical trial in which 351 patients received either CYRAMZA 8 mg/kg intravenously every two weeks or placebo every two weeks and Study 2, a double-blind, randomized (1:1) clinical trial in which 656 patients received paclitaxel 80 mg/m2 on days 1, 8, and 15 of each 28-day cycle plus either CYRAMZA 8 mg/kg intravenously every two weeks or placebo every two weeks. Both trials excluded patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2 or greater, uncontrolled hypertension, major surgery within 28 days, or patients receiving chronic anti-platelet therapy other than once daily aspirin. Study 1 excluded patients with bilirubin ≥1.5 mg/dL and Study 2 excluded patients with bilirubin >1.5 times the upper limit of normal. CYRAMZA Administered as a Single Agent Among 236 patients who received CYRAMZA (safety population) in Study 1, median age was 60 years, 28% were women, 76% were White, and 16% were Asian. Patients in Study 1 received a median of 4 doses of CYRAMZA; the median duration of exposure was 8 weeks, and 32 (14% of 236) patients received CYRAMZA for at least six months. CYRAMZA® (ramucirumab) injection RB-G HCP BS 29APR2015

PRINTER VERSION 1 OF 3

In Study 1, the most common adverse reactions (all grades) observed in CYRAMZAtreated patients at a rate of ≥10% and ≥2% higher than placebo were hypertension and diarrhea. The most common serious adverse events with CYRAMZA were

anemia (3.8%) and intestinal obstruction (2.1%). Red blood cell transfusions were given to 11% of CYRAMZA-treated patients versus 8.7% of patients who received placebo.

Table 1: Adverse Reactions Occurring at Incidence Rate ≥5% and a ≥2% Difference Between Arms in Patients Receiving CYRAMZA in Study 1 CYRAMZA (8 mg/kg) Placebo N=236 N=115 Adverse Reactions (MedDRA)a System Organ Class All Grades Grade 3-4 All Grades Grade 3-4 (Frequency %) (Frequency %) (Frequency %) (Frequency %) Gastrointestinal Disorders Diarrhea 14 1 9 2 Metabolism and Nutrition Disorders Hyponatremia 6 3 2 1 Nervous System Disorders Headache 9 0 3 0 Vascular Disorders Hypertension 16 8 8 3 a

MedDRA Version 15.0.

Clinically relevant adverse reactions reported in ≥1% and <5% of CYRAMZA-treated patients in Study 1 were: neutropenia (4.7% CYRAMZA versus 0.9% placebo), epistaxis (4.7% CYRAMZA versus 0.9% placebo), rash (4.2% CYRAMZA versus 1.7% placebo), intestinal obstruction (2.1% CYRAMZA versus 0% placebo), and arterial thromboembolic events (1.7% CYRAMZA versus 0% placebo). Across clinical trials of CYRAMZA administered as a single agent, clinically relevant adverse reactions (including Grade ≥3) reported in CYRAMZA-treated patients included proteinuria, gastrointestinal perforation, and infusion-related reactions. In Study 1, according to laboratory assessment, 8% of CYRAMZA-treated patients developed proteinuria versus 3% of placebo-treated patients. Two patients discontinued CYRAMZA due to proteinuria. The rate of gastrointestinal perforation in Study 1 was 0.8% and the rate of infusion-related reactions was 0.4%.

CYRAMZA Administered in Combination with Paclitaxel Among 327 patients who received CYRAMZA (safety population) in Study 2, median age was 60 years, 31% were women, 63% were White, and 33% were Asian. Patients in Study 2 received a median of 9 doses of CYRAMZA; the median duration of exposure was 18 weeks, and 93 (28% of 327) patients received CYRAMZA for at least six months. In Study 2, the most common adverse reactions (all grades) observed in patients treated with CYRAMZA plus paclitaxel at a rate of ≥30% and ≥2% higher than placebo plus paclitaxel were fatigue, neutropenia, diarrhea, and epistaxis. The most common serious adverse events with CYRAMZA plus paclitaxel were neutropenia (3.7%) and febrile neutropenia (2.4%); 19% of patients treated with CYRAMZA plus paclitaxel received granulocyte colony-stimulating factors. Adverse reactions resulting in discontinuation of any component of the CYRAMZA plus paclitaxel combination in 2% or more patients in Study 2 were neutropenia (4%) and thrombocytopenia (3%).

Table 2: Adverse Reactions Occurring at Incidence Rate ≥5% and a ≥2% Difference Between Arms in Patients Receiving CYRAMZA plus Paclitaxel in Study 2 Adverse Reactions (MedDRA) System Organ Class Blood and Lymphatic System Disorders Neutropenia Thrombocytopenia Gastrointestinal Disorders Diarrhea Gastrointestinal hemorrhage events Stomatitis General Disorders and Administration Site Disorders Fatigue/Asthenia Peripheral edema Metabolism and Nutrition Disorders Hypoalbuminemia Renal and Urinary Disorders Proteinuria Respiratory, Thoracic, and Mediastinal Disorders Epistaxis Vascular Disorder Hypertension

CYRAMZA plus Paclitaxel (N=327) All Grades Grade ≥3 (Frequency %) (Frequency %) 54 13

41 2

31 6

19 2

32 10 20

4 4 1

23 6 7

2 2 1

57 25

12 2

44 14

6 1

Clinically relevant adverse reactions reported in ≥1% and <5% of the CYRAMZA plus paclitaxel treated patients in Study 2 were sepsis (3.1% CYRAMZA plus paclitaxel versus 1.8% placebo plus paclitaxel) and gastrointestinal perforations (1.2% CYRAMZA plus paclitaxel versus 0.3% for placebo plus paclitaxel). 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 treatment-emergent anti-ramucirumab antibodies by an enzyme-linked immunosorbent assay (ELISA). Neutralizing antibodies were detected in 14 of CYRAMZA® (ramucirumab) injection RB-G HCP BS 29APR2015

CYRAMZA RB-G HCP BS 29APR2015 - 7 x 10

Placebo plus Paclitaxel (N=329) All Grades Grade ≥3 (Frequency %) (Frequency %)

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. CYRAMZA® (ramucirumab) injection RB-G HCP BS 29APR2015

PRINTER VERSION 2 OF 3

DRUG INTERACTIONS No pharmacokinetic interactions were observed between ramucirumab and paclitaxel. 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 drugassociated 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. 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. 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. DOSAGE AND ADMINISTRATION Do not administer CYRAMZA as an intravenous push or bolus. CYRAMZA® (ramucirumab) injection RB-G HCP BS 29APR2015

CYRAMZA RB-G HCP BS 29APR2015 - 7 x 10

Recommended Dose and Schedule The recommended dose of CYRAMZA either as a single agent or in combination with weekly paclitaxel is 8 mg/kg every 2 weeks administered as an intravenous infusion over 60 minutes. Continue CYRAMZA until disease progression or unacceptable toxicity. When given in combination, administer CYRAMZA prior to administration of paclitaxel. 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-related 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 6 mg/kg every 2 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 5 mg/kg every 2 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 paclitaxel, refer to the current 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.

RB-G HCP BS 29APR2015

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A7 FEATURED PRODUCTS

A34 REGIMEN & MONOGRAPH INDEX

Drug Descriptions of Cabometyx and Imlygic

-112 CANCER THERAPY REGIMENS & 1 DRUG MONOGRAPHS

A9 LATEST NEWS

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

Headlines in Oncology Research and Practice

A15 IN THE PIPELINE

1 Bone Cancer

The Latest on Oncology Drugs

3 Brain Cancer

A22 IN THE CLINIC NCCN Patient-focused Educational Materials for Non-Hodgkin Lymphoma JOHN SCHIESZER

A23

EXPERT PERSPECTIVE Immunotherapy Q&A Session With Aude G. Chapuis, MD JIM DALEY

20 Endocrine Cancer

 26 Gastrointestinal Cancer

 44 Genitourinary Cancer

 54 Gynecologic Cancer

60 Head and Neck Cancer

A24

FEATURE Pipeline Series: Research Advances in Non-small Cell Lung Cancer Treatment JASON HOFFMAN, PharmD, RPh

A32

 5 Breast Cancer

 61 Hematologic Cancer

83 Lung Cancer 91 Sarcoma 92 Skin Cancer 97 Associated Hematological Disorders

VIEWPOINT Mental Disorder Risk High During Cancer Treatment and Before Diagnosis

113 ALPHABETICAL INDEX

CARLOS HARRISON

118 MANUFACTURERS INDEX

Cancer Therapy Advisor (ISSN 2375-558X), July/August 2016, Volume 2, Number 6. Published 6 times annually by Haymarket Media, Inc., 275 7th Avenue, 10th 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. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publisher.

CancerTherapyAdvisor.com | JULY/AUGUST 2016 | CANCER THERAPY ADVISOR A5

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EDITORIAL & BUSINESS STAFF

EDITORIAL ADVISORY BOARD

Managing Editor, Haymarket Oncology

Barbara Ann Burtness, MD

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Yale Cancer Center  New Haven, CT

Senior Manager, Drug Information

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Fox Chase Cancer Center  Philadelphia, PA

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Contact the Editor: editor.cancertherapyadvisor@haymarketmedia.com

A6 CANCER THERAPY ADVISOR | JULY/AUGUST 2016 | CancerTherapyAdvisor.com

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LATEST NEWS | IMMUNOTHERAPY

WNT/β-catenin Pathway Signaling Activated in Most Solid Tumors WNT/β-catenin pathway signaling is associated with T cell exclusion and is activated in most human solid tumors, including colon, kidney, and lung tumors, according to a study presented at the 2016 American Society of Clinical Oncology® annual meeting. “The T cell-inflamed tumor microenvironment is characterized by expression of immune-inhibitory pathways and predicts patient outcomes to immunotherapy,” said lead investigator Jason J. Luke, MD, assistant professor of medicine and medical oncologist at The University of Chicago Medicine in Illinois. To better understand the molecular mechanisms underpinning the absence of a T cell response in solid tumors, investigators assessed the role of the WNT/β-catenin pathway. “β-catenin represses CCL4, leading to a lack of Batf3+ recruitment, failed T cell priming, and non-response to checkpoint blockade,” Dr Luke noted. For the study, researchers collected gene expression data from The Cancer Genome Atlas (TCGA) and segregated the data using a T cell-inflamed gene expression signature to identify patient samples by immune phenotype. They then identified gene expression changes predicted to trigger the β-catenin signaling pathway and performed immunohistochemistry on tumor samples to determine if a correlation between the presence of nuclear β-catenin and the lack of a T cell infiltrate exists. Results showed that predicted activating mutations in CTNNB1 or inactivating mutations in Axin1, Axin2, APC1, and APC2 were observed within 13 tumor histologies ranging in frequency from 9% in esophageal tumors to 67% in colon tumors. Researchers also identified 12 further histologies harboring elevated expression of β-catenin pathway elements, including WNT ligands. Only 3 tumor types, pancreatic, thyroid, and paraganglioma, did not exhibit activation that was associated with absence of immune signatures.

Immunohistochemistry further demonstrates an inverse correlation between β-catenin and CD8+ T cells. “Activation of WNT/β-catenin signaling likely contributes to the non-T cell-inflamed phenotype across many cancers,” Dr Luke concluded. “β-catenin as a mediator of immune exclusion may represent a rational therapeutic target for combination immunotherapy.”

Advanced Mismatch Repair Deficiency Tumors Respond to Pembrolizumab Patients with mismatch repair deficiency cancers may receive durable clinical benefit with pembrolizumab, study results presented to an audience of oncology professionals at the 2016 American Society of Clinical Oncology ® annual meeting have shown.1 “Mismatch repair deficiency refers to deficiency in proteins responsible for DNA mismatch repair,” said lead investigator Dung T. Le, MD, assistant professor of oncology at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, Maryland. “These include MSH2, MSH6, MLH1, and PMS2.” For the phase 2 study, researchers enrolled 30 patients with varying types of cancer, including 9 patients with endometrial cancer, 4 patients with pancreatic cancer, 4 patients with ampullary cancers, 3 patients with biliary cancers, 4 patients with small bowel cancers, 3 patients with gastric cancers, 1 patient with thyroid cancer, 1 patient with prostate cancer, and 1 patient with sarcoma. All of the enrolled patients had metastatic disease, and 53% had liver metastases. Patients were only eligible if they had received at least 1 prior line of therapy. For PD-1 blockade therapy, all participants received pembrolizumab 10 mg/kg IV every 2 weeks. Results showed that at a median follow-up of 10 months, objective response rate and disease control rate were 53% (95% confidence interval, 36-70) and 70% (95% confidence interval, 52-83), respectively. In terms of safety, Dr Le noted that expected toxicities were manageable. “Mismatch repair-deficient cancers are responsive to checkpoint blockade with anti-PD-1,” Dr Le concluded. “Durable clinical responses were noted across tumors with mismatch repair deficiency, including endometrial, gastric, duodenal, pancreatic, ampullary, and biliary cancer.” Importantly, mismatch repair deficiency can be determined using existing commercially available tests.

“Further randomized controlled trials are needed to prospectively establish benefit of treating patients past first progression for individual patients but these results would be unlikely to significantly change major FDA regulatory end point results or benefit/risk determination,” Dr Kazandijan concluded.

A14 CANCER THERAPY ADVISOR | JULY/AUGUST 2016 | CancerTherapyAdvisor.com

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IN THE PIPELINE Gazyva Goes Head-toHead with Rituxan in Follicular Lymphoma Study Genentech announced positive results from the pivotal phase 3 GALLIUM study evaluating a head-to-head comparison of Gazyva (obinutuzumab) vs. Rituxan (rituximab) for the treatment of patients with previously untreated follicular lymphoma, the most common type of indolent non-Hodgkin lymphoma (iNHL). The GALLIUM study is a global, open-label, multicenter, randomized, two-arm, phase 3 study evaluating the efficacy and safety of Gazy va (obinutuzumab) plus chemotherapy (CHOP, CVP or bendamustine) followed by Gazyva alone compared to Rituxan plus chemotherapy followed by Rituxan alone in patients with previously untreated iNHL for up to 2 years. The primary endpoint was investigator-assessed progression-free survival (PFS) in patients with follicular lymphoma. Secondary endpoints included PFS assessed by independent review committee (IRC), PFS in the overall study population (iNHL), response rate (overall response, ORR; and complete response (CR), overall survival (OS), disease-free survival (DFS), and safety. Results from the preplanned interim analysis showed that patients treated with a Gazyva-based regimen had a significant reduction in the risk of disease worsening or death (PFS) compared to a Rituxan-based regimen. Adverse events observed for either Gazyva or Rituxan regimens were consistent with results from previous clinical trials. Detailed study data will be presented at an upcoming medical meeting and submitted to regulatory agencies for approval. Gazyva is a CD20-directed cytolytic monoclonal antibody currently

indicated for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL), in combination with chlorambucil, and for the treatment of patients with follicular lymphoma (FL) who relapsed after, or are refractory to, a rituximab-containing regimen, in combination with bendamustine followed by Gazyva monotherapy.

combination with paclitaxel in patients with advanced gastric and GEJ cancer.

For more information call (800) 821-8590 or visit Gene.com.

Ariad Pharmaceuticals announced the initiation of the first part of a rolling New Drug Application (NDA) submission to the US Food and Drug Administration (FDA) for its investigational agent, brigatinib, for the treatment of patients with anaplastic lymphoma kinase positive (ALK+) nonsmall cell lung cancer (NSCLC) who are resistant to crizotinib. Brigatinib is currently being evaluated in a global phase 2 trial, which reported positive preliminary results at this year’s American Society of Clinical Oncology® annual meeting. Data showed that 54% of patients treated with brigatinib 180mg regimen achieved a confirmed objective response; the study’s primary endpoint. Brigatinib was found to have a tolerable safety profile. The Company has also initiated a phase 3 trial to evaluate brigatinib in comparison to crizotinib. The FDA previously granted brigatinib Breakthrough Therapy designation for the treatment of patients with crizotinib-resistant ALK+ NSCLC and Orphan Drug designation for the treatment of ALK+ NSCLC. Ariad is seeking accelerated approval and plans to request a priority review for the NDA. The rolling submission will occur in 3 parts and is expected to be complete in the third quarter of 2016. Brigatinib is an anaplastic lymphoma kinase (ALK) inhibitor.

FDA Grants Napabucasin Orphan Drug Status for Gastric Cancer Boston Biomedical announced that the US Food and Drug Administration (FDA) has granted Orphan Drug designation for its investigational compound, napabucasin, for the treatment of gastric cancer, including gastroesophageal junction (GEJ) cancer. Napabucasin is an orally administered cancer stemness inhibitor designed to target STAT3 signaling pathways, thereby inhibiting stemness, the ability of cancer stem cells (CSCs) to self-renew and differentiate into heterogeneous cancer cells. Data from a phase 1b/2 study for napabucasin in gastric/GEJ cancer were previously presented at the 2015 American Society of Clinical Oncology ® annual meeting. The study found that treatment with napabucasin can be combined with weekly paclitaxel in patients with advanced pre-treated gastric/GEJ cancer. In heavily pre-treated patients, lesion regression, objective responses and prolonged stable disease were observed. Boston Biomedical is currently conducting the BRIGHTER study, a phase 3 clinical trial for napabucasin in

For more information visit BostonBiomedical.com.

Initial NDA for Investigational ALK Inhibitor Submitted to FDA

For more information visit Ariad.com.

CancerTherapyAdvisor.com | JULY/AUGUST 2016 | CANCER THERAPY ADVISOR A15

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ALONG THEIR TREATMENT JOURNEY...

STIVARGA® (regorafenib) OFFERS A DIFFERENT APPROACH AS A MULTIKINASE INHIBITOR Prescribe STIVARGA to give your previously treated patients with metastatic colorectal cancer (mCRC) a treatment option to prolong their survival STIVARGA is indicated for patients with mCRC who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild-type, an anti-EGFR therapy.

In the phase 3 CORRECT trial: • M edian overall survival (OS): 6.4 months (95% CI, 5.8-7.3) with STIVARGA vs 5.0 months (95% CI, 4.4-5.8) with placebo1 – 2 3% reduction in the risk of death, hazard ratio (HR): 0.77 (95% CI, 0.64-0.94; P=.0102)1 • Median progression-free survival (PFS): 2.0 months (95% CI, 1.9-2.3) with STIVARGA vs 1.7 months (95% CI, 1.7-1.8) with placebo1 – 51% reduction in the risk of disease progression or death, HR: 0.49 (95% CI, 0.42-0.58; P<.0001)1 • 27% and 25% of patients received 2 or fewer lines of systemic therapy in the STIVARGA and placebo arms, respectively2 • 7 4% and 75% of patients received at least 3 prior lines of systemic therapy in the STIVARGA and placebo arms, respectively 2 Evaluate patients early and often to monitor for adverse events (AEs)

Indication STIVARGA is indicated for the treatment of patients with metastatic colorectal cancer (CRC) who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild-type, an anti-EGFR therapy. Important Safety Information WARNING: HEPATOTOXICITY • Severe and sometimes fatal hepatotoxicity has been observed in clinical trials. • Monitor hepatic function prior to and during treatment. • Interrupt and then reduce or discontinue STIVARGA for hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis, depending upon severity and persistence. Hepatotoxicity: Severe drug-induced liver injury with fatal outcome occurred in 0.3% of 1200 STIVARGA-treated patients across all clinical trials. In metastatic colorectal cancer (mCRC), fatal hepatic failure occurred in 1.6% of patients in the STIVARGA arm and 0.4% of patients in the placebo arm; all the patients with hepatic failure had metastatic disease in the liver.

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Important Safety Information (continued) Liver Function Monitoring: Obtain liver function tests (ALT, AST, and bilirubin) before initiation of STIVARGA and monitor at least every 2 weeks during the first 2 months of treatment. Thereafter, monitor monthly or more frequently as clinically indicated. Monitor liver function tests weekly in patients experiencing elevated liver function tests until improvement to less than 3 times the upper limit of normal (ULN) or baseline values. Temporarily hold and then reduce or permanently discontinue STIVARGA, depending on the severity and persistence of hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis. Hemorrhage: STIVARGA caused an increased incidence of hemorrhage. The overall incidence (Grades 1-5) was 21% with STIVARGA compared to 8% with placebo in mCRC. Fatal hemorrhage occurred in 4 of 632 (0.6%) STIVARGA-treated patients and involved the respiratory, gastrointestinal, or genitourinary tracts. Permanently discontinue STIVARGA in patients with severe or life-threatening hemorrhage and monitor INR levels more frequently in patients receiving warfarin. Please see additional Important Safety Information and brief summary of full Prescribing Information, including the Boxed Warning, on the following pages.

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Patient Support Program • $0 Co-Pay* Assistance for privately-insured patients • Benefit verification/prior authorization denial and appeal information • Specialty Pharmacy Provider (SPP) identification • Alternate coverage research for the uninsured and underinsured • Referral of qualified patients to charitable organizations for assistance with their out-of-pocket expenses

• Information on Medicare Part D plan •M edicaid application and enrollment •P atient education materials — Patient starter kits — Refill reminders • Education on adverse event management • Answers to questions for patients and caregivers

* Patients who are enrolled in any type of government insurance or reimbursement programs are not eligible. As a condition precedent of the co-payment support provided under this program, e.g., co-pay refunds, participating patients and pharmacies are obligated to inform insurance companies and third-party payors of any benefi ts they receive and the value of this program, and may not participate if this program is prohibited by or conflicts with their private insurance policy, as required by contract or otherwise. Void where prohibited by law, taxed, or restricted. Patients enrolled in Bayer’s Patient Assistance Program are not eligible. Bayer may determine eligibility, monitor participation, equitably distribute product and modify or discontinue any aspect of the REACH program at any time, including but not limited to this commercial co-pay assistance program.

Important Safety Information (continued) Dermatological Toxicity: STIVARGA caused an increased incidence of hand-foot skin reaction (HFSR) (also known as palmar-plantar erythrodysesthesia [PPE]) and severe rash, frequently requiring dose modification. The overall incidence of HFSR was increased with STIVARGA compared to placebo in mCRC (45% vs 7%). The incidence of Grade 3 HFSR (17% vs 0%), Grade 3 rash (6% vs <1%), serious adverse reactions of erythema multiforme (0.2% vs 0%), and Stevens-Johnson syndrome (0.2% vs 0%) was higher in STIVARGA-treated patients. Toxic epidermal necrolysis occurred in 0.17% of 1200 STIVARGA-treated patients across all clinical trials. Withhold STIVARGA, reduce the dose, or permanently discontinue depending on the severity and persistence of dermatologic toxicity. ®

Hypertension: STIVARGA caused an increased incidence of hypertension (30% with STIVARGA vs 8% with placebo in mCRC). Hypertensive crisis occurred in 0.25% of 1200 STIVARGA-treated patients across all clinical trials. Do not initiate STIVARGA until blood pressure is adequately controlled. Monitor blood pressure weekly for the first 6 weeks of treatment and then every cycle, or more frequently, as clinically indicated. Temporarily or permanently withhold STIVARGA for severe or uncontrolled hypertension. Cardiac Ischemia and Infarction: STIVARGA increased the incidence of myocardial ischemia and infarction (1.2% with STIVARGA vs 0.4% with placebo). Withhold STIVARGA in patients who develop new or acute cardiac ischemia or infarction, and resume only after resolution of acute cardiac ischemic events if the potential benefits outweigh the risks of further cardiac ischemia. Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS occurred in 1 of 1200 STIVARGA-treated patients across all clinical trials. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Confirm the diagnosis of RPLS with MRI and discontinue STIVARGA in patients who develop RPLS.

Gastrointestinal Perforation or Fistula: Gastrointestinal perforation or fistula occurred in 0.6% of 1200 patients treated with STIVARGA across all clinical trials; this included 4 fatal events. Permanently discontinue STIVARGA in patients who develop gastrointestinal perforation or fistula. Wound Healing Complications: Treatment with STIVARGA should be stopped at least 2 weeks prior to scheduled surgery. Resuming treatment after surgery should be based on clinical judgment of adequate wound healing. STIVARGA should be discontinued in patients with wound dehiscence. Embryo-Fetal Toxicity: STIVARGA can cause fetal harm when administered to a pregnant woman. Use effective contraception during treatment and up to 2 months after completion of therapy. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Nursing Mothers: Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from STIVARGA, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Most Frequently Observed Adverse Drug Reactions in mCRC (≥30%): The most frequently observed adverse drug reactions (≥30%) in STIVARGA-treated patients vs placebo-treated patients in mCRC, respectively, were: asthenia/fatigue (64% vs 46%), decreased appetite and food intake (47% vs 28%), HFSR/ PPE (45% vs 7%), diarrhea (43% vs 17%), mucositis (33% vs 5%), weight loss (32% vs 10%), infection (31% vs 17%), hypertension (30% vs 8%), and dysphonia (30% vs 6%). References: 1. STIVARGA Prescribing Information. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc; 2015. 2. Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for previously treatment metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381(9863):303-312.

© 2016. Bayer. All rights reserved. 100 Bayer Boulevard, PO Box 915, Whippany, NJ 07981-0915 USA STIVARGA®, REACH®, Bayer®, and the Bayer Cross® are registered trademarks of Bayer. PP-900-US-1950 02/16 Printed in USA

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STIVARGA® (regorafenib) tablets, for oral use Initial U.S. Approval: 2012 BRIEF SUMMARY OF PRESCRIBING INFORMATION CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION WARNING: HEPATOTOXICITY • S evere and sometimes fatal hepatotoxicity has been observed in clinical trials [see Warnings and Precautions (5.1)]. • Monitor hepatic function prior to and during treatment [see Warnings and Precautions (5.1)]. • Interrupt and then reduce or discontinue Stivarga for hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis, depending upon severity and persistence [see Dosage and Administration (2.2)]. 1 INDICATIONS AND USAGE 1.1 Colorectal Cancer ® Stivarga is indicated for the treatment of patients with metastatic colorectal cancer (CRC) who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild type, an anti-EGFR therapy. 1.2 Gastrointestinal Stromal Tumors Stivarga is indicated for the treatment of patients with locally advanced, unresectable or metastatic gastrointestinal stromal tumor (GIST) who have been previously treated with imatinib mesylate and sunitinib malate. 4 CONTRAINDICATIONS None 5 WARNINGS AND PRECAUTIONS 5.1 Hepatotoxicity Severe drug induced liver injury with fatal outcome occurred in 0.3% of 1200 Stivargatreated patients across all clinical trials. Liver biopsy results, when available, showed hepatocyte necrosis with lymphocyte infiltration. In Study 1, fatal hepatic failure occurred in 1.6% of patients in the regorafenib arm and in 0.4% of patients in the placebo arm; all the patients with hepatic failure had metastatic disease in the liver. In Study 2, fatal hepatic failure occurred in 0.8% of patients in the regorafenib arm [see Adverse Reactions (6.1)]. Obtain liver function tests (ALT, AST and bilirubin) before initiation of Stivarga and monitor at least every two weeks during the first 2 months of treatment. Thereafter, monitor monthly or more frequently as clinically indicated. Monitor liver function tests weekly in patients experiencing elevated liver function tests until improvement to less than 3 times the ULN or baseline. Temporarily hold and then reduce or permanently discontinue Stivarga depending on the severity and persistence of hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis [see Dosage and Administration (2.2)]. 5.2 Hemorrhage Stivarga caused an increased incidence of hemorrhage. The overall incidence (Grades 1-5) was 21% and 11% in Stivarga-treated patients compared to 8% and 3% in placebo-treated patients in Studies 1 and 2. Fatal hemorrhage occurred in 4 of 632 (0.6%) of Stivarga-treated patients in Studies 1 and 2 and involved the respiratory, gastrointestinal, or genitourinary tracts. Permanently discontinue Stivarga in patients with severe or life-threatening hemorrhage. Monitor INR levels more frequently in patients receiving warfarin [see Clinical Pharmacology (12.3)]. 5.3 Dermatological Toxicity Stivarga caused increased incidences of adverse reactions involving the skin and subcutaneous tissues (72% versus 24% in Study 1 and 78% versus 24% in Study 2), including hand-foot skin reaction (HFSR) also known as palmar-plantar erythrodysesthesia (PPE), and severe rash requiring dose modification. The overall incidence of HFSR was higher in Stivarga-treated patients, (45% versus 7% in Study 1 and 67% versus 12% in Study 2), than in the placebo-treated patients. Most cases of HFSR in Stivarga-treated patients appeared during the first cycle of treatment (69% and 71% of patients who developed HFSR in Study 1 and Study 2, respectively). The incidence of Grade 3 HFSR (17% versus 0% in Study 1 and 22% versus 0% in Study 2), Grade 3 rash (6% versus <1% in Study 1 and 7% versus 0% in Study 2), serious adverse reactions of erythema multiforme (0.2% vs. 0% in Study 1) and Stevens Johnson Syndrome (0.2% vs. 0% in Study 1) was higher in Stivarga-treated patients [see Adverse Reactions (6.1)]. Toxic epidermal necrolysis occurred in 0.17% of 1200 Stivarga-treated patients across all clinical trials. Withhold Stivarga, reduce the dose, or permanently discontinue Stivarga depending on the severity and persistence of dermatologic toxicity [see Dosage and Administration (2.2)]. Institute supportive measures for symptomatic relief. 5.4 Hypertension Stivarga caused an increased incidence of hypertension (30% versus 8% in Study 1 and 59% versus 27% in Study 2) [see Adverse Reactions (6.1)]. Hypertensive crisis occurred in 0.25% of 1200 Stivarga-treated patients across all clinical trials. The onset of hypertension occurred during the first cycle of treatment in most patients who developed hypertension (72% in Study 1 and Study 2). Do not initiate Stivarga unless blood pressure is adequately controlled. Monitor blood pressure weekly for the first 6 weeks of treatment and then every cycle, or more frequently, as clinically indicated. Temporarily or permanently withhold Stivarga for severe or uncontrolled hypertension [see Dosage and Administration (2.2)]. 5.5 Cardiac Ischemia and Infarction Stivarga increased the incidence of myocardial ischemia and infarction in Study 1 (1.2% versus 0.4%) [see Adverse Reactions (6.1)]. Withhold Stivarga in patients who develop new or acute onset cardiac ischemia or infarction. Resume Stivarga only after resolution of acute cardiac ischemic events, if the potential benefits outweigh the risks of further cardiac ischemia. 5.6 Reversible Posterior Leukoencephalopathy Syndrome (RPLS) Reversible Posterior Leukoencephalopathy Syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, occurred in one of 1200 Stivarga-treated patients across all clinical trials. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. Discontinue Stivarga in patients who develop RPLS.

PP-900-US-1950 Stivarga mCRC HCP Updated Journal Ad_CTA.indd 4

5.7 Gastrointestinal Perforation or Fistula Gastrointestinal perforation or fistula occurred in 0.6% of 1200 patients treated with Stivarga across all clinical trials; this included four fatal events. In Study 2, 2.1% (4/188) of Stivargatreated patients who were treated during the blinded or open-label portion of the study developed gastrointestinal fistula or perforation; of these, two cases of gastrointestinal perforation were fatal. Permanently discontinue Stivarga in patients who develop gastrointestinal perforation or fistula. 5.8 Wound Healing Complications No formal studies of the effect of regorafenib on wound healing have been conducted. Since vascular endothelial growth factor receptor (VEGFR) inhibitors such as regorafenib can impair wound healing, treatment with regorafenib should be stopped at least 2 weeks prior to scheduled surgery. The decision to resume regorafenib after surgery should be based on clinical judgment of adequate wound healing. Regorafenib should be discontinued in patients with wound dehiscence. 5.9 Embryo-Fetal Toxicity Stivarga can cause fetal harm when administered to a pregnant woman. Regorafenib was embryolethal and teratogenic in rats and rabbits at exposures lower than human exposures at the recommended dose, with increased incidences of cardiovascular, genitourinary, and skeletal malformations. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)]. 6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: • Hepatotoxicity [See Warnings and Precautions (5.1)] • Hemorrhage [See Warnings and Precautions (5.2)] • Dermatological Toxicity [See Warnings and Precautions (5.3)] • Hypertension [See Warnings and Precautions (5.4)] • Cardiac Ischemia and Infarction [See Warnings and Precautions (5.5)] • Reversible Posterior Leukoencephalopathy Syndrome (RPLS) [See Warnings and Precautions (5.6)] • Gastrointestinal Perforation or Fistula [See Warnings and Precautions (5.7)] 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 rate observed in practice. The most frequently observed adverse drug reactions (≥20%) in patients receiving Stivarga are asthenia/fatigue, HFSR, diarrhea, decreased appetite/food intake, hypertension, mucositis, dysphonia, infection, pain (not otherwise specified), decreased weight, gastrointestinal and abdominal pain, rash, fever, and nausea. The most serious adverse drug reactions in patients receiving Stivarga are hepatotoxicity, hemorrhage, and gastrointestinal perforation. 6.1 Clinical Trials Experience Colorectal Cancer The safety data described below, except where noted, are derived from a randomized (2:1), double-blind, placebo-controlled trial (Study 1) in which 500 patients (median age 61 years; 61% men) with previously-treated metastatic colorectal cancer received Stivarga as a single agent at the dose of 160 mg daily for the first 3 weeks of each 4 week treatment cycle and 253 patients (median age 61 years; 60% men) received placebo. The median duration of therapy was 7.3 (range 0.3, 47.0) weeks for patients receiving Stivarga. Due to adverse reactions, 61% of the patients receiving Stivarga required a dose interruption and 38% of the patients had their dose reduced. Drug-related adverse reactions that resulted in treatment discontinuation were reported in 8.2% of Stivarga-treated patients compared to 1.2% of patients who received placebo. Hand-foot skin reaction (HFSR) and rash were the most common reasons for permanent discontinuation of Stivarga. Table 1 compares the incidence of adverse reactions (≥10%) in patients receiving Stivarga and reported more commonly than in patients receiving placebo (Study 1). Table 1 Adverse drug reactions (≥10%) reported in patients treated with Stivarga in Study 1 and reported more commonly than in patients receiving placebo Stivarga Placebo (N=500) (N=253) Adverse Reactions Grade Grade All ≥3 All ≥3 % % % % General disorders and administration site conditions Asthenia/fatigue 64 15 46 9 Pain 29 3 21 2 Fever 28 2 15 0 Metabolism and nutrition disorders Decreased appetite and food intake 47 5 28 4 Skin and subcutaneous tissue disorders 45 17 7 0 HFSR/PPE 26 6 4 <1 Rash a Gastrointestinal disorders Diarrhea 43 8 17 2 Mucositis 33 4 5 0 Investigations Weight loss 32 <1 10 0 Infections and infestations Infection 31 9 17 6 Vascular disorders 30 8 8 <1 Hypertension 21 2 8 <1 Hemorrhage b Respiratory, thoracic and mediastinal disorders Dysphonia 30 0 6 0 Nervous system disorders Headache 10 <1 7 0 The term rash represents reports of events of drug eruption, rash, erythematous rash, generalized rash, macular rash, maculo-papular rash, papular rash, and pruritic rash. Fatal outcomes observed.

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Laboratory Abnormalities Laboratory abnormalities observed in Study 1 are shown in Table 2. Table 2 Laboratory test abnormalities reported in Study 1

Laboratory Parameter Blood and lymphatic system disorders Anemia Thrombocytopenia Neutropenia Lymphopenia Metabolism and nutrition disorders Hypocalcemia Hypokalemia Hyponatremia Hypophosphatemia Hepatobiliary disorders Hyperbilirubinemia Increased AST Increased ALT Renal and urinary disorders Proteinuria Investigations Increased INR c Increased Lipase Increased Amylase a b c

Stivarga (N=500 a) Grade b All 3 % % 79 41 3 54

5 2 1 9

Laboratory Abnormalities Laboratory abnormalities observed in Study 2 are shown in Table 4. Table 4 Laboratory test abnormalities reported in Study 2

4 %

Placebo (N=253 a) Grade b All 3 % %

4 %

1 <1 0 0

66 17 0 34

0 0 0 0

3 <1 0 3

59 26 30 57

1 4 7 31

<1 0 1 1

18 8 22 11

1 <1 4 4

0 0 0 0

45 65 45

10 5 5

3 1 1

17 46 30

5 4 3

3 1 <1

24 46 26

4 9 2

N/A 2 <1

17 19 17

2 3 2

N/A 2 <1

Blood and lymphatic system disorders Thrombocytopenia Neutropenia Lymphopenia Metabolism and nutrition disorders Hypocalcemia Hypokalemia Hypophosphatemia Hepatobiliary disorders Hyperbilirubinemia Increased AST Increased ALT Renal and urinary disorders Proteinuria Investigations Increased Lipase

4 %

Placebo (N=66 a) Grade b All 3 4 % % %

13 16 30

1 2 8

0 0 0

2 12 24

0 3 3

2 0 0

17 21 55

2 3 20

0 0 2

5 3 3

0 0 2

0 0 0

33 58 39

3 3 4

1 1 1

12 47 39

2 3 2

0 0 0

-c

% based on number of patients with post-baseline samples which may be less than 132 (regorafenib) or 66 (placebo). CTCAE, v4.0. c No Grade 4 denoted in CTCAE, v4.0. a

% based on number of patients with post-baseline samples which may be less than 500 (regorafenib) or 253 (placebo). Common Terminology Criteria for Adverse Events (CTCAE), v3.0. International normalized ratio: No Grade 4 denoted in CTCAE, v3.0.

Gastrointestinal Stromal Tumors The safety data described below are derived from a randomized (2:1), double-blind, placebocontrolled trial (Study 2) in which 132 patients (median age 60 years; 64% men) with previously-treated GIST received Stivarga as a single agent at a dose of 160 mg daily for the first 3 weeks of each 4 week treatment cycle and 66 patients (median age 61 years; 64% men) received placebo. The median duration of therapy was 22.9 (range 0.1, 50.9) weeks for patients receiving Stivarga. Dose interruptions for adverse events were required in 58% of patients receiving Stivarga and 50% of patients had their dose reduced. Drug-related adverse reactions that resulted in treatment discontinuation were reported in 2.3% of Stivarga-treated patients compared to 1.5% of patients who received placebo. Table 3 compares the incidence of adverse reactions (≥10%) in GIST patients receiving Stivarga and reported more commonly than in patients receiving placebo (Study 2). Table 3 Adverse reactions (≥10%) reported in patients treated with Stivarga in Study 2 and reported more commonly than in patients receiving placebo Stivarga Placebo (N=132) (N=66) Adverse Reactions Grade Grade All ≥3 All ≥3 % % % % Skin and subcutaneous tissue disorders 67 22 12 2 HFSR/PPE 30 7 3 0 Rash a Alopecia 24 2 2 0 General disorders and administration site conditions Asthenia/Fatigue 52 4 39 2 Fever 21 0 11 2 Vascular disorders Hypertension 59 28 27 5 Hemorrhage 11 4 3 0 Gastrointestinal disorders Diarrhea 47 8 9 0 Mucositis 40 2 8 2 Nausea 20 2 12 2 Vomiting 17 <1 8 0 Respiratory, thoracic and mediastinal disorders Dysphonia 39 0 9 0 Infections and infestations Infection 32 5 5 0 Metabolism and nutrition disorders 31 <1 21 3 Decreased appetite and food intake 18 0 6 0 Hypothyroidism b Nervous system disorders Headache 16 0 9 0 Investigations Weight loss 14 0 8 0 Musculoskeletal and connective tissue disorders Musculoskeletal stiffness 14 0 3 0 a

Laboratory Parameter

Stivarga (N=132 a) Grade b All 3 % %

The term rash represents reports of events of rash, erythematous rash, macular rash, maculo-papular rash, papular rash and pruritic rash. Hypothyroidism incidence based on subset of patients with normal TSH and no thyroid supplementation at baseline.

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6.2 Postmarketing Experience The following adverse reaction has been identified during postapproval use of Stivarga. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: • hypersensitivity reaction 7 DRUG INTERACTIONS 7.1 Effect of Strong CYP3A4 Inducers on Regorafenib Co-administration of a strong CYP3A4 inducer (rifampin) with a single 160 mg dose of Stivarga decreased the mean exposure of regorafenib, increased the mean exposure of the active metabolite M-5, and resulted in no change in the mean exposure of the active metabolite M-2. Avoid concomitant use of Stivarga with strong CYP3A4 inducers (e.g. rifampin, phenytoin, carbamazepine, phenobarbital, and St. John’s Wort) [see Clinical Pharmacology (12.3)]. 7.2 Effect of Strong CYP3A4 Inhibitors on Regorafenib Co-administration of a strong CYP3A4 inhibitor (ketoconazole) with a single 160 mg dose of Stivarga increased the mean exposure of regorafenib and decreased the mean exposure of the active metabolites M-2 and M-5. Avoid concomitant use of Stivarga with strong inhibitors of CYP3A4 activity (e.g. clarithromycin, grapefruit juice, itraconazole, ketoconazole, nefazodone, posaconazole, telithromycin, and voriconazole) [see Clinical Pharmacology (12.3)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.9)] Risk Summary Based on its mechanism of action, Stivarga can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies with Stivarga in pregnant women. Regorafenib was embryolethal and teratogenic in rats and rabbits at exposures lower than human exposures at the recommended dose, with increased incidences of cardiovascular, genitourinary, and skeletal malformations. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Animal Data In embryo-fetal development studies, a total loss of pregnancy (100% resorption of litter) was observed in rats at doses as low as 1 mg/kg (approximately 6% of the recommended human dose, based on body surface area) and in rabbits at doses as low as 1.6 mg/kg (approximately 25% of the human exposure at the clinically recommended dose measured by AUC). In a single dose distribution study in pregnant rats, there was increased penetration of regorafenib across the blood-brain barrier in fetuses compared to dams. In a repeat dose study with daily administration of regorafenib to pregnant rats during organogenesis, findings included delayed ossification in fetuses at doses > 0.8 mg/kg (approximately 5% of the recommended human dose based on body surface area) with dose-dependent increases in skeletal malformations including cleft palate and enlarged fontanelle at doses ≥ 1 mg/kg (approximately 10% of the clinical exposure based on AUC). At doses ≥ 1.6 mg/ kg (approximately 11% of the recommended human dose based on body surface area), there were dose-dependent increases in the incidence of cardiovascular malformations, external abnormalities, diaphragmatic hernia, and dilation of the renal pelvis. In pregnant rabbits administered regorafenib daily during organogenesis, there were findings of ventricular septal defects evident at the lowest tested dose of 0.4 mg/kg (approximately 7% of the AUC in patients at the recommended dose). At doses of ≥ 0.8 mg/kg (approximately 15% of the human exposure at the recommended human dose based on AUC), administration of regorafenib resulted in dose-dependent increases in the incidence of additional cardiovascular malformations and skeletal anomalies as well as significant adverse effects on the urinary system including missing kidney/ureter; small, deformed and malpositioned kidney; and hydronephrosis. The proportion of viable fetuses that were male decreased with increasing dose in two rabbit embryo-fetal toxicity studies.

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8.3 Nursing Mothers It is unknown whether regorafenib or its metabolites are excreted in human milk. In rats, regorafenib and its metabolites are excreted in milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Stivarga, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and efficacy of Stivarga in pediatric patients less than 18 years of age have not been established. In 28-day repeat dose studies in rats there were dose-dependent findings of dentin alteration and angiectasis. These findings were observed at regorafenib doses as low as 4 mg/kg (approximately 25% of the AUC in humans at the recommended dose). In 13-week repeat dose studies in dogs there were similar findings of dentin alteration at doses as low as 20 mg/kg (approximately 43% of the AUC in humans at the recommended dose). Administration of regorafenib in these animals also led to persistent growth and thickening of the femoral epiphyseal growth plate. 8.5 Geriatric Use Of the 632 Stivarga-treated patients enrolled in Studies 1 and 2, 37% were 65 years of age and over, while 8% were 75 and over. No overall differences in safety or efficacy were observed between these patients and younger patients. 8.6 Hepatic Impairment Stivarga is eliminated mainly via the hepatic route. No clinically important differences in the mean exposure of regorafenib or the active metabolites M-2 and M-5 were observed in patients with hepatocellular carcinoma and mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment compared to patients with normal hepatic function [see Clinical Pharmacology (12.3)]. No dose adjustment is recommended in patients with mild or moderate hepatic impairment. Closely monitor patients with hepatic impairment for adverse reactions [see Warnings and Precautions (5.1)]. Stivarga is not recommended for use in patients with severe hepatic impairment (Child-Pugh Class C), as it has not been studied in this population. 8.7 Renal Impairment No clinically relevant differences in the mean exposure of regorafenib and the active metabolites M-2 and M-5 were observed in patients with mild renal impairment (CLcr 60-89 mL/min) compared to patients with normal renal function following regorafenib 160 mg daily for 21 days [see Clinical Pharmacology (12.3)]. No dose adjustment is recommended for patients with mild renal impairment. Limited pharmacokinetic data are available from patients with moderate renal impairment (CLcr 30-59 mL/min). Stivarga has not been studied in patients with severe renal impairment or end-stage renal disease. 8.8 Females and Males of Reproductive Potential Contraception Use effective contraception during treatment and up to 2 months after completion of therapy. Infertility There are no data on the effect of Stivarga on human fertility. Results from animal studies indicate that regorafenib can impair male and female fertility [see Nonclinical Toxicology (13.1)]. 10 OVERDOSAGE The highest dose of Stivarga studied clinically is 220 mg per day. In the event of suspected overdose, interrupt Stivarga, institute supportive care, and observe until clinical stabilization. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Studies examining the carcinogenic potential of regorafenib have not been conducted. Regorafenib itself did not demonstrate genotoxicity in in vitro or in vivo assays; however, a major human active metabolite of regorafenib, (M-2), was positive for clastogenicity, causing chromosome aberration in Chinese hamster V79 cells. Dedicated studies to examine the effects of regorafenib on fertility have not been conducted; however, there were histological findings of tubular atrophy and degeneration in the testes, atrophy in the seminal vesicle, and cellular debris and oligospermia in the epididymides in male rats at doses similar to those in human at the clinical recommended dose based on AUC. In female rats, there were increased findings of necrotic corpora lutea in the ovaries at the same exposures. There were similar findings in dogs of both sexes in repeat dose studies at exposures approximately 83% of the human exposure at the recommended human dose based on AUC. These findings suggest that regorafenib may adversely affect fertility in humans.

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13.2 Animal Toxicology and/or Pharmacology In a chronic 26-week repeat dose study in rats there was a dose-dependent increase in the finding of thickening of the atrioventricular valve. At a dose that resulted in an exposure of approximately 12% of the human exposure at the recommended dose, this finding was present in half of the examined animals. 17 PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling (Patient Information). Inform your patients of the following: • Stivarga may cause severe or life-threatening liver damage. Inform patients that they will need to undergo monitoring for liver damage and to immediately report any signs or symptoms of severe liver damage to their health care provider. • Stivarga can cause severe bleeding. Advise patients to contact their health care provider for any episode of bleeding. • Stivarga can cause hand-foot skin reactions or rash elsewhere. Advise patients to contact their health care provider if they experience skin changes associated with redness, pain, blisters, bleeding, or swelling. • Stivarga can cause or exacerbate existing hypertension. Advise patients they will need to undergo 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. • Stivarga increased the risk for myocardial ischemia and infarction. Advise patients to seek immediate emergency help if they experience chest pain, shortness of breath, or feel dizzy or like passing out. • Contact a healthcare provider immediately if they experience severe pains in their abdomen, persistent swelling of the abdomen, high fever, chills, nausea, vomiting, severe diarrhea (frequent or loose bowel movements), or dehydration. • Stivarga may complicate wound healing. Advise patients to inform their health care provider if they plan to undergo a surgical procedure or had recent surgery. • Inform patients that regorafenib can cause fetal harm. Advise women of reproductive potential and men of the need for effective contraception during Stivarga treatment and for up to 2 months after completion of treatment. Instruct women of reproductive potential to immediately contact her health care provider if pregnancy is suspected or confirmed during or within 2 months of completing treatment with Stivarga. • Advise nursing mothers that it is not known whether regorafenib is present in breast milk and discuss whether to discontinue nursing or to discontinue regorafenib. • Advise patients to swallow the Stivarga tablet whole with water at the same time each day with a low-fat meal. Inform patients that the low-fat meal should contain less than 600 calories and less than 30% fat. • Inform patients to take any missed dose on the same day, as soon as they remember, and that they must not take two doses on the same day to make up for a dose missed on the previous day. • Inform patients to store medicine in the original container. Do not place medication in daily or weekly pill boxes. Any remaining tablets should be discarded 7 weeks after opening the bottle. Tightly close bottle after each opening and keep the desiccant in the bottle.

Manufactured in Germany

Manufactured for:

6708303BS

2/24/16 11:31 AM

IN THE CLINIC | BY JOHN SCHIESZER

NCCN has published patient guidelines for diffuse large B-cell, follicular lymphoma, mantle cell lymphoma, and peripheral T-cell lymphoma.

he National Comprehensive Cancer Network (NCCN) has just published new patient education materials for non-Hodgkin lymphomas to help educate and empower patients and promote better communication between patients and their health care teams.1 The new patient-focused guidelines highlight many of the dramatic changes that have occurred in the standards of care. It is hoped oncologists will promote the use of these materials as tools in clinical practice. “Because the NCCN Guidelines for Patients are based on the NCCN Guidelines, they can help patients to be better informed of the array of treatment choices they have and guide them to work with their health care team to choose the option that best fits their individual needs,” said Marcie Reeder, MPH, who is the executive director of the NCCN Foundation. In addition to the 6 new titles including chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, and peripheral T-cell lymphoma, the NCCN Guidelines for Patients Library also added quick guide versions of each, which are 1-page summaries with links to specific information contained in the full booklet. The guidelines explain what the new treatment options are,

such as targeted therapy, radioimmunotherapy, immunomodulator, and chemoprotectants, and what side effects patients can expect with each type of treatment. “These patient-friendly versions of the NCCN Guidelines have the same vital content. It is crucial that patients have a reference that they can use to understand all of their treatment options, especially with the many recent changes to the standard of care. When patients are informed with credible information, conversations between patient and providers are much more productive,” Ms Reeder told Cancer Therapy Advisor.

Seema Ali Bhat, MD, who is an assistant professor of oncology and a staff physician at the Lymphoma/Myeloma Service at Roswell Park Cancer Institute in Buffalo, New York, said based on recent advances in the understanding of the biology of follicular lymphoma and mantle cell lymphoma, newer treatment options have emerged for both of these diseases. “For patients with mantle cell lymphoma who are 65 or older who are not considered transplant candidates, rituximab maintenance until progression is the new standard of care for up-front treatment. For relapsed/refractory mantle cell lymphoma, newer options are available, like the BTK inhibitor ibrutinib, the proteasome inhibitor bortezomib, and the immunomodulator lenalidomide, all US Food and Drug Administration (FDA)-approved in the recent years for this lymphoma,” Dr Bhat told Cancer Therapy Advisor. “For follicular lymphoma, one of the major changes in recent years has been the introduction of maintenance rituximab. Also, the first-in-its-class PI3d kinase inhibitor idelalisib was recently approved by the FDA for the treatment Continued on page A31

A light microscopy of a Hodgkin lymphoma cell.

NCCN Patient-focused Educational Materials for Non-Hodgkin Lymphoma

A22 CANCER THERAPY ADVISOR | JULY/AUGUST 2016 | CancerTherapyAdvisor.com

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7/6/16 2:38 PM

EXPERT PERSPECTIVE | BY JIM DALEY

Immunotherapy Q&A Session With Aude G. Chapuis, MD How will breakthroughs in vaccine-based immunotherapies effect patients with cancer and clinical practice?

Aude G. Chapuis, MD, is a medical oncologist and adult hematopoietic stem cell transplant physician with a background in immunology and adoptive T-cell transfer studies in humans. She is an assistant professor at the University of Washington School of Medicine in Seattle, Washington. Dr Chapuis spoke to Cancer Therapy Advisor about the state of vaccine-based immunotherapy.

Cancer Therapy Advisor (CTA): The field of vaccine-based immunotherapy is rapidly developing. Where do you see it going in the next 5 to 10 years? DR CHAPUIS: The challenge with vaccine-based immunotherapy is that many vaccines have been geared to boost a pre-existing dysfunctional immune response. With the advent of novel vaccine strategies that engage de novo responses and oncolytic viruses, we may see a rapid revival of this approach— especially if they can be administered with checkpoint inhibitors and agents that stimulate immune cells, such as the stimulating antibody-targeting CD40. Adoptive immunotherapy strategies may also be useful in this context to determine which tumor antigens need

to be targeted and how many and what kind of cells need to be present for tumor control, thus determining the type of immune responses that vaccine strategies need to generate.

CTA: How durable are some of the recent breakthroughs? DR CHAPUIS: These breakthroughs are going to be durable for CD19-expressing tumors. The current data might change the landscape, and we may be treating patients with certain lymphomas and acute lymphoblastic leukemia with chimeric antigen receptor (CAR) T cells up front. In fact, companies are now trying to find ways to deliver T-cell products to smaller hospitals to accommodate this treatment modality. CTA : What are some of the most promising immunotherapies being implemented? DR CHAPUIS: In my opinion, gene-modified cells that express a T-cell receptor (TCR) or a CAR are going to be promising. Many targets are being sought both in the solid tumor and liquid tumor worlds, and it might be that combinations of CARs and TCRs are necessary

to obtain complete responses. The combination of these cells with checkpoint inhibitors is also exciting.

CTA: Are we on the cusp of any new discoveries that you’re particularly excited about? DR CHAPUIS: For immunotherapy to control tumors and prevent their growth for as long as the patient is alive, we need a reservoir of cells that specifically recognize the tumor and leave other tissues untouched. These cells must persist for years and give rise to effector cells that can react to putative tumor growth instantly. All research to obtain such cells is exciting, including trials that look at what type of native cells should be used to insert TCR and CAR genes, trials that look at different tumor targets, and trials that assess whether combinations of the cells with checkpoint inhibitors can enhance survival of the cells and migration into the tumor microenvironment. In particular, I would look out for trials that examine tumor tissue after immunotherapy to provide the most relevant data. CTA: Can immunotherapy offer anything in terms of preventing cancer? DR CHAPUIS: Once these therapies have a proven effect and safety in the therapeutic setting, it is plausible that certain high-risk patient populations could receive them as prevention. Although if they work as well as we think they will, immunotherapy for prevention might not be necessary. Instead, patients could receive immunotherapy as soon as they are diagnosed. ■

Many targets are being sought both in the solid tumor and liquid tumor worlds, and it might be that combinations of CARs and TCRs are necessary to obtain complete responses. CancerTherapyAdvisor.com | JULY/AUGUST 2016 | CANCER THERAPY ADVISOR A23

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7/6/16 2:50 PM

FEATURE

BY JASON HOFFMAN, PharmD, RPh

he American Cancer Society estimates that approximately 224,390 new cases of lung cancer, of which 85% to 90% will be non-small cell lung cancer (NSCLC), will be diagnosed in the United States in 2016. About 158,080 patients will die from the disease, leading to more deaths from lung cancer than colon cancer, breast cancer, and prostate cancer combined.1 As with many other cancer types, kinase inhibitors have drastically improved the treatment landscape for metastatic NSCLC. Although the mainstay of advanced or metastatic NSCLC systemic therapy continues to be chemotherapy, the US Food and Drug Administration (FDA) has now approved erlotinib, afatinib, gefitinib, and osimertinib for patients with sensitizing epidermal growth factor receptor (EGFR) mutation-positive tumors. Likewise, crizotinib, ceritinib, alectinib are indicated for patients with anaplastic lymphoma kinase (ALK) rearrangements. Immunotherapeutic agents like bevacizumab, pembrolizumab, ramucirumab, and nivolumab are also used in this setting. The NSCLC treatment pipeline includes additional targeted therapies, immunotherapies, and chemotherapy

A review of current and future potential treatment options for patients with metastatic NSCLC with Gregory A. Masters, MD.

Chest Xray of advanced NSCLC.

that have already demonstrated safety and efficacy in phase 2 and 3 trials. Cancer Therapy Advisor spoke with Gregory A. Masters, MD, attending physician at the Helen F. Graham Cancer Center in Newark, Deleware, to clarify which therapies he believes are the most promising for metastatic NSCLC treatment. “There has been a really tremendous shift in the treatment for NSCLC,” said Dr Masters, who is also an associate professor at the Thomas Jefferson University Medical School in Philadelphia, Pennsylvania, and has served on the Thoracic Malignancies Steering Committee at the National Cancer Institute. “Ten or 15 years ago, we were using chemotherapy almost exclusively,” Dr Masters explained. “We were just starting to use some of the targeted drugs but without a lot of understanding of how and why they worked or for whom they worked best. We were at a bit of a standstill until the molecular biology started to catch up.” “It is really over the last 5 or 6 years that we have understood all of these molecular mutations that occur in NSCLC, and how many of those can be driving forces for the growth and spread of cancer,” Dr Masters told Cancer Therapy Advisor. “Developing drugs that target those mechanisms of growth has really changed the way we treat patients.”

Pipeline Series: Research Advances in Non-small Cell Lung Cancer Treatment

A24 CANCER THERAPY ADVISOR | JULY/AUGUST 2016 | CancerTherapyAdvisor.com

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7/6/16 2:41 PM

FEATURE Rociletinib Rociletinib is an oral kinase of mutant EGFR, including the T790M mutation that is often present in tumors that are resistant to other kinase inhibitors. In a single-arm, phase 1/2 study of 345 patients with EGFR-mutant NSCLC who had received at least 1 EGFR inhibitor previously, researchers found that the overall response rate with rociletinib was 49% among those harboring a T790M mutation and 36% among others. The most frequently reported adverse events were hyperglycemia (40%), diarrhea (28%), nausea (23%), fatigue (21%), and decreased appetite (17%).2 In April 2016, however, the FDA voted 12 to 1 in favor of requiring Clovis Oncology to complete a phase 3 trial to evaluate the efficacy and safety of rociletinib in this treatment setting. Their decision was based on the lack of comparative data with another standard therapy, as well as uncertainty as to why patients were switched from the recommended 500 mg dose to the 625 mg dose. “Both rociletinib and osimertinib were developed for patients who developed a T790M mutations to an EGFR inhibitor. Osimertinib was approved by the FDA, possibly in part because it was first, but I believe the studies showed a little better toxicity profile,” Dr Masters said. “There were concerns about toxicity that the FDA thought that rociletinib did not match up to osimertinib.” The phase 3 trial evaluating the efficacy and safety of rociletinib will be completed in 2018. Cabozantinib Cabozantinib is a small molecule inhibitor of multiple receptor tyrosine kinases, including MET, VEGFR2, and RET. It is already FDA approved for the treatment of patients with progressive, metastatic medullary thyroid cancer, and patients with advanced renal cell

carcinoma who have received prior anti-angiogenic therapy.3 In a phase 2 study of 115 patients with EGFR wild-type NSCLC, researchers compared the efficacy and safety of everolimus to that of cabozantinib and everolimus plus cabozantinib. Participants were randomly assigned 1:1:1 to receive everolimus 150 mg orally once daily, cabozantinib 60 mg orally once daily, or everolimus plus cabozantinib 40 mg daily. Results showed that at a median follow-up of 8.5 months, median progression-free survival was 3.9 months (hazard ratio 0.33; 80% CI, 0.22-0.49; P = .0002) with cabozantinib and 4.1 months (hazard ratio 0.31; 80% CI, 0.21-0.46; P = .0002) compared with 1.9

A phase 2 study reviewed the safety and efficacy of cabozantinib in patients with NSCLC. months with everolimus. Median overall survival was significantly longer with cabozantinib and the combination in contrast with everolimus alone (P = .02). Grade 3 or 4 treatment-related hypertension and mucositis were more frequently reported with cabozantinib and grade 3 to 4 diarrhea was more common with the drug combination. Overall worst grade toxicities were significantly more common with cabozantinib alone and everolimus plus cabozantinib. “The RET gene arrangement occurs in only 1% to 2% of all NSCLC cases, but cabozantinib appears to have some activity in that group and looks quite promising in this small subset

of patients,” Dr Masters said. “It fits in with our desire to understand each individual cancer and to give the most appropriate treatment for the individual driving mutations.” Brigatinib Crizotinib is indicated for the treatment of patients with metastatic NSCLC whose tumors are ALK-positive, and ceritinib and alectinib were each granted accelerated approval for patients who have progressed on or are intolerant to crizotinib.4 Now, brigatinib, an investigational kinase inhibitor, exhibited dual inhibitory activity against ALK and EGFR. An updated analysis from a phase 1/2 study in 79 patients with ALK-positive NSCLC demonstrated a 1-year overall survival rate of 100% among 8 evaluable crizotinib-naïve patients and 81% among 71 evaluable patients who received prior crizotinib therapy. Further, brigatinib conferred a median progression-free survival of 13.4 months among those with prior crizotinib therapy and had not yet been reached in crizotinib-naive patients. The most common treatment-emergent adverse events were nausea, fatigue, diarrhea, headache, and cough. The efficacy and safety of brigatinib are also being evaluated in the pivotal phase 2 ALTA trial and the phase 3 ALTA 1L trial, to assess the drug’s use in the frontline treatment setting. “Although brigatinib is similar to ceritinib and alectinib, having multiple options for patients who do not tolerate 1 option is always great for patients,” Dr Masters noted. Durvalumab and Tremelimumab Findings from a phase 1 expansion study presented at the European Lung Cancer Conference in 2016 demonstrated encouraging activity and favorable toxicity with durvalumab in combination

CancerTherapyAdvisor.com | JULY/AUGUST 2016 | CANCER THERAPY ADVISOR A25

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For mCRPC patients with symptomatic bone metastases1

Introduce Xofigo® at the first sign of progression on hormonal therapy1*

SI G N I F I C A N T LY E X T E N D OV E R A L L S U R V I VA L ( OS )

1,2a

MME EDDI AI ANNOOSSWI INT HA NO RE XWP ILTOHROAT U TO RC YO NA CNOA M LYIST A I SN1,2b T U S E O F A B I R AT E R O N E 9 a 100

HR=0.695 (95% CI: 0.581-0.832)

Probability of survival (%)

14.9 MONTHS

Planned course of Xofigo treatment is 6 doses

80 70 60 50 40

for Xofigo + BSOC (n=614) (95% CI: 13.9-16.1)

30 %

reduction in the risk of death vs placebo (HR=0.695)1,2

11.3 MONTHS

for placebo + BSOC (n=307) (95% CI: 10.4-12.8)

20 10 0 0

41 14

18 7

7 4

1 2

0 1

0 0

Time (months) Xofigo 6 1 4 Placebo 3 0 7

578 288

504 228

369 157

277 104

178 67

105 39

60 24

In the prespecified interim analysis.1 An exploratory updated OS analysis was performed before patient crossover, incorporating an additional 214 events, resulting in findings consistent with the interim analysis.1

*In ALSYMPCA, best standard of care (BSOC) was defined as antihormonal agents, local external beam radiation therapy (EBRT), ketoconazole, and treatment with glucocorticoids.2

XOFIGO® IS INDICATED for the treatment of patients with castration-resistant prostate cancer (CRPC), symptomatic bone metastases and no known visceral metastatic disease.

with myelosuppression were observed in 1% of Xofigo-treated patients compared to 0.3% of patients treated with placebo. The incidence of infection-related deaths (2%), serious infections (10%), and febrile neutropenia (<1%) was similar for patients treated with Xofigo and placebo. Myelosuppression— notably thrombocytopenia, neutropenia, pancytopenia, and leukopenia—has been reported in patients treated with Xofigo. Important Safety Information Monitor patients with evidence of compromised bone marrow • Contraindications: Xofigo is contraindicated in women who reserve closely and provide supportive care measures when are or may become pregnant. Xofigo can cause fetal harm clinically indicated. Discontinue Xofigo in patients who when administered to a pregnant woman experience life-threatening complications despite supportive • Bone Marrow Suppression: In the randomized trial, 2% of care for bone marrow failure patients in the Xofigo arm experienced bone marrow failure • Hematological Evaluation: Monitor blood counts at baseline or ongoing pancytopenia, compared to no patients treated and prior to every dose of Xofigo. Prior to first administering with placebo. There were two deaths due to bone marrow Xofigo, the absolute neutrophil count (ANC) should be failure. For 7 of 13 patients treated with Xofigo bone marrow failure was ongoing at the time of death. Among the 13 patients ≥1.5 × 109/L, the platelet count ≥100 × 109/L, and hemoglobin ≥10 g/dL. Prior to subsequent administrations, the ANC should who experienced bone marrow failure, 54% required blood be ≥1 × 109/L and the platelet count ≥50 × 109/L. Discontinue transfusions. Four percent (4%) of patients in the Xofigo Xofigo if hematologic values do not recover within 6 to 8 weeks arm and 2% in the placebo arm permanently discontinued therapy due to bone marrow suppression. In the randomized after the last administration despite receiving supportive care trial, deaths related to vascular hemorrhage in association

PP-600-US-2234_US_Journal_Ad_FR1.indd 1-2

• Prespecified interim analysis: median OS was 14.0 months for Xofigo (95% Conf idence interval [CI]: 12.1-15.8) vs 11.2 months for placebo (95% CI: 9.0-13.2)1 – P=0.00185; Hazard ratio [HR]=0.695 (95% CI: 0.552-0.875)

• Concomitant Use With Chemotherapy: Safety and efficacy of concomitant chemotherapy with Xofigo have not been established. Outside of a clinical trial, concomitant use of Xofigo in patients on chemotherapy is not recommended due to the potential for additive myelosuppression. If chemotherapy, other systemic radioisotopes, or hemibody external radiotherapy are administered during the treatment period, Xofigo should be discontinued • Administration and Radiation Protection: Xofigo should be received, used, and administered only by authorized persons in designated clinical settings. The administration of Xofigo is associated with potential risks to other persons from radiation or contamination from spills of bodily fluids such as urine, feces, or vomit. Therefore, radiation protection precautions must be taken in accordance with national and local regulations • Adverse Reactions: The most common adverse reactions (≥10%) in the Xofigo arm vs the placebo arm, respectively, were nausea (36% vs 35%), diarrhea (25% vs 15%), vomiting (19% vs 14%), and

peripheral edema (13% vs 10%). Grade 3 and 4 adverse events were reported in 57% of Xofigo-treated patients and 63% of placebo-treated patients. The most common hematologic laboratory abnormalities in the Xofigo arm (≥10%) vs the placebo arm, respectively, were anemia (93% vs 88%), lymphocytopenia (72% vs 53%), leukopenia (35% vs 10%), thrombocytopenia (31% vs 22%), and neutropenia (18% vs 5%) References: 1. Xofigo® (radium Ra 223 dichloride) injection [prescribing information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc.; March 2016. 2. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369(3):213-223.

Please see following pages for brief summary of full Prescribing Information.

radium Ra 223 dichloride INJECTION

Learn more about Xofigo at hcp.xofigo-us.com

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For mCRPC patients with symptomatic bone metastases1

Introduce Xofigo® at the first sign of progression on hormonal therapy1*

SI G N I F I C A N T LY E X T E N D OV E R A L L S U R V I VA L ( OS )

1,2a

MME EDDI AI ANNOOSSWI INT HA NO RE XWP ILTOHROAT U TO RC YO NA CNOA M LYIST A I SN1,2b T U S E O F A B I R AT E R O N E 9 a 100

HR=0.695 (95% CI: 0.581-0.832)

Probability of survival (%)

14.9 MONTHS

Planned course of Xofigo treatment is 6 doses

80 70 60 50 40

for Xofigo + BSOC (n=614) (95% CI: 13.9-16.1)

30 %

reduction in the risk of death vs placebo (HR=0.695)1,2

11.3 MONTHS

for placebo + BSOC (n=307) (95% CI: 10.4-12.8)

20 10 0 0

41 14

18 7

7 4

1 2

0 1

0 0

Time (months) Xofigo 6 1 4 Placebo 3 0 7

578 288

504 228

369 157

277 104

178 67

105 39

60 24

*In ALSYMPCA, best standard of care (BSOC) was defined as antihormonal agents, local external beam radiation therapy (EBRT), ketoconazole, and treatment with glucocorticoids.2

XOFIGO® IS INDICATED for the treatment of patients with castration-resistant prostate cancer (CRPC), symptomatic bone metastases and no known visceral metastatic disease.

PP-600-US-2234_US_Journal_Ad_FR1.indd 1-2

Please see following pages for brief summary of full Prescribing Information.

radium Ra 223 dichloride INJECTION

Learn more about Xofigo at hcp.xofigo-us.com

5/20/16 5:44 PM

XOFIGO (radium Ra 223 dichloride) Injection, for intravenous use Initial U.S. Approval: 2013 BRIEF SUMMARY oF pREScRIBIng InFoRMAtIon conSULt pAcKAgE InSERt FoR FULL pREScRIBIng InFoRMAtIon 1 INDICATIONS AND USAGE Xofigo® is indicated for the treatment of patients with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastatic disease. 2 DOSAGE AND ADMINISTRATION 2.3 Instructions for Use/Handling General warning Xofigo (an alpha particle-emitting pharmaceutical) should be received, used and administered only by authorized persons in designated clinical settings. The receipt, storage, use, transfer and disposal Xofigo are subject to the regulations and/or appropriate licenses of the competent official organization. Xofigo should be handled by the user in a manner which satisfies both radiation safety and pharmaceutical quality requirements. Appropriate aseptic precautions should be taken. Radiation protection The administration of Xofigo is associated with potential risks to other persons (e.g., medical staff, caregivers and patient’s household members) from radiation or contamination from spills of bodily fluids such as urine, feces, or vomit. Therefore, radiation protection precautions must be taken in accordance with national and local regulations. For drug handling Follow the normal working procedures for the handling of radiopharmaceuticals and use universal precautions for handling and administration such as gloves and barrier gowns when handling blood and bodily fluids to avoid contamination. In case of contact with skin or eyes, the affected area should be flushed immediately with water. In the event of spillage of Xofigo, the local radiation safety officer should be contacted immediately to initiate the necessary measurements and required procedures to decontaminate the area. A complexing agent such as 0.01 M ethylene-diamine-tetraacetic acid (EDTA) solution is recommended to remove contamination. For patient care Whenever possible, patients should use a toilet and the toilet should be flushed several times after each use. When handling bodily fluids, simply wearing gloves and hand washing will protect caregivers. Clothing soiled with Xofigo or patient fecal matter or urine should be washed promptly and separately from other clothing. Radium-223 is primarily an alpha emitter, with a 95.3% fraction of energy emitted as alpha-particles. The fraction emitted as beta-particles is 3.6%, and the fraction emitted as gamma-radiation is 1.1%. The external radiation exposure associated with handling of patient doses is expected to be low, because the typical treatment activity will be below 8,000 kBq (216 microcurie). In keeping with the As Low As Reasonably Achievable (ALARA) principle for minimization of radiation exposure, it is recommended to minimize the time spent in radiation areas, to maximize the distance to radiation sources, and to use adequate shielding. Any unused product or materials used in connection with the preparation or administration are to be treated as radioactive waste and should be disposed of in accordance with local regulations. The gamma radiation associated with the decay of radium-223 and its daughters allows for the radioactivity measurement of Xofigo and the detection of contamination with standard instruments. 4 CONTRAINDICATIONS Xofigo is contraindicated in pregnancy. Xofigo can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Xofigo is not indicated for use in women. Xofigo is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus [see Use in Specific Populations (8.1)]. 5 WARNINGS AND PRECAUTIONS 5.1 Bone Marrow Suppression In the randomized trial, 2% of patients on the Xofigo arm experienced bone marrow failure or ongoing pancytopenia compared to no patients treated with placebo. There were two deaths due to bone marrow failure and for 7 of 13 patients treated with Xofigo, bone marrow failure was ongoing at the time of death. Among the 13 patients who experienced bone marrow failure, 54% required blood transfusions. Four percent (4%) of patients on the Xofigo arm and 2% on the placebo arm permanently discontinued therapy due to bone marrow suppression. In the randomized trial, deaths related to vascular hemorrhage in association with myelosuppression were observed in 1% of Xofigo-treated patients compared to 0.3% of patients treated with placebo. The incidence of infectionrelated deaths (2%), serious infections (10%), and febrile neutropenia (<1%) were similar for patients treated with Xofigo and placebo. Myelosuppression; notably thrombocytopenia, neutropenia, pancytopenia, and leukopenia; has been reported in patients treated with Xofigo. In the randomized trial, complete blood counts (CBCs) were obtained every 4 weeks prior to each dose and the nadir CBCs and times of recovery were not well characterized. In a separate singledose phase 1 study of Xofigo, neutrophil and platelet count nadirs occurred 2 to 3 weeks after Xofigo administration at doses that were up to 1 to 5 times the recommended dose, and most patients recovered approximately 6 to 8 weeks after administration [see Adverse Reactions (6)].

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Hematologic evaluation of patients must be performed at baseline and prior to every dose of Xofigo. Before the first administration of Xofigo, the absolute neutrophil count (ANC) should be ≥ 1.5 x 109/L, the platelet count ≥ 100 x 109/L and hemoglobin ≥ 10 g/dL. Before subsequent administrations of Xofigo, the ANC should be ≥ 1 x 109/L and the platelet count ≥ 50 x 109/L. If there is no recovery to these values within 6 to 8 weeks after the last administration of Xofigo, despite receiving supportive care, further treatment with Xofigo should be discontinued. Patients with evidence of compromised bone marrow reserve should be monitored closely and provided with supportive care measures when clinically indicated. Discontinue Xofigo in patients who experience lifethreatening complications despite supportive care for bone marrow failure. The safety and efficacy of concomitant chemotherapy with Xofigo have not been established. Outside of a clinical trial, concomitant use with chemotherapy is not recommended due to the potential for additive myelosuppression. If chemotherapy, other systemic radioisotopes or hemibody external radiotherapy are administered during the treatment period, Xofigo should be discontinued. 6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in another section of the label: • Bone Marrow Suppression [see Warnings and Precautions (5.1)] 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 practice. In the randomized clinical trial in patients with metastatic castration-resistant prostate cancer with bone metastases, 600 patients received intravenous injections of 55 kBq/kg (1.49 microcurie/kg) of Xofigo and best standard of care and 301 patients received placebo and best standard of care once every 4 weeks for up to 6 injections. Prior to randomization, 58% and 57% of patients had received docetaxel in the Xofigo and placebo arms, respectively. The median duration of treatment was 20 weeks (6 cycles) for Xofigo and 18 weeks (5 cycles) for placebo. The most common adverse reactions (≥ 10%) in patients receiving Xofigo were nausea, diarrhea, vomiting, and peripheral edema (Table 3). Grade 3 and 4 adverse events were reported among 57% of Xofigo-treated patients and 63% of placebo-treated patients. The most common hematologic laboratory abnormalities in Xofigo-treated patients (≥ 10%) were anemia, lymphocytopenia, leukopenia, thrombocytopenia, and neutropenia (Table 4). Treatment discontinuations due to adverse events occurred in 17% of patients who received Xofigo and 21% of patients who received placebo. The most common hematologic laboratory abnormalities leading to discontinuation for Xofigo were anemia (2%) and thrombocytopenia (2%). Table 3 shows adverse reactions occurring in ≥ 2% of patients and for which the incidence for Xofigo exceeds the incidence for placebo. Table 3: Adverse Reactions in the Randomized Trial System/Organ Class Xofigo (n=600) Placebo (n=301) Preferred Term Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4 % % % % Blood and lymphatic system disorders Pancytopenia 2 1 0 0 Gastrointestinal disorders Nausea 36 2 35 2 Diarrhea 25 2 15 2 Vomiting 19 2 14 2 General disorders and administration site conditions Peripheral edema 13 2 10 1 Renal and urinary disorders Renal failure and impairment 3 1 1 1 Laboratory Abnormalities Table 4 shows hematologic laboratory abnormalities occurring in > 10% of patients and for which the incidence for Xofigo exceeds the incidence for placebo. Table 4: Hematologic Laboratory Abnormalities Hematologic Xofigo (n=600) Placebo (n=301) Laboratory Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4 Abnormalities % % % % Anemia 93 6 88 6 Lymphocytopenia 72 20 53 7 Leukopenia 35 3 10 <1 Thrombocytopenia 31 3 22 <1 Neutropenia 18 2 5 <1 Laboratory values were obtained at baseline and prior to each 4-week cycle. As an adverse reaction, grade 3-4 thrombocytopenia was reported in 6% of patients on Xofigo and in 2% of patients on placebo. Among patients who received Xofigo, the laboratory abnormality grade 3-4 thrombocytopenia occurred in 1% of docetaxel naïve patients and in 4% of patients who had received prior docetaxel. Grade 3-4 neutropenia occurred in 1% of docetaxel naïve patients and in 3% of patients who have received prior docetaxel.

Fluid Status Dehydration occurred in 3% of patients on Xofigo and 1% of patients on placebo. Xofigo increases adverse reactions such as diarrhea, nausea, and vomiting which may result in dehydration. Monitor patients’ oral intake and fluid status carefully and promptly treat patients who display signs or symptoms of dehydration or hypovolemia. Injection Site Reactions Erythema, pain, and edema at the injection site were reported in 1% of patients on Xofigo. Secondary Malignant Neoplasms Xofigo contributes to a patient’s overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure may be associated with an increased risk of cancer and hereditary defects. Due to its mechanism of action and neoplastic changes, including osteosarcomas, in rats following administration of radium-223 dichloride, Xofigo may increase the risk of osteosarcoma or other secondary malignant neoplasms [see Nonclinical Toxicology (13.1)]. However, the overall incidence of new malignancies in the randomized trial was lower on the Xofigo arm compared to placebo (<1% vs. 2%; respectively), but the expected latency period for the development of secondary malignancies exceeds the duration of follow up for patients on the trial. Subsequent Treatment with Cytotoxic Chemotherapy In the randomized clinical trial, 16% patients in the Xofigo group and 18% patients in the placebo group received cytotoxic chemotherapy after completion of study treatments. Adequate safety monitoring and laboratory testing was not performed to assess how patients treated with Xofigo will tolerate subsequent cytotoxic chemotherapy. 7 DRUG INTERACTIONS No formal clinical drug interaction studies have been performed. Subgroup analyses indicated that the concurrent use of bisphosphonates or calcium channel blockers did not affect the safety and efficacy of Xofigo in the randomized clinical trial. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Category X [see Contraindications (4)] Xofigo can cause fetal harm when administered to a pregnant woman based on its mechanism of action. While there are no human or animal data on the use of Xofigo in pregnancy and Xofigo is not indicated for use in women, maternal use of a radioactive therapeutic agent could affect development of a fetus. Xofigo is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with Xofigo. 8.3 Nursing Mothers Xofigo is not indicated for use in women. It is not known whether radium-223 dichloride is excreted in human milk. Because many drugs are excreted in human milk, and because of potential for serious adverse reactions in nursing infants from Xofigo, a decision should be made whether to discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and efficacy of Xofigo in pediatric patients have not been established. In single- and repeat-dose toxicity studies in rats, findings in the bones (depletion of osteocytes, osteoblasts, osteoclasts, fibro-osseous lesions, disruption/ disorganization of the physis/growth line) and teeth (missing, irregular growth, fibro-osseous lesions in bone socket) correlated with a reduction of osteogenesis that occurred at clinically relevant doses beginning in the range of 22 – 88 kBq (0.59 - 2.38 microcurie) per kg body weight. 8.5 Geriatric Use Of the 600 patients treated with Xofigo in the randomized trial, 75% were 65 years of age and over and while 33% were 75 years of age and over. No dosage adjustment is considered necessary in elderly patients. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Patients with Hepatic Impairment No dedicated hepatic impairment trial for Xofigo has been conducted. Since radium-223 is neither metabolized by the liver nor eliminated via the bile, hepatic impairment is unlikely to affect the pharmacokinetics of radium-223 dichloride [see Clinical Pharmacology (12.3)]. Based on subgroup analyses in the randomized clinical trial, dose adjustment is not needed in patients with mild hepatic impairment. No dose adjustments can be recommended for patients with moderate or severe hepatic impairment due to lack of clinical data. 8.7 Patients with Renal Impairment No dedicated renal impairment trial for Xofigo has been conducted. Based on subgroup analyses in the randomized clinical trial, dose adjustment is not needed in patients with existing mild (creatinine clearance [CrCl] 60 to 89 mL/min) or moderate (CrCl 30 to 59 mL/min) renal impairment. No dose adjustment can be recommended for patients with severe renal impairment (CrCl less than 30 mL/ min) due to limited data available (n = 2) [see Clinical Pharmacology (12.3)].

8.8 Males of Reproductive Potential Contraception Because of potential effects on spermatogenesis associated with radiation, advise men who are sexually active to use condoms and their female partners of reproductive potential to use a highly effective contraceptive method during and for 6 months after completing treatment with Xofigo. Infertility There are no data on the effects of Xofigo on human fertility. There is a potential risk that radiation by Xofigo could impair human fertility [see Nonclinical Toxicology (13.1)]. 10 OVERDOSAGE There have been no reports of inadvertent overdosing of Xofigo during clinical studies. There is no specific antidote. In the event of an inadvertent overdose of Xofigo, utilize general supportive measures, including monitoring for potential hematological and gastrointestinal toxicity, and consider using medical countermeasures such as aluminum hydroxide, barium sulfate, calcium carbonate, calcium gluconate, calcium phosphate, or sodium alginate. Single Xofigo doses up to 274 kBq (7.41 microcurie) per kg body weight were evaluated in a phase 1 clinical trial and no dose-limiting toxicities were observed. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Animal studies have not been conducted to evaluate the carcinogenic potential of radium-223 dichloride. However, in repeat-dose toxicity studies in rats, osteosarcomas, a known effect of bone-seeking radionuclides, were observed at clinically relevant doses 7 to 12 months after the start of treatment. The presence of other neoplastic changes, including lymphoma and mammary gland carcinoma, was also reported in 12- to 15-month repeat-dose toxicity studies in rats. Genetic toxicology studies have not been conducted with radium-223 dichloride. However, the mechanism of action of radium-223 dichloride involves induction of double-strand DNA breaks, which is a known effect of radiation. Animal studies have not been conducted to evaluate the effects of radium-223 dichloride on male or female fertility or reproductive function. Xofigo may impair fertility and reproductive function in humans based on its mechanism of action. 17 PATIENT COUNSELING INFORMATION Advise patients: • To be compliant with blood cell count monitoring appointments while receiving Xofigo. Explain the importance of routine blood cell counts. Instruct patients to report signs of bleeding or infections. • To stay well hydrated and to monitor oral intake, fluid status, and urine output while being treated with Xofigo. Instruct patients to report signs of dehydration, hypovolemia, urinary retention, or renal failure / insufficiency. • There are no restrictions regarding contact with other people after receiving Xofigo. Follow good hygiene practices while receiving Xofigo and for at least 1 week after the last injection in order to minimize radiation exposure from bodily fluids to household members and caregivers. Whenever possible, patients should use a toilet and the toilet should be flushed several times after each use. Clothing soiled with patient fecal matter or urine should be washed promptly and separately from other clothing. Caregivers should use universal precautions for patient care such as gloves and barrier gowns when handling bodily fluids to avoid contamination. When handling bodily fluids, wearing gloves and hand washing will protect caregivers. • Who are sexually active to use condoms and their female partners of reproductive potential to use a highly effective method of birth control during treatment and for 6 months following completion of Xofigo treatment.

Manufactured for:

Bayer HealthCare Pharmaceuticals Inc. Whippany, NJ 07981 Manufactured in Norway Xofigo is a trademark of Bayer Aktiengesellschaft. © 2013, Bayer HealthCare Pharmaceuticals Inc. All rights reserved. Revised: March 2016 6708401BS

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PP-600-US-2234_US_Journal_Ad_FR1.indd 3-4

Manufactured for:

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FEATURE with gefitinib in TKI-naive patients with EGFR-mutant NSCLC.5 The best objective response rate was 77.8% with gefitinib monotherapy and 80.0% with gefitinib monotherapy followed by concurrent durvalumab plus gefitinib. One patient in the gefitinib arm achieved a complete response while the others had partial responses. Stable disease lasting for 8 weeks or more occurred in 2 and 1 patients in the gefitinib arm and the combination arm, respectively. Durvalumab is also being evaluated with a checkpoint inhibitor, tremelimumab, which blocks CTLA-4 in patients with locally advanced or metastatic NSCLC. Early results of a phase 1b trial showed that the combination induced a confirmed objective response rate of 23%.6 “Certainly the PD-1 inhibitors, and we can pretty safely say the PD-L1 inhibitors, have a role in the treating lung cancer, melanoma, bladder cancer, and other malignancies, but the question is, how do we then do our best at combining the different drugs available to get the best value and efficacy without going too far in the way of toxicity and cost?” Dr Masters said. Durvalumab, a human IgG1 anti-programmed cell death-ligand-1 (PD-L1) antibody, blocks the interaction among PD-L1, PD-1, and CD80 with high affinity and selectivity. Nedaplatin Nedaplatin is a second-generation platinum compound that is associated with a lower frequency of nausea/vomiting and nephrotoxicity than cisplatin. A phase 3 trial demonstrated significantly longer overall survival with nedaplatin plus docetaxel in contrast with cisplatin plus docetaxel in patients with advanced or relapsed squamous cell carcinoma of the lung.7 Researchers enrolled 355 Japanese patients with stage IIIB/IV squamous

NSCLC or postoperative recurrence and randomly assigned them 1:1 to receive nedaplatin 100 mg/m2 IV or cisplatin 80 mg/m2 IV with docetaxel 60 mg/m2 IV every 3 weeks for up to 6 cycles. Results showed that median overall survival was 13.6 months with nedaplatin vs 11.4 months with cisplatin (hazard ratio 0.81;

Nedaplatin is associated with a lower frequency of nausea/ vomiting and nephrotoxicity than cisplatin. 90% CI, 0.67-0.98; P = .037). Nedaplatin was also associated with a longer progression-free survival than cisplatin (hazard ratio 0.83; 90% CI, 0.69-1.00; P = .050). Grade 3 or 4 treatment-related nausea, fatigue, hyponatremia, and hypokalemia were more common in the cisplatin group, while grade 3 or higher neutropenia and thrombocytopenia were more frequent with nedaplatin. There was no difference in grade 3 or higher febrile neutropenia between the 2 treatment arms. “It is unclear if those differences in efficacy and toxicity will translate to a meaningful improvement in our patients,” Dr Masters said. Cilengitide Cilengitide is an integrin inhibitor that, when added to cetuximab and platinum-based chemotherapy, has demonstrated potential clinical activity in patients with EGFR-expressing NSCLC.8 For the multicenter, open-label, controlled phase 2 study, researchers enrolled 169 patients with advanced NSCLC and randomly assigned them 1:1 to receive cetuximab plus

platinum-based chemotherapy alone or combined with cilengitide 2000 mg intravenously once weekly. Results showed that median progression-free survival was 6.2 months in the cilengitide arm vs 5.0 months in the control arm (hazard ratio 0.72; P = .085). For patients with an EGFR histoscore of 200 or more, progression-free survival was 6.8 months and 5.6 months in the cilengitide and control arms, respectively (hazard ratio 0.57; P = .0446). Researchers found that median overall survival was 13.6 months in the cilengitide arm and 9.7 months in the control arm (hazard ratio 0.81; P = .265), and in patients with an EGFR histoscore of 200 or more, median overall survival was 13.2 and 11.8 months, respectively (hazard ratio 0.95; P = .855). Further studies are warranted to evaluate cilengitide’s utility in advanced NSCLC. “When we started to look at angiogenesis, there was some thought that maybe we had found the answer for treating all cancers but unfortunately it turned out like most other stories that it played a role but it was not going to be the final answer,” Dr Masters told Cancer Therapy Advisor. “This new small molecule anti-angiogenic drug could have a role in the treatment of NSCLC; it is an area we want to pursue because no one treatment will be right for every patient or for every cancer.” BCD-021 (Bevacizumab Biosimilar) BCD-021 is a compound being investigated as a biosimilar agent to bevacizumab. An international, phase 3 trial evaluating its equivalence to bevacizumab in 138 patients with advanced non-squamous NSCLC demonstrated non-inferiority in this setting.9 The study enrolled patients with stage IIIB/IV disease and randomly assigned them to receive BCD-021 or

A30 CANCER THERAPY ADVISOR | JULY/AUGUST 2016 | CancerTherapyAdvisor.com

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FEATURE bevacizumab 15 mg/kg in combination with paclitaxel 175 mg/m2 and carboplatin AUC 6 every 3 weeks for up to 6 cycles until disease progression or until unacceptable toxicity. Results showed that overall response rate was about 42% with BCD-021 and approximately 39% with bevacizumab. There was no significant difference in complete response rate, partial response rate, stable disease, and progression rate between the 2 treatment arms. The adverse event profiles of BCD-021 and bevacizumab were deemed equivalent.

2. Sequist LV, Goldman JW, Wakelee HA,

of PD-L1 status [news release]. London,

of rociletinib (CO-1686) in plasma-geno-

United Kingdom: AstraZeneca; February

typed T790M-positive non-small cell lung

8, 2016. http://www.businesswire.

cancer (NSCLC) patients (pts). J Clin Oncol.

com/news/home/20160207005035/

2015;33(suppl; abstr 8001).

en/ASTRAZENECA%E2%80%99S-

3. Neal JW, Dahlberg SE, Wakelee HA, Aisner SC, Bowden M, Carbone DP, et al. Cabozantinib (C), erlotinib (E) or the combination (E+C) as second- or third-line therapy

COMBINATION-DURVALUMABTREMELIMUMAB-SHOWS-CLINICALACTIVITY. Accessed July 6, 2016. 7. Shukuya T, Yamanaka T, Seto T, Daga H, Goto

in patients with EGFR wild-type (wt) non-

K, Saka H, et al. Nedaplatin plus docetaxel

small cell lung cancer (NSCLC): A random-

versus cisplatin plus docetaxel for advanced

ized phase 2 trial of the ECOG-ACRIN Cancer

or relapsed squamous cell carcinoma of the

Research Group (E1512). J Clin Oncol.

lung (WJOG5208L): a randomised, open-la-

2015;33(suppl; abstr 8003).

Checkpoint Inhibitors “I don’t think we know the full story on nivolumab, pembrolizumab, or atezolizumab yet. Although those drugs are not brand new, we are still figuring out if they can be used in different settings,” Dr Masters concluded. “We will see studies coming out evaluating checkpoint inhibitors in the adjuvant setting, in combination with radiation therapy, and in earlier settings like as first-line therapy with chemotherapy.” ■

in non-small cell lung cancer irrespective

Camidge R, Yu HA, Varga A, et al. Efficacy

4. ARIAD presents updated phase 1/2 clinical data on brigatinib in patients with alk+

bel, phase 3 trial. Lancet Oncol. doi: 10.1016/ S1470-2045(15)00305-8. 8. Vansteenkiste J, Barlesi F, Waller CF,

non-small cell lung cancer [news release].

Bennouna J, Gridelli C, Goekkurt E, et al.

Cambridge, MA: ARIAD Pharmaceuticals;

Cilengitide combined with cetuximab and

April 15, 2016. http://investor.ariad.com/

platinum-based chemotherapy as first-line

phoenix.zhtml?c=118422&p=irol-newsArti-

treatment in advanced non-small cell lung

cle&ID=2157495. Accessed July 6, 2016.

cancer (NSCLC) patients: results of an

5. Gibbons DL, Chow LQ, Kim D, Kim S, Yeh T,

open-label, randomized, controlled phase

Song X, et al. Efficacy, safety and tolerability

II study (CERTO) [published electronically

of MEDI4736 (durvalumab [D]), a human

ahead of print May 4, 2015]. Ann Oncol. doi:

IgG1 anti-programmed cell death-ligand-1 (PD-L1) antibody, combined with gefitinib

10.1093/annonc/mdv219. 9. Filon O, Orlov S, Burdaeva O, Kopp MV, Kotiv

(G): a phase I expansion in TKI-naïve

B, Alekseev, S, et al. Efficacy and safety of

References

patients (pts) with EGFR mutant NSCLC.

BCD-021, bevacizumab biosimilar candidate,

1. Key statistics for lung cancer. American Cancer

Oral presentation at: European Lung Cancer

compared to Avastin: Results of international

Society website. May 10, 2016. http://www.

Conference 2016; April 13-16, 2016; Geneva,

multicenter randomized double blind

cancer.org/cancer/lungcancer-non-smallcell/

Switzerland.

phase III study in patients with advanced

detailedguide/non-small-cell-lung-cancer-keystatistics. Accessed July 6, 2016.

In The Clinic Continued from page A22

of relapsed follicular lymphoma that has not responded to at least 2 prior systemic therapies.” Lenalidomide has been shown to boost the immune system and work in the same way as angiogenesis inhibitors. This oral agent is given in cycles of treatment days followed by rest. A

6. Astrazeneca’s combination of durvalumab with tremelimumab shows clinical activity

typical cycle is 3 weeks of treatment and 1 week of rest. It is hoped that lenalidomide and idelalisib as well as other agents now in development will help improve morbidity and mortality among patients with lymphoma. Dr Bhat said the clinical landscape will be changing dramatically over the next 12 to 24 months. “These new options generate excitement amongst investigators to integrate

non-squamous NSCLC. J Clin Oncol. 2015;33(suppl; abstr 8057).

these new therapies rapidly into rational combinations to achieve maximum response rates and disease control and possibly cure and minimize toxicity in the coming years,” said Dr Bhat. ■ Reference 1. NCCN Guidelines for Patients. National Comprehensive Cancer Network website. https://www.nccn.org/patients/guidelines/ cancers.aspx#nhl. Accessed June 1, 2016.

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VIEWPOINT | BY CARLOS HARRISON

Mental Disorder Risk High During Cancer Treatment and Before Diagnosis Study results emphasize the need for psychological management and mental disorder screening.

atients with cancer run a higher risk of mental disorders not only as they undergo treatment but also as much as a year before diagnosis, a newly published cohort study involving a decade’s worth of patient data from more than 3 million individuals reported in JAMA Oncology.1 “The dramatic risk increases seen immediately after cancer diagnosis are not surprising and corroborate previous findings on highly increased risks of cardiovascular diseases and suicide right after cancer diagnosis,” the study’s corresponding author, Donghao Lu, MD, PhD candidate of the department of medical epidemiology and biostatistics at the Karolinska Institutet in Sweden, told Cancer Therapy Advisor. “However, the clearly elevated risks during the year before diagnosis are new.” The possible causes, Dr Lu and his coauthors suggested, could involve both the emotional toll and the physical effects of the cancer itself. “Besides the potential effect of psychological stress experienced during the diagnostic workup,” they wrote, “prediagnostic cancer symptoms and paraneoplastic syndrome (eg, anemia) may also contribute to the increased risk of mental disorders and increased use of psychiatric medications during the prediagnostic period.” The study involved 304,118 patients with a first cancer diagnosis between January 1, 2001, and December 31,

2010, and 3,041,174 cancer-free individuals. The researchers excluded anyone with previous psychiatric comorbidities in the 2 years before diagnosis. For each patient with cancer, the researchers randomly selected 10 of the cancer-free individuals and matched them based on birth year and sex. In total, the study identified 3355 patients with a new diagnosis of the studied mental disorders during the prediagnostic period and another 10,296

The possible causes could involve both the emotional toll and the physical effects of the cancer itself. post-diagnosis. The analysis calculated that hazard ratios (HRs) for psychiatric symptoms started to increase 10 months before cancer diagnosis (HR, 1.1; 95% CI, 1.1 - 1.2) and peaked immediately following diagnosis. They peaked more so in women (HR, 7.6; 95% CI, 6.8 - 8.6) than in men (HR, 5.4; 95% CI, 4.6 - 6.3) and remained elevated for up to 10 years after diagnosis, although not as strikingly. The authors noted largely similar results for all individual mental disorders studied — including depression,

anxiety, substance abuse, somatoform/ conversion disorder, and stress reaction/ adjustment disorder — with comparable rate elevations before cancer diagnosis among all of the disorders. However, immediately after diagnosis, the highest rate increase was noted for stress reaction/adjustment disorder. The team also identified an increased use of psychiatric medications beginning the month before cancer diagnosis (12.2% vs 11.7%; corrected P = .04). The use of the medications peaked at around 3 months after diagnosis (18.1% vs 11.9%; corrected P < .001) and then remained elevated 2 years after diagnosis (15.4% vs 12.7%; corrected P < .001). “Increased use [of these medications] was most pronounced for lung, [central nervous system], and severe cancers, whereas no increased use was noted for nonmelanoma skin cancer,” they said. The authors also noted that “not only does living with cancer induce severe psychological stress, but being diagnosed as having a cancer is also highly stressful.” And that, Dr Lu told Cancer Therapy Advisor, provides evidence for incorporating long-term psychological care into cancer treatment strategies from the start. “Our findings support the existing guidelines of integrating psychological management into cancer care,” he said. “And they call for extended vigilance for multiple mental disorders starting from the time of the cancer diagnostic workup.” ■ Reference 1. Lu D, Andersson ML, Fall K, Hultman CM, Czene K, Valdimarsdóttir U, Fang F. Clinical diagnosis of mental disorders immediately before and after cancer diagnosis: a nationwide matched cohort study in Sweden [published online ahead of print April 28, 2016]. JAMA Oncol. doi: 10.1001/ jamaoncol.2016.0483.

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REGIMEN & MONOGRAPH INDEX CANCER THERAPY REGIMENS & DRUG MONOGRAPHS

Bone Cancer

3 Brain Cancer 5 Breast Cancer

 Breast Cancer (Invasive)  Breast Cancer (Recurrent or Metastatic)

20 Endocrine Cancer 26 Gastrointestinal Cancer

 Rectal Cancer

44 Genitourinary Cancer

 Testicular Cancer

54 Gynecologic Cancer

 Endometrial Carcinoma

 Uterine Sarcoma

60 Head and Neck Cancer 61 Hematologic Cancer

 Chronic Myeloid Leukemia (CML)

83 Lung Cancer 91 Sarcoma 92 Skin Cancer 97 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. © 2016 Haymarket Media, Inc.

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DRUG MONOGRAPHS

BONE CANCER HALAVEN Eisai

℞

Non-taxane microtubule dynamics inhibitor. Eribulin mesylate 0.5mg/mL, soln for IV inj. Indications: Treatment of unresectable or metastatic liposarcoma in patients who have received prior anthracycline-containing regimen. Adults: Give by IV inj over 2–5mins. 1.4mg/m² on Days 1 and 8 of a 21-day cycle. Mild hepatic impairment (Child-Pugh A) or moderate-to-severe renal impairment (CrCl 15–49mL/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 prior to each dose; 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): insufficient data. Pregnancy. Use effective contraception during treatment and for ≥2 weeks (females) or 3.5 months (male partners) after final dose. Nursing mothers: not recommended (during and for 2 weeks after final dose). 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, abdominal pain, pyrexia, hypokalemia, hypocalcemia; 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

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 3xULN and 8xULN continue therapy with weekly monitoring until ALT returns to Grade 1 or baseline. If ALT >8xULN 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>3xULN recurs, permanently discontinue. Permanently discontinue if ALT>3xULN and bilirubin >2xULN. 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, interstitial lung disease (ILD)/pneumonitis, GI perforation or fistula. Monitor BP and manage hypertension promptly. Discontinue if severe and persistent hypertension

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DRUG MONOGRAPHS

BONE CANCER (despite antihypertensives and dose reduction), if repeat episodes of proteinuria (despite dose reductions), thrombotic microangiopathy, serious infection, ILD or pneumonitis 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, ILD/pneumonitis, 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 skeletally-mature 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 (esp. 1st weeks of initiating), phosphorus, magnesium levels and Vit.D intake in susceptible patients (eg, severe renal impairment, receiving dialysis). Risk of osteonecrosis of the jaw in diabetes, gingival infections. Perform oral exam and preventive

dentistry before and regularly during therapy. Maintain good oral hygiene. Avoid invasive dental procedures during treatment; consider temporary discontinuation if procedure is necessary. Evaluate for atypical fractures if thigh/groin pain develops; consider withholding therapy until risk/benefit assessment. Monitor for hypercalcemia after treatment discontinuation in patients with growing skeletons. Embryo-fetal toxicity. Pregnancy (Cat.D); use highly effective contraception during therapy, and for at least 5 months after last dose. Nursing mothers: not recommended (may impair mammary gland development/lactation). Interactions: Concomitant other denosumabcontaining products (eg, Prolia): not recommended. Concomitant drugs that can lower calcium levels; monitor. Concomitant immunosuppressants, angiogenesis inhibitors, systemic corticosteroids; increased risk of osteonecrosis of the jaw. Adverse reactions: Fatigue, asthenia, hypophosphatemia, nausea, arthralgia, headache, back pain, pain in extremity, dyspnea, decreased appetite, peripheral edema, vomiting, anemia, constipation, diarrhea; osteonecrosis of the jaw, hypocalcemia (may be fatal), hypersensitivity reactions (discontinue if occur). How supplied: Single-use vial (1.7mL)—1

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

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: In adults and children with tuberous sclerosis complex (TSC) for the treatment of subependymal giant cell astrocytoma (SEGA) that requires therapeutic intervention but cannot be curatively resected. 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. Females of reproductive potential must use effective contraception during therapy and for 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

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DRUG MONOGRAPHS

BRAIN CANCER for 5 consecutive days if tolerated; continue until disease progression, discontinue if minimum dose not tolerated. Children: Not established. 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. Interactions: Concomitant carbamazepine, phenytoin, sulfamethoxazole/trimethoprim may complicate myelosuppression assessment. May be potentiated by valproic acid. 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 (may be fatal). 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 life-threatening 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

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)

2–3

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

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CANCER TREATMENT REGIMEN

BREAST CANCER Breast Cancer (Invasive) 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.

Neoadjuvant/Adjuvant Chemotherapy Note: All recommendations are Category 2A unless otherwise indicated.

REGIMEN

DOSING

Preferred Regimens for HER2-negative Disease1 Dose-dense AC followed by paclitaxel Day 1: Doxorubicin 60mg/m2 IV (Category 1)2 Day 1: Cyclophosphamide 600mg/m2 IV. Repeat cycle every 14 days for 4 cycles, followed by: Day 1: Paclitaxel 175mg/m2 via 3-hour IV infusion. Repeat cycle every 14 days for 4 cycles (all cycles are with filgrastim support). Dose-dense AC followed by weekly paclitaxel (Category 1)2

Day 1: Doxorubicin 60mg/m2 IV Day 1: Cyclophosphamide 600mg/m2 IV. Repeat cycle every 14 days for 4 cycles, followed by: Day 1: Paclitaxel 80mg/m2 via 1-hour IV infusion weekly for 12 weeks.

TC (Category 1)3

Day 1: Docetaxel 75mg/m2 IV Day 1: Cyclophosphamide 600mg/m2 IV. Repeat cycle every 21 days for 4 cycles (all cycles are with filgrastim support).

Other Regimens for HER2-negative Disease1 Dose-dense A (Category 1)2

Day 1: Doxorubicin 60mg/m2 IV Day 1: Cyclophosphamide 600mg/m2 IV. Repeat cycle every 14 days for 4 cycles (all cycles are with filgrastim support).

AC (Category 2B)4

Day 1: Doxorubicin 60mg/m2 IV Day 1: Cyclophosphamide 600mg/m2 IV. Repeat cycle every 21 days for 4 cycles.

TAC (Category 1)5

Day 1: Docetaxel 75mg/m2 IV Day 1: Doxorubicin 50mg/m2 IV Day 1: Cyclophosphamide 500mg/m2 IV. Repeat cycle every 21 days for 6 cycles (all cycles are with filgrastim support).

CMF (Category 1)6

Days 1–14: Cyclophosphamide 100mg/m2 orally Days 1 and 8: Methotrexate 40mg/m2 IV Days 1 and 8: 5-fluorouracil 600mg/m2 IV. Repeat cycle every 28 days for 6 cycles.

AC followed by docetaxel (Category 1)7

Day 1: Doxorubicin 60mg/m2 IV Day 1: Cyclophosphamide 600mg/m2 IV. Repeat cycle every 21 days for 4 cycles, followed by: Day 1: Docetaxel 100mg/m2 IV. Repeat cycle every 21 days for 4 cycles.

AC followed by weekly paclitaxel (Category 1)8

Day 1: Doxorubicin 60mg/m2 IV Day 1: Cyclophosphamide 600mg/m2 IV. Repeat cycle every 21 days for 4 cycles, followed by: Day 1: Paclitaxel 80mg/m2 by 1-hour IV infusion weekly for 12 weeks.

EC (Category 1)9

Day 1: Epirubicin 100mg/m2 IV Day 1: Cyclophosphamide 830mg/m2 IV. Repeat cycle every 21 days for 8 cycles.

FEC followed by docetaxel (Category 1)10

Day 1: 5-fluorouracil 500mg/m2 IV Day 1: Epirubicin 100mg/m2 IV Day 1: Cyclophosphamide 500mg/m2 IV. Repeat cycle every 21 days for 3 cycles, followed by: Day 1: Docetaxel 100mg/m2 IV. Repeat cycle every 21 days for 3 cycles. continued

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CANCER TREATMENT REGIMEN

BREAST CANCER Breast Cancer (Invasive) Treatment Regimens Other Regimens for HER2-negative Disease (continued) REGIMEN

DOSING

FEC followed by weekly paclitaxel (Category 1)11

Day 1: 5-fluorouracil 600mg/m2 IV Day 1: Epirubicin 90mg/m2 IV Day 1: Cyclophosphamide 600mg/m2 IV. Repeat cycle every 21 days for 4 cycles, followed by: Paclitaxel 100mg/m2 IV infusion weekly for 8 weeks.

FAC followed by weekly paclitaxel (Category 1)

Days 1 and 8 OR 1 and 4: 5-fluorouracil 500mg/m2 IV Day 1: Doxorubicin 50mg/m2 IV (or via 72-hour continuous infusion) Day 1: Cyclophosphamide 500mg/m2 IV. Repeat cycle every 21 days for 6 cycles, followed by: Paclitaxel 80mg/m2 via 1-hour IV infusion weekly for 12 weeks.

Preferred Regimens for HER2-positive Disease1 AC followed by paclitaxel with trastuzumab12

Day 1: Doxorubicin 60mg/m2 IV Day 1: Cyclophosphamide 600mg/m2 IV. Repeat cycle every 21 days for 4 cycles, followed by: Day 1: Paclitaxel 80mg/m2 via 1-hour IV infusion weekly for 12 weeks, with: Trastuzumab 4mg/kg IV with first dose of paclitaxel, followed by: Trastuzumab 2mg/kg IV weekly to complete 1 year of treatment. As an alternative, trastuzumab 6mg/kg IV every 21 days may be used following the completion of paclitaxel, and given to complete 1 year of trastuzumab treatment. Cardiac monitoring at baseline, 3, 6, and 9 months.

AC followed by paclitaxel with trastuzumab + pertuzumab

Day 1: Doxorubicin 60mg/m2 IV Day 1: Cyclophosphamide 600mg/m2 IV. Repeat cycle every 21 days for 4 cycles, followed by: Day 1: Pertuzumab 840mg IV followed by 420mg IV Day 1: Trastuzumab 8mg/kg IV followed by 6mg/kg IV Days 1, 8, and 15: Paclitaxel 80mg/m2 IV. Repeat cycle every 21 days for 4 cycles. Day 1: Trastuzumab 6mg/kg IV. Repeat cycle every 21 days to complete 1 year of trastuzumab therapy. Cardiac monitoring at baseline, 3, 6, and 9 months.

Dose-dense AC followed by paclitaxel with trastuzumab13

Day 1: Doxorubicin 60mg/m2 IV Day 1: Cyclophosphamide 600mg/m2 IV. Repeat cycle every 14 days for 4 cycles, followed by: Day 1: Paclitaxel 175mg/m2 via 3-hour IV infusion. Repeat cycle every 14 days for 4 cycles, plus: Trastuzumab 4mg/kg IV with first dose of paclitaxel, followed by: Trastuzumab 2mg/kg IV weekly to complete 1 year of treatment. As an alternative, trastuzumab 6mg/kg IV every 21 days may be used following the completion of paclitaxel, and given to complete 1 year of trastuzumab treatment. Cardiac monitoring at baseline, 3, 6, and 9 months.

TCH14

Day 1: Docetaxel 75mg/m2 IV Day 1: Carboplatin AUC 6mg • min/mL IV. Repeat cycle every 21 days for 6 cycles, with: Day 1: Trastuzumab 4mg/kg IV week 1, followed by 2mg/kg IV for 17 weeks, followed by: Trastuzumab 6mg/kg IV every 21 days to complete 1 year of trastuzumab therapy, OR Trastuzumab 8mg/kg IV week 1, followed by: Trastuzumab 6mg/kg IV every 21 days to complete 1 year of trastuzumab therapy. Cardiac monitoring at baseline, 3, 6, and 9 months.

TCH chemotherapy + pertuzumab15

Day 1: Trastuzumab 8mg/kg IV followed by 6mg/kg IV Day 1: Pertuzumab 840mg IV followed by 420mg IV Day 1: Docetaxel 75mg/m2 IV Day 1: Carboplatin AUC 6mg • min/mL IV. Repeat cycle every 21 days for 6 cycles, followed by: Day 1: Trastuzumab 6mg/kg IV every 21 days to complete 1 year of trastuzumab therapy. Cardiac monitoring at baseline, 3, 6, and 9 months.

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CANCER TREATMENT REGIMEN

BREAST CANCER Other Regimens for HER2-positive Disease1 REGIMEN

DOSING

AC followed by docetaxel with trastuzumab14

Day 1: Doxorubicin 60mg/m2 IV Day 1: Cyclophosphamide 600mg/m2 IV. Repeat cycle every 21 days for 4 cycles, followed by: Day 1: Docetaxel 100mg/m2 IV. Repeat cycle every 21 days for 4 cycles, with: Trastuzumab 4mg/kg IV week 1, followed by 2mg/kg IV weekly for 11 weeks, followed by: Day 1: Trastuzumab 6mg/kg IV every 21 days to complete 1 year of trastuzumab therapy. Cardiac monitoring at baseline, 3, 6, and 9 months.

AC followed by docetaxel with trastuzumab and pertuzumab15

Day 1: Doxorubicin 60mg/m2 IV Day 1: Cyclophosphamide 600mg/m2 IV. Repeat cycle every 21 days for 4 cycles, followed by: Day 1: Pertuzumab 840mg IV followed by 420mg IV Day 1: Trastuzumab 8mg/kg IV followed by 6mg/kg IV Day 1: Docetaxel 75–100mg/m2 IV. Repeat cycle every 21 days for 4 cycles, followed by: Day 1: Trastuzumab 6mg/kg IV every 21 days to complete 1 year of trastuzumab therapy. Cardiac monitoring at baseline, 3, 6, and 9 months.

Docetaxel + cyclophosphamide + trastuzumab16

Day 1: Docetaxel 75mg/m2 IV Day 1: Cyclophosphamide 600mg/m2 IV. Repeat cycle every 21 days for 4 cycles, with: Trastuzumab 4mg/kg IV week 1, followed by: Trastuzumab 2mg/kg IV weekly for 11 weeks, followed by: Trastuzumab 6mg/kg IV every 21 days to complete 1 year of trastuzumab therapy, OR Trastuzumab 8mg/kg IV week 1, followed by: Trastuzumab 6mg/kg IV every 21 days to complete 1 year of treatment. Cardiac monitoring at baseline, 3, 6, and 9 months.

FEC followed by pertuzumab + trastuzumab + docetaxel15

Day 1: Fluorouracil 500mg/m2 IV Day 1: Epirubicin 100mg/m2 IV Day 1: Cyclophosphamide 600mg/m2 IV. Repeat cycle every 21 days for 3 cycles, followed by: Day 1: Pertuzumab 840mg IV followed by 420mg IV Day 1: Trastuzumab 8mg/kg IV followed by 6mg/kg IV Day 1: Docetaxel 75–100mg/m2 IV. Repeat cycle every 21 days for 3 cycles, followed by: Day 1: Trastuzumab 6mg/kg IV every 21 days to complete 1 year of trastuzumab therapy. Cardiac monitoring at baseline, 3, 6, and 9 months.

FEC followed by pertuzumab + trastuzumab + paclitaxel15

Day 1: Fluorouracil 500mg/m2 IV Day 1: Epirubicin 100mg/m2 IV Day 1: Cyclophosphamide 600mg/m2 IV. Repeat cycle every 21 days for 3 cycles, followed by: Day 1: Pertuzumab 840mg IV followed by 420mg IV Day 1: Trastuzumab 8mg/kg IV followed by 6mg/kg IV Days 1, 8, and 15: Paclitaxel 80mg/m2 IV. Repeat cycle every 21 days for 3 cycles, followed by: Day 1: Trastuzumab 6mg/kg IV every 21 days to complete 1 year of trastuzumab therapy. Cardiac monitoring at baseline, 3, 6, and 9 months.

Paclitaxel + trastuzumab17

Day 1: Paclitaxel 80mg/m2 IV weekly for 12 weeks, plus Trastuzumab 4mg/kg IV with first dose of paclitaxel, followed by: Day 1: Trastuzumab 2mg/kg IV weekly to complete 1 year of treatment. As an alternative, trastuzumab 6mg/kg IV every 21 days may be used following the completion of paclitaxel, and given to complete 1 year of trastuzumab therapy. Cardiac monitoring at baseline, 3, 6, and 9 months. continued

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CANCER TREATMENT REGIMEN

BREAST CANCER Breast Cancer (Invasive) Treatment Regimens Other Regimens for HER2-positive Disease1 (continued) REGIMEN

DOSING

Pertuzumab + trastuzumab + docetaxel followed by FEC18

Day 1: Pertuzumab 840mg IV followed by 420mg IV Day 1: Trastuzumab 8mg/kg IV followed by 6mg/kg IV Day 1: Docetaxel 75–100mg/m2 IV. Repeat cycle every 21 days for 4 cycles, followed by adjuvant therapy: Day 1: Fluorouracil 600mg/m2 IV Day 1: Epirubicin 90mg/m2 IV Day 1: Cyclophosphamide 600mg/m2 IV. Repeat cycle every 21 days for 3 cycles, followed by: Day 1: Trastuzumab 6mg/kg IV every 21 days to complete 1 year of trastuzumab therapy. Cardiac monitoring at baseline, 3, 6, and 9 months.

Pertuzumab + trastuzumab + paclitaxel followed by FEC18

Day 1: Pertuzumab 840mg IV followed by 420mg IV Day 1: Trastuzumab 8mg/kg IV followed by 6mg/kg IV Days 1, 8, and 15: Paclitaxel 80mg/m2 IV. Repeat cycle every 21 days for 4 cycles, followed by adjuvant therapy: Day 1: Fluorouracil 600mg/m2 IV Day 1: Epirubicin 90mg/m2 IV Day 1: Cyclophosphamide 600mg/m2 IV. Repeat cycle every 21 days for 3 cycles, followed by: Day 1: Trastuzumab 6mg/kg IV every 21 days to complete 1 year of trastuzumab therapy. Cardiac monitoring at baseline, 3, 6, and 9 months.

References 1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer V.1.2016. Available at: http://www.nccn. org/professionals/physician_gls/pdf/breast.pdf. Accessed February 24, 2016. 2. Citron ML, Berry DA, Cirrincione C, et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol. 2003;21(8):1431–1439. Erratum in: J Clin Oncol. 2003;21(11):2226. 3. Jones S, Holmes F, O’Shaughnessey J, et al. Docetaxel with cyclophosphamide is associated with an overall survival benefit compared with doxorubicin and cyclophosphamide: 7-year follow-up of US Oncology Research trial 9735. J. Clin Oncol. 2009;27(8):1177–1183. 4. Fisher B, Brown AM, Dimitrov NV, et al. Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with six months of cyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifen-nonresponsive tumors: Results from NSABP B-15. J Clin Oncol. 1990;8(9):1483–1496. 5. Martin. Pienkowski T, Mackey J, et al. Adjuvant docetaxel for node-positive breast cancer. N Engl J. Med. 2005;352(22):2302–2313. 6. Goldrhirsch A, Colleoni M, Coates AS, et al. Adding adjuvant CMF chemotherapy to either radiotherapy or tamoxifen: are all CMFs alike? The International Breast Cancer Study Group (IBCSG). Ann Oncol. 1998;9(5):489–493. 7. von Minckwitz G, Raab G, Caputo A, et al. Doxorubicin with cyclophosphamide followed by docetaxel every 21 days compared with doxorubicin and docetaxel every 14 days as preoperative treatment in operable breast cancer: the GEPARDUO study of the German Breast Group. J Clin Oncol. 2005;23(12):2676–2685. 8. Sparano JA, Wang M, Martino S, et al. Weekly paclitaxel in adjuvant treatment of breast cancer. N Engl J Med. 2008; 358(16):1663–1671. 9. Piccart MJ, Di Leo A, Beauduin M, et al. Phase III trial comparing two dose levels of epi-

10. 11. 12. 13. 14. 15.

16. 17. 18.

rubicin combined with cyclophosphamide with cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer. J Clin Oncol. 2001;19(12): 3103–3110. Roche H, Fumoleau P, Spielmann M, et al. Sequential adjuvant epirubicin-based and docetaxel chemotherapy for node-positive breast cancer patients: The FNCLCC PACS 001 trial. J Clin Oncol. 2006;24(6):5664–5671. Martin M, Rodriguez-Lescure A, Ruiz A, et al. Randomized phase 3 trial of fluorouracil, epirubicin, and cyclophosphamide alone or followed by paclitaxel for early breast cancer. J NatI Cancer Inst. 2008;100(11):805–814. Romond EH, Perez EZ, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2 positive breast cancer. N Engl J Med. 2005;353(16):1673–1684. Dang C, Fornier M, Sugarman S, et al. The safety of dose-dense doxorubicin and cyclophosphamide followed by paclitaxel with trastuzumab in HER-2/neu overexpressed/amplified breast cancer. J. Clin Oncol. 2008;26(8): 1216–1222. Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 2011;365(14): 1273–1283. Schneeweiss A, Chia S, Hickish T, et al. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline–containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol. 2013;24(9):2278–2284. Jones SE, Collea R, Paul D, et al. Adjuvant docetaxel and cyclophosphamide plus trastuzumab in patients with HER2-amplified early stage breast cancer: a single-group, open-label, phase 2 study. Lancet Oncol. 2013;14(11):1121–1128. Tolaney S, Barry W, Dang C, et al. A phase II study of paclitaxel (T) and trastuzumab (H) (APT trial) for node-negative, HER2-positive breast cancer (BC). [abstract]. San Antonio Breast Cancer Symposium 2013; Abstract S1–04. Gianni L, Pienkowski T, Im YH, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomized multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;13(1):25–32. (Revised 2/2016) © 2016 by Haymarket Media, Inc.

Simplify your search for quality Oncology CME/CE. Visit myCME.com/Oncology.

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CANCER TREATMENT REGIMEN

BREAST CANCER Breast Cancer (Recurrent or Metastatic) 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.

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

Preferred Single Agents1 REGIMEN

DOSING

Doxorubicin

Day 1: Doxorubicin 60–75mg/m2 IV. Repeat cycle every 21 days. OR Day 1: Doxorubicin 20mg/m2 IV. Repeat cycle weekly.

Pegylated liposomal doxorubicin4

Day 1: Pegylated liposomal doxorubicin 50mg/m2 IV. Repeat cycle every 28 days

Paclitaxel5,6

Day 1: Paclitaxel 175mg/m2 IV. Repeat cycle every 21 days. OR Day 1: 80mg/m2 IV. Repeat cycle weekly.

Capecitabine7

Days 1–14: Capecitabine 1,000–1,250mg/m2 orally twice daily. Repeat cycle every 21 days.

Gemcitabine8

Days 1, 8, and 15: Gemcitabine 800–1,200mg/m2 IV. Repeat cycle every 28 days.

Vinorelbine9

Day 1: Vinorelbine 25mg/m2 IV. Repeat cycle weekly.

Eribulin10

Days 1 and 8: Eribulin 1.4mg/m2 IV. Repeat cycle every 21 days.

2,3

Other Single Agents1 Cyclophosphamide11

Days 1–21: Cyclophosphamide 50mg orally daily. Repeat cycle every 28 days.

Carboplatin12

Day 1: Carboplatin AUC 6mg • min/mL IV. Repeat cycle every 21–28 days.

Docetaxel13-15

Day 1: Docetaxel 60–100mg/m2 IV. Repeat cycle every 21 days. OR Day 1: Docetaxel 35mg/m2 IV. Repeat cycle weekly for 6 weeks followed by a 2-week rest, then repeat.

Albumin-bound paclitaxel16,17

Days 1, 8, and 15: Albumin-bound paclitaxel 100mg/m2 or 125mg/m2 IV. Repeat cycle every 28 days. OR Day 1: Albumin-bound paclitaxel 260mg/m2 IV. Repeat cycle every 21 days.

Cisplatin18

Day 1: Cisplatin 75mg/m2 IV. Repeat cycle every 21 days.

Epirubicin19

Day 1: Epirubicin 60–90mg/m2 IV. Repeat cycle every 21 days.

Ixabepilone20

Day 1: Ixabepilone 40mg/m2 IV. Repeat cycle every 21 days. continued

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BREAST CANCER Breast Cancer (Recurrent or Metastatic) Treatment Regimens Chemotherapy Combinations1 REGIMEN

DOSING

CAF21

Days 1–14: Cyclophosphamide 100mg/m2 orally Days 1 and 8: Doxorubicin 30mg/m2 IV Days 1 and 8: 5-fluorouracil 500mg/m2 IV. Repeat cycle every 28 days.

FAC22

Days 1 and 8 OR 1 and 4: 5-fluorouracll 500mg/m2 IV Day 1: Doxorubicin 50mg/m2 IV (or by 72-hour continuous infusion) Day 1: Cyclophosphamide 500mg/m2 IV. Repeat cycle every 21 days.

FEC23

Days 1 and 8: Cyclophosphamide 400mg/m2 IV Days 1 and 8: Epirubicin 50mg/m2 IV Days 1 and 8: 5-fluorouracil 500mg/m2 IV. Repeat cycle every 28 days.

AC24

Day 1: Doxorubicin 60mg/m2 IV Day 1: Cyclophosphamide 600mg/m2 IV. Repeat cycle every 21 days.

EC25

Day 1: Epirubicin 75mg/m2 IV Day 1: Cyclophosphamide 600mg/m2 IV. Repeat cycle every 21 days.

CMF26

Days 1–14: Cyclophosphamide 100mg/m2 orally Days 1 and 8: Methotrexate 40mg/m2 IV Days 1 and 8: 5-fluorouracll 600mg/m2 IV. Repeat cycle every 28 days.

Docetaxel + capecitabine27

Day 1: Docetaxel 75mg/m2 IV Days 1–14: Capecitabine 950mg/m2 orally twice daily. Repeat cycle every 21 days.

GT28

Day 1: Paclitaxel 175mg/m2 IV Days 1 and 8: Gemcitabine 1,250mg/m2 IV (following paclitaxel on day 1). Repeat cycle every 21 days.

Gemcitabine + carboplatin29

Days 1 and 8: Gemcitabine 1,000mg/m2 Days 1 and 8: Carboplatin AUC 2mg • min/mL IV. Repeat cycle every 21 days.

Paclitaxel + bevacizumab30

Days 1, 8, and 15: Paclitaxel 90mg/m2 by 1-hour IV Days 1 and 15: Bevacizumab 10mg/kg IV days 1 and 15. Repeat cycle every 28 days.

Preferred First-line Agents for HER2-positive Disease1 General treatment note: All trastuzumab-containing regimens require cardiac monitoring at baseline and at 3, 6, and 9 months.1

Pertuzumab + trastuzumab + docetaxel (Category 1)31

Day 1: Pertuzumab 840mg IV followed by 420mg IV Day 1: Trastuzumab 8mg/kg IV followed by 6mg/kg IV Day 1: Docetaxel 75–100mg/m2 IV. Repeat cycle every 21 days.

Pertuzumab + trastuzumab + paclitaxel32,33

Day 1: Pertuzumab 840mg IV followed by 420mg IV cycled every 21 days, plus Day 1: Trastuzumab 4mg/kg IV followed by 2mg/kg IV weekly OR trastuzumab 8mg/kg IV followed by 6mg/kg IV cycled every 21 days, plus Day 1: Paclitaxel 80mg/m2 IV weekly OR paclitaxel 175mg/m2 cycled every 21 days.

Other First-line Agents For HER2-positlve Disease1 Ado-trastuzumab emtansine (T-DM1)34

Day 1: Ado-trastuzumab emtansine 3.6mg/kg IV. Repeat cycle every 21 days.

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BREAST CANCER Other First-line Agents For HER2-positlve Disease1 (continued) REGIMEN

DOSING

Paclitaxel + carboplatin + trastuzumab33,35

Day 1: Carboplatin AUC 6mg • min/mL IV Day 1: Paclitaxel 175mg/m2 IV cycled every 21 days, plus Day 1: Trastuzumab 4mg/kg IV followed by 2mg/kg IV weekly OR Day 1: Trastuzumab 8mg/kg IV followed by 6mg/kg IV every 21 days.

Weekly paclitaxel + carboplatin + trastuzumab33,36

Days 1, 8, and 15: Paclitaxel 80mg/m2 IV plus carboplatin AUC 2mg • min/mL cycled every 21 days, plus Day 1: Trastuzumab 4mg/kg IV followed by 2mg/kg IV weekly OR Day 1: Trastuzumab 8mg/kg IV followed by 6mg/kg IV every 21 days.

Trastuzumab + paclitaxel33,37,38

Day 1: Paclitaxel 175mg/m2 IV cycled every 21 days OR Day 1: Paclitaxel 80–90mg/m2 IV weekly, plus Day 1: Trastuzumab 4mg/kg IV followed by 2mg/kg IV weekly OR Day 1: Trastuzumab 8mg/kg IV followed by 6mg/kg IV every 21 days.

Trastuzumab + docetaxel33,39,40

Day 1: Docetaxel 80–100mg/m2 IV cycled every 21 days OR Days 1, 8, and 15: Docetaxel 35mg/m2 IV weekly, plus Day 1: Trastuzumab 4mg/kg IV followed by 2mg/kg IV weekly OR Day 1: Trastuzumab 8mg/kg IV followed by 6mg/kg IV every 21 days.

Trastuzumab + vinorelbine33,41

Day 1: Vinorelbine 25mg/m2 IV weekly OR Days 1 and 8: Vinorelbine 30-35mg/m2 IV cycled every 21 days, plus Day 1: Trastuzumab 4mg/kg IV followed by 2mg/kg IV weekly OR Day 1: Trastuzumab 8mg/kg IV followed by 6mg/kg IV every 21 days.

Trastuzumab + capecitabine33,42,43

Days 1–14: Capecitabine 1,000–1,250mg/m2 orally twice daily cycled every 21 days, plus Day 1: Trastuzumab 4mg/kg IV followed by 2mg/kg IV weekly OR Day 1: Trastuzumab 8mg/kg IV followed by 6mg/kg IV every 21 days.

Agents for Trastuzumab-exposed HER2-positive Disease1 Lapatinib + capecitabine44

Days 1–21: Lapatinib 1,250mg orally daily Days 1–14: Capecitabine 1,000mg/m2 orally twice daily. Repeat cycle every 21 days.

Trastuzumab + capecitabine33,37,43,45

Trastuzumab + lapatinib33,46

Lapatinib 1,000mg orally daily, plus Day 1: Trastuzumab 4mg/kg IV followed by 2mg/kg IV weekly OR Day 1: Trastuzumab 8mg/kg IV followed by 6mg/kg IV every 21 days.

sus conventional doxorubicin for first-line treatment of metastatic breast cancer. Ann Oncol. 2004;15(3):440–449. 5. Seidman AD, Tiersten A, Hudis C, et al. Phase II trial of paclitaxel by 3-hour infusion as initial and salvage chemotherapy for metastatic breast cancer. J Clin Oncol. 1995;13(10):2575–2581. 6. Perez EA, Vogel CL, Irwin DH, et al. Multicenter phase II trial of weekly paclitaxel in women with metastatic breast cancer. J Clin Oncol. 2001;19(22):4216–4223. 7. Bajetta E, Procopio G, Celio L, et al. Safety and efficacy of two different doses of capecitabine in the treatment of a dvanced breast cancer in older women. J Clin Oncol. 2005;23(10):2155–2161.

continued

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BREAST CANCER Breast Cancer (Recurrent or Metastatic) Treatment Regimens References (continued) 8. Seidman AD. Gemcitabine as single-agent therapy in the management of advanced breast cancer. Oncology. (Williston Park) 2001;15(2 suppl 3):11–14. 9. Zelek L, Barthier S, Riofrio M, et al. Weekly vinorelbine is an effective palliative regimen after failure with anthracyclines and taxanes in metastatic breast carcinoma. Cancer. 2001; 92(9):2267–2272. 10. Cortes J, O’Shaughnessy J, Loesch O, et al. Eribulin monotherapy versus treatment of physicians choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomized study. Lancet. 2011;377(9769):914–923. 11. Licchetta A, Correale P, Migali C, et al. Oral metronomic chemo- hormonal-therapy of metastatic breast cancer with cyclophosphamide and megestrol acetate. J Chemother. 2010;22(3):201–204. 12. Isakoff S J, Goss PE, Mayer EL, et al. TBCRCOO9: A multi-center phase II study of cisplatin or carboplatin for metastatic triple-negative breast cancer and evaluation of p631p73 as a biomarker of response [abstract). J Clin Oncol. 2011;29 (15_suppl): Abstract 1025. 13. Burris HA 3rd. Single-agent docetaxel (Taxotere) in randomized phase Ill trials. Semin Oncol. 1999;26(3 suppl 9):1–6. 14. Harvey V, Mouridsen H, Semiglazov V, et al: Phase Ill trial comparing three doses of docetaxel for second-line treatment of advanced breast cancer. J Clin Oncol. 2006;24(31): 4963–4970. 15. Rivera E, Mejia JA, Arun BK, et al. Phase 3 study comparing the use of docetaxel on an every-3-week versus weekly schedule in the treatment of metastatic breast cancer. Cancer. 2008;112(7):1455–1461. 16. Gradishar W, Tjulandin S. Davidson N, et al. Phase Ill trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol. 2005;23(31):7794–7803. 17. Gradishar W, Dimitry K, Sergey C, et al. Significantly longer progression-free survival with nab-paclitaxel compared with docetaxel as first-line therapy for metastatic breast cancer. J Clin Oncol. 2009;27(22):3611–3619. 18. Silver DR, Richardson AL, EkIund AC, et al. Efficacy of neoadjuvant cisplatin in triple-negative breast cancer. J Clin Oncol. 2010;28(7):1145–1153. 19. Bastholt L, Dalmark M, Gjedde SB, et al. Dose-response relationship of epirubicin in the treatment of postmenopausal patients with metastatic breast cancer a randomized study of epirubicin at four different dose levels performed by the Danish Breast Cancer Cooperative Group. J Clin Oncol. 1996;14(4):1146–1155. 20. Perez E, Lerzo G, Pivot X, et al. Efficacy and safety of ixabepilone (BMS-247550) in a phase II study of patients with advanced breast cancer resistant to an anthracycline, a taxane, and capecitabine. J Clin Oncol. 2007;25(23): 3407–3414. 21. Bull JM, Tormey DC, Li SH, et al. A randomized comparative trial of adriamycin versus methotrexate in combination drug therapy. Cancer. 1978;41(5):1649–1657. 22. Hortobagyi GN, Gutterman JU, Blumenschein GR, et al. Combination chemoimmunotherapy of metastatic breast cancer with 5-fluorouracil, adriamycin, cyclophosphamide, and BCG. Cancer. 1979;43(4):1225–33. 23. Ackland SR, Anton A, Breithach GR, et al. Dose-intensive epirubicin-based chemotherapy is superior to an intensive intravenous cyclophosphamide, methotrexate, and fluorouracil regimen in metastatic breast cancer a randomized multinational study. J Clin Oncol. 2001;19(4):943–953. 24. Nabholtz JM, Falkson C, Campos O, et al. Docetaxel and doxorubicin compared with doxorubicin and cyclophosphamide as first-line chemotherapy for metastatic breast cancer results of a randomized, multicenter, phase Ill trial. J Clin Oncol. 2003;21(6):968–975. 25. Langley RE, Carmichel J, Jones AL, et al. Phase Ill trial of epirubicin plus paclitaxel compared with epirubicin plus cyclophosphamide as first-line chemotherapy for metastatic breast cancer United Kingdom Cancer Research Institute. J Clin Oncol. 2005;23(33):8322–8330. 26. Bonadonna G, Brusamolino E, Valagussa P, et al. Combination chemotherapy as an adjuvant treatment in operable breast cancer. N Engl J Med. 1976;294(8):405–410. 27. Mavroudis D, Papakotoulas P, Ardavanis A, et al; Breast Cancer Investigators of the Hellenic Oncology Research Group. Randomized phase III trial comparing docetaxel plus epirubicin versus docetaxel plus capecitabine as first-line treatment in women with advanced breast cancer. Ann Oncol. 2010;21(1):48–54.

28. Albain KS, Nag S, Calderillo-Ruiz G, et al. Gemcitabine plus paclitaxel versus paclitaxel monotherapy in patients with metastatic breast cancer and prior anthracycline treatment. J Clin Oncol. 2008;26(24):3950–3957. 29. O’Shaughnessy J, Schwartzberg LS, Danso MA, et al. A randomized phase ill study of iniparib (BSI-201) in combination with gemcitabine/carboplatin (GIC) in metastatic triple-negative breast cancer (TNBC). [abstract]. J Clin Oncol. 2011; 29(Suppl_15):Abstract 1007. 30. Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizurriab versus paclitaxel alone for metastatic breast cancer. N EngI J Med. 2007;357(26):2666–2676. 31. Baselga J, Cones J, Kim SB, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N EngI J Med. 2012;366(2):109–119. 32. Datko F, D’Andrea G, Dickler M, et al. Phase II study of pertuzumab, trastuzumab, and weekly paclitaxel in patients with metastatic HER2-overexpressing metastatic breast cancer [abstract]. Cancer Research. 2012;72: Abstract P5-18–20. 33. Leyland-Jones B, Gelmon K, Ayoub JP, et al. Pharmacokinetics, safety, and efficacy of trastuzumab administered every three weeks in combination with paclitaxel. J Clin Oncol. 2003;21(21): 3965–3971. 34. Verma S, Miles O, Gianni L, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N EngI J Med. 2012;367(19):1783–1791. 35. Robert N, Leyland-Jones B, Asmar L, et al. Randomized phase III study of trastuzumab, paclitaxel, and carboplatin compared with trastuzumab and paclitaxel in women with HER-2-overexpressing metastatic breast cancer. J Clin Oncol. 2006;24(18):2786–2792. 36. Perez EA, Suman VJ, Rowland KM, et al. Two concurrent phase II trials of paclitaxel/ carboplatin/trastuzumab (weekly or every-3-week schedule) as first-line therapy in women with HER2-overexpressing metastatic breast cancer: NCCTG study 983252. Clin Breast Cancer. 2005;6(5):425–432. 37. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N EngI J Med. 2001;344(11):783–792. 38. Seidman A, Berry DA, Cirrincione C, et al. Randomized phase Ill trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol 9840. J Clin Oncol. 2008;26(10):1642–1649. 39. Marty M, Cognetti F, Maraninchi O, et al. Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 study group. J Clin Oncol. 2005;23(19):4265–4274. 40. Esteva FJ, Valero V, Booser O, et al. Phase II study of weekly docetaxel and trastuzumab for patients with HER-2-overexpressing metastatic breast cancer. J Clin Oncol. 2002;20(7):1800–1808. 41. Burstein HJ, Keshaviah A, Baron AD, et al. Trastuzumab plus vinorelbine or taxane chemotherapy for HER2-overexpressing metastatic breast cancer the trastuzumab and vinorelbine or taxane study. Cancer. 2007;110(5):965–972. 42. von Minckwitz G, du Bois A, Schmidt M, et al. Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer a German breast group 26/breast international group 03-05 study. J Clin Oncol. 2009;27(12):1999–2006. 43. Cobleigh MA, Vogel CL, Tripathy D, et al. Multinational study of the efficacy and safety of humanized anti-l-IER2 ruonodonal antibody in women who have HER2overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol. 1999; 17(9):2639–2648. 44. Geyer C, Forster J, Undquist O, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 2006:355(26):2733–2743. 45. Bartsch R, Wenzel C, Altorjai G, et al. Capecitabine and trastuzumab in heavily pretreated metastatic breast cancer. J Clin Oncol. 2007;25(25):3853–3858. 46. Blackwell KL, Burstein H, Storniolo AM, et al. Randomized study of lapatinib alone or in combination with trastuzumab in women with ErbB2-positive. Trastuzumab-refractory metastatic breast cancer. J Clin Oncol. 2010;28(7):1124–1130. (Revised 4/2016) © 2016 by Haymarket Media, Inc.

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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 >5XULN or AST >10XULN): 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, HER2negative 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. Females of reproductive potential must use effective contraception during therapy and for 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 nonalcoholic, 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

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DRUG MONOGRAPHS

BREAST CANCER therapy to complete a total of 5yrs of hormonal therapy; advanced breast cancer with disease progression after tamoxifen therapy. 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

DELATESTRYL Endo

CIII

Androgen. Testosterone enanthate 200mg/mL; IM inj; in sesame oil; contains chlorobutanol. Indications: Testosterone replacement therapy in adult males with congenital or acquired primary hypogonadism or hypogonadotropic hypogonadism. To stimulate puberty in males with delayed puberty. Limitations of use: not established in men with age-related hypogonadism. 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). 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

EVISTA Lilly

℞

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 proteinbound 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 (HR)-positive metastatic breast cancer in postmenopausal women with disease progression following

℞

antiestrogen therapy. In combination with palbociclib: HR-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer in women with disease progression after endocrine 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. For combination therapy: give with palbociclib 125mg daily with food for 21 days, followed by 7 days off; in pre/perimenopausal women: also treat with LHRH agonists. Moderate hepatic impairment: 250mg (as one 5mL injection) on Days 1, 15, 29, then once per month thereafter. Other dose modification: see full labeling. Children: Not established. Warnings/Precautions: Bleeding diatheses, thrombocytopenia, or anticoagulant use. Moderate-to-severe hepatic impairment. Embryofetal toxicity. Pregnancy: do testing within 7 days prior to initiating; use effective contraception during therapy and for 1 year after last dose. Nursing mothers: not recommended (during therapy and for 1 year after last dose). Adverse reactions: Inj site pain, nausea, vomiting, 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

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DRUG MONOGRAPHS

BREAST CANCER 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 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 high-dose 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 inj over 2–5mins. 1.4mg/m² on Days 1 and 8 of a 21-day cycle. Mild hepatic impairment (Child-Pugh A) or moderate-to-severe renal impairment (CrCl 15–49mL/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 prior to each dose; 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 (ChildPugh C): insufficient data. Pregnancy. Use effective contraception during treatment and for ≥2 weeks (females) or 3.5 months (male partners) after final dose. Nursing mothers: not recommended (during and for 2 weeks after final dose). 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, abdominal pain, pyrexia, hypokalemia, hypocalcemia; 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 multi-modality 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 FDAapproved tests for specific tumor type (breast or gastric/gastroesophageal adenocarcinoma). Embryo-fetal toxicity (eg, oligohydramnios): exclude pregnancy status before initiation. Pregnancy: avoid; use effective contraception during and for 7 months after therapy. Nursing mothers. Interactions: Increased cardiomyopathy with anthracycline-containing chemotherapy. Increased toxicity with other myelosuppressives. Adverse reactions: Fever, diarrhea, nausea, chills, infections, increased cough, headache, CHF, insomnia, fatigue, dyspnea, rash, neutropenia, anemia, thrombocytopenia, stomatitis, mucosal inflammation, weight loss, nasopharyngitis, dysgeusia, myalgia, thrombosis/embolism; severe infusion reactions, febrile neutropenia/exacerbation of chemotherapy-induced neutropenia, pulmonary toxicity (eg, interstitial pneumonitis),

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DRUG MONOGRAPHS

BREAST CANCER cardiomyopathy (eg, left ventricular myocardial dysfunction). 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: Treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer in combination with letrozole as initial endocrine based therapy in postmenopausal women, or fulvestrant in women with disease progression following endocrine therapy. 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 or with fulvestrant 500mg on Days 1, 15, 29, and once monthly thereafter. In the combination fulvestrant therapy: should treat with LHRH agonists according to clinical practice standards. 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/day. Children: Not studied. Warnings/Precautions: Monitor CBCs 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 infections, 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 3 weeks (females) or 3 months (males) after last dose. Nursing mothers: not recommended (during and for 3 weeks after last dose). Interactions: Avoid concomitant strong CYP3A inhibitors (eg, clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole), grapefruit or grapefruit juice; if unavoidable, reduce dose (see Adults). Avoid concomitant strong CYP3A inducers (eg, phenytoin, rifampin, carbamazepine, enzalutamide, St. John’s wort) or moderate CYP3A inducers (eg, modafinil). 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, infections, fatigue, anemia, nausea, stomatitis, headache, alopecia, diarrhea, thrombocytopenia, constipation, decreased appetite, vomiting, rash, asthenia, peripheral neuropathy, epistaxis; pulmonary embolism. 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 >2.5XULN or bilirubin >1XULN (in combination with capecitabine). Warnings/Precautions: Monitor CBC and liver function at baseline, then periodically. Hepatic impairment (ALT or AST >10XULN or bilirubin >3XULN: not recommended; ALT or AST >5XULN: 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, palmar-plantar 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 >3XULN and with total bilirubin >2XULN. 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.

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DRUG MONOGRAPHS

BREAST CANCER 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. 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 embryofetal toxicity; verify pregnancy status prior to initiation. 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 7 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 estrogendependent 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

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 non-hormonal 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.

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DRUG MONOGRAPHS

BREAST CANCER 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 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 non-hormonal 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.

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

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).

℞

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. 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, 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).

TYKERB GlaxoSmithKline

℞

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DRUG MONOGRAPHS

BREAST CANCER 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. 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

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.

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 >5XULN or AST >10XULN): 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: In adults with progressive neuroendocrine tumors of pancreatic origin (PNET) or progressive, well-differentiated, nonfunctional neuroendocrine tumors (NET) of gastrointestinal or lung origin 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. Preexisting 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. Females of reproductive potential must use effective contraception during therapy and for 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,

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DRUG MONOGRAPHS

ENDOCRINE CANCER 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) 236-9933 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 60mg daily, resume at 60mg if tolerated, otherwise discontinue. Concomitant strong CYP3A4 inhibitors: 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). Pregnancy (Cat.D). Females of reproductive potential should use effective contraception during and up to 4 months after therapy completion. 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: 7x80mg and 21x20mg caps); 100mg daily-dose carton—4 blister cards (each: 7x80mg and 7x20mg caps); 60mg daily-dose carton—4 blister cards (each: 21x20mg 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 lifethreatening 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

Access Cancer Therapy Advisor treatment regimens in a user-friendly format. CancerTherapyAdvisor.com/TreatmentRegimens.

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DRUG MONOGRAPHS

ENDOCRINE CANCER 2 weeks after treatment completion. Nursing mothers: not recommended. 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 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

ONIVYDE Merrimack

℞

Topoisomerase inhibitor. Irinotecan 43mg/10mL; liposomal dispersion for IV infusion after dilution. Indications: In combination with fluorouracil and leucovorin, for treatment of metastatic adenocarcincoma of the pancreas after disease progression following gemcitabine-based therapy. Limitations of use: as a single agent, not for the treatment of metastatic adenocarcinoma of the pancreas. Adults: Do not substitute for other irinotecan HCl-containing drugs. Give by IV infusion over 90 mins prior to fluorouracil and leucovorin. 70mg/m2 every 2 weeks. If homozygous UGT1A1*28 allele: initially 50mg/m2; may increase to 70mg/m2 as tolerated in subsequent cycles. If serum bilirubin >ULN: no dose recommended. Premedicate with corticosteroid and antiemetic 30 mins prior to infusion. Dose modifications: see full labeling. Children: Not established. Warnings/Precautions: Severe and lifethreatening neutropenia, neutropenic sepsis, diarrhea can occur. Monitor CBCs on Days 1 and 8 of every cycle and more frequently if indicated; withhold if ANC <1500/mm3 or neutropenic fever occurs; reduce dose in subsequent cycles for Grade 3–4 neutropenia or neutropenic fever after recovery. Bowel obstruction: do not administer. Withhold for Grade 2–4 diarrhea; initiate loperamide if late onset or atropine IV/SC (unless contraindicated) if early onset; resume at reduced dose after recovery to Grade 1. Withhold if new or progressive dyspnea, cough, and fever occurs, pending evaluation; discontinue if interstitial lung disease confirmed. Permanently discontinue if severe hypersensitivity reaction occurs. Females of reproductive potential should use effective contraception during therapy and for 1 month after final dose; males should use condoms during and for 4 months after final dose. Pregnancy. Nursing mothers: not recommended (during therapy and for 1 month after final dose). Interactions: Avoid concomitant strong CYP3A4 inducers (eg, rifampin, phenytoin, carbamazepine, rifabutin, rifapentine, phenobarbital, St. John’s wort) if possible; substitute non-enzyme inducing therapies at least 2 weeks before initiating irinotecan. Avoid concomitant strong CYP3A4 (eg, clarithromycin, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telaprevir, voriconazole) or UGT1A1 inhibitors (eg, atazanavir, gemfibrozil, indinavir) if possible; discontinue CYP3A inhibitors at least 1 week before initiating irinotecan. Adverse reactions: Diarrhea, fatigue/asthenia, vomiting, nausea, decreased appetite, stomatitis, pyrexia; neutropenic fever or sepsis, dehydration, septic shock, pneumonia, acute renal failure, thrombocytopenia. How supplied: Single-dose vial—1

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.

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DRUG MONOGRAPHS

ENDOCRINE CANCER 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 >3XULN or transaminases >5XULN, 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

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.

Take advantage of our free online medical calculators at CancerTherapyAdvisor.com/MedicalCalculators.

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DRUG MONOGRAPHS

ENDOCRINE CANCER 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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CANCER TREATMENT REGIMEN

GASTROINTESTINAL CANCER Rectal 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 • Consists of regimens that include both concurrent chemotherapy and radiotherapy and adjuvant chemotherapy. • Six months of perioperative therapy is preferred in the adjuvant therapy setting. • Following a shortage of leucovorin, the FDA approved levoleucovorin in combination with 5-FU for the palliative treatment of patients with advanced metastatic colorectal cancer. Levoleucovorin 200mg/m2 is the equivalent of leucovorin 400mg/m2. Note: All recommendations are Category 2A unless otherwise indicated.

Postoperative Adjuvant Therapy for Patients Not Receiving Preoperative Therapy1 REGIMEN

DOSING

Day 1: Oxaliplatin 85mg/m2 IV over 2 hours + leucovorin 400mg/m2 IV over 2 hours, followed by 5-FU 400mg/m2 IV mFOLFOX6 (oxaliplatin + leucovorin + 5-fluorouracil [5-FU])2–4a bolus, followed by 5-FU 1,200mg/m2/day IV × 2 days (total 2,400mg/m2) as a 46–48-hour continuous infusion. Repeat cycle every 2 weeks for a total of 6 months perioperative therapy. Capecitabine5

Days 1–14: Capecitabine 1,250mg/m2 orally twice daily. Repeat cycle every 3 weeks for 6 months perioperative therapy.

CapeOX (oxaliplatin + capecitabine)6,7 Day 1: Oxaliplatin 130mg/m2 IV over 2 hours Days 1–14: Capecitabine 1,000mg/m2 orally twice daily. Repeat cycle every 3 weeks for 6 months perioperative therapy. Simplified biweekly infusional 5-FU/ LV (sLV5FU2)8b

Day 1: Leucovorin 400mg/m2 IV, followed by 5-FU 400mg/m2 IV bolus, followed by 5-FU 1,200mg/m2/day IV × 2 days (total 2,400mg/m2) as a 46–48 hour continuous infusion. Repeat cycle every 2 weeks for 6 months perioperative therapy.

5-FU + leucovorin9

5-FU 500mg/m2 IV bolus weekly x 6 + leucovorin 500mg/m2 IV weekly x 6, each 8-week cycle. Repeat cycle every 8 weeks for 6 months perioperative therapy.

Concurrent Chemotherapy + Radiotherapy1 External beam radiotherapy [XRT] + 5-FU10

Days 1–5 OR 1–7: 5-FU 225mg/m2 IV over 24 hours during XRT.

XRT + 5-FU + leucovorin11c

Days 1–4: 5-FU 400mg/m2 IV bolus + leucovorin 20mg/m2 IV bolus. Repeat cycle during weeks 1 and 5 of XRT.

XRT + capecitabine12,13

Days 1–5: Capecitabine 825mg/m2 twice daily + XRT. Repeat cycle weekly for 5 weeks.

Chemotherapy for Advanced or Metastatic Disease1 mFOLFOX62–4ab

Day 1: Oxaliplatin 85mg/m2 IV over 2 hours + leucovorin 400mg/m2 IV over 2 hours followed by 5-FU 400mg/m2 IV bolus, followed by 5-FU 1,200mg/m2/day IV × 2 days (total 2,400mg/m2) as a 46–48-hour continuous infusion. Repeat cycle every 2 weeks.

mFOLFOX6 + bevacizumab3,14abd

Day 1: Oxaliplatin 85mg/m2 IV over 2 hours + leucovorin 400mg/m2 IV over 2 hours, followed by 5-FU 400mg/m2 IV bolus, followed by 5-FU 1,200mg/m2/day IV × 2 days (total 2,400mg/m2) as a 46–48-hour continuous infusion Day 1: Bevacizumab 5mg/kg IV. Repeat cycle every 2 weeks.

mFOLFOX6 + panitumumab3,15ab (KRAS/NRAS wild-type gene only)

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CANCER TREATMENT REGIMEN

GASTROINTESTINAL CANCER Chemotherapy for Advanced or Metastatic Disease1 (continued) REGIMEN

DOSING

FOLFOX + cetuximab2,16ab (KRAS/NRAS wild-type gene only)

Day 1: Oxaliplatin 85mg/m2 IV over 2 hours + leucovorin 400mg/m2 IV over 2 hours, followed by 5-FU 400mg/m2 IV bolus, followed by 5-FU 1,200mg/m2/day IV × 2 days (total 2,400mg/m2) as a 46–48-hour continuous infusion PLUS Day 1: Cetuximab 400mg/m2 IV over 2 hours first infusion, then 250mg/m2 IV over 60 minutes weekly. OR Day 1: Cetuximab 500mg/m2 IV over 2 hours every 2 weeks.

CapeOX6,7e

Day 1: Oxaliplatin 130mg/m2 IV Days 1–14: Capecitabine 850–1,000mg/m2 orally twice daily. Repeat cycle every 3 weeks.

CapeOX + bevacizumab6,7,17de

Day 1: Oxaliplatin 130mg/m2 IV Days 1–14: Capecitabine 850–1,000mg/m2 orally twice daily Day 1: Bevacizumab 7.5mg/kg IV. Repeat cycle every 3 weeks.

FOLFIRI18b

Day 1: Irinotecan 180mg/m2 IV over 30–90 minutes + leucovorin 400mg/m2 IV, to match duration of irinotecan infusion, followed by 5-FU 400mg/m2 IV bolus, followed by 5-FU 1,200mg/m2/day IV × 2 days (total 2,400mg/m2) as a 46–48-hour continuous infusion. Repeat cycle every 2 weeks.

FOLFIRI + bevacizumab18,19bd

FOLFIRI + cetuximab18, 20,21b (KRAS/NRAS wild-type gene only)

Day 1: Irinotecan 180mg/m2 IV + leucovorin 400mg/m2 IV, to match duration off irinotecan infusion, followed by 5-FU 400mg/m2 IV bolus, followed by 5-FU 1,200mg/m2/day IV × 2 days (total 2,400mg/m2) as a 46–48-hour continuous infusion. Repeat cycle every 2 weeks. PLUS Day 1: Cetuximab 400mg/m2 IV over 2 hours first infusion, then 250mg/m2 IV over 60 minutes weekly. OR Day 1: Cetuximab 500mg/m2 IV over 2 hours every 2 weeks.

FOLFIRI + panitumumab17,22b (KRAS/ NRAS wild-type gene only)

FOLFIRI + ziv-aflibercept23b

Day 1: Irinotecan 180mg/m2 IV + leucovorin 400mg/m2 IV, followed by 5-FU 400mg/m2 IV bolus, followed by 5-FU 1,200mg/m2/day IV × 2 days (total 2,400mg/m2) as a 46–48-hour continuous infusion Day 1: Ziv-aflibercept 4mg/kg IV. Repeat cycle every 2 weeks.

Capecitabine24

Days 1–14: Capecitabine 850–1,250mg/m2 orally twice daily. Repeat cycle every 3 weeks.

Capecitabine + bevacizumab17,24d

Days 1–14: Capecitabine 850–1,250mg/m2 orally twice daily Day 1: Bevacizumab 7.5mg/kg IV. Repeat cycle every 3 weeks.

Bolus or infusional 5-FU/leucovorin (Roswell-Park Regimen)25

Days 1, 8, 15, 22, 29, and 36: Leucovorin 500mg/m2 IV over 2 hours, followed by 5-FU 500mg/m2 IV bolus 1 hour after start of leucovorin. Repeat cycle every 8 weeks.

Simplified biweekly infusional 5-FU/ LV (sLV5FU2)18

Day 1: Leucovorin 400mg/m2 IV over 2 hours, followed by 5-FU 400mg/m2 IV bolus, followed by 5-FU 1,200mg/m2/day IV × 2 days (total 2,400mg/m2) as a 46–48-hour continuous infusion. Repeat cycle every 2 weeks. continued

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CANCER TREATMENT REGIMEN

GASTROINTESTINAL CANCER Rectal Cancer Treatment Regimens Chemotherapy for Advanced or Metastatic Disease1 (continued) REGIMEN

DOSING

Weekly 5-FU + leucovorin26,27

Day 1: Leucovorin 20mg/m2 IV over 2 hours, followed by 5-FU 500mg/m2 IV bolus 1 hour after start of leucovorin. Repeat cycle weekly. OR Day 1: Leucovorin 500mg/m2 IV, followed by 5-FU 2,600mg/m2 continuous infusion. Repeat cycle weekly.

IROX28

Day 1: Oxaliplatin 85mg/m2 IV + irinotecan 200mg/m2 IV over 30–90 minutes. Repeat cycle every 3 weeks.

FOLFOXIRI ± bevacizumab29,30bd

Day 1: Irinotecan 165mg/m2 IV + oxaliplatin 85mg/m2 IV + leucovorin 400mg/m2 IV Days 1 and 2: 5-FU 1,600mg/m2/day continuous infusion IV over 48 hours ± Day 1: Bevacizumab 5mg/kg IV. Repeat cycle every 2 weeks.

Irinotecan31,32

Days 1 and 8: Irinotecan 125mg/m2 IV over 30–90 minutes. Repeat cycle every 3 weeks. OR Day 1: Irinotecan 180mg/m2 IV over 30–90 minutes. Repeat cycle every 2 weeks. OR Day 1: Irinotecan 300–350mg/m2 IV over 30–90 minutes. Repeat cycle every 3 weeks.

Cetuximab + irinotecan21 (KRAS/NRAS wild-type gene only)

Day 1: Cetuximab 400mg/m2 IV first infusion, then 250mg/m2 IV every 7 days OR Day 1: Cetuximab 500mg/m2 IV every 2 weeks + Day 1: Irinotecan 300–350mg/m2 IV over 30–90 minutes every 3 weeks. OR Day 1: Irinotecan 180mg/m2 IV over 30–90 minutes every 2 weeks. OR Days 1 and 8: Irinotecan 125mg/m2 IV over 30–90 minutes every 3 weeks.

Cetuximab21,33 (KRAS/NRAS wild-type gene only)

Cetuximab 400mg/m2 first infusion, then 250mg/m2 IV weekly. OR Cetuximab 500mg/m2 IV over 2 hours every 2 weeks.

Panitumumab34 (KRAS/NRAS wild-type gene only)

Day 1: Panitumumab 6mg/kg IV over 60 minutes. Repeat cycle every 2 weeks.

Regorafenib35f

Days 1–21: Regorafenib 160mg orally once daily. Repeat cycle every 28 days.

Trifluridine/tipiracil36

Days 1–5 and 8–12: Trifluridine/tipiracil 35mg/m2 up to a maximum of 80mg/m2 per dose (based on the trifluridine component) orally twice daily. Repeat every 28 days.

a Oxaliplatin may instead be infused at 1mg/m2/min, a shorter time rate than 2 hours. If this shorter infusion time is used, leucovorin infusion time should be matched to the oxaliplatin infusion time. b NCCN recommends limiting chemotherapy orders to 24-hour units (ie, 1,200mg/m2/day NOT 2,400mg/m2 over 48 hours) to minimize medical errors. c Bolus 5-FU/leucovorin/XRT is an option for patients not able to tolerate capecitabine or infusional 5-FU. d Bevacizumab may be safely given at a rate of 0.5mg/kg/minute (5mg/kg over 10 minutes and 7.5mg/kg over 15 minutes). e Most of the safety and efficacy data for this regimen have come from Europe, where a capecitabine starting dose of 1,000mg/m2 twice daily for 14 days, repeated every 21 days, is standard. Evidence suggests North American patients may experience greater toxicity with capecitabine (as well as with other fluoropyrimidines) than European patients, necessitating the use of a lower dose of capecitabine. The relative efficacy of CapeOx with lower starting doses of capecitabine has not been addressed in large-scale randomized trials. f It is common practice to start at a lower dose of regorafenib (80 or 120mg) and escalate, as tolerated.

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CANCER TREATMENT REGIMEN

GASTROINTESTINAL CANCER References 1. NCCN Clinical Practice Guidelines in Oncology™. Rectal Cancer. v 2.2016. Available at: http://www.nccn.org/professionals/physician_gls/pdf/rectal.pdf. Accessed May 3, 2016. 2. Andre T, Boni C, Mounedji-Boudiaf L, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N EngI J Med. 2004;350:2343–2351. 3. Cheeseman SL, Joel SP, Chester JD, et al. A “modified deGramont” regimen of fluorouracil, alone and with oxaliplatin, for advanced colorectal cancer. Br J Cancer. 2002;87(4):393–399. 4. Maindrault-Goebel F, deGramont A, Louvet C, et al. Evaluation of oxaliplatin dose intensity in bimonthly leucovorin and 48-hour 5-fluorouracil continuous infusion regimens (FOLFOX) in pretreated metastatic colorectal cancer. Oncology Multidisciplinary Research Group (GERCOR). Ann Oncol. 2000;11(11):1477–1483. 5. Twelves C, Wong A, Nowacki MP, et al. Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med. 2005;354(26):2696–2704. 6. Schmoll HJ, Cartwright T, Tabernero J, et al. Phase III trial of capecitabine plus oxaliplatin as adjuvant therapy for stage III colon cancer: a planned safety analysis in 1,864 patients. J Clin Oncol. 2007;25(1):102–109. 7. Haller DG, Tabernero J, Maroun J, et al. Capecitabine plus oxaliplatin compared with fluorouracil and folinic acid as adjuvant therapy for stage III colon cancer. J Clin Oncol. 2011;29(11):1465–1471. 8. André T, Louvet C, Maindrault-Goebel F, et al. CPT-11 (irinotecan) addition to bimonthly, high-dose leucovorin and bolus and continuous-infusion 5-fluorouracil (FOLFIRI) for pretreated metastatic colorectal cancer. GERCOR. Eur J Cancer. 1999;35(9):1343–1347. 9. Petrelli N, Douglass HO Jr, Herrare L, et al. The modulation of fluorouracil with leucovorin in metastatic colorectal carcinoma: a prospective randomized phase III trial. Gastrointestinal Tumor Study Group. J Clin Oncol. 1989;7(10):1419–1426. Erratum in: J Clin Oncol. 1990;8(1):185. 10. O’Connell MJ, Martenson JA, Wieand HS, et al. Improving adjuvant therapy for rectal cancer by combining protracted-infusion fluorouracil with radiation therapy after curative surgery. N Engl J Med. 1994;331(8):502–507. 11. Tepper JE, O’Connell M, Niedzwiecki D, et al. Adjuvant therapy in rectal cancer: analysis of stage, sex, and local control—final report of intergroup 0114. J Clin Oncol. 2002;20(7):1744–1750. 12. O’Connell MJ, Colangelo LH, Beart RW, et al. Capecitabine and oxaliplatin in the preoperative multimodality treatment of rectal cancer: surgical end points from National Surgical Adjuvant Breast and Bowel Project trial R-04. J Clin Oncol. 2014;32(18):1927–1934. 13. Hofheinz R, Wenz FK, Post S et al. Capecitabine (Cape) versus 5-fluorouracil (5-FU)-based (neo)adjuvant chemotherapy (CRT) for locally advanced rectal cancer (LARC): long-term results of a randomized, phase III trial [abstract]. J Clin Oncol. 2011;29(suppl):3504. 14. Emmanouilides C, Sfakiotaki G, Androulakis N, et al. Front-line bevacizumab in combination with oxaliplatin, leucovorin and 5-fluorouracil (FOLFOX) in patients with metastatic colorectal cancer: a multicenter phase II study. BMC Cancer. 2007;7:91. 15. Douillard JY, Siena S, Cassidy J, et al. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol. 2010;28(31):4697–4705. 16. Venook AP, Niedzwiecki D, Lenz H-J, et al. CALGB/SWOG 80405: Phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab or cetuximab for patients with KRAS wild-type untreated metastatic adenocarcinoma of the colon or rectum [abstract]. ASCO Meeting Abstracts 2014;32:LBA3. Available at: http://meeting.ascopubs.org/cgi/content/abstract/32/15_suppl/LBA3 17. Saltz LB, Clarke S, Diaz-Rubio E, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008;26(12):2013–2019. 18. Andre T, Louvet C, Maindrault-Goebel F, et al. CPT-11 (irinotecan) addition to bimonthly, high-dose leucovorin and bolus and continuous-infusion 5-fluorouracil (FOLFIRI) for pretreated metastatic colorectal cancer. Eur J Cancer. 1999;35(9):1343–1347. 19. Fuchs CS, Marshall J, Mitchell E, et al. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic

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colorectal cancer: results from the BICC-C Study. J Clin Oncol. 2007;25(30):4779–4786. Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004;351(4):337–345. Martin-Martorell P, Roselló S, Rodriguez-Braun, et al. Biweekly cetuximab and irinotecan in advanced colorectal cancer patients progressing after at least one previous line of chemotherapy: results of a phase II single institution trial. Br J Cancer. 2008; 99(3):455–458. Peeters M, Price TJ, Cervantes A, et al. Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol. 2010;28(31):4706–4713. Van Cutsem E, Tejpar S, Vanbeckevoort D, et al. Intrapatient cetuximab dose escalation in metastatic colorectal cancer according to the grade of early skin reactions: the randomized EVEREST study. J Clin Oncol. 2012;30(23): 2861–2868. Van Cutsem E, Twelves C, Cassidy J, et al; Xeloda Colorectal Cancer Study Group. Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. J Clin Oncol. 2001;19(21):4097–4106. Wolmark N, Rockette H, Fisher B, et al. The benefit of leucovorin-modulated fluorouracil as postoperative adjuvant therapy for primary colon cancer: results from National Surgical Adjuvant Breast and Bowel Protocol C-03. J Clin Oncol. 1993;11(10): 1879–1887. Jager E, Heike M, Bernhard H, et al. Weekly high-dose leucovorin versus low-dose leucovorin combined with fluorouracil in advanced colorectal cancer: results of a randomized multicenter trial. Study Group for Palliative Treatment of Metastatic Colorectal Cancer Study Protocol 1. J Clin Oncol. 1996;14(8): 2274–2279. Douillard JY, Cunningham D, Roth AD, et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multi-centre randomised trial. Lancet. 2000;355(9209):1041–1047. Haller DG, Rothenberg ML, Wong AO, et al. Oxaliplatin plus irinotecan compared with irinotecan alone as second-line treatment after single-agent fluoropyrimidine therapy for metastatic colorectal carcinoma. J Clin Oncol. 2008;26(28): 4544–4550. Loupakis F, Cremonlini C, Masi G et al. FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of metastatic colorectal cancer: Results of the phase III randomized TRIBE trial. J Clin Oncol. 2013;31 (suppl 4): abstract 336. Falcone A, Ricci S, Brunetti I, et al. Gruppo Oncologico Nord Ovest. Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest. J Clin Oncol. 2007;25(13): 1670–1676. Cunningham D, Pyrhönen S, James RD, et al. Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet. 1998;352(9138):1413–1418. Fuchs CS, Moore MR, Harker G, Villa L, Rinaldi D, Hecht JR. Phase III comparison of two irinotecan dosing regimens in second-line therapy of metastatic colorectal cancer. J Clin Oncol. 2003;21(5):807–814. Van Cutsem E, Tabernero J, Lakomy R, et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves s urvival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol. 2012;30(28): 3499–3506. Van Cutsem E, Peeters M, Siena S, et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol. 2007; 25(13):1658–1664. Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381(9863): 303–312. Mayer RJ, Van Cutsem E, Falcone A, et al. RECOURSE Study Group. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med. 2015;372(20):1909–1919.

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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

decreased appetite; arterial thromboembolic events, proteinuria, GI perforation, infusionrelated reactions. How supplied: Single-dose vial (10mL, 50mL)—1 ℞

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 fluoropyrimidineor 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 infusion-related 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,

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 full labeling. Premedicate with antiemetics. Give by IV infusion every two weeks for a total of 6 months (12 cycles) for adjuvant use or until disease progression or unacceptable toxicity for advanced disease. 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 full labeling for dose adjustments. Children: Not established. Contraindications: Known allergy to other platinum compounds. Warnings/Precautions: Monitor for allergic reactions; discontinue if occurs; do not rechallenge. Have epinephrine, corticosteroids, antihistamines available during infusion. Monitor for neuropathy; reduce dose or discontinue if needed. Severe neutropenia: delay therapy until neutrophils ≥1.5 × 109/L; withhold for sepsis or septic shock; reduce dose after recovery. Monitor WBCs with differential, hemogloblin, platelets, blood chemistries (including ALT, AST, bilirubin, creatinine) before each cycle. Discontinue if interstitial lung disease or pulmonary fibrosis is suspected. Patients with CHF, bradyarrhythmias, concomitant drugs known to prolong the QT interval, and electrolyte abnormalities: monitor ECG. Correct hypokalemia or hypomagnesemia prior to initiation; monitor periodically during therapy. Congenital long QT syndrome; avoid. Renal impairment. 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, fatigue, stomatitis; allergic reactions, pulmonary fibrosis (may be fatal), hepatotoxicity, QT prolongation, ventricular arrhythmias, rhabdomyolysis (may be fatal; discontinue if occurs). Testing considerations: ERCC1 overexpression How supplied: Single-use vials (50mg, 100mg)—1

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DRUG MONOGRAPHS

GASTROINTESTINAL CANCER 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. 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 high-dose 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

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DRUG MONOGRAPHS

GASTROINTESTINAL CANCER (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, StevensJohnson 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

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 FDAapproved tests for specific tumor type (breast or gastric/gastroesophageal adenocarcinoma). Embryo-fetal toxicity (eg, oligohydramnios): exclude pregnancy status before initiation. Pregnancy: avoid; use effective contraception during and for 7 months after therapy. Nursing mothers. Interactions: Increased cardiomyopathy with anthracycline-containing chemotherapy. Increased toxicity with other myelosuppressives. 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 chemotherapy-induced 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 trimethoprimsulfamethoxazole. Adverse reactions: Leukopenia, thrombocytopenia, infection, GI upset, stomatitis, constipation, lethargy, malaise, fatigue, alopecia, dermatitis, anorexia; seizures, syncope. How supplied: Single-use vials—1

LONSURF Taiho Oncology

℞

Antineoplastic thymidine-based nucleoside analog + thymidine phosphorylase inhibitor. Trifluridine, tipiracil; 15mg/6.14mg, 20mg/8.19mg; tabs. Indications: Treatment of metastatic colorectal cancer in patients previously treated with fluoropyrimidine-, oxaliplatin- and irinotecanbased chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy. Adults: Take within 1 hour after completion of AM & PM meals. Initially 35mg/m2 twice daily on Days 1–5 and 8–12 of each 28-day cycle until disease progression or unacceptable toxicity; max 80mg per dose (based on trifluridine component). Dose modifications: see full labeling. Children: Not established. Warnings/Precautions: Obtain CBC prior to and on Day 15 of each cycle, and as clinically indicated. Do not initiate cycle until ANC ≥1,500/mm3 or febrile neutropenia is resolved, platelets ≥75,000/mm3 or Grade 3/4 nonhematological adverse reactions resolved to Grade 0/1. Withhold dose if ANC <500/mm3 or febrile neutropenia, platelets <50,000/mm3, or Grade 3/4 non-hematological adverse reactions occur; upon recovery, resume at a reduced dose (see full labeling). Moderate or severe hepatic impairment: not studied. Moderate renal impairment: may require dose modification; severe (CrCl <30mL/min) or ESRD: not studied. Elderly. Pregnancy. Females of reproductive potential must use effective contraception during treatment; males must use condoms during and for ≥3 months after final dose. Nursing mothers: not recommended (during treatment and for 1 day after final dose). Adverse reactions: Anemia, neutropenia, asthenia/fatigue, nausea, thrombocytopenia, decreased appetite, diarrhea, vomiting, abdominal pain, pyrexia. How supplied: Tabs—20, 40, 60

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DRUG MONOGRAPHS

GASTROINTESTINAL CANCER

℞

metastatic gastrointestinal stromal tumor (GIST) who have been previously treated with imatinib mesylate or sunitinib malate. Adults: Swallow whole with water after a low-fat 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)

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

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.

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

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

Simplify your search for quality Oncology CME/CE. Visit myCME.com/Oncology.

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DRUG MONOGRAPHS

GASTROINTESTINAL CANCER 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

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 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 Sanofi US and Regeneron

℞

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 ≥1.5x109/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

PHARMACOLOGIC CLASS The chemical/therapeutic class of the drug is listed in italics.

34 CANCER THERAPY ADVISOR | JULY/AUGUST 2016 | CancerTherapyAdvisor.com

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B:8.625” T:7.75” S:7”

MAKE VOTRIENT YOUR CHOICE FOR FIRST-LINE ADVANCED RCC Phase 3, randomized, double-blind, placebo-controlled, multicenter trial to evaluate the efficacy and safety of VOTRIENT® (pazopanib) tablets in first-line or cytokine-pretreated patients (N=435) with advanced renal cell carcinoma (RCC) of clear cell or predominantly clear cell histology. Patients with locally advanced or metastatic RCC were randomized (2:1) to receive either VOTRIENT 800 mg once daily or placebo.

• Median overall progression-free survival (PFS) of 9.2 months vs 4.2 months with placebo (HR=0.46 [95% CI, 0.34-0.62], P<0.001)1

T:10.5”

S:10”

CI, conﬁdence interval; HR, hazard ratio.

B:11.25”

• Median ﬁrst-line PFS of 11.1 months vs 2.8 months with placebo (HR=0.40 [95% CI, 0.27-0.60], P<0.001)1,2

Indication VOTRIENT is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).

Important Safety Information for VOTRIENT® (pazopanib) tablets WARNING: HEPATOTOXICITY Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. See “Warnings and Precautions,” Section 5.1, in complete Prescribing Information. Please see additional Important Safety Information on subsequent pages.

For more information, visit VOTRIENT.com.

Please see Brief Summary of Prescribing Information, including Boxed WARNING, on adjacent pages.

VORCC17104-01_A_Size_DR.indd Client: Novartis / Voitrent Job Description: Voitrent Ad A Size Job #: VORCC17104-01 Stage: DISK RELEASE Round: 1

Eric Lehmann

11-23-2015 11:01 AM

Print Scale: None Fonts: Frutiger, Nexa Images: GettyImages-469851543_Journal_AD04_CMYK.eps (CMYK; 328 ppi, -328 ppi; Users:elehman Ink Density: 300% n:Desktop:VORCC17...es-469851543_Journal_AD04_CMYK.eps), VOT_dose_W.eps (Users:elehmann:D esktop:VORCC17...-01_A_Size_DR:Links:VOT_dose_W.eps) Bleed: 8.625" x 11.25" Trim: 7.75" x 10.5" Safety: 7" x 10" Folded Size: None Gutter: None Scale: 1" = 1"

Colors: Cyan Magenta Yellow Black

B:16.375” T:15.5” S:14.75”

CHOOSE MORE THAN 6 YEARS

FIRST-LINE EFFICACY

SAFETY AND DOSING SAFETY AND TOLERABILITY PROFILE

SIGNIFICANT IMPROVEMENTS IN PFS

1,2

OVERALL (N=435)

FIRST LINE (n=233)

11.1vs 9.2 vs MONTHS MONTHS 4.2 Placebo 2.8 Placebo MONTHS VOTRIENT

HR=0.46 (95% CI, 0.34-0.62) P<0.0011

MONTHS VOTRIENT

Phase 3, randomized, double-blind, placebocontrolled multicenter trial to evaluate the efficacy and safety of VOTRIENT® (pazopanib) tablets in first-line or cytokine-pretreated patients (N=435) with advanced clear cell or predominantly clear cell histology. Patients with locally advanced or metastatic RCC were randomized (2:1) to receive either VOTRIENT 800 mg once daily or placebo.

HR=0.40 (95% CI, 0.27-0.60) P<0.0011,2

NATIONAL COMPREHENSIVE CANCER NETWORK® (NCCN®) CATEGORY 1 RECOMMENDATION

All Grades (%)

Fatigue

Asthenia

Hand-foot syndrome

Stomatitis

Mucositis

4 x 200 mg

• Available in 200-mg tablets • Recommended starting dose is 800 mg • Must be taken without food at least 1 hour before or 2 hours after a meal

Not actual size.

• Initial dose reduction should be 400 mg, and additional dose decrease or increase should be in 200-mg steps based on individual tolerability

VOTRIENT is indicated for the treatment of patients with advanced renal cell carcinoma.

For additional information on dosing modiﬁcation based on drug interactions, please see next page.

Important Safety Information for VOTRIENT® (pazopanib) tablets (cont)

Hepatic Toxicity and Hepatic Impairment: Severe and fatal hepatotoxicity has occurred. Patients older than 65 years are at an increased risk. Increases in serum transaminase levels (ALT, AST) and bilirubin were observed. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks). In patients with preexisting moderate hepatic impairment, the starting dose of VOTRIENT should be reduced to 200 mg per day or alternatives to VOTRIENT should be considered. Treatment with VOTRIENT is not recommended in patients with severe hepatic impairment. Concomitant use of VOTRIENT and simvastatin increases the risk of ALT elevations and should be undertaken with caution [see Drug Interactions]. Before the initiation of treatment and regularly during treatment, monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. QT Prolongation and Torsades de Pointes: Prolonged QT intervals and arrhythmias,

Arterial Thromboembolic Events: Arterial thromboembolic events have been observed, including fatal events (0.3%, 2/586) in the RCC trials. In the randomized RCC trial, 2% (5/290) of patients receiving VOTRIENT experienced myocardial infarction or ischemia, 0.3% (1/290) had a cerebrovascular accident, and 1% (4/290) had an event of transient ischemic attack. No arterial thromboembolic events were reported in patients who received placebo. Use with caution in patients who are at increased risk for these events or have a history of these events. Do not use VOTRIENT in patients who have had an arterial thromboembolic event in the past 6 months.

including torsades de pointes, have occurred. Use with caution in patients with a history of QT interval prolongation, patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant preexisting cardiac disease. Baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes (eg, calcium, magnesium, potassium) within the normal range should be performed.

on each arm. Monitor blood pressure (BP), and manage promptly using a combination of antihypertensive therapy and dose modification of VOTRIENT (interruption and reinitiation at a reduced dose based on clinical judgment). Carefully monitor patients for clinical signs or symptoms of CHF. Baseline and periodic evaluation of LVEF is recommended in patients at risk of cardiac dysfunction, including previous anthracycline exposure.

Cardiac Dysfunction: Cardiac dysfunction, such as congestive heart failure (CHF) and decreased left ventricular ejection fraction (LVEF), has occurred. In the overall safety population for RCC (N=586), cardiac dysfunction was observed in 0.6% (4/586) of patients without routine onstudy LVEF monitoring. In a randomized RCC trial of VOTRIENT compared with sunitinib, in patients who had baseline and follow-up LVEF measurements, myocardial dysfunction occurred in 13% (47/362) of patients on VOTRIENT compared with 11% (42/369) of patients on sunitinib. CHF occurred in 0.5% of patients

Hemorrhagic Events: Fatal hemorrhagic events were reported in 0.9% (5/586) of patients in the RCC trials. In the randomized RCC trial, 13% (37/290) of patients treated with VOTRIENT compared to 5% (7/145) of patients on placebo experienced at least 1 hemorrhagic event. The most common hemorrhagic events were hematuria (4%), epistaxis (2%), hemoptysis (2%), and rectal hemorrhage (1%). VOTRIENT should not be used in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal (GI) hemorrhage in the past 6 months.

VORCC17104-01_A_Size_DR.indd Client: Novartis / Voitrent Job Description: Voitrent Ad A Size Job #: VORCC17104-01 Stage: DISK RELEASE Round: 1

Venous Thromboembolic Events (VTEs): VTEs have occurred, including venous thrombosis and fatal pulmonary emboli. In the randomized RCC trial, VTEs were reported in 1% of patients treated with VOTRIENT and in

1% of patients treated with placebo. Monitor for signs and symptoms. Thrombotic Microangiopathy (TMA): TMA, including thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) has been reported in clinical trials of VOTRIENT as monotherapy, in combination with bevacizumab, and in combination with topotecan. VOTRIENT is not indicated for use in combination with other agents. Six of the 7 TMA cases occurred within 90 days of the initiation of VOTRIENT. Improvement of TMA was observed after treatment was discontinued. Monitor for signs and symptoms of TMA. Permanently discontinue VOTRIENT in patients developing TMA. Manage as clinically indicated. GI Perforation and Fistula: In RCC trials, GI perforation or fistula was reported in 0.9% (5/586) of patients receiving VOTRIENT. Fatal

perforation events occurred in 0.3% (2/586) of these patients. Use with caution in patients at risk for these events, and monitor for signs and symptoms. Interstitial Lung Disease (ILD)/Pneumonitis: ILD/pneumonitis, which can be fatal, has been reported in 0.1% of patients in the clinical trials treated with VOTRIENT. Monitor patients for ILD/pneumonitis and discontinue VOTRIENT if symptoms of ILD or pneumonitis develop. Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS has been reported and may be fatal. Permanently discontinue VOTRIENT in patients developing RPLS. Hypertension (HTN): HTN, including hypertensive crisis, has occurred in clinical trials. HTN occurs early in the course of treatment (approximately 40% of cases occurred by Day 9,

Please see additional Important Safety Information on next page. Please see Brief Summary of Prescribing Information, including Boxed WARNING, on adjacent pages.

Eric Lehmann

Fonts: Frutiger, Nexa Images: T9GPA035_pazopanib_200mg_capsule.ai (Users:elehmann:Desktop:VORCC17...9GPA035_ pazopanib_200mg_capsule.ai), VOT_dose_4C.eps (Users:elehmann:Desktop:VORCC17...01_A_Size_ DR:Links:VOT_dose_4C.eps)

11-23-2015 11:01 AM Print Scale: None Ink Density: 300% Bleed: 8.625" x 11.25" Trim: 7.75" x 10.5" Safety: 7" x 10" Folded Size: None Gutter: None Scale: 1" = 1"

Colors: Cyan Magenta Yellow Black

B:11.25”

Grade 3/4 (%)

ONCE-DAILY ORAL DOSING1

S:10”

NCCN

Pazopanib (VOTRIENT ) has a Category 1 recommendation as a first-line therapy in the NCCN Clinical Practice Guidelines In Oncology (NCCN® Guidelines) for relapsed or stage IV unresectable RCC of predominant clear cell histology. NCCN Guidelines® also include other therapies as first-line treatment options. Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.3 ®

A LOW INCIDENCE OF GRADE 3/4 ADVERSE REACTIONS WITH VOTRIENT1,4:

T:10.5”

• Serious adverse reactions included hepatotoxicity, QT prolongation and torsades de pointes, cardiac dysfunction, hemorrhagic events, arterial and venous thromboembolic events, thrombotic microangiopathy, gastrointestinal perforation and fistula, interstitial lung disease/pneumonitis, reversible posterior leukoencephalopathy syndrome, hypertension, impaired wound healing, hypothyroidism, proteinuria, infection, increased toxicity with other cancer therapies, increased toxicity in developing organs, and fetal harm • Adverse reactions occurring in ≥10% of patients who received VOTRIENT were diarrhea, hypertension, hair color changes, nausea, anorexia, vomiting, fatigue, asthenia, abdominal pain, and headache

• A median PFS of 7.4 months vs 4.2 months with placebo in cytokine-pretreated patients (HR=0.54 [95% CI, 0.35-0.84], P<0.001)1,2

ST-LINE CATEGORY 1

• Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended

B:16.375” T:15.5” S:14.75”

CHOOSE MORE THAN 6 YEARS

FIRST-LINE EFFICACY

SAFETY AND DOSING SAFETY AND TOLERABILITY PROFILE

SIGNIFICANT IMPROVEMENTS IN PFS

1,2

OVERALL (N=435)

FIRST LINE (n=233)

11.1vs 9.2 vs MONTHS MONTHS 4.2 Placebo 2.8 Placebo MONTHS VOTRIENT

HR=0.46 (95% CI, 0.34-0.62) P<0.0011

MONTHS VOTRIENT

HR=0.40 (95% CI, 0.27-0.60) P<0.0011,2

NATIONAL COMPREHENSIVE CANCER NETWORK® (NCCN®) CATEGORY 1 RECOMMENDATION

All Grades (%)

Fatigue

Asthenia

Hand-foot syndrome

Stomatitis

Mucositis

4 x 200 mg

• Available in 200-mg tablets • Recommended starting dose is 800 mg • Must be taken without food at least 1 hour before or 2 hours after a meal

Not actual size.

• Initial dose reduction should be 400 mg, and additional dose decrease or increase should be in 200-mg steps based on individual tolerability

VOTRIENT is indicated for the treatment of patients with advanced renal cell carcinoma.

For additional information on dosing modiﬁcation based on drug interactions, please see next page.

Important Safety Information for VOTRIENT® (pazopanib) tablets (cont)

VORCC17104-01_A_Size_DR.indd Client: Novartis / Voitrent Job Description: Voitrent Ad A Size Job #: VORCC17104-01 Stage: DISK RELEASE Round: 1

Please see additional Important Safety Information on next page. Please see Brief Summary of Prescribing Information, including Boxed WARNING, on adjacent pages.

Eric Lehmann

11-23-2015 11:01 AM Print Scale: None Ink Density: 300% Bleed: 8.625" x 11.25" Trim: 7.75" x 10.5" Safety: 7" x 10" Folded Size: None Gutter: None Scale: 1" = 1"

Colors: Cyan Magenta Yellow Black

B:11.25”

Grade 3/4 (%)

ONCE-DAILY ORAL DOSING1

S:10”

NCCN

A LOW INCIDENCE OF GRADE 3/4 ADVERSE REACTIONS WITH VOTRIENT1,4:

T:10.5”

• A median PFS of 7.4 months vs 4.2 months with placebo in cytokine-pretreated patients (HR=0.54 [95% CI, 0.35-0.84], P<0.001)1,2

ST-LINE CATEGORY 1

• Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended

B:8.625” T:7.75” S:7”

Important Safety Information for VOTRIENT® (pazopanib) tablets (cont) and 90% of cases occurred in the first 18 weeks). BP should be well controlled prior to initiating VOTRIENT® (pazopanib) tablets, monitored early after starting treatment (no longer than 1 week), and frequently thereafter. Treat increased BP promptly with standard antihypertensive therapy and dose reduction or interruption of VOTRIENT, as clinically warranted. Discontinue VOTRIENT if there is evidence of hypertensive crisis or if HTN is severe and persistent despite antihypertensive therapy and dose reduction of VOTRIENT. Approximately 1% of patients required permanent discontinuation of VOTRIENT because of HTN. Wound Healing: VOTRIENT may impair wound healing. Interruption of therapy is recommended in patients undergoing surgical procedures; treatment with VOTRIENT should be stopped at least 7 days prior to scheduled surgery. VOTRIENT should be discontinued in patients with wound dehiscence. Hypothyroidism: Hypothyroidism was reported in 7% (19/290) of patients treated with VOTRIENT in the randomized RCC trial and in no patients receiving placebo. Monitoring of thyroid function tests is recommended.

L ipase Elevations: In a single-arm RCC trial, increases in lipase values were observed for 27% (48/181) of patients. In the RCC trials of VOTRIENT, clinical pancreatitis was observed in <1% (4/586) of patients. neumothorax: Two of 290 patients treated P with VOTRIENT and no patients on the placebo arm in the randomized RCC trial developed a pneumothorax. Bradycardia: In the randomized trial of VOTRIENT for the treatment of RCC, bradycardia based on vital signs (<60 beats per minute) was observed in 19% (52/280) of patients treated with VOTRIENT and in 11% (16/144) of patients on the placebo arm. Drug Interactions: Coadministration with strong CYP3A4 inhibitors (eg, ketoconazole, ritonavir, clarithromycin) increases concentrations of pazopanib and should be avoided, but, if warranted, reduce the dose of VOTRIENT to 400 mg. Avoid grapefruit and grapefruit juice. Concomitant use of strong CYP3A4 inducers (eg, rifampin) should be avoided due to the potential to decrease concentrations of pazopanib. VOTRIENT should not be used

YP Substrates: Concomitant use of VOTRIENT C with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended. Coadministration may result in inhibition of the metabolism of these products and create the potential for serious adverse events. oncomitant use of VOTRIENT and simvastatin C increases the incidence of ALT elevations. If a patient develops ALT elevations, follow dosing guidelines for VOTRIENT, consider alternatives to VOTRIENT, or consider discontinuing simvastatin. There are insufficient data to assess the risk of concomitant administration of alternative statins and VOTRIENT. Drugs That Raise Gastric pH: Avoid concomitant use of VOTRIENT with drugs that raise gastric pH (eg, esomeprazole) due to the potential to decrease concentrations of pazopanib. Consider short-acting antacids in place of proton pump inhibitors (PPIs) and H2 receptor antagonists. Separate antacid and pazopanib dosing by several hours. Adverse Reactions in the Randomized RCC Trial: A dose interruption was required for 42% of patients on VOTRIENT. The VOTRIENT dose was reduced for 36% of patients. The most common adverse reactions (≥20%) for VOTRIENT vs placebo were diarrhea (52% vs 9%), HTN (40% vs 10%), hair color changes (depigmentation) (38% vs 3%), nausea (26% vs 9%), anorexia (22% vs 10%), and vomiting (21% vs 8%).

T:10.5”

Increased Toxicity with Other Cancer Therapy: VOTRIENT is not indicated for use in combination with other agents. Increased toxicity and mortality have been observed in clinical trials administering VOTRIENT in combination with lapatinib or with pemetrexed. The fatal toxicities observed included pulmonary hemorrhage, GI hemorrhage, and sudden death. A safe and effective combination dose has not been established with these regimens.

Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity. Patients should be advised how to manage mild diarrhea and to notify their health care provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact.

Concomitant treatment with strong inhibitors of P-glycoprotein (PgP) or breast cancer resistance protein (BCRP) should be avoided due to risk of increased exposure to pazopanib.

B:11.25”

Infection: Serious infections (with or without neutropenia), some with fatal outcomes, have been reported. Monitor for signs and symptoms, and treat active infection promptly. Consider interruption or discontinuation of VOTRIENT.

Pregnancy Category D: VOTRIENT can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant while taking VOTRIENT.

in patients who cannot avoid chronic use of CYP3A4 inducers.

S:10”

Proteinuria: In the randomized RCC trial, proteinuria was reported as an adverse reaction in 9% (27/290) of patients receiving VOTRIENT, leading to discontinuation of treatment in 2 patients. There were no reports of proteinuria in patients receiving placebo. Monitor urine protein at baseline and periodically as clinically indicated. Interrupt treatment for 24-hour urine protein ≥3 grams, and discontinue for repeat episodes despite dose reductions.

Increased Toxicity in Developing Organs: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. VOTRIENT is not indicated for use in pediatric patients. Animal studies have demonstrated pazopanib can severely affect organ growth and maturation during early postnatal development, and resulted in toxicity to the lungs, liver, heart, and kidney, and in death. VOTRIENT may potentially cause serious adverse effects on organ development in pediatric patients, particularly in patients younger than 2 years of age.

Laboratory abnormalities occurring in >10% of patients and more commonly (≥5%) in patients taking VOTRIENT vs placebo included increases in ALT (53% vs 22%), AST (53% vs 19%), glucose (41% vs 33%), and total bilirubin (36% vs 10%); decreases in phosphorus (34% vs 11%), sodium (31% vs 24%), magnesium (26% vs 14%), and glucose (17% vs 3%); and leukopenia (37% vs 6%), neutropenia (34% vs 6%), thrombocytopenia (32% vs 5%), and lymphocytopenia (31% vs 24%).

Please see Brief Summary of Prescribing Information, including Boxed WARNING, on adjacent pages. References: 1. VOTRIENT® (pazopanib) Tablets [package insert]. Research Triangle Park, NC: GSK; 2015. 2. Sternberg CN, Davis ID, Mardiak J, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol. 2010;28(6):1061-1068. 3. Referenced with permission from the NCCN Clinical Practice Guidelines In Oncology (NCCN Guidelines®) for Kidney Cancer V.1.2016. © National Comprehensive Cancer Network, Inc 2015. All rights reserved. Accessed October 23, 2015. To view the most recent and complete version of the guideline, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 4. Data on file. Novartis; 2011.

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080

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BRIEF SUMMARY VOTRIENT® (pazopanib) tablets The following is a brief summary only; see full prescribing information for complete product information. WARNING: HEPATOTOXICITY Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended [See Warnings and Precautions (5.1)]. 1 INDICATIONS AND USAGE VOTRIENT is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).

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5 WARNINGS AND PRECAUTIONS 5.1 Hepatic Toxicity and Hepatic Impairment: In clinical trials with VOTRIENT, hepatotoxicity, manifested as increases in serum transaminases (ALT, AST) and bilirubin, was observed. This hepatotoxicity can be severe and fatal. Patients older than 65 years are at greater risk for hepatotoxicity [see Use in Specific Populations (8.5)]. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks) [see Dosage and Administration (2.2)]. In the randomized RCC trial, ALT >3 X ULN was reported in 18% and 3% of the groups receiving VOTRIENT and placebo, respectively. ALT >10 X ULN was reported in 4% of patients who received VOTRIENT and in <1% of patients who received placebo. Concurrent elevation in ALT >3 X ULN and bilirubin >2 X ULN in the absence of significant alkaline phosphatase >3 X ULN occurred in 2% (5/290) of patients on VOTRIENT and 1% (2/145) on placebo. Two-tenths percent of the patients (2/977) from trials that supported the RCC indication died with disease progression and hepatic failure. Monitor serum liver tests before initiation of treatment with VOTRIENT and at Weeks 3, 5, 7, and 9. Thereafter, monitor at Month 3 and at Month 4, and as clinically indicated. Periodic monitoring should then continue after Month 4. Patients with isolated ALT elevations between 3 X ULN and 8 X ULN may be continued on VOTRIENT with weekly monitoring of liver function until ALT return to Grade 1 or baseline. Patients with isolated ALT elevations of >8 X ULN should have VOTRIENT interrupted until they return to Grade 1 or baseline. If the potential benefit for reinitiating treatment with VOTRIENT is

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2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosing: The recommended starting dose of VOTRIENT is 800 mg orally once daily without food (at least 1 hour before or 2 hours after a meal) [see Clinical Pharmacology (12.3) of full prescribing information]. The dose of VOTRIENT should not exceed 800 mg. Do not crush tablets due to the potential for increased rate of absorption which may affect systemic exposure [see Clinical Pharmacology (12.3) of full prescribing information]. If a dose is missed, it should not be taken if it is less than 12 hours until the next dose. 2.2 Dose Modification Guidelines: In RCC, the initial dose reduction should be 400 mg, and additional dose decrease or increase should be in 200-mg steps based on individual tolerability. Hepatic Impairment: No dose adjustment is required in patients with mild hepatic impairment. In patients with moderate hepatic impairment, alternatives to VOTRIENT should be considered. If VOTRIENT is used in patients with moderate hepatic impairment, the dose should be reduced to 200 mg per day. VOTRIENT is not recommended in patients with severe hepatic impairment [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) of full prescribing information]. Concomitant Strong CYP3A4 Inhibitors: The concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir, clarithromycin) increases pazopanib concentrations and should be avoided. Consider an alternate concomitant medication with no or minimal potential to inhibit CYP3A4. If coadministration of a strong CYP3A4 inhibitor is warranted, reduce the dose of VOTRIENT to 400 mg. Further dose reductions may be needed if adverse effects occur during therapy [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) of full prescribing information]. Concomitant Strong CYP3A4 Inducer: The concomitant use of strong CYP3A4 inducers (e.g., rifampin) may decrease pazopanib concentrations and should be avoided. Consider an alternate concomitant medication with no or minimal enzyme induction potential. VOTRIENT should not be used in patients who cannot avoid chronic use of strong CYP3A4 inducers [see Drug Interactions (7.1)].

considered to outweigh the risk for hepatotoxicity, then reintroduce VOTRIENT at a reduced dose of no more than 400 mg once daily and measure serum liver tests weekly for 8 weeks [see Dosage and Administration (2.2)]. Following reintroduction of VOTRIENT, if ALT elevations >3 X ULN recur, then VOTRIENT should be permanently discontinued. If ALT elevations >3 X ULN occur concurrently with bilirubin elevations >2 X ULN, VOTRIENT should be permanently discontinued. Patients should be monitored until resolution. VOTRIENT is a uridine diphosphate (UDP)-glucuronosyl transferase 1A1 (UGT1A1) inhibitor. Mild, indirect (unconjugated) hyperbilirubinemia may occur in patients with Gilbert’s syndrome [see Clinical Pharmacology (12.5) of full prescribing information]. Patients with only a mild indirect hyperbilirubinemia, known Gilbert’s syndrome, and elevation in ALT >3 X ULN should be managed as per the recommendations outlined for isolated ALT elevations. Concomitant use of VOTRIENT and simvastatin increases the risk of ALT elevations and should be undertaken with caution and close monitoring [see Drug Interactions (7.4)]. Insufficient data are available to assess the risk of concomitant administration of alternative statins and VOTRIENT. In patients with pre-existing moderate hepatic impairment, the starting dose of VOTRIENT should be reduced or alternatives to VOTRIENT should be considered. Treatment with VOTRIENT is not recommended in patients with pre-existing severe hepatic impairment, defined as total bilirubin >3 X ULN with any level of ALT [see Dosage and Administration (2.2), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3) of full prescribing information]. 5.2 QT Prolongation and Torsades de Pointes: In the RCC trials of VOTRIENT, QT prolongation (≥500 msec) was identified on routine electrocardiogram monitoring in 2% (11/558) of patients. Torsades de pointes occurred in <1% (2/977) of patients who received VOTRIENT in the monotherapy trials. In the randomized RCC trial, 1% (3/290) of patients who received VOTRIENT had post-baseline values between 500 to 549 msec. None of the 145 patients who received placebo on the trial had postbaseline QTc values ≥500 msec. VOTRIENT should be used with caution in patients with a history of QT interval prolongation, in patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant pre-existing cardiac disease. When using VOTRIENT, baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes (e.g., calcium, magnesium, potassium) within the normal range should be performed. 5.3 Cardiac Dysfunction: In clinical trials with VOTRIENT, events of cardiac dysfunction such as decreased left ventricular ejection fraction (LVEF) and congestive heart failure have occurred. In the overall safety population for RCC (N=586), cardiac dysfunction was observed in 0.6% (4/586) of patients without routine on-study LVEF monitoring. In a randomized RCC trial of VOTRIENT compared with sunitinib, myocardial dysfunction was defined as symptoms of cardiac dysfunction or ≥15% absolute decline in LVEF compared with baseline or a decline in LVEF of ≥10% compared with baseline that is also below the lower limit of normal. In patients who had baseline and follow up LVEF measurements, myocardial dysfunction occurred in 13% (47/362) of patients on VOTRIENT compared with 11% (42/369) of patients on sunitinib. Congestive heart failure occurred in 0.5% of patients on each arm. Blood pressure should be monitored and managed promptly using a combination of anti-hypertensive therapy and dose modification of VOTRIENT (interruption and re-initiation at a reduced dose based on clinical judgment) [see Warnings and Precautions (5.11)]. Patients should be carefully monitored for clinical signs or symptoms of congestive heart failure. Baseline and periodic evaluation of LVEF is recommended in patients at risk of cardiac dysfunction including previous anthracycline exposure. 5.4 Hemorrhagic Events: Fatal hemorrhage occurred in 0.9% (5/586) in the RCC trials. In the randomized RCC trial, 13% (37/290) of patients treated with VOTRIENT and 5% (7/145) of patients on placebo experienced at least 1 hemorrhagic event. The most common hemorrhagic events in the patients treated with VOTRIENT were hematuria (4%), epistaxis (2%), hemoptysis (2%), and rectal hemorrhage (1%). Nine of 37 patients treated with VOTRIENT who had hemorrhagic events experienced serious events including pulmonary, gastrointestinal, and genitourinary hemorrhage. One percent (4/290) of patients treated with VOTRIENT died from hemorrhage compared with no (0/145) patients on placebo. In the overall safety population in RCC (N=586), cerebral/intracranial hemorrhage was observed in <1% (2/586) of patients treated with VOTRIENT. VOTRIENT has not been studied in patients who have a history of hemoptysis, cerebral hemorrhage, or clinically significant gastrointestinal hemorrhage in the past 6 months and should not be used

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6 ADVERSE REACTIONS 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 practice. Potentially serious adverse reactions with VOTRIENT included hepatotoxicity, QT prolongation and torsades de pointes, cardiac dysfunction, hemorrhagic events, arterial and venous thromboembolic events, thrombotic microangiopathy, gastrointestinal perforation and fistula, Interstitial Lung Disease (ILD)/Pneumonitis, Reversible Posterior Leukoencephalopathy Syndrome (RPLS), hypertension, infection, and increased toxicity with other cancer therapies [see Warnings and Precautions (5.1-5.11, 5.15-5.16)]. Renal Cell Carcinoma: The safety of VOTRIENT has been evaluated in 977 patients in the monotherapy trials which included 586 patients with RCC at the time of NDA submission. With a median duration of treatment of 7.4 months (range 0.1 to 27.6), the most commonly observed adverse reactions (≥20%) in the 586 patients were diarrhea, hypertension, hair color change, nausea, fatigue, anorexia, and vomiting. The data described below reflect the safety profile of VOTRIENT in 290 RCC patients who participated in a randomized, doubleblind, placebo-controlled trial [see Clinical Studies (14.1) of full prescribing information]. The median duration of treatment was 7.4 months (range 0 to 23) for patients who received VOTRIENT and 3.8 months (range 0 to 22) for the placebo arm. Forty-two percent of patients on VOTRIENT required a dose interruption. Thirty-six percent of patients on VOTRIENT were dose reduced. Table 1 presents the most common adverse reactions occurring in ≥10% of patients who received VOTRIENT.

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was reported as an adverse reaction in 4% (26/586) of patients. Proactive monitoring of thyroid function tests is recommended. 5.14 Proteinuria: In the randomized RCC trial, proteinuria was reported as an adverse reaction in 9% (27/290) of patients receiving VOTRIENT and in no patients receiving placebo. In 2 patients, proteinuria led to discontinuation of treatment with VOTRIENT. Baseline and periodic urinalysis during treatment is recommended with follow up measurement of 24-hour urine protein as clinically indicated. Interrupt VOTRIENT and dose reduce for 24-hour urine protein ≥3 grams; discontinue VOTRIENT for repeat episodes despite dose reductions [see Dosage and Administration (2.2)]. 5.15 Infection: Serious infections (with or without neutropenia), including some with fatal outcome, have been reported. Monitor patients for signs and symptoms of infection. Institute appropriate anti-infective therapy promptly and consider interruption or discontinuation of VOTRIENT for serious infections. 5.16 Increased Toxicity with Other Cancer Therapy: VOTRIENT is not indicated for use in combination with other agents. Clinical trials of VOTRIENT in combination with pemetrexed and lapatinib were terminated early due to concerns over increased toxicity and mortality. The fatal toxicities observed included pulmonary hemorrhage, gastrointestinal hemorrhage, and sudden death. A safe and effective combination dose has not been established with these regimens. 5.17 Increased Toxicity in Developing Organs: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. VOTRIENT is not indicated for use in pediatric patients. Based on its mechanism of action, pazopanib may have severe effects on organ growth and maturation during early post-natal development. Administration of pazopanib to juvenile rats less than 21 days old resulted in toxicity to the lungs, liver, heart, and kidney and in death at doses significantly lower than the clinically recommended dose or doses tolerated in older animals. VOTRIENT may potentially cause serious adverse effects on organ development in pediatric patients, particularly in patients younger than 2 years of age [see Use in Specific Populations (8.4)]. 5.18 Pregnancy: VOTRIENT can cause fetal harm when administered to a pregnant woman. Based on its mechanism of action, VOTRIENT is expected to result in adverse reproductive effects. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. There are no adequate and well-controlled studies of VOTRIENT in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT [see Use in Specific Populations (8.1)].

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in those patients. 5.5 Arterial Thromboembolic Events: Fatal arterial thromboembolic events were observed in 0.3% (2/586) of patients in the RCC trials. In the randomized RCC trial, 2% (5/290) of patients receiving VOTRIENT experienced myocardial infarction or ischemia, 0.3% (1/290) had a cerebrovascular accident and 1% (4/290) had an event of transient ischemic attack. No arterial thromboembolic events were reported in patients who received placebo. VOTRIENT should be used with caution in patients who are at increased risk for these events or who have had a history of these events. VOTRIENT has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months and should not be used in those patients. 5.6 Venous Thromboembolic Events: In trials of VOTRIENT, venous thromboembolic events (VTE) including venous thrombosis and fatal pulmonary embolus (PE) have occurred. In the randomized RCC trial, the rate of venous thromboembolic events was 1% in both arms. There were no fatal pulmonary emboli in the RCC trial. Monitor for signs and symptoms of VTE and PE. 5.7 Thrombotic Microangiopathy: Thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) has been reported in clinical trials of VOTRIENT as monotherapy, in combination with bevacizumab, and in combination with topotecan. VOTRIENT is not indicated for use in combination with other agents. Six of the 7 TMA cases occurred within 90 days of the initiation of VOTRIENT. Improvement of TMA was observed after treatment was discontinued. Monitor for signs and symptoms of TMA. Permanently discontinue VOTRIENT in patients developing TMA. Manage as clinically indicated. 5.8 Gastrointestinal Perforation and Fistula: In the RCC trials, gastrointestinal perforation or fistula occurred in 0.9% (5/586) of patients receiving VOTRIENT. Fatal perforations occurred in 0.3% (2/586) of these patients in the RCC trials. Monitor for signs and symptoms of gastrointestinal perforation or fistula. 5.9 Interstitial Lung Disease (ILD)/Pneumonitis: ILD/pneumonitis, which can be fatal, has been reported in association with VOTRIENT. In clinical trials, ILD/pneumonitis occurred in 0.1% of patients treated with VOTRIENT. Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis and discontinue VOTRIENT in patients developing ILD or pneumonitis. 5.10 Reversible Posterior Leukoencephalopathy Syndrome: Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been reported in patients receiving VOTRIENT and may be fatal. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances. Mild to severe hypertension may be present. The diagnosis of RPLS is optimally confirmed by magnetic resonance imaging. Permanently discontinue VOTRIENT in patients developing RPLS. 5.11 Hypertension: In clinical trials, hypertension (systolic blood pressure ≥150 or diastolic blood pressure ≥100 mm Hg) and hypertensive crisis were observed in patients treated with VOTRIENT. Blood pressure should be well controlled prior to initiating VOTRIENT. Hypertension occurs early in the course of treatment (40% of cases occurred by Day 9 and 90% of cases occurred in the first 18 weeks). Blood pressure should be monitored early after starting treatment (no longer than one week) and frequently thereafter to ensure blood pressure control. Approximately 40% of patients who received VOTRIENT experienced hypertension. Grade 3 hypertension was reported in 4% to 7% of patients receiving VOTRIENT [see Adverse Reactions (6.1)]. Increased blood pressure should be treated promptly with standard anti-hypertensive therapy and dose reduction or interruption of VOTRIENT as clinically warranted. VOTRIENT should be discontinued if there is evidence of hypertensive crisis or if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction. Approximately 1% of patients required permanent discontinuation of VOTRIENT because of hypertension [see Dosage and Administration (2.2)]. 5.12 Wound Healing: No formal trials on the effect of VOTRIENT on wound healing have been conducted. Since vascular endothelial growth factor receptor (VEGFR) inhibitors such as pazopanib may impair wound healing, treatment with VOTRIENT should be stopped at least 7 days prior to scheduled surgery. The decision to resume VOTRIENT after surgery should be based on clinical judgment of adequate wound healing. VOTRIENT should be discontinued in patients with wound dehiscence. 5.13 Hypothyroidism: Hypothyroidism, confirmed based on a simultaneous rise of TSH and decline of T4, was reported in 7% (19/290) of patients treated with VOTRIENT in the randomized RCC trial. No patients on the placebo arm had hypothyroidism. In RCC trials of VOTRIENT, hypothyroidism

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Table 1. Adverse Reactions Occurring in ≥10% of Patients with RCC Who Received VOTRIENT VOTRIENT

Placebo

(N = 290)

(N = 145)

All Grade Gradesa 3 Adverse Reactions

Grade All Grade 4 Gradesa 3

Grade 4

Diarrhea

Hypertension

Hair color changes

Nausea

Anorexia

Vomiting

Fatigue

Asthenia

Abdominal pain

Headache

National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. Other adverse reactions observed more commonly in patients treated with VOTRIENT than placebo and that occurred in <10% (any grade) were alopecia (8% versus <1%), chest pain (5% versus 1%), dysgeusia (altered taste) (8% versus <1%), dyspepsia (5% versus <1%), dysphonia (4% versus <1%), facial edema (1% versus 0%), palmarplantar erythrodysesthesia (hand-foot syndrome) (6% versus <1%), proteinuria (9% versus 0%), rash (8% versus 3%), skin depigmentation (3% versus 0%), and weight decreased (9% versus 3%).

(N = 145)

All Grade Gradesa 3 Parameters

Leukopenia

Neutropenia

Thrombocytopenia Lymphocytopenia

Grade All Grade 4 Gradesa 3

Grade 4

ALT increased

AST increased

Glucose increased

Total bilirubin increased

Hematologic

Chemistry

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(N = 145)

All Grade Gradesa 3

Grade All Grade 4 Gradesa 3

Grade 4

Parameters

Phosphorus decreased

Sodium decreased

Magnesium decreased

Glucose decreased

National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity in the clinical trials. Patients should be advised how to manage mild diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact. Lipase Elevations: In a singlearm RCC trial, increases in lipase values were observed for 27% (48/181) of patients. Elevations in lipase as an adverse reaction were reported for 4% (10/225) of patients and were Grade 3 for 6 patients and Grade 4 for 1 patient. In the RCC trials of VOTRIENT, clinical pancreatitis was observed in <1% (4/586) of patients. Pneumothorax: Two of 290 patients treated with VOTRIENT and no patient on the placebo arm in the randomized RCC trial developed a pneumothorax. Bradycardia: In the randomized trial of VOTRIENT for the treatment of RCC, bradycardia based on vital signs (<60 beats per minute) was observed in 19% (52/280) of patients treated with VOTRIENT and in 11% (16/144) of patients on the placebo arm. Bradycardia was reported as an adverse reaction in 2% (7/290) of patients treated with VOTRIENT compared to <1% (1/145) of patients treated with placebo. 6.2 Postmarketing Experience: The following adverse reactions have been identified during post-approval use of VOTRIENT. Because these reactions are reported voluntarily from a population of uncertain size it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure. Eye Disorders: Retinal detachment/tear. Gastrointestinal Disorders: Pancreatitis

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Placebo

(N = 290)

Placebo

(N = 290)

7 DRUG INTERACTIONS 7.1 Drugs that Inhibit or Induce Cytochrome P450 3A4 Enzymes: In vitro studies suggested that the oxidative metabolism of pazopanib in human liver microsomes is mediated primarily by CYP3A4, with minor contributions from CYP1A2 and CYP2C8. Therefore, inhibitors and inducers of CYP3A4 may alter the metabolism of pazopanib. CYP3A4 Inhibitors: Coadministration of pazopanib with strong inhibitors of CYP3A4 (e.g., ketoconazole, ritonavir, clarithromycin) increases pazopanib concentrations and should be avoided. Consider an alternate concomitant medication with no or minimal potential to inhibit CYP3A4 [see Clinical Pharmacology (12.3) of full prescribing information]. If coadministration of a strong CYP3A4 inhibitor is warranted, reduce the dose of VOTRIENT to 400 mg [see Dosage and Administration (2.2)]. Grapefruit or grapefruit juice should be avoided as it inhibits CYP3A4 activity and may also increase plasma concentrations of pazopanib. CYP3A4 Inducers: CYP3A4 inducers such as rifampin may decrease plasma pazopanib concentrations. Consider an alternate concomitant medication with no or minimal enzyme induction potential. VOTRIENT should not be used if chronic use of strong CYP3A4 inducers cannot be avoided [see Dosage and Administration (2.2)]. 7.2 Drugs that Inhibit Transporters: In vitro studies suggested that pazopanib is a substrate of P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP). Therefore, absorption and subsequent elimination of pazopanib may be influenced by products that affect Pgp and BCRP. Concomitant treatment with strong inhibitors of Pgp or BCRP should be avoided due to risk of increased exposure to pazopanib. Selection of alternative concomitant medicinal products

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Table 2. Selected Laboratory Abnormalities Occurring in >10% of Patients with RCC Who Received VOTRIENT and More Commonly (≥5%) in Patients Who Received VOTRIENT Versus Placebo

VOTRIENT

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Additional adverse reactions from other clinical trials in RCC patients treated with VOTRIENT are listed below: Musculoskeletal and Connective Tissue Disorders: Arthralgia, muscle spasms. Table 2 presents the most common laboratory abnormalities occurring in >10% of patients who received VOTRIENT and more commonly (≥5%) in patients who received VOTRIENT versus placebo.

VOTRIENT

Table 2. Selected Laboratory Abnormalities Occurring in >10% of Patients with RCC Who Received VOTRIENT and More Commonly (≥5%) in Patients Who Received VOTRIENT Versus Placebo

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with no or minimal potential to inhibit Pgp or BCRP should be considered. 7.3 Effects of Pazopanib on CYP Substrates: Results from drug-drug interaction trials conducted in cancer patients suggest that pazopanib is a weak inhibitor of CYP3A4, CYP2C8, and CYP2D6 in vivo, but had no effect on CYP1A2, CYP2C9, or CYP2C19 [see Clinical Pharmacology (12.3) of full prescribing information]. Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended. Coadministration may result in inhibition of the metabolism of these products and create the potential for serious adverse events [see Clinical Pharmacology (12.3) of full prescribing information]. 7.4 Effect of Concomitant Use of VOTRIENT and Simvastatin: Concomitant use of VOTRIENT and simvastatin increases the incidence of ALT elevations. Across monotherapy studies with VOTRIENT, ALT >3 X ULN was reported in 126/895 (14%) of patients who did not use statins, compared with 11/41 (27%) of patients who had concomitant use of simvastatin. If a patient receiving concomitant simvastatin develops ALT elevations, follow dosing guidelines for VOTRIENT or consider alternatives to VOTRIENT [see Warnings and Precautions (5.1)]. Alternatively, consider discontinuing simvastatin [see Warnings and Precautions (5.1)]. Insufficient data are available to assess the risk of concomitant administration of alternative statins and VOTRIENT. 7.5 Drugs that Raise Gastric pH: In a drug interaction trial in patients with solid tumors, concomitant administration of pazopanib with esomeprazole, a proton pump inhibitor (PPI), decreased the exposure of pazopanib by approximately 40% (AUC and Cmax). Therefore, concomitant use of VOTRIENT with drugs that raise gastric pH should be avoided. If such drugs are needed, short-acting antacids should be considered in place of PPIs and H2 receptor antagonists. Separate antacid and pazopanib dosing by several hours to avoid a reduction in pazopanib exposure [see Clinical Pharmacology (12.3) of full prescribing information].

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10 OVERDOSAGE Pazopanib doses up to 2,000 mg have been evaluated in clinical trials. Dose-limiting toxicity (Grade 3 fatigue) and Grade 3 hypertension were each observed in 1 of 3 patients dosed at 2,000 mg daily and

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8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy: Pregnancy Category D [see Warnings and Precautions (5.18)]. VOTRIENT can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of VOTRIENT in pregnant women. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. Administration of pazopanib to pregnant rats during organogenesis at a dose level of ≥3 mg/kg/day (approximately 0.1 times the human clinical exposure based on AUC) resulted in teratogenic effects including cardiovascular malformations (retroesophageal subclavian artery, missing innominate artery, changes in the aortic arch) and incomplete or absent ossification. In addition, there was reduced fetal body weight, and pre- and post-implantation embryolethality in rats administered pazopanib at doses ≥3 mg/kg/day. In rabbits, maternal toxicity (reduced food consumption, increased post-implantation loss, and abortion) was observed at doses ≥30 mg/kg/day (approximately 0.007 times the human clinical exposure). In addition, severe maternal body weight loss and 100% litter loss were observed at doses ≥100 mg/kg/day (0.02 times the human clinical exposure), while fetal weight was reduced at doses ≥3 mg/kg/day (AUC not calculated). If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT. 8.3 Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VOTRIENT, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. In rats, weaning occurs at Day 21 postpartum which approximately equates to a human pediatric age of 2 years. In a juvenile animal toxicology study performed in rats, when animals were dosed from Day 9 through Day 14 postpartum (pre-weaning), pazopanib caused abnormal organ growth/maturation in the kidney, lung, liver and heart at approximately 0.1 times the clinical exposure, based on AUC in adult patients receiving VOTRIENT. At approximately 0.4 times the clinical exposure (based on the AUC in adult patients), pazopanib administration resulted in mortality. In repeat-dose toxicology studies in rats including 4-week, 13-week, and 26-week administration, toxicities in bone, teeth, and nail beds were observed at doses ≥3 mg/kg/day (approximately 0.07 times the human clinical exposure

based on AUC). Doses of 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC) were not tolerated in 13- and 26-week studies and animals required dose reductions due to body weight loss and morbidity. Hypertrophy of epiphyseal growth plates, nail abnormalities (including broken, overgrown, or absent nails) and tooth abnormalities in growing incisor teeth (including excessively long, brittle, broken and missing teeth, and dentine and enamel degeneration and thinning) were observed in rats at doses ≥30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC) at 26 weeks, with the onset of tooth and nail bed alterations noted clinically after 4 to 6 weeks. Similar findings were noted in repeat-dose studies in juvenile rats dosed with pazopanib beginning Day 21 postpartum (post-weaning). In the postweaning animals, the occurrence of changes in teeth and bones occurred earlier and with greater severity than in older animals. There was evidence of tooth degeneration and decreased bone growth at doses ≥30 mg/kg (approximately 0.1 to 0.2 times the AUC in human adults at the clinically recommended dose). Pazopanib exposure in juvenile rats was lower than that seen at the same dose levels in adult animals, based on comparative AUC values. At pazopanib doses approximately 0.5 to 0.7 times the exposure in adult patients at the clinically recommended dose, decreased bone growth in juvenile rats persisted even after the end of the dosing period. Finally, despite lower pazopanib exposures than those reported in adult animals or adult humans, juvenile animals administered 300 mg/kg/dose pazopanib required dose reduction within 4 weeks of dosing initiation due to significant toxicity, although adult animals could tolerate this same dose for at least 3 times as long [see Warnings and Precautions (5.17)]. 8.5 Geriatric Use: In pooled clinical trials with VOTRIENT, 30% (618/2080) of patients were aged >65 years. Patients aged >65 years had an increase in ALT elevations of >3 X ULN compared to patients aged <65 years (23% versus 18%) [see Warnings and Precautions (5.1)]. In clinical trials with VOTRIENT for the treatment of RCC, 33% (196/582) of patients were aged ≥65 years. No overall differences in safety or effectiveness of VOTRIENT were observed between these patients and younger patients. However, patients >60 years of age may be at greater risk for an ALT >3 X ULN. Other reported clinical experience has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Hepatic Impairment: In clinical studies for VOTRIENT, patients with total bilirubin ≤1.5 X ULN and AST and ALT ≤2 X ULN were included [see Warnings and Precautions (5.1)]. An analysis of data from a pharmacokinetic study of pazopanib in patients with varying degrees of hepatic dysfunction suggested that no dose adjustment is required in patients with mild hepatic impairment [either total bilirubin within normal limit (WNL) with ALT > ULN or bilirubin >1 X to 1.5 X ULN regardless of the ALT value]. The maximum tolerated dose in patients with moderate hepatic impairment (total bilirubin >1.5 X to 3 X ULN regardless of the ALT value) was 200 mg per day (N=11). The median steady-state Cmax and AUC(0-24) achieved at this dose was approximately 40% and 29%, respectively, of that seen in patients with normal hepatic function at the recommended daily dose of 800 mg. The maximum dose explored in patients with severe hepatic impairment (total bilirubin >3 X ULN regardless of the ALT value) was 200 mg per day (N=14). This dose was not well tolerated. Median exposures achieved at this dose were approximately 18% and 15% of those seen in patients with normal liver function at the recommended daily dose of 800 mg. Therefore, VOTRIENT is not recommended in these patients [see Clinical Pharmacology (12.3) of full prescribing information]. 8.7 Renal Impairment: Patients with renal cell cancer and mild/moderate renal impairment (creatinine clearance ≥30 mL/min) were included in clinical trials for VOTRIENT. There are no clinical or pharmacokinetic data in patients with severe renal impairment or in patients undergoing peritoneal dialysis or hemodialysis. However, renal impairment is unlikely to significantly affect the pharmacokinetics of pazopanib since <4% of a radiolabeled oral dose was recovered in the urine. In a population pharmacokinetic analysis using 408 patients with various cancers, creatinine clearance (30-150 mL/min) did not influence clearance of pazopanib. Therefore, renal impairment is not expected to influence pazopanib exposure, and dose adjustment is not necessary.

B:8.625” T:7.75” S:7”

1,000 mg daily, respectively. Treatment of overdose with VOTRIENT should consist of general supportive measures. There is no specific antidote for overdosage of VOTRIENT. Hemodialysis is not expected to enhance the elimination of VOTRIENT because pazopanib is not significantly renally excreted and is highly bound to plasma proteins.

Client: Novartis / Voitrent Job Description: Voitrent Ad A Size Job #: VORCC17104-01 Stage: DISK RELEASE Round: 1

T:10.5”

VORCC17104-01_A_Size_DR.indd

VOTRIENT is a registered trademark of the GSK group of companies.

Eric Lehmann

Fonts: None Images: 77744-10 Votrient A-size Brief Master.pdf (Users:elehmann:Desktop:VORCC17...0 Votrient A-size Brief Master.pdf)

11-23-2015 11:01 AM Print Scale: None Ink Density: 300% Bleed: 8.625" x 11.25" Trim: 7.75" x 10.5" Safety: 7" x 10" Folded Size: None Gutter: None Scale: 1" = 1"

Colors: Black

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17 PATIENT COUNSELING INFORMATION See Medication Guide. The Medication Guide is contained in a separate leaflet that accompanies the product. However, inform patients of the following: • Therapy with VOTRIENT may result in hepatobiliary laboratory abnormalities. Monitor serum liver tests (ALT, AST, and bilirubin) prior to initiation of VOTRIENT and at Weeks 3, 5, 7, and 9. Thereafter, monitor at Month 3 and at Month 4, and as clinically indicated. Inform patients that they should report signs and symptoms of liver dysfunction to their healthcare provider right away. • Prolonged QT intervals and torsades de pointes have been observed. Patients should be advised that ECG monitoring may be performed. Patients should be advised to inform their physicians of concomitant medications. • ILD has been reported in association with VOTRIENT. Patients should be advised to report pulmonary signs or symptoms indicative of ILD or pneumonitis.

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13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies with pazopanib have not been conducted. However, in a 13-week study in mice, proliferative lesions in the liver including eosinophilic foci in 2 females and a single case of adenoma in another female was observed at doses of 1,000 mg/kg/day (approximately 2.5 times the human clinical exposure based on AUC). Pazopanib did not induce mutations in the microbial mutagenesis (Ames) assay and was not clastogenic in both the in vitro cytogenetic assay using primary human lymphocytes and in the in vivo rat micronucleus assay. Pazopanib may impair fertility in humans. In female rats, reduced fertility including increased pre-implantation loss and early resorptions were noted at dosages ≥30 mg/kg/day (approximately 0.4 times the human clinical exposure based on AUC). Total litter resorption was seen at 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC). Post-implantation loss, embryolethality, and decreased fetal body weight were noted in females administered doses ≥10 mg/kg/day (approximately 0.3 times the human clinical exposure based on AUC). Decreased corpora lutea and increased cysts were noted in mice given ≥100 mg/kg/day for 13 weeks and ovarian atrophy was noted in rats given ≥300 mg/kg/day for 26 weeks (approximately 1.3 and 0.85 times the human clinical exposure based on AUC, respectively). Decreased corpora lutea was also noted in monkeys given 500 mg/kg/day for up to 34 weeks (approximately 0.4 times the human clinical exposure based on AUC). Pazopanib did not affect mating or fertility in male rats. However, there were reductions in sperm production rates and testicular sperm concentrations at doses ≥3 mg/kg/day, epididymal sperm concentrations at doses ≥30 mg/kg/day, and sperm motility at ≥100 mg/kg/day following 15 weeks of dosing. Following 15 and 26 weeks of dosing, there were decreased testicular and epididymal weights at doses of ≥30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC); atrophy and degeneration of the testes with aspermia, hypospermia and cribiform change in the epididymis was also observed at this dose in the 6-month toxicity studies in male rats.

• Cardiac dysfunction (such as CHF and LVEF decrease) has been observed in patients at risk (e.g., prior anthracycline therapy) particularly in association with development or worsening of hypertension. Patients should be advised to report hypertension or signs and symptoms of congestive heart failure. • Serious hemorrhagic events have been reported. Patients should be advised to report unusual bleeding. • Arterial thrombotic events have been reported. Patients should be advised to report signs or symptoms of an arterial thrombosis. • Reports of pneumothorax and venous thromboembolic events including pulmonary embolus have been reported. Patients should be advised to report if new onset of dyspnea, chest pain, or localized limb edema occurs. • Advise patients to inform their doctor if they have worsening of neurological function consistent with RPLS (headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances). • Hypertension and hypertensive crisis have been reported. Patients should be advised to monitor blood pressure early in the course of therapy and frequently thereafter and report increases of blood pressure or symptoms such as blurred vision, confusion, severe headache, or nausea and vomiting. • GI perforation or fistula has occurred. Advise patients to report signs and symptoms of a GI perforation or fistula. • VEGFR inhibitors such as VOTRIENT may impair wound healing. Advise patients to stop VOTRIENT at least 7 days prior to a scheduled surgery. • Hypothyroidism and proteinuria have been reported. Advise patients that thyroid function testing and urinalysis will be performed during treatment. • Serious infections including some with fatal outcomes have been reported. Advise patients to promptly report any signs or symptoms of infection. • Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant. • Gastrointestinal adverse reactions such as diarrhea, nausea, and vomiting have been reported with VOTRIENT. Patients should be advised how to manage diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs. • Patients should be advised to inform their healthcare providers of all concomitant medications, vitamins, or dietary and herbal supplements. • Patients should be advised that depigmentation of the hair or skin may occur during treatment with VOTRIENT. • Patients should be advised to take VOTRIENT without food (at least 1 hour before or 2 hours after a meal).

CANCER TREATMENT REGIMEN

GENITOURINARY CANCER Testicular 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.

Primary Chemotherapy for Germ Cell Tumors1 Note: All recommendations are Category 2A unless otherwise indicated.

REGIMEN

DOSING

Etoposide + cisplatin

Days 1–5: Etoposide 100mg/m2 IV + cisplatin 20mg/m2 IV. Repeat cycle every 3 weeks for 4 cycles.

Bleomycin + etoposide + cisplatin3

Days 1–5: Cisplatin 20mg/m2 IV + etoposide 100mg/m2 IV Days 1, 8, and 15 OR Days 2, 9, or 16: Bleomycin 30 units IV weekly. Repeat cycle every 3 weeks for 3 cycles.

Etoposide + ifosfamide + cisplatin + Day 1 (before ifosfamide): Mesna 120mg/m2 by slow IV push mesna4 Days 1–5: Etoposide 75mg/m2 IV + mesna 1,200mg/m2 continuous IV infusion + ifosfamide 1,200mg/m2 IV + cisplatin 20mg/m2. Repeat cycle every 3 weeks for 4 cycles.

Second-line Chemotherapy For Metastatic Germ Cell Tumors1 Conventional-dose Chemotherapy Regimens Vinblastine + ifosfamide + cisplatin + mesna5

Days 1–2: Vinblastine 0.11mg/kg IV push; plus Days 1–5: Mesna 400mg/m2 IV every 8 hours + ifosfamide 1,200mg/m2 IV + cisplatin 20mg/m2 IV. Repeat cycle every 3 weeks.

Paclitaxel + ifosfamide + mesna + cisplatin6

Day 1: Paclitaxel 250mg/m2 IV Days 2–5: Ifosfamide 1,500mg/m2 IV + cisplatin 25mg/m2 IV + mesna 500mg/m2 IV before ifosfamide, and then 4 and 8 hours after each dose of ifosfamide. Repeat cycle every 3 weeks.

High-dose Chemotherapy Regimens Carboplatin + etoposide7

Carboplatin 700mg/m2 IV + etoposide 750mg/m2 IV. Administer 5, 4, and 3 days before peripheral blood stem cell infusion for 2 cycles.

Paclitaxel + ifosfamide + mesna + carboplatin + etoposide8

Day 1: Paclitaxel 200mg/m2 IV over 24 hours Days 2–4: Ifosfamide 2,000mg/m2 over 4 hours with mesna protection Repeat every 14 days for 2 cycles; followed by Days 1–3: Carboplatin AUC 7-8mg • min/mL IV over 60 minutes + etoposide 400mg/m2 IV. Administer with peripheral blood stem cell support at 14- to 21-day intervals for 3 cycles.

Subsequent Chemotherapy For Metastatic Germ Cell Tumors1 Gemcitabine + oxaliplatin9–11

Days 1 and 8: Gemcitabine 1,000mg/m2 IV, plus Day 1: Oxaliplatin 130mg/m2 IV Repeat cycle every 3 weeks. OR Days 1 and 8: Gemcitabine 1,250mg/m2 IV, plus Day 1: Oxaliplatin 130mg/m2 IV. Repeat cycle every 3 weeks.

Gemcitabine + paclitaxel12,13

Days 1, 8, and 15: Gemcitabine 1,000mg/m2 IV over 30 minutes + paclitaxel 100mg/m2 IV over 1 hour. Repeat every 4 weeks for a maximum of 6 cycles.

Gemcitabine + paclitaxel + oxaliplatin14

Days 1 and 8: Gemcitabine 800mg/m2 IV + paclitaxel 80mg/m2 IV Day 1: Oxaliplatin 130mg/m2 IV. Repeat every 3 weeks for at least 2 cycles.

Etoposlde15

Etoposlde 50mg/m2 orally daily until progression or toxicity.

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CANCER TREATMENT REGIMEN

GENITOURINARY CANCER References 1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology™. Testicular Cancer. v 2.2016. Available at: http://www.nccn.org/professionals/ physician_gls/pdf/testicular.pdf. Accessed March 2, 2016. 2. Xiao H, Mazumdar M, Bajorin DF, et al. Long-term follow-up of patients with goodrisk germ cell tumors treated with etoposide and cisplatin. J Clin Oncol. 1997;15(7):2553–2558. 3. Saxman SB, Finch D, Gonin R, Einhorn LH. Long-term follow-up of a phase III study of three versus four cycles of bleomycin, etoposide, and cisplatin in favorable-prognosis germ-cell tumors: the Indiana University experience. J Clin Oncol. 1998;16(2):702–706. 4. Nichols CR, Catalano PJ, Crawford ED, et al. Randomized comparison of cisplatin and etoposide and either bleomycin or ifosfamide in treatment of advanced disseminated germ cell tumors: an Eastern Cooperative Oncology Group, Southwest Oncology Group, and Cancer and Leukemia Group B Study. J Clin Oncol. 1998;16(4):1287–1293. 5. Loehrer PJ Sr, Lauer R, Roth BJ, et al. Salvage therapy in recurrent germ cell cancer: ifosfamide and cisplatin plus either vinblastine or etoposide. Ann Intern Med. 1988;109(7):540–546. Erratum in: Ann Intern Med. 1988;109(10):846. 6. Kondagunta GV, Bacik J, Donadio A, et al. Combination of paclitaxel, ifosfamide, and cisplatin is an effective second-line therapy for patients with relapsed testicular germ cell tumors. J Clin Oncol. 2005;23(27):6549–6555. 7. Einhorn LH, Williams SD, Chamness A, et al. High-dose chemotherapy and stemcell rescue for metastatic germ-cell tumors. N Engl J Med. 2007;357(4):340–348. 8. Feldman DR, Sheinfeld J, Bajorin DF, et al. TI-CE high-dose chemotherapy for patients with previously treated germ cell tumors: results and prognostic factor anal-

9. 10.

11. 12.

13. 14.

15.

ysis. J Clin Oncol. 2010; 28(10):1706–1713. Erratum in: J Clin Oncol. 2010;28(34):5126. Pectasides D, Pectasides M, Farmakis D, et al. Gemcitabine and oxaliplatin (GEMOX) in patients with cisplatin-refractory germ cell tumors: a phase II study. Ann Oncol. 2004;15(3):493–497. Kollmannsberger C, Beyer J, Liersch R, et al. Combination chemotherapy with gemcitabine plus oxaliplatin in patients with intensively pretreated or refractory germ cell cancer: a study of the German Testicular Cancer Study Group. J Clin Oncol. 2004;22(1):108–114. De Giorgi U, Rosti G, Aieta M, et al. Phase II study of oxaliplatin and gemcitabine salvage chemotherapy in patients with cisplatin-refractory nonseminomatous germ cell tumor. Eur Urol. 2006;50(5):1032–1039. Einhorn LH, Brames MJ, Juliar B, Williams SD. Phase II study of paclitaxel plus gemcitabine salvage chemotherapy for germ cell tumors after progression following high-dose chemotherapy with tandem transplant. J Clin Oncol. 2007; 25(5):513–516. Mulherin B, Brames MJ, Einhorn L. Long-term survival with paclitaxel and gemcitabine for germ cell tumors after progression following high-dose chemotherapy with tandem transplants. J Clin Oncol. 2011;29(Suppl):Abstract 4562. Bokemeyer C, Oechsle K, Honecker F, et al. Combination chemotherapy with gemcitabine, oxaliplatin, and paclitaxel in patients with cisplatin-refractory or multiply relapsed germ-cell tumors: a study of the German Testicular Cancer Study Group. Ann Oncol. 2008;19(3):448–453. Miller JC, Einhorn LH. Phase II study of daily oral etoposide in refractory germ cell tumors. Semin Oncol. 1990;17 (1 Supp 2):36–39. (Revised 3/2016) © 2016 by Haymarket Media, Inc.

Visit CancerTherapyAdvisor.com • Browse oncology news and resources •

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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. Females of reproductive potential must use effective contraception during therapy and for 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 nonalcoholic, 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, non-GI fistula formation, arterial or venous thromboembolic events, posterior reversible encephalopathy syndrome, infusion reactions, ovarian failure. How supplied: Single-use vial—1

CABOMETYX Exelixis Kinase inhibitor. Cabozantinib 20mg, 40mg, 60mg; tabs. Indications: Treatment of advanced renal cell carcinoma (RCC) in patients who have received prior anti-angiogenic therapy.

℞

Adults: Swallow whole. 60mg daily. Do not eat at least 2 hours before or 1 hour after dose. Continue until disease progression or unacceptable toxicity. Stop treatment at least 28 days prior to scheduled surgery (including dental). Withhold for Grade 4 adverse reactions, Grade 3 or intolerable Grade 2 adverse reactions that are unmanageable. Upon improvement to Grade 1 or to baseline, reduce dose as follows: previously on 60mg daily, resume at 40mg daily; previously on 40mg daily, resume at 20mg daily; previously on 20mg daily, resume at 20mg if tolerated, otherwise discontinue. Concomitant a strong CYP3A4 inhibitor: reduce daily dose by 20mg; resume dose used prior to starting inhibitor 2–3 days after discontinuation of inhibitor. Concomitant a strong CYP3A4 inducer: increase daily dose by 20mg; resume dose used prior to starting inducer 2–3 days after discontinuation of inducer. Max daily dose: 80mg. Mild or moderate hepatic impairment: initially 40mg once daily. Children: Not studied. Warnings/Precautions: Do not substitute with cabozantinib capsules. Permanently discontinue if the following occurs: unmanageable GI perforation/fistula, severe hemorrhage, serious arterial thromboembolic events (eg, MI, cerebral infarction), hypertensive crisis or severe hypertension despite optimal medical management, nephrotic syndrome, reversible posterior leukoencephalopathy syndrome. Recent history or risk of severe hemorrhage: do not administer. Monitor for GI perforations/fistulas. Monitor BP regularly; withhold for hypertension inadequately controlled with medical management; resume at reduced dose when resolved. Withhold therapy if intolerable Grade 2 diarrhea, unmanageable Grade 3/4 diarrhea, or Grade 2/3 palmarplantar erythrodysesthesia syndrome (PPES) develops until improvement to Grade 1; resume at reduced dose. Severe hepatic impairment: not recommended. Pregnancy; can cause fetal harm. Females of reproductive potential should use effective contraception during and for 4 months after therapy completion. Nursing mothers: not recommended (during and for 4 months after therapy completion). Interactions: Avoid concomitant strong CYP3A4 inhibitors (eg, boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telithromycin, voriconazole, grapefruit or grapefruit juice) and strong CYP3A4 inducers (eg, rifampin, phenytoin, carbamazepine, phenobarbital, rifabutin, rifapentine, St. John’s Wort); if unavoidable, see Adult dose. Adverse reactions: Diarrhea, fatigue, nausea, decreased appetite, PPES, hypertension, vomiting, weight decreased, constipation, lab abnormalities. How supplied: Tabs—30

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DRUG MONOGRAPHS

GENITOURINARY CANCER 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 >2xULN 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). 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

℞

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

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DRUG MONOGRAPHS

GENITOURINARY CANCER FIRMAGON Ferring

℞

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 ≥2xULN: not recommended. Warnings/Precautions: Monitor liver function at baseline, monthly for first 4 months, then periodically, and if liver dysfunction occurs; if ALT >2xULN or jaundice occurs, discontinue and monitor closely until resolution. Monitor prostate specific antigen (PSA). Consider monitoring methemoglobin levels in patients susceptible to aniline toxicity (e.g., 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. 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 moderateto-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, grade 2 peripheral neuropathy: delay treatment and/or reduce dose to 20mg/m2 (see full labeling). Discontinue if grade ≥3 peripheral neuropathy or if any reactions persist after dosing at 20mg/m2. Hepatic impairment: (mild): reduce starting dose to 20mg/m2; (moderate): reduce to 15mg/m2. If concomitant a strong CYP3A inhibitor necessary, consider a 25% cabazitaxel dose reduction. Children: Not established. Contraindications: Baseline neutrophil count ≤1,500cells/mm3. Allergy to polysorbate 80. Severe hepatic impairment (total bilirubin >3XULN). Warnings/Precautions: Increased risk of neutropenia complications; consider G-CSF prophylaxis. Do CBC weekly in 1st cycle and before each subsequent cycle. Patients with hemoglobin <10g/dL. 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 (monitor). ESRD (CrCl <15mL/min). Elderly (increased susceptibility to adverse reactions); monitor closely. Pregnancy (Cat.D); avoid. Nursing mothers: not recommended. Interactions: Potentiated by strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin,

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DRUG MONOGRAPHS

GENITOURINARY CANCER voriconazole); avoid. Antagonized by strong CYP3A4 inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital). Increased GI toxicity with concomitant steroids, NSAIDs, antiplatelets, anticoagulants. Adverse reactions: Bone marrow suppression (esp. neutropenia, anemia, leukopenia, thrombocytopenia), diarrhea (may be fatal), fatigue, nausea, vomiting, constipation, asthenia, abdominal pain, hematuria, back pain, anorexia, peripheral neuropathy, pyrexia, dyspnea, dysgeusia, cough, arthralgia, alopecia; febrile neutropenia, 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-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. ℞ 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. ℞ 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. 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; druginduced hepatitis, QT prolongation. How supplied: Tabs—120

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: Advanced renal cell carcinoma (RCC) in patients who have received prior antiangiogenic therapy. Adults: Give as IV infusion over 60mins. 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; permanently discontinue or withhold, 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 3 (with ipilimumab) or 4 colitis, AST/ALT >5XULN or total bilirubin >3XULN, SCr >6XULN, Grade 4 hypophysitis, Grade 3 or 4 adrenal insufficiency, Grade 4 hyperglycemia, Grade 4 rash, immune-mediated encephalitis, recurring Grade 3 or 4 adverse reaction, requirement for ≥10mg/day prednisone (or equivalent) for >12 weeks, or persistent Grade 2 or 3 adverse reactions lasting ≥12 weeks. Grade 2 pneumonitis, Grade 2 or 3 (as single agent) colitis, AST/ALT >3–5XULN or total bilirubin >1.5–3XULN, SCr >1.5–6XULN, new onset moderate-to-severe neurologic symptoms, any other Grade 2 or 3 adverse reactions; withhold dose, give corticosteroids, and when resolved, consider re-initiation. Discontinue if severe or life-threatening infusion reactions occur. Monitor for abnormal liver tests, elevated serum creatinine, hyperglycemia,

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DRUG MONOGRAPHS

GENITOURINARY CANCER and thyroid function prior to and during treatment; give replacement therapy for hypothyroidism. Moderate or severe hepatic impairment: not studied. Pregnancy: avoid. Use effective contraception during therapy and for ≥5 months after final dose. Nursing mothers: not recommended. Adverse reactions: Asthenic conditions, cough, nausea, rash, dyspnea, diarrhea, constipation, decreased appetite, back pain, arthralgia; immune-mediated reactions (may be fatal). How supplied: Single-use vial (4mL, 10mL)—1

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, 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

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. 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 interferon-alfa. 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

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DRUG MONOGRAPHS

GENITOURINARY CANCER 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; preservative-free. 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). 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 >1–1.5xULN or AST > ULN but bilirubin ≤ ULN: reduce to 15mg/week; >1.5xULN: contraindicated. See Interactions. Children: Not recommended. Contraindications: Bilirubin >1.5xULN. 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

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DRUG MONOGRAPHS

GENITOURINARY CANCER 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. 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 3xULN and 8xULN continue therapy with weekly monitoring until ALT returns to Grade 1 or baseline. If ALT >8xULN 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>3xULN recurs, permanently discontinue. Permanently discontinue if ALT>3xULN and bilirubin >2xULN. 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, interstitial lung disease (ILD)/pneumonitis, 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, serious infection, ILD or pneumonitis 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,

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DRUG MONOGRAPHS

GENITOURINARY CANCER 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, ILD/pneumonitis, 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 X 109/L, platelets ≥100 X 109/L and hemoglobin ≥10g/dL. Before subsequent doses, the ANC should be ≥1 X 109/L and platelets ≥50 X 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 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

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CANCER TREATMENT REGIMEN

GYNECOLOGIC CANCER Endometrial Carcinoma 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.

Systemic Therapy for Recurrent, Metastatic, or High-risk Endometrial Carcinoma1 Note: All recommendations are Category 2A unless otherwise indicated.

REGIMEN

DOSING

Chemotherapy Regimens Carboplatin + paclitaxel2,3

Day 1: Carboplatin AUC 5–6mg•min/mL IV over 1 hour + paclitaxel 175mg/m2 IV over 3 hours. Repeat cycle every 3 weeks for 6 to 9 cycles.

Cisplatin + doxorubicin4,5a

Day 1: Doxorubicin 60mg/m2 IV followed by cisplatin 50mg/m2 over 1 hour Day 2–11 (optional): Granulocyte colony-stimulating factor 5mcg/kg/day subcutaneously. Repeat every 3 weeks for maximum of 7 cycles.

Cisplatin + doxorubicin + paclitaxel4,5b

Day 1: Doxorubicin 45mg/m2 IV + cisplatin 50mg/m2 IV Day 2: Paclitaxel 160mg/m2 IV over 3 hours Days 3–12: Filgrastim 5mcg/kg SQ (or pegfilgrastim 6mg on day 3 only). Repeat every 3 weeks for 6–7 cycles.

Carboplatin + docetaxel6–8c

Day 1: Docetaxel 60–75mg/m2 IV over 1 hour; followed by carboplatin AUC 6mg•min/mL IV over 1 hour. Repeat every 3 weeks for 6 cycles.

Ifosfamide + paclitaxel (Category 1 for carcinosarcoma)9

Day 1: Paclitaxel 135mg/m2 IV over 3 hours Days 1–3: Ifosfamide 1.6g/m2/day IV (reduced to 1.2g/m2/day if patient received prior radiation). Repeat cycle every 3 weeks for 8 cycles.

Cisplatin + ifosfamide (for carcinosarcoma)10

Days 1–4: Cisplatin 20mg/m2/day IV over 15 minutes + ifosfamide 1.5g/m2/day IV over 1 hour Day 1: Mesna 120mg/m2 IV bolus over 15 minutes (loading dose) Days 1–4: Mesna 1.5g/m2/day continuous IV infusion. Repeat cycle every 3 weeks for 3 cycles.

Cisplatin11

Day 1: Cisplatin 50mg/m2 IV. Repeat cycle every 3 weeks.

Carboplatin12

Day 1: Carboplatin 400mg/m2 IV. Repeat cycle every 3 weeks

Doxorubicin13

Day 1: Doxorubicin 60mg/m2 IV. Repeat cycle every 4 weeks.

Liposomal doxorubicin14

Day 1: Liposomal doxorubicin 50mg/m2 IV over 1 hour. Repeat cycle every 4 weeks.

Paclitaxel15

Day 1: Paclitaxel 110–200mg/m2 IV. Repeat cycle every 3 weeks.

Topotecan16

Days 1–5: Topotecan 1.5mg/m2/day IV (reduced to 1.2mg/m2 if patients received prior pelvic radiation). Repeat cycle every 3 weeks.

Bevacizumab17

Day 1: Bevacizumab 15mg/kg IV. Repeat cycle every 3 weeks.

Temsirolimus18

Temsirolimus 25mg IV weekly. Repeat cycle every 4 weeks.

Docetaxel (Category 2B)19

Days 1, 8, and 15: Docetaexel 36mg/m2 IV over 1 hour. Repeat cycle every 4 weeks.

Ifosfamide (for carcinosarcoma)9

Days 1–3: Ifosfamide 2g/m2/day IV + mesna 2g IV beginning 15 minutes before ifosfamide infusion. Repeat cycle every 3 weeks for 8 cycles.

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CANCER TREATMENT REGIMEN

GYNECOLOGIC CANCER Systemic Therapy for Recurrent, Metastatic, or High-risk Endometrial Carcinoma1 REGIMEN

DOSING

Hormonal Therapyd Megestrol + alternating tamoxifen20

Megestrol acetate 80mg orally twice daily for 3 weeks alternating with tamoxifen 20mg orally twice daily for 3 weeks.

Tamoxifen21

Tamoxifen 20mg orally twice daily until disease progression or unacceptable toxicity.

Progesterone agents

This regimen was included in the NCCN guidelines but no reference was provided to indicate appropriate agents or dosages, as no particular dose, drug, or schedule has been found to be superior.

Aromatase inhibitors

This regimen was included in the NCCN guidelines but no reference was provided to indicate appropriate agents or dosages, as no particular dose, drug, or schedule has been found to be superior.

General treatment notes: • Participation in clinical trial is strongly recommended. • Multi-agent chemotherapy regimens preferred over single agents, if tolerated. • Cisplatin, carboplatin, liposomal doxorubicin, paclitaxel, and docetaxel may cause drug reactions. • Chemotherapy regimens can be used for all carcinoma histologies. Carcinosarcomas are now considered and treated as high-grade carcinomas. However, ifosfamide-based regimens were previously used for carcinosarcomas. a b c d

Patients who have received prior pelvic radiotherapy or who are older than 65 years should receive a reduction in the starting dose of doxorubicin, to 45mg/m2. The cisplatin/doxorubicin/paclitaxel regimen is not widely used because of concerns about toxicity. Docetaxel may be considered for patients in whom paclitaxel is contraindicated. Hormonal therapy may be used for lower grade endometrioid histologies only (ie, not for G3 endometrioid, serous carcinoma, clear cell carcinoma, or carcinosarcoma), preferably in patients with small tumor volume or an indolent growth pace.

References 1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology™. Uterine Neoplasms. v 2.2016. Available at: http://www.nccn.org/professionals/physician_gls/pdf/uterine.pdf. Accessed March 22, 2016. 2. Miller D, Filiaci V, Fleming G, et al. Randomized phase III noninferiority trial of first line chemotherapy for metastatic or recurrent endometrial carcinoma: a Gynecologic Oncology Group study [abstract]. Gynecol Oncol. 2012:125:771. 3. Sorbe B, Andersson H, Boman K, et al. Treatment of primary advanced and recurrent endometrial carcinoma with a combination of carboplatin and paclitaxel-long-term follow-up. Int J Gynecol Cancer. 2008;18(4):803–808. 4. Fleming GF, Brunetto VL, Cella D, et al. Phase III trial of doxorubicin plus cisplatin with or without paclitaxel plus filgrastim in advanced endometrial carcinoma: a Gynecologic Oncology Group Study. J Clin Oncol. 2004;22(11):2159–2166. 5. Homesley HD, Filiaci V, Gibbons SK, et al. A randomized phase III trial in advanced endometrial carcinoma of surgery and volume directed radiation followed by cisplatin and doxorubicin with or without paclitaxel: A Gynecologic Oncology Group study. Gynecol Oncol. 2009;112(3):543–552. 6. Scribner DR Jr, Puls LE, Gold MA. A phase II evaluation of docetaxel and carboplatin followed by tumor volume directed pelvic plus or minus paraaortic irradiation for stage III endometrial cancer. Gynecol Oncol. 2012;125(2):388–393. 7. Geller MA, Ivy JJ, Ghebre R, et al. A phase II trial of carboplatin and docetaxel followed by radiotherapy given in a “Sandwich” method for stage III, IV, and recurrent endometrial cancer. Gynecol Oncol. 2011;121(1):112–117. 8. Nomura H, Aoki D, Takahashi F, et al. Randomized phase II study comparing docetaxel plus cisplatin, docetaxel plus carboplatin, and paclitaxel plus carboplatin in patients with advanced or recurrent endometrial carcinoma: a Japanese Gynecologic Oncology Group study (JGOG2041). Ann Oncol. 2011;22(3):636–642. 9. Homesley HO, Filiaci V, Markman M, et al. Phase III trial of ifosfamide with or without paclitaxel in advanced uterine carcinosarcoma: a Gynecologic Oncology Group Study. J Clin Oncol. 2007:25(5):526–531. 10. Wolfson AH, Brady MF, Rocereto TF, et al. A gynecologic oncology group randomized trial of whole abdominal irradiation (WAI) vs cisplatin-ifosfamide-mesna (CIM) in optimally debulked stage I-IV carcinosarcoma (CS) of the uterus. J Clin Oncol. 2006;24(18S):5001.

11. Thigpen JT, Blessing JA, Lagasse LD. Phase II trial of cisplatin as first-line chemotherapy in patients with advanced or recurrent endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 1989;33(1):68–70. 12. Van Wijk FH, Lhomme C, Bolis G, et al. Phase II study of carboplatin in patients with advanced or recurrent endometrial carcinoma: a trial of the EORTC Gynaecological Cancer Group. Eur J Cancer. 2003;39(1):78–85. 13. Aapro MS, van Wijk FH, Bolis G, et al. Doxorubicin versus doxorubicin and cisplatin in endometrial carcinoma: definitive results of a randomized study (55872) by the EORTC Gynaecological Cancer Group. Ann Oncol. 2003;14(3):441–448. 14. Muggia FM, Blessing JA, Sorosky J, Reid GC. Phase II trial of the pegylated liposomal doxorubicin in previously treated metastatic endometrial cancer: a Gynecologic Oncology Group study. J Clin Oncol. 2002;20(9):2360–2364. 15. Lincoln S, Blessing JA, Lee RB, Rocereto TF. Activity of paclitaxel as second-line chemotherapy in endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 2003;88(3):277–281. 16. Wadler S, Levy DE, Lincoln ST, et al. Topotecan is an active agent in the first-line treatment of metastatic or recurrent endometrial carcinoma: Eastern Cooperative Oncology Group Study E3E93. J Clin Oncol. 2003;21(11):2110–2114. 17. Aghajanian C, Sill MW, Darcy KM, et al. Phase II trial of bevacizumab in recurrent or persistent endometrial: a Gynecologic Oncology Group study. J Clin Oncol. 2011;29(16):2259–2265. 18. Oza AM, Elit L, Tsao MS, et al. Phase II study of temsirolimus in women with recurrent or metastatic endometrial cancer: a trial of the NCIC Clinical Trials Group. J Clin Oncol. 2011;29(24):3278–3285. 19. Garcia AA, Blessing JA, Nolte S, Mannel RS. A phase II evaluation of weekly docetaxel in the treatment of recurrent or persistent endometrial carcinoma: a study by the Gynecologic Oncology Group. Gynecol Oncol. 2008;111(1):22–26. 20. Fiorica JV, Brunetto VL, Hanjani P, et al. Phase II trial of alternating courses of megestrol acetate and tamoxifen in advanced endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 2004;92(1):10–14. 21. Thigpen T, Brady MF, Homesley HD, Soper JT, Bell J. Tamoxifen in the treatment of advanced or recurrent endometrial carcinoma: a Gynecologic Oncology Group study. J Clin Oncol. 2001;19(2):364–367. (Revised 4/2016) © 2016 by Haymarket Media, Inc.

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GYNECOLOGIC CANCER Uterine Sarcoma 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.

Systemic Therapy for Uterine Sarcoma1 Note: All recommendations are Category 2A unless otherwise indicated.

REGIMEN

DOSING

Combination Regimens Docetaxel + gemcitabine2ab

Days 1 and 8: Gemcitabine 900mg/m2 IV over 90 minutes followed by docetaxel 100mg/m2 IV over 60 minutes on day 8 followed by Days 9–15: Granulocyte colony-stimulating factor (G-CSF) 150μ/m2 SQ Or Pegfilgrastim 6mg SQ on day 9 OR 10. Repeat cycle every 3 weeks until disease progression or toxicity occurs.

Doxorubicin + ifosfamide3

Day 1: Doxorubicin 50mg/m2 over 15 minutes followed by ifosfamide 5g/m2 via 24-hour continuous IV admixed with mesna 6g/m2 36-hour continuous IV. Repeat cycle every 3 weeks if counts allow.

Doxorubicin + dacarbazine4

Day 1: Doxorubicin 60mg/m2 IV. Days 1–4: Dacarbazine 750mg/m2 IV via continuous infusion for 96 hours. Repeat cycle every 3 weeks.

Gemcitabine + dacarbazine5

Day 1: Gemcitabine 10mg/m2/min IV over 180 minutes followed by dacarbazine 500mg/m2 IV over 20 minutes. Repeat every 2 weeks for a total of 12 cycles.

Gemcitabine + vinorelbine6

Days 1 and 8: Vinorelbine 25mg/m2 IV over 10 minutes followed by gemcitabine 800mg/m2 IV over 90 minutes. Repeat cycle every 21 days.

Single-agent Regimens Dacarbazine5

Day 1: Dacarbazine 1200mg/m2 IV over 20 minutes. Repeat cycle every 3 weeks for total of 8 cycles.

Doxorubicin7

Day 1: Doxorubicin 75mg/m2 IV bolus. Repeat every 3 weeks.

Epirubicin8

Day 1: Epirubicin 75mg/m2 IV bolus. Repeat every 3 weeks.

Eribulin9

Days 1 and 8: Eribulin 1.4mg/m2 IV. Repeat every 21 days until disease progression or unacceptable toxicity.

Gemcitabine10

Days 1, 8, and 15: Gemcitabine 1,000mg/m2 IV over 30 minutes. Repeat every 4 weeks.

Ifosfamide11

Days 1–5: Ifosfamide 1.5gm/m2 IV daily with mesna.

Liposomal doxorubicin12

Day 1: Liposomal doxorubicin 50mg/m2. Repeat every 4 weeks.

Pazopanib13

Pazopanib 800mg orally once daily until disease progression or unacceptable toxicity.

Temozolomide12

Temozolomide 50–75mg/m2 daily for 6 of 8 weeks.

Trabectedin

Trabectedin 1.5mg/m2 via 24-hour continuous IV infusion. Repeat once every 3 weeks.

Vinorelbine (Category 2B)18

Days 1 and 8: Vinorelbine 30mg/m2. Repeat every 21 days.

Docetaxel (Category 3)19

Days 1, 8, and 15: Docetaxel 36mg/m2 IV over 1 hour. Repeat every 28 days until disease progression or unacceptable toxicity.

14-17c

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CANCER TREATMENT REGIMEN

GYNECOLOGIC CANCER Hormone Therapy1d REGIMEN

DOSING

Medroxyprogesterone acetate (Category 2B for ER/PR-positive uLMS), megestrol acetate (Category 2B for ER/PR-positive uLMS), aromatase inhibitors, gonadotropin-releasing hormone analogs (Category 2B for low-grade ESS and ER/PR-positive uLMS) Abbreviations: ER = estrogen receptor; ESS = endometrial stromal sarcoma; PR = progesterone receptor; SQ = subcutaneous; uLMS = uterine leiomyosarcoma; UUS = undifferentiated uterine sarcoma. a Preferred for uLMS. b Patients with prior pelvic irradiation received gemcitabine 675mg/m2 IV and docetaxel 75mg/m2 IV. c For uLMS that has been treated with a prior anthracycline-containing regimen. d For low-grade ESS or hormone-receptor positive (ER/PR) uLMS; preferably there is small tumor volume or an indolent growth pace.

References 1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Uterine Neoplasms V.2.2016. Available at: http://www. nccn.org/professionals/physician_gls/pdf/uterine.pdf. Accessed March 17, 2016. 2. Hensley ML, Blessing JA, Mannel R, Rose PG. Fixed-dose rate gemcitabine plus docetaxel as first-line therapy for metastatic uterine leiomyosarcoma: a Gynecologic Oncology Group phase II trial. Gynecol Oncol. 2008;109(3):329–334. 3. Sutton G, Blessing JA, Malfetano JH. Ifosfamide and doxorubicin in the treatment of advanced leiomyosarcomas of the uterus: a Gynecologic Oncology Group study. Gynecol Oncol. 1996;62(2): 226–229. 4. Zalupski M, Metch B, Balcerzak S, et al. Phase III comparison of doxorubicin and dacarbazine given by bolus versus infusion in patients with soft-tissue sarcomas: a Southwest Oncology Group study. J Natl Cancer Inst. 1991;83(13):926–932. 5. Garcia-Del-Muro X, Lopez-Pousa A, Maurel J, et al. Randomized phase II study comparing gemcitabine plus dacarbazine versus dacarbazine alone in patients with previously treated soft tissue sarcoma: a Spanish Group for Research on Sarcomas study. J Clin Oncol. 2011;29(18):2528–2533. 6. Dileo P, Morgan J, Zahrieh D, et al. Gemcitabine and vinorelbine combination chemotherapy for patients with advanced soft tissue sarcomas. Cancer. 2007;109(9):1863–1869. 7. Judson I, Radford JA, Harris M, et al. Randomized phase II trial of pegylated liposomal doxorubicin (DOXIL/CAELYX) versus doxorubicin in the treatment of advanced or metastatic soft tissue sarcoma: a study by the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer. 2001;37(7):870–877. 8. Mouridsen HT, Bastholt L, Somers R, et al. Adriamycin versus epirubicin in advanced soft tissue sarcomas. A randomized phase II/phase III study of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer Clin Oncol. 1987;23(10): 1477–1483. 9. Schöffski P, Maki RG, Italiano A, et al. Randomized, open-label, multicenter, phase III study of eribulin versus dacarbazine in patients (pts) with leiomyosarcoma (LMS) and adipocytic sarcoma (ADI). J Clin Oncol. 2015;33(18_suppl):LBA10502.

10. Look KY, Sandler A, Blessing JA, et al. Phase II trial of gemcitabine as second-line chemotherapy of uterine leiomyosarcoma: a Gynecologic Oncology Group (GOG) Study. Gynecol Oncol. 2004;92(2):644–647. 11. Sutton GP, Blessing JA, Barrett RJ, et al. Phase II trial of ifosfamide and mesna in leiomyosarcoma of the uterus: a Gynecologic Oncology Group study. Am J Obstet Gynecol. 1992;166(2):556–559. 12. Amant F, Coosemans A, Debiec-Rychter M, et al. Clinical management of uterine sarcomas. Lancet Oncol. 2009;10(12):1188–1198. 13. van der Graaf WT, Blay JY, Chawla SP, et al. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2012;379(9829):1879–1886. 14. Gajdos C, Elias A. Trabectedin: safety and efficacy in the treatment of advanced sarcoma. Clin Med Insights Oncol. 2011;5:35–43. 15. Demetri GD, Chawla SP, von Mehren M, et al. Efficacy and safety of trabectedin in patients with advanced or metastatic liposarcoma or leiomyosarcoma after failure of prior anthracyclines and ifosfamide: results of a randomized phase II study of two different schedules. J Clin Oncol. 2009;27(25):4188–4196. 16. Fayette J, Boyle H, Chabaud S, et al. Efficacy of trabectedin for advanced sarcomas in clinical trials versus compassionate use programs: analysis of 92 patients treated in a single institution. Anticancer Drugs. 2010;21(1):113–119. 17. Pautier P, Floquet A, Chevreau C, et al; French Sarcoma Group. Trabectedin in combination with doxorubicin for first-line treatment of advanced uterine or soft-tissue leiomyosarcoma (LMS-02): a non-randomised, multicentre, phase 2 trial. Lancet Oncol. 2015;16(4):457–464. 18. Muggia F, Blessing JA, Method M. Evaluation of vinorelbine in persistent or recurrent squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. Gynecol Oncol. 2004;92(2):639–643. 19. Garcia AA, Blessing JA, Nolte S, Mannel RS. A phase II evaluation of weekly docetaxel in the treatment of recurrent or persistent endometrial carcinoma: a study by the Gynecologic Oncology Group. Gynecol Oncol. 2008;111(1):22–26.

Visit OncologyNurseAdvisor.com for practical clinical information geared toward oncology nurses and other cancer care professionals.

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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. Platinum-resistant 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

℞

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

HEXALEN Eisai 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 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.

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DRUG MONOGRAPHS

GYNECOLOGIC CANCER 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

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)

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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 postinfusion. 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

℞

Antimetabolite. Hydroxyurea 500mg; caps. Indications: Adjunct with irradiation therapy in locally advanced squamous cell carcinomas of the head and neck, excluding the lip.

Adults: Base dose on ideal or actual weight, whichever is less. Individualize. Initially 15mg/kg/day. Renal impairment (CrCl <60mL/min or ESRD): initially 7.5mg/kg/day; give dose following dialysis (monitor). Dose modifications: see full labeling. Children: Not established. Warnings/Precautions: Risk of severe myelosuppression; reduce dose or discontinue if necessary. Monitor blood counts at baseline and at least once a week during therapy. Correct severe anemia before starting. Markedly depressed bone marrow function: do not initiate. Monitor for malignancies. Avoid sun exposure. Previous irradiation therapy (monitor for skin erythema) or chemotherapy. Macrocytosis may mask folic acid deficiency; prophylactic folic acid is recommended. Myeloproliferative disorders; discontinue if cutaneous vasculitic ulcerations occur. Renal or hepatic impairment. Elderly. Embryo-fetal toxicity. Pregnancy; avoid. Exclude pregnancy prior to initiating; use effective contraception during and for ≥6 months (females) or ≥1 year (males) after therapy. Nursing mothers: not recommended. Interactions: Avoid concomitant didanosine, with or without stavudine, or other antiretrovirals (may cause pancreatitis [monitor], fatal hepatotoxicity, peripheral neuropathy). Avoid live vaccines. Increased risk of vasculitic toxicities with interferon therapy. May cause falsely elevated results in urea, uric acid, and lactic acid assays. Adverse reactions: Leukopenia, thrombocytopenia, anemia, GI upset, anorexia; secondary malignancies, macrocytosis. Note: Wear disposable gloves when handling caps or bottle. How supplied: Caps—100

TREXALL Teva

℞

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.

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.

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CANCER TREATMENT REGIMEN

HEMATOLOGIC CANCER Leukemia Treatment Regimens: Chronic Myeloid Leukemia (CML) 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.

Primary Treatment1 Note: All recommendations are Category 2A unless otherwise indicated.

REGIMEN

DOSING

Ph positive or BCR-ABL positive2-9

Imatinib 400mg orally daily (Category 1). OR Nilotinib 300mg orally twice daily (Category 1). OR Dasatinib 100mg orally daily (Category 1).

3 Month Evaluation BCR-ABL1/ABL1< 10% (IS) or PCyR, if QPCR (IS) not available2-9

Continue current regimen.

If response of BCR-ABL1 transcripts > 10% (IS) or lack of PCyR on bone marrow cytogenetics, if QPCR (IS) not available9-12* • Evaluate patient compliance and drug–drug interactions, consider mutational analysis and bone marrow cytogenetics

Primary Treatment with Imatinib Change therapy to alternate TKI. OR Imatinib dose may be increased to a maximum of 800mg, if tolerated and evaluate for hematopoietic stem cell transplantation (HSCT) depending on response to tyrosine kinase inhibitor (TKI) therapy. Primary Treatment with Nilotinib or Dasatinib Continue same dose of nilotinib or dasatinib. OR Change therapy to alternate TKI (other than imatinib) and evaluate for HSCT depending on response to TKI therapy.

6 Month Evaluation1 BCR-ABL1/ABL1 ≤ 10% by QPCR (IS) or ≥ PCyR , if QPCR (IS) not available2-9

Continue current regimen.

If response of BCR-ABL1 transcripts Change therapy to alternate TKI (other than imatinib) and evaluate for HSCT depending on response to TKI therapy. > 10% (IS) or lack of PCyR on bone marrow cytogenetics, if QPCR (IS) not available13* • Evaluate patient compliance and drug–drug interactions, consider mutational analysis and bone marrow cytogenetics

12 Month Evaluation and Beyond1† Complete cytogenetic response or BCR-ABL1 transcripts ≤1% but > 0.1% by QPCR (IS)2-9,14

Continue current regimen.

PCyR or BCR-ABL1 transcripts ≤ 10% but > 1% by QPCR (IS)10*,14 • Evaluate patient compliance and drug–drug interactions, consider mutational analysis and bone marrow cytogenetics

Change therapy to alternate TKI (preferred) (other than imatinib). OR Continue same dose of TKI. OR Increase dose of imatinib to a maximum dose of 800mg, as tolerated (if not candidate for alternate TKI or omacetaxine). continued

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HEMATOLOGIC CANCER Leukemia Treatment Regimens: Chronic Myeloid Leukemia (CML) 12 Month Evaluation and Beyond1† (continued) REGIMEN

DOSING

Less than PCyR or BCR-ABL1 transcripts > 10% by QPCR (IS)10* • Evaluate patient compliance and drug–drug interactions, consider mutational analysis

Change therapy to alternate TKI (other than imatinib) and evaluate for HSCT depending on response to TKI.

Cytogenetic relapse10* • Evaluate patient compliance and drug–drug interactions, mutational analysis

Change therapy to alternate TKI (preferred) (other than imatinib). OR Increase dose of imatinib to a maximum dose of 800mg, as tolerated (if not candidate for alternate TKI or omacetaxine) and evaluate for HSCT depending on response to TKI therapy.

Advanced Phase1 Accelerated phase15-32‡

Imatinib 600mg orally daily. OR Dasatinib 140mg orally daily (70mg twice daily). OR Nilotinib 400mg orally twice daily. OR Bosutinib 500mg orally daily. OR Ponatinib 45mg orally daily. OR Omacetaxine 1.25mg/m2 SC twice daily on days 1–14 cycled every 28 days until hematologic response, followed by omacetaxine 1.25mg/m2 SC twice daily on days 1–7 cycled every 28 days until disease progression or unacceptable toxicity. AND Consider HSCT based on response.

Blast phase—lymphoid15-32

ALL-type induction chemotherapy, plus TKI followed by HSCT, if feasible. OR TKI followed by HSCT, if feasible.

Blast phase—myeloid15-32

AML-type induction chemotherapy, plus TKI followed by HSCT, if feasible. OR TKI followed by HSCT, if feasible.

* Alternate TKIs include dasatinib, nilotinib, bosutinib, and ponatinib. † Repeat bone marrow evaluation at 3 months to document CCyR, if < CCyR, treat as per < PCrR. ‡ Ponatinib is a treatment option for patients with a T315I mutation or for patients with disease that has not responded to 2 or more TKI therapies.

References 1. NCCN Clinical Practice Guidelines in Oncology™. Chronic Myelogenous Leukemia. v 1.2016. Available at: http://www. nccn.org/pro fessionals/physician_gls/pdf/cml. pdf. Accessed November 12, 2015. 2. Kantarjian HM, Shah NP, Hochhaus A, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010;28:398–404. 3. Kantarjian HM, Shah NP, Cortes JE, et al. Dasatinib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION). Blood. 2012;119:1123–1129. 4. Hochhaus A, Kim D-W, Shah NP, et al. Four-year (yr) follow-up of p atients (pts) with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) receiving dasatinib or imatinib: efficacy based on early response [abstract]. Blood. 2013;122:Abstract 653. 5. Larson RA, Hochhaus A, Hughes TP, et al. Nilotinib vs imatinib in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: ENESTnd 3-year follow-up. Leukemia. 2012;26:2197–2203.

6. Hughes TP, Saglio G, Kantarjian HM, et al. Early molecular response predicts outcomes in patients with chronic myeloid leukemia in chronic phase treated with frontline nilotinib or imatinib. Blood. 2014;123:1353–1360. 7. O’Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and lowdose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003;348:994–1004. 8. Saglio G, Kim DW, Issaragrisil S, et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010;362:2251–2259. 9. Cortes JE, Jones D, O’Brien S, et al. Results of dasatinib therapy in patients with early chronic-phase chronic myeloid leukemia. J Clin Oncol. 2010;28:398–404. 10. Hanfstein B, Muller MC, Hehlmann R, et al. Early molecular and cytogenetic response is predictive for long-term progression-free and overall survival in chronic myeloid leukemia (CML). Leukemia. 2012;26:2096–2102. 11. Jabbour E, Kantarjian HM, Saglio G, et al. Early response with dasatinib or imatinib

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HEMATOLOGIC CANCER References (continued) 12.

13.

14. 15. 16. 17. 18. 19. 20.

21.

in chronic myeloid leukemia: 3-year follow-up from a randomized phase 3 trial (DASISION). Blood. 2014;123:494–500. Yeung DT, Osborn MP, White DL, et al. Early switch to nilotinib does not overcome the adverse outcome for CML patients failing to achieve early molecular response on imatinib, despite excellent overall outcomes in the TIDEL II trial [abstract]. Blood. 2012;120:Abstract 3771. Kim DD, Lee H, Kamel-Reid S, Lipton JH. BCR-ABL1 transcript at 3 months predicts long-term outcomes following second generation tyrosine kinase inhibitor therapy in the patients with chronic myeloid leukaemia in chronic phase who failed imatinib. Br J Haematol. 2013;160:630–639. Falchi L, Kantarjian HM, Wang X, et al. Significance of deeper molecular responses in patients with chronic myeloid leukemia in early chronic phase treated with tyrosine kinase inhibitors. Am J Hematol. 2013;88:1024–1029. Talpaz M, Silver RT, Druker BJ, et al. Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study. Blood. 2002;99:1928–1937. Kantarjian HM, Cortes J, O’Brien S, et al. Imatinib mesylate (STI571) therapy for Philadelphia chromosome-positive chronic myelogenous leukemia in blast phase. Blood. 2002; 99:3547–3553. Kantarjian HM, O’Brien S, Cortes JE, et al. Treatment of Philadelphia chromosome-positive, accelerated-phase chronic myelogenous leukemia with imatinib mesylate. Clin Cancer Res. 2002;8:2167–2176. Sawyers CL, Hochhaus A, Feldman E, et al. Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study. Blood. 2002;99:3530–3539. Palandri F, Castagnetti F, Testoni N, et al. Chronic myeloid leukemia in blast crisis treated with imatinib 600 mg: outcome of the patients alive after a 6-year follow-up. Haematologica. 2008;93:1792–1796. Palandri F, Castagnetti F, Alimena G, et al. The long-term durability of cytogenetic responses in patients with accelerated phase chronic myeloid leukemia treated with imatinib 600 mg: the GIMEMA CML Working Party experience after a 7-year follow-up. Haematologica. 2009;94:205–212. Silver RT, Cortes J, Waltzman R, et al. Sustained durability of responses and improved progression-free and overall survival with imatinib treatment for accelerated phase and blast crisis chronic myeloid leukemia: long-term follow-up of the STI571 0102 and 0109 trials. Haematologica. 2009;94:743–744.

21. Silver RT, Cortes J, Waltzman R, et al. Sustained durability of responses and improved progression-free and overall survival with imatinib treatment for accelerated phase and blast crisis chronic myeloid leukemia: long-term follow-up of the STI571 0102 and 0109 trials. Haematologica. 2009;94:743–744. 22. Rea D, Etienne G, Nicolini F, et al. First-line imatinib mesylate in patients with newly diagnosed accelerated phase-chronic myeloid leukemia. Leukemia. 2012;26:2254–2259. 23. Ohanian M, Kantarjian HM, Quintas-Cardama A, et al. Tyrosine kinase inhibitors as initial therapy for patients with chronic myeloid leukemia in accelerated phase. Clin Lymphoma Myeloma Leuk. 2014;14:155-162.e1. 24. Apperley JF, Cortes JE, Kim D-W, et al. Dasatinib in the treatment of chronic myeloid leukemia in accelerated phase after imatinib failure: the START A trial. J Clin Oncol. 2009;27: 3472–3479. 25. Cortes J, Kim DW, Raffoux E, et al. Efficacy and safety of dasatinib in imatinib-resistant or –intolerant patients with chronic myeloid leukiemia in blast phase. Leukemia. 2008; 22:2176–2183. 26. Kantarjian H, Cortes J, Kim DW, et al. Phase 3 study of dasatinib 140 mg once daily versus 70 mg twice daily in patients with chronic myeloid leukemia in accelerated phase resistant or intolerant to imatinib: 15-month median follow-up. Blood. 2009;113:6322–6329. 27. Le Coutre PD, Giles FJ, Hochhaus A, et al. Nilotinib in patients with Ph+ chronic myeloid leukemia in accelerated phase following imatinib resistance or intolerance: 24-month follow-up results. Leukemia. 2012;26:1189–1194. 28. Giles FJ, Kantarjian HM, le Coutre PD, et al. Nilotinib is effective in imatinib-resistant or –intolerant patients with chronic myeloid leukemia in blastic phase. Leukemia. 2012;26: 959–962. 29. Gambacorti-Passerini C, Cortes JE, Khoury HJ, et al. Safety and efficacy of bosutinib in patients with AP and BP CML and ph+ ALL following resistance/intolerance to imatinib and other TKIs: Update from study SKI-200 [abstract]. J Clin Oncol. 2010;28(15_suppl):Abstract 6509. 30. Sokal JE, Baccarani M, Russo D, Tura S. Staging and prognosis in chronic myelogenous leukemia. Semin Hematol. 1988;25:49–61. 31. Nicolini FE, Khoury HJ, Akard L, et al. Omacetaxine mepesuccinate for patients with accelerated phase chronic myeloid leukemia with resistance or intolerance to two or more tyrosine kinase inhibitors. Haematologica. 2013;98: e78–79. 32. Cortes JE, Kim D-W, Pinilla-Ibarz J, et al. Long-term follow-up of ponatinib efficacy and safety in the phase 2 PACE trial [abstract]. Blood. 2014;124:Abstract 3135.

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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 patients with classical Hodgkin lymphoma (HL) after failure of autologous hematopoietic stem cell transplant (auto-HSCT) or after failure of ≥2 prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates or are at high risk of relapse or progression as post-auto-HSCT consolidation. Treatment of patients with systemic anaplastic large cell lymphoma (sALCL) after failure of ≥1 prior multi-agent chemotherapy regimen. Adults: Give by IV infusion over 30mins. 1.8mg/kg up to max 180mg/dose every 3 weeks; continue until disease progression or unacceptable toxicity. Post-auto-HSCT consolidation: initiate within 4–6 weeks post-auto-HSCT or upon recovery from auto-HSCT; max 16 cycles. Mild hepatic impairment: initially 1.2mg/kg up to 120mg. 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 G-CSF prophylaxis for subsequent cycles; recurrent Grade 4: consider discontinue or dose reduction to 1.2mg/kg. Patients with prior infusion-related reaction: premedicate with APAP, antihistamine, and corticosteroid for subsequent doses. 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; delay, change dose, or discontinue if new or worsening symptoms occur. Monitor for infusion-related reactions; permanently discontinue and treat if anaphylaxis occurs. Monitor CBCs prior to each dose and frequently for fever or Grade 3 or 4 neutropenia; delay, reduce, discontinue dose or consider G-CSF prophylaxis 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 for pulmonary toxicity; if symptoms occur, withhold dose during evaluation and until improvement. 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 (eg, SJS, TEN) occur. GI complications: evaluate and treat if new or worsening GI symptoms develop. Embryo-fetal toxicity. Pregnancy: verify status before initiation; avoid and use effective contraception during and for ≥6 months after final dose. 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. 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 Novartis

℞

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 fludarabine-based therapy is considered inappropriate. Extended treatment of patients who are in complete or partial response after at least two lines of therapy for recurrent or progressive CLL. Treatment of CLL refractory to fludarabine and alemtuzumab.

Adults: Premedicate with acetaminophen (oral), antihistamine (oral or IV), corticosteroid (IV) 30mins to 2hrs prior to each infusion. Give by IV infusion (rate varies with dose and during infusion); see full labeling. Previously untreated: initially 300mg on Day 1, then 1 week later by 1000mg on Day 8 (Cycle 1), followed by 1000mg on Day 1 of subsequent 28-day cycles for at least 3 cycles until best response or max 12 cycles. Extended treatment: initially 300mg on Day 1, then by 1000mg 1 week later on Day 8, followed by 1000mg 7 weeks later and every 8 weeks thereafter for up to max 2 years. Refractory: initially 300mg on Day 1, then 1 week later by 2000mg weekly for 7 doses, followed 4 weeks later by 2000mg every 4 weeks for 4 doses. Dose modification for infusion reactions: see full labeling. 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 <0.5x109/L or platelet count <25x109/L: decrease dose by 25% (750mg/m2); discontinue if recurrent ANC <0.5x109/L or platelet count <25x109/L nadirs after 2 dose reductions;

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HEMATOLOGIC CANCER Non-hematologic 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 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

BENDEKA Teva

℞

Alkylating agent. Bendamustine HCl 25mg/mL; soln for IV infusion after dilution; preservative-free. 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 10mins. 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 10mins. 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 frequently; restart treatment based on ANC and platelet count recovery. Monitor for signs of infection. Monitor for infusion or skin reactions, tumor lysis syndrome. Renal or hepatic impairment. Avoid extravasation. Pregnancy (Cat.D); avoid during and for 3 months after therapy cessation. Nursing mothers: not recommended. Interactions: May be potentiated by CYP1A2 inhibitors (eg, fluvoxamine, ciprofloxacin) or antagonized by CYP1A2 inducers (eg, omeprazole, smoking); if needed, consider alternatives. Adverse reactions: Lymphopenia, anemia, leukopenia, thrombocytopenia, neutropenia, pyrexia, nausea, vomiting, fatigue, diarrhea, constipation, anorexia, cough, headache, weight loss, dyspnea, stomatitis; 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: Multi-dose vial (4mL)—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

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HEMATOLOGIC CANCER 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 >5XULN or if bilirubin rises >3XULN. 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, 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

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HEMATOLOGIC CANCER 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, platelets, and coagulation parameters during the 5 days of therapy. Discontinue if hypotension develops during administration. 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. Discontinue immediately if Grade ≥3 liver enzyme and/or bilirubin elevation occurs. 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 hepatic toxicity. Caution with drugs that affect BP or cardiac function; monitor. Adverse reactions: Nausea, vomiting, diarrhea, headache, rash, pruritus, pyrexia, fatigue, palmar-plantar 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), hepatotoxicity (may be fatal), embryo-fetal toxicity. How supplied: Single-use vial (20mL)—1

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 X 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

DARZALEX Janssen Biotech

℞

CD38-directed monoclonal antibody. Daratumumab 100mg/mL, 400mg/20mL; per vial; soln for IV infusion after dilution; contains mannitol; preservative-free. Indications: Treatment of multiple myeloma in patients who have received ≥3 prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent or who are doublerefractory to a PI and an immunomodulatory agent. Adults: Premedicate with IV corticosteroid, oral antipyretic, oral or IV antihistamine 1 hour prior to every infusion; and give oral corticosteroid on the 1st and 2nd day after all infusions. Give only as IV infusion. 16mg/kg weekly on Weeks 1–8, every 2 weeks on Weeks 9–24, then every 4 weeks on Week 25 onwards until disease progression. Infusion rates and modifications for infusion reactions: see full labeling. Prophylaxis for herpes zoster reactivation: initiate antiviral prophylaxis within 1 week of starting therapy and continue for 3 months after treatment. Children: Not established. Warnings/Precautions: Should be administered by a healthcare professional with immediate access to emergency equipment and appropriate medical support. Monitor for infusion reactions; interrupt treatment for infusion reactions of any severity. Permanently discontinue if life-threatening (Grade 4) infusion reactions occur; for Grade 1, 2, or 3 reactions, reduce the infusion rate when restarting the infusion. History of obstructive pulmonary disorders: may require additional post-infusion drugs; consider prescribing short- or long-acting bronchodilators and inhaled corticosteroids. Interference with cross-matching and RBC antibody screening; type/screen patients prior to initiating treatment. Moderate-to-severe hepatic impairment. Pregnancy. Females of reproductive

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER potential should use effective contraception during treatment and for 3 months after. Nursing mothers. Interactions: Interferes with Indirect Antiglobulin (Coombs) Test, serum protein electrophoresis and immunofixation assays leading to false (+) results. Adverse reactions: Infusion reactions, fatigue, nausea, back pain, pyrexia, cough, upper respiratory tract infection. How supplied: Single-dose 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

EMPLICITI Bristol-Myers Squibb

℞

SLAMF7-directed immunostimulatory antibody. Elotuzumab 300mg, 400mg; per vial; lyophilized pwd for IV infusion after reconstitution; preservative-free. Indications: In combination with lenalidomide and dexamethasone, for the treatment of patients with multiple myeloma who have received 1–3 prior therapies. Adults: Give by IV infusion at initial rate of 0.5mL/min; may increase stepwise if no reactions develop; max rate 2mL/min. After 4 cycles, infusion rate may be increased up to max 5mL/min. Administer with lenalidomide and dexamethasone (see full labeling for dosing schedule). 10mg/kg every week for the first 2 cycles then every 2 weeks thereafter; continue until disease progression or unacceptable toxicity. Premedicate with dexamethasone, H1 blocker, H2 blocker, and acetaminophen before each infusion. Dose modifications: see full labeling. Children: Not established. Contraindications: Consult lenalidomide and dexamethasone prescribing information for contraindications before starting therapy. Warnings/Precautions: Interrupt infusion if Grade ≥2 infusion reactions occur and manage appropriately. Monitor for development of infections and treat promptly. Monitor for second primary malignancies. Monitor liver function periodically; discontinue if Grade

≥3 elevation of liver enzymes occur; consider resuming after return to baseline values. Pregnancy: not studied. Nursing mothers: not recommended. Interactions: May interfere with correct response classification in SPEP and serum immunofixation assays. Adverse reactions: Fatigue, diarrhea, pyrexia, constipation, cough, peripheral neuropathy, nasopharyngitis, upper respiratory tract infection, decreased appetite, pneumonia. Note: For lenalidomide and dexamethasone specific dosing and safety information, refer to the respective full prescribing labels. How supplied: Single-dose vial—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 ≥2XULN 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 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

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HEMATOLOGIC CANCER (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: In combination with chlorambucil, for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL). In combination with bendamustine followed by Gazyva monotherapy, for the treatment of

patients with follicular lymphoma (FL) who relapsed after, or are refractory to, a rituximabcontaining regimen. Adults: See full labeling. Premedicate (eg, glucocorticoid, APAP, antihistamine) before each infusion. Provide prophylactic hydration and antihyperuricemics to those at high risk of TLS. Give by IV infusion for 6 treatment cycles (28 days duration). CLL: Cycle 1: 100mg on Day 1 at 25mg/hr over 4 hours; 900mg on Day 2 at 50mg/hr, can increase at 50mg/hr every 30mins to max 400mg/hr; 1000mg on Days 8 and 15 at 100mg/hr if no infusion reaction occurred previously, and increased by 100mg/hr increments every 30mins to max 400mg/hr; Cycles 2–6: 1000mg on Day 1 at 100mg/hr if no infusion reaction occurred previously, and increased by 100mg/hr increments every 30mins to max 400mg/hr. FL: Cycle 1: 1000mg on Day 1 at 50mg/hr, can increase at 50mg/hr every 30mins to max 400mg/hr; 1000mg on Days 8 and 15 at 100mg/hr if no infusion reaction occurred previously, and increased by 100mg/hr increments every 30mins to max 400mg/hr; Cycles 2–6: 1000mg on Day 1 at 100mg/hr if no infusion reaction occurred previously, and increased by 100mg/hr increments every 30mins to max 400mg/hr; followed by Gazyva monotherapy: 1000mg every 2 months for 2 years at 100mg/hr if no infusion reaction occurred previously, and increased by 100mg/hr increments every 30mins to max 400mg/hr. Management of infusion reactions, premedication: 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 progressive multifocal leukoencephalopathy (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 post-infusion period for severe reactions. Risk of TLS in high tumor burden, high circulating lymphocyte count (>25 × 109/L), or renal impairment. Active infection: do not administer. Risk of neutropenia; monitor for signs of infection. Severe or prolonged neutropenia, give antimicrobial prophylaxis until resolved to Grade 1 or 2; consider antiviral and antifungal prophylaxis. Monitor for thrombocytopenia and hemorrhagic events esp.

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HEMATOLOGIC CANCER during the 1st cycle; obtain blood and platelet counts frequently; transfusion of blood products may be necessary. Hepatic or renal impairment (CrCl <30mL/min). Pregnancy; risk of fetal B-cell depletion. Nursing mothers. Interactions: Concomitant live viral vaccines: not recommended during treatment and until B-cell recovery (esp. neonates/infants if exposed to Gazyva in utero). 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, nausea, diarrhea; HBV reactivation, PML, TLS, infections. 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 newly-diagnosed 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/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

℞

Antimetabolite. Hydroxyurea 500mg; caps. Indications: Resistant chronic myeloid leukemia. Adults: Base dose on ideal or actual weight, whichever is less. Individualize. Initially

15mg/kg/day. Renal impairment (CrCl <60mL/min or ESRD): initially 7.5mg/kg/day; give dose following dialysis (monitor). Dose modifications: see full labeling. Children: Not established. Warnings/Precautions: Risk of severe myelosuppression; reduce dose or discontinue if necessary. Monitor blood counts at baseline and at least once a week during therapy. Correct severe anemia before starting. Markedly depressed bone marrow function: do not initiate. Monitor for malignancies. Avoid sun exposure. Previous irradiation therapy (monitor for skin erythema) or chemotherapy. Macrocytosis may mask folic acid deficiency; prophylactic folic acid is recommended. Myeloproliferative disorders; discontinue if cutaneous vasculitic ulcerations occur. Renal or hepatic impairment. Elderly. Embryo-fetal toxicity. Pregnancy; avoid. Exclude pregnancy prior to initiating; use effective contraception during and for ≥6 months (females) or ≥1 year (males) after therapy. Nursing mothers: not recommended. Interactions: Avoid concomitant didanosine, with or without stavudine, or other antiretrovirals (may cause pancreatitis [monitor], fatal hepatotoxicity, peripheral neuropathy). Avoid live vaccines. Increased risk of vasculitic toxicities with interferon therapy. May cause falsely elevated results in urea, uric acid, and lactic acid assays. Adverse reactions: Leukopenia, thrombocytopenia, anemia, GI upset, anorexia; secondary malignancies, macrocytosis. Note: Wear disposable gloves when handling caps or bottle. How supplied: Caps—100

ICLUSIG ARIAD

℞

Kinase inhibitor. Ponatinib 15mg, 30mg, 45mg; tabs; contains lactose. Indications: Treatment of adults with T315Ipositive chronic, accelerated, or blast phase chronic myeloid leukemia (CML) or T315Ipositive 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 or hepatic impairment: reduce to 30mg once daily. Dose modification for hematologic and non-hematologic 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

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER 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. Monitor and manage BP elevations; interrupt, reduce dose or discontinue if not controlled; evaluate for renal artery stenosis if significant worsening, labile or treatment-resistant hypertension occurs. 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 <1.5XULN. Monitor for neuropathy; consider interrupting and evaluate if suspected. Conduct eye exams at baseline and periodically during treatment. 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). 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—30, 60, 180; 30mg—30; 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). 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. Monitor for new

onset or uncontrolled hypertension; adjust and/or initiate anti-hypertensives as appropriate. 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; avoid during and for 1 month after treatment cessation. Nursing mothers: not recommended. Interactions: Concomitant strong CYP3A inhibitors taken chronically (eg, ritonavir, indinavir, nelfinavir, saquinavir, boceprevir, telaprevir, nefazodone): not recommended; for short-term (≤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; monitor. 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, cough. How supplied: Caps—90, 120

INTRON A Merck

℞

Visit OncologyNurseAdvisor.com for practical clinical information geared toward oncology nurses and other cancer care professionals.

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER literature for appropriate preparation and route and for dose adjustments. Children: Not recommended. Contraindications: Decompensated liver disease. Autoimmune hepatitis. 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; discontinue if neutrophil count <0.5 X109/L or platelets 25X109/L. Permanently discontinue if severe (Grade 3) hepatic injury or decompensation (Child-Pugh score >6 [Class B and C]) develop. Thyroid abnormalities; discontinue if uncontrolled by medication. 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, dental and periodontal disorders; others (see full labeling). How supplied: Pwd (w. diluent): 10million, 18million, 50million IU/vial—1; 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; 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. Moderateto-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 >200X109/L: initially 20mg twice daily. Platelets 100–200X109/L: initially 15mg twice daily. Platelets 50–<100X109/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 <50X109/L or ANC <0.5X109/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 ≥50X109/L (see full labeling). Dose modifications for patients starting treatment with platelets 50–<100X109/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 <50X109/L, or ANC <1.0X109/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 ≥100X109/L; if platelets 50–<100X109/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. Increases in lipid parameters including total-C, LDL, triglycerides; assess 8–12 weeks after starting and treat if hyperlipidemia develops. 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), Hepatitis B. How supplied: Tabs—60

KYPROLIS Onyx

℞

Proteasome inhibitor. Carfilzomib 60mg/vial; lyophilized pwd for IV inj after reconstitution; preservative-free. Indications: In combination with dexamethasone or lenalidomide plus dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma who have received 1–3 lines of therapy. As a single agent for the treatment of patients with relapsed or refractory multiple myeloma who have received ≥1 lines of therapy. Adults: See full labeling. Hydrate prior to and following administration as needed. Premedicate with dexamethasone prior to all Cycle 1 doses, during subsequent cycles, and if infusion reactions occur. Give by IV 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). Lenalidomide/dexamethasone combination: Infuse over 10 mins. In Cycle 1: initially 20mg/m2 per dose on Days 1 and 2; if tolerated increase to 27mg/m2 on Day 8 and subsequent cycles.

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HEMATOLOGIC CANCER From Cycle 13, omit the Day 8 and 9 doses. Discontinue carfilzomib after Cycle 18. See full labeling for lenalidomide and dexamethasone dosing. Dexamethasone combination: Infuse over 30 mins. In Cycle 1: initially 20mg/m2 per dose on Days 1 and 2; if tolerated increase to 56mg/m2 on Day 8 and subsequent cycles. Monotherapy: initially 20mg/m2 per dose in Cycle 1 on Days 1 and 2; if tolerated increase to 27mg/m2 on Day 8 (by 10-min infusion regimen) or 56mg/m2 on Day 8 (by 30-min infusion regimen) and continue same dose for subsequent cycles. From Cycle 13, omit the Day 8 and 9 doses. All: 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: Monitor for signs/symptoms of cardiac failure or ischemia; evaluate promptly if toxicity is suspected. Increased risk of cardiac complications in patients with NYHA Class III and IV heart failure, recent MI, conduction abnormalities, angina, uncontrolled arrhythmias; do full medical assessment prior to starting. Pulmonary hypertension; if suspected, withhold therapy until resolved; may consider restarting after reevaluate. Discontinue if pulmonary toxicity occurs. Monitor for dyspnea or tumor lysis syndrome (TLS), 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, electrolytes (eg, potassium) regularly; reduce or withhold dose as needed. Hepatic impairment (monitor enzymes). Give thromboprophylaxis for combination therapy. Consider antiviral prophylaxis to prevent herpes zoster reactivation. Elderly (≥75yrs). Pregnancy; avoid. Use effective contraception during and for ≥30 days (females) or ≥90 days (males) after therapy completion. Nursing mothers. Interactions: Increased risk of thrombosis with oral or hormonal contraceptives; consider alternatives during combination therapy. Adverse reactions: Anemia, neutropenia, diarrhea, dyspnea, fatigue, thrombocytopenia, pyrexia, insomnia, muscle spasm, cough, upper RTI, hypokalemia, nausea, headache, peripheral edema; cardiac events, pulmonary HTN, acute kidney injury, infusion reactions, TLS, 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

℞

Alkylating agent. 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.

Access Cancer Therapy Advisor treatment regimens in a user-friendly format. CancerTherapyAdvisor.com/TreatmentRegimens.

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HEMATOLOGIC CANCER 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

NINLARO Takeda

℞

Proteasome inhibitor. Ixazomib 2.3mg, 3mg, 4mg; gel caps. Indications: In combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least 1 prior therapy.

Adults: Swallow whole. Take ≥1hr before or ≥2hrs after food. Initially 4mg once weekly on Days 1, 8, and 15 of a 28-day cycle; continue until disease progression or unacceptable toxicity. Give with lenalidomide 25mg daily on Days 1–21 and dexamethasone 40mg on Days 1, 8, 15, and 22. Moderate or severe hepatic impairment, severe renal impairment, or ESRD on dialysis: initially 3mg. Prior to new cycle, ensure ANC ≥1,000/mm3, platelets ≥75,000/mm3, recovery of non-hematologic toxicities to baseline or Grade ≤1. Dose modifications: see full labeling. Children: Not established. Warnings/Precautions: Thrombocytopenia: monitor platelets at least monthly during treatment; consider more frequently for first 3 cycles. Adjust dose for Grade 3/4 GI symptoms or Grade ≥2 rash. Monitor for peripheral neuropathy; adjust dose if worsens. Adjust dosing of dexamethasone or ixazomib if Grade 3/4 peripheral edema symptoms occur. Hepatic impairment; monitor enzymes regularly and adjust for Grade 3/4 symptoms. Severe renal impairment or ESRD. Pregnancy; avoid. Males and females of reproductive potential must use effective contraception during therapy and for 90 days after final dose. Nursing mothers: not recommended. Interactions: Avoid concomitant strong CYP3A inducers (eg, rifampin, phenytoin, carbamazepine, St. John’s Wort). Adverse reactions: Diarrhea, constipation, thrombocytopenia, peripheral neuropathy, nausea, peripheral edema, vomiting, back pain; rash, hepatotoxicity. How supplied: Caps—1, 3

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, 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

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HEMATOLOGIC CANCER 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 >3xULN): 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. Pre-existing liver disease (monitor more frequently). Obtain CBCs with differential, hemoglobin, hematocrit, platelets; discontinue if severe bone marrow suppression occurs. ThiopurineS-methyltransferase (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 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

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HEMATOLOGIC CANCER 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 single-agent 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 singleagent 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, Stevens-Johnson 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 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 chromosome-positive 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. Treat until disease progression or unable to tolerate. 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: Monitor for signs/symptoms of cardiac dysfunction; treat appropriately if occur. Congenital long QT syndrome. Proarrhythmic conditions. Cumulative high-dose anthracycline therapy. Hypokalemia, hypomagnesemia; correct electrolyte imbalances before starting and during 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 every 2 weeks for 12 weeks, then every 3 months thereafter (chronic phase CML) or weekly for the first 2 months, then monthly thereafter (advanced phase CML or

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HEMATOLOGIC CANCER Ph+ ALL). Permanently discontinue if severe skin reactions (eg, Stevens-Johnson syndrome) occur. Increased risk of tumor lysis syndrome in advanced stage disease and/or high tumor burden. Maintain adequate hydration. Correct uric acid levels before therapy and monitor electrolytes. Hepatic impairment. Elderly. Pregnancy. Use effective contraception during and for 30 days after last dose. 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, diarrhea, headache, dyspnea, musculoskeletal pain, rash, fatigue, nausea, severe hemorrhage (eg, CNS, GI); QT prolongation, cardiac events, PAH, severe skin reactions. 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. 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 >3xULN 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.

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HEMATOLOGIC CANCER 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 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). Consider dose reduction, delay, or discontinuation in those who develop NCI CTC Grade 3/4 adverse reactions. 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. Monitor blood and platelet counts. Monitor for signs/symptoms of bleeding including petechiae, epistaxis, and

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HEMATOLOGIC CANCER GI bleed. 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, thrombocytopenia. 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 25mg, 100mg; per vial; lyophilized pwd for IV infusion after reconstitution; preservative-free. 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 30mins. 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 60mins. 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 frequently; restart treatment based on ANC and platelet count recovery. Monitor for signs of infection or reactivation of infections (eg, hepatitis B, CMV, tuberculosis, herpes zoster); treat promptly if occur. Monitor for infusion or skin reactions, tumor lysis syndrome. Renal or hepatic impairment. Avoid extravasation. Pregnancy (Cat.D); avoid during and for 3 months after therapy cessation. Nursing mothers: not recommended. Interactions: May be potentiated CYP1A2 inhibitors (eg, fluvoxamine, ciprofloxacin) or antagonized by CYP1A2 inducers (eg, omeprazole, smoking); if needed, consider alternatives. Adverse reactions: Lymphopenia, anemia, leukopenia, thrombocytopenia, neutropenia, pyrexia, nausea, vomiting, fatigue, diarrhea, constipation, anorexia, cough, headache, weight loss, dyspnea, stomatitis, increased bilirubin, increased AST/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—1

TREXALL Teva

℞

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 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);

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER 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

℞

Alkylating agent. 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 moderately-to-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

(Cat.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-to-severe 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 adjustment. Diabetes (closely monitor blood glucose). History of syncope. Avoid dehydration; give fluids and electrolytes. Heart disease (monitor for CHF). Interrupt therapy and

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER 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), French-American-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 >5XULN. 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. Rotate SC inj sites. 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, BUN or SCr elevation). See full labeling. Children: Not established. Contraindications: Advanced malignant hepatic tumors. Warnings/Precautions: Myelosuppression. Monitor CBCs frequently for response and/or toxicity, at a minimum, prior to each dosing cycle. Renal or hepatic impairment. High tumor burden. Monitor serum bicarbonate, 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, anemia, thrombocytopenia, vomiting, pyrexia, leukopenia,

diarrhea, inj site erythema, constipation, neutropenia, ecchymosis, petechiae, rigors, weakness, hypokalemia; renal failure/tubular acidosis, hepatic coma. 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.

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER 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. 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: Hypercalcemia of malignancy. Limitations 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 indicated. 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 0.5mg/dL from a normal pre-treatment level, or by 1mg/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 invasive dental surgery (do preventative dental work before therapy). Pregnancy (Cat.D). Nursing mothers: not recommended. Interactions: Avoid concomitant other bisphosphonates. Additive hypocalcemic effect with aminoglycosides, calcitonin, loop diuretics. Caution with other nephrotoxic drugs. 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; osteonecrosis of the jaw, 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 non-Hodgkin 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 >3XULN, monitor weekly until resolved; if ALT/AST >5XULN, 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 >5XULN or AST >10XULN): 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

ALECENSA Genentech

℞

Kinase inhibitor. Alectinib 150mg; 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. Adults: Swallow whole. Take with food. 600mg twice daily until disease progression or unacceptable toxicity. Dose modifications or dose reduction schedule: see full labeling. Children: Not established. Warnings/Precautions: Monitor liver function tests (eg, ALT, AST, total bilirubin) every 2 weeks for the first 2 months, then periodically during treatment; test more frequently if transaminase and bilirubin elevated; withhold, resume at reduced dose, or permanently discontinue based on severity. Evaluate if presence of worsening respiratory symptoms; withhold if ILD/pneumonitis diagnosed; permanently discontinue if no other cause identified. Monitor HR, BP regularly. If non-life-threatening symptomatic bradycardia occurs, withhold until asymptomatic or HR ≥60bpm; permanently discontinue in case(s) of recurrence or lifethreatening bradycardia if no contributing concomitant medication identified. Assess CPK every 2 weeks for the first month and as clinically indicated; withhold, resume, or reduce dose based on severity. Pregnancy. Females of reproductive potential should use effective contraception during treatment and for 1 week after final dose; males should use effective contraception during treatment and for 3 months after final dose. Nursing mothers: not recommended (during and for 1 week after final dose). Interactions: Increased bradycardia with concomitant antihypertensives or other drugs known to cause bradycardia. Adverse reactions: Fatigue, constipation, edema, myalgia; hepatotoxicity, ILD/pneumonitis, bradycardia, CPK elevation, embryo-fetal toxicity. How supplied: Caps—240

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

℞

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 non-squamous, 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.

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YOUR ALK+ NSCLC

PATIENT MAY BE

AT RISK FOR…

THE DEVELOPMENT OF MUTATIONS AND THE THREAT OF ACQUIRED RESISTANCE First-line treatment with a targeted therapy has improved outcomes for patients with ALK+ NSCLC (anaplastic lymphoma kinase–positive non–small cell lung cancer), with increases in response rates and progression-free survival versus standard chemotherapy.1 Unfortunately, these benefits were short-lived, as many patients experienced disease progression in less than a year. 2 While the incidence of ALK+ NSCLC remains relatively low and various studies show conflicting results, one study suggested that ALK-rearranged NSCLC doubles the risk of progression or recurrence at 5 years, and also drives the development of many metastases.3,4 Most ALK+ NSCLC patients who have responded to a first-line ALK-inhibitor treatment ultimately relapse, in part, due to acquired resistance.5,6 Acquired resistance can emerge from a wide spectrum of resistant mutations.6,7

References: 1. Toyokawa G, Seto T, Takenoyama M, Ichinose Y. Cancer Metastasis Rev. 2015;34(4):797-805. 2. Solomon BJ, Mok T, Kim D-W, et al; for the PROFILE 1014 Investigators. N Engl J Med. 2014;371(23):2167-2177. 3. Kwak EL, Bang Y-J, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non–small-cell lung cancer. N Engl J Med. 2010;363(18):16931703. doi:10.1056/NEJMoa1006448. 4. Zhang I, Zaorsky NG, Palmer JD, Mehra R, Lu B. Lancet Oncol. 2015;16(13):e510-e521. 5. Katayama R, Lovly CM, Shaw AT. Clin Cancer Res. 2015; 21(10):2227-2235. 6. Toyokawa G, Seto T. Oncol Res Treat. 2015;38(6):291-298. 7. Camidge DR, Doebele RC. Nat Rev Clin Oncol. 2012;9(5):268-277.

VISIT ALKPROGRESSION.COM FOR MORE INFORMATION.

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YOUR ALK+ NSCLC

PATIENT MAY BE

AT RISK FOR…

VISIT ALKPROGRESSION.COM FOR MORE INFORMATION.

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DRUG MONOGRAPHS

LUNG CANCER 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: 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 FDAapproved 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; 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

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. Obtain LFTs periodically during treatment. Monitor closely in moderate-to-severe renal impairment or severe hepatic impairment; adjust dose if not tolerated. Embryo-fetal toxicity. Females of reproductive potential should use effective contraception during therapy and for at least 2 weeks after final dose. Pregnancy (Cat.D). Nursing mothers: not recommended (during therapy and for 2 weeks after final dose). Interactions: Potentiated by P-gp inhibitors (eg, ritonavir, cyclosporine A, ketoconazole, itraconazole, erythromycin, verapamil, quinidine, tacrolimus, nelfinavir, saquinavir, amiodarone). Antagonized by P-gp inducers (eg, rifampicin, carbamazepine, phenytoin, phenobarbital, St. John’s wort). Adverse reactions: Diarrhea, rash/dermatitis acneiform, stomatitis, paronychia, dry skin, decreased appetite, nausea, vomiting, pruritus; bullous/exfoliative skin disorders, interstitial lung disease, hepatotoxicity, keratitis. How supplied: Tabs—30

HYCAMTIN GlaxoSmithKline ℞

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 have not been established in patients whose tumors have other EGFR mutations. Treatment of patients with metastatic squamous NSCLC progressing after platinum-based chemotherapy. Adults: Take on an empty stomach at least 1 hr before or 2 hrs after a meal. 40mg once daily until disease progression or not tolerated. Severe renal impairment (CrCl 15–29mL/min): 30mg once daily. Concomitant P-gp inhibitors: reduce afatinib daily dose by 10mg if not tolerated; resume previous dose after discontinuing the inhibitor. Concomitant P-gp inducers: increase afatinib daily dose by 10mg as tolerated; resume previous dose 2–3 days after discontinuing the inducer. Dose modification: see full labeling.

℞

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.

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DRUG MONOGRAPHS

LUNG CANCER 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

IRESSA AstraZeneca

℞

Tyrosine kinase inhibitor. Gefitinib 250mg; tabs. Indications: First-line treatment of metastatic non-small cell lung cancer (NSCLC) with EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test. Limitations of use: not established in metastatic NSCLC with EGFR mutations other than exon 19 deletions or exon 21 substitution mutations. Adults: May disperse tabs in water; drink immediately or give via NG tube. Give 250mg once daily until disease progression or unacceptable toxicity occurs. Dose modifications for adverse reactions: see full labeling. Concomitant strong CYP3A4 inducers: increase to 500mg daily; resume at 250mg seven days after discontinuation of the CYP3A4 inducer. Children: Not established.

Warnings/Precautions: Permanently discontinue if confirmed interstitial lung disease (ILD), severe hepatic impairment, GI perforation, or persistent ulcerative keratitis occurs. Withhold for up to 14 days if acute onset or worsening pulmonary symptoms, NCI CTCAE Grade ≥2 ALT and/or AST elevations, Grade ≥3 diarrhea or skin reactions, or severe or worsening ocular disorders (including keratitis) occurs. Interrupt or discontinue therapy if severe bullous and exfoliative skin disorders develop. Obtain periodic LFTs. Moderate and severe hepatic impairment; monitor. Use effective contraception during treatment and for at least 2 weeks after completion. Pregnancy, nursing mothers: not recommended. Interactions: Potentiated by strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole); monitor. Antagonized by strong CYP3A4 inducers (eg, rifampicin, phenytoin, tricyclics); see Adults. May be antagonized by drugs that increase gastric pH (eg, H2-blockers, antacids); take gefitinib 6 hours after or 6 hours before an H2-blocker or antacid. Avoid concomitant PPIs; if necessary, take gefitinib 12 hours after last dose or 12 hours before next PPI dose. May potentiate warfarin; monitor INR. Adverse reactions: Skin reactions, diarrhea, vomiting, decreased appetite, stomatitis; ILD, hepatotoxicity, GI perforation, ocular disorders. Testing considerations: EGFR mutation analysis. How supplied: Tabs—30

MUSTARGEN Recordati

℞

Alkylating agent. 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

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,

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DRUG MONOGRAPHS

LUNG CANCER 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 non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. Adults: Give as IV infusion over 60mins. 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; permanently discontinue or withhold, and give corticosteroids (at 1–2mg/kg/day prednisone equivalents) based on severity of event. Permanently discontinue for any lifethreatening or Grade 4 adverse reaction, Grade 3 or 4 pneumonitis, Grade 3 (with ipilimumab) or 4 colitis, AST/ALT >5XULN or total bilirubin >3XULN, SCr >6XULN, Grade 4 hypophysitis, Grade 3 or 4 adrenal insufficiency, Grade 4 hyperglycemia, Grade 4 rash, immune-mediated encephalitis, recurring Grade 3 or 4 adverse reaction, requirement for ≥10mg/day prednisone (or equivalent) for >12 weeks, or persistent Grade 2 or 3 adverse reactions lasting ≥12 weeks. Grade 2 pneumonitis, Grade 2 or 3 (as single agent) colitis, AST/ALT >3–5XULN or total bilirubin >1.5–3XULN, SCr >1.5–6XULN, new onset moderate-to-severe neurologic symptoms, any other Grade 2 or 3 adverse reactions; withhold dose, give corticosteroids, and when resolved, consider re-initiation. Discontinue if severe or lifethreatening infusion reactions occur. Monitor for abnormal liver tests, elevated serum creatinine, hyperglycemia, and thyroid function prior to and during treatment; give replacement therapy for hypothyroidism. Moderate or severe hepatic impairment: not studied. Pregnancy: avoid. Use effective contraception during therapy and for ≥5 months after final dose. Nursing mothers: not recommended. Adverse reactions: Fatigue, dyspnea, musculoskeletal pain, decreased appetite, cough, nausea, constipation; immune-mediated reactions (may be fatal). How supplied: Single-use vial (4mL, 10mL)—1

PORTRAZZA Lilly

℞

Human epidermal growth factor receptor (EGFR) inhibitor. Necitumumab 800mg/50mL; soln for IV infusion after dilution; preservativefree.

Indications: In combination with gemcitabine and cisplatin, for first-line treatment of metastatic squamous non-small cell lung cancer. Limitations of use: not for treatment of non-squamous nonsmall cell lung cancer. Adults: Give by IV infusion over 60 mins prior to gemcitabine and cisplatin infusion. 800mg on Days 1 and 8 of each 3-week cycle; continue until disease progression or unacceptable toxicity. May premedicate with diphenhydramine HCl (or equivalent) if previously experienced a Grade 1/2 infusion-related reaction. Dose modifications: see full labeling. Children: Not established. Warnings/Precautions: Risk of cardiopulmonary arrest and/or sudden death, hypomagnesemia. History of coronary artery disease, CHF, or arrhythmias. Monitor serum electrolytes (eg, magnesium, potassium, calcium) prior to each infusion during therapy and for 8 weeks after last dose; withhold for Grade 3/4 electrolyte abnormalities and may resume once improved to Grade ≤2. Discontinue if serious or life-threatening venous/arterial thromboembolic events or infusion-related reactions occur. Discontinue if Grade 4 skin reactions or Grade 3 skin induration/fibrosis occurs. Limit sun exposure. Pregnancy. Use effective contraception during treatment and for 3 months after last dose. Nursing mothers: not recommended (during therapy and for 3 months after last dose). Adverse reactions: Rash, dermatitis acneiform, vomiting, diarrhea, thromboembolic events, hypomagnesemia, hypocalcemia, hypokalemia; cardiopulmonary arrest, dermatologic toxicities, infusion reactions, embryo-fetal toxicity. How supplied: Single-use vial—1

TAGRISSO AstraZeneca

℞

Kinase inhibitor. Osimertinib 40mg, 80mg; tabs. Indications: Treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC), as detected by an FDAapproved test, who have progressed on or after EGFR tyrosine kinase inhibitor therapy. Adults: 80mg once daily until disease progression or unacceptable toxicity. If swallowing difficulty, may disperse tab in 4tbsps (~50mL) of non-carbonated water only; stir and swallow immediately or give through NG tube; then rinse container with 4–8oz water and drink immediately or give through NG tube. Dose modification: see full labeling. Children: Not established. Warnings/Precautions: Confirm presence of T790M mutation prior to treatment initiation. Permanently discontinue if interstitial lung disease (ILD)/pneumonitis is confirmed; QTc interval prolongation with signs/symptoms of life-threatening arrhythmia; persistent, asymptomatic LV dysfunction that does not

resolve within 4 weeks; symptomatic CHF; or if no improvement of Grade ≥3 adverse reaction within 3 weeks occurs. Withhold dose if worsening respiratory symptoms indicative of ILD occur or if QTc interval >500msec on ≥2 separate ECGs. Monitor ECGs and electrolytes periodically in patients with congenital long QTc syndrome, CHF, electrolyte abnormalities, or those who are taking drugs known to prolong the QTc interval. Assess LVEF by echocardiogram or MUGA scan prior to initiation and every 3 months during treatment. Severe renal impairment (CrCl <30mL/min) or ESRD. Moderate or severe hepatic impairment. Pregnancy. Females of reproductive potential should use effective contraception during and for 6 weeks after final dose; males with female partners of reproductive potential should use effective contraception during and for 4 months after final dose. Nursing mothers: not recommended (during and for 2 weeks after final dose). Interactions: Avoid concomitant with strong CYP3A inhibitors (eg, telithromycin, itraconazole, ritonavir, nefazodone); if no other alternative, monitor closely. Avoid concomitant with strong CYP3A inducers (eg, phenytoin, rifampicin, carbamazepine, St. John’s Wort). Avoid concomitant with sensitive substrates of CYP3A, BCRP, or CYP1A2 with narrow therapeutic indices (eg, fentanyl, cyclosporine, quinidine, ergots, phenytoin, carbamazepine). Adverse reactions: Diarrhea, rash, dry skin, nail toxicity. How supplied: Tabs—30

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 platinum-based 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

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DRUG MONOGRAPHS

LUNG CANCER 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 >3XULN or transaminases >5XULN, 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. 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)

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. Treatment of metastatic NSCLC that is ROS1-positive. 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, or those who are taking drugs

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DRUG MONOGRAPHS

LUNG CANCER known to prolong the 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. Discontinue if onset of severe visual loss; perform eye evaluation. Hepatic impairment. Severe renal impairment. Embryo-fetal toxicity. Pregnancy; avoid. Use effective contraception during therapy and for at least 45 days (females) or 90 days (males) after final dose. Nursing mothers: not recommended (during therapy and for 45 days after final dose). 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 disorders, nausea, diarrhea, vomiting, constipation, edema, upper RTI, decreased appetite, dysgeusia, 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. If concomitant use of strong CYP3A4 inhibitors unavoidable: reduce ceritinib dose by 1/3. 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. Patients with CHF, bradyarrhythmias, electrolyte abnormalities, or those who are taking drugs known to prolong the QTc interval; 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; fasting serum glucose, lipase, amylase prior to initiation and periodically thereafter. Monitor for 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: See Adults. Potentiated by strong CYP3A4 inhibitors (eg, ritonavir, macrolides, ketoconazole, nefazodone), grapefruit juice; avoid. 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, nondihydropyridine CCBs, clonidine, digoxin). Adverse reactions: Diarrhea, nausea, vomiting, abdominal pain, constipation, elevated transaminases, fatigue, decreased appetite; bradycardia, hepatotoxicity, ILD/pneumonitis, QTc prolongation, hyperglycemia, pancreatitis. 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

℞ 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 full labeling. 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: Decompensated liver disease. Autoimmune hepatitis. 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; discontinue if neutrophil count <0.5 X109/L or platelets 25X109/L. Permanently discontinue if severe (Grade 3) hepatic injury or decompensation (Child-Pugh score >6 [Class B and C]) develop. Thyroid abnormalities; discontinue if uncontrolled by medication. 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, dental and periodontal disorders; others (see full labeling). How supplied: Pwd (w. diluent): 10million, 18million, 50million IU/vial—1; Soln (multidose vials): 18million, 25million IU/vial—1

PANRETIN Eisai

INTRON A Merck

℞

Alpha interferon. Interferon alfa-2b, recombinant; 10 million, 18 million, or 50 million IU per vial; pwd; for inj after reconstitution/dilution; preservativefree; contains albumin.

℞

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

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

SKIN CANCER COTELLIC Genentech

prior to initiation, periodically during treatment, and as clinically indicated for signs/symptoms of rhabdomyolysis. Avoid sun exposure. Moderate or severe hepatic impairment, severe renal impairment: not studied. Pregnancy. Females of reproductive potential should use effective contraception during treatment and for 2 weeks after final dose. Nursing mothers: not recommended (during therapy and for 2 weeks after final dose). Interactions: Avoid concomitant strong or moderate CYP3A inhibitors. If short-term (≤14 days) use of moderate CYP3A inhibitors is unavoidable for patients taking cobimetinib 60mg, reduce to 20mg and resume at previous dose upon discontinuing the CYP3A inhibitor; for patients taking cobimetinib 20mg or 40mg, use alternative. Avoid concomitant strong or moderate CYP3A inducers (eg, carbamazepine, efavirenz, phenytoin, rifampin, St. John’s wort). Adverse reactions: Diarrhea, photosensitivity, nausea, pyrexia, vomiting, increased GGT, CPK, ALT/AST and alkaline phosphatase, hypophosphatemia, lymphopenia, hyponatremia. How supplied: Tabs—63

℞

Kinase inhibitor. Cobimetinib 20mg; tabs. Indications: In combination with vemurafenib 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 for treatment of wild-type BRAF melanoma. Adults: Confirm presence of BRAF V600E or V600K mutation prior to initiation. In combination with vemurafenib: 60mg once daily for first 21 days of each 28-day cycle until disease progression or unacceptable toxicity. Dose modifications: see full labeling. Children: Not established. Warnings/Precautions: Review full labeling for vemurafenib prior to initiation. Monitor for new malignancies (cutaneous and non-cutaneous); perform skin evaluations prior to initiation, every 2 months during therapy, and for 6 months after discontinuation. Monitor for signs/symptoms of bleeding; withhold if Grade 3 hemorrhagic events occur; resume at lower dose if improved to Grade 0/1 within 4 weeks; discontinue if no improvement. Risk of cardiomyopathy; assess LVEF prior to initiation, after 1 month, and then every 3 months thereafter until discontinuation. Patients with baseline LVEF below institutional lower limit of normal or <50%: not established. Interrupt, reduce dose, or discontinue if severe skin reactions occur. Perform eye exams at regular intervals and for any visual disturbances. Manage serous retinopathy with treatment interruption, dose reduction, or discontinuation. Permanently discontinue if retinal vein occlusion occurs. Monitor liver tests prior to initiation, monthly during treatment, or more frequently as indicated; dose interruption, reduction, or discontinuation if Grade 3/4 abnormalities occur. Obtain baseline CPK and creatinine levels

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).

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)

2–3

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

INTERPRETATION OF CHILD-PUGH SCORES 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%

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SKIN CANCER 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

IMLYGIC Amgen

℞

Genetically modified oncolytic viral therapy. Talimogene laherparepvec 106 (1 million) PFU/mL, 108 (100 million) PFU/mL; susp for intralesional inj; preservative-free. Indications: Treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrent after initial surgery. Limitations of use: not shown to improve overall survival or have an effect on visceral metastases. Adults: See full labeling. Inject intralesionally into cutaneous, subcutaneous, and/or nodal lesions that are visible, palpable, or detectable by ultrasound guidance. Total inj volume per treatment visit: max 4mL for all injected lesions combined. Initial dose: up to 4mL of 106 (1 million) PFU/mL. 2nd dose: up to 4mL of 108 (100 million) PFU/mL given 3 weeks later. All subsequent doses (including reinitiation): up to 4mL of 108 (100 million) PFU/mL given 2 weeks apart. Continue for ≥6 months unless other treatment required or until no injectable lesions to treat; reinitiate if new lesions appear after a complete response. Children: Not established. Contraindications: Immunocompromised or pregnant patients. Warnings/Precautions: For intralesional inj only. Avoid accidental exposure (esp. skin, eyes, mucous membranes) and direct contact with patient’s

injected lesions, dressings, or body fluids. Advise patients to avoid inadvertent transfer of drug to other areas of the body (eg, touching/scratching inj sites or occlusive dressings). Evaluate lesions if suspected herpetic infection occurs. Inj site complications (eg, necrosis or ulceration of tumor tissue, cellulitis, systemic bacterial infection). Persistent infection or delayed healing of inj site. Underlying autoimmune disease. Multiple myeloma or plasmacytoma. Pregnancy. Women of childbearing potential should use effective method of contraception. Nursing mothers: not recommended. Interactions: Acyclovir or other antiherpetic viral agents may interfere with efficacy. Adverse reactions: Fatigue, chills, pyrexia, nausea, influenza-like illness, inj site pain; immune-mediated events. Note: Report suspected herpetic lesions to Amgen at (855) 465-9442. How supplied: Single-use vial (1mL)—1

INTRON A Merck

℞

Alpha interferon. Interferon alfa-2b, recombinant; 10 million, 18 million, or 50 million IU per vial; pwd; for inj after reconstitution/dilution; preservativefree; contains albumin. ℞ 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 full labeling for appropriate preparation and route and for dose adjustments. Children: Not recommended. Contraindications: Decompensated liver disease. Autoimmune hepatitis. 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; discontinue if neutrophil count <0.5 X109/L or platelets 25X109/L. Permanently discontinue if severe (Grade 3) hepatic injury or decompensation (Child-Pugh score >6 [Class B and C]) develop. Thyroid abnormalities; discontinue if uncontrolled by medication. Diabetes. Coagulation disorders. Maintain adequate hydration. Monitor blood, thyroid, visual and liver function before and

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SKIN CANCER 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, dental and periodontal disorders; others (see full labeling). How supplied: Pwd (w. diluent): 10million, 18million, 50million IU/vial—1; Soln (multidose vials): 18million, 25million IU/vial—1

KEYTRUDA Merck

℞

Human programmed death receptor-1 (PD-1)-blocking antibody. Pembrolizumab 50mg/vial; lyophilized pwd for IV infusion after reconstitution; 25mg/mL; per vial; soln for IV infusion after dilution; both: preservative-free. 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 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 pneumonitis; withhold dose if Grade 2 pneumonitis; permanently discontinue if Grade 3 or 4 develops. Monitor for 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. Monitor for hyperglycemia and other diabetes symptoms; withhold if severe hyperglycemia until controlled. Permanently discontinue if any severe or Grade 3 immunemediated adverse reaction recurs and for any life-threatening immune-mediated adverse reaction. Monitor for infusion-related reactions; permanently discontinue if Grade 3 or 4 develops. 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; renal failure, dyspnea, pneumonia, cellulitis; immune-mediated disorders, infusion-related reactions. How supplied: Single-use vial 50mg—1; Singleuse vial 25mg/mL—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 FDA-approved 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

ODOMZO Novartis

℞

Hedgehog pathway inhibitor. Sonidegib 200mg; caps. Indications: Treatment of adults with locally advanced basal cell carcinoma (BCC) that has recurred following surgery or radiation, or those who are not candidates for surgery or radiation therapy. Adults: Take on empty stomach. 200mg once daily until disease progression or unacceptable toxicity. Dose modifications: see full labeling. Children: Not established. Warnings/Precautions: Risk of embryo-fetal death or severe birth defects in pregnant women. Verify pregnancy status of females of reproductive potential prior to initiation. Advise females to use effective contraception during therapy and for at least 20 months after the last dose; male patients must use condoms and not to donate semen during therapy and for at least 8 months after last dose. Advise patients not to donate blood or blood products during therapy and for at least 20 months after last dose. Risk of musculoskeletal adverse reactions accompanied by serum creatine kinase (CK) elevations; temporarily interrupt or discontinue based on severity of reactions. Obtain baseline serum CK and creatinine (SCr) levels prior to initiation; periodically during treatment and as clinically indicated. Obtain serum CK and SCr levels at least weekly in those with musculoskeletal adverse reactions with concurrent serum CK elevation >2.5XULN until symptoms resolve. Pregnancy. Nursing mothers: not recommended during therapy and for 20 months after last dose. Interactions: Avoid concomitant strong CYP3A inhibitors (eg, saquinavir, telithromycin, ketoconazole, itraconazole, voriconazole, posaconazole, nefazodone) or moderate CYP3A inhibitors (eg, atazanavir, diltiazem, fluconazole); if moderate CYP3A inhibitor use necessary, administer for <14 days and monitor closely. Avoid concomitant strong or moderate CYP3A inducers (eg, carbamazepine, efavirenz, modafinil, phenobarbital, phenytoin, rifabutin, rifampin, St. John’s Wort). Adverse reactions: Muscle spasms, alopecia, dysgeusia, fatigue, nausea, musculoskeletal pain, diarrhea, decreased weight, decreased appetite, myalgia, abdominal pain, headache, pain, vomiting, pruritus; anemia, hyperglycemia, increased SCr, CK, and LFTs. Note: To report exposure to Odomzo during pregnancy, call Novartis at (888) 669-6682. How supplied: Caps—30

OPDIVO Bristol-Myers Squibb

℞

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SKIN CANCER disease progression following ipilimumab and, if BRAF V600 mutation (+), a BRAF inhibitor. In combination with ipilimumab for BRAF V600 wild-type, unresectable or metastatic melanoma. Adults: Give as IV infusion over 60mins. 3mg/kg every 2 weeks until disease progression or unacceptable toxicity. In combination with ipilimumab: 1mg/kg (followed by ipilimumab on the same day) every 3 weeks for 4 doses, then followed by 3mg/kg every 2 weeks (as single agent) 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; permanently discontinue or withhold, 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 3 (with ipilimumab) or 4 colitis, AST/ALT >5XULN or total bilirubin >3XULN, SCr >6XULN, Grade 4 hypophysitis, Grade 3 or 4 adrenal insufficiency, Grade 4 hyperglycemia, Grade 4 rash, immune-mediated encephalitis, recurring Grade 3 or 4 adverse reaction, requirement for ≥10mg/day prednisone (or equivalent) for >12 weeks, or persistent Grade 2 or 3 adverse reactions lasting ≥12 weeks. Grade 2 pneumonitis, Grade 2 or 3 (as single agent) colitis, AST/ALT >3–5XULN or total bilirubin >1.5–3XULN, SCr >1.5–6XULN, new onset moderate-to-severe neurologic symptoms, any other Grade 2 or 3 adverse reactions; withhold dose, give corticosteroids, and when resolved, consider re-initiation. Discontinue if severe or lifethreatening infusion reactions occur. Monitor for abnormal liver tests, elevated serum creatinine, hyperglycemia, and thyroid function prior to and during treatment; give replacement therapy for hypothyroidism. Moderate or severe hepatic impairment: not studied. Pregnancy: avoid. Use effective contraception during therapy and for ≥5 months after final dose. Nursing mothers: not recommended. Adverse reactions: Rash, pruritus, cough, URTI, peripheral edema; also with Ipilimumab: headache, vomiting, colitis, dehydration; immunemediated reactions (may be fatal). 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 <0.5x109/L, platelets <50x109/L, ECOG PS ≥2, or for non-hematologic toxicity ≥ Grade 3. Resume at reduced dose (see full labeling) when: ANC ≥0.5x109/L, platelets ≥50x109/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

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SKIN CANCER 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-tosevere 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. 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 nonhormonal 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. Adjuvant treatment of cutaneous melanoma in patients with pathologic involvement of regional lymph nodes >1mm who have undergone complete resection, including total lymphadenectomy. Adults: Give by IV infusion over 90 mins. Unresectable, metastatic: 3mg/kg every 3 weeks for a maximum of 4 doses; may delay doses if toxicity occurs, but all treatment must be given within 16 weeks of the first dose. Adjuvant: 10mg/kg every 3 weeks for 4 doses, followed by 10mg/kg every 12 weeks for up to 3 years; may omit doses if toxicity occurs. Dose modifications: see full labeling. Children: Not established. Warnings/Precautions: Severe and fatal immune-mediated adverse reactions can develop. Permanently discontinue therapy and initiate systemic high-dose corticosteroids for severe, persistent, or recurring immunemediated reactions. Withhold dose for moderate immune-mediated adverse reactions until return to baseline, improvement to mild severity, or complete resolution, and patient is receiving <7.5mg prednisone or equivalent per day. Monitor for enterocolitis, hepatitis, dermatitis, neuropathy, endocrinopathy, and others including ocular manifestations; perform clinical chemistries including LFTs, ACTH levels, and thyroid tests at baseline and before each dose. Moderate or severe hepatic impairment. Pregnancy; avoid. Use effective contraception during therapy and for 3 months after final dose. Nursing mothers: not recommended (during therapy and for 3 months after final dose). Adverse reactions: Fatigue, diarrhea, pruritus, rash, colitis, headache, weight loss, nausea, pyrexia, decreased appetite, vomiting, insomnia. 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. Concomitant or sequential administration with radiation treatment; monitor closely. 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, radiation sensitization and recall. How supplied: Tabs—112, 120

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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 polysorbate 80. ℞ Also: ARANESP SINGLEJECT Darbepoetin alfa 10mcg/0.4mL, 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 polysorbate 80. Indications: Anemia of chronic kidney disease (CKD), including patients on and not on dialysis. Chemotherapy-induced anemia in patients with non-myeloid malignancies.

Adults: Initiate only when hemoglobin (Hgb) <10g/dL. CKD (on dialysis): initially 0.45mcg/kg IV or SC once weekly; or 0.75mcg/kg IV or SC once every 2 weeks. Patients on hemodialysis: IV route is recommended. CKD (not on dialysis): initially 0.45mcg/kg SC or IV given once at 4 week intervals. Reduce or interrupt dose if Hgb >10g/dL (not on dialysis) or >11g/dL (on dialysis). Cancer: initially 2.25mcg/kg SC once weekly or 500mcg SC once every 3 weeks. Discontinue after completion of chemotherapy course. Use lowest dose sufficient to avoid red blood cell transfusion. Converting from epoetin alfa, and for dose adjustments: see full labeling. Children: Initiate only when hemoglobin (Hgb) <10g/dL. CKD: initially 0.45mcg/kg SC or IV once weekly; patients with CKD (not on dialysis): may also initiate at 0.75mcg/kg once every 2 weeks. Reduce or interrupt dose if Hgb >12g/dL. Cancer: not established. Contraindications: Uncontrolled hypertension. Do not use in patients with pure red cell aplasia due to erythropoietin antibodies. Warnings/Precautions: See full labeling. Increased risk of death, MI, stroke, venous thromboembolism, vascular thrombosis with Hgb >11g/dL in CKD. Increased risk of tumor progression or recurrence in breast, NSCLC, head and neck, lymphoid, cervical cancers. 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. 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, 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: CKD: hypertension, dyspnea, peripheral edema, cough, procedural hypotension. Cancer: abdominal pain, edema, thrombovascular events. How supplied: Single-dose vials (25, 40, 60, 100, 150mcg)—4; Single-dose vial (200, 300mcg)—1; Single-dose prefilled syringes (10, 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.

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ASSOCIATED HEMATOLOGICAL DISORDERS 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

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) X 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

℞

Antimetabolite. 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 and toxic range. If blood counts toxic, discontinue until hematologic recovery, see full labeling for dosage adjustments. Renal impairment (CrCl <60mL/min or ESRD): initially 7.5mg/kg/day; give dose following dialysis (monitor). Children: Not established. Warnings/Precautions: Risk of severe myelosuppression. Monitor blood counts at baseline and during therapy; interrupt or reduce dose if necessary. Markedly depressed bone marrow function: do not initiate. Monitor for malignancies. Avoid sun exposure. Macrocytosis may mask folic acid deficiency; prophylactic folic acid is recommended. Myeloproliferative disorders; discontinue if cutaneous vasculitic ulcerations occur. Obtain fetal hemoglobin (HbF) levels every 3–4 months; may be used to assess efficacy. Renal or hepatic impairment. Elderly. Embryo-fetal toxicity. Pregnancy; avoid. Exclude pregnancy prior to initiating; use effective contraception during and for ≥6 months (females) or ≥1 year (males) after therapy. Nursing mothers: not recommended. Interactions: Avoid concomitant didanosine, with or without stavudine, or other antiretrovirals (may cause pancreatitis [monitor], fatal hepatotoxicity, peripheral neuropathy). Avoid live vaccines. Increased risk of vasculitic toxicities with interferon therapy. May cause falsely elevated results in urea, uric acid, and lactic acid assays. Adverse reactions: Leukopenia, thrombocytopenia, anemia, neutropenia, GI upset, anorexia, hair loss, macrocytosis, bleeding, melanonychia; secondary malignancies. 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); preservative-free.

℞

℞ 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 HIV-infected patients. Chemotherapyinduced 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. Zidovudine-treated 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,

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DRUG MONOGRAPHS

ASSOCIATED HEMATOLOGICAL DISORDERS 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 (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

℞

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 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.

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) X 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.

Visit OncologyNurseAdvisor.com for practical clinical information geared toward oncology nurses and other cancer care professionals.

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DRUG MONOGRAPHS

ASSOCIATED HEMATOLOGICAL DISORDERS 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. 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; preservativefree. 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: ≥18yrs: 3.75mg IM once per month for up to 3 months. Children: <18yrs: not applicable. Also: LUPRON DEPOT-3 MONTH 11.25mg ℞ Leuprolide acetate 11.25mg; depot susp for IM inj; preservative-free. Adults: ≥18yrs: 11.25mg IM once every 3 months (1 injection). Do not split doses. Children: <18yrs: 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 Endo

℞

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

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DRUG MONOGRAPHS

ASSOCIATED HEMATOLOGICAL DISORDERS 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. Zidovudine-treated HIV patients: if serum erythropoietin ≤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. Chemotherapyinduced: 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; Singleuse 1mL vials (40000 Units/mL)—4; Multidose 2mL vials (10000 Units/mL)—4, 6; Multidose 1mL vials (20000 Units/mL)—4, 6

PROMACTA GlaxoSmithKline

℞

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 ≥50x109/L; max 150mg daily. Monitoring, dose adjustment, and discontinuation: see full labeling. Children: Not established. Warnings/Precautions: Increased risk of hepatic decompensation in patients with chronic hepatitis C in combination 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 ≥3xULN 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: Potentiates 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. Separate dosing by at least 2hrs before or 4hrs after food/drugs containing polyvalent cations (eg, Fe+2, Ca+2, Al+3, Mg+2, Se+2, Zn+2). Adverse reactions: Nausea, diarrhea, fatigue, cough, headache, pain, dyspnea, pyrexia, dizziness, febrile neutropenia, ecchymosis, muscle spasms, arthralgia, rhinorrhea; hepatotoxicity, hemorrhage, thrombotic/thromboembolic complications, cataracts. How supplied: Tabs—30

REVLIMID Celgene

℞

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,

Access Cancer Therapy Advisor treatment regimens in a user-friendly format. CancerTherapyAdvisor.com/TreatmentRegimens.

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DRUG MONOGRAPHS

ASSOCIATED HEMATOLOGICAL DISORDERS 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, 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

℞

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: <10 yrs: 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

℞

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 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

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DRUG MONOGRAPHS

ASSOCIATED HEMATOLOGICAL DISORDERS Bleeding disorders

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

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 transfusion-related 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

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ASSOCIATED HEMATOLOGICAL DISORDERS 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 (nonactivated); 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 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/lifethreatening 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

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ASSOCIATED HEMATOLOGICAL DISORDERS 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. 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

NEUMEGA Pfizer

℞

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)

℞

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

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ASSOCIATED HEMATOLOGICAL DISORDERS 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

NPLATE Amgen

℞

Thrombopoietin receptor agonist. Romiplostim (recombinant) 250mcg, 500mcg; per vial; lyophilized pwd for SC inj after reconstitution; contains sucrose and mannitol; preservativefree. 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 ≥50x109/L. ≥18yrs: initially: 1mcg/kg weekly; may increase by 1mcg/kg if platelets <50x109/L; max: 10mcg/kg weekly. May reduce by 1mcg/kg if platelets >200x109/L for 2 consecutive weeks. Do not dose if platelets >400x109/L; resume Nplate at a dose reduced by 1mcg/kg when platelets fall to <200x109/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. 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 ≥50x109/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 ≥3xULN 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.

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ASSOCIATED HEMATOLOGICAL DISORDERS 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

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)

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DRUG MONOGRAPHS

ASSOCIATED HEMATOLOGICAL DISORDERS WILATE Octapharma

WINRHO SDF

℞

Emergent BioSolutions

Coagulation factor complex. Von Willebrand Factor/Factor VIII Complex (human); 500 IU VWF:RCo and 500 IU FVIII activities per 5mL; 1000 IU VWF:RCo and 1000 IU FVIII activities per 10mL; pwd for IV injection after reconstitution; preservative-free; solventdetergent treated. Indications: On-demand treatment and control of bleeding episodes in patients with von Willebrand disease (VWD). Perioperative management of bleeding in patients with VWD. 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 as needed. Major bleed: 40–60 IU/kg once, then 20–40 IU/kg every 12–24 hours as needed. Surgery (give loading dose within 3hrs before); Minor: 30–60 IU/kg once, then 15–30 IU/kg every 12–24 hours; Major: 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, minor surgery), 5–7 days (major hemorrhage), or ≥6 days (major surgery). See full labeling. Warnings/Precautions: 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. Nursing mothers. Adverse reactions: Urticaria, dizziness, hypersensitivity reactions; antibody formation. How supplied: Kit—1 (w. diluent, supplies)

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; preservative-free. 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)

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)

2–3

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

INTERPRETATION OF CHILD-PUGH SCORES 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%

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DRUG MONOGRAPHS

ASSOCIATED HEMATOLOGICAL DISORDERS 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 benefits prior to treatment and discontinue if sickle cell crisis develops. Hepatic or moderate-to-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 nonHodgkin’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 for SC inj; preservative-free.

℞

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. To increase survival in patients acutely exposed to myelosuppressive doses of radiation. Adults and Children: See full labeling. ≥45kg: Chemotherapy-induced neutropenia: Do not give between 14 days before and 24 hours after chemotherapy. 6mg SC once per chemotherapy cycle. Acute radiation syndrome: 2 doses, each of 6mg SC; give 1st dose as soon as possible after exposure to radiation levels >2 gray (Gy), then a 2nd dose one week later. Pediatrics weighing 31–44kg: 4mg; 21–30kg: 2.5mg; 10–20kg: 1.5mg; <10kg: 0.1mg/kg. Direct administration of prefilled syringe with doses <6mg is not recommended. Warnings/Precautions: Monitor CBC and platelets before and during therapy. Monitor for splenomegaly, splenic rupture, acute respiratory distress syndrome (ARDS); evaluate if fever, lung infiltrates, or respiratory distress occurs; discontinue if ARDS diagnosed. Monitor for glomerulonephritis; consider dose reduction or interruption if treatment-related. Permanently discontinue if serious allergic reactions develop. Sickle cell disease: may cause severe sickle cell crises. Myeloid malignancies. Myelodysplasia. Acrylic adhesive allergy (On-body injector). Pregnancy (Cat.C). Nursing mothers. Interactions: May cause transient (+) changes in bone-imaging test results. Adverse reactions: Bone or extremity pain; anaphylaxis, ARDS, splenic rupture, glomerulonephritis, leukocytosis, capillary leak syndrome (monitor closely if occurs). How supplied: Prefilled syringe—1; Onpro Kit—1 (prefilled syringe + On-body injector)

NEUPOGEN Amgen

℞

Granulocyte colony stimulating factor. Filgrastim 600mcg/mL; for SC inj 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 or consolidation chemotherapy treatment of adults with AML. To reduce duration of neutropenia and related sequelae in patients

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DRUG MONOGRAPHS

ASSOCIATED HEMATOLOGICAL DISORDERS with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by bonemarrow 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 acute 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

ZARXIO Sandoz

℞

Granulocyte colony stimulating factor. Filgrastimsndz 300mcg/0.5mL, 480mcg/0.8mL; for SC inj 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 or 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 bonemarrow 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.

Warnings/Precautions: Monitor blood, including CBC and differential and platelets, before and during therapy (myelosuppressive chemotherapy: monitor twice weekly; BMT: monitor frequently; SCN: monitor during initial 4 weeks of therapy and during 2 weeks after dose adjustment) then monthly for the 1st year. 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 acute respiratory distress syndrome (ARDS); discontinue if ARDS occurs. Confirm diagnosis and do appropriate pretreatment hematological workup in SCN. Permanently discontinue if serious allergic reactions occur. Sickle cell disease (may cause sickle cell crisis). Evaluate if glomerulonephritis is suspected; consider dose reduction or interruption if causality is likely. Abnormal cytogenetics or myelodysplastic syndrome. Chronic myeloid leukemia. Hold dose if cutaneous vasculitis occurs; resume at reduced dose after symptoms resolve and the ANC decreased. Avoid simultaneous chemoand radiation therapy. Latex allergy. Pregnancy (Cat.C). Nursing mothers. Interactions: May cause transient (+) boneimaging results. Adverse reactions: Pyrexia, pain, rash, cough, dyspnea, epistaxis, bone pain, headache, anemia, diarrhea, hypoesthesia, alopecia; capillary leak syndrome (monitor), thrombocytopenia. How supplied: Single-use prefilled syringes (0.5mL, 0.8mL)—1, 10 (w. needle guard)

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DRUG MONOGRAPHS

ASSOCIATED HEMATOLOGICAL DISORDERS Miscellaneous hematological agents

CINRYZE Shire

℞

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 <50x109/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

BRAND NAME The main name under which the product and all other dosage forms in the monograph are marketed.

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DRUG MONOGRAPHS

ASSOCIATED HEMATOLOGICAL DISORDERS 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 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 Shire

℞

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

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.

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Brand name–bold type Generic name–light type Medical condition–red type *-product contains other active ingredients ext-external inj-injectable.

A Abiraterone Zytiga Abraxane (inj) cancer, breast cancer, pancreatic non-small cell lung cancer Actinic keratoses Adcetris (inj) Ado-trastuzumab Kadcyla Afatinib Gilotrif Afinitor cancer, breast cancer, renal progressive neuroendocrine tumors of pancreatic origin (pnet) progressive non-functional neuroendocrine tumors (net) of gastrointestinal or lung origin subependymal giant cell astrocytoma (sega) Aldesleukin Proleukin (inj) Alecensa Alectinib Alecensa Alemtuzumab Campath (inj) Alimta (inj) Alitretinoin Panretin (ext) Altretamine Hexalen Amicar Aminocaproic acid Amicar Anadrol-50 Anaplastic astrocytoma Anastrozole Arimidex Anemia Angioedema, hereditary Anti-inhibitor Coagulant Complex Feiba (inj) Anti-thymocyte globulin Atgam (inj)* Antihemophilic Factor VIII Helixate FS (inj) Humate-P (inj)* ReFacto (inj) Xyntha (inj) Aplastic anemia Aranesp (inj) Arimidex Aromasin Arranon Arsenic trioxide Trisenox (inj)

53 13 20 83 92 64 16 86 13 46 20 20 3 50, 95 83 83 66 83 91 58 103 103 97 3 13 97–102 111–112 104 97 104 104 107 108 97 97 13 13 64 80

ALPHABETICAL INDEX

Arzerra (inj) 64 Asparaginase Erwinia chrysanthemi Erwinaze (inj) 68 Atgam (inj) 97 Atypical hemolytic uremic syndrome 102 Avastin (inj) cancer, cervical 3, 30, 46, 58, 83 cancer, colorectal 3, 30, 46, 58, 83 cancer, ovarian 3, 30, 58, 83 cancer, renal 3, 30, 46, 58, 83 glioblastoma 3, 30, 46, 58, 83 non-small cell lung cancer 3, 30, 46, 58, 83 Axitinib Inlyta 48 Azacitidine Vidaza (inj) 81

B Basal cell carcinoma BCG, live TheraCys (inj) Beleodaq (inj) Belinostat Beleodaq (inj) Bendamustine Bendeka (inj) Treanda (inj) Bendeka (inj) Bevacizumab Avastin (inj) Bexarotene Targretin Targretin (ext) Bexxar Bicalutamide Casodex Bifera BiferaRx Bleeding Blinatumomab Blincyto (inj) Blincyto (inj) Bone metastases Bortezomib Velcade (inj) Bosulif Bosutinib Bosulif Brentuximab vedotin Adcetris (inj) Busulfan Busulfex (inj) Myleran Busulfex (inj)

92, 94 51 64 64 65 79 65 3, 30, 46, 58, 83 77 78 65 47 97 98 103–105, 107 65 65 2, 82 80 66 66 64 66 74 66

C C1 inhibitor Cinryze (inj)

111

Cabazitaxel Jevtana (inj) Cabometyx Cabozantinib Cabometyx Cometriq Campath (inj) Cancer, bladder Cancer, breast

48 46

46 21 66 51–52 1, 13–19, 21, 31–32, 34, 47, 59–60, 79, 89 Cancer, cervical 3, 30, 46, 58, 83, 86 Cancer, colorectal 3, 15, 19, 21, 30–34, 46, 58, 60, 83 Cancer, GI 15, 30, 32 Cancer, head and neck 1, 4, 18, 31, 59–60, 79, 89 Cancer, liver 33, 49 Cancer, lung 1, 18, 58–60, 73, 79, 83, 86–89 Cancer, ovarian 3, 30, 58–59, 68, 83, 86, 91 Cancer, pancreatic 15, 20–23, 31, 33, 50, 88 Cancer, prostate 14, 47–50, 52–53 Cancer, renal 3, 30, 33, 46, 48–52, 58, 83, 95 Cancer, sarcoma 1 Cancer, stomach 15, 21, 31 Cancer, testicular 48 Cancer, thyroid 20–22, 33, 49 Capecitabine Xeloda 19, 34 Caprelsa 20 Carfilzomib Kyprolis (inj) 72 Carimune NF (inj) 103 Casodex 47 Ceritinib Zykadia 90 Cerubidine (inj) 66 Cetuximab Erbitux (inj) 31, 60 Chlorambucil Leukeran 73 Chorioadenoma destruens 1, 18, 59–60, 79, 89 Choriocarcinoma, gestational 1, 18, 59–60, 79, 89 Chronic kidney disease 100 Cinryze (inj) 111 Clofarabine Clolar (inj) 67 Clolar (inj) 67 Cobimetinib Cotellic 92 Colorectal cancer 31 Cometriq 21 Congenital Factor VIII deficiency 107 Congenital Factor XIII deficiency 103 Congenital fibrinogen deficiency 107 Corifact (inj) 103 Cotellic 92 Crizotinib Xalkori 89 Cyanocobalamin Nascobal (nasal) 100

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ALPHABETICAL INDEX Cyklokapron (inj) Cyramza (inj) cancer, gi cancer, lung Cytarabine DepoCyt (inj)

103 30 86 68

D Dabrafenib Tafinlar Dacogen (inj) Daratumumab Darzalex (inj) Darbepoetin alfa Aranesp (inj) Darzalex (inj) Dasatinib Sprycel Daunorubicin Cerubidine (inj) Decitabine Dacogen (inj) Deferasirox Exjade Deferiprone Ferriprox Degarelix Firmagon (inj) Delatestryl Delestrogen (inj) Denileukin diftitox Ontak (inj) Denosumab Xgeva (inj) DepoCyt (inj) Dermatofibrosarcoma protuberans DexFerrum (inj) Dinutuximab Unituxin (inj) Docusate sodium Ferralet 90* Doxil (inj) cancer, ovarian kaposi’s sarcoma multiple myeloma Doxorubicin, liposomal Doxil (inj) Droxia

96 67 67 97 67 76 66 67 111 111 48 14 47 74 2 68 31, 70, 93 98 4 99 58, 68, 91 58, 68, 91 58, 68, 91 58, 68, 91 98

E Ecallantide Kalbitor (inj) Eculizumab Soliris (inj) Efudex (ext) Eligard Elotuzumab Empliciti (inj)

112 102 92 47 68

Brand name–bold type Generic name–light type Medical condition–red type *-product contains other active ingredients ext-external inj-injectable.

Eloxatin (inj) Eltrombopag Promacta Emcyt Empliciti (inj) Enzalutamide Xtandi Epoetin alfa Epogen (inj) Procrit (inj) Epogen (inj) Erbitux (inj) cancer, colorectal cancer, head and neck Eribulin Halaven (inj) Erivedge Erlotinib Tarceva Erwinaze (inj) Erythema nodosum leprosum Esophageal varices Estrace cancer, breast cancer, prostate Estradiol Estrace Estradiol valerate Delestrogen (inj) Estramustine Emcyt Estrogens, conjugated Premarin Estrogens, esterified Menest Ethamolin (inj) Ethanolamine Ethamolin (inj) Everolimus Afinitor Evista Exemestane Aromasin Exjade

30 101, 106 47 68 53 98 101 98 31, 60 31, 60 1, 15 92 23, 88 68 78 104 14, 47 14, 47 14, 47 47 47 17, 50 49 104 104 3, 13, 20, 46 14 13 111

F Factor VIII complex Wilate (inj)* Factor XIII Corifact (inj) Farydak Faslodex (inj) Feiba (inj) Femara Feraheme (inj) Ferralet 90 Ferric carboxymaltose Injectafer

108 103 68 14 104 14 99 99 100

Ferriprox Ferrlecit (inj) Fibrinogen RiaSTAP (inj) Filgrastim Neupogen (inj) Filgrastim-sndz Zarxio (inj) Firazyr (inj) Firmagon (inj) Fludara (inj) Fludarabine Fludara (inj) Fluorouracil Efudex (ext) Fluorouracil Fluorouracil cancer, breast cancer, colorectal cancer, pancreatic cancer, stomach Flutamide Folic acid BiferaRx* Ferralet 90* Folic acid Trinsicon* Fulvestrant Faslodex (inj) Fusilev (inj)

111 99 107 109 110 112 48 69 69 92 15, 21, 31 15, 21, 31 15, 21, 31 15, 21, 31 15, 21, 31 48 98 99 99 102 14 31

G Gamunex-C (inj) 104 Gazyva (inj) 69 Gefitinib Iressa 87 GI stromal tumors 22, 31, 33, 50, 70, 93 Gilotrif 86 Gleevec dermatofibrosarcoma protuberans 31, 70, 93 gi stromal tumors 31, 70, 93 hypereosinophilic syndrome 31, 70, 93 leukemia, acute myeloid 31, 70, 93 leukemia, chronic eosinophilic 31, 70, 93 leukemia, chronic myelogenous 31, 70, 93 mastocytosis 31, 70, 93 myelodysplastic syndromes 31, 70, 93 Glioblastoma 3, 30, 46, 58, 83 Granix (inj) 109

H Halaven (inj) cancer, breast 15 cancer, sarcoma 1 Helixate FS (inj) 104 Hematopoietic stem cell mobilizer 112 Hemophilia 103–104 Hemophilia A 104, 107–108

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Brand name–bold type Generic name–light type Medical condition–red type *-product contains other active ingredients ext-external inj-injectable. Herceptin (inj) cancer, breast 15, 32 cancer, gi 15, 32 Hexalen 58 Histrelin Vantas 52 Hodgkin lymphoma 64 Hodgkin’s disease 73, 87 Humate-P (inj) 104 Hycamtin cancer, cervical 58, 86 cancer, lung 58, 86 cancer, ovarian 58, 86 Hydatidiform mole 1, 18, 59–60, 79, 89 Hydrea cancer, head and neck 60 leukemia, chronic myeloid 70 Hydroxyurea Droxia 98 Hydrea 60, 70 Hypercalcemia 82 Hypereosinophilic syndrome 31, 70, 93 Hypogonadism 14

lymphoma, follicular melanoma

71, 91, 93 71, 91, 93

Iodine I 131 Tositumomab Bexxar*

Ipilimumab Yervoy (inj)

Iressa

Irinotecan Onivyde (inj)

Iron (as carbonyl) Ferralet 90*

Iron (as dextran complex) DexFerrum (inj) INFeD (inj)

98 99

Iron (as ferumoxytol) Feraheme (inj)

Iron (as polysaccharide iron complex + heme iron polypeptide) Bifera BiferaRx*

97 98

Iron (as sucrose) Venofer (inj)

102

Iron deficiency anemia

100

Iron fumarate Trinsicon*

102

Iron gluconate Ferrlecit (inj) Nulecit (inj)

99 100

Istodax

Ixabepilone Ixempra (inj)

Ixazomib Ninlaro

Ixempra (inj)

I Ibrance Ibritumomab Zevalin (inj) Ibrutinib Imbruvica Icatibant Firazyr (inj) Iclusig Idamycin (inj) Idarubicin Idamycin (inj) Idelalisib Zydelig Idiopathic thrombocytopenic purpura Ifex (inj) Ifosfamide Ifex (inj) Imatinib Gleevec Imbruvica Imlygic (inj) Immune globulin Carimune NF (inj) Gamunex-C (inj) Privigen (inj) Immunomodulators INFeD (inj) Injectafer Inlyta Interferon alfa-2b Intron A (inj) Intron A (inj) kaposi’s sarcoma leukemia, hairy cell

ALPHABETICAL INDEX

112 70 71 71 82 103–104, 106–108 48 48 31, 70, 93 71 93 103 104 106 109 99 100 48

J Jakafi

Jevtana (inj)

K Kadcyla Kalbitor (inj) Kaposi’s sarcoma

16 112 58, 68, 71, 91, 93

KCentra (inj)

105

Keytruda (inj)

Kyprolis (inj)

L Lanreotide Somatuline Depot (inj)

Lapatinib Tykerb

71, 91, 93

Lenalidomide Revlimid

71, 91, 93 71, 91, 93

Lenvatinib Lenvima

75, 101 21

Lenvima Letrozole Femara Leucovorin anemia cancer, colorectal Leukemia Leukemia, acute lymphoblastic

21 14

100 32 73, 87 65, 67–68, 70, 73–76, 81 Leukemia, acute lymphocytic 66, 75 Leukemia, acute myeloid 31, 70–71, 93 Leukemia, acute nonlymphocytic 66, 77 Leukemia, acute promyelocytic 80–81 Leukemia, B-cell chronic lymphocytic 66, 69 Leukemia, chronic eosinophilic 31, 70, 93 Leukemia, chronic lymphocytic 64–65, 69, 71, 76, 79, 82 Leukemia, chronic myelogenous 31, 66, 70, 74, 76–78, 93 Leukemia, chronic myeloid 70 Leukemia, hairy cell 71, 91, 93 Leukemia, T-cell acute lymphoblastic 64 Leukeran 73 Leukine (inj) 109 Leuprolide Eligard 47 Lupron Depot 3.75mg (inj) 100 Lupron Depot 7.5mg (inj) 49 Levoleucovorin Fusilev (inj) 31 Lonsurf 32 Lupron Depot 3.75mg (inj) 100 Lupron Depot 7.5mg (inj) 49 Lymphocyte immune globulin Atgam (inj)* 97 Lymphoma, cutaneous T-cell 72, 74, 77–78, 80, 82 Lymphoma, follicular 71, 82, 91, 93 Lymphoma, malignant 73 Lymphoma, mantle cell 71, 80 Lymphoma, peripheral T-cell 64, 72 Lymphoma, small lymphocytic 82 Lymphoma, T-cell lymphoblastic 64 Lymphomatous meningitis 68 Lymphosarcoma 73, 87 Lynparza 59

M Malignant pleural mesothelioma Mantle cell lymphoma Marqibo (inj) Mastocytosis Mechlorethamine Mustargen (inj) Valchlor (ext) Mekinist Melanoma Melanoma, metastatic

83 75 73 31, 70, 93 73, 87 80 94 71, 91–96 50, 95

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ALPHABETICAL INDEX Menest Mercaptopurine Purinethol Purixan Methotrexate Trexall Methoxsalen Uvadex Mozobil (inj) Multiple myeloma

49 75 75 1, 18, 59–60, 79, 89 80 112 58, 67–68, 72, 74–75, 78, 80, 82, 91

Mustargen (inj) cancer, lung hodgkin’s disease leukemia lymphosarcoma mycosis fungoides polycythemia vera Mycosis fungoides

73, 87 73, 87 73, 87 73, 87 73, 87 73, 87 1, 18, 59–60, 73, 79, 87, 89 Mycosis fungoides-type cutaneous T-cell lymphoma 80 Myelodysplastic syndromes 31, 67, 70, 81, 93 Myleran 74

Non-small cell lung cancer Nplate (inj) Nulecit (inj)

Odomzo

Ofatumumab Arzerra (inj)

Olaparib Lynparza

Omacetaxine mepesuccinate Synribo (inj)

Oncaspar (inj)

Onivyde (inj)

Ontak (inj)

Opdivo (inj) cancer, lung cancer, renal melanoma

88 49 94

Oprelvekin Neumega (inj)

105

Osimertinib Tagrisso

Oxaliplatin Eloxatin (inj)

Oxymetholone Anadrol-50

100 87

13, 20, 83

Palbociclib Ibrance

Panitumumab Vectibix (inj)

64 47, 51–52 109 105 109 4 22, 33, 50 109–110

Panobinostat Farydak

Panretin (ext)

Pegaspargase Oncaspar (inj)

33, 49 33, 49 22, 33, 49

Pegfilgrastim Neulasta (inj)

109

Peginterferon alfa-2b Sylatron (inj)

78 74 105

Pembrolizumab Keytruda (inj)

Pemetrexed Alimta (inj)

Perjeta (inj)

Pertuzumab Perjeta (inj)

Plerixafor Mozobil (inj)

112

49, 88, 94 1, 18, 59–60, 65, 76, 79, 81, 89 3, 23, 30, 46, 58, 83, 86–90 106 100

O Obinutuzumab Gazyva (inj)

Paclitaxel, protein-bound Abraxane (inj)

Paroxysmal nocturnal hemoglobinuria

102

Pazopanib Votrient

1, 52

Poisoning/overdose Polycythemia vera

Portrazza (inj) 88 Premarin cancer, breast 17 cancer, prostate 50 Privigen (inj) 106 Procrit (inj) 101 Progressive neuroendocrine tumors of pancreatic origin (pNET) 20 Progressive non-functional neuroendocrine tumors (NET) of gastrointestinal or lung origin 20 Proleukin (inj) cancer, renal 50, 95 melanoma, metastatic 50, 95 Promacta anemia 101 thrombocytopenia 106 Prothrombin complex concentrate (human) KCentra (inj) 105 Provenge (inj) 50 Purinethol 75 Purixan 75

N Nascobal (nasal) Navelbine (inj) Necitumumab Portrazza (inj) Nelarabine Arranon Neoplasms Neulasta (inj) Neumega (inj) Neupogen (inj) Neuroblastoma Neuroendocrine tumors Neutropenia Nexavar cancer, liver cancer, renal cancer, thyroid Nilotinib Tasigna Ninlaro Nitropress (inj) Nivolumab Opdivo (inj) Non-Hodgkin’s lymphoma

Brand name–bold type Generic name–light type Medical condition–red type *-product contains other active ingredients ext-external inj-injectable.

111 72–73, 87

Pomalidomide Pomalyst

Pomalyst

Ponatinib Iclusig

Radium Ra 223 dichloride Xofigo (inj) Raloxifene Evista Ramucirumab Cyramza (inj) Recothrom ReFacto (inj) Regorafenib Stivarga Revlimid anemia mantle cell lymphoma multiple myeloma Rho(D) immune globulin Rhophylac (inj) WinRho SDF (inj) Rhophylac (inj) RiaSTAP (inj) Rituxan (inj) Rituximab Rituxan (inj) Romidepsin Istodax Romiplostim Nplate (inj) Ruxolitinib Jakafi

53 14 30, 86 107 107 33 101 75 75 107 108 107 107 76 76 72 106 72

S Sargramostim Leukine (inj) Sickle cell anemia Sipuleucel-T Provenge (inj)

109 98 50

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Brand name–bold type Generic name–light type Medical condition–red type *-product contains other active ingredients ext-external inj-injectable. Skeletal-related events Sodium nitroprusside Nitropress (inj) Soliris (inj) Soltamox Somatuline Depot (inj) Sonidegib Odomzo Sorafenib Nexavar Sprycel Stivarga Subependymal giant cell astrocytoma (SEGA) Sunitinib Sutent Superficial basal cell carcinoma Surgical bleed Sutent cancer, pancreatic gi stromal tumors neuroendocrine tumors Sylatron (inj) Synribo (inj) Systemic anaplastic large cell lymphoma (sALCL)

2 105 102 17 22 94 22, 33, 49 76 33 3 22, 33, 50 92 105 22, 33, 50 22, 33, 50 22, 33, 50 95 77 64

T Tabloid Tafinlar Tagrisso Talimogene laherparepvec Imlygic (inj) Tamoxifen Soltamox Tamoxifen Tarceva cancer, pancreatic non-small cell lung cancer Targretin Targretin (ext) Tasigna Tbo-filgrastim Granix (inj) Temodar Temozolomide Temodar Temsirolimus Torisel (inj) Teniposide Vumon (inj) Testosterone enanthate Delatestryl Thalidomide Thalomid Thalomid TheraCys (inj) Thioguanine Tabloid

77 96 88 93 17 18 23, 88 23, 88 77 78 78 109 3 3 51 81 14 78 78 51 77

Thrombin Recothrom Thrombin-JMI Thrombin-JMI Thrombocytopenia Tipiracil Lonsurf* Topotecan Hycamtin Torisel (inj) Tositumomab Bexxar* Trametinib Mekinist Tranexamic acid Cyklokapron (inj) Trastuzumab Herceptin (inj) Treanda (inj) Trelstar (inj) Tretinoin Vesanoid Trexall cancer, breast cancer, head and neck cancer, lung chorioadenoma destruens choriocarcinoma, gestational hydatidiform mole mycosis fungoides non-hodgkin’s lymphoma Trifluridine Lonsurf* Trinsicon Triptorelin Trelstar (inj) Trisenox (inj) Tykerb

ALPHABETICAL INDEX Venofer (inj) 107 107 107 105–106 32 58, 86 51

Vinorelbine Navelbine (inj)

Vismodegib Erivedge VKA reversal

Von Willebrand Factor Humate-P (inj)* Wilate (inj)*

15, 32 79 52 81 1, 18, 59–60, 79, 89 1, 18, 59–60, 79, 89 1, 18, 59–60, 79, 89

92 105 104, 108 104 108

Vorinostat Zolinza

Votrient cancer, renal cancer, sarcoma

52 1

Vumon (inj)

W Wilate (inj)

108

WinRho SDF (inj)

108

1, 18, 59–60, 79, 89 1, 18, 59–60, 79, 89 1, 18, 59–60, 79, 89 1, 18, 59–60, 79, 89 1, 18, 59–60, 79, 89 32 102 52 80 18

X Xalkori Xeloda cancer, breast cancer, colorectal

4 80

80 52 52 20 52 34 80 96

89 19, 34 19, 34

Xgeva (inj)

Xofigo (inj)

Xtandi Xyntha (inj)

53 108

Y Yervoy (inj)

V Valchlor (ext) Valrubicin Valstar Valstar Vandetanib Caprelsa Vantas Vectibix (inj) Velcade (inj) Vemurafenib Zelboraf

Vincristine sulfate liposome Marqibo (inj)

Von Willebrand disease

U Unituxin (inj) Uvadex

Vidaza (inj)

103

102

Vesanoid

Z Zaltrap (inj)

Zarxio (inj)

110

Zelboraf

Zevalin (inj)

Ziv-aflibercept Zaltrap (inj)

Zoledronic acid Zometa

Zolinza

Zometa

Zydelig

Zykadia

Zytiga

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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 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 Merrimack Pharmaceuticals, Inc. (844) 441-6225 Millennium Pharmaceuticals, Inc. (866) 835-2233 Mission Pharmacal Company (210) 696-8400 (800) 292-7364 Novartis Pharmaceuticals Corp (800) 693-9993 (973) 503-8300 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 Roche Laboratories (800) 526-6367 (973) 235-5000 Sandoz (609) 627-8500 Sanofi Aventis (800) 446-6267 (800) 633-1610 Sanofi Pasteur, Inc. (800) 822-2463 Sanofi US and Regeneron (800) 633-1610 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 Taiho Oncology (609) 750-5300 Takeda Pharmaceuticals North America, Inc. (877) 825-3327 (847) 383-3000 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 Warner Chilcott Laboratories (800) 521-8813 (973) 442-3200 ZymoGenetics, Inc. (800) 775-6686 (206) 442-6600

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TARGETING CANCER STEM CELL PATHWAYS AND STEMNESS Not all cells within a tumor are equal Despite current advances in cancer therapy, tumor recurrence and metastasis remain a clinical challenge.1 A potential new approach to address this is the targeting of a subset of the tumor cell population known as cancer stem cells (CSCs). CSCs are highly tumorigenic, unlike bulk tumor cells.2 Molecular surface markers for CSCs have been demonstrated within multiple solid and hematologic tumor types, supporting the notion that not all cells within a tumor are equal.3,4 This is the basis of the CSC model.2

The CSC model may help explain tumor recurrence The CSC model is a radical departure from the clonal evolution model. In the clonal evolution model, all cells within a malignant tumor have similar tumorigenic activity.5 By contrast, in the CSC model only a subset of tumor cells, CSCs, have tumor-initiating capability.2 Cancers are organized in a cellular hierarchy, with the CSCs at their apex having tumor-initiating capability.5 One important clinical implication of the CSC model is that it may help to explain why early tumor shrinkage is often poorly predictive of overall survival.6,7 While conventional therapies kill the bulk of non-stem cancer cells, resulting in tumor shrinkage, CSCs may remain viable and later reestablish the tumor, leading to relapse.8 Tumors with increased expression of genes associated with CSCs have also been correlated with lower overall survival in breast and lung cancers.9

Stemness of CSCs may lead to tumorigenicity The heterogeneous high tumorigenicity of CSCs may be a direct result of their stemness. In both normal stem cells and CSCs, stemness is defined by the characteristics of self-renewal and differentiation.8 Unlike normal stem cells, which differentiate into healthy, mature, cell types, CSCs differentiate into cancer cells. The stemness of CSCs is maintained by several signaling pathways that are overexpressed and overactivated, including JAK-STAT, Wnt/Î˛-catenin, Hedgehog, Nanog, Notch, TGF-Î˛, Hippo-YAP/TAZ, and PI3K/Akt.10-14 These stemness pathways maintain stemness and promote tumorigenicity. This makes CSCs phenotypically different from non-stem cancer cells and confers therapy resistance.4 References: 1. Li Y, Rogoff HA, Keates S, et al. Suppression of cancer relapse and metastasis by inhibiting cancer stemness. Proc Natl Acad Sci U S A. 2015;112(6):1839-1844. 2. Fanali C, Lucchetti D, Farina M, et al. Cancer stem cells in colorectal cancer from pathogenesis to therapy: controversies and perspectives. World J Gastroenterol. 2014;20(4):923-942. 3. Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med. 1997;3(7):730-737. 4. Botchkina G, Ojima I. Prostate and colon cancer stem cells as a target for anti-cancer drug development. In: Shostak S, ed. Cancer Stem Cells Theories and Practice. Rijeka, Croatia: InTech; 2011. 5. Marjanovic ND, Weinberg RA, Chaffer CL. Cell plasticity and heterogeneity in cancer. Clin Chem. 2013;59(1):168-179. 6. Coart E, Saad ED, Shi Q, et al. Trial-level association between response-based endpoints and progression-free/overall survival in 1st-line therapy for metastatic colorectal cancer in the ARCAD database. J Clin Oncol. 2015;33(suppl 3; abstr 666). 7. Zabor EC, Heller G, Schwartz LH, Chapman PB. Correlating surrogate endpoints with overall survival at the individual patient level in BRAFV600E-mutated metastatic melanoma patients treated with vemurafenib. Clin Cancer Res. 2016;22(6):1341-1347. 8. Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001;414(6859):105-111. 9. Liu R, Wang X, Chen GY, et al. The prognostic role of a gene signature from tumorigenic breast-cancer cells. N Engl J Med. 2007;356(3):217-226. 10. Kim JK, Jeon HY, Kim H. The molecular mechanisms underlying the therapeutic resistance of cancer stem cells. Arch Pharm Res. 2015;38(3):389-401. 11. Karamboulas C, Ailles L. Developmental signaling pathways in cancer stem cells of solid tumors. Biochim Biophys Acta. 2013;1830(2):2481-2495. 12. Hernandez-Vargas H, Ouzounova M, Le Calvez-Kelm F, et al. Methylome analysis reveals Jak-STAT pathway deregulation in putative breast cancer stem cells. Epigenetics. 2011;6(4):428-439. 13. Watabe T, Miyazono K. Roles of TGF-beta family signaling in stem cell renewal and differentiation. Cell Res. 2009;19(1):103-115. 14. Mo JS, Park HW, Guan KL. The Hippo signaling pathway in stem cell biology and cancer. EMBO Rep. 2014;15(6):642-656. 15. Yao D, Dai C, Peng S. Mechanism of the mesenchymal-epithelial transition and its relationship with metastatic tumor formation. Mol Cancer Res. 2011;9(12):1608-1620. 16. Fabregat I, Malfettone A, Soukupova J. New insights into the crossroads between EMT and stemness in the context of cancer. J Clin Med. 2016;5(3):E37. 17. Gupta PB, Onder TT, Jiang G, et al. Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell. 2009;138(4):645-659. 18. Rycaj K, Tang DG. Cancer stem cells and radioresistance. Int J Radiat Biol. 2014;90(8):615621. 19. Li X, Lewis MT, Huang J, et al. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer Inst. 2008;100(9):672-679. 20. Lagadec C, Vlashi E, Della Donna L, Dekmezian C, Pajonk F. Radiation-induced reprogramming of breast cancer cells. Stem Cells. 2012;30(5):833-844. 21. Visvader JE, Lindeman GJ. Cancer stem cells: current status and evolving complexities. Cell Stem Cell. 2012;10(6):717-728. 22. Oh SJ, Noh KH, Lee YH, et al. Targeting stemness is an effective strategy to control EML4-ALK+ non-small cell lung cancer cells. Oncotarget. 2015;6(37):40255-40267. EDU-NPS-0108 6/2016 ÂŠ2016 Boston Biomedical

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Epithelial-mesenchymal transition (EMT) of CSCs may lead to metastasis CSCs are also able to transform to a mesenchymal state by the process of EMT. In this state, CSCs become highly migratory and invasive and therefore prone to metastasis.13,15 After spreading to a distant site, they can undergo mesenchymal-epithelial transition and become tumorigenic, colonizing the new site.15 This is a potential mechanism for how CSCs contribute to metastasis and recurrence. Some evidence suggests that EMT and stemness may be coupled, as they are mediated by many of the same factors.16

CSCs are highly resistant to conventional cancer therapies Although current chemotherapies and radiotherapy can kill most non-stem cancer cells, CSCs remain highly resistant.17,18 Further, conventional therapies have been shown to increase the percentage of CSCs within malignant residual tumors.19,20 Many mechanisms that mediate the therapy resistance of CSCs have been identified, including overactivated stemness signaling.10 A key implication of the CSC model for cancer treatment is that both CSCs and non-stem cancer cells should be targeted to reduce tumor recurrence and metastasis.19,21 Several approaches to targeting CSCs are being studied, including stemness-associated signaling pathways that may mediate tumorigenesis, metastasis, and resistance.1,22 The next generation of cancer therapeutics is in development with investigational agents designed to inhibit stemness pathways.1

Learn more at www.bostonbiomedical.com

Boston Biomedical is developing the next generation of cancer therapeutics with drugs designed to inhibit cancer stemness pathways. Clinical trials are underway with the goal of reducing recurrence and metastasis.

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