Cancer Therapy Advisor July/August 2015 Issue by Haymarket Media

JULY/AUGUST 2015 | VOL I, ISSUE 6

CancerTherapyAdvisor.com

CancerTherapyAdvisor

A16 CME ACTIVITY

Trends and Topics in the Management of Advanced Prostate Cancer

FEATURING Cancer Therapy Regimens and Oncology Drug Monographs from

A debate between experts on clinical opinions that can create challenges in the treatment of prostate cancer.

1 Bone Cancer 3 Brain Cancer 5 Breast Cancer 12 Endocrine Cancer

A24 FEATURE

 16 Gastrointestinal Cancer

The 1%: Unraveling The Causes and Optimal Treatment Options for Men with Breast Cancer

 27 Genitourinary Cancer 37 Gynecologic Cancer 40 Head and Neck Cancer

A28 VIEWPOINT

Results of Nivolumab CheckMate 057 Study May Change Treatment of NSCLC

 41 Hematologic Cancer  63 Lung Cancer 76 Sarcoma 77 Skin Cancer

JULY/AUGUST 2015 | VOL I, ISSUE 6

A30 IN THE CLINIC

Enoxaparin Efficacious, Feasible for Prevention of CTE in Advanced Pancreatic Cancer

A26 EXPERT PERSPECTIVE A Case Study from an Oncology Sexual Health Clinic: Sexual Dysfunction Evaluation

81 Associated Hematological

Disorders



Regimen included

B:17.5 in T:17 in S:14 in

CYRAMZA® (ramucirumab) PLUS PACLITAXEL SIGNIFICANTLY EXTENDED OVERALL SURVIVAL (OS)1

2 FDA APPROVALS

RAINBOW OS: MEDIAN - MONTHS (95% CI)*1

For use both as monotherapy and in combination with paclitaxel

1.0

CYRAMZA + paclitaxel (8.5, 10.8)

OS PROBABILITY

0.8

9.6

MONTHS

30% INCREASE IN MEDIAN OS

0.6

Hazard Ratio=0.81 (0.68, 0.96); P=0.017

0.4

7.4

0.2

MONTHS

CYRAMZA as a single agent, or in combination with paclitaxel, is indicated for the treatment of patients with advanced or metastatic gastric or gastroesophageal (GE) junction adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinumcontaining chemotherapy.

MAJOR OUTCOME MEASURE

CYRAMZA + paclitaxel Placebo + paclitaxel (6.3, 8.4)

Placebo + paclitaxel

0.0 0

TIME FROM RANDOMIZATION (MONTHS) Number at Risk

CYRAMZA 330 + paclitaxel Placebo 335 + paclitaxel

308

267

228

185

148

116

294

241

180

143

109

• The percentage of deaths at the time of analysis was 78% (256 patients) and 78% (260 patients) in the CYRAMZA plus paclitaxel and placebo plus paclitaxel treatment arms, respectively1 The phase III RAINBOW trial evaluated the efficacy and safety of CYRAMZA plus paclitaxel vs placebo plus paclitaxel in patients with locally advanced or metastatic gastric or GE junction adenocarcinoma with disease progression on or after prior fluoropyrimidine- and platinum-containing chemotherapy. Major efficacy outcome measure was OS. Supportive efficacy outcome measures were progression-free survival (PFS) and objective response rate (ORR). All patients were Eastern Cooperative Oncology Group performance status 0 or 1. Prior to enrollment, 97% of patients had progressed during treatment or within 4 months after the last dose of first-line chemotherapy for metastatic disease. Twenty-five percent of patients had received anthracycline in combination with platinum/fluoropyrimidine therapy, while 75% did not. Patients were randomized 1:1 to CYRAMZA 8 mg/kg (n=330) or placebo (n=335) every 2 weeks (on days 1 and 15) of each 28-day cycle. Patients in both arms received paclitaxel 80 mg/m2 on days 1, 8, and 15 of each 28-day cycle.1,3 CI=confidence interval. *Intent-to-treat (ITT) population. † ITT population. ORR was defined as complete plus partial response. Disease progression and tumor response were assessed by investigators in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.2

CYRAMZA PLUS PACLITAXEL ALSO SIGNIFICANTLY DELAYED DISEASE PROGRESSION AND PROVIDED SIGNIFICANTLY GREATER ORR VS PLACEBO PLUS PACLITAXEL (SUPPORTIVE EFFICACY OUTCOME MEASURES)*1 • Median PFS with CYRAMZA plus paclitaxel was 4.4 months (95% CI: 4.2, 5.3) vs 2.9 months (95% CI: 2.8, 3.0) with placebo plus paclitaxel (hazard ratio 0.64 [95% CI: 0.54, 0.75]; P<0.001)1 - The percentage of events at the time of analysis was 85% (279 patients) and 88% (296 patients), respectively • Significantly more patients responded to CYRAMZA combined with paclitaxel (28%; 95% CI: 23, 33) than to placebo plus paclitaxel (16%; 95% CI: 13, 20) (P<0.001)†1,2

IMPORTANT SAFETY INFORMATION FOR CYRAMZA

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. 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.

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 CYRAMZAtreated 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.

CLIENT: Lilly

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 HCP ISI 24APR2015 References: 1. CYRAMZA (ramucirumab) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2015. 2. Wilke H, Muro K, Van Cutsem E, et al; for the RAINBOW Study Group. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014;15(11):1224-1235. 3. Data on file, Eli Lilly and Company. ONC09302014b. RB97064

05/2015 PRINTED IN USA

“A size”

ARTIST: MC

LOCATION: Mechanicals

COLLECT DATE:

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M02 CP M

ACD

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

FINISH SIZE: 17” wide x 11” high

JOB#: 29889-23

• 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%). • 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).

i n s er v

T:11 in

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

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.

B:11.25 in

Warnings and Precautions

VISIT WWW.CYRAMZAHCP.COM FOR MORE INFORMATION, INCLUDING CYRAMZA MONOTHERAPY TRIAL DATA

S:9.625 in

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.

B:17.5 in T:17 in S:14 in

CYRAMZA® (ramucirumab) PLUS PACLITAXEL SIGNIFICANTLY EXTENDED OVERALL SURVIVAL (OS)1

2 FDA APPROVALS

RAINBOW OS: MEDIAN - MONTHS (95% CI)*1

For use both as monotherapy and in combination with paclitaxel

1.0

CYRAMZA + paclitaxel (8.5, 10.8)

OS PROBABILITY

0.8

9.6

MONTHS

30% INCREASE IN MEDIAN OS

0.6

Hazard Ratio=0.81 (0.68, 0.96); P=0.017

0.4

7.4

0.2

MONTHS

MAJOR OUTCOME MEASURE

CYRAMZA + paclitaxel Placebo + paclitaxel (6.3, 8.4)

Placebo + paclitaxel

0.0 0

TIME FROM RANDOMIZATION (MONTHS) Number at Risk

CYRAMZA 330 + paclitaxel Placebo 335 + paclitaxel

308

267

228

185

148

116

294

241

180

143

109

IMPORTANT SAFETY INFORMATION FOR CYRAMZA

CLIENT: Lilly

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

05/2015 PRINTED IN USA

“A size”

ARTIST: MC

LOCATION: Mechanicals

COLLECT DATE:

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

M02 CP M

ACD

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

FINISH SIZE: 17” wide x 11” high

JOB#: 29889-23

i n s er v

T:11 in

B:11.25 in

Warnings and Precautions

VISIT WWW.CYRAMZAHCP.COM FOR MORE INFORMATION, INCLUDING CYRAMZA MONOTHERAPY TRIAL DATA

S:9.625 in

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 IN THE PIPELINE

A30 IN THE CLINIC Enoxaparin Efficacious, Feasible for Prevention of CTE in Advanced Pancreatic Cancer

The Latest on Oncology Drugs

JASON HOFFMAN, PharmD, RPh

A8 LATEST NEWS Headlines in Oncology Research and Practice

A10

FEATURED PRODUCTS Drug Descriptions of Cyramza, Farydak, and Unituxin

A32 REGIMEN & MONOGRAPH INDEX 1-117 CANCER THERAPY REGIMENS & DRUG MONOGRAPHS Highlighted topics () contain both treatment regimens and drug monographs.

A16 CME ACTIVITY Prostate Cancer Concepts and Controversies: Trends and Topics in the Management of Advanced Prostate Cancer

A24

1 Bone Cancer

3 Brain Cancer 5 Breast Cancer

FEATURE

12 Endocrine Cancer

The 1%: Unraveling the Drivers of Breast Cancer in Men

 16 Gastrointestinal Cancer

 27 Genitourinary Cancer

37 Gynecologic Cancer

DEB HUGHES, MS

A26

EXPERT PERSPECTIVE

40 Head and Neck Cancer

A Case Study from an Oncology Sexual Health Clinic: Sexual Dysfunction Evaluation

 41 Hematologic Cancer

 63 Lung Cancer

DON S. DIZON, MD

76 Sarcoma 77 Skin Cancer

A28 VIEWPOINT Results of Nivolumab CheckMate 057 Study May Change Treatment of NSCLC

81 Associated Hematological Disorders

LESLIE BURGESS

106 ALPHABETICAL INDEX

Cancer Therapy Advisor (ISSN 2375-558X), July/August 2015, Volume 1, Number 6. Published 6 times annually by Haymarket Media, Inc., 114 West 26th Street, 4th Floor, New York, NY 10001. For Advertising Sales, Editorial and Subscription information call (646) 638-6000 (M–F, 9am–5pm, ET). Standard Postage paid at Orem, UT. Postmaster: Send changes of address to Cancer Therapy Advisor, c/o Direct Medical Data, 10255 W. Higgins Rd., Suite 280, Rosemont, IL 60018. 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 2015 | CANCER THERAPY ADVISOR A5

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EDITORIAL & BUSINESS STAFF

EDITORIAL ADVISORY BOARD

Managing Editor, Haymarket Oncology

Barbara Ann Burtness, MD

Lauren Burke

Yale Cancer Center  New Haven, CT

Senior Manager, Drug Information

Steven J. Cohen, MD

Anissa Lee, RPh

Group Art Director, Haymarket Medical Jennifer Dvoretz

Assistant Art Director Livvie Zurlini

Production Manager Krassi Varbanov (646) 638-6018

Database/Composition Manager Karen Wahl

Fox Chase Cancer Center  Philadelphia, PA

E. David Crawford, MD University of Colorado, Denver  Aurora, CO

Isabel Cunningham, MD Columbia University College of Physicians & Surgery  New York, NY

Don S. Dizon, MD, FACP Massachusetts General Hospital Cancer Center  Boston, MA

Jeffrey M. Farma, MD Fox Chase Cancer Center  Philadelphia, PA

Edith A. Perez, MD Mayo Clinic  Jacksonville, FL

Circulation Manager Paul Silver

Vice President, Sales & Business Development Scott Bugni (917) 882-0658; scott.bugni@haymarketmedia.com

Account Manager Henry Amato (646) 638-6096; henry.amato@haymarketmedia.com

Neal D. Shore, MD, FACS Atlantic Urology Clinics  Myrtle Beach, SC

Mark A. Socinski, MD UPMC Cancer Pavilion  Pittsburgh, PA

Mario Sznol, MD Yale Cancer Center  New Haven, CT

Senior Director of Operations, Haymarket Oncology Audra Schlesinger

HAYMARKET MEDIA INC.

Publisher, Haymarket Oncology

Editorial Office

Chad Holloway (201) 799-4878; chad.holloway@haymarketmedia.com

Senior Vice President, Clinical Communications John Pal

Chief Operating Officer John Crewe

Chief Executive Officer Lee Maniscalco

140 East Ridgewood Avenue, Suite 176N Paramus, NJ 07652

Business Office 114 West 26th Street, 4th Floor New York, NY 10001

Subscriptions: www.CancerTherapyAdvisor.com/Subscription

Contact the Editor: editor.cancertherapyadvisor@haymarketmedia.com

A6 CANCER THERAPY ADVISOR | JULY/AUGUST 2015 | CancerTherapyAdvisor.com

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IN THE PIPELINE Orphan Drug Status Granted to Ovarian Cancer Therapy Cerulean Pharma announced that the U.S. Food and Drug Administration (FDA) has granted Orphan Drug designation to CRLX101 for the treatment of ovarian cancer. The company is studying the use of CRLX101 in combination with other treatments for relapsed ovarian cancer. Currently a phase 2 trial of CRLX101 plus Avastin is enrolling patients and a phase 1b trial of CRLX101 plus weekly paclitaxel is expected to start enrolling patients in the second quarter of 2015. CR LX101 is a t umor-targeted nanoparticle-drug conjugate (NDC) designed to concentrate in tumors and slowly release camptothecin inside tumor cells. CRLX101 inhibits both topoisomerase 1 and hypoxia-inducible factor-1α (HIF-1α). For more information visit CeruleanRx.com.

Progression-Free Survival Seen With Enzalutamide for Prostate Cancer in Phase 2 Trial Astellas Pharma and Medivation announced data from the phase 2 STRI V E trial comparing Xtandi (enzalutamide) and bicalutamide in non-metastatic (M0) and metastatic (M1) prostate cancer patients whose disease progressed despite treatment with a luteinizing hormone-releasing hormone (LHRH) analogue therapy following surgical castration. The STRIVE trial randomly assigned 257 patients with metastatic prostate cancer and 139 patients with non-metastatic prostate cancer whose disease

progressed despite treatment with a LHRH analogue therapy or following surgical castration. The primary endpoint of the trial was progression-free survival (PFS), defined as time from randomization to radiographic (bone or soft tissue) progression, PSA progression (defined by Prostate Cancer Working Group 2 criteria), or death due to any cause, whichever occurs first. The study achieved its primary endpoint demonstrating a statistically significant increase in PFS for enzalutamide compared with bicalutamide (HR=0.24; 95% CI, 0.18–0.32; P<0.0001). The median PFS was 19.4 months in the enzalutamide arm and 5.7 months in the bicalutamide arm.

the other in combination with gemcitabine vs. gemcitabine and placebo in patients with locally advanced unresectable or metastatic pancreatic cancer (the MAESTRO trial). Evofosfamide is also being investigated in a phase 2 trial for the treatment of non-squamous nonsmall cell lung cancer (NSCLC), and in earlier-stage clinical trials of other solid tumors and hematological malignancies.

For more information visit Astellas.com or Medivation.com.

Bristol-Myers Squibb announced that the U.S. Food and Drug Administration (FDA) has accepted for filing and has granted Priority Review to the supplemental Biologics License Application (sBLA) for Opdivo (nivolumab) for the treatment of previously untreated patients with unresectable or metastatic melanoma. The sBLA submission includes data from CheckMate-066, which evaluated Opdivo in treatment-naïve patients with BRAF wild-type advanced melanoma as compared to dacarbazine chemotherapy (DTIC). Opdivo, a human programmed death receptor-1 (PD-1) blocking antibody, is already indicated for treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. It is also approved for metastatic squamous non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy

Evofosfamide Fast Tracked for Advanced Pancreatic Cancer Merck KGaA announced that the U.S. Food and Drug Administration (FDA) has granted Fast Track status to evofosfamide in combination with gemcitabine, for the treatment of previously untreated patients with metastatic or locally advanced unresectable pancreatic cancer. Evofosfamide is an investigational hypoxia-activated prodrug that is thought to be activated under severe tumor hypoxic conditions. The FDA had previously granted evofosfamide both Orphan Drug designation and Fast Track status for the treatment of soft tissue sarcoma and pancreatic cancer. Evofosfamide is currently under evaluation in two phase 3 trials: one in combination with doxorubicin vs. doxorubicin alone in patients with locally advanced unresectable or metastatic soft tissue sarcoma (the TH-CR-406 trial), and

For more information call (781) 681-2393 or visit EMDSerono.com.

Opdivo sBLA Under Priority Review for New Melanoma Indication

For more information call (800) 321-1335 or visit BMS.com.

CancerTherapyAdvisor.com | JULY/AUGUST 2015 | CANCER THERAPY ADVISOR A7

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FEATURED PRODUCT

Farydak Rx Company: Novartis Pharmacologic class: Histone deacetylase (HDAC) inhibitor Active ingredients: Panobinostat 10mg, 15mg, 20mg; capsules. Indication: Multiple myeloma, in patients who have received at least two prior regimens (including bortezomib and an immunomodulatory agent), in combination with bortezomib and dexamethasone.

Pharmacology: Panobinostat inhibits the enzymatic activity of HDACs at nanomolar concentrations which results in increased acetylation of histone proteins, leading to transcriptional activation. Accumulation of acetylated histones and other proteins induces cell cycle arrest and/or apoptosis of some transformed cells. Clinical trials: The efficacy and safety of Farydak with bortezomib and dexamethasone was evaluated in a randomized, double-blind, placebo-controlled, multicenter study in 768 patients with relapsed multiple myeloma who had received 1â&#x20AC;&#x201C;3 prior

Pharmacology: Dinutuximab binds to cell surface GD2 and induces cell lysis of GD2-expressing cells through antibody-dependent cell-mediated c y t ot ox ic it y a nd c omple me ntdependent cytotoxicity.

Unituxin Rx

Company: United Therapeutics Pharmacologic class: GD2-binding monoclonal antibody. Active ingredients: Dinutuximab 3.5mg/mL; solution for IV infusion after dilution; preservative-free. Indications: In combination with granulocyte-macrophage 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.

Clinical trials: The safet y and efficacy of Unituxin was evaluated in a randomized, open-label, multicenter trial conducted in pediatric patients with high-risk neuroblastoma. Patients were randomized between Day 50 and Day 77 post-autologous stem cell transplantation. Pat ie nt s r a n d o m i z e d t o t h e Unituxin/RA arm (n=113) received up to five cycles of dinutuximab in combination with GM-CSF or IL-2 plus RA, followed by one cycle of RA alone. Patients randomized to the RA arm (n=113) received six cycles of RA. Dinutuximab was administered at a dose of 17.5mg/m 2/day on four consecutive days. Patients in both

lines of therapy. Patients were randomized to bortezomib and dexamethasone with Farydak or placebo. The primary endpoint was progression-free survival (PFS). A prespecified subgroup analysis (n=193) showed the benefit:risk was greater in this heavily pretreated population than the overall trial population. The median PFS was 10.6 months in the Farydak arm vs. 5.8 months in the placebo arm (HR 0.52; [95% CI: 0.36, 0.76]). For more clinical trial data, see full labeling. For more information view the concise drug monograph on page 48.

treatment arms received six cycles of RA at a dose of 160mg/m 2/day orally (for patients weighing >12kg) or 5.33mg/kg/day (for patients weighing â&#x2030;¤12kg) in two divided doses for 14 consecutive days. The major efficacy outcome measure was investigator-assessed event-free survival (EFS), defined as the time from randomizat ion to t he f irst occurrence of relapse, progressive disease, secondary malignancy, or death. There were 33 (29%) events in the Unituxin/RA arm vs. 50 (44%) in the RA arm (HR 0.57; [95% CI: 0.37, 0.89]; P= 0.01). Overall survival (OS) was also evaluated. After observing improvement in EFS based on the seventh interim analysis, termination of accrual was recommended. For more clinical trial data, see full labeling. For more information view the concise drug monograph on page 4.

A10 CANCER THERAPY ADVISOR | JULY/AUGUST 2015 | CancerTherapyAdvisor.com

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FEATURED PRODUCT Pharmacology: Ramucirumab is a vascular endothelial growth factor receptor 2 (VEGFR2) antagonist that specifically binds VEGF Receptor 2 and blocks binding of V EGFR ligands, V EGF-A, V EGF-C, and VEGF-D. As a result, ramucirumab inhibits ligand-stimulated activation of VEGF Receptor 2, thereby inhibiting ligand-induced proliferation, and migration of human endothelial cells.

Cyramza Rx

Company: Eli Lilly and Company Pharmacologic class: Human IgG1 monoclonal antibody. Active ingredients: Ramucirumab 10mg/mL; per vial; solution for IV infusion after dilution; preservative-free. Indication: As a single agent, or in combination with paclitaxel, for treatment of advanced or metastatic, gastric or gastroesophageal junction adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy. In combination with FOLFIRI (irinotecan, folinic acid, and 5-fluorouracil), for the treatment of metastatic colorectal cancer (mCRC) with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine. In combination with docetaxel, for treatment of metastatic non-small cell lung cancer (NSCLC) with disease progression on or after platinum-based chemotherapy; patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to initiation.

Clinical trials: Study 4 was a multinational, randomized, double-blind study of Cyramza plus FOLFIRI vs. placebo plus FOLFIRI that involved a total of 1072 patients. Patients were required to have ECOG PS 0 or 1 and to have disease progression within 6 months of the last dose of first-line therapy. Patients with mCRC, who had disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine were randomized 1:1 to receive either Cyramza IV 8mg/kg (n=536) or placebo (n=536), in combination with FOLFIRI every 2 weeks. The major efficacy outcome measure was overall survival and the supportive efficacy outcome measure was progression-free survival. Efficacy results demonstrated that overall survival was statistically significantly improved in patients who received Cyramza plus FOLFIRI as compared to patients who received placebo plus FOLFIRI (HR 0.85; [95% CI: 0.73, 0.98]; P-value=0.023). Progressionfree survival was also statistically significantly improved in patients who received Cyramza plus FOLFIRI as compared to patients who received placebo plus FOLFIRI (HR 0.79; [95% CI: 0.70, 0.90]; P-value <0.001). For more clinical trial data, see full labeling.

Read the Latest in Cancer News For the latest oncology headlines visit CancerTherapyAdvisor.com

New content is published throughout the day to ensure that you are informed when it comes to current cancer treatment information and clinical research. To have the news delivered right to your inbox, sign up for our e-newsletters at CancerTherapyAdvisor.com/ Newsletters. We can send you the latest news every day or once a week— whatever you prefer!

For more information view the concise drug monographs on pages 22 and 71.

CancerTherapyAdvisor.com | JULY/AUGUST 2015 | CANCER THERAPY ADVISOR A11

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

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

100 90 80

PFS probability (%)

1 pathway. 2 targets. TWICE THE IMPACT

20.2 months

70 60

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

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

10.2 months

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

30 20

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

10 0 0

Number of patients at risk IBR+LET LET

84 81

67 48

21 6

13 3

8 3

5 1

Months 60 36

47 28

36 19

28 14

IBR=Ibrance; LET=letrozole.

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

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

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

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

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

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

Important Safety Information

Pregnancy and lactation: Based on the mechanism of action, IBRANCE can cause fetal harm. Advise females with reproductive potential to use effective contraception during therapy with IBRANCE and for at least 2 weeks after the last dose. Advise females to contact their healthcare provider if they become pregnant or if pregnancy is suspected during treatment with IBRANCE. Advise women not to breastfeed while on IBRANCE therapy because of the potential for serious adverse reactions in nursing infants from IBRANCE. Additional hematologic abnormalities: Decreases in hemoglobin (83% vs 40%), leukocytes (95% vs 26%), lymphocytes (81% vs 35%), and platelets (61% vs 16%) occurred at a higher rate in patients treated with IBRANCE plus letrozole vs letrozole alone. Adverse reactions: The most common all causality adverse reactions (≥10%) of any grade reported in patients treated with IBRANCE plus letrozole vs letrozole alone in the phase II study included neutropenia (75% vs 5%), leukopenia (43% vs 3%), fatigue (41% vs 23%), anemia (35% vs 7%), upper respiratory infection (31% vs 18%), nausea (25% vs 13%), stomatitis (25% vs 7%), alopecia (22% vs 3%), diarrhea (21% vs 10%), thrombocytopenia (17% vs 1%), decreased appetite (16% vs 7%), vomiting (15% vs 4%), asthenia (13% vs 4%), peripheral neuropathy (13% vs 5%), and epistaxis (11% vs 1%).

Neutropenia: Neutropenia is frequently reported with IBRANCE therapy. In the randomized phase II study, Grade 3 (57%) or 4 (5%) decreased neutrophil counts were reported in patients receiving IBRANCE plus letrozole. Febrile neutropenia can occur. Monitor complete blood count prior to starting IBRANCE and at the beginning of each cycle, as well as Day 14 of the first two cycles, and as clinically indicated. For patients who experience Grade 3 neutropenia, consider repeating the complete blood count monitoring 1 week later. Dose interruption, dose reduction, or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia. Infections: Infections have been reported at a higher rate in patients treated with IBRANCE plus letrozole (55%) compared with letrozole alone (34%). Grade 3 or 4 infections occurred in 5% of patients treated with IBRANCE plus letrozole vs no patients treated with letrozole alone. Monitor patients for signs and symptoms of infection and treat as medically appropriate. Pulmonary embolism (PE): PE has been reported at a higher rate in patients treated with IBRANCE plus letrozole (5%) compared with no cases in patients treated with letrozole alone. Monitor patients for signs and symptoms of PE and treat as medically appropriate.

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

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

100 90 80

PFS probability (%)

1 pathway. 2 targets. TWICE THE IMPACT

20.2 months

70 60

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

10.2 months

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

30 20

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

10 0 0

Number of patients at risk IBR+LET LET

84 81

67 48

21 6

13 3

8 3

5 1

Months 60 36

47 28

36 19

28 14

IBR=Ibrance; LET=letrozole.

Important Safety Information

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

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Important Safety Information (continued) Grade 3/4 adverse reactions reported (≥10%) occurring at a higher incidence in the IBRANCE® (palbociclib) plus letrozole vs letrozole alone group include neutropenia (54% vs 1%) and leukopenia (19% vs 0%). The most frequently reported serious adverse events in patients receiving IBRANCE were pulmonary embolism (4%) and diarrhea (2%). General dosing information: The recommended dose of IBRANCE is 125 mg taken orally once daily for 21 days followed by 7 days off treatment in 28-day cycles. IBRANCE should be taken with food and in combination with letrozole 2.5 mg once daily continuously. Patients should be encouraged to take their dose at approximately the same time each day. Capsules should be swallowed whole. No capsule should be ingested if it is broken, cracked, or otherwise not intact. If a patient vomits or misses a dose, an additional dose should not be taken that day. The next prescribed dose should be taken at the usual time. Management of some adverse reactions may require temporary dose interruption/delay and/or dose reduction, or permanent discontinuation. Dose modification of IBRANCE is recommended based on individual safety and tolerability. Drug interactions: Avoid concurrent use of strong CYP3A inhibitors. If patients must be administered a strong CYP3A inhibitor, reduce the IBRANCE dose to 75 mg/day. If the strong inhibitor is discontinued, increase the IBRANCE dose (after 3–5 half-lives of the inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor. Grapefruit or grapefruit juice may increase plasma concentrations of IBRANCE and should be avoided. Avoid concomitant use of strong and moderate CYP3A inducers. The dose of the sensitive CYP3A substrates with a narrow therapeutic index may need to be reduced as IBRANCE may increase their exposure. Hepatic and renal impairment: IBRANCE has not been studied in patients with moderate to severe hepatic impairment or in patients with severe renal impairment (CrCl <30 mL/min). Dose Modification and Management – Non-Hematologic Toxicities

Brief Summary of Prescribing Information ®

IBRANCE (palbociclib) capsules Initial US Approval: 2015 INDICATIONS AND USAGE IBRANCE is indicated in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease. This indication is approved under accelerated approval based on progression-free survival (PFS) [see Clinical Studies]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. DOSAGE AND ADMINISTRATION General Dosing Information. The recommended dose of IBRANCE is a 125 mg capsule taken orally once daily for 21 consecutive days followed by 7 days off treatment to comprise a complete cycle of 28 days. IBRANCE should be taken with food in combination with letrozole 2.5 mg once daily given continuously throughout the 28-day cycle. [see Clinical Pharmacology]. Patients should be encouraged to take their dose at approximately the same time each day. If the patient vomits or misses a dose, an additional dose should not be taken that day. The next prescribed dose should be taken at the usual time. IBRANCE capsules should be swallowed whole (do not chew, crush or open them prior to swallowing). No capsule should be ingested if it is broken, cracked, or otherwise not intact. Dose Modification. Dose modification of IBRANCE is recommended based on individual safety and tolerability. Management of some adverse reactions [see Warnings and Precautions] may require temporary dose interruptions/delays and/or dose reductions, or permanent discontinuation. If dose reduction is required the first recommended dose reduction is 100 mg/day and the second dose reduction is 75 mg/day. If further dose reduction below 75 mg/day is required, discontinue the treatment. Dose Modification and Managementa – Hematologic Toxicities CTCAE Grade

Dose Modifications

CTCAE Grade

Dose Modifications

Grade 1 or 2

No dose adjustment is required.

Grade 3b

No dose adjustment is required. Consider repeating complete blood count monitoring one week later. Withhold initiation of next cycle until recovery to Grade ≤2.

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

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

Grade 4b

Withhold IBRANCE and initiation of next cycle until recovery to Grade ≤2. Resume at next lower dose.

Grading according to CTCAE Version 4.0. ANC=absolute neutrophil count; CTCAE=Common Terminology Criteria for Adverse Events. a Monitor complete blood count prior to the start of IBRANCE therapy and at the beginning of each cycle, as well as on Day 14 of the first two cycles, and as clinically indicated. b E xcept lymphopenia (unless associated with clinical events, e.g., opportunistic infections).

Grade 1 or 2

No dose adjustment is required.

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

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

See manufacturer’s prescribing information for the coadministered product, letrozole, dose adjustment guidelines in the event of toxicity and other relevant safety information or contraindications. Dose Modifications for Use With Strong CYP3A Inhibitors. Avoid concomitant use of strong CYP3A inhibitors and consider an alternative concomitant medication with no or minimal CYP3A inhibition. If patients must be coadministered a strong CYP3A inhibitor, reduce the IBRANCE dose to 75 mg once daily. If the strong inhibitor is discontinued, increase the IBRANCE dose (after 3–5 half-lives of the inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor [see Drug Interactions and Clinical Pharmacology]. DOSAGE FORMS AND STRENGTHS 125 mg capsules: opaque hard gelatin capsules, size 0, with caramel cap and body, printed with white ink “Pfizer” on the cap, “PBC 125” on the body. 100 mg capsules: opaque hard gelatin capsules, size 1, with caramel cap and light orange body, printed with white ink “Pfizer” on the cap, “PBC 100” on the body. 75 mg capsules: opaque hard gelatin capsules, size 2, with light orange cap and body, printed with white ink “Pfizer” on the cap, “PBC 75” on the body. CONTRAINDICATIONS: None WARNINGS AND PRECAUTIONS Neutropenia. Decreased neutrophil counts have been observed in clinical trials with IBRANCE. Grade 3 (57%) or 4 (5%) decreased neutrophil counts were reported in patients receiving IBRANCE plus letrozole in the randomized clinical trial (Study 1). Median time to first episode of any grade neutropenia per laboratory data was 15 days (13–117 days). Median duration of Grade ≥3 neutropenia was 7 days [see Adverse Reactions]. Febrile neutropenia events have been reported in the IBRANCE clinical program, although no cases of febrile neutropenia have been observed in Study 1. Monitor complete blood count prior to starting IBRANCE therapy and at the beginning of each cycle, as well as on Day 14 of the first two cycles, and as clinically indicated. Dose interruption, dose reduction or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia [see Dosage and Administration]. Infections. Infections have been reported at a higher rate in patients treated with IBRANCE plus letrozole compared to patients treated with letrozole alone in Study 1. Grade 3 or 4 infections occurred in 5% of patients treated with IBRANCE plus letrozole whereas no patients treated with letrozole alone experienced a Grade 3 or 4 infection. Monitor patients for signs and symptoms of infection and treat as medically appropriate. Pulmonary Embolism. Pulmonary embolism has been reported at a higher rate in patients treated with IBRANCE plus letrozole (5%) compared with no cases in patients treated with letrozole alone in Study 1. Monitor patients for signs and symptoms of pulmonary embolism and treat as medically appropriate. Embryo-Fetal Toxicity. Based on findings in animals and mechanism of action, IBRANCE can cause fetal harm. IBRANCE caused embryo-fetal toxicities in rats and rabbits at maternal exposures that were greater than or equal to 4 times the human clinical exposure based on area under the curve (AUC). Advise females of reproductive potential to use effective contraception during therapy with IBRANCE and for at least two weeks after the last dose [see Use in Specific Populations and Clinical Pharmacology].

ADVERSE REACTIONS Clinical Studies Experience. Because clinical trials are conducted under varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice. The safety of IBRANCE (125 mg/day) plus letrozole (2.5 mg/day) versus letrozole alone was evaluated in Study 1. The data described below reflect exposure to IBRANCE in 83 out of 160 patients with ER-positive, HER2-negative advanced breast cancer who received at least 1 dose of treatment in Study 1. The median duration of treatment for palbociclib was 13.8 months while the median duration of treatment for letrozole on the letrozole-alone arm was 7.6 months. Dose reductions due to an adverse reaction of any grade occurred in 38.6% of patients receiving IBRANCE plus letrozole. No dose reduction was allowed for letrozole in Study 1. Permanent discontinuation due to an adverse event occurred in 7 of 83 (8%) patients receiving IBRANCE plus letrozole, and in 2 of 77 (3%) patients receiving letrozole alone. Adverse reactions leading to discontinuation for those patients receiving IBRANCE plus letrozole included neutropenia (6%), asthenia (1%), and fatigue (1%). The most common adverse reactions (≥10%) of any grade reported in patients in the IBRANCE plus letrozole arm were neutropenia, leukopenia, fatigue, anemia, upper respiratory infection, nausea, stomatitis, alopecia, diarrhea, thrombocytopenia, decreased appetite, vomiting, asthenia, peripheral neuropathy, and epistaxis. The most frequently reported serious adverse reactions in patients receiving IBRANCE plus letrozole were pulmonary embolism (3 of 83; 4%) and diarrhea (2 of 83; 2%). An increased incidence of infections events was observed in the palbociclib plus letrozole arm (55%) compared to the letrozole alone arm (34%). Febrile neutropenia events have been reported in the IBRANCE clinical program, although no cases were observed in Study 1. Grade ≥3 neutropenia was managed by dose reductions and/or dose delay or temporary discontinuation consistent with a permanent discontinuation rate of 6% due to neutropenia [see Dosage and Administration]. The following table presents adverse drug reactions (≥10%) reported in patients who received IBRANCE plus letrozole or letrozole alone. Adverse Reactions* (≥10%) in Study 1 IBRANCE + Letrozole (N=83) Letrozole Alone (N=77) System Organ Class All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 Any Adverse Drug Reaction (%) (%) (%) (%) (%) (%) Infections and infestations a URI 31 1 0 18 0 0 Blood and lymphatic system disorders Neutropenia 75 48 6 5 1 0 Leukopenia 43 19 0 3 0 0 Anemia 35 5 1 7 1 0 Thrombocytopenia 17 2 0 1 0 0 Metabolism and nutrition disorders Decreased appetite 16 1 0 7 0 0 Nervous system disorders Peripheral neuropathyb 13 0 0 5 0 0 Respiratory, thoracic, and mediastinal disorders Epistaxis 11 0 0 1 0 0 Gastrointestinal disorders Stomatitisc 25 0 0 7 1 0 Nausea 25 2 0 13 1 0 Diarrhea 21 4 0 10 0 0 Vomiting 15 0 0 4 1 0 Skin and subcutaneous tissue disorders d e Alopecia 22 N/A N/A 3 N/A N/A General disorders and administration site conditions Fatigue 41 2 2 23 1 0 Asthenia 13 2 0 4 0 0

* Adverse Reaction rates reported in the table include all reported events regardless of causality. Grading according to CTCAE Version 3.0. CTCAE=Common Terminology Criteria for Adverse Events; N=number of subjects; N/A=not applicable; URI=Upper respiratory infection. a URI includes: Influenza, Influenza like illness, Laryngitis, Nasopharyngitis, Pharyngitis, Rhinitis, Sinusitis, Upper respiratory tract infection. b Peripheral neuropathy includes: Neuropathy peripheral, Peripheral sensory neuropathy. c Stomatitis includes: Aphthous stomatitis, Cheilitis, Glossitis, Glossodynia, Mouth ulceration, Mucosal inflammation, Oral pain, Oropharyngeal discomfort, Oropharyngeal pain, Stomatitis. d Grade 1 events - 21%; Grade 2 events - 1%. e Grade 1 events - 3%. Laboratory Abnormality for Patients in Study 1 Laboratory Abnormality White blood cells decreased Neutrophils decreased Lymphocytes decreased Hemoglobin decreased Platelets decreased N=number of patients.

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

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

coadministration of IBRANCE with a strong CYP3A inhibitor cannot be avoided, reduce the dose of IBRANCE [see Dosage and Administration and Clinical Pharmacology]. Effect of CYP3A Inducers. Coadministration of a strong CYP3A inducer (rifampin) decreased the plasma exposure of palbociclib in healthy subjects by 85%. Avoid concomitant use of strong CYP3A inducers (e.g., phenytoin, rifampin, carbamazepine and St John’s Wort) [see Clinical Pharmacology]. Coadministration of moderate CYP3A inducers may also decrease the plasma exposure of IBRANCE. Avoid concomitant use of moderate CYP3A inducers (e.g., bosentan, efavirenz, etravirine, modafinil, and nafcillin) [see Clinical Pharmacology]. Drugs That May Have Their Plasma Concentrations Altered by Palbociclib. Coadministration of midazolam with multiple doses of IBRANCE increased the midazolam plasma exposure by 61%, in healthy subjects, compared with administration of midazolam alone. The dose of the sensitive CYP3A substrate with a narrow therapeutic index (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, everolimus, fentanyl, pimozide, quinidine, sirolimus and tacrolimus) may need to be reduced as IBRANCE may increase their exposure [see Clinical Pharmacology]. USE IN SPECIFIC POPULATIONS Pregnancy. Based on findings in animals and mechanism of action, IBRANCE can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology]. In animal studies, palbociclib was teratogenic and fetotoxic at maternal exposures that were ≥4 times the human clinical exposure based on AUC at the recommended human dose. There are no available human data informing the drug-associated risk. Advise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is 2–4% and of miscarriage is 15–20% of clinically recognized pregnancies. Lactation. There are no data on the presence of palbociclib in human milk, the effects of IBRANCE on the breastfed child, or the effects of IBRANCE on milk production. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from IBRANCE, advise a nursing woman to discontinue breastfeeding during treatment with IBRANCE. Females and Males of Reproductive Potential. Advise females of reproductive potential to use effective contraception during treatment with IBRANCE and for at least two weeks after the last dose. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with IBRANCE [see Use in Specific Populations]. Based on findings in animals, male fertility may be compromised by treatment with IBRANCE [see Carcinogenesis, Mutagenesis, Impairment of Fertility]. Pediatric Use. The safety and efficacy of IBRANCE in pediatric patients have not been studied. Geriatric Use. Of 84 patients who received IBRANCE in Study 1, 37 patients (44%) were ≥65 years of age and 8 patients (10%) were ≥75 years of age. No overall differences in safety or effectiveness of IBRANCE were observed between these patients and younger patients but greater sensitivity of some older individuals cannot be ruled out. Hepatic Impairment. Based on a population pharmacokinetic analysis that included 183 patients, where 40 patients had mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin >1.0 to 1.5 × ULN and any AST), mild hepatic impairment had no effect on the exposure of palbociclib. The pharmacokinetics of palbociclib have not been studied in patients with moderate or severe hepatic impairment (total bilirubin >1.5 × ULN and any AST) [see Clinical Pharmacology]. Renal Impairment. Based on a population pharmacokinetic analysis that included 183 patients, where 73 patients had mild renal impairment (60 mL/min ≤ CrCl <90 mL/min) and 29 patients had moderate renal impairment (30 mL/min ≤ CrCl <60 mL/min), mild and moderate renal impairment had no effect on the exposure of palbociclib. The pharmacokinetics of palbociclib have not been studied in patients with severe renal impairment [see Clinical Pharmacology]. OVERDOSAGE There is no known antidote for IBRANCE. The treatment of overdose of IBRANCE should consist of general supportive measures. PATIENT COUNSELING INFORMATION • Advise patients to immediately report any signs or symptoms of myelosuppression or infection, such as fever, chills, dizziness, shortness of breath, weakness or any increased tendency to bleed and/or to bruise [see Warnings and Precautions]. • Advise patients to immediately report any signs or symptoms of pulmonary embolism, such as shortness of breath, chest pain, tachypnea, and tachycardia [see Warnings and Precautions]. • Advise patients to take IBRANCE with food and swallow IBRANCE capsules whole. • I BRANCE may interact with grapefruit. Patients should not consume grapefruit products while on treatment with IBRANCE. • I nform patients to avoid strong CYP3A inhibitors and strong CYP3A inducers. • Advise patients to inform their health care providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Drug Interactions]. • I f the patient vomits or misses a dose, an additional dose should not be taken that day. The next prescribed dose should be taken at the usual time. IBRANCE capsules should be swallowed whole (do not chew, crush or open them prior to swallowing). No capsule should be ingested if it is broken, cracked, or otherwise not intact. • Advise females of reproductive potential to use effective contraception during IBRANCE therapy and for at least two weeks after the last dose. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with IBRANCE [see Warnings and Precautions and Use in Specific Populations]. Rx only Issued: February 2015 ULN=upper limit of normal. 705404-01 © 2015 Pfizer Inc. All rights reserved. May 2015

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Brief Summary of Prescribing Information ®

Dose Modifications

CTCAE Grade

Dose Modifications

Grade 1 or 2

No dose adjustment is required.

Grade 3b

No dose adjustment is required. Consider repeating complete blood count monitoring one week later. Withhold initiation of next cycle until recovery to Grade ≤2.

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

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

Grade 4b

Withhold IBRANCE and initiation of next cycle until recovery to Grade ≤2. Resume at next lower dose.

Grade 1 or 2

No dose adjustment is required.

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

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

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CME ACTIVITY EDUCATIONAL OBJECTIVES: After participating in this educational activity, participants should be better able to: • Discuss new developments aimed at refining risk stratification for patients diagnosed with prostate cancer, with a focus on emerging biomarker assays. • Evaluate current recommendations regarding target serum testosterone levels with androgen deprivation therapy (ADT) and formulate an opinion on whether lower levels are more clinically desirable. • Appraise 2 clinical opinions on the sequencing of treatments in late-stage prostate cancer and formulate an opinion on whether or not to apply certain principles of this discussion into practice. TO COMPLETE THE ACTIVITY, PRE-TEST, POST-TEST, EVALUATION FORM, AND CLAIM YOUR CERTIFICATE: Go to myCME.com/ProstateDebate

This activity is provided by Haymarket Medical Education (HME). Release Date: April 30, 2015 Expiration Date: April 29, 2016 Program Faculty: Priya Wanchoo, MD, CHCP (Course Director), VP and Medical Director, Haymarket Medical Education, Paramus, NJ Philip W. Kantoff, MD, Director, Lank Center for Genitourinary Oncology, Vice Chair and Chief, Division of Solid Tumor Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, The Jerome and Nancy Kohlberg Professor of Medicine, Harvard Medical School, Boston, MA Neal D. Shore, MD, FACS, Medical Director, Carolina Urologic Research Center, Atlantic Urology Clinics, Myrtle Beach, SC Estimated time to complete the educational activity: 1 hour Target Audience: Urologists and oncologists and NPs and PAs who treat patients with prostate cancer. Accreditation Statement: Haymarket Medical Education is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. Statement of Need: Androgen deprivation therapy has been the mainstay for the management of advanced or metastatic prostate cancer. However, controversies remain and practice gaps exist in patient care. For example, a significant portion of patients fail to reach castrate levels of androgens after hormonal therapy, and debate exists regarding the appropriate target level. Intermittent androgen deprivation is also currently under evaluation as an alternative to continuous hormonal therapy. While an exciting time for the treatment of prostate cancer, differing clinical opinions make it challenging for clinicians to carefully evaluate the risks and benefits associated with management and treatment approaches.

Credit Designation: Haymarket Medical Education designates this enduring activity for a maximum of 1.00 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Conflict of Interest Disclosure Policy: In accordance with the ACCME Standards for Commercial Support, HME requires that individuals in a position to control the content of an educational activity disclose all relevant financial relationships with any commercial interest. HME resolves all conflicts of interest to ensure independence, objectivity, balance, and scientific rigor in all its educational programs. Faculty Disclosure: The faculty reported the following financial relationships with commercial interests whose products or services may be mentioned in this CME activity: Dr. Wanchoo has no relevant financial relationships to disclose. Dr. Kantoff is a consultant for Amgen USA, Archimedes Pharma US, Inc., Bayer, BN Immunotherapeutics, Celgene, Dendreon, Exelixis, Genomic Health, Gtx, Janssen, Millennium/Prometrika, MorphoSys, Pfizer, and Teva Oncogenix. He is on the scientific advisory boards of Astellas,. Auven Therapeutics, Bellicum, BIND Biosciences, Inc., Blend Therapeutics, Endocyte/TRM Oncology, Metamark, Medivation, MTG Therapeutics, OncoCellMDX, Progenics Pharmaceuticals, Sotio, Sanofi, and Tokai. He receives research support from Amgen USA, Astellas, Bayer, BN Immunotherapeutics, Dendreon, Exelixis, Janssen, Medivation, OncoGenex, and Sanofi. He reports an investment interest in Bellicum, BIND Biosciencies, Inc., Blend Therapeutics, and Metamark. He is on the Data Safety Monitoring Board for Genentech/Roche, Merck, and OncoGenex. Dr. Shore is a consultant for Astellas, Bayer, Dendreon, Janssen, Millennium, Sanofi, Medivation, and Ferring. Publishing Staff, Planners, and Managers Dislcosures: The HME staff involved in the planning and content review of this activity have no relevant financial relationships to disclose.

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CME ACTIVITY

Prostate Cancer Concepts and Controversies: Trends and Topics in the Management of Advanced Prostate Cancer Two experts in the field of prostate cancer debate important topics that can create challenges in the treatment of advanced or metastatic disease.

INTRODUCTION Will assays that assess specific biomarkers in a biopsy from a patient with prostate cancer (PC) enable greater refinement of current PC risk stratification? Is the historical definition of serum testosterone levels required to effect “castration” in need of revision, given recent clinical data? Finally, what is the ideal sequencing of the numerous approved agents in late-stage PC? This newsletter will focus on these key topics of debate in the PC field, and will be presented in a facultyperspective format. Two physicians who are leaders in the field, Dr. Philip Kantoff and Dr. Neal Shore, will present their thoughts on these subjects.

A colored scanning electron micrograph of prostate cancer cells.

Risk Stratiﬁcation in the Newly Diagnosed Patient: New Developments Current PC Risk-Stratification Limitations

Prostate-specific antigen (PSA) testing is the most widely used screening test for PC detection, and is considered the most useful biomarker for PC decision making. Since the introduction of PSA testing, age-adjusted, PC–related

mortality rates have fallen in both the US and Europe.1 However, there is evidence that PSA-based screening programs result in the detection of many cases of asymptomatic PC with tumors that will either not progress or will progress so slowly that it would have remained asymptomatic in the patient’s lifetime. Consequently, PSA-based screening oftentimes results in overdiagnosis, leading to overtreatment,

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CME ACTIVITY which exposes many patients to unnecessary, potentially harmful treatment. In 2012, the US Preventative Services Task Force recommended against PSAbased screening for PC.2 One approach to reducing overdiagnosis and overtreatment includes risk stratification of patients, including considering each individual patient’s risk of PC. Dr. Shore points out that assays are now available, which assess specific biomarkers in a patient’s biopsy that ultimately provide additional, personalized prognostic information and may aid in guiding physicians’ and patients’ decision making regarding interventional strategies for those with newly diagnosed PC. PC Biomarker Assays: Introduction

There are 3 tissue-based molecular assays that are currently far along in development and/or are available for use (see Table 1). These assays can be performed on most formalin-fixed, paraffin-embedded prostate specimens, meaning that for each of these assays a repeat biopsy is not necessary.4,10 For example, the Prolaris® test has been demonstrated to be successful in 93% of radical prostatectomy specimens and 79% of diagnostic prostate biopsy specimens.4 Dr. Shore notes, “Nonpublished and anecdotal reports suggest quality not sufficient (QNS) rates range from 5 to 15%, depending upon volume of malignant tissue obtained and forwarded for either genomic or proteomic analysis. However, we await prospective data reports on actual QNS rates per individual assay, as this may have eventual practical implications concerning selecting amongst the available assays.” PC Biomarker Assays: Current Utility

Dr. Shore believes that biomarker analysis gives patients and physicians

TABLE 1. PC Biomarker Assays Assay and Company Prolaris® Myriad Genetics Laboratories

Oncotype DX® Prostate Cancer Assay Genomic Health

ProMark™ Metamark

Description • Analyzes expression of 31 genes involved in cell-cycle progression (CCP) to give a so-called “CCP score”3,4 •D eveloped based on the rationale that CCP genes in other tumor types (ie, breast) have prognostic value and have influenced clinical care3 •P rognostic when applied in prospective-retrospective designs for biochemical recurrence or metastasis after radical prostatectomy, for survival when men were observed after diagnosis on transurethral resection of the prostate or diagnostic needle biopsy, and for biochemical recurrence and survival after external beam-radiation therapy4 • I nterim results of the PROCEDE-1000 clinical utility trial indicate CCP risk assessment score aided in patientphysician consensus on a personalized treatment decision, often with major reductions in interventional treatment burden (Figure 1)5 • Analyzes expression of 17 genes across 4 different pathways (androgen signaling, stromal response, proliferation, and cellular organization) to give a so-called “Genomic Prostate Score” (GPS)6,7 •D eveloped from evaluation of a diagnostic prostate biopsy and radical prostatectomy series from Cleveland Clinic and validated in a diagnostic prostate biopsy and radical prostatectomy series from the University of California, San Francisco4 •G PS performed in the diagnostic prostate biopsy has provided information beyond usual clinical data that predict the likelihood of Gleason sum 7 or extraprostatic disease on radical prostatectomy4 •O ncotype DX Observational Study is an ongoing prospective clinical utility trial assessing the GPS • Analyzes levels of 12 proteins predictive of PC aggressiveness and lethality to generate a ProMark™ risk score8-10 •D eveloped by analyzing prostatectomy tissue cores derived from areas of high and low Gleason score via microarray; biomarkers were selected based on their ability to reflect true prostate pathology, regardless of whether they were measured on cores with high or low Gleason score8-10 •S tudies indicate the ProMark risk score correlates strongly with pathological outcome regardless of biopsy-sampling variation9,10

an additional metric to determine the disease risk. He comments, “For someone who is being considered for active surveillance, if their (biomarker) score is low-risk, they may have greater comfort after discussing it with their physician to maintain a course of active surveillance.” He further points out that the opposite is also true, that patients with biomarker analyses that reveal higher risk may be

less comfortable with an active surveillance strategy. The 2015 National Comprehensive Cancer Net work (NCCN) PC guidelines support this sentiment, stating that A merican men continue to underselect active surveillance for very-low- or low-risk PC, largely due to uncertainty about the risk of disease progression, which could be reduced by use of molecular biomarkers.4

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CME ACTIVITY “Underselection of active surveillance is largely due to uncertainty about the risk of disease progression, which could be reduced by use of molecular biomarkers.” —Dr. Shore

Dr. Kantoff agrees that these tests have utility in that they use the biopsy specimen to attempt to predict what is present at the time of radical prostatectomy. He points out that the difficulty with relying on Gleason score alone at biopsy is that it may not be truly reflective of what is in the gland at the time of radical prostatectomy (which is the major determinant of outcome to date), particularly for those patients with Gleason score 3+3 or 3+4. Indeed, accurate prediction for progression risk for these patients is hampered by biopsy sampling error and pathologist grading discordance, which can result in inaccurate prostate pathology assessment.10 However, Dr. Kantoff states, “I’m a little more cautious at this point in time than Dr. Shore is about the clinical utility of these tests. I think we need more information. Some of my patients want these tests performed. I am still not sure that I can yet make clinical decisions based on these tests.” However, he remains hopeful that these tests or others will be developed that will provide definitive guidance and spare patients who don’t require treatment. Dr. Shore notes that while the 2 genomic-based assays are now currently available, the Centers for Medicare and Medicaid Services (CMS) do not reimburse health care providers or facilities for running them. A CMS division known as the MolDX (molecular diagnostics) program is responsible for local coverage determination (LCD) ie, determination of a billing code. Per this program, in order to be reimbursed for running assays such as these, the assays must first undergo assay validation,

followed by clinical validation, before a clinical utility study can be completed. The final step of this course provides information that can guide a physician when recommending a course of action for a patient with a particular score. The final results of a clinical utility trial for Prolaris® (PROCEDE-1000) are expected in mid-2015, while a clinical utility trial for the Oncotype DX® prostate cancer assay is currently underway.5 Target Serum Testosterone Levels Clinical Significance of Serum Testosterone Levels

Achieving and maintaining effective suppression of serum testosterone levels in men treated with androgen deprivation therapy (ADT) is one of the essential strategies in the management of PC.4 Traditionally, serum testosterone castration levels were considered to be achieved when testosterone levels were <50 ng/dL. Current NCCN guidelines

continue to use a serum testosterone level of <50 ng/dL, yet note that the optimal level of serum testosterone to effect castration has yet to be determined.4 The European Association of Urology (EAU) guidelines recommend levels of <20 ng/dL to define levels of castration.11 Are Lower Serum Testosterone Levels More Desirable?

Dr. Kantoff points out that there is controversy surrounding the <50 ng/dL serum testosterone target, concerning whether or not this level is sufficient to be considered castration and, secondly, if that level is reflective of the levels in the tissue itself. He notes for this second point that after luteinizing hormone-releasing hormone (LHRH) therapy or an orchiectomy, there is still sufficient androgen remaining in the patient’s tumor tissue to stimulate the androgen receptor. Indeed, it has been shown that androgens in patients who have undergone castration persist.12 He goes on to question, “If you achieve

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CME ACTIVITY lower levels of testosterone in the blood and, as a consequence of that, lower levels of testosterone in the tissue, will it make a difference?” A recent paper by Klotz et al in the context of a large randomized study suggests that achieving lower testosterone is associated with improved outcomes. This study was done largely before the use of the newer androgen-receptor signaling agents and begs the following questions: 1) Would this differential be overcome with the subsequent use of these agents later in disease, and 2) Would the use of these agents earlier in the disease make a meaningful difference in lowering available testosterone or inhibiting testosterone signaling above and beyond what can be achieved later in the disease course?13 How Should “Castration Levels” of Serum Testosterone be Defined?

The optimal castration level continues to be debated and has not been conclusively established. Current data suggest that the new target for either surgical or chemical castration is a serum testosterone level of lower than 20 ng/dL to maximize therapeutic outcomes.14 While this lower level is typically achieved by patients receiving

Apero is et iusande ntenienisima pre odit acest est rera plignim nobis et provita tiorionseque ea doluptaquo surgical orchiectomy, several studies have shown that approximately 20% of patients fail to achieve a testosterone level of 20 ng/dL with current LHRH agonists.15 Patients who fail to reach serum testosterone levels of <20 ng/dL are also more likely to have higher PSA

values, but the clinical importance of this finding has not been established.15 Dr. Kantoff suggests that this question could be answered by comparing patients receiving initial, standard ADT vs patients receiving initial, standard ADT plus a drug like abiraterone, which will lower tissue levels of testosterone more profoundly than using an LHRH analog alone. The only rubric that he considers significant in this kind of study is whether or not patients who achieve lower serum and lower tissue androgen levels live longer. He notes, “No one has shown, in a prospective fashion, whether (lower tissue and serum androgen levels) make a difference. So I think it’s an interesting theoretical concept at this point, and there is some retrospective data supportive of the idea.” As discussed by Dr. Shore, a retrospective study by Morote et al14 found that mean survival free of androgenindependent progression (AIP) in patients with nonmetastatic PC on continuous ADT was longest in patients with serum testosterone levels <20 ng/dL, followed by those with levels between 20 ng/dL and 50 ng/dL, while those with levels >50 ng/ dL had the shortest mean survival free of AIP. This study investigated the clinically significant threshold of testosterone related to mean survival free of AIP and determined that 32 ng/dL was the lowest serum testosterone level that was able to significantly distinguish patient groups. More recently, the PR-7 study randomly assigned patients experiencing biochemical failure after radiation therapy or surgery plus radiation therapy to continuous androgen deprivation or intermittent androgen deprivation. Patients with first-year nadir testosterone consistently >20 ng/dL had significantly higher risks of dying as a result of disease (20 ng/dL to 50 ng/dL: hazard ratio [HR], 2.08; 95% CI, 1.28 to 3.38; >50 ng/dL: HR, 2.93; 95% CI, 0.70 to 12.30) and developing

hormone resistance (20 ng/dL to 50 ng/ dL: HR, 1.62; 95% CI, 1.20 to 2.18; >50 ng/dL: HR, 1.90; 95% CI, 0.77 to 4.70). Maximum testosterone ≥50 ng/dL predicted for a higher risk of dying as a result

Apero is et iusande ntenienisima pre odit acest est rera plignim nobis et provita tiorionseque ea doluptaquo of disease (P=.02). The authors of this study recommend ADT to be modified to ensure that serum testosterone levels of <20 ng/dL are achieved.13 Dr. Shore went on to point out that perhaps the most critical patient population to study the effect of lower serum testosterone levels in would be those who are newly diagnosed, androgen-sensitive, and considered high-risk (ie, those who would typically fail prostatectomy or radiation), as these are the patients with the greatest risk of dying of PC–specific mortality. A pilot study has been completed examining whether combinations of agents (goserelin combined with dutasteride [ZD], bicalutamide and dutasteride [ZBD], and bicalutamide, dutasteride, and ketoconazole [ZBDK]) that target testicular, adrenal, and prostate androgen production would suppress prostate androgens and androgen receptor signaling more effectively than testicular androgen suppression (ie, traditional ADT) alone, and further, if this would enhance pathologic responses. This study determined that the groups receiving combination therapy had substantially lower prostate dihydrotestosterone (DHT) concentrations, more frequent PSA nadirs of <20 ng/dL, and more frequent pathologic complete and near-complete responses (Figure 2).12

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CME ACTIVITY However, despite combination treatment, the combined activity of residual testosterone and DHT levels in the prostate remained at concentrations capable of activating androgen receptor signaling. In other words, treatment failure here was likely still occurring due to ineffective and incomplete androgen receptor pathway suppression. The authors suggest combining effective androgen synthesis inhibitors (ie, abiraterone) with more potent androgen receptor antagonists (ie, enzalutamide) as a reasonable strategy for assessing whether highly active ADT is an effective treatment approach.12 Another recent study by Taplin et al16 concluded that neoadjuvant treatment with an LHRH agonist (LHRHa) plus abiraterone acetate (AA) prior to prostatectomy for localized high-risk PC suppresses tissue androgens more effectively than LHRHa alone. The primary objective of this study was to evaluate whether the addition of AA to LHRHa would reduce prostate tissue androgens compared with LHRHa alone at 12 weeks.

Addition of AA in fact decreased mean serum testosterone by 73% and DHT by 43% and also decreased intraprostatic levels of testosterone and DHT by 37% and 86%, respectively. Thus, while prostatectomy alone is inadequate therapy for many patients with high-risk localized PC, neoadjuvant systemic therapy may provide an opportunity to improve cure rates. More research is needed to identify which patients may benefit from this therapy, as well as to establish an optimal treatment regimen.16 Dr. Shore noted that this study and others are to be applauded, as not a lot of headway has been made in improving the treatment of newly diagnosed and high-risk patients. Sequencing of Agents in Late-Stage PC While a variety of chemotherapies are now approved for use in late-stage, or metastatic castration-resistant PC (mCRPC), Dr. Kantoff points out that currently there is very little data at this point to guide the sequencing of treatment.

Docetaxel

Docetaxel became available for use beyond initial hormone therapy starting in 2004. The utility of docetaxel in mCRPC in men was measured by median survival differences, which was about 2 to 3 months compared to mitoxantrone.4,17 However, Dr. Kantoff feels that, “Median survival differences are misleading in general, because it’s really mostly for investigators to determine the magnitude of the effect on a population and whether a drug actually has activity. But it doesn’t mean much to the individual patient, [because] not all patients respond. Median survival captures just a small part of the story, and we’re still left in a situation where we are not very good at selecting the appropriate patient for the appropriate drug at the appropriate time. So we’re left with median survivals, hazard ratios, but not good biomarkers or predictive markers for response to therapy and benefit.” Instead, clinical factors and side effects play a large role in deciding treatment sequence.4

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CME ACTIVITY While ADT has long been the primary standard of care for management of metastatic hormone-sensitive disease, the CHAARTED trial recently challenged this concept, reporting a statistically significant clinical benefit with the addition of docetaxel to ADT in this earlier metastatic setting. The CHAARTED trial has demonstrated that docetaxel in combination with ADT improved overall survival

It remains unclear if combination therapy could be used in hormone-refractory disease. compared with ADT alone by ~13-14 months in patients with advanced, hormone-sensitive disease and ~17 months in patients with advanced, high-volume disease.18,19 Dr. Kantoff estimates that these results have the capacity to positively impact between 10% and 30% of patients with metastatic, hormone-sensitive disease. However, he points out that it remains unclear if combination therapy such as this could be used in patients with hormone-refractory disease that— despite having no radiographic evidence of metastases—in all likelihood does have metastases. Dr. Shore also points out that there is a pervasive thought in both the patient and provider communities that chemotherapy-containing regimens are incredibly toxic and difficult to deal with, when, in fact, most patients do very well with these therapies, as highlighted by the results of the CHAARTED trial. Immunotherapy

Sipuleucel-T is designed to induce an immune response targeted against prostatic acid phosphatase (PAP), an antigen

expressed in most prostate cancers.20 Dr. Kantoff notes sipuleucel-T is the first drug he considers in an mCRPC treatment paradigm from a sequencing perspective, because of the dosing regimen; the recommended course of therapy is 3 complete doses, given at approximately 2-week intervals.20 Dr. Kantoff feels it’s best to get an immunotherapy into patients earlier in the disease. Dr. Shore notes that he’s excited about the use of immunotherapy, as these agents don’t lower testosterone levels and thus aren’t associated with the comorbidities associated with testosterone depletion (eg, loss of libido and muscle mass, depression, fatigue, etc).4 In his opinion, these agents in the future may represent a significant advance in the treatment of biochemical-failure patients. Moreover, these agents can continue to work after the treatment itself is discontinued (ie, they “have memory”), in contrast to ADT or cytotoxic chemotherapies, making these an exciting addition to the mCRPC treatment landscape.21 Androgen Signaling Pathway Inhibitors

Enzalutamide and abiraterone both act to inhibit androgen signaling and are approved for use in mCRPC. In this setting, both agents extend median survival by ~4 to 5 months. 22,23 Dr. Kantoff considers these agents after sipuleucel-T in an mCRPC treatment paradigm. In his experience, there are 3 sets of patients that emerge after treatment with these agents: • Those that don’t respond (ie, PSA levels continue to climb) • Those whose PSA levels go down, but gradually drift upward again • Those who profoundly respond and remain on therapy anywhere from 6 months to many years There is data that suggests crossresistance between enzalutamide and abiraterone.4 As such, Dr. Kantoff goes

on to state, “Where maybe a couple years ago I was using one followed by the other, I do that less frequently now than I did in the past.” Also of note is that a small fraction of mCRPC patients bear splice variants of the androgen receptor and do not respond very well to these agents. Dr. Shore also notes that he’s eager to see the results of ongoing trials examining the efficacy of these 2 agents in combination. Docetaxel, Cabazitaxel, Radium-223, and Beyond

Further along in the treatment paradigm, Dr. Kantoff considers the following: • Docetaxel or cabazitaxel, if the patient hasn’t already received docetaxel, and rapid progression or aggressive disease is a concern • Radium-223 for the patient who has relatively asymptomatic disease with bony disease only (ie, not for a patient where rapid progression is a concern, as it is a monthly treatment) Dr. Kantoff notes that if docetaxel or cabazitaxel are used first, radium-223 can be used subsequently. After these options are exhausted, he suggests going back to enzalutamide and abiraterone, whichever one wasn’t used previously. He does point out that he doesn’t know if the efficacy of these agents is better if they are not used sequentially. Conclusion Both Drs. Shore and Kantoff agree that active surveillance is underutilized and overtreatment of patients is a common problem. These issues may be addressed via assessment of specific biomarkers in a patient’s biopsy to guide physicians and patients to the best course of action. Both also noted that several recent, smaller, retrospective studies suggest that serum testosterone levels <20 ng/dL may provide additional clinical benefit compared with the current recommended level of <50 ng/dL, but more research

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CME ACTIVITY is needed to determine if this truly makes a difference in patient outcomes. With little guidance available to physicians to determine an ideal sequencing of agents in late-stage PC, Drs. Shore and Kantoff provided insight into their own clinical practices and thought processes when determining a treatment course of action for their patients. ■

with clinically low- and intermediate-risk

15. Kawakami J, Morales A. Clinical sig-

prostate cancer. Published online ahead of

nificance of suboptimal hormonal levels

print, Nov. 2014. Eur Urol. 2014.

in men with prostate cancer treated

7. Amin MB, Lin DW, Gore JL, et al. The critical role of the pathologist in determining eligibility for active surveillance as

with LHRH agonists. Can Urol Assoc

J.2013;7(3-4):E226-230. 16. Taplin M-E, Montgomery B, Logothetis CJ,

a management option in patients with

et al. Intense androgen-deprivation therapy

prostate cancer. Arch Pathol Lab Med.

with abiraterone acetate plus leuprolide

2014;138(10):1387-1405.

acetate in patients with localized high-risk

8. Shipitsin M, Small C, Giladi E, et al.

prostate cancer: results of a randomized

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1. Roobol MJ, Carlsson SV. Risk stratification

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in prostate cancer screening. Nat Rev Urol.

phosphor-S6 and phosphor-PRAS40 as

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predictive protein biomarkers for prostate

2. US Preventative Services Task Force. Final recommendation statement:

cancer lethality. Proteome Sci. 2014;12:40. 9. Shipitsin M, Small C, Choudhury S, et al.

17. Taxotere® (docetaxel) prescribing information. Bridgewater, NJ: Sanofi-aventis; May 2010. 18. Sweeney C, Chen Y-H, Carducci MA, et

prostate cancer screening. Released

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predicting prostate cancer aggressiveness

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RecommendationStatementFinal/prostate-

Br J Cancer. 2014;111(6):1201-1212.

newly metastatic prostate cancer (mPrCa):

cancer-screening. Accessed March 24,

10. Saad F, Shipitsin M, Choudhary S, et al.

an ECOG-led phase III randomized trial.

Distinguishing aggressive versus nonag-

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gressive prostate cancer using a novel prog-

Oncology Annual Meeting; May-June 2014;

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nostic proteomics biopsy test, ProMark. J

Chicago, IL. Abstract LBA2. J Clin Oncol.

nature derived from cell cycle proliferation

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genes for recurrence and death from pros-

11. Heidenreich A, Bastian PJ, Bellmunt J, et

2014;32(suppl 5; abstr LBA2). 19. Liaw BC, Shevach J, Oh WK. Systemic

tate cancer: a retrospective study in two

al. EAU guidelines on prostate cancer. Part

therapy for treatment of hormone-sensitive

cohorts. Lancet Oncol. 2011;12(3):245-255.

II: Treatment of advanced, relapsing, and

metastatic prostate cancer: from intermit-

castration-resistant prostate cancer. Eur

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Comprehensive Cancer Network, Inc.

Targeted androgen pathway suppression in

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localized prostate cancer: a pilot study.

physician_gls/PDF/prostate.pdf. Accessed

J Clin Oncol. 2014;32(3):229-237.

March 24, 2015.

13. Klotz L, O’Callaghan C, Ding K, et al. Nadir

motherapy. Curr Urol Rep. 2015;16(13):486. 20. Provenge® (sipuleucel-T) prescribing information. Seattle, WA: Dendreon Corporation; October 2014. 21. Beer TM, Glode LM, Lance RS, et al. Openlabel, multicenter study of sipuleucel-T in

testosterone within first year of androgen-

men with metastatic castrate-resistant

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deprivation therapy (ADT) predicts for time to

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Inc; January 2015.

US, Inc; September 2014. 23. Zytiga® (abiraterone acetate) prescribing

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FEATURE

BY DEBRA HUGHES, MS

pink ribbon with a blue dot—the last ribbon issued by t he Breast Cancer Research Fou ndat ion (BCRF) before founder Evelyn Lauder died in 2011—was significant to Fatima Cardoso, MD, who has been working tirelessly since 2006 to bring awareness of breast cancer in males. The blue dot represents the 1% of breast cancer that occurs in males. The American Cancer Society estimates that in 2015 in the United States, about 2,350 new cases of invasive breast cancer will be diagnosed and 440 men will die.1 What happened in 2006, Dr. Cardoso, Director of the Breast Cancer Unit at Champalimaud Cancer Center in Lisbon, Portugal, told Cancer Therapy Advisor, was that she had several male patients with metastatic breast cancer and turned to the literature to determine how best to treat them. “Nothing existed to help me,” she said, so she had to treat them as if they were females with breast cancer. However, she couldn’t help but believe there were differences, so she decided to raise interest in breast cancer in males. Today, a search on ClinicalTrials. gov using the search terms “male”, “breast”, and “cancer” returns a list of 130 studies that are currently recruiting men, with interventions ranging from

While research on breast cancer in men is growing, more is needed to offer the best treatment options to this subset of patients.

chemotherapy, small molecule inhibitors, and vaccines to radiation therapy. This delights Dr. Cardoso, who has pushed for protocols to include men, despite the limited number of patients available to recruit: breast cancer in men is rare, about 100 times less common than among women.1 In 2010, the incidence rate was 1.2 cases per 100,000 men.2 Dr. Cardoso, who is also Secretary General of the European Organisation for Research and Treatment of Cancer (EORTC), is leading the International Male Breast Cancer Program 3 with Sharon H. Giordano, MD, MPH, Professor, Department of Breast Medical Oncolog y, Universit y of Texas MD Anderson Cancer Center in Houston, TX. Coordinated by EORTC, with support from 10 collaborators worldwide, the three-part program was created to characterize breast cancer in males as well as to develop specific treatments and improve outcomes. In part one, the program analyzed more than 1,800 cases of male breast cancer treated from 1990 to 2010 within the network of 23 centers in nine countries, the largest group ever studied. Part two, which is now open, is creating a prospective registry of all male patients with breast cancer treated at the network centers over a period of 30 months. Dr. Cardoso told Cancer

The 1%: Unraveling The Causes and Optimal Treatment Options for Men with Breast Cancer

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FEATURE Therapy Advisor that the rapid accrual to this registry, primarily from the Netherlands, is demonstrating the feasibility of moving quickly to part three of the program, prospective clinical trials. The first study, a phase 2 trial in 100 to 150 patients, will evaluate a new drug to treat male breast cancer. She

Because of the low rate of incidence, mammography is not recommended for BC detection in men. said negotiations with a pharmaceutical company are currently ongoing. Dr. Cardoso presented initial results from part one of the program, a joint effort by the EORTC, Translational Breast Cancer Research Consortium, Breast International Group, and the North American Breast Cancer Group, at the 2014 San Antonio Breast Cancer Symposium in December.4 For the 1,822 patients enrolled, clinical data, long term outcomes, and local pathology were centrally analyzed at EORTC. Of these, 1,473 (1,384 from the European Union and 89 from the United States), had formalin-fixed, paraffin-embedded (FFPE) samples available that were analyzed for histology, grade, and estrogen receptor (ER), progesterone receptor (PR), androgen receptor (AR), HER2, and Ki67 status at one of three central labs located in the United Kingdom, the Netherlands, and the United States.4 Median age at diagnosis was 68.5; about 90% were between ages 57 and 79 or older, and 63% were diagnosed from 2001 to 2010.4

The results showed that “male breast cancer is usually ER-positive, PR-positive, and AR-positive and of luminal A-like subtype; 5% were HER2-positive and less than 1% were triple-negative breast cancer,” she reported. A total of 56% of patients had T1 tumors at diagnosis but only 4% had undergone breast-conserving surgery. Although estrogen receptor was highly positive in 90% of patients, adjuvant endocrine therapy, primarily tamoxifen, was given in only 77% of patients.4 Median overall survival (OS) was 10.4 years for patients with nonmetastatic node-negative disease; 8.4 years for those with nonmetastatic node-positive disease; and 2.6 years for those with metastatic disease. A significant improvement in OS was observed over time. High expression of ER and PR were prognostic for better outcome, whereas tumor grade, Ki67 expression, and immunohistochemistry subtypes were not prognostic. “In-depth characterization of samples is ongoing,” she noted.4 Risk factors for breast cancer in males include obesity, family history of male or female breast cancer, exogenous estrogen or testosterone use, BRCA gene mutations, Klinefelter syndrome, radiation exposure, and testicular disorders.5 Due to its low incidence, mammography is not recommended to detect breast cancer in men.6 By age 70, the estimated cumulative risk of breast cancer for men carrying germline mutations in the BRCA2 gene is 6.8%, for BRCA1 mutation carriers it is 1.2%.7 Incidence of breast cancer in males increases with age, with rates higher in African American men than in white men.8 Since 2000, death rates for male breast cancer have decreased 1.8% per year. 6 A population-based

study found that male patients with breast cancer have later disease onset and more advanced disease compared with female patients; however, they have lower risk of death from breast cancer than comparable female patients.9 A recent study documented a higher risk of death in black men diagnosed with early-stage breast cancer age 18 to 64 compared with white men that “was significantly reduced after accounting for differences in insurance and income,” as this did not hold true for older black men, possibly because of uniform health coverage through Medicare. The authors said these findings suggest “that poverty may play an important role in racial disparities in breast cancer mortality.”10 Dr. Cardoso credits the BCRF with being one of her earliest supporters, providing funding for research on breast cancer in men since 2007. Results of this research led to a 2008 workshop, proceedings of which were published in the Journal of Clinical Oncology in 2010.11 Further networking between

Men with breast cancer cannot be treated with the same methods as female breast cancer patients. the Breast International Group and The North American Breast Cancer Group resulted in creation of the International Breast Cancer Program. She has two important messages for her colleagues: given the available data, it’s no longer acceptable to treat male patients with breast cancer as if they were postmenopausal females—and Continued on page A31

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EXPERT PERSPECTIVE | BY DON S. DIZON, MD

A Case Study from an Oncology Sexual Health Clinic: Sexual Dysfunction Evaluation A case report that looks into a breast cancer survivor experiencing severe headaches seemingly related to sexual climax. The Oncology Sexual He a lt h C l i n ic at t he Massachuset ts G ener a l Ho spit a l in Boston, MA, was established in late 2012 and aims to provide resources for patients who experience changes related to sexuality, sexual relationships, and intimacy after a diagnosis and/or treatment for cancer–an area that has proven to be great need and interest within the oncology community. A LIVESTRONG survey in 2010, which included over 3,000 cancer survivors, reported that over 60% of respondents had sexual function and satisfaction issues after cancer, making it the third most frequently reported physical concern in this group of patients.1 While sexual health concerns are common among the general population, we must constantly keep an open mind to concerns related to sexual health in cancer survivors, because as illustrated in this case study, not all concerns are related to their prior treatment for cancer. Case Joan* is a 65 year old woman with a remote history of ductal carcinoma in situ (DCIS) who was referred to the Oncology Sexual Health Clinic for evaluation of sexual dysfunction. She stated that she experiences severe

headaches during sex and that they occur near climax. The headaches occur regardless of whether she achieved climax alone or with a partner, and the headaches do not occur at any other time. Ultimately, the headaches were severe enough that she had abstained from sexual activity for the past 6 years. She described the headaches as “crushing,” located in her frontal and temporal regions with radiation down both sides of her face. There were no associated symptoms, and, specifically, she denied tingling or numbness, seizures, or loss of consciousness. Of note, the headaches had not changed in character or occurred with any other physical activities. As she was no longer sexually active, she was not currently experiencing the headaches, however, she longed for sexual relations and a new partner–something that she had not been able to maintain because of the headaches. Prior to the onset of symptoms Joan reported a very fulfilling sexual life, without issues of attraction, pain, or orgasm. She denied any conscious precipitating event, including prior histories of physical or emotional abuse, sexual trauma, or other life-altering circumstances. Her family history was notable for a brother who sustained and succumbed to a subarachnoid hemorrhage 10 years previously.

She had sought medical help when the headaches first started, and underwent radiologic imaging with brain MRI. This was reportedly negative without evidence of prior ischemic events or aneurysms. In terms of her cancer history, she had been diagnosed with right breast ductal carcinoma in situ 8 years prior, for which she was treated with mastectomy, at which time she also underwent a contralateral prophylactic mastectomy with immediate reconstructions. She was on no medications and her social history was otherwise unrevealing. On exam she was well-appearing. Her cranial nerve examination and a gross neurologic examination were normal.

QUESTION: Based on Joan’s presentation and description of her pain symptoms, what is most likely her diagnosis? a. Complicated migraine b. Situational Anxiety Disorder c. Metastatic brain cancer d. Benign Sexual Headache e. Subarachnoid bleed

The answer: D, Benign Sexual Headache Discussion For patients with a history of DCIS, a common consideration is the use of endocrine therapy for secondary prevention. The most commonly administered agent is tamoxifen,1 though accumulating data suggest that for postmenopausal women, aromatase inhibitors may also be effective. 2 However, endocrine therapies are also associated with sexual dysfunction in breast cancer survivors, with the most common symptoms being related to vulvovaginal side effects,

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EXPERT PERSPECTIVE which commonly includes pain related to penetrative intercourse (dyspareunia). However, Joan was not taking either of these medications to explain her symptoms. In addition, she did not appear to have any concerns of her body image, which could lead to issues with intimacy or attraction. Indeed, she appeared quite comfortable in her own skin, and presented with a desire to be with a partner. Given that she had a prior evaluation to rule out an anatomic etiology, the long-standing nature of her symptoms, and the specific events that incited her headaches, her likely diagnosis is benign sexual headache (BSH; also referred to as coital cephalagia, primary sexual headache). BSH is a clinically recognized headache disorder that occurs exclusively during, or immediately after sexual activity. It is a rare condition with a reported incidence of 0.25% to 1.0% in the general population.3 The diagnosis is one of exclusion and more serious etiologies must be ruled out, including subarachnoid hemorrhage, cerebral infarction, or reversible vascular phenomenon.4-6 Further classification of BSH can be made relative to the timing of symptom onset during sexual intercourse (eg, pre-orgasmic, or type 1; orgasmic, or type 2; or following orgasm, type 3).6 The etiology of BSH remains unclear, likely due to

the rarity of the condition. Although the presence of another primary headache syndrome appears to be a risk factor for BSH,7 it was not present in this patient. Following the exclusion of more ominous conditions, patients with BSH have a favorable prognosis. Treatments are available, and despite the lack of high-quality data, they appear to be effective. For patients with frequent

Gillette Center for Gynecologic Oncology and the Department of Obstetrics & Gynecology in Boston, MA. Don Dizon, MD, a specialist in gynecologic oncologist at the Gillette Center for Gynecologic Oncology and director, Oncology Sexual Health Clinic, Massachusetts General Hospital Cancer Center in Boston, MA. Reference 1. Eng-Wong J, Costantino JP, Swain SM. The impact of systemic therapy following ductal carcinoma in situ. J Natl Cancer Inst

Monogr. 2010;2010(41):200-203.

The diagnosis is one of exclusion, where more serious potential causes are first ruled out by the physician.

2. Olin JL, St Pierre M. Aromatase inhibitors in breast cancer prevention. Ann

Pharmacother. 2014;48(12):1605-1610. 3. Rasmussen BK, Olesen J. Symptomatic and nonsymptomatic headaches in a general population. Neurology. 1992;4(6):1225-1231. 4. Headache Classification Committee of the International Headache Society (IHS). The

and regularly occurring headaches associated with sex, indomethacin (25 mg/day to 50 mg/day) or propranolol (40 mg/day to 200 mg/day) taken before intercourse may be of use, though more frequent administration may be indicated as prevention.6 ■

International Classification of Headache Disorders, 3rd edition (beta version).

Cephalalgia. 2013;33(9):629-808. 5. Valença MM, Valença LP, Bordini CA, et al. Cerebral vasospasm and headache during sexual intercourse and masturbatory orgasms. Headache. 2004;44:244–248. 6. Frese A, Rahmann A, Gregor N, et al.

This article was written by: Ashleigh Long,

Headache associated with sexual activ-

PhD, a student at the University of Kentucky

ity: prognosis and treatment options.

College of Medicine in Lexington, KY. Marcela del Carmen, MD, a gynecologic oncologist at the Massachusetts General Hospital Cancer Center’s

Cephalalgia. 2007;27:1265–1270. 7. Ostergaard JR, Kraft M. Benign coital headache. Cephalalgia. 1992;12:353–355.

Visit CancerTherapyAdvisor.com/PublishersAlliance to read a selection of oncology-focused articles from leading medical publishers.

Publishers Alliance

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VIEWPOINT | BY LESLIE BURGESS

Results of Nivolumab CheckMate 057 Study May Change Treatment of NSCLC In patients with nonsquamous NSCLC, nivolumab improved survival compared with docetaxel.

he PD-1 immune checkpoint inhibitor nivolumab improves s u r v i v a l c omp a re d w it h docetaxel for subsequent treatment of advanced nonsquamous non-small cell lung cancer (NSCLC), as shown in results of the phase 3 CheckMate 057 study presented in at the 2015 Americal Society of Clinical Oncology (ASCO) annual meeting in Chicago, IL.1 Options for treatment of patients with nonsquamous NSCLC who progress after initial therapy are limited—principally docetaxel is used if that agent was not part of prior therapy.2 In a previous phase 3 trial, nivolumab demonstrated improved survival compared with docetaxel for the treatment of previously treated squamous NSCLC. This led to its approval in March 2015 as subsequent therapy of squamous NSCLC. Patients in the CheckMate 057 study had progressed after treatment with platinum-based doublet chemotherapy (CT) (and, if eligible, a tyrosine kinase inhibitor), a guideline-recommended first-line therapy for nonsquamous NSCLC. They were randomly assigned to subsequent treatment with nivolumab (3 mg/kg every 2 weeks; 292 patients) or docetaxel (75 mg/m2 every 3 weeks; 290 patients); both drugs were continued until progression or discontinuation due to toxicity.

The primary efficacy endpoint of the study was overall survival (OS). Treatment with nivolumab significantly improved median OS, with a hazard ratio for death of 0.73 (95% CI: 0.59, 0.89; P=0.00155) compared with docetaxel. One-year OS was 50.5% with nivolumab versus 39.0% with docetaxel.1

One-year OS was 50.5% with nivolumab versus 39.0% with docetaxel. Other study endpoints included progression-free survival (PFS), objective response rate (ORR), and nivolumab efficacy by PD-L1 expression. Significantly more patients had an objective response (19.2% vs. 12.4%; P=0.0235). At the time of the analysis, the median duration of response to nivolumab was 17.1 months, compared with 5.6 months for docetaxel. No difference between nivolumab and docetaxel was observed in median PFS (2.3 months vs. 4.2 months; P=0.393). PD-L1 expression was associated

A28 CANCER THERAPY ADVISOR | JULY/AUGUST 2015 | CancerTherapyAdvisor.com

with improved efficacy for patients treated with nivolumab. Also of note, subgroup analysis favored nivolumab over docetaxel in all categories, except patients 75 years of age or older, never smokers, and those positive for EGFR mutations. Treatment-related adverse reactions of grade 3 to 5 severity occurred at a higher rate with docetaxel (53.7%) than with nivolumab (10.5%).1 Luis Paz-Ares, MD, PhD, from the Hospital Universitario Virgen Del Rocio, Spain, presented the results at ASCO. He noted that “CheckMate 057 is the second phase 3 trial to demonstrate superior survival with nivolumab over docetaxel” in advanced NSCLC. Roy S. Herbst, MD, PhD, from the Yale Comprehensive Cancer Center in New Haven, CT, commented that this study showed “a particularly long benefit” and that nivolumab is less toxic than docetaxel. Although PD-L1 expression was associated with improved survival and ORR, he noted that even patients without PD-L1 expression did at least as well as those treated with docetaxel. Dr. Herbst added that the survival benefit across multiple patient subgroups combined with lower toxicity recommends nivolumab as a new standard of care for patients with previously treated nonsquamous NSCLC. ■ Reference 1. Paz-Ares L, Horn L, Borghaei H, et al. Phase III, randomized trial (CheckMate 057) of nivolumab versus docetaxel in advanced non-squamous cell non-small cell lung cancer. J Clin

Oncol. 2015;33(Suppl):Abst LBA109. http://meetinglibrary.asco.org/content/154634-156. Accessed June 1, 2015.

Bristol-Myers Squibb At The Forefront Of Immuno-Oncology Research

Educational materials about Immuno-Oncology (I-O) for your patients and caregivers. At Bristol-Myers Squibb we are dedicated to helping healthcare providers educate patients and caregivers about I-O. Our full suite of educational materials to support this mission are available for download at: www.immunooncologyhcp.com Topics covered for patients and caregivers include: • Living and coping with cancer • Immune system basics • Immune system and cancer • How is immunotherapy different from other types of treatments? • and more…

Topics covered for healthcare providers include: • Immune system basics • Immune system and cancer • How is immunotherapy different from other types of treatments? • Types of immunotherapies • Immune system pathways being researched • and more…

Download and print copies of these resources to use within your practice today! www.immunooncologyhcp.com

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Cancer Therapy Advisor - Page 4/C - Issue Date July/August

IN THE CLINIC | BY JASON HOFFMAN, P

harmD,

RPh

Enoxaparin Efficacious, Feasible for Prevention of VTE in Advanced Pancreatic Cancer Recent research builds upon existing data related to enoxaparin and VTE complication prevention in patients with advanced pancreatic cancer. in the enoxaparin group (HR 0.12; 95% CI: 0.03, 0.52; P = 0.001).1 In addition, five of the 152 patients in the observation are experienced major bleeding events versus seven of 160 patients in the enoxaparin arm (HR 1.4; 95% CI: 0.35,3.72; P=1.0).1 The overall cumulative incidence rates of symptomatic V TEs were 15.1% and 6.4% in the observation and enoxaparin groups, respectively (HR 0.40; 95% CI: 0.19, 0.83; P=0.01).

rimar y pharmacologic prevention of symptomatic venous thromboembolic events (VTEs) in outpatients with advanced pancreatic cancer is highly efficacious and feasible, a study published in the Journal of Clinical Oncology has shown.1 Uwe Pelzer, MD, PhD, from Charité Universitätsmedizin Berlin in Germany, and colleagues enrolled 312 patients with histologically proven advanced pancreatic cancer and randomly assigned them 1:1 to receive ambulant first-line chemotherapy and prophylactic use of enoxaparin 1 mg/kg subcutaneously daily or chemotherapy alone.1 Chemotherapy either consisted of gemcitabine monotherapy 1 g/m 2 intravenously on days 1, 8, and 15 in 28-day cycles, or gemcitabine 1 g/m2 intravenously plus fluorouracil 750 mg/ m 2 continuous intravenous infusion, folinic acid 200 mg/m2 intravenously, and cisplatin 30 mg/m2 intravenously on days 1 and 8 in 21-day cycles.1 After 3 months, all patients received gemcitabine alone with or without enoxaparin 40 mg daily. Enoxaparin was dose-adjusted based on patients’ platelet count and kidney function.1 Results of the study showed that within the first 3 months, 15 of 152 patients randomly assigned to the observation group experienced symptomatic VTEs compared with two of the 160 patients

Researchers found no difference in progression-free survival (P=0.64) and overall survival (P=0.44) between the two treatment arms.1 According to the American Cancer Societ y, 48,960 people w i l l be diagnosed with pancreatic cancer in 2015 and 40,560 will die of the disease.2 Advanced pancreatic cancer accounts for the highest rates of V TEs in patients with cancer, which can result in impaired quality of life, delayed cancer treatment, longer hospitalizations, and higher costs.1 The National Comprehensive Cancer Network (NCCN) guidelines currently recommend enoxaparin or dalteparin, both of which are types of low molecular weight heparin (LMWH), as well as fondaparinux, unfractionated heparin, and warfarin, for the prevention of cancer-associated VTEs in the outpatient and inpatient settings.3 The findings of this study build upon existing data in that primary

Illustration of deep vein thrombosis, a common type of venous thrombosis, where a formation of a blood clot occurs in a deep vein (most often in the legs).

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IN THE CLINIC Because of the low rate of incidence, mammography is not recommended for BC detection in men. prophylaxis of VTEs with enoxaparin ef fect ively prevents t hese major complications in ambulatory patients with advanced pancreatic cancer without decreasing the efficacy of chemotherapy.1 Clinicians prescribing enoxaparin to patients should be aware that

Feature Continued from page A25

especially not with aromatase inhibitors, as these agents may actually hurt patients—and that everyone needs to continue to advocate for males to enter clinical trials of new agents. ■ References 1. American Cancer Society. Breast Cancer in

enoxaparin should be dose adjusted in patients with a creatinine clearance less than 30 mL/min and enoxparin should be dosed using total or actual body weight in obese patients depending on patient’s weight.4 Clinicians should obtain peak and trough anti-Factor Xa levels, as well as complete blood counts and stool occult blood tests periodically, and monitor patients for signs of bleeding.4 ■

from the CONKO-004 trial. J Clin Oncol. 2015;33(18):2028-2034. 2. What are the key statistics about pancreatic cancer?. American Cancer Society website. http://www.cwancer.org/cancer/ pancreaticcancer/detailedguide/pancreatic-cancer-key-statistics. Updated January 9, 2015. Accessed June 22, 2015. 3. NCCN Clinical Practice Guidelines in Oncology. Hodgkin Lymphoma. V2.2015. Available at: http://www.nccn.org/professionals/physician_gls/pdf/vte.pdf.

References

Accessed June 22, 2015.

1. Pelzer U, Opitz B, Deutschinoff G, et al.

4. Enoxaparin (Lovenox) [prescribing infor-

Efficacy of prophylactic low-molecular

mation]. Bridgewater, NJ: Sanofi-Aventis.

weight heparin for ambulatory patients with

http://products.sanofi.us/lovenox/

advanced pancreatic cancer: outcomes

lovenox.html.

4. Cardoso F, Bartlett J, Slaets L, et al.

8. Goodman MT, Tung KH, Wilkens LR.

Characterization of male breast cancer:

Comparative epidemiology of breast

First results of the EORTC10085/TBCRC/

cancer among men and women in the US,

BIG/NABCG International Male BC

1996 to 2000. Cancer Causes Control.

Program. S6-05. Presented at: 2014 San

2006;17(2):127-136.

Antonio Breast Cancer Symposium; p48. 5. Ruddy KJ, Winer EP. Male breast

9. Miao H, Verkooijen HM, Chia KS, et al. Incidence and outcome of male

cancer: risk factors, biology, diagnosis,

breast cancer: an international

treatment, and survivorship. Ann Oncol.

population-based study. J Clin Oncol.

2013;24(6):1434-1443. 6. American Cancer Society. Breast Cancer

2011;29(33):4381-4386. 10. Sineshaw HM, Freedman RA, Ward EM, et

Men. Available at: http://www.cancer.org/acs/

Facts & Figures 2013-2014. Atlanta:

al. Black/White Disparities in Receipt of

groups/cid/documents/webcontent/003091-

American Cancer Society, Inc. 2013.

Treatment and Survival Among Men With

pdf.pdf.Accessed May 8, 2015.

Available at: http://www.cancer.org/acs/

Early-Stage Breast Cancer. J Clin Oncol.

groups/content/@research/documents/

May 4, 2015. [Epub ahead of print] pii:

2. Anderson WF, Devesa SS. Breast carcinoma in men. Cancer. 2005;103(2):432-433. 3. ClinicalTrials.gov. Male breast cancer: understanding the biology for

document/acspc-042725.pdf. Accessed May 8, 2015. 7. Tai YC, Domchek S, Parmigiani G, Chen S.

JCO.2014.60.5584. 11. Korde LA, Zujewski JA, Kamin L, et al. Multidisciplinary meeting on male

improved patient care. NCT01101425.

Breast cancer risk among male BRCA1 and

Available at: https://clinicaltrials.gov/ct2/

BRCA2 mutation carriers. J Natl Cancer

recommendations. J Clin Oncol.

show/NCT01101425. Accessed May 8, 2015.

Inst. 2007;99(23):1811-1814.

2010;28(12):2114-2122.

breast cancer: Summary and research

Read more clinical commentary on topics in oncology at CancerTherapyAdvisor.com

CancerTherapyAdvisor.com | JULY/AUGUST 2015 | CANCER THERAPY ADVISOR A31

REGIMEN & MONOGRAPH INDEX CANCER THERAPY REGIMENS & DRUG MONOGRAPHS

Bone Cancer

3 Brain Cancer 5 Breast Cancer 12 Endocrine Cancer 16 Gastrointestinal Cancer  Anal Carcinoma  Gallbladder Carcinoma and Intrahepatic

Cholangiocarcinoma  Hepatocellular Carcinoma  Pancreatic Adenocarcinoma

27 Genitourinary Cancer  Testicular Cancer

37 Gynecologic Cancer 40 Head and Neck Cancer 41 Hematologic Cancer  Non-Hodgkin Lymphoma: Follicular Lymphoma

63 Lung Cancer  Lung Cancer

76 Sarcoma 77 Skin Cancer 81

Associated Hematological Disorders

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

IMPORTANT INFORMATION FOR ALL READERS CANCER THERAPY ADVISOR (CTA) is an up-to-date guide to commonly prescribed pharmaceuticals, as well as certain OTC products. It has been produced to provide an easily accessible reminder of basic information useful to review when prescribing medications, such as specific indications for use, dosage, and a checklist of precautions, interactions, and adverse drug reactions. Reference should always be made to each drug being coadmin istered. The information it contains is intended solely for use by the medical profession. IT IS NOT INTENDED FOR LAY READERS. This reference has been assembled and edited by an experienced staff of pharmacists uti lizing information available from FDA-approved labeling. Distinctions have not necessarily been made between those reactions that are well-documented and/or clinically significant, and those that carry only a theoretical risk. A renowned board of consulting medical specialists has also independently reviewed the product references. However, although every effort is made to assure accuracy, the information in CTA is not necessarily reviewed by the supplier of a particular drug. If any questions arise about information in CTA, the physician should verify it against labeling or by contacting the company marketing the drug. The publisher and editors do not warrant or guarantee any of the products described or the information describing them. THE PUBLISHER AND EDITORS DO NOT ASSUME, AND HEREBY EXPRESSLY DISCLAIM ANY LIABILITY WHATSOEVER FOR ANY ERRORS OR OMISSIONS IN SUCH INFORMATION OR FOR ANY USE OF ANY OF THE PRODUCTS LISTED. No prescription drug should be used except on the advice of, and as directed by, a physician. The training and experience of a physician are essential to forming any opinion on the appropriateness of a specific drug for a specific patient. The information in this publication is not by itself sufficient for a lay person—or even a physician—to evaluate the risks and benefits of taking any particular drug. In reaching professional judgments on whether to prescribe a pharmaceutical, which to prescribe, and under what regimen, the physician should thoroughly understand the options available for any clinical application, the potential effectiveness of each product, and the associated risks and side effects. This knowledge should be considered in light of the special circumstances of the patient, for each patient is unique. No single reference can substitute for medical training and experience. The physician must be familiar with the full product labeling, provided by the manufacturer or distributor of the drug, of every product he or she prescribes, as well as the relevant medical literature. Certain additional qualifications are important in using this book. First, CTA has been deliberately kept concise, with a standardized format, so that it could be a convenient reference tool. This means that lengthy and detailed explanations about certain aspects of drugs commonly found in labeling are omitted or condensed. Second, by revising and reprinting quarterly, CTA should be one of the most up-to-date guides to prescription drugs now available in print. Only the current issue should be used. The prescribing decision is ultimately the responsibility of the physician. CTA is offered to assist physicians in this area. © 2015 Haymarket Media, Inc.

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DRUG MONOGRAPHS

BONE CANCER Methotrexate injection

℞

Bedford

Folic acid antagonist. Methotrexate 25mg/mL; soln for IV, IM, intra-arterial, or intrathecal administration after dilution; preservative-free. ℞ Also: Methotrexate for injection Methotrexate 1g/vial; pwd for IV, IM, intra-arterial, or intrathecal administration after dilution; preservative-free. Indications: Non-metastatic osteosarcoma in patients who have undergone surgical resection or amputation for the primary tumor (high-dose therapy with leucovorin rescue). Adults: Initially 12g/m2 IV infusion over 4 hours; may be increased to 15g/m2; see literature for leucovorin rescue dosing with high-dose methotrexate. Children: See literature. Contraindications: Pregnancy (Cat.X). Nursing mothers. Warnings/Precautions: Be fully familiar with this drug’s toxicity before use. Discontinue if malignant lymphomas occur. Obtain baseline and monitor CBCs with differential, platelet counts, chest X-ray, and hepatic, renal and pulmonary function. During therapy monitor hematology monthly, renal and hepatic function every 1–2 months, more often if increasing dose or predisposed to toxicity (eg, dehydration). Discontinue immediately if blood counts drop significantly. Rule out pregnancy in women of childbearing potential; use effective contraception during therapy and for at least 1 ovulatory cycle afterwards for women and for at least 3 months afterwards for men. Interrupt therapy if vomiting, diarrhea, stomatitis, or pulmonary symptoms occur. Hepatic or renal impairment. Obesity. Diabetes. Peptic ulcer. Ulcerative colitis. Infection. Dehydration. Folate deficiency. Ascites, pleural effusions: evacuate fluid, monitor for toxicity and reduce dose or discontinue if needed. Elderly (use low doses and monitor closely). Debilitated. Interactions: Avoid live virus vaccines. Toxicity increased by NSAIDs, salicylates, phenytoin, sulfonylureas, sulfonamides, probenecid, folic acid antagonists. May be potentiated by penicillins (monitor), tetracyclines, chloramphenicol, non-absorbable broad spectrum antibiotics. May be antagonized by folic acid. May potentiate theophylline, mercaptopurine. Increased risk of soft tissue necrosis and osteonecrosis with radiotherapy. Caution with other hepatotoxic drugs (eg, azathioprine, retinoids, sulfasalazine) and nephrotoxic agents (eg, cisplatin).

Adverse reactions: Ulcerative stomatitis, leukopenia, nausea, GI upset, malaise, fatigue, chills, fever, dizziness, infection, myelosuppression, hepatotoxicity, renal toxicity, CNS toxicity, seizures (esp in children); interstitial pneumonitis, tumor lysis syndrome, skin reactions (may be fatal; eg, toxic epidermal necrolysis, Stevens-Johnson syndrome). How supplied: Soln (2mL, 4mL, 8mL, 10mL)–10 (single-use vials); pwd (1 gram)–1 (single-use vial)

VOTRIENT GlaxoSmithKline

℞

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. Monitor liver tests before starting and at Weeks 3, 5, 7, and 9, thereafter at Months 3 and 4, then periodically. If ALT between 3×ULN and 8×ULN continue therapy with weekly monitoring until ALT returns to Grade 1 or baseline. If ALT >8×ULN interrupt therapy until ALT returns to Grade 1 or baseline; may consider reintroducing at a reduced dose, measure liver tests weekly for 8 weeks; if ALT>3×ULN recurs, permanently discontinue. Permanently discontinue if ALT>3×ULN and bilirubin >2×ULN. Gilbert’s syndrome (see full labeling). History of QT prolongation. Cardiac dysfunction risk: evaluate LVEF at baseline and periodically; monitor for CHF. Monitor ECG, electrolytes (eg, calcium, magnesium, potassium), thyroid. History of hemoptysis, cerebral, or clinically significant GI hemorrhage in the past 6 months: not recommended. Risk of arterial thrombotic events (within previous 6 months: not recommended). Monitor for VTE, PE, infection, proteinuria (reduce dose if 24-hour urine protein ≥3g), thrombotic microangiopathy, GI perforation or fistula. Monitor BP and

manage hypertension promptly. Discontinue if severe and persistent hypertension (despite antihypertensives and dose reduction), if repeat episodes of proteinuria (despite dose reductions), thrombotic microangiopathy, or serious infection occurs. Stop therapy at least 7 days before surgery; discontinue in patients with wound dehiscence. Pregnancy (Cat.D), nursing mothers: not recommended. Interactions: See Adult dosing: Potentiated by strong CYP3A4 inhibitors, grapefruit juice. Avoid concomitant strong Pgp or BCRP inhibitors. Antagonized by strong CYP3A4 inducers. Concomitant drugs with narrow therapeutic windows metabolized by CYP3A4, CYP2D6, or CYP2C8: not recommended. Increased risk of ALT elevations with concomitant simvastatin; caution and monitor closely; follow dosing guidelines or consider alternatives to pazopanib, or discontinuing simvastatin if develops. Separate antacids by several hours. Caution with concomitant drugs that prolong QT interval (eg, antiarrhythmics). Adverse reactions: Diarrhea, hypertension, hair color changes, nausea, anorexia, vomiting, fatigue, decreased weight, decreased appetite, tumor pain, musculoskeletal pain, headache, dysgeusia, dyspnea, skin hypopigmentation; hepatoxicity, QT prolongation, hemorrhagic events, arterial thrombotic events (eg, MI, angina, ischemic stroke, TIA), venous thrombotic events (eg, VTE, PE), GI perforation or fistula, impaired wound healing, hypothyroidism, proteinuria, infection, reversible posterior leukoencephalopathy syndrome (discontinue if occurs). How supplied: Tabs–120

XGEVA Amgen

℞

Osteoclast inhibitor (RANKL inhibitor). Denosumab 120mg/vial (70mg/mL); soln for SC inj; preservative-free. Indications: Treatment of adults and skeletallymature adolescents with giant cell tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity. Adults: Give by SC inj into upper arm, upper thigh, or abdomen. 120mg once every 4 weeks with additional 120mg doses on Days 8 and 15 of the 1st month of therapy. Children: Not established (interferes with bone growth and dentition). Contraindications: Pre-existing hypocalcemia. Warnings/Precautions: Correct hypocalcemia before starting; ensure adequate daily calcium, magnesium, and Vit.D intake, esp. in renal impairment (CrCl <30mL/min). Monitor calcium,

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DRUG MONOGRAPHS

BONE CANCER phosphorus, magnesium levels in susceptible patients (eg, severe renal impairment, receiving dialysis). Monitor for osteonecrosis of the jaw. Perform oral exam and preventive dentistry before and regularly during therapy. Maintain good oral hygiene. Avoid invasive dental procedures during treatment. Evaluate for atypical fractures if thigh/groin pain develops; consider withholding therapy until risk/benefit

assessment. Pregnancy (Cat.D); use highly effective contraception during therapy, and for at least 5 months after last dose. Nursing mothers: avoid (may impair mammary gland development/ lactation). Interactions: Concomitant other denosumabcontaining products (eg, Prolia): not recommended. Concomitant drugs that can lower calcium levels; monitor.

Adverse reactions: Fatigue, asthenia, hypophosphatemia, nausea, arthralgia, headache, back pain, pain in extremity, dyspnea, decreased appetite, peripheral edema, vomiting, anemia, constipation, diarrhea; osteonecrosis of jaw, severe hypocalcemia (may be fatal), anaphylactic reactions (discontinue if occurs). How supplied: Single-use vial (1.7mL)–1

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

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

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

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

Cyclophosphamide (CTX, Cytoxan) IV: ≤1,500mg/m2 Cyclophosphamide (CTX) oral ≥100mg/m2/day Cytarabine (ARA-C) IV: >200mg/m2 Dactinomycin (Cosmegen) IV Daunorubicin (Cerubidine) IV Doxorubicin IV: ≤60mg/m2 Epirubicin (Ellence) IV: ≤90mg/m2 Estramustine (Emcyt) oral Etoposide (VP-16) oral

Idarubicin (Idamycin) IV Ifosfamide (Ifex) IV: <2g/m2 Interferon alpha (IFN-alfa, Intron A) IV: ≥10 million IU/m2 Irinotecan (CPT-11, Camptosar) IV Lomustine (CCNU, CeeNU) oral Melphalan (L-PAM, Alkeran) IV Methotrexate (MTX) IV: ≥250mg/m2 Oxaliplatin (Eloxatin) IV Temozolomide (Temodar) IV; oral >75mg/ m2/day

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

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

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

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

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

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

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

References

Adapted from: 1. Kris MG, Hesketh PJ, Somerfield MR, et al. American Society of Clinical Oncology Guideline for Antiemetics in Oncology: Update 2006. J Clin Oncol 2006;24:2932–2947. 2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology; v.1.2012: Antiemesis. (Rev. 6/2014) Available at: http://www.nccn.org/professionals/physician_gls/PDF/antiemesis.pdf. Accessed August 8, 2012.

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DRUG MONOGRAPHS

BRAIN CANCER AFINITOR Novartis

℞

mTOR kinase inhibitor. Everolimus 2.5mg, 5mg, 7.5mg, 10mg; tabs. ℞ Also: AFINITOR DISPERZ Everolimus 2mg, 3mg, 5mg; tabs for oral susp. Indications: Subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis complex (TSC) in adults and children who require therapeutic intervention but are not candidates for curative surgical resection. Adults and Children: <1yr: not recommended. Swallow tabs whole with water or use Disperz tabs administered as a suspension only. Take at the same time each day either consistently with or without food. Prepare suspension using 5mL of water in an oral syringe or 25mL of water in a drinking glass; max 10mg dose per syringe or glass. ≥1yrs: initially 4.5mg/m2 once daily. Do not combine the 2 dosage forms to achieve the desired total dose. Use therapeutic drug monitoring to guide subsequent dosing. Adjust dose at 2 week intervals as needed to achieve and maintain trough concentrations of 5–15ng/mL (see full labeling). Severe hepatic impairment: initiate at 2.5mg/m2 once daily. Concomitant strong CYP3A4/PgP inhibitors: avoid; moderate CYP3A4/PgP inhibitors: initiate at 2.5mg/m2 once daily, if CYP3A4/PgP inhibitor discontinued, after 2–3 days, return to dose used prior to initiating moderate inhibitor. Concomitant strong CYP3A4 inducers: avoid, if required, then initiate at 9mg/m2 once daily; if discontinued, then return to dose used prior to initiating strong inducer. Continue therapy until disease progression or unacceptable toxicity occurs. Dose modifications for adverse reactions, or others: see full labeling. Contraindications: Allergy to other rapamycin derivatives. Warnings/Precautions: Monitor for new or worsening respiratory symptoms. Increased risk of infections; some may be severe or fatal; monitor and treat promptly if occur. Pre-existing invasive fungal infections: treat before starting. Monitor for signs of wound-related complications. Peri-surgical period. Hepatic impairment (see Adult dose). Monitor CBCs, renal function, lipids, and blood glucose prior to starting and periodically thereafter. Avoid close contact with those who have received live vaccines. Pediatrics: complete childhood vaccination series according to ACIP guidelines prior to initiation. Elderly. Women of childbearing potential should use effective method of contraception during and up to 8 weeks after treatment. Pregnancy (Cat.D), nursing mothers: not recommended. Interactions: Avoid live vaccines. Potentiated by strong CYP3A4/PgP inhibitors (eg,

ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole), grapefruit or grapefruit juice; avoid. Caution with moderate CYP3A4/PgP inhibitors (eg, amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem); reduce everolimus dose if used. Antagonized by strong CYP3A4/PgP inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital), St. John’s Wort; avoid. Adverse reactions: Pneumonitis (interrupt, reduce dose and/or manage with corticosteroids; if severe, discontinue; may reintroduce daily dose at approx. 50% lower than previously administered), infections (discontinue if invasive systemic fungal infection develops), stomatitis (treat with non-alcoholic, non-peroxide mouthwash), diarrhea, nausea, abdominal pain, rash, fatigue, edema, fever, asthenia, cough, headache, decreased appetite; increased serum creatinine, blood glucose, lipids; decreased hemoglobin, platelets, neutrophils, serum phosphate; proteinuria, renal failure, others (see full labeling). How supplied: Tabs, Disperz–28 (4 blister cards × 7 tabs)

AVASTIN Genentech

℞

Angiogenesis inhibitor. Bevacizumab 100mg, 400mg; per vial; soln for IV infusion after dilution; preservative-free. Indications: Glioblastoma, as a single agent for patients with progressive disease following prior therapy. Adults: Give by IV infusion. Infuse 1st dose over 90 mins; if tolerated, infuse 2nd dose over 60 mins, and subsequent doses over 30 mins. 10mg/kg every 2 weeks. Children: Not established. Warnings/Precautions: Risk of GI perforations, surgery and wound healing complications, and hemorrhage. Do not start therapy before or for at least 28 days after surgery; allow surgical incisions to completely heal (see full labeling). Do not administer if recent history of hemoptysis of ≥ ½-teaspoon of red blood. Permanently discontinue if GI perforation, tracheoesophageal fistula, any grade 4 fistula, or grade 4 venous thromboembolic event. Discontinue if fistula involving internal organ, wound healing complications, hemorrhage, severe arterial thromboembolic event (ATE), hypertensive crisis or encephalopathy, posterior reversible encephalopathy syndrome, or nephrotic syndrome occurs; suspend therapy if severe hypertension, moderate-to-severe

proteinuria (resume when <2g/24hrs), or severe infusion reaction occurs. Avoid in ovarian cancer if evidence of recto-sigmoid involvement by pelvic exam, bowel involvement on CT scan, or symptoms of bowel obstruction. History of arterial thromboembolism. Diabetes. Monitor BP every 2–3 weeks. Monitor proteinuria by dipstick urine analysis; if ≥2+, do further assessment with a 24-hour urine collection. Elderly. Increased risk of ovarian failure; inform females of reproductive potential prior to starting therapy. Pregnancy (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 and fistulae, wound dehiscence/impaired healing, necrotizing fasciitis (discontinue if occurs), hemorrhage, non-GI fistula formation, arterial or venous thromboembolic events, posterior reversible encephalopathy syndrome, infusion reactions, ovarian failure, neutropenia, and infection. How supplied: Single-use vial–1

TEMODAR Merck

℞

Alkylating agent. Temozolomide 5mg, 20mg, 100mg, 140mg, 180mg, 250mg; caps. Also: TEMODAR INJECTION ℞ Temozolomide 100mg; per vial; lyophilized pwd for IV infusion after reconstitution; contains mannitol. Indications: Newly diagnosed glioblastoma multiforme. Refractory anaplastic astrocytoma. Adults: See full labeling for monitoring and dose adjustment guidelines. IV: Infuse over 90 mins. Oral caps: Swallow whole with water; take on empty stomach at bedtime to reduce nausea, pretreat with antiemetics. Glioma: Concomitant phase, for newly diagnosed: 75mg/m2 daily for 42 days with focal radiotherapy; Maintenance phase, Cycle 1: 150mg/m2 once daily for 5 consecutive days, then 23 days off; for Cycles 2 through 6: increase to 200mg/m2 once daily for 5 consecutive days if tolerated, then 23 days off. Anaplastic astrocytoma: 150mg/m2 once daily for 5 consecutive days per 28-day treatment cycle; increase dose in subsequent cycles to 200mg/m2 if tolerated; continue until disease progression, discontinue if minimum dose not tolerated. Children: Not established. 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

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DRUG MONOGRAPHS

BRAIN CANCER 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. Glioblastoma: monitor for and provide prophylaxis against P. carinii pneumonia (PCP). Severe renal or hepatic impairment. Avoid inhalation, and skin/mucous membrane contact, of capsule

contents. Elderly. Pregnancy (Cat.D), nursing mothers: not recommended. See full labeling. Interactions: Valproic acid may increase temozolomide levels. Concomitant carbamazepine, phenytoin, sulfamethoxazole/trimethoprim may complicate myelosuppression assessment. Adverse reactions: Alopecia, fatigue, nausea, vomiting, anorexia, constipation, headache,

convulsions, rash, hemiparesis, diarrhea, asthenia, fever, dizziness, abnormal coordination, viral infection, amnesia, insomnia, edema; myelosuppression (may be dose-limiting; see full labeling), hepatotoxicity; others. How supplied: Caps 5mg, 20mg, 100mg, 140mg 180mg–5, 14; 250mg–5; Single-use vials–1

HIGH-ALERT MEDICATIONS High-alert medications are drugs that bear a heightened risk of causing significant patient harm when they are used in error. Although mistakes may or may not be more common with these drugs, the consequences of an error are clearly more devastating to patients. This list may be used to determine which medications require special safeguards to reduce the risk of errors. This may include strategies such as standardizing the ordering, storage, preparation, and administration of these products;

improving access to information about these drugs; limiting access to high-alert medications; using auxiliary labels and automated alerts; and employing redundancies such as automated or independent doublechecks when necessary. (Note: manual independent double-checks are not always the optimal error-reduction strategy and may not be practical for all of the medications on the list).

SPECIFIC MEDICATIONS Epinephrine, subcutaneous

Oxytocin, IV

Epoprostenol (Flolan), IV

Nitroprusside sodium for injection

Insulin U-500 (special emphasis)

Potassium chloride for injection concentrate

Magnesium sulfate injection

Potassium phosphates injection

Methotrexate, oral, non-oncologic use

Promethazine, IV

Opium tincture

Vasopressin, IV or intraosseous

CLASSES/CATEGORIES OF MEDICATIONS Adrenergic agonists, IV (eg, epinephrine, phenylephrine, norepinephrine) Adrenergic antagonists, IV (eg, propranolol, metoprolol, labetalol) Anesthetic agents, general, inhaled and IV (eg, propofol, ketamine) Antiarrhythmics, IV (eg, lidocaine, amiodarone) Antithrombotic agents, including: • Anticoagulants (eg, warfarin, low-molecular-weight heparin, IV unfractionated heparin) • Factor Xa inhibitors (eg, fondaparinux, apixaban, rivaroxaban)

• Direct thrombin inhibitors (eg, argatroban, bivalirudin, dabigatran etexilate) • Thrombolytics (eg, alteplase, reteplase, tenecteplase) • Glycoprotein IIb/IIIa inhibitors (eg, eptifibatide)

Cardioplegic solutions Chemotherapeutic agents, parenteral and oral Dextrose, hypertonic, (20% or greater) Dialysis solutions, peritoneal and hemodialysis Epidural or intrathecal medications Hypoglycemics, oral Inotropic medications, IV (eg, digoxin, milrinone) Insulin, subcutaneous and IV Liposomal forms of drugs (eg, liposomal amphotericin B) and conventional counterparts (eg, amphotericin B desoxycholate) Moderate sedation agents, IV (eg, dexmedetomidine, midazolam) Moderate sedation agents, oral, for children (eg, chloral hydrate) Narcotics/opioids IV, transdermal, oral (including liquid concentrates, immediate and sustained-release forms) Neuromuscular blocking agents (eg, succinylcholine, rocuronium, vecuronium) Parenteral nutrition preparations Radiocontrast agents, IV Sterile water for injection, inhalation, and irrigation (excluding pour bottles) in containers of 100mL or more Sodium chloride for injection, hypertonic, greater than 0.9% concentration Notes Based on error reports submitted to the Institute of Safe Medication Practices (ISMP) National Medication Errors Reporting Program, reports of harmful errors in the literature, and input from practitioners and safety experts, ISMP created and periodically updates a list of potential high-alert medications. During May and June 2014, practitioners responded to an ISMP survey designed to identify which medications were most frequently considered high-alert drugs by individuals and organizations. Further, to assure relevance and completeness, the clinical staff at ISMP, members of the ISMP advisory board, and safety experts throughout the US were asked to review the potential list. This list of drugs and drug categories reflects the collective thinking of all who provided input. References Source: Institute for Safe Medication Practices. High-Alert Medications. 2014. Available at: http://www.ismp.org/Tools/institutionalhighAlert.asp

(Rev. 11/2014)

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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 minutes 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. Monitor for sensory neuropathy, sepsis, or pneumonitis. Hepatic or renal dysfunction. Contains human albumin; remote risk of viral transmission. Use appropriate contraception (men and women). Pregnancy (Cat.D), nursing mothers: not recommended. Interactions: May potentiate or be potentiated by CYP2C8 and/or CYP3A4 inducers (eg, rifampin, carbamazepine, phenytoin, efavirenz, nevirapine) and/or inhibitors (eg, ketoconazole, other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir, nelfinavir). Adverse reactions: Bone marrow suppression (eg, neutropenia, anemia), infections, alopecia, sensory neuropathy (may require dose reduction or interruption), peripheral neuropathy, GI upset, mucositis, fatigue/asthenia, myalgia/arthralgia, abnormal ECG; alkaline phosphatase or AST elevation; dyspnea, edema, hypotension, rash (may be serious); rare: thrombotic events. How supplied: Single-use vial–1

AFINITOR Novartis mTOR kinase inhibitor. Everolimus 2.5mg, 5mg, 7.5mg, 10mg; tabs. Indications: Postmenopausal women with advanced hormone receptor-positive, HER2-

℞

negative breast cancer (advanced HR+ BC) in combination with exemestane after failure of treatment with letrozole or anastrozole. Adults: Swallow tabs whole with water. Take at the same time each day either consistently with or without food. 10mg once daily. Mild hepatic impairment (Child-Pugh class A): 7.5mg daily, may reduce to 5mg if not tolerated. Moderate hepatic impairment (Child-Pugh class B): 5mg daily, may be reduce to 2.5mg if not tolerated. Severe hepatic impairment (Child-Pugh class C): max 2.5mg daily if benefits outweigh risk. Concomitant moderate CYP3A4/PgP inhibitors: reduce to 2.5mg once daily; may consider increasing to 5mg if tolerated. If moderate inhibitor is discontinued, allow 2–3 days washout period before increasing everolimus dose; return to dose used prior to initiating the moderate inhibitor. Concomitant strong CYP3A4/PgP inducers: consider doubling the daily dose by increments of 5mg or less. If strong inducer is discontinued, consider washout period of 3–5 days before returning to the dose used prior to initiating the strong inducer. Continue therapy until disease progression or unacceptable toxicity occurs. Dose modifications for adverse reactions, or others: see full labeling. Children: Not recommended. Contraindications: Allergy to other rapamycin derivatives. Warnings/Precautions: Monitor for new or worsening respiratory symptoms. Increased risk of infections; some may be severe or fatal; monitor and treat promptly if occur. Pre-existing invasive fungal infections: treat before starting. Monitor for signs of wound-related complications. Peri-surgical period. Hepatic impairment (see Adult dose). Monitor CBCs, renal function, lipids, and blood glucose prior to starting and periodically thereafter. Avoid close contact with those who have received live vaccines. Pediatrics: complete childhood vaccination series according to ACIP guidelines prior to initiation. Elderly. Women of childbearing potential should use effective method of contraception during and up to 8 weeks after treatment. Pregnancy (Cat.D), nursing mothers: not recommended. Interactions: Avoid live vaccines. Potentiated by strong CYP3A4/PgP inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole), grapefruit or grapefruit juice; avoid. Caution with moderate CYP3A4/PgP inhibitors (eg, amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem); reduce everolimus dose if used. Antagonized by

strong CYP3A4/PgP inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital), St. John’s Wort; avoid. Adverse reactions: Pneumonitis (interrupt, reduce dose and/or manage with corticosteroids; if severe, discontinue; may reintroduce daily dose at approx. 50% lower than previously administered), infections (discontinue if invasive systemic fungal infection develops), stomatitis (treat with non-alcoholic, non-peroxide mouthwash), diarrhea, nausea, abdominal pain, rash, fatigue, edema, fever, asthenia, cough, headache, decreased appetite; increased serum creatinine, blood glucose, lipids; decreased hemoglobin, platelets, neutrophils, serum phosphate; proteinuria, renal failure, others (see full labeling). How supplied: Tabs–28 (4 blister cards × 7 tabs)

ARIMIDEX AstraZeneca

℞

Aromatase inhibitor. Anastrozole 1mg; tabs. Indications: In postmenopausal women: adjuvant treatment of hormone receptor-positive early breast cancer; first-line treatment of hormone receptor-positive or unknown locally advanced or metastatic breast cancer; advanced breast cancer with disease progression after tamoxifen therapy. Adults: 1mg once daily. Advanced disease: continue until tumor progression. Children: Not applicable. Contraindications: Women who are or may become pregnant. Pregnancy (Cat.X). Warnings/Precautions: Pre-existing ischemic heart disease. Severe hepatic impairment. Monitor bone mineral density, cholesterol. Nursing mothers: not recommended. Interactions: Antagonized by tamoxifen, estrogens; do not give concomitantly. Adverse reactions: Hot flashes, asthenia, arthritis, pain, arthralgia, pharyngitis, hypertension, depression, nausea, vomiting, rash, osteoporosis, fractures, back pain, insomnia, headache, peripheral edema, lymphedema, dyspnea, dizziness, paresthesia, vaginal bleeding, cough, hypercholesterolemia. How supplied: Tabs–30

AROMASIN Pfizer

℞

Aromatase inactivator. Exemestane 25mg; tabs. Indications: In postmenopausal women: adjuvant treatment of estrogen-receptor positive early breast cancer after 2–3yrs of tamoxifen therapy to complete a total of 5yrs of hormonal therapy; advanced breast cancer with disease progression after tamoxifen therapy.

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DRUG MONOGRAPHS

BREAST CANCER Adults: Give after a meal. 25mg once daily. Concomitant strong CYP3A4 inducers (see Interactions): 50mg once daily. Children: Not established. Contraindications: Pregnancy (Cat.X). Premenopausal women. Warnings/Precautions: Hepatic or renal insufficiency. Osteoporosis; assess bone mineral density (BMD) at start of treatment. Monitor all patients for BMD loss and treat as appropriate. Perform routine assessment of Vit. D levels prior to initiation; supplement if deficient. Nursing mothers: not recommended. Interactions: Antagonized by strong CYP3A4 inducers (eg, rifampicin, phenytoin, carbamazepine, phenobarbital, St. John’s wort). Adverse reactions: Hot flashes, fatigue, arthralgia, headache, insomnia, increased sweating, nausea, increased appetite; reductions in bone mineral density. How supplied: Tabs–30

Adults: 10mg 3 times daily for at least 3 months. Children: Not applicable. Contraindications: Thrombophlebitis. Thromboembolic disorders. Cerebrovascular disorders. Abnormal undiagnosed genital bleeding. Estrogen-depended neoplasias. Liver dysfunction or disease. Pregnancy (Cat.X). Warnings/Precautions: Asthma (2mg tabs). Hepatic dysfunction. Conditions aggravated by fluid retention. Cardiovascular disorders, arterial vascular disease, and risks factors (eg, hypertension, diabetes, obesity, SLE). Familial hyperlipoprotenemia. Monitor BP. Discontinue if jaundice occurs and before prolonged immobilization (eg, surgery). Nursing mothers. Adverse reactions: See literature. GI upset, headache, hypertension, edema, hypercalcemia, gallbladder or thromboembolic disease, gynecomastia, impotence, impaired glucose tolerance. How supplied: Tabs–100

DELATESTRYL Endo

EVISTA Lilly

CIII

Androgen. Testosterone enanthate 200mg/mL; IM inj; in sesame oil; contains chlorobutanol. Indications: Inoperable metastatic mammary cancer in females who are 1–5 years postmenopausal. Adults: Give by deep IM inj into gluteal muscle. 200–400mg once every 2–4 weeks. Max 400mg/month. Monitor closely. Children: Not established. Contraindications: Male breast or prostate cancer. Pregnancy (Cat.X). Warnings/Precautions: Discontinue if jaundice, abnormal liver function, hypercalcemia, or edema occurs. Monitor liver function, hemoglobin, hematocrit, cholesterol, urine, serum calcium. Preexisting cardiac, hepatic, or renal dysfunction. History of MI or coronary artery disease. Monitor for venous thromboembolism; discontinue if suspected. Elderly. Nursing mothers: not recommended. Interactions: May potentiate oral anticoagulants, oxyphenbutazone. May alter insulin requirements. Increased risk of edema with ACTH, corticosteroids. May affect thyroid levels. Adverse reactions: Amenorrhea, menstrual irregularities, inhibition of gonadotropin secretion, virilization; others: inj site reactions, peliosis hepatis, edema, hepatic carcinoma, nausea, jaundice, hirsutism, acne, polycythemia, headache, anxiety, depression, paresthesia, altered libido, fluid and electrolyte disturbances, suppression of clotting factors, increased serum cholesterol. How supplied: Multidose vial (5mL)–1

ESTRACE Warner Chilcott Estrogen. Estradiol 0.5mg, 1mg, 2mg+; scored tabs; +contains tartrazine. Indications: Palliative treatment of metastatic breast cancer in select patients (see literature).

℞

Selective estrogen receptor modulator (SERM). Raloxifene HCl 60mg; tabs. Indications: Reduction in risk of invasive breast cancer in postmenopausal women: with osteoporosis and/or at high risk for invasive breast cancer. Adults: 60mg once daily. Children: Not recommended. Contraindications: Active or history of venous thromboembolic events. Nursing mothers. Pregnancy (Cat.X). Women who may become pregnant. Warnings/Precautions: Not for use in premenopausal women. Concomitant systemic estrogen therapy: not recommended. Discontinue 72 hours before, and during prolonged immobilization; resume when fully ambulatory. Coronary heart disease or risk of coronary event (increased risk of death due to stroke). Hepatic dysfunction. Moderate to severe renal impairment. Interactions: May antagonize warfarin; monitor. Avoid concomitant cholestyramine, other anion exchange resins. Caution with other highly protein-bound drugs (eg, diazepam, diazoxide, lidocaine). Adverse reactions: Hot flashes, leg cramps, peripheral edema, flu syndrome, arthralgia, sweating; rare: venous thromboembolic events. How supplied: Tabs–30, 100, 2000

FASLODEX AstraZeneca Estrogen receptor antagonist. Fulvestrant 50mg/mL; soln for IM inj. Indications: Hormone receptor positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy. Adults: Give by IM inj slowly (1–2 mins/ injection). 500mg (as two 5mL injections, one

℞

in each buttock) on days 1, 15, 29, then once per month thereafter. Moderate hepatic impairment: 250mg (as one 5mL injection) on days 1, 15, 29, then once per month thereafter. Children: Not applicable. Warnings/Precautions: Bleeding diatheses, thrombocytopenia, or anticoagulant use. Moderate to severe hepatic impairment. Pregnancy (Cat.D; avoid); exclude pregnancy before starting. Nursing mothers: not recommended. Adverse reactions: Inj site pain, GI upset, bone pain, arthralgia, headache, back pain, fatigue, pain in extremity, hot flash, anorexia, asthenia, musculoskeletal pain, cough, dyspnea, constipation; increased hepatic enzymes, hypersensitivity reactions. How supplied: Prefilled syringe kit (2 × 5mL)–1

FEMARA Novartis

℞

Aromatase inhibitor. Letrozole 2.5mg; tabs. Indications: In postmenopausal women: Adjuvant treatment of hormone receptor positive early breast cancer; Extended adjuvant treatment of early breast cancer after 5 years of adjuvant tamoxifen therapy; First-line treatment of hormone receptor positive or unknown, locally advanced or metastatic breast cancer; Treatment of advanced breast cancer with disease progression following antiestrogen therapy. Adults: 2.5mg once daily. Continue until tumor progression is evident. Adjuvant or extended adjuvant therapy: treat for at least 24 months (see literature). Severe hepatic impairment or cirrhosis: 2.5mg every other day. Children: Not applicable. Contraindications: Women of premenopausal endocrine status. Pregnancy (Cat.X). Warnings/Precautions: Severe renal or hepatic impairment. Monitor bone mineral density, serum cholesterol. Nursing mothers. Adverse reactions: Pain (bone, musculoskeletal, and others), hot flashes, arthralgia, flushing, asthenia, edema, headache, dizziness, hypercholesterolemia, sweating increased, GI upset, fatigue, dyspnea, cough, insomnia, hypertension, alopecia, anorexia, weight changes, hypercalcemia, pleural effusion, vertigo; thromboembolic or cardio- or cerebrovascular events (rare). How supplied: Tabs–30

Fluorouracil (various)

℞

Antimetabolite. Fluorouracil 50mg/mL; soln for IV inj. Indications: Palliative management of carcinoma of the breast. Adults: Give by IV inj. 12mg/kg once daily for 4 successive days; max 800mg/day. If no toxicity is observed, 6mg/kg are given on the 6th, 8th, 10th, and 12th days unless toxicity occurs. Maintenance therapy: repeat dosage of 1st course every 30 days after the last day of the previous course

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DRUG MONOGRAPHS

BREAST CANCER of treatment; or give a maintenance dose of 10–15mg/kg per week as a single dose; max: 1g/week. Poor risk patients: see literature for dose adjustments. Children: Not recommended. Contraindications: Poor nutritional state. Depressed bone marrow function. Potentially serious infections. Warnings/Precautions: Narrow margin of safety; monitor for toxicity. Consider hospitalization for 1st course. History of highdose pelvic irradiation. Previous use of alkylating agents. Widespread involvement of bone marrow by metastatic tumors. Renal or hepatic impairment. Discontinue if signs of toxicity appear (eg, stomatitis, esophagopharyngitis, leukopenia, intractable vomiting, diarrhea, GI ulceration or bleeding, thrombocytopenia, hemorrhage). Monitor WBCs with differential before each dose. Avoid extravasation. Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended. Interactions: Potentiated by leucovorin. Adverse reactions: Stomatitis, esophagopharyngitis, GI upset, anorexia, leukopenia, alopecia, dermatitis, hand-foot syndrome; others. Testing considerations: TS (thymidylate synthase), MSI (microsatellite instability), DPD (dihydropyrimidine dehydrogenase). How supplied: Contact supplier.

HALAVEN Eisai

℞

Non-taxane microtubule dynamics inhibitor. Eribulin mesylate 0.5mg/mL, soln for IV inj. Indications: Treatment of metastatic breast cancer in patients who have previously received at least two chemotherapeutic regimens for metastatic disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting. Adults: Give by IV injection over 2–5mins. 1.4mg/m2 on Days 1 and 8 of a 21-day cycle. Mild hepatic impairment (Child-Pugh A) or moderate renal impairment (CrCl 30–50mL/min): 1.1mg/m2 on Days 1 and 8 of a 21-day cycle. Moderate hepatic impairment (Child-Pugh B): 0.7mg/m2 on Days 1 and 8 of a 21-day cycle. Hold dose for ANC <1000/mm3, platelets <75000/mm3, or grade 3 or 4 non-hematological toxicities. Delay or reduce dose according to toxicities; see full labeling. Do not re-escalate dose after it is reduced. Children: <18yrs: not established. Warnings/Precautions: Monitor CBCs; increase frequency of monitoring if grade 3 or 4

cytopenias develop, delay and reduce subsequent doses if febrile neutropenia or grade 4 neutropenia lasting >7 days develops. Monitor for peripheral neuropathy; withhold dose if grade 3 or 4 peripheral neuropathy develops until resolution to grade 2 or less. Congenital long QT syndrome: avoid. CHF, bradyarrhythmias, electrolyte abnormalities: monitor ECG for prolonged QT interval. Correct electrolyte abnormalities (K+, Mg+) before treatment; monitor. Severe hepatic impairment (Child-Pugh C) or severe renal impairment (CrCl<30mL/min): insufficient data. Pregnancy (Cat.D), nursing mothers: not recommended. Interactions: Caution with other drugs that prolong QT interval (eg, Class IA and III antiarrhythmics); monitor. Adverse reactions: Neutropenia, anemia, asthenia/fatigue, alopecia, peripheral neuropathy, nausea, constipation, febrile neutropenia; possible QT prolongation, elevated liver enzymes. Note: Do not mix with dextrose-containing solutions. Do not administer in same line as other drugs or fluids. How supplied: Single-use vial (2mL)–1

HERCEPTIN Genentech

℞

Human epidermal growth factor receptor (HER2) inhibitor. Trastuzumab 440mg/vial; lyophilized pwd for IV infusion after reconstitution and dilution; preservative-free. Indications: HER2-overexpressing metastatic breast cancer as a single agent in patients who have received one or more chemotherapy regimens; or in combination with paclitaxel in patients who have not received chemotherapy. Adjuvant treatment in HER2-overexpressing, node-positive or node-negative breast cancer (as a single agent following multi-modality anthracycline based therapy; in combination with doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel; or in combination with docetaxel and carboplatin). Adults: Do not substitute for or with adotrastuzumab emtansine. Give as IV infusion. Initially 4mg/kg over 90 mins, followed by 2mg/kg over 30 mins weekly; administer until tumor progression. Adjuvant treatment (administer trastuzumab weekly for 52 weeks; therapy >52 weeks: not recommended); In combination therapy: with doxorubicin and cyclophosphamide, followed by either paclitaxel or docetaxel; or with docetaxel/carboplatin: initially 4mg/kg over 90 mins, followed by

2mg/kg over 30 mins once weekly for the 1st 12 weeks (concurrently w. paclitaxel or docetaxel) or 1st 18 weeks (concurrently w. docetaxel/carboplatin). One week after the last trastuzumab weekly dose, give trastuzumab 6mg/kg over 30–90 mins every 3 weeks. Following 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 FDA-approved tests for specific tumor type (breast or gastric/gastroesophageal adenocarcinoma). Elderly. Pregnancy (Cat.D); use adequate contraception during and at least 6 months after therapy. Nursing mothers: not recommended. Interactions: Increased cardiomyopathy with anthracycline-containing chemotherapy. Increased toxicity with other myelosuppressives. Potentiated by paclitaxel. Adverse reactions: Fever, diarrhea, nausea, chills, infections, increased cough, headache, CHF, insomnia, fatigue, dyspnea, rash, neutropenia, anemia, stomatitis, mucosal inflammation, nasopharyngitis, dysgeusia, myalgia, thrombosis/embolism; severe infusion reactions, febrile neutropenia/exacerbation of chemotherapy-induced neutropenia, pulmonary toxicity (eg, interstitial pneumonitis), cardiomyopathy (eg, left ventricular myocardial dysfunction); pregnant women: possible oligohydramnios (monitor). Note: Enroll pregnant women with breast cancer who are using trastuzumab in the MotHER-the Herceptin Pregnancy Registry (800) 690-6720. Testing considerations: HER2 protein overexpression How supplied: Vial–1 (w. diluent)

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CancerTherapyAdvisor.com | MAY/JUNE 2015 | CANCER THERAPY ADVISOR 7

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DRUG MONOGRAPHS

BREAST CANCER IBRANCE Pfizer

℞

Kinase inhibitor. Palbociclib 75mg, 100mg, 125mg; capsules. Indications: In combination with letrozole, for the treatment of postmenopausal women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)negative advanced breast cancer as initial endocrine-based therapy for metastatic disease. Adults: Swallow whole. Take with food. 125mg once daily for 21 days followed by 7 days off to complete a 28-day cycle, in combination with letrozole 2.5mg once daily continuously throughout the 28-day cycle. Dose modification for adverse reactions: First reduction: 100mg/day; Second dose reduction: 75mg/day; discontinue if <75mg/day required. Dose modification for hematologic or non-hematologic toxicities: see full labeling. Concomitant strong CYP3A inhibitors: avoid and consider alternative drug; if use necessary, reduce palbociclib dose to 75mg. Children: Not evaluated. Warnings/Precautions: Monitor CBC prior to initiation and at start of each cycle, as well as Day 14 of first 2 cycles, and as clinically indicated. Interrupt, reduce dose, or delay starting treatment cycles if Grade 3 or 4 neutropenia develops. Monitor for signs/symptoms of infection and pulmonary embolism; treat appropriately if develop. Moderate or severe hepatic impairment. Severe renal impairment. Pregnancy: avoid. Use effective contraception during therapy and for at least 2 weeks after last dose. Lactation: discontinue nursing. Interactions: Avoid concomitant strong CYP3A inhibitors (eg, clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, verapamil, voriconazole), grapefruit or grapefruit juice; if unavoidable, reduce dose (see Adults). Avoid concomitant strong CYP3A inducers (eg, phenytoin, rifampin, carbamazepine, St. John’s wort) or moderate CYP3A inducers (eg, bosentan, efavirenz, etravirine, modafinil, nafcillin). May potentiate midazolam or other CYP3A substrates with narrow therapeutic index (eg, alfentanil, cyclosporine, dihydroergotamine, ergotamine, everolimus, fentanyl, pimozide, quinidine, sirolimus, tacrolimus); reduce dose of these drugs. Adverse reactions: Neutropenia, leukopenia, fatigue, anemia, upper respiratory infection, nausea, stomatitis, alopecia, diarrhea, thrombocytopenia, decreased appetite, vomiting, asthenia, peripheral neuropathy, epistaxis. How supplied: Caps–21

IXEMPRA Bristol-Myers Squibb

℞

Epothilone microtubule inhibitor. Ixabepilone 15mg/vial, 45mg/vial; pwd for IV infusion after constitution and dilution; diluent contains alcohol, polyoxyethylated castor oil.

Indications: Metastatic or locally advanced breast cancer: In combination with capecitabine after failure of an anthracycline and a taxane; and as monotherapy after failure of an anthracycline, a taxane, and capecitabine. Adults: Pretreat with both H1 and H2 blockers 1hr before infusion; and with steroid if previous hypersensitivity reaction occurred. 40mg/m2 by IV infusion over 3hrs, once every 3wks. Use max body surface area (BSA) of 2.2m2 to calculate dose if BSA >2.2m2. Moderate hepatic impairment (as monotherapy): initially 20mg/m2 per dose; max 30mg/m2 per dose (see literature). Neuropathy, myelosuppression, concomitant strong CYP3A4 inhibitors: reduce dose. Concomitant strong CYP3A4 inducers: consider gradual dose increases. See literature. Children: Not recommended. Contraindications: Baseline neutrophils <1500cells/mm3 or platelets <100,000cells/mm3. AST or ALT >2.5×ULN or bilirubin >1×ULN (in combination with capecitabine). Warnings/Precautions: Monitor CBC and liver function at baseline, then periodically. Hepatic impairment (ALT or AST >10×ULN or bilirubin >3×ULN: not recommended; ALT or AST >5×ULN: limited data, use caution). Diabetes. Neuropathy. Cardiac disease (discontinue if cardiac ischemia or cardiac dysfunction occurs). Monitor for signs/ symptoms of neuropathy, neutropenia. Pregnancy (Cat.D), nursing mothers: not recommended. Interactions: Potentiated by strong CYP3A4 inhibitors (eg, azole antifungals, protease inhibitors, certain macrolides, nefazodone, grapefruit juice); avoid. Caution with mild or moderate CYP3A4 inhibitors; consider alternative agents. Antagonized by strong CYP3A4 inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, dexamethasone, phenobarbital); avoid. Avoid St. John’s wort. Adverse reactions: Peripheral sensory neuropathy, fatigue, asthenia, myalgia, arthralgia, alopecia, GI upset, stomatitis, mucositis, musculoskeletal pain, palmarplantar erythrodysesthesia syndrome, anorexia, abdominal pain, nail disorder, constipation; myelosuppression (neutropenia, leukopenia, anemia, thrombocytopenia); hypersensitivity reactions; others. How supplied: Kit–1 vial (w. diluent)

KADCYLA Genentech

℞

HER2-targeted antibody-drug conjugate. Adotrastuzumab emtansine 100mg, 160mg; per vial; powder; for IV infusion after reconstitution. Indications: Treatment in patients with HER2positive (+), metastatic breast cancer (MBC) who previously received trastuzumab and a taxane, separately or in combination. Patients should have either: received prior therapy for metastatic disease or developed disease recurrence during or within 6 months of completing adjuvant therapy. Adults: Give by IV infusion only over 90 minutes 3.6mg/kg max every 3 weeks (21-day cycle) until

disease progression or unacceptable toxicity. Subsequent infusions may be given over 30 minutes if previously tolerated. Monitor closely for possible SC infiltration during infusion. Dose modifications: see full labeling. Children: Not established. Warnings/Precautions: Do not substitute for or with trastuzumab. Hepatotoxicity; monitor serum transaminases and bilirubin prior to starting and to each dose; reduce dose or discontinue if occurs. Risk of left ventricular dysfunction. Assess LVEF prior to initiation and every 3 months during treatment; interrupt and discontinue as appropriate. Risk of embryofetal 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 (Category D); use adequate contraception during and at least 6 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 (see full labeling). Adverse reactions: Fatigue, nausea, musculoskeletal pain, thrombocytopenia, headache; increased transaminases, constipation. How supplied: Single-use vial–1

Megestrol acetate (various)

℞

Progestin. Megestrol acetate 20mg, 40mg; scored tabs. Indications: Palliative treatment of advanced breast carcinoma. Adults: 40mg 4 times daily. Children: Not applicable. Warnings/Precautions: History of thromboembolic disease. Diabetes. Monitor for adrenal insufficiency. Pregnancy (Cat.D), nursing mothers: not recommended. Interactions: May increase insulin requirements. Decreases indinavir levels. Adverse reactions: Weight gain, thromboembolic events, heart failure, GI upset, edema, breakthrough menstrual bleeding, dyspnea, tumor flare, hyperglycemia, alopecia, hypertension, carpal tunnel syndrome, mood changes, hot flashes, malaise, asthenia, lethargy, sweating, rash. How supplied: Contact supplier.

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DRUG MONOGRAPHS

BREAST CANCER PERJETA Genentech

℞

Human epidermal growth factor receptor (HER2) dimerization inhibitor. Pertuzumab 420mg/14mL (30mg/mL); soln for IV infusion; preservativefree. 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 embryo-fetal toxicity. Pretreatment LVEF value of ≤50%, history of CHF, decreases in LVEF to <50% during prior trastuzumab therapy, uncontrolled hypertension, recent MI, serious cardiac arrythmia requiring treatment or a cumulative prior anthracycline exposure to >360mg/m2 of doxorubicin or its equivalent: not studied. Assess LVEF at baseline and at regular intervals (eg, every 3 months in metastatic setting, and every 6 weeks in the neoadjuvant setting) during treatment; if LVEF is <45%, or is 45% to 49% with a ≥10% absolute decrease below the pretreatment value, withhold (pertuzumab + trastuzumab) and repeat LVEF within 3 weeks; discontinue if LVEF has not improved. Monitor for signs/symptoms of infusion reactions; slow or interrupt infusion and treat if occurs; discontinue if severe. Test and confirm for HER2 protein overexpression using FDA-approved tests by labs with demonstrated proficiency. Pregnancy (Cat.D); use adequate contraception during and at least 6 months after therapy. Nursing mothers: not recommended.

Adverse reactions: Diarrhea, alopecia, neutropenia, nausea, fatigue, rash, peripheral neuropathy; hypersensitivity (monitor), decreases in LVEF; pregnant women: possible oligohydramnios (monitor). Note: Encourage women who are exposed to Perjeta during pregnancy to enroll in the MotHER Pregnancy Registry: (800) 690-6720. How supplied: Single-use vial–1

PREMARIN Pfizer

℞

Estrogen. Conjugated estrogens 0.3mg, 0.45mg, 0.625mg, 0.9mg, 1.25mg; tabs. Indications: Treatment of breast cancer (for palliation only) in appropriately selected women and men with metastatic disease. Adults: 10mg 3 times daily for at least 3 months. Children: Not applicable. Contraindications: Known, suspected, or history of breast cancer, except in appropriately selected patients being treated for metastatic disease. Known or suspected estrogen-dependent neoplasia. Undiagnosed abnormal genital bleeding. Pulmonary embolism/DVT (active or history of). Arterial thromboembolism (eg, stroke, MI; active or history of). Liver dysfunction or disease. Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders. Known or suspected pregnancy (Cat.X). Warnings/Precautions: Not for prevention of cardiovascular disease. Use for shortest duration consistent with treatment goals and risks. Reevaluate periodically. Patients with an intact uterus should almost always receive a progestin with systemic estrogens to avoid endometrial hyperplasia. Discontinue if cardiovascular events occur or are suspected; if jaundice occurs; and during immobilization or at least 4–6 weeks before surgery associated with thromboembolism. Hepatic dysfunction. Conditions aggravated by fluid retention. Gallbladder disease. Bone disease associated with hypercalcemia. Hereditary angioedema. Do initial complete physical and repeat annually (include BP, mammogram, PAP smear). Adolescents. Nursing mothers: not recommended. Adverse reactions: See literature. Increased risk of cardiovascular events, estrogen-dependent carcinoma, gallbladder disease, thromboembolic disorders, hepatic tumors. GI upset, breakthrough bleeding, edema, weight changes, mastodynia, hypertension, depression, anaphylactic reactions, angioedema, intolerance to contact lenses. How supplied: Tabs 0.3mg, 0.625mg, 1.25mg–100, 1000; 0.45mg, 0.9mg–100

SOLTAMOX ORAL

℞

SOLUTION DARA BioSciences

Antiestrogen. Tamoxifen (as citrate) 10mg/5mL; licorice and aniseed flavors; sugar-free; contains alcohol. Indications: Treatment of metastatic breast cancer in men and women. Axillary node-positive breast cancer in postmenopausal women after surgery + irradiation. Axillary node-negative breast cancer in women after surgery + irradiation. Reduction in risk of invasive breast cancer in women with ductal carcinoma in situ (DCIS) after surgery + radiation. Reduction in breast cancer incidence in high-risk women. Adults: Treatment: 20–40mg/day; give doses >20mg in divided doses (AM and PM). Reduction of incidence in high-risk women or DCIS: 20mg once daily for 5 years. Children: Not recommended. Contraindications: For reduction in incidence in high-risk women and women with DCIS: concomitant coumarin anticoagulants, history of deep vein thrombosis or pulmonary embolism. Warnings/Precautions: See literature. Do gynecological exam at least annually. DCIS and risk reduction: consider increased risk of uterine cancer (endometrial adenocarcinoma, uterine sarcoma), stroke and pulmonary embolism. Women with advanced disease: discontinue if severe hypercalcemia occurs. Monitor blood, lipids, liver function, for thromboembolism symptoms (eg, leg swelling, unexplained shortness of breath), and for uterine changes/ cancer (eg, pelvic pain or pressure); promptly investigate any abnormal vaginal bleeding. Breast cancer treatment: history of thromboembolic events. Pregnancy (Cat.D); avoid. Premenopausal: use effective nonhormonal contraception during and within 2 months of discontinuing therapy; begin therapy during menses or, if irregular menses, obtain (−) B-hCG pregnancy test first. Nursing mothers: not recommended. Interactions: See Contraindications. May potentiate oral anticoagulants; if co-administered, monitor PT. Concomitant anastrozole: not recommended. Antagonizes letrozole. Plasma levels reduced by CYP3A4 inducers (eg, rifampin, aminoglutethimide). Cytotoxic drugs increase risk of thrombotic events. Potentiated by bromocriptine. Adverse reactions: Hot flashes, vaginal discharge, altered menses, oligomenorrhea, nausea, cough, edema, fatigue, abdominal cramps, bone and tumor pain (in advanced disease), local disease flare, hypercalcemia,

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DRUG MONOGRAPHS

BREAST CANCER 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.

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: 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, 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)

TYKERB GlaxoSmithKline

℞

Tyrosine kinase inhibitor. Lapatinib 250mg; tabs. Indications: In combination with capecitabine, for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 and who have received prior therapy including an anthracycline, a taxane, and trastuzumab. Limitation of use: patients should have disease progression on trastuzumab before initiating Tykerb in combination with capecitabine. In combination with letrozole for the treatment of postmenopausal women with hormone receptor positive metastatic breast cancer that overexpresses HER2 for whom hormonal therapy is indicated. Adults: Take 1hr before or 1hr after a meal (capecitabine should be taken with food or within 30mins after food). HER2 metastatic breast cancer: 1250mg (5 tabs) once daily on Days 1–21 continuously in combination with capecitabine 2000mg/m2/day (administered orally in 2 doses approx. 12hrs apart) on Days 1–14 in a repeating 21 day cycle; continue until disease progression or unacceptable toxicity occurs. After recovery from left ventricular ejection fraction (LVEF) decrease: 1000mg/day. Severe hepatic dysfunction (Child-Pugh Class C): 750mg/day (no clinical data for this dose adjustment). Concomitant potent CYP3A4 inducers: may titrate up to 4500mg/day (no clinical data for this dose adjustment). Hormone receptor positive, HER2 positive metastatic breast cancer: 1500mg (6 tabs) once daily continuously in combination with letrozole 2.5mg once daily. After recovery from LVEF decrease: 1250mg/day. Severe hepatic dysfunction: 1000mg/day (no clinical data for this dose adjustment). Concomitant potent CYP3A4 inducers: may titrate up to 5500mg/day (no clinical data for this dose adjustment). For both: Concomitant potent CYP3A4 inhibitors: 500mg/day (no clinical data for this dose adjustment). Interrupt if diarrhea is NCI CTC grade 3, or grade 1 or 2 with complicating features develop; may restart at lower dose (reduced from 1250mg/day to 1000mg/day or from 1500mg/day to 1250mg/day) when resolves ≤ grade 1; permanently discontinue if diarrhea is grade 4. Other toxicities: discontinue if ≥grade 2 NCI CTC toxicity occurs; may restart at 1250mg/day if toxicity improves to grade 1; if recurs, may restart at 1000mg/day (with capecitabine); 1250mg/day (w. letrozole). Children: Not established. Warnings/Precautions: Confirm normal LVEF before starting. Discontinue if ≥grade 2 decrease in LVEF occurs, or if LVEF falls below institution’s lower limit of normal; may restart after at least 2 weeks at reduced dose if asymptomatic and LVEF recovers. Conditions

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DRUG MONOGRAPHS

BREAST CANCER 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 Roche

℞

Fluoropyrimidine. Capecitabine (prodrug of 5-fluorouracil) 150mg, 500mg; tabs. Indications: Metastatic breast cancer resistant to both paclitaxel and an anthracycline-containing 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 literature. Give cyclically (2 weeks on, 1 week off). 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 literature); 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 recommended. Contraindications: Severe renal impairment (CrCl <30mL/min). Dihydropyrimidine dehydrogenase deficiency. Pregnancy (Cat.D), nursing mothers: not recommended. Warnings/Precautions: Hepatic or renal dysfunction. Coronary artery disease. Elderly (≥80years). Interactions: Potentiated by leucovorin. Monitor warfarin, other CYP2C9 substrates, phenytoin. Adverse reactions: Diarrhea, lymphopenia, necrotizing enterocolitis, hand-and-foot syndrome, GI upset, stomatitis, fatigue, dermatitis, anorexia, cardiotoxicity, bone marrow suppression, blood dyscrasias, hyperbilirubinemia, paresthesias, eye irritation, fever, headache, edema, dizziness, insomnia, myalgia, dehydration, nail disorder, limb pain, skin discoloration, alopecia. Testing considerations: TS (thymidylate synthase), MSI (microsatellite instability), DPD (dihydropyrimidine dehydrogenase) How supplied: Tabs 150mg–60; 500mg–120

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

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 minutes on Days 1, 8, and 15 of each 28-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. Monitor for sensory neuropathy, sepsis, or pneumonitis. Hepatic or renal dysfunction. Contains human albumin; remote risk of viral transmission. Use appropriate contraception (men and women). Pregnancy (Cat.D), nursing mothers: not recommended. Interactions: May potentiate or be potentiated by CYP2C8 and/or CYP3A4 inducers (eg, rifampin, carbamazepine, phenytoin, efavirenz, nevirapine) and/or inhibitors (eg, ketoconazole, other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir, nelfinavir). Adverse reactions: Bone marrow suppression (eg, neutropenia, anemia), infections, alopecia, sensory neuropathy (may require dose reduction or interruption), peripheral neuropathy, GI upset, mucositis, fatigue/asthenia, myalgia/arthralgia, abnormal ECG; alkaline phosphatase or AST elevation; dyspnea, edema, hypotension, rash (may be serious); rare: thrombotic events. How supplied: Single-use vial–1

AFINITOR Novartis

℞

mTOR kinase inhibitor. Everolimus 2.5mg, 5mg, 7.5mg, 10mg; tabs. Indications: Progressive neuroendocrine tumors of pancreatic origin (PNET) in adults with unresectable, locally advanced or metastatic disease. Not for treating functional carcinoid tumors. Adults: Swallow tabs whole with water. Take at the same time each day either consistently with or without food. 10mg once daily. Mild hepatic impairment (Child-Pugh class A): 7.5mg daily, may reduce to 5mg if not tolerated. Moderate hepatic impairment (Child-Pugh class B): 5mg daily, may be reduce to 2.5mg if not tolerated. Severe hepatic impairment (Child-Pugh class C): max 2.5mg daily if benefits outweigh risk.

Concomitant moderate CYP3A4/PgP inhibitors: reduce to 2.5mg once daily; may consider increasing to 5mg if tolerated. If moderate inhibitor is discontinued, allow 2–3 days washout period before increasing everolimus dose; return to dose used prior to initiating the moderate inhibitor. Concomitant strong CYP3A4/PgP inducers: consider doubling the daily dose by increments of 5mg or less. If strong inducer is discontinued, consider washout period of 3–5 days before returning to the dose used prior to initiating the strong inducer. Continue therapy until disease progression or unacceptable toxicity occurs. Dose modifications for adverse reactions, or others: see full labeling. Children: Not recommended. Contraindications: Allergy to other rapamycin derivatives. Warnings/Precautions: Monitor for new or worsening respiratory symptoms. Increased risk of infections; some may be severe or fatal; monitor and treat promptly if occur. Pre-existing invasive fungal infections: treat before starting. Monitor for signs of wound-related complications. Peri-surgical period. Hepatic impairment (see Adult dose). Monitor CBCs, renal function, lipids, and blood glucose prior to starting and periodically thereafter. Avoid close contact with those who have received live vaccines. Pediatrics: complete childhood vaccination series according to ACIP guidelines prior to initiation. Elderly. Women of childbearing potential should use effective method of contraception during and up to 8 weeks after treatment. Pregnancy (Cat.D), nursing mothers: not recommended. Interactions: Avoid live vaccines. Potentiated by strong CYP3A4/PgP inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole), grapefruit or grapefruit juice; avoid. Caution with moderate CYP3A4/PgP inhibitors (eg, amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem); reduce everolimus dose if used. Antagonized by strong CYP3A4/PgP inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital), St. John’s Wort; avoid. Adverse reactions: Pneumonitis (interrupt, reduce dose and/or manage with corticosteroids; if severe, discontinue; may reintroduce daily dose at approx. 50% lower than previously administered), infections (discontinue if invasive systemic fungal infection develops), stomatitis (treat with non-alcoholic, non-peroxide mouthwash), diarrhea, nausea, abdominal pain, rash, fatigue, edema, fever, asthenia, cough, headache, decreased appetite; increased serum creatinine, blood glucose, lipids; decreased hemoglobin, platelets, neutrophils, serum phosphate; proteinuria, renal failure, others (see full labeling). How supplied: Tabs–28 (4 blister cards × 7 tabs)

CAPRELSA AstraZeneca

℞

Kinase inhibitor. Vandetanib 100mg, 300mg, tabs. Indications: Symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease. Adults: Do not crush tabs. May disperse tabs in 2oz noncarbonated water for oral or NGT administration; avoid contact of dispersion with skin, mucous membranes. 300mg once daily. Renal impairment (CrCl<50mL/min): initially 200mg once daily. Dose adjustments for adverse reactions: see full labeling. Do not take a missed dose within 12hrs of the next dose. Children: Not established. Contraindications: Congenital long QT syndrome. Warnings/Precautions: Hypocalcemia, hypokalemia, hypomagnesemia, QTcF interval >450msec, history of torsades de pointes, bradyarrhythmias, uncompensated heart failure, recent hemoptysis: not recommended. Ventricular arrhythmias. Recent MI. Monitor electrolytes (esp. K+, Ca++, Mg++), TSH, and ECG for QT prolongation at baseline, 2–4 weeks and 8–12 weeks after starting, then every 3 months, and after dose reductions or dose interruptions >2 weeks; reduce dose as needed. Correct electrolyte disturbances before starting. Maintain serum K+ at least 4mEq/mL. Hepatic impairment (Child-Pugh B or C): not recommended. Interrupt therapy and follow-up if acute or worsening pulmonary symptoms, QTcF >500msec, or CTCAE Grade ≥3 toxicity occurs. Monitor for heart failure; consider discontinuing if occurs. Discontinue if confirmed interstitial lung disease, severe ischemic cerebrovascular event, hemorrhage, uncontrolled hypertension, or posterior leukoencephalopathy symptoms (RPLS) occur. Avoid sun, UV light. Elderly. Pregnancy (Cat.D) (may cause fetal harm; use appropriate effective contraception during and for 4 months after stopping therapy), nursing mothers: not recommended. Interactions: Avoid strong CYP3A4 inducers (eg, rifampicin, St. John’s Wort). Avoid other drugs that can prolong QT interval (eg, amiodarone, disopyramide, procainamide, sotalol, dofetilide, chloroquine, clarithromycin, dolasetron, granisetron, haloperidol, pimozide, methadone, moxifloxacin). Potentiates OCT2 transporters (eg, metformin), digoxin; monitor. Adverse reactions: Diarrhea/colitis (suspend if severe), rash, acneiform dermatitis, nausea, hypertension, headache, upper respiratory tract infections, decreased appetite, abdominal pain, hypocalcemia, hypoglycemia, increased ALT; QT prolongation, torsades de pointes, sudden death, severe skin reactions (eg, Stevens-Johnson syndrome; discontinue if occurs). Note: Prescribers and pharmacies must enroll in the Caprelsa REMS program by calling (800) 2369933 or visit www.caprelsarems.com. How supplied: Tabs–30

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DRUG MONOGRAPHS

ENDOCRINE CANCER 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 inhibitor: reduce daily dose by 40mg; resume dose used prior to starting inhibitor 2–3 days after discontinuation of inhibitor. Concomitant strong CYP3A4 inducers: increase daily dose by 40mg; resume dose used prior to starting inducer 2–3 days after discontinuation of inducer. Max daily dose: 180mg. Children: Not studied. Warnings/Precautions: Permanently discontinue if the following occurs: GI or non-GI perforation/fistula formation, severe hemorrhage, serious arterial thromboembolic events (eg, MI, cerebral infarction), nephrotic syndrome, malignant hypertension, hypertensive crisis, persistent uncontrolled hypertension despite optimal medical management, osteonecrosis of the jaw, reversible posterior leukoencephalopathy syndrome. Moderate to severe hepatic impairment: not recommended. Recent history of hemorrhage, hemoptysis: avoid. Stop treatment at least 28 days prior to scheduled surgery (including invasive dental procedures); withhold dose if dehiscence or wound healing complications require medical intervention. Monitor for bleeding, hypertension, proteinuria (measure urine protein regularly). Use effective contraception during and up to 4 months after completion of therapy. Pregnancy (Cat.D). Nursing mothers: not recommended. Interactions: Avoid concomitant strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole, grapefruit or grapefruit juice) and strong CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, St. John’s Wort): see Adult dose.

Adverse reactions: Diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome, decreased weight/appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, constipation, increased AST, ALT, alkaline phosphatase, lymphopenia, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, hyperbilirubinemia. How supplied: 140mg daily-dose carton–4 blister cards (each: 7×80mg and 21×20mg caps); 100mg daily-dose carton–4 blister cards (each: 7×80mg and 7×20mg caps); 60mg daily-dose carton–4 blister cards (each: 21×20mg caps)

Fluorouracil (various)

℞

Antimetabolite. Fluorouracil 50mg/mL; soln for IV inj. Indications: Palliative management of carcinoma of the pancreas. Adults: Give by IV inj. 12mg/kg once daily for 4 successive days; max 800mg/day. If no toxicity is observed, 6mg/kg are given on the 6th, 8th, 10th, and 12th days unless toxicity occurs. Maintenance therapy: repeat dosage of 1st course every 30 days after the last day of the previous course of treatment; or give a maintenance dose of 10–15mg/kg per week as a single dose; max: 1g/ week. Poor risk patients: see literature for dose adjustments. Children: Not recommended. Contraindications: Poor nutritional state. Depressed bone marrow function. Potentially serious infections. Warnings/Precautions: Narrow margin of safety; monitor for toxicity. Consider hospitalization for 1st course. History of highdose pelvic irradiation. Previous use of alkylating agents. Widespread involvement of bone marrow by metastatic tumors. Renal or hepatic impairment. Discontinue if signs of toxicity appear (eg, stomatitis, esophagopharyngitis, leukopenia, intractable vomiting, diarrhea, GI ulceration or bleeding, thrombocytopenia, hemorrhage). Monitor WBCs with differential before each dose. Avoid extravasation. Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended. Interactions: Potentiated by leucovorin. Adverse reactions: Stomatitis, esophagopharyngitis, GI upset, anorexia, leukopenia, alopecia, dermatitis, hand-foot syndrome; others. Testing considerations: TS (thymidylate synthase), MSI (microsatellite instability), DPD (dihydropyrimidine dehydrogenase). How supplied: Contact supplier.

LENVIMA Eisai

℞

Kinase inhibitor. Lenvatinib 4mg, 10mg; capsules. Indications: Treatment of locally recurrent or metastatic, progressive, radioactive iodinerefractory differentiated thyroid cancer. Adults: 24mg once daily until disease progression or unacceptable toxicity occurs. Severe renal impairment (CrCl <30mL/min) or severe hepatic impairment (Child-Pugh C): 14mg once daily. Dose modifications for adverse reactions or lab abnormalities: see full labeling. Children: Not established. Warnings/Precautions: Control blood pressure prior to treatment; monitor after 1 week, every 2 weeks for the first 2 months, and then at least monthly thereafter during therapy. Discontinue if life-threatening hypertension, Grade 4 cardiac dysfunction or hemorrhage, arterial thrombotic event, hepatic failure, nephrotic syndrome, GI perforation or life-threatening fistula, or severe and persistent neurologic symptoms occur. Withhold if Grade 3 hypertension persists despite therapy, Grade 3 cardiac dysfunction or hemorrhage, ≥Grade 3 liver impairment or QT prolongation, Grade 3 or 4 renal failure/impairment, ≥2g of proteinuria/24hrs, or reversible posterior leukoencephalopathy syndrome (RPLS) occurs. Monitor for signs/symptoms of cardiac decompensation. Monitor liver function prior to treatment, every 2 weeks for the first 2 months, then at least monthly during treatment. Monitor for proteinuria prior to, and periodically during treatment. Dehydration. Hypovolemia. Congenital long QT syndrome, CHF, bradyarrhythmias, or those taking Class Ia or III antiarrhythmic drugs; monitor ECGs. Monitor and correct electrolyte abnormalities. Monitor blood calcium levels at least monthly; replace as needed during treatment. Monitor thyroid stimulating hormone levels monthly; adjust replacement therapy as needed. Pregnancy: avoid. Use effective contraception during treatment and for at least 2 weeks after treatment completion. Lactation: discontinue nursing. Adverse reactions: Hypertension, fatigue, diarrhea, arthralgia/myalgia, decreased appetite, weight decreased, nausea, stomatitis, headache, vomiting, proteinuria, palmar-plantar erythrodysesthesia syndrome, abdominal pain, dysphonia. How supplied: Blister cards–6

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

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DRUG MONOGRAPHS

ENDOCRINE CANCER LYSODREN Bristol-Myers Squibb

℞

Adrenal cytotoxic agent. Mitotane 500mg; scored tabs. Indications: Inoperable adrenal cortical carcinoma. Adults: 2–6g/day in divided doses (3–4 times/day). Doses may be increased incrementally to 9–10g/day. Max: 18–19g/day. Continue as long as clinical benefit observed. Children: Not established. Warnings/Precautions: Discontinue temporarily following shock or severe trauma. Hepatic disease. Remove any tumor tissues from metastatic masses prior to therapy to minimize possible infarction and hemorrhage. Long-term administration of high doses: assess behavioral and neurological function. May need concomitant steroid replacement; measure free cortisol and ACTH levels. Surgery. Pregnancy (Cat.D); use effective contraception during and after discontinuation until mitotane levels are undetectable. Nursing mothers: not recommended. Interactions: Concomitant oral anticoagulants, CYP3A4 substrates; monitor for change in dose requirements. Adverse reactions: Anorexia, nausea, vomiting, diarrhea, lethargy, somnolence, dizziness, vertigo, rash; prolonged bleeding. How supplied: Tabs–100

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 (ChildPugh 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; druginduced hepatitis, QT prolongation. How supplied: Tabs–120

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 disease: monitor LVEF at baseline and periodically thereafter; interrupt or reduce dose if LVEF <50% and >20% below baseline; discontinue if CHF occurs. History of QT prolongation or proarrythmic conditions (eg, bradycardia, electrolyte disturbances); perform periodic ECG, monitor electrolytes. Monitor BP. Suspend therapy if severe hypertension, seizures, or pancreatitis develops. Obtain CBCs, platelets, serum chemistries at start of each cycle. Concomitant exposure to risk factors (eg, IV bisphosphonates therapy or dental disease) may increase the risk of osteonecrosis of the jaw; avoid or consider preventive dentistry prior to treatment. Risk of tumor lysis syndrome: monitor closely in RCC and GIST patients with high tumor burden. Monitor for thyroid dysfunction; obtain baseline levels prior to treatment. Monitor blood glucose levels during and after treatment discontinuation. Monitor

for proteinuria; perform baseline and periodic urinalyses; interrupt and reduce dose if 24-hr urine protein ≥3g; discontinue if nephrotic syndrome or repeat urine protein ≥3g persists. Undergoing major surgery. Stress (monitor for adrenal insufficiency). Discontinue if severe cutaneous reactions (eg, erythema multiforme, SJS, TEN) develop; do not restart if diagnosis suspected. ESRD on dialysis. Severe hepatic impairment. Pregnancy (Cat.D; avoid). Nursing mothers: not recommended. Interactions: May be potentiated by strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole), grapefruit; consider reducing dose or use alternate drug. May be antagonized by CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital); consider increasing dose or use alternate drug. Concomitant St. John’s wort: not recommended. Caution with concomitant antiarrhythmics. Adverse reactions: Fatigue, asthenia, fever, diarrhea, nausea, vomiting, mucositis/ stomatitis, dyspepsia, abdominal pain, constipation, hypertension, peripheral edema, rash, hand-foot syndrome, skin discoloration, dry skin, hair color changes, altered taste, headache, back pain, arthralgia, extremity pain, cough, dyspnea, anorexia, bleeding; hepatotoxicity, left ventricular dysfunction, QT prolongation, osteonecrosis of the jaw, tumor lysis syndrome, thyroid dysfunction, impaired wound healing, hypoglycemia, 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

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DRUG MONOGRAPHS

ENDOCRINE CANCER discontinuing therapy if severe renal failure due to dehydration, or acute/worsening ocular disorders occur. Monitor LFTs periodically; withhold in patients without history of hepatic impairment for total bilirubin >3×ULN or transaminases >5×ULN, or in patients with history of hepatic impairment or biliary obstruction for doubling of bilirubin or tripling of transaminases over baseline. Discontinue if abnormal LFTs do not improve or resolve within 3 weeks. Withhold for persistent severe diarrhea unresponsive to loperamide, severe rash, or grade 3–4 keratitis. Monitor renal function, serum electrolytes, pulmonary function, INR, prothrombin time. History of peptic ulcers or diverticular disease. Pregnancy (Cat.D); use effective contraception during therapy and at least 2 weeks after the last dose. Nursing mothers: not recommended. Interactions: Potentiated by CYP3A4 inhibitors (eg, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, voriconazole, grapefruit) and CYP1A2 inhibitors (eg, ciprofloxacin); avoid if possible. Plasma levels decreased by CYP3A4 inducers (eg, rifampin, rifabutin, rifapentine, phenytoin, carbamazepine, phenobarbital, St. John’s wort), proton pump inhibitors or H2 blockers (take erlotinib 10hrs after and at least 2hrs before next dose), and smoking; avoid if possible. Increased risk of GI perforation with concomitant anti-angiogenic agents, steroids, NSAIDs, taxane-based

chemotherapy. Monitor for bleeding with oral anticoagulants, NSAIDs. Adverse reactions: Rash, diarrhea, nausea, vomiting, anorexia, fatigue, elevated LFTs, unexplained pulmonary symptoms (eg, dyspnea, cough, fever; discontinue and follow-up if occurs), stomatitis, infection; rare: GI perforation (may be fatal), ocular disorders (eg, conjunctivitis, keratitis, corneal ulceration/perforation), MI/ischemia, hemolytic anemia, cerebrovascular accidents, interstitial lung disease; hepatic or renal failure and hepatorenal syndrome (may be fatal); bullous, blistering and exfoliative skin conditions (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis). Testing considerations: K-RAS mutation analysis, EGFR amplification analysis How supplied: Tabs–30

THYROGEN Genzyme

℞

Thyroid stimulating hormone (recombinant). Thyrotropin alfa 1.1mg/vial; lyophilized pwd for IM inj after reconstitution; contains mannitol. Indications: Adjunctive diagnostic tool for serum thyroglobin (Tg) testing with or without radioiodine imaging in the follow-up of patients with well-differentiated thyroid cancer. Adjunctive treatment for radioiodine ablation of thyroid tissue remnants in patients who have undergone a near-total or total thyroidectomy for welldifferentiated thyroid cancer and who do not have evidence of metastatic thyroid cancer.

Adults: ≥16yrs: Give by IM inj into the buttock. 0.9mg, followed by a second 0.9mg injection 24 hours later. For radioiodine imaging or remnant ablation, give radioiodine 24 hours after the second Thyrogen injection. Children: <16yrs: not established. Warnings/Precautions: See full labeling. Reports of death in patients who are not thyroidectomized or with distant metastatic thyroid cancer wthin 24hrs after administration. Heart disease, extensive metastatic disease, or other serious underlying illnesses; increased risk of Thyrogen-induced hyperthyroidism, consider hospitalization for administration and post-administration observation. Caution patients regarding possible neurologic symptoms. Consider pretreatment with glucocorticoids in those whose tumor expansion may compromise vital anatomic structures (eg, trachea, CNS, lung metastases). Thyroglobulin (Tg) antibodies may render Tg levels uninterpretable; consider further evaluation with thyroid hormone withdrawal scan. Previous bovine TSH treatment. Residual thyroid tissue. End-stage renal disease. Elderly (increased risk of cardiac effects). Pregnancy (Cat.C). Nursing mothers. Adverse reactions: Nausea, headache, fatigue, influenza-like symptoms; death (in nonthyroidectomized or with distant metastatic thyroid cancer), stroke and other neurologic events, sudden rapid tumor enlargement in distant metastatic thyroid cancer. How supplied: 2-vial kit–2 vials of Thyrogen; 4-vial kit–2 vials of Thyrogen + 2 vials of diluent

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%

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

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CANCER TREATMENT REGIMEN

GASTROINTESTINAL CANCER Esophageal and Esophagogastric Junction 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.

Preoperative Chemoradiation1 Note: All recommendations are Category 2A unless otherwise indicated.

REGIMEN

DOSING

Preferred Regimens Paclitaxel + carboplatin (Category 1)2 Day 1: Paclitaxel 50mg/m2 IV + carboplatin AUC 2mg/mL × min IV Repeat weekly for 5 weeks (Days 1, 8, 15, 22, and 29). Cisplatin + 5-fluorouracil (5-FU) Days 1 and 29: Cisplatin 75–100mg/m2 IV (Category 1)3,4 Days 1–4 and 29–32: 5-FU 750–1,000mg/m2 IV continuous infusion over 24 hours on a 35-day cycle. OR Days 1–5: Cisplatin 15mg/m2 IV daily Days 1–5 and Days 22–26: 5-FU 800 mg/m2 IV continuous infusion over 24 hours. Cycled every 21 days for 2 cycles. Oxaliplatin + 5-FU + leucovorin5 Day 1: Oxaliplatin 85mg/m2 and leucovorin 200mg/m2 followed by 5-FU 400mg/m2 bolus, then 1,600mg/m2 46-hour continuous infusion; the first 3 cycles were delivered during radiotherapy (RT), the other 3 after RT for 6 bimonthly 14 days) cycles. Cisplatin + capecitabine (Category 1)6 Day 1: Cisplatin 30mg/m2 IV Days 1–5: Capecitabine 800mg/m2 orally twice daily Repeat cycle weekly for 5 weeks. Oxaliplatin + 5-FU (Category 1)7 Days 1, 15, and 29: Oxaliplatin 85mg/m2 IV Days 1–33: 5-FU 180mg/m2 IV. Oxaliplatin + capecitabine Days 1, 15, and 29: Oxaliplatin 85mg/m2 IV (Category 1)8 Days 1–5: Capecitabine 625mg/m2 orally twice daily for 5 weeks. Other Regimens Irinotecan + cisplatin (Category 2B)9 Paclitaxel + 5-FU (Category 2B)10 Paclitaxel + capecitabine (Category 2B)10

Days 1, 8, 22, and 29: Irinotecan 65mg/m2 IV plus cisplatin 30mg/m2 IV. Day 1: Paclitaxel 45mg/m2 IV weekly Days 1–5: 5-FU 300mg/m2 IV continuous infusion Repeat cycle weekly for 5 weeks. Day 1: Paclitaxel 45–50mg/m2 IV Days 1–5: Capecitabine 625–825mg/m2 orally BID Repeat cycle weekly for 5 weeks.

Perioperative Chemotherapy (including esophagogastric junction)1 ECF (epirubicin + cisplatin + 5-FU) (Category 1)11 ECF modifications12

5-FU + cisplatin (Category 1)13

Day 1: Epirubicin 50mg/m2 IV bolus and cisplatin 60mg/m2 IV Days 1–21: 5-FU 200mg/m2 IV continuous infusion over 24 hours daily. Repeat cycle every 21 days for 3 cycles preoperatively and 3 cycles postoperatively.* Day 1: Epirubicin 50mg/m2 IV; cisplatin 60mg/m2 IV Days 1–21: 5-FU 200mg/m2 IV continuous infusion once daily; cycled every 21 days for 3 cycles preoperatively and 3 cycles postoperatively. OR Day 1: Epirubicin 50mg/m2 IV; oxaliplatin 130mg/m2 IV Days 1–21: 5-FU 200mg/m2 IV continuous infusion over 24 hours; cycled every 21 days for 3 cycles preoperatively and 3 cycles postoperatively. OR Day 1: Epirubicin 50mg/m2 IV; oxaliplatin 130mg/m2 IV Days 1–21: Capecitabine 625mg/m2 orally twice daily. Cycled every 21 days for 3 cycles preoperatively and 3 cycles postoperatively. Day 1: Cisplatin 100mg/m2 IV Days 1–5: 5-FU 800mg/m2 IV continuous infusion over 24 hours daily; cycled every 28 days for 2–3 cycles preoperatively and 3-4 cycles postoperatively for a total of 6 cycles.

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GASTROINTESTINAL CANCER Definitive Chemoradiation (Nonsurgical)1 REGIMEN

DOSING

Preferred Regimens Cisplatin + 5-FU (Category 1)14

Day 1: Cisplatin 75–100mg/m2 IV Days 1–4: 5-FU 750–1,000mg/m2/day continuous IV infusion over 24 hours daily. Repeat cycle every 28 days for 2–4 cycles for 2 cycles with radiation followed by 2 cycles without radiation.

Oxaliplatin + 5-FU (Category 1)7,15

Days 1, 15, and 29: Oxaliplatin 85mg/m2 IV for 3 doses Days 1–33: 5-FU 180mg/m2 IV daily. OR Day 1: Oxaliplatin 85mg/m2 IV Day 1: Leucovorin 400mg/m2 IV Day 1: 5-FU 400mg/m2 IVP Days 1 and 2: 5-FU 800mg/m2 continuous IV over 24 hours daily. Repeat cycle every 14 days for 3 cycles with radiation followed by 3 cycles without radiation.

Cisplatin + capecitabine (Category 1)6 Day 1: Cisplatin 30mg/m2 IV Days 1–5: Capecitabine 800mg/m2 orally twice daily. Repeat cycle weekly for 5 weeks. Oxaliplatin + capecitabine (Category 1)8 Days 1, 15, and 29: Oxaliplatin 85mg/m2 IV Days 1–5: Capecitabine 625mg/m2 orally twice daily for 5 weeks. Paclitaxel + carboplatin2

Day 1: Paclitaxel 50mg/m2 IV and carboplatin AUC 2 mg/mL × min IV once weekly for 5 weeks.

Other Regimens Paclitaxel + cisplatin16

Days 1, 8, 15, and 22: Paclitaxel 60mg/m2 IV Day 1: Cisplatin 75mg/m2 IV given for 1 cycle.

Docetaxel + cisplatin17,18

Days 1 and 22: Docetaxel 60mg/m2 IV Days 1 and 22: Cisplatin 60–80mg/m2 IV given for 1 cycle. OR Day 1: Docetaxel 20–30mg/m2 IV Day 1: Cisplatin 20–30mg/m2 IV given for weekly for 5 weeks.

Irinotecan + cisplatin (Category 2B)9

Days 1, 8, 22, and 29: Irinotecan 65mg/m2 IV Days 1, 8, 22, and 29: Cisplatin 30mg/m2 IV.

Paclitaxel + 5-FU(Category 2B)10

Day 1: Paclitaxel 45mg/m2 IV weekly Days 1–5: 5-FU 300mg/m2 IV continuous infusion daily. Repeat cycle weekly for 5 weeks.

Paclitaxel + capecitabine (Category 2B)10

Day 1: Paclitaxel 45–50mg/m2 IV Days 1–5: Capecitabine 625–825mg/m2 PO twice daily. Repeat cycle weekly for 5 weeks.

Postoperative Chemoradiation (for adenocarcinoma or gastroesophageal junction only)1 5-FU + leucovorin18,19

Days 1–5: 5-FU 425mg/m2/day IV and leucovorin 20mg/m2/day IV, followed by chemoradiotherapy beginning 4 weeks after the start of the initial cycle of chemotherapy. Chemoradiotherapy: 4,500cGy of radiation at 180cGy/day, 5 days/week for 5 weeks, with 5-FU 400mg/m2/day IV and leucovorin 20mg/m2/day IV on the first 4 and the last 3 days of radiotherapy. At 1 month following completion of radiotherapy, two 5-day cycles of 5-FU 425mg/m2/day IV and leucovorin 20mg/m2/day IV; given 1 month apart. NOTE: The NCCN panel acknowledges that the Intergroup 0116 Trial formed the basis for postoperative adjuvant chemoradiation strategy. However, the panel does not recommend the above specified doses or schedule of cytotoxic agents because of concerns regarding toxicity. The panel recommends one of the following modifications instead:

Capecitabine20,21

Days 1–14: Capecitabine 750–1000mg/m2 orally twice daily; cycled every 28 days; 1 cycle before and 2 cycles after chemoradiation.

5-FU + leucovorin22

Days 1, 2, 15, and 16: Leucovorin 200mg/m2 IV as 2-hour infusion followed by 5-FU 400mg/m2 IV pyelogram and a 22-hour infusion of 5-FU 600mg/m2.

5-FU with radiation23

Days 1–5 OR Days 1–7: 5-FU 200–250mg/m2 IV continuous infusion over 24 hours daily, once weekly for 5 weeks.

Capecitabine with radiation6

Days 1–5 OR Days 1–7: Capecitabine 625–825mg/m2 orally twice daily, once weekly for 5 weeks. continued

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GASTROINTESTINAL CANCER Esophageal and Esophagogastric Junction Cancer Treatment Regimens Metastatic or Locally Advanced Cancer (where local therapy is not indicated)1 REGIMEN

DOSING

First-line therapy Trastuzumab + chemotherapy (for HER2-neu malignancies)24

Day 1: Trastuzumab 8mg/kg IV loading dose (Cycle 1 only); followed by trastuzumab 6mg/kg IV every 3 weeks, plus chemotherapy (Category 2B). OR Day 1 of Cycle 1: Trastuzumab 6mg/kg IV loading dose, then 4mg/kg IV every 4 days Day 1: Cisplatin 80mg/m2 IV, plus Days 1–14: Capecitabine 1000mg/m2 orally twice daily OR Days 1–5: 5-FU 800mg/m2 continuous IV infusion (Category 1). Repeat cycle every 21 days for 6 cycles.

Preferred Regimens DCF (docetaxel + cisplatin + 5-FU) (Category 1)25

Day 1: Docetaxel 75mg/m2 IV + cisplatin 75mg/m2 IV Days 1–5: 5-FU 1,000mg/m2 IV continuous infusion over 24 hours, daily. Repeat cycle every 28 days.

DCF (docetaxel + leucovorin + cisplatin + 5-FU)26

Day 1: Docetaxel 40mg/m2 IV + leucovorin 400mg/m2 IV + 5-FU 400mg/m2 IV, plus Days 1 and 2: 5-FU 1000mg/m2 IV continuous infusion over 24 hours (total 2000mg/m2), followed by Day 3: Cisplatin 40mg/m2 IV. Repeat cycle every 14 days.

DCF (docetaxel + cisplatin + 5-FU)27

Day 1: Docetaxel 60mg/m2 IV plus cisplatin 60mg/m2 IV Days 1–4: 5-FU 750mg/m2 IV continuous infusion over 24 hours daily. Repeat cycle every 21 days.

DCF (docetaxel + cisplatin + 5-FU)28

Day 1: Docetaxel 75mg/m2 IV plus cisplatin 75mg/m2 IV Days 1–14: 5-FU 300mg/m2 IV continuous infusion over 24 hours daily. Repeat cycle every 21 days.

Modified DCF (docetaxel + oxaliplatin Day 1: Docetaxel 50mg/m2 IV plus leucovorin 200mg/m2 IV plus oxaliplatin 85mg/m2 plus 5-FU 2600mg/m2 IV + leucovorin + 5-FU)29 continuous infusion over 24 hours. Repeat cycle every 14 days. Modified DCF (docetaxel + oxaliplatin Day 1: Docetaxel 50mg/m2 IV plus oxaliplatin 85mg/m2 + 5-FU)30 Days 1 and 2: 5-FU 1200mg/m2 IV continuous infusion over 24 hours. Repeat cycle every 14 days. Modified DCF (docetaxel + carboplatin + 5-FU) (Category 2B)31

Day 1: Docetaxel 75mg/m2 Day 2: Carboplatin AUC 6mg/mL × min Days 1–3: 5-FU 1200mg/m2 IV continuous infusion over 24 hours daily. Repeat cycle every 21 days.

ECF (epirubicin + cisplatin + 5-FU) (Category 1)32,33

Day 1: Epirubicin 50mg/m2 IV bolus + cisplatin 60mg/m2 IV Days 1–21: 5-FU 200mg/m2 IV continuous infusion over 24 hours daily. Repeat cycle every 21 days.

ECF modifications (epirubicin + oxaliplatin + 5-FU) (Category 1)33

Days 1: Epirubicin 50mg/m2 IV plus oxaliplatin 130mg/m2 IV Days 1–21: 5-FU 200mg/m2 IV continuous infusion over 24 hours. Repeat cycle every 21 days.

ECF modifications (epirubicin + cisplatin + capecitabine) (Category 1)33

Day 1: Epirubicin 50mg/m2 IV plus cisplatin 60mg/m2 IV Days 1–21: Capecitabine 625mg/m2 IV orally twice daily. Repeat cycle every 21 days.

ECF modifications (epirubicin + oxaliplatin + capecitabine) (Category 1)33

Day 1: Epirubicin 50mg/m2 IV plus oxaliplatin 130mg/m2 IV Days 1–21: Capecitabine 625mg/m2 IV orally twice daily. Repeat cycle every 21 days.

Fluoropyrimidine and cisplatin (5-FU + cisplatin) (Category 1)34†

Day 1: Cisplatin 100mg/m2 IV Days 1–4: 5-FU 1,000mg/m2 IV continuous infusion over 24 hours daily doses of 250mg/m2 IV over 60 minutes.

Fluoropyrimidine and cisplatin (5-FU + cisplatin + leucovorin) (Category 1)29,35

Day 1: Cisplatin 50mg/m2 IV Day 1: Leucovorin 200mg/m2 IV Day 1: 5-FU 2,000mg/m2 IV continuous infusion over 24 hours. Repeat cycle every 14 days.

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GASTROINTESTINAL CANCER Metastatic or Locally Advanced Cancer (where local therapy is not indicated)1 (continued) REGIMEN

DOSING

Preferred Regimens (continued) Fluoropyrimidine and cisplatin (capecitabine + cisplatin) (Category 1)36

Day 1: Cisplatin 80mg/m2 IV Day 1–14: Capecitabine 1,000mg/m2 orally twice daily. Repeat cycle every 3 weeks.

Fluoropyrimidine and oxaliplatin (oxaliplatin + leucovorin + 5-FU)36,37

Day 1: Oxaliplatin 85mg/m2 IV plus leucovorin 400mg/m2 IV plus 5-FU 400mg/m2 IVP Days 1 and 2: 5-FU 1200mg/m2 IV continuous infusion over 24 hours daily. Repeat cycle every 14 days. OR Day 1: Oxaliplatin 85mg/m2 IV plus leucovorin 200mg/m2 IV plus 5-FU 400mg/m2 IVP plus 5-FU 2600mg/m2 IV continuous infusion over 24 hours daily. Repeat cycle every 14 days.

Fluoropyrimidine and oxaliplatin (oxaliplatin + capecitabine)38

Day 1: Oxaliplatin 130mg/m2 IV Days 1–14: Capecitabine 1000mg/m2 orally twice daily. Repeat cycle every 21 days.

5-FU and irinotecan (irinotecan + leucovorin + 5-FU) (Category 1)39–41

Day 1: Irinotecan 80mg/m2 IV plus leucovorin 500mg/m2 IV plus 5-FU 2000mg/m2 IV continuous infusion over 24 hours, weekly for 6 weeks followed by 1 week off treatment OR Weekly for 6 weeks followed by 2 weeks off treatment. OR Day 1: Irinotecan 180mg/m2 IV plus leucovorin 400mg/m2 IV plus 5-FU 400mg/m2 IVP Day 1–2: 5-FU 1200mg/m2 IV continuous infusion over 24 hours. Repeat cycle every 14 days.

Other Regimens Paclitaxel + cisplatin or carboplatin42–44

Day 1: Paclitaxel 135–200mg/m2 IV Day 2: Cisplatin 75mg/m2 IV Repeat cycle every 21 days. OR Day 1: Paclitaxel 90mg/m2 IV plus cisplatin 75mg/m2 IV Repeat cycle every 14 days. OR Day 1: Paclitaxel 200mg/m2 IV plus carboplatin AUC 5mg/mL × min. Repeat cycle every 21 days.

Docetaxel + cisplatin28,45,46

Day 1: Docetaxel 70–85mg/m2 IV plus cisplatin 70–75mg/m2 IV. Repeat cycle every 21 days.

Docetaxel + irinotecan (Category 1)47

Days 1 and 8: Docetaxel 35mg/m2 IV plus irinotecan 50mg/m2 IV. Repeat cycle every 21 days.

Fluoropyridimine40,48,49

Day 1: Leucovorin 400mg/m2 IV plus 5-FU 400mg/m2 IVP Days 1 and 2: 5-FU 1200mg/m2 IV continuous infusion over 24 hours daily. Repeat cycle every 14 days. OR Days 1–5: 5-FU 800mg/m2 IV continuous infusion over 24 hours daily. Repeat cycle every 28 days. OR Days 1–14: Capecitabine 1000–1250mg/m2 orally twice daily. Repeat cycle every 21 days.

Taxane50–52

Day 1: Docetaxel 75–100mg/m2 IV. Repeat cycle every 21 days. OR Day 1: Paclitaxel 135–250mg/m2 IV. Repeat cycle every 21 days. OR Days 1, 8, 15, and 22: Paclitaxel 80mg/m2 IV once weekly. Repeat cycle every 28 days. continued

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GASTROINTESTINAL CANCER Esophageal and Esophagogastric Junction Cancer Treatment Regimens Second-line Therapy1 REGIMEN

DOSING

Trastuzumab + chemotherapy (NOTE: for HER2-neu malignancies)24

Day 1: Trastuzumab 8mg/kg IV loading dose (Cycle 1 only); followed by trastuzumab 6mg/kg IV every 3 weeks, plus chemotherapy (Category 2B). OR Day 1 of Cycle 1: Trastuzumab 6mg/kg IV loading dose, then 4mg/kg IV every 4 days. Chemotherapy: Day 1: Cisplatin 80mg/m2 IV, plus Days 1–14: Capecitabine 1000mg/m2 orally twice daily OR Days 1–5: 5-FU 800mg/m2 continuous IV infusion. Repeat cycle every 21 days for 6 cycles.

Preferred Regimens Ramucirumab + paclitaxel (for adenocarcinoma) (Category 1 for EGJ adenocarcinoma; Category 2A for esophageal adenocarcinoma)53

Days 1 and 15: Ramucirumab 8mg/kg IV Days 1, 8, and 15: Paclitaxel 80mg/m2 IV. Repeat cycle every 28 days.

Ramucirumab (for adenocarcinoma) Days 1 and 15: Ramucirumab 8mg/kg IV. (Category 1 for EGJ adenocarcinoma; Repeat cycle every 28 days. Category 2A for esophageal adenocarcinoma)54 Docetaxel (Category 1)50

Day 1: Docetaxel 75–100mg/m2 IV Repeat cycle every 21 days.

Paclitaxel (Category 1)51,52,55

Day 1: Paclitaxel 135–250mg/m2 IV Repeat cycle every 21 days. OR Day 1: Paclitaxel 80mg/m2 IV once weekly Repeat cycle every 28 days. OR Days 1, 8, and 15: Paclitaxel 80 mg/m2 IV. Repeat cycle every 28 days.

Irinotecan (Category 1)55–57

Day 1: Irinotecan 250–350mg/m2 IV Repeat cycle every 21 days. OR Day 1: Irinotecan 150–180mg/m2 IV Repeat cycle every 14 days. OR Days 1 and 8: Irinotecan 125mg/m2 IV. Repeat cycle every 21 days.

Other Regimens Irinotecan + cisplatin37,58

Days 1 and 8: Irinotecan 65mg/m2 IV plus cisplatin 25–30mg/m2 IV. Repeat cycle every 21 days.

Irinotecan + fluoropyridimine (Category 2B)59

Day 1: Irinotecan 250mg/m2 IV Days 1–14: Capecitabine 1000mg/m2 PO BID daily. Repeat cycle every 21 days

Irinotecan + fluoropyridimine (Category 2B)40,60

Day 1: Irinotecan 180mg/m2 IV plus leucovorin 400mg/m2 IV plus 5-FU 400mg/m2 IVP Days 1 and 2: 5-FU 600–1200mg/m2/day IV continuous infusion on days 1 and 2. Repeat cycle every 14 days.

Docetaxel + irinotecan (Category 2B)47

Days 1 and 8: Docetaxel 35mg/m2 IV plus irinotecan 50mg/m2 IV. Repeat cycle every 21 days.

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GASTROINTESTINAL CANCER Second-line Therapy1 (continued) REGIMEN

DOSING

Alternative Regimens for Consideration Mitomycin + irinotecan (Category 2B)61–63

Day 1: Mitomycin 6mg/m2 IV Days 2 and 9: Irinotecan 125mg/m2. Repeat cycle every 28 days. OR Days 1 and 15: Irinotecan 150mg/m2 IV Day 1: Mitomycin 8mg/m2 IV. Repeat cycle every 28 days. OR Day 1: Irinotecan 125mg/m2 IV plus mitomycin 5mg/m2 IV. Repeat cycle every 14 days.

Mitomycin + leucovorin + 5-FU (Category 2B)64

Days 1 and 22: Mitomycin 10mg/m2 IV Day 1: Leucovorin 500mg/m2 IV plus 5-FU 2600mg/m2/day IV continuous infusion. Weekly for 6 weeks, followed by 2 weeks off treatment.

General Treatment Notes1 Chemotherapy regimens should be chosen in the context of performance status, medical comorbidities, toxicity profile, and HER2-neu expression (for adenocarcinoma only). Two-drug cytotoxic regimens are preferred for patients with advanced disease because of lower toxicity, Three-drug cytotoxic regimens should be reserved for medically fit patients with good PS and access to frequent toxicity evaluation. Doses and schedules for any regimen that is not derived from category 1 evidence is a suggestion, and subject to appropriate modifications depending on the circumstances, Infusional fluorouracil and capecitabine may be used interchangeably (except as indicated). Cisplatin and oxaliplatin may be used interchangeably depending on toxicity profile. * Modified regimens substituting oxaliplatin and/or capecitabine are also acceptable. † May be coupled with cetuximab administered as an initial dose of cetuximab 400 mg/m2 IV on Day 1 over 120 minutes; followed by weekly doses of 250 mg/m2 IV over 60 minutes.

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continued

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GASTROINTESTINAL CANCER Esophageal And Esophagogastric Junction Cancer Treatment Regimens References (continued) 25. Van Cutsem E, Moiseyenko VM, Tjulandin S, et al. V325 Study Group. Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group. J Clin Oncol. 2006;24:4991–4997. 26. Shah MA, Shibata S, Stoller RG, et al; MSKCC Gastric Cancer Consortium. Random assignment multicenter phase II study of modified docetaxel, cisplatin, fluorouracil (mDCF) versus DCF with growth factor support (GCSF) in metastatic gastroesophageal adenocarcinoma (GE). J Clin Oncol. 2010;28 (Suppl 15):4010. 27. Ozal G, Dogan M, Akbulut H, et al., The safety and efficacy of modified-dose docetaxel, cisplatin, and 5-fluorouracil (mDCF) combination in the front-line treatment of advanced gastric cancer [abstract 113]. Presented at the 2010 Gastrointestinal Cancers Symposium. 28. Roth AD, Fazio N, Stupp R, et al; Swiss Group for Clinical Cancer Research. Docetaxel, cisplatin, and fluorouracil; docetaxel and cisplatin; and epirubicin, cisplatin, and fluorouracil as systemic treatment for advanced gastric carcinoma: a randomized phase II trial of the Swiss Group for Clinical Cancer Research. J Clin Oncol. 2007;25:3217–3223. 29. Al-Batran S-E, Hartmann JT, Probst S, et al. Phase III trial in metastatic gastroesophageal adenocarcinoma with fluorouracil, leucovorin plus either oxaliplatin or cisplatin: a study of the Arbeitsgemeinschaft Internistische Onkologie. J Clin Oncol. 2008;26:1435–1442. 30. Shankaran V, Mulcahy MF, Hochster HS, et al. Docetaxel, oxaliplatin and 5-fluorouracil for the treatment of metastatic or unresectable gastric or gastroesophageal junction (GEJ) adenocarcinomas: preliminary results of a phase II study [abstract]. Presented at the Gastrointestinal Cancers Symposium 2009;Abstract 47. 31. Elkerm YM, Elsaid A, Al-Batran S, et al. Final results of a phase II trial of docetaxelcarboplatin-FU in locally advanced gastric carcinoma [abstract]. Presented at the 2008 Gastrointestinal Cancers Symposium. Abstract 38. 32. Ross P, Nicolson M, Cunningham D, et al. Prospective randomized trial comparing mitomycin, cisplatin, and protracted venous-infusion fluorouracil (PVI 5-FU) With epirubicin, cisplatin, and PVI 5-FU in advanced esophagogastric cancer. J Clin Oncol. 2002;20:1996–2004. 33. Cunningham D, Starling N, Rao S, et al. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008;358:36–46. 34. Lorenzen S, Brucher B, Zimmermann F, et al. Neoadjuvant continuous infusion of weekly 5-fluorouracil and escalating doses of oxaliplatin plus concurrent radiation in locally advanced oesophageal squamous cell carcinoma: results of a phase I/II trial. Br J Cancer. 2008;99:1020–1026. 35. Bouché O, Raoul JL, Bonnetain F, et al; Fédération Francophone de Cancérologie Digestive Group. Randomized multicenter phase II trial of a biweekly regimen of fluorouracil and leucovorin (LV5FU2), LV5FU2 plus cisplatin, or LV5FU2 plus irinotecan in patients with previously untreated metastatic gastric cancer: a Federation Francophone de Cancerologie Digestive Group Study—FFCD 9803. J Clin Oncol. 2004;22:4319–4328. 36. Kang YK, Kang WK, Shin DB, et al. Capecitabine/cisplatin versus 5-fluorouracil/ cisplatin as first-line therapy in patients with advanced gastric cancer: a randomised phase III noninferiority trial. Ann Oncol. 2009;20:666–673. 37. Enzinger PC, Burtness B, Hollis D, et al. CALGB 80403/ECOG 1206: A randomized phase II study of three standard chemotherapy regimens (ECF, IC, FOLFOX) plus cetuximab in metastatic esophageal and GE junction cancer [abstract 4006]. J Clin Oncol. 2010; 28 (suppl 15):4007. 38. Kim GM, Jeung HC, Rha SY, et al. A randomized phase II trial of S-1-oxaliplatin versus capecitabine-oxaliplatin in advanced gastric cancer. Eur J Cancer. 2012;48:518–526. 39. Dank M, Zaluski J, Barone C, et al. Randomized phase III study comparing irinotecan combined with 5-fluorouracil and folinic acid to cisplatin combined with 5-fluorouracil in chemotherapy naive patients with advanced adenocarcinoma of the stomach or esophagogastric junction. Ann Oncol. 2008;19:1450–1457. 40. 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;35:1343–1347. 41. Wolff K, Wein A, Reulbach U, et al. Weekly high-dose 5-fluorouracil as a 24-h infusion and sodium folinic acid (AIO regimen) plus irinotecan in patients with locally advanced nonresectable and metastatic adenocarcinoma or squamous cell carcinoma of the oesophagus: a phase II trial. Anticancer Drugs. 2009;20:165–173. 42. Ilson DH, Forastiere A, Arquette M, et al. A phase II trial of paclitaxel and cisplatin in patients with advanced carcinoma of the esophagus. Cancer J. 2000;6:316–323. 43. Petrasch S, Welt A, Reinacher A, et al. Chemotherapy with cisplatin and paclitaxel in patients with locally advanced, recurrent or metastatic oesophageal cancer. Br J Cancer. 1998;78:511–514.

44. Gadgeel SM, Shields AF, Heilbrun LK, et al. Phase II study of paclitaxel and carboplatin in patients with advanced gastric cancer. Am J Clin Oncol. 2003;26:37–41. 45. Ajani JA, Fodor MB, Tjulandin SA, et al. Phase II multi-institutional randomized trial of docetaxel plus cisplatin with or without fluorouracil in patients with untreated, advanced gastric, or gastroesophageal adenocarcinoma. J Clin Oncol. 2005;23:5660–5667. 46. Kim JY, Do YR, Park KU, et al. A multi-center phase II study of docetaxel plus cisplatin as first-line therapy in patients with metastatic squamous cell esophageal cancer. Cancer Chemother Pharmacol. 2010;66:31–36. 47. Burtness B, Gibson M, Egleston B, et al. Phase II trial of docetaxel-irinotecan combination in advanced esophageal cancer. Ann Oncol. 2009;20:1242–1248. 48. Ohtsu A, Shimada Y, Shirao K, et al. Randomized phase III trial of fluorouracil alone versus fluorouracil plus cisplatin versus uracil and tegafur plus mitomycin in patients with unresectable, advanced gastric cancer: The Japan Clinical Oncology Group Study (JCOG9205). J Clin Oncol. 2003;21:54–59. 49. Hong YS, Song SY, Lee SI, et al. A phase II trial of capecitabine in previously untreated patients with advanced and/or metastatic gastric cancer. Ann Oncol. 2004;15:1344–1347. 50. Albertsson M, Johansson B, Friesland S, et al. Phase II studies on docetaxel alone every third week, or weekly in combination with gemcitabine in patients with primary locally advanced, metastatic, or recurrent esophageal cancer. Med Oncol. 2007;24(4):407–412. 51. Ajani JA, Ilson DH, Daugherty K, et al. Activity of taxol in patients with squamous cell carcinoma and adenocarcinoma of the esophagus. J Natl Cancer Inst. 1994;86:1086–1091. 52. Ilson DH, Wadleigh RG, Leichman LP, et al. Paclitaxel given by a weekly 1-h infusion in advanced esophageal cancer. Ann Oncol. 2007;18:898–902. 53. Wilke H, Muro K, Van Cutsem E, et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-esophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014;1224–1235. 54. Fuchs CS, Tomasek J, Yong CJ, et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-esophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2014;383:31–39. 55. Ueda S, Hironaka S, Yasui H, et al; West Japan Oncology Group. Randomized phase III study of irinotecan (CPT-11) versus weekly paclitaxel (wPTX) for advanced gastric cancer (AGC) refractory to combination chemotherapy (CT) of fluoropyrimidine plus platinum (FP): WJOG4007 trial. J Clin Oncol. 2012;30:15s (suppl; abstr 4002). 56. Thuss-Patience PC, Kretzschmar A, Deist T, et al. Irinotecan versus best supportive care (BSC) as second-line therapy in gastric cancer: A randomized phase III study of the Arbeitsgemeinschaft Internistische Onkologie (AIO). J Clin Oncol. 2009;27:15s (suppl; abstr 4540). 57. Fuchs CS, Moore MR, Harker G, et al. Phase III comparison of two irinotecan dosing regimens in second-line therapy of metastatic colorectal cancer. J Clin Oncol. 2003;21:807–814. 58. Ilson DH. Phase II trial of weekly irinotecan/cisplatin in advanced esophageal cancer. Oncology (Williston Park). 2004;18(14 Suppl 14):22–25. 59. Leary A, Assersohn L, Cunningham D, et al. A phase II trial evaluating capecitabine and irinotecan as second line treatment in patients with oesophago-gastric cancer who have progressed on, or within 3 months of platinum-based chemotherapy. Cancer Chemother Pharmacol. 2009;64:455–462. 60. Di Lauro L, Fattoruso SI, Giacinti L, et al. Second-line chemotherapy with FOLFIRI in patients with metastatic gastric cancer (MGC) not previously treated with fluoropyrimidines. J Clin Oncol. 2009;27:15s (suppl; abstr 4549). 61. Lustberg MB, Bekaii-Saab T, Young D, et al. Phase II randomized study of two regimens of sequentially administered mitomycin C and irinotecan in patients with unresectable esophageal and gastroesophageal adenocarcinoma. J Thorac Oncol. 2010;5:713–718. 62. Giuliani F, Molica S, Maiello E, et al. Irinotecan (CPT-11) and mitomycin-C (MMC) as second-line therapy in advanced gastric cancer: a phase II study of the Gruppo Oncologico dell’ Italia Meridionale (prot. 2106).Am J Clin Oncol. 2005;28:581–585. 63. Bamias A, Papamichael D, Syrigos K, et al. Phase II study of irinotecan and mitomycin C in 5-fluorouracil-pretreated patients with advanced colorectal and gastric cancer. J Chemother. 2003;15:275–281. 64. Hofheinz RD, Hartung G, Samel S, et al. High-dose 5-fluorouracil/folinic acid in combination with three-weekly mitomycin C in the treatment of advanced gastric cancer. A phase II study. Onkologie. 2002;25:255–260.

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GASTROINTESTINAL CANCER Pancreatic Adenocarcinoma 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.

Metastatic Disease1 Note: All recommendations are Category 2A unless otherwise indicated.

REGIMEN

DOSING

Good Performance Status FOLFIRINOX (oxaliplatin + irinotecan + 5-fluorouracil [5-FU]/leucovorin) (Category 1)2

Day 1: Oxaliplatin 85mg/m2 IV + irinotecan 180mg/m2 IV + leucovorin 400mg/m2 IV, followed by a 5-FU bolus of 400mg/m2 and a 46-hour continuous 5-FU infusion of 2,400mg/m2. Repeat cycle every 2 weeks until disease progression.

Gemcitabine + albumin-bound paclitaxel (Category 1)3

Days 1, 8, and 15: Nab-paclitaxel 125mg/m2 IV + gemcitabine 1,000mg/m2 IV. Repeat cycle every 4 weeks until disease progression.

Gemcitabine + erlotinib (Category 1)4

Cycle 1 (8-week cycle): Days 1, 8, 15, 22, 29, 36, and 43: Gemcitabine 1,000mg/m2 IV follow by a 1-week rest Days 1–56: Erlotinib 100mg PO daily, followed by: Subsequent cycles (4-week cycle): Days 1, 8, and 15: Gemcitabine 1,000mg/m2 IV over 30 minutes Days 1–28: Erlotinib 100mg PO daily.

Gemcitabine + capecitabine5

Days 1, 8, and 15: Gemcitabine 1,000mg/m2 IV Days 1–21: Capecitabine 1,660mg/m2 PO daily (830mg/m2 twice daily). Repeat cycle every 4 weeks until disease progression.

Gemcitabine + cisplatin6

Days 1 and 15: Gemcitabine 1,000mg/m2 IV + cisplatin 50mg/m2 IV. Repeat cycle every 4 weeks until disease progression.

GTX (Fixed-dose rate gemcitabine + docetaxel + capecitabine) (Category 2B)7

Days 1–14: Capecitabine 750mg/m2 PO twice daily Days 4 and 11: Gemcitabine 750mg/m2 IV + docetaxel 30mg/m2 IV. Repeat cycle every 21 days until disease progression.

Fluoropyrimidine (5-FU + leucovorin or capecitabine) + oxaliplatin (Category 2B)8,9

Days 1, 8, 15, and 22: Leucovorin 200mg/m2 IV followed by 5-FU 2g/m2 continuous IV infusion over 24 hours Days 8 and 22: Oxaliplatin 85mg/m2 IV. After a rest of 3 weeks, repeat cycle on day 43. OR Age ≤ 65 years and ECOG performance status 0 to 1: Day 1: Oxaliplatin 130mg/m2 IV Days 1–14: Capecitabine 1,000mg/m2 twice daily. Repeat cycle every 3 weeks. Age > 65 years and ECOG performance status 2: Day 1: Oxaliplatin 110mg/m2 IV Days 1–14: Capecitabine 750mg/m2 twice daily. Repeat cycle every 3 weeks.

Poor Performance Status Gemcitabine (Category 1)1

Days 1, 8, and 15: Gemcitabine 1,000mg/m2 IV over 30 minutes. Repeat cycle every 28 days.

Fixed-dose rate gemcitabine (Category 2B)1

Days 1, 8, and 15: Gemcitabine 10mg/m2/minute IV. Repeat cycle every 28 days.

Capecitabine (Category 2B)1

Days 1–14: Capecitabine 1,000mg/m2 PO twice daily. Repeat cycle every 3 weeks for up to 52 weeks. continued

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GASTROINTESTINAL CANCER Pancreatic Adenocarcinoma Treatment Regimens Second-Line Therapy1 Principles of Chemotherapy: • Second line chemotherapy may consist of gemcitabine-based therapy for those previously treated with fluoropyrimidine-based therapy, and of fluoropyrimidine-based therapy for those previously treated with gemcitabine-based therapy. Results of the CONKO-003 trial demonstrated a significant improvement in overall survival with the addition of oxaliplatin to 5-FU/leucovorin.

Locally Advanced Disease1 Principles of Chemotherapy: • Depending on performance status, mono- or combination systemic chemotherapy may be considered as initial therapy prior to chemoradiation for appropriate patients with locally advanced, unresectable disease. • Patients should be evaluated for recovery from hematologic and nonhematologic toxicity prior to initiation of chemoradiation. • Patients who progress with metastatic disease are not candidates for chemoradiation unless required for palliative purposes.

Adjuvant Disease1 REGIMEN

DOSING

Gemcitabine (Category 1)10

Days 1, 8, and 15: Gemcitabine 1,000mg/m2 IV over 30 minutes. Repeat cycle every 28 days.

5-FU + leucovorin (Category 1)11

Days 1–5: Leucovorin 20mg/m2 IV bolus, followed by 5-FU 425mg/m2 IV bolus. Repeat cycle every 4 weeks.

Gemcitabine + Radiation12

Prior to chemoradiation: Days 1, 8 and 15: Gemcitabine 1,000mg/m2 IV; initiate 1–2 weeks prior to chemoradiation (50.4Gy + 5-FU 250mg/m2/day). After chemoradiation: Days 1, 8 and 15: Gemcitabine 1,000mg/m2 IV; initiate 3–5 weeks following chemoradiation. Repeat cycle every 4 weeks for 3 months.

Continuous infusion 5-FU + Radiation12

Prior to chemoradiation: Days 1–21: 5-FU 250mg/m2/day continuous IV infusion; initiate 1–2 weeks prior to chemoradiation (50.4Gy + 5-FU 250mg/m2/day). After chemoradiation: Days 1–28: 5-FU 250mg/m2/day continuous IV infusion; initiate 3–5 weeks following chemoradiation. Repeat cycle every 6 weeks for 3 months.

Capecitabine (Category 2B)1

Days 1–14: Capecitabine 1,000mg/m2 PO twice daily. Repeat cycle every 3 weeks for up to 52 weeks.

Principles of Chemotherapy: • The CONKO-001 trial demonstrated significant improvements in disease-free survival and overall survival with use of postoperative gemcitabine as adjuvant chemotherapy versus observation in resectable pancreatic adenocarcinoma.10 • ESPAC-3 study results showed no significant difference in overall survival between 5-FU/leucovorin versus gemcitabine following surgery. When the groups receiving adjuvant 5-FU/leucovorin and adjuvant gemcitabine were compared, median survival was 23.0 months and 23.6 months, respectively.11 • The use of gemcitabine-based chemotherapy is frequently combined, sequentially, with 5-FU-based chemoradiotherapy. • No significant differences were observed in the RTOG 97-04 study comparing pre- and post-chemoradiation 5-FU with pre- and post-chemoradiation gemcitabine for postoperative adjuvant treatment.12 • For patients who relapse after receiving adjuvant therapy, subsequent therapy may consist of gemcitabine or gemcitabine-based combination therapy for patients previously treated with fluoropyrimidine-based therapy, or fluoropyrimidine-based therapy (e.g., 5-FU/ leucovorin/oxaliplatin21 or CapeOx) for patients previously treated with gemcitabine-based therapy.

Neoadjuvant Therapy1 Principles of Chemotherapy: • There is limited evidence to recommend specific neoadjuvant regimens off-study, and practices vary with regard to the use of chemotherapy and chemoradiation. Acceptable regimens include FOLFIRINOX or gemcitabine + albumin-bound paclitaxel. Subsequent chemoradiation is sometimes included.

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GASTROINTESTINAL CANCER References 1.

2. 3. 4.

Referenced with permission from NCCN Clinical Practice Guidelines in Oncology™. Pancreatic Adenocarcinoma. v 1.2015. Available at: http://www.nccn.org/ professionals/physician_gls/pdf/pancreatic.pdf. Accessed January 30, 2015. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364:1817–1825. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369:1691–1703. Moore MJ, Goldstein D, Hamm J, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer. A phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007; 25:1960–1966. Cunningham D, Chau I, Stocken D D, et al. Phase III randomized comparison of gemcitabine (GEM) versus gemcitabine plus capecitabine (GEM-CAP) in patients with advanced pancreatic cancer. J Clin Oncol. 2009; 27:5513–5518. Oliver GR, Sugar E, Laheru D, et al. Family history of cancer and sensitivity to platinum chemotherapy in pancreatic adenocarcinoma [abstract]. Presented at: 2010 ASCO Gastrointestinal Cancers Symposium; January 22–24, 2010; Orlando, Florida. Abstract 180.

7. 8.

9. 10. 11. 12.

Fine RL, Fogelman DR, Schreibman SM, et al. The gemcitabine, docetaxel, and capecitabine (GTX) regimen for metastatic pancreatic cancer: a retrospective analysis. Cancer Chemother Pharmacol. 2008;61:167–175. Pelzer U, Schwaner I, Stieler J, et al. Best supportive care (BSC) versus oxaliplatin, folinic acid and 5-fluorouracil (OFF) plus BSC in patients for second-line advanced pancreatic cancer: a phase III-study from the German CONKO-study group. Eur J Cancer. 2011;47:1676–1681. Xiong HQ, Varadhachary GR, Blais JC, et al. A phase ll trial of oxaliplatin plus capecitabine (xelox) as second-line therapy for patients with advanced pancreatic cancer. Cancer. 2008;113:2046–2052. Oettle H, Neuhaus P, Hochhaus A, et al. Adjuvant Chemotherapy With Gemcitabine and Long-term Outcomes Among Patients With Resected Pancreatic Cancer: The CONKO-001 Randomized Trial. JAMA. 2013;310(14):1473–1481. Neoptolemos J, Buchler M, Stocken DD, Bassi C, et al. Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA. 2010;304:1073–1081. Regine, WF Winter KA, Abrams RA et al. Fluorouracil vs. gemcitabine chemotherapy before and after fluorouracil-based chemoradiation after resection of pancreatic adenocarcinoma. A randomized controlled trial. JAMA. 2008; 299:1019–1026.

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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 (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 and fistulae, wound dehiscence/impaired healing, necrotizing fasciitis (discontinue if occurs), hemorrhage, non-GI fistula formation, arterial or venous thromboembolic events, posterior reversible encephalopathy syndrome, infusion reactions, ovarian failure, neutropenia, and infection. How supplied: Single-use vial–1

CYRAMZA Lilly

℞

Human IgG1 monoclonal antibody. Ramucirumab 10mg/mL; per vial; soln for IV infusion after dilution; preservative-free. Indications: As a single agent, or in combination with paclitaxel, for treatment of advanced or metastatic, gastric or gastro-esophageal junction adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinumcontaining chemotherapy. 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. 8mg/kg every 2 weeks; 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. Pregnancy (Cat.C); avoid; use effective contraception during therapy and for ≥3 months after completion. Nursing mothers: not recommended. Adverse reactions: Hypertension, diarrhea, headache, fatigue, hyponatremia, anemia, intestinal obstruction, neutropenia, epistaxis, stomatitis/mucosal inflammation, rash, arterial thromboembolic events, proteinuria, GI perforation, infusion-related reactions. How supplied: Single-dose vial (10mL, 50mL)–1

ELOXATIN Sanofi Aventis

℞

Alkylating agent (organoplatinum complex). Oxaliplatin 5mg/mL; soln for IV infusion after dilution; preservative-free. Indications: Adjuvant treatment for Stage III colon cancer in patients who have undergone complete resection of the primary tumor (in combination with infusional 5-FU/LV). Treatment of advanced colorectal cancer (in combination with infusional 5-FU/LV). Adults: See literature. Premedicate with antiemetics. Give by IV infusion every two

weeks for a total of 6 months (eg, 12 cycles). Day 1: 85mg/m2 + leucovorin, followed by 5-FU. Day 2: Leucovorin followed by 5-FU. Severe renal impairment: initially 65mg/m2. Neuropathy, other toxicities: see literature for dose adjustments. Children: Not recommended. Warnings/Precautions: Have epinephrine, corticosteroids, antihistamines available during infusion. Discontinue if interstitial lung disease or pulmonary fibrosis suspected. Monitor for neuropathy; reduce dose or discontinue if needed. Renal impairment. Monitor WBCs with differential, hemogloblin, platelets, blood chemistries (including ALT, AST, bilirubin, creatinine) before each treatment. Avoid extravasation. Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended. Interactions: Caution with concomitant nephrotoxic agents. Monitor oral anticoagulants. Adverse reactions: Peripheral sensory neuropathy, neutropenia, thrombocytopenia, anemia, GI upset, increased liver enzymes, emesis, fatigue, stomatitis; hypersensitivity reactions (monitor), pulmonary fibrosis (may be fatal), hepatotoxicity. Testing considerations: ERCC1 overexpression How supplied: Single-use vials (50mg, 100mg, 200mg)–1

ERBITUX Bristol-Myers Squibb

℞

Epidermal growth factor receptor blocker. Cetuximab 100mg/vial, 200mg/vial; soln for IV infusion; preservative-free. Indications: K-Ras mutation-negative (wildtype), EGFR-expressing metastatic colorectal carcinoma: 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 irinotecanand oxaliplatin-based regimens or if irinotecanintolerant). Not recommended for use with K-Ras mutation-positive or K-Ras somatic mutations in codon 12 or 13. Adults: Pretreat with H1 blocker. Give by IV infusion (use filter); max rate: 10mg/min. Initial dose: 400mg/m2 once over 2 hours; then 250mg/m2 once weekly over 1 hour until disease progression or unacceptable toxicity. Complete administration 1 hour prior to FOLFIRI. Permanently reduce infusion rate by 50% if Grade 1 or 2 and nonserious Grade 3 infusion reaction occurs; permanently discontinue if Grade 3 or 4 serious reaction occurs. Monitor patient during and for 1 hr post-infusion. Skin toxicity: see full labeling. Children: Not recommended. Warnings/Precautions: Confirm K-Ras mutation status and EGFR expression for colorectal cancer. Discontinue if severe infusion reactions or interstitial lung disease occur. Monitor for infusion reactions, cardiopulmonary arrest, pulmonary toxicity, skin inflammation/ infection; avoid sun, UV light. Additive cutaneous reactions with irradiation. Cardiovascular

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DRUG MONOGRAPHS

GASTROINTESTINAL CANCER diseases (w. irradiation or platinum-based therapy with 5-FU). Monitor electrolytes (eg, magnesium, potassium, calcium) during and after cetuximab therapy. Pregnancy (Cat.C). Nursing mothers: not recommended. Interactions: Increased mucositis (Grade 3–4), radiation recall syndrome, acneiform rash, cardiac events, and electrolyte disturbances with radiation and cisplatin. Adverse reactions: Cutaneous reactions (pruritus, nail changes), acneform rash, headache, diarrhea, infection, asthenia, mucositis, weight loss, xerostomia, dehydration, electrolyte abnormalities; infusion reactions (may be severe: eg, bronchospasm, dyspnea), interstitial lung disease, cardiopulmonary arrest, hypomagnesemia, fever, sepsis, kidney failure, pulmonary embolus; others (see full labeling). Testing considerations: EGFR amplification analysis, K-RAS mutation analysis, B-RAF mutation analysis. How supplied: Single-use vials–1

Fluorouracil (various)

℞

Antimetabolite. Fluorouracil 50mg/mL; soln for IV inj. Indications: Palliative management of carcinoma of the colon, rectum, and stomach. Adults: Give by IV inj. 12mg/kg once daily for 4 successive days; max 800mg/day. If no toxicity is observed, 6mg/kg are given on the 6th, 8th, 10th, and 12th days unless toxicity occurs. Maintenance therapy: repeat dosage of 1st course every 30 days after the last day of the previous course of treatment; or give a maintenance dose of 10–15mg/kg per week as a single dose; max: 1g/ week. Poor risk patients: see literature for dose adjustments. Children: Not recommended. Contraindications: Poor nutritional state. Depressed bone marrow function. Potentially serious infections. Warnings/Precautions: Narrow margin of safety; monitor for toxicity. Consider hospitalization for 1st course. History of highdose pelvic irradiation. Previous use of alkylating agents. Widespread involvement of bone marrow by metastatic tumors. Renal or hepatic impairment. Discontinue if signs of toxicity appear (eg, stomatitis, esophagopharyngitis, leukopenia, intractable vomiting, diarrhea, GI ulceration or bleeding, thrombocytopenia, hemorrhage). Monitor WBCs with differential before each dose. Avoid extravasation. Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended. Interactions: Potentiated by leucovorin.

Adverse reactions: Stomatitis, esophagopharyngitis, GI upset, anorexia, leukopenia, alopecia, dermatitis, hand-foot syndrome; others. Testing considerations: TS (thymidylate synthase), MSI (microsatellite instability), DPD (dihydropyrimidine dehydrogenase). How supplied: Contact supplier.

FUSILEV Spectrum

℞

Folate analogue. Levoleucovorin (as calcium pentahydrate) 50mg/vial; pwd for IV inj after reconstitution; contains mannitol 50mg/vial; 175mg/17.5mL; soln for IV inj; preservative-free. Indications: Palliative treatment of advanced metastatic colorectal cancer in combination with 5-fluorouracil (5-FU). Adults: Administer levoleucovorin and 5-FU separately to avoid precipitate formation. Regimen 1: give levoleucovorin at 100mg/m2 by slow IV inj over a minimum of 3 minutes, followed by 5-FU at 370mg/m2 by IV inj. Regimen 2: give levoleucovorin at 10mg/m2 by IV inj, followed by 5-FU at 425mg/m2 by IV inj. Both: Treat daily for 5 days. Five-day treatment course may be repeated at 4 week (28 days) intervals for 2 courses, and then repeated at 4–5 week (28–35 days) intervals provided that patient recovered completely from toxic effects from prior treatment course. Dose adjustments for subsequent treatment course: see literature. Children: Not recommended. Warnings/Precautions: Not for treating pernicious anemia and megaloblastic anemia. Elderly. Debilitated. Pregnancy (Cat.C). Nursing mothers. Interactions: Potentiates 5-fluorouracil toxicity. Antagonizes TMP/SMZ. Antagonizes anticonvulsants (eg, phenobarbital, primidone, phenytoin). May be affected by drugs that affect MTX elimination. Adverse reactions: Stomatitis, nausea, diarrhea. How supplied: Single-use vial (pwd, soln)–1

GLEEVEC Novartis

℞

Kinase inhibitor. Imatinib (as mesylate) 100mg, 400mg; scored tabs. Indications: Kit (CD117) (+) unresectable and/or metastatic malignant GI stromal tumors (GIST). Adjuvant treatment of adults following complete gross resection of Kit (CD117) (+) GIST. Adults: Take with food and water. May disperse tab in water or apple juice and take promptly. ≥18yrs: GIST: 400mg once daily; up to 800mg daily (given as 400mg twice daily) may be considered if clinically indicated. Adjuvant GIST treatment: 400mg once daily; 36 months of

treatment recommended (see full labeling). If severe non-hematologic reactions develop: interrupt dose; resume at a lower dose in hepatic dysfunction. Severe hepatic impairment: reduce dose by 25%. Renal or hematologic reactions: see full labeling. Avoid concomitant strong CYP3A4 inducers (eg, rifampin): if needed, increase imatinib dose by at least 50%. Children: Not recommended. Warnings/Precautions: Hepatic or renal impairment. Monitor weight and for fluid retention regularly; CBCs weekly for 1st month, bi-weekly for 2nd month, then periodically (eg, every 2–3 months); liver function at baseline then monthly or as needed; GI symptoms at baseline. Cardiovascular disease or risk factors; monitor. Immunosuppression and potential toxicities (liver, kidney, cardiac) from long-term use. Monitor for tumor lysis syndrome; correct clinically significant dehydration and treat high uric acid levels before initiating therapy. Monitor growth in children. Possible cardiogenic shock/LV dysfunction in conditions with high eosinophil levels (eg, HES/CEL, MDS/MPD, ASM); consider concomitant systemic steroid prophylaxis (1–2mg/kg) for 1 or 2 wks if abnormal ECG or serum troponin. Monitor TSH levels in thyroidectomy patients undergoing levothyroxine replacement. Pregnancy (Cat.D); avoid. Use highly effective contraception during treatment. Nursing mothers: not recommended. Interactions: Avoid grapefruit juice. Potentiated by CYP3A4 inhibitors (eg, azole antifungals, protease inhibitors, nefazodone, clarithromycin, telithromycin). Antagonized by strong CYP3A4 inducers (eg, dexamethasone, fosphenytoin, phenytoin, phenobarbital, carbamazepine, oxcarbamazepine, primidone, St. John’s wort, rifampin, rifabutin, rifampicin); consider alternatives. May potentiate drugs metabolized by CYP3A4 (eg, benzodiazepines, dihydropyridine calcium channel blockers, cyclosporine, ergots, alfentanil, fentanyl, pimozide, quinidine, certain statins, sirolimus, tacrolimus), CYP2D6, or CYP2C9 (use heparin instead of warfarin). Adverse reactions: Edema (may be severe), nausea, vomiting, musculoskeletal pain, diarrhea, muscle cramps, rash (may be severe; eg, erythema multiforme, Stevens-Johnson syndrome), fatigue, abdominal pain, dizziness, blurred vision, somnolence, fever, headache, cough, arthralgia/myalgia, dyspnea, hypokalemia, night sweats, anorexia, pruritus, hemorrhage, anemia, neutropenia, thrombocytopenia, weight gain, renal or hepatotoxicity, immunosuppression, hypothyroidism; rare: severe CHF, LV dysfunction. How supplied: 100mg–90; 400mg–30

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DRUG MONOGRAPHS

GASTROINTESTINAL CANCER HERCEPTIN Genentech

℞

Human epidermal growth factor receptor (HER2) inhibitor. Trastuzumab 440mg/vial; lyophilized pwd for IV infusion after reconstitution and dilution; preservative-free. Indications: HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma, in combination with cisplatin and capecitabine or 5-fluorouracil, in patients who have not received prior treatment. Adults: Do not substitute for or with adotrastuzumab emtasine. Give as IV infusion. Initially 8mg/kg over 90 mins, followed by 6mg/kg over 30–90 mins every 3 weeks until disease progression. Infusion reactions or cardiomyopathy: see full labeling. Children: Not established. Warnings/Precautions: Increased risk of cardiomyopathy. Conduct cardiac assessment (eg, history, physical exam, LVEF) at baseline, every 3 months during and after therapy or every 6 months for ≥2yrs after therapy (if adjuvant); repeat LVEF at 4 week intervals if dose is withheld due to significant left ventricular cardiac dysfunction. Interrupt therapy if dyspnea or significant hypotension occurs; consider discontinuing permanently if severe infusion reactions, CHF, pulmonary toxicity, or significant left ventricular myocardial dysfunction develops. Symptomatic intrinsic lung disease. Extensive tumor involvement of the lungs. Test for HER2 protein overexpression and HER2 gene amplification using FDA-approved tests for specific tumor type (breast or gastric/ gastroesophageal adenocarcinoma). Elderly. Pregnancy (Cat.D); use adequate contraception during and at least 6 months after therapy. Nursing mothers: not recommended. Interactions: Increased cardiomyopathy with anthracycline-containing chemotherapy. Increased toxicity with other myelosuppressives. Potentiated by paclitaxel. Adverse reactions: Diarrhea, fatigue, anemia, stomatitis, weight loss, upper respiratory tract infections, fever, thrombocytopenia, mucosal inflammation, nasopharyngitis, dysgeusia, infections; severe infusion reactions, febrile neutropenia/exacerbation of chemotherapyinduced neutropenia, pulmonary toxicity (eg, interstitial pneumonitis), cardiomyopathy (eg, left ventricular myocardial dysfunction); pregnant women: possible oligohydramnios (monitor). Testing considerations: HER2 protein overexpression How supplied: Vial–1 (w. diluent)

Leucovorin Teva

℞

Folic acid derivative. Leucovorin calcium 100mg/vial, 350mg/vial; lyophilized pwd for IV or IM inj after reconstitution; preservative-free. Indications: Palliative treatment of advanced colorectal cancer in combination with 5-fluorouracil.

Adults: Max IV infusion rate: 160mg/min. 200mg/m2 by slow IV inj over a minimum of 3 minutes, followed by 5-fluorouracil (370mg/m2); or 20mg/m2 IV followed by 5-fluorouracil (425mg/m2); both regimens: daily for 5 days, may be repeated at 4-week intervals for 2 courses and then repeated at 4–5 week intervals (if completely recovered from toxic effects of previous course). Children: See literature. Contraindications: Pernicious anemia and other megaloblastic anemias due to Vit. B12 deficiency. Warnings/Precautions: Do not administer intrathecally. CNS metastases. Monitor CBCs with differential, platelets, electrolytes, liver function tests prior to each treatment, then periodically. Elderly. Debilitated. Pregnancy (Cat.C). Nursing mothers. Interactions: Potentiates toxicity of 5-fluorouracil; use lower 5-fluorouracil dose. May antagonize phenobarbital, phenytoin, and primidone. Caution with trimethoprimsulfamethoxazole. Adverse reactions: Leukopenia, thrombocytopenia, infection, GI upset, stomatitis, constipation, lethargy, malaise, fatigue, alopecia, dermatitis, anorexia; seizures, syncope. How supplied: Single-use vials–1

NEXAVAR Bayer and Onyx

℞

Multikinase inhibitor. Sorafenib 200mg; tabs. Indications: Unresectable hepatocellular carcinoma. Adults: Take on an empty stomach. 400mg twice daily. If toxicity occurs, may reduce dose to 400mg once daily; if further dose reduction required, may reduce dose to 400mg every other day (see full labeling). Concomitant strong CYP3A4 inducers: consider increasing dose, monitor for toxicity. Children: Not established. Contraindications: Concomitant carboplatin/ paclitaxel in patients with squamous cell lung cancer. Warnings/Precautions: Avoid in congenital long QT syndrome. Monitor patients with CHF, bradyarrhythmias, drugs known to prolong the QT interval, electrolyte abnormalities. Discontinue if severe dermatologic toxicity, hypertension, GI perforation, hemorrhage, cardiac ischemia, MI occurs. Suspend therapy before major surgery. Monitor BP weekly during the first 6 weeks and thereafter. Monitor hepatic function regularly; discontinue if transaminases significantly elevated. Severe hepatic impairment (Child-Pugh C) or on dialysis. Use effective contraception during and for 2 weeks after stopping treatment. Pregnancy (Cat.D), nursing mothers: not recommended. Interactions: See Contraindications. Avoid strong CYP3A4 inducers (eg, St. John’s Wort, dexamethasone, phenytoin, carbamazepine, rifabutin, rifampin, phenobarbital) and neomycin;

may decrease sorafenib levels. May potentiate warfarin (monitor PT & INR), other drugs metabolized by UGT1A1 or UGT1A9 pathway, or substrates of CYP2B6, CYP2C8, CYP2C9, P-gp. Concomitant Class Ia and III antiarrhythmics; may prolong QT interval. Adverse reactions: Dermatologic toxicity (eg, rash, hand-foot skin reaction, alopecia, pruritus, dry skin, Stevens-Johnson syndrome, toxic epidermal necrolysis), fatigue, weight loss, diarrhea, anorexia, abdominal pain, hypertension, hemorrhage, electrolyte abnormalities; druginduced hepatitis, QT prolongation. How supplied: Tabs–120

PHOTOFRIN Pinnacle Biologics

℞

Photosensitizing agent. Porfimer (as sodium) 75mg/vial; pwd for IV inj after reconstitution; preservative-free. Indications: Palliation of patients with completely obstructing esophageal cancer or partially obstructing esophageal cancer who cannot be satisfactorily treated with Nd:YAG laser therapy. Ablation of high-grade dysplasia in Barrett’s esophagus patients who do not undergo esophagectomy. Adults: See literature. Give by slow IV inj over 3–5 minutes. 2mg/kg then illumination with laser light 40–50 hours following injection. Esophageal cancer: 2nd course may be given at a minimum of 30 days after initial therapy; max 3 courses (separated by ≥30 days). Ablation of high-grade dysplasia in Barrett’s esophagus: 2nd course may be given at a minimum of 90 days after initial therapy; max 3 courses (separated by ≥90 days). Children: Not recommended. Contraindications: Porphyria. Existing tracheoesophageal or bronchoesophageal fistula. Tumors eroding into a major blood vessel. Emergency treatment of patients with severe acute respiratory distress caused by an obstructing endobronchial lesion. Esophageal or gastric varices. Esophageal ulcers >1cm in diameter. Warnings/Precautions: Avoid direct sunlight or bright indoor light; wear dark sunglasses when outdoors. Increased risk of fatal massive hemoptysis with large, centrally located tumors, cavitating tumors, extensive tumor extrinsic to the bronchus. Caution with endobronchial tumors in locations where treatment-induced inflammation could obstruct airway. Avoid extravasation. Pregnancy (Cat.C; use adequate contraception), nursing mothers: not recommended. Interactions: Increased risk of photosensitivity reactions with other photosensitizing agents (eg, tetracyclines, sulfonamides, phenothiazines, sulfonylurea hypoglycemic agents, thiazide diuretics, griseofulvin, fluoroquinolones). May be antagonized by dimethyl sulfoxide, β-carotene, ethanol, formate, mannitol, allopurinol, calcium channel blockers, prostaglandin synthesis

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DRUG MONOGRAPHS

GASTROINTESTINAL CANCER inhibitors, drugs that decreased clotting, vasoconstriction or platelet aggregation (eg, thromboxane A2 inhibitors), glucocorticoid hormones. Separate radiotherapy by 2–4 weeks. Adverse reactions: Photosensitivity reactions (eg, erythema, swelling, itching, burning sensation, feeling hot, blisters), fluid imbalance, chest pain, fever, pain, abdominal pain, GI upset, constipation, mucositis, ocular sensitivity, dyspnea, pleural effusion, anemia, fistula formation, fatal massive hemoptysis, others. How supplied: Vial–1

STIVARGA Bayer

℞

Kinase inhibitor. Regorafenib 40mg; tablets. Indications: Treatment of patients with metastatic colorectal cancer 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. Treatment of patients with locally advanced, unresectable or metastatic gastrointestinal stromal tumor (GIST) who have been previously treated with imatinib mesylate or sunitinib malate. Adults: Swallow whole with a low-fat breakfast (contains <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)

SUTENT Pfizer

℞

Multikinase inhibitor. Sunitinib (as malate) 12.5mg, 25mg, 37.5mg, 50mg; gelatin caps. Indications: Gastrointestinal stromal tumor (GIST) after disease progression on or intolerance to imatinib mesylate. Adults: 50mg once daily for 4 weeks, then 2 weeks off (see full labeling). May adjust dose in increments or decrements of 12.5mg. Concomitant strong CYP3A4 inhibitors (see Interactions): may reduce dose to 37.5mg daily. Concomitant strong CYP3A4 inducers (see Interactions): may increase to max 87.5mg daily. Children: Not established. Warnings/Precautions: Hepatotoxicity; may be severe or fatal. Monitor liver function tests before starting, during each cycle of treatment and as clinically needed; interrupt if Grade 3 or 4 hepatic adverse events occur and discontinue if no resolution; if severe liver function changes or signs/symptoms of failure, do not restart. Cardiovascular disease: monitor LVEF at baseline and periodically thereafter; 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, 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.

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DRUG MONOGRAPHS

GASTROINTESTINAL CANCER 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 Roche

Interactions: Potentiated by leucovorin. Monitor warfarin, other CYP2C9 substrates, phenytoin. Adverse reactions: Diarrhea, lymphopenia, necrotizing enterocolitis, hand-and-foot syndrome, GI upset, stomatitis, fatigue, dermatitis, anorexia, cardiotoxicity, bone marrow suppression, blood dyscrasias, hyperbilirubinemia, paresthesias, eye irritation, fever, headache, edema, dizziness, insomnia, myalgia, dehydration, nail disorder, limb pain, skin discoloration, alopecia. Testing considerations: TS (thymidylate synthase), MSI (microsatellite instability), DPD (dihydropyrimidine dehydrogenase) How supplied: Tabs 150mg–60; 500mg–120

ZALTRAP

℞

Regeneron and Sanofi Aventis

℞

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 literature. Give cyclically (2 weeks on, 1 week off). 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 literature); 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 recommended. Contraindications: Severe renal impairment (CrCl <30mL/min). Dihydropyrimidine dehydrogenase deficiency. Pregnancy (Cat.D), nursing mothers: not recommended. Warnings/Precautions: Hepatic or renal dysfunction. Coronary artery disease. Elderly (≥80years).

Fusion protein. Ziv-aflibercept 25mg/mL; soln for IV infusion after dilution; preservativefree. Indications: In combination with 5-fluorouracil, leucovorin, irinotecan (FOLFIRI) for patients with metastatic colorectal cancer (mCRC) that is resistant to or has progressed following an oxaliplatin-containing regimen. Adults: Start ziv-aflibercept prior to any component of the FOLFIRI regimen on treatment day. Give 4mg/kg as an IV infusion over 1hr every 2 weeks; continue until disease progression or unacceptable toxicity. For recurrent or severe hypertension, suspend until controlled. Upon resumption, permanently reduce to 2mg/kg. For recurrent proteinuria, suspend until proteinuria <2g per 24hrs, then permanently reduce to 2mg/kg. Children: Not established. Warnings/Precautions: Increased risk of hemorrhage; monitor for signs/symptoms. Do not start in patients with severe hemorrhage; discontinue if develops. Monitor for GI perforation, fistula formation, compromised wound healing; discontinue if occurs. Suspend therapy at least 4 weeks prior to elective surgery; do not resume for at least 4 weeks following major surgery and until wound is fully healed. Monitor BP every 2 weeks and treat appropriately if hypertension occurs; temporarily suspend until controlled; discontinue if hypertensive crisis/ encephalopathy occurs. Discontinue if arterial thromboembolic events (eg, transient ischemic attack, cerebrovascular accident, angina pectoris) occur. Monitor for proteinuria; suspend if proteinuria ≥2g per 24hrs; discontinue if nephrotic syndrome or thrombotic microangiopathy occurs. Monitor CBC with differential at baseline and prior to start of each cycle; delay until neutrophils ≥1.5×109/L. Risk of severe diarrhea and dehydration esp. in elderly (monitor). Discontinue if reversible posterior leukoencephalopathy syndrome occurs.

Pregnancy (Cat.C). Use effective contraception during and up to 3 months after the last dose. Nursing mothers: not recommended. Adverse reactions: Leukopenia, diarrhea, neutropenia, proteinuria, AST/ALT increased, stomatitis, fatigue, thrombocytopenia, hypertension, weight decreased, decreased appetite, epistaxis, abdominal pain, dysphonia, serum creatinine increased, headache. How supplied: Single-use vials (100mg/4mL)–1, 3; (200mg/8mL)–1

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.

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

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DRUG MONOGRAPHS

GENITOURINARY CANCER AFINITOR Novartis

℞

mTOR kinase inhibitor. Everolimus 2.5mg, 5mg, 7.5mg, 10mg; tabs. Indications: In adults with advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib. In adults with renal angiomyolipoma and tuberous sclerosis complex (TSC), not requiring immediate surgery. Adults: Swallow tabs whole with water. Take at the same time each day either consistently with or without food. 10mg once daily. Mild hepatic impairment (Child-Pugh class A): 7.5mg daily, may reduce to 5mg if not tolerated. Moderate hepatic impairment (Child-Pugh class B): 5mg daily, may be reduce to 2.5mg if not tolerated. Severe hepatic impairment (Child-Pugh class C): max 2.5mg daily if benefits outweigh risk. Concomitant moderate CYP3A4/PgP inhibitors: reduce to 2.5mg once daily; may consider increasing to 5mg if tolerated. If moderate inhibitor is discontinued, allow 2–3 days washout period before increasing everolimus dose; return to dose used prior to initiating the moderate inhibitor. Concomitant strong CYP3A4/PgP inducers: consider doubling the daily dose by increments of 5mg or less. If strong inducer is discontinued, consider washout period of 3–5 days before returning to the dose used prior to initiating the strong inducer. Continue therapy until disease progression or unacceptable toxicity occurs. Dose modifications for adverse reactions, or others: see full labeling. Children: Not recommended. Contraindications: Allergy to other rapamycin derivatives. Warnings/Precautions: Monitor for new or worsening respiratory symptoms. Increased risk of infections; some may be severe or fatal; monitor and treat promptly if occur. Pre-existing invasive fungal infections: treat before starting. Monitor for signs of wound-related complications. Peri-surgical period. Hepatic impairment (see Adult dose). Monitor CBCs, renal function, lipids, and blood glucose prior to starting and periodically thereafter. Avoid close contact with those who have received live vaccines. Pediatrics: complete childhood vaccination series according to ACIP guidelines prior to initiation. Elderly. Women of childbearing potential should use effective method of contraception during and up to 8 weeks after treatment. Pregnancy (Cat.D), nursing mothers: not recommended. Interactions: Avoid live vaccines. Potentiated by strong CYP3A4/PgP inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin,

ritonavir, indinavir, nelfinavir, voriconazole), grapefruit or grapefruit juice; avoid. Caution with moderate CYP3A4/PgP inhibitors (eg, amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem); reduce everolimus dose if used. Antagonized by strong CYP3A4/PgP inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital), St. John’s Wort; avoid. Adverse reactions: Pneumonitis (interrupt, reduce dose and/or manage with corticosteroids; if severe, discontinue; may reintroduce daily dose at approx. 50% lower than previously administered), infections (discontinue if invasive systemic fungal infection develops), stomatitis (treat with non-alcoholic, non-peroxide mouthwash), diarrhea, nausea, abdominal pain, rash, fatigue, edema, fever, asthenia, cough, headache, decreased appetite; increased serum creatinine, blood glucose, lipids; decreased hemoglobin, platelets, neutrophils, serum phosphate; proteinuria, renal failure, others (see full labeling). How supplied: Tabs–28 (4 blister cards × 7 tabs)

AVASTIN Genentech

℞

Angiogenesis inhibitor. Bevacizumab 100mg, 400mg; per vial; soln for IV infusion after dilution; preservative-free. Indications: Metastatic renal cell carcinoma (mRCC) in combination with interferon alfa. Adults: Give by IV infusion. Infuse 1st dose over 90 mins; if tolerated, infuse 2nd dose over 60 mins, and subsequent doses over 30 mins. 10mg/kg every 2 weeks with interferon alfa. Children: Not established. Warnings/Precautions: Do not start therapy before or for at least 28 days after surgery; allow surgical incisions to completely heal (see full labeling). History of hemoptysis of ≥ ½-teaspoon of red blood: do not administer. Discontinue if GI perforation, non-GI fistula formation, wound healing complications, serious hemorrhage, severe arterial or Grade 4 venous thromboembolic events, hypertensive crisis, nephrotic syndrome, or posterior reversible encephalopathy syndrome occurs; suspend therapy if severe hypertension, moderate to severe proteinuria (resume when <2g/24hrs), or severe infusion reaction occurs. Cardiovascular disease. Diabetes. Monitor BP every 2–3 weeks. Monitor proteinuria by dipstick urine analysis. Elderly. Increased risk of ovarian failure; inform females of reproductive potential prior to starting therapy. Pregnancy (Cat.C). Nursing mothers: not recommended. Adverse reactions: Epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration,

dry skin, rectal hemorrhage, lacrimation disorder, back pain, exfoliative dermatitis; GI perforation, wound dehiscence/impaired healing, necrotizing fasciitis (discontinue if occurs), hemorrhage, non-GI fistula formation, arterial or venous thromboembolic events, posterior reversible encephalopathy syndrome, infusion reactions, ovarian failure. How supplied: Single-use vial–1

CASODEX AstraZeneca

℞

Antiandrogen. Bicalutamide 50mg; tabs. Indications: In combination with luteinizing hormone-releasing hormone (LHRH) analogue in stage D2 metastatic prostate carcinoma. Adults: Take at the same time each day. 50mg daily. Start treatment at same time as starting LHRH analogue. Children: Not applicable. Contraindications: Women of childbearing potential. Pregnancy (Cat.X). Warnings/Precautions: Moderate to severe hepatic impairment. Monitor prostate specific antigen and hepatic function (discontinue if ALT >2×ULN or if jaundice occurs). Nursing mothers. Interactions: Monitor oral anticoagulants. Adverse reactions: Hot flashes, gynecomastia, breast pain, diarrhea, pain, asthenia, infection, dyspnea, impotence, loss of libido, others (see literature); rare: hepatitis. How supplied: Tabs–30, 100

DELESTROGEN JHP

℞

Estrogen. Estradiol valerate 10mg/mL (in a vehicle containing chlorobutanol 5mg and sesame oil), 20mg/mL (in a vehicle containing benzyl benzoate 224mg, benzyl alcohol 20mg, and castor oil), 40mg/mL (in a vehicle containing benzyl benzoate 447mg, benzyl alcohol 20mg, and castor oil); soln for IM inj. Indications: Advanced androgen-dependent carcinoma of the prostate (for palliation only). Adults: Give by deep IM inj into upper, outer quadrant of gluteal muscle. 30mg or more every 1 or 2 weeks. Children: Not applicable. Contraindications: Thrombophlebitis. Thromboembolic disorders. Cerebrovascular disorders. Abnormal undiagnosed genital bleeding. Estrogen-depended neoplasias. Liver dysfunction or disease. Pregnancy (Cat.X). Warnings/Precautions: Hepatic dysfunction. Conditions aggravated by fluid retention. Cardiovascular disorders, arterial vascular disease, and risks factors (eg, hypertension, diabetes, obesity, SLE). Familial

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DRUG MONOGRAPHS

GENITOURINARY CANCER 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

℞

Sanofi Aventis

GnRH analogue. Leuprolide acetate 7.5mg per inj; ext-rel susp; for SC inj. ℞ Also: ELIGARD 22.5mg 3-MONTH Leuprolide acetate 22.5mg per inj; ext-rel susp; for SC inj. ℞ Also: ELIGARD 30mg 4-MONTH Leuprolide acetate 30mg per inj; ext-rel susp; for SC inj. ℞ Also: ELIGARD 45mg 6-MONTH 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. Monitor serum testosterone, PSA periodically. Adverse reactions: Malaise, fatigue, hot flashes/sweats, testicular atrophy, gynecomastia, local reactions, asthenia, 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

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

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: Severe renal or hepatic impairment. Congenital long QT syndrome. Electrolyte imbalances. CHF. Monitor serum PSA. Discontinue if serious hypersensitivity reaction occurs; do not rechallenge. Nursing mothers: not recommended. Interactions: Caution with Class IA (eg, quinidine, procainamide) or Class III (eg, amiodarone, sotalol) antiarrhythmics.

Adverse reactions: Inj site reactions (eg, pain, erythema, swelling, induration), hot flashes, increased weight, fatigue, increased transaminases, increased gammaglutamyltransferase; QT prolongation. How supplied: Treatment Initiation pack (120mg/vial)–2 (w. supplies) Treatment Maintenance pack (80mg/vial)–1 (w. supplies)

Flutamide (various)

℞

Antiandrogen. Flutamide 125mg; caps. Indications: In combination with LHRH agonists (GnRH analogues) in locally confined stage B2–C and stage D2 metastatic prostate carcinoma. Adults: 250mg every 8 hrs. Children: Not applicable. Contraindications: Severe hepatic impairment. ALT ≥2×ULN: not recommended. Warnings/Precautions: Monitor liver function at baseline, monthly for first 4 months, then periodically, and if liver dysfunction occurs; if ALT >2×ULN or jaundice occurs, discontinue and monitor closely until resolution. Monitor prostate specific antigen (PSA). Consider monitoring methemoglobin levels in patients susceptible to aniline toxicity (eg, G6PD deficiency, smokers, hemoglobin M disease). Pregnancy (Cat.D); not for use in women. Interactions: Monitor warfarin. Adverse reactions: Diarrhea, hot flashes, loss of libido, impotence, GI disturbances, gynecomastia, rash, edema, hypertension, CNS effects, blood dyscrasias, urine discoloration, liver failure. How supplied: Contact supplier.

IFEX Baxter

℞

Alkylating agent. Ifosfamide 1g, 3g; per vial; pwd for IV infusion after reconstitution. Indications: Third-line adjunctive treatment of germ cell testicular cancer. 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.

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DRUG MONOGRAPHS

GENITOURINARY CANCER Adverse reactions: Alopecia, GI upset, hematuria, CNS toxicity, infection, renal or liver dysfunction, phlebitis, fever, urotoxicity (eg, hemorrhagic cystitis), leukopenia, thrombocytopenia. How supplied: Single-dose vials–1

INLYTA Pfizer

℞

Kinase inhibitor. Axitinib 1mg, 5mg; tabs. Indications: Treatment of advanced renal cell carcinoma (RCC) after failure of one prior systemic therapy. Adults: Take 12hrs apart. Swallow whole with a glass of water. Initially 5mg twice daily. If tolerated for at least two consecutive weeks with no adverse reactions >Grade 2, normotensive, and not receiving antihypertensives, may increase dose to 7mg twice daily, then 10mg twice daily. May reduce dose from 5mg twice daily to 3mg twice daily, then 2mg twice daily if additional dose reduction required. Concomitant strong CYP3A4/5 inhibitors: avoid; if warranted, decrease Inlyta dose by approximately ½. If strong CYP3A4/5 inhibitor discontinued, return Inlyta dose (after 3–5 half-lives of the inhibitor) to that used prior to CYP3A4/5 inhibitor initiation. Moderate hepatic impairment: decrease dose by approximately ½. Children: Not studied. Warnings/Precautions: Control and monitor BP prior to and during therapy; discontinue if severe and persistent hypertension (despite antihypertensive therapy and dose reduction). Risk of thromboembolic events. Untreated brain metastasis, recent active GI bleed: not recommended. Interrupt therapy if bleeding requires medical intervention. Monitor for signs/symptoms of cardiac failure during therapy; permanently discontinue if occurs. GI perforation and fistula formation; monitor. Monitor thyroid, liver function (ALT, AST, bilirubin), and for proteinuria before starting therapy, then periodically. Reduce dose or temporarily interrupt for moderate-to-severe proteinuria. Risk of reversible posterior leukoencephalopathy syndrome (discontinue if occurs). Stop treatment at least 24hrs prior to scheduled surgery. Severe hepatic impairment. End-stage renal disease. Pregnancy (Cat.D); avoid. Use adequate contraception during therapy. Nursing mothers: not recommended. Interactions: See Adult dose. Avoid strong CYP3A4/5 inhibitors (eg, grapefruit juice, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin,

voriconazole), CYP3A4/5 inducers (eg, rifampin, dexamethasone, phenytoin, carbamazepine, rifabutin, rifapentin, phenobarbital, St. John’s wort), moderate CYP3A4/5 inducers (eg, bosentan, efavirenz, etravirine, modafinil, nafcillin). Adverse reactions: Diarrhea, nausea, vomiting, hypertension, fatigue, decreased appetite, dysphonia, palmar-plantar erythrodysesthesia (hand-foot) syndrome, weight decreased, asthenia, constipation. How supplied: Tabs 1mg–180; 5mg–60

JEVTANA Sanofi Aventis

℞

Antimicrotubule agent. Cabazitaxel 60mg/1.5mL; soln for IV infusion after dilution; contains polysorbate 80, diluent contains ethanol. Indications: In combination with prednisone, hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing regimen. Adults: Pretreat with IV antihistamine, corticosteroid, and H2 blocker 30 mins before each dose (see full labeling) and with antiemetic (IV or oral as needed). 25mg/m2 by IV infusion over 1hr every 3 weeks, with oral prednisone 10mg/day during treatment. Do not treat if neutrophil count ≤1,500 cells/mm3. Prolonged grade ≥3 neutropenia (>1 week), febrile neutropenia, grade ≥3 diarrhea: delay treatment and/or reduce dose to 20mg/m2 (see full labeling). Discontinue if reactions persist after dosing at 20mg/m2. Children: Not established. Contraindications: Baseline neutrophil count ≤1,500cells/mm3. Allergy to polysorbate 80. Warnings/Precautions: Do CBC weekly in 1st cycle and before each subsequent cycle. Increased risk of neutropenia complications; consider G-CSF prophylaxis. Discontinue if hypersensitivity reactions occur. Increased risk of GI disorders in patients with neutropenia, age, or history of pelvic radiotherapy, adhesions, ulceration, and GI bleeding. Evaluate and treat if serious GI toxicity occurs; treatment delay or discontinuation may be needed. Hepatic impairment: not recommended. Severe renal impairment (CrCl <30mL/min) or ESRD. Elderly (increased susceptibility to adverse reactions); monitor closely. Pregnancy (Cat.D); avoid. Nursing mothers: not recommended. Interactions: Avoid concomitant strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) (may potentiate cabazitaxel); caution with moderate CYP3A4 inhibitors. Avoid

concomitant strong CYP3A4 inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital) (may antagonize cabazitaxel). Avoid St. John’s Wort. Increased GI toxicity with concomitant steroids, NSAIDs, antiplatelets, anticoagulants. Adverse reactions: Bone marrow suppression (esp. neutropenia, anemia, leukopenia, thrombocytopenia), febrile neutropenia, diarrhea (may be fatal), nausea, vomiting, constipation, fatigue, asthenia, abdominal pain, hematuria, back pain, anorexia, peripheral neuropathy, pyrexia, dyspnea, dysgeusia, cough, arthralgia, alopecia; renal failure, hypersensitivity reactions (eg, rash, hypotension, bronchospasm). How supplied: Kit (single-use vial + diluent)–1

Leuprolide acetate (various)

℞

GnRH analogue. Leuprolide acetate 5mg/mL; soln for SC inj; contains benzyl alcohol. Indications: Palliative treatment of advanced prostatic carcinoma. Adults: 1mg SC daily. Rotate inj site. Children: Not applicable. Contraindications: Women. 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. Risk of QT prolongation: long-term androgen deprivation therapy, congenital long QT syndrome, electrolyte abnormalities, or CHF, and concomitant Class IA or III antiarrhythmics. Instruct patient on correct self administration. Interactions: Concomitant Class IA (eg, quinidine, procainamide) or Class III (eg, amiodarone, sotalol) 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 upset, pain, cardiovascular events, CNS and antiandrogenic effects, asthenia, spinal cord compression; hyperglycemia, anaphylactoid, photosensitivity. How supplied: Contact supplier.

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.

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CancerTherapyAdvisor.com | MAY/JUNE 2015 | CANCER THERAPY ADVISOR 39

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DRUG MONOGRAPHS

GENITOURINARY CANCER ℞ Also: LUPRON DEPOT-6 MONTH 45mg Leuprolide acetate 45mg; depot susp for IM inj. Adults: 45mg as single IM inj every 6 months (24 weeks). Do not split doses. Children: Not applicable. ℞ Also: LUPRON DEPOT-3 MONTH 22.5mg Leuprolide acetate 22.5mg; depot susp for IM inj. Adults: 22.5mg IM inj every 3 months (84 days). Do not split doses. Children: Not applicable. ℞ Also: LUPRON DEPOT-4 MONTH 30mg Leuprolide acetate 30mg; depot susp for IM inj; preservative-free. Adults: 30mg as single IM inj every 4 months (16 weeks). Do not split doses. Children: Not applicable. Contraindications: Pregnancy (Cat.X). Warnings/Precautions: Metastatic vertebral lesions. Urinary obstruction. Monitor serum testosterone, PSA, acid phosphatase. Increased risk of diabetes, MI, sudden cardiac death, stroke; monitor blood glucose, HbA1c, and for signs/ symptoms of CVD during therapy. History of seizures. Risk of QT prolongation: long-term androgen deprivation therapy, congenital long QT syndrome, electrolyte abnormalities, or CHF. Correct and monitor electrolyte abnormalities; consider monitoring ECGs. Instruct patient on correct self administration. Nursing mothers: not recommended. Interactions: Concomitant antiarrhythmics may prolong the QT interval. Adverse reactions: Hot flashes/sweats, inj site reaction, initial worsening of signs/symptoms (eg, bone pain, urinary tract obstruction, hematuria), edema, GI disorders, pain, cardiovascular events, CNS and antiandrogenic effects, asthenia, testicular atrophy, urinary disorders, spinal cord compression; hyperglycemia, anaphylactoid, photosensitivity. How supplied: Depot kit–1 (prefilled dualchamber syringe w. supplies)

MENEST Pfizer

℞

Estrogen. Esterified estrogens 0.3mg, 0.625mg, 1.25mg, 2.5mg; tabs. Indications: Palliative treatment of androgendependent advanced prostate cancer. Adults: 1.25–2.5mg 3 times daily. Children: Not applicable. Contraindications: Thrombophlebitis. Thromboembolic disorders. Cerebrovascular or coronary artery disease. Pregnancy (Cat.X). Warnings/Precautions: Hepatic dysfunction. Gallbladder disease. Conditions aggravated by fluid retention. Familial hyperlipoproteinemia. Discontinue if jaundice occurs. Nursing mothers. Adverse reactions: See literature. Migraine, depression, edema, weight changes, hypertension, GI upset, gynecomastia, impotence. How supplied: Tabs 2.5mg–50 0.3mg, 0.625mg, 1.25mg–100

Mitoxantrone HCl (various)

℞

Topoisomerase II inhibitor. Mitoxantrone (as HCl) 2mg/mL; soln for IV infusion after dilution; preservative-free. Indications: Treatment of pain in advanced hormone-refractory prostrate cancer in combination with corticosteroids. Adults: Give as a short IV infusion. 12–14mg/m2 every 21 days. Children: Not established. Warnings/Precautions: Risk of myelosuppression esp. in high doses (>14mg/m2 daily for 3 days); do not administer if baseline neutrophil count <1500 cell/mm3, except in ANLL. Increased risk of cardiotoxicity with pre-existing cardiovascular disease, prior radiotherapy to mediastinal/pericardial area, or previous anthracycline therapy. Assess cardiac history, physical exam, ECG, and LVEF prior to therapy. Increased risk of secondary acute myeloid leukemia. Hepatic impairment. Monitor CBCs, platelets, liver function tests prior to each course. Monitor for signs of infection. Avoid extravasation. Pregnancy (Cat.D); avoid. Nursing mothers: not recommended. Interactions: Caution with concomitant cardiotoxic drugs. Adverse reactions: Myelosuppression, nausea, vomiting, infection, fever, fatigue, alopecia, dyspnea, hypersensitivity reactions, bluishgreen urine, sclera discoloration, hyperuricemia (monitor), menstrual disorders, amenorrhea, interstitial pneumonitis; cardiotoxicity (eg, CHF). How supplied: Contact supplier.

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

NILANDRON Covis

℞

Antiandrogen. Nilutamide 150mg; tabs. Indications: Metastatic prostate cancer (Stage D2), as an adjunct to surgical castration. Adults: 300mg once daily for 30 days then 150mg once daily, starting day of or day after surgical castration. Children: Not applicable. Contraindications: Severe hepatic impairment or respiratory insufficiency. Warnings/Precautions: Obtain baseline liver and pulmonary function tests and chest X-ray. Monitor for interstitial pneumonitis; discontinue if occurs. Monitor liver function for first 4 months then periodically; discontinue if ALT > 2×ULN or jaundice occurs. May discolor urine or sclera. Pregnancy (Cat.C): not for use in women. Nursing mothers. Interactions: Monitor drugs metabolized by CYP450 (eg, Vit. K antagonists, theophylline, phenytoin); may need to adjust dose. May cause alcohol intolerance. Adverse reactions: Hot flushes, impaired night vision, GI upset, increased liver enzymes, constipation, dizziness, abnormal vision, hypertension, hepatitis, interstitial pneumonitis. How supplied: Tabs–30

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

40 CANCER THERAPY ADVISOR | MAY/JUNE 2015 | CancerTherapyAdvisor.com

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In men with mCRPC who progressed on ADT

The story for ZYTIGA® has significantly evolved. Presenting…

mCRPC = metastatic castration-resistant prostate cancer; ADT = androgen-deprivation therapy.

INDICATION

Contraindications—ZYTIGA® is not indicated for use in women. ZYTIGA® can cause fetal harm (Pregnancy Category X) when administered to a pregnant woman and is contraindicated in women who are or may become pregnant. Hypertension, Hypokalemia, and Fluid Retention Due to Mineralocorticoid Excess—Use with caution in patients with a history of cardiovascular disease or with medical conditions that might be compromised by increases in blood pressure, hypokalemia, or fluid retention. ZYTIGA® may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition. Safety has not been established in patients with LVEF <50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in Study 2) because these patients were excluded from these randomized clinical trials. Control hypertension and correct hypokalemia before and during treatment. Monitor blood pressure, serum potassium, and symptoms of fluid retention at least monthly. Adrenocortical Insufficiency (AI)—AI was reported in patients receiving ZYTIGA® in combination with prednisone, after an interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of AI if prednisone is stopped or withdrawn, if prednisone dose is reduced, or if the patient experiences unusual stress. Symptoms and signs of AI may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA®. Perform appropriate tests, if indicated, to confirm AI. Increased dosages of corticosteroids may be used before, during, and after stressful situations. Hepatotoxicity—Monitor liver function and modify, withhold, or discontinue ZYTIGA® dosing as recommended (see Prescribing Information for more information). Measure serum transaminases [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] and bilirubin levels prior to starting treatment with ZYTIGA®, every two weeks for the first three months of treatment, and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the upper limit of normal (ULN) or the bilirubin rises above three times the ULN, interrupt ZYTIGA® treatment and closely monitor liver function. Please see additional Important Safety Information on the next pages. Please see brief summary of full Prescribing Information on subsequent pages.

Date: 05/27/15 Customer Code: 028723-150129 File Name: 028723-150129_730460_v1 (pg 1 Right Hand Start) Size: 7.75" x 10.5" Colors: CMYK Description: Zytiga PRO 302 A size Master Pub: Cancer Therapy Advisor Online Edition (7/1/15 Online Issue) K

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IMPORTANT SAFETY INFORMATION

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ZYTIGA® (abiraterone acetate) in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC).

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In men with mCRPC who progressed on ADT, consider ZYTIGA® (abiraterone acetate) first.

Final analysis of the pivotal phase 3 trial.*

Every day tells a story.

*Study Design: ZYTIGA®, in combination with prednisone, was evaluated in a phase 3, randomized, double-blind, placebo-controlled, multicenter trial in patients with mCRPC who had not received prior chemotherapy (N=1,088). Patients were using a luteinizing hormone-releasing hormone (LHRH) agonist or were previously treated with orchiectomy. In the ZYTIGA® arm, patients received ZYTIGA® 1,000 mg orally once daily + prednisone 5 mg orally twice daily. In the placebo arm, patients received placebo orally once daily + prednisone 5 mg orally twice daily. In this study, the co-primary efficacy end points were OS and radiographic progression-free survival (rPFS). Select exclusion criteria included AST and/or ALT ≥ 2.5X ULN, liver metastases, moderate or severe pain, opiate use for cancer pain, and visceral organ metastases. † At a prespecified final analysis for OS, 65% (354/546) of patients treated with ZYTIGA® + prednisone compared with 71% (387/542) of patients treated with placebo + prednisone had died. ‡Prednisone, as a single agent, is not approved for the treatment of prostate cancer. § rPFS was assessed with the use of sequential imaging studies and was defined by bone scan identification of 2 or more new bone lesions with confirmation (Prostate Cancer Working Group 2 [PCWG2] criteria) and/or modified Response Evaluation Criteria In Solid Tumors (RECIST) criteria for progression of soft tissue lesions. Analysis of rPFS utilized centrally reviewed radiographic assessment of progression. IIAt the prespecified rPFS analysis, 150 (28%) of patients treated with ZYTIGA® + prednisone and 251 (46%) of patients treated with placebo + prednisone had radiographic progression.

Please see brief summary of full Prescribing Information on subsequent pages.

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2015 3/15 028723-150129

Date: 05/27/15 Customer Code: 028723-150129 File Name: 028723-150129_730460_v1 (pg 2 Left Hand) Size: 7.75" x 10.5" Colors: CMYK Description: Zytiga PRO 302 A size Master Pub: Cancer Therapy Advisor Online Edition (7/1/15 Online Issue) K

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Increased ZYTIGA® Exposures With Food—ZYTIGA® must be taken on an empty stomach. No food should be eaten for at least two hours before the dose of ZYTIGA® is taken and for at least one hour after the dose of ZYTIGA® is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state. Adverse Reactions—The most common adverse reactions (≥10%) are fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection, and contusion. The most common laboratory abnormalities (>20%) are anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT, and hypokalemia.

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IMPORTANT SAFETY INFORMATION

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After a median 4 years (49 months) of follow-up…

ZYTIGA® (abiraterone acetate) + prednisone achieved a median overall survival (OS) of almost 3 years (34.7 months).1† • 4.4 months improvement in median OS—34.7 months with ZYTIGA® + prednisone vs 30.3 months with placebo + prednisone (active compound)‡ Co-primary end point—median OS: hazard ratio (HR)=0.81; 95% CI: 0.70, 0.93; P=0.0033. Co-primary end point—rPFS: median not reached for ZYTIGA® + prednisone vs a median of 8.28 months for placebo + prednisone; HR=0.425; 95% CI: 0.347, 0.522; P<0.0001.§II

With a median 49 months of follow-up, there were no notable changes in the safety profile of ZYTIGA® + prednisone since the previously reported interim analyses.1 In your patients with mCRPC…

CONSIDER ZYTIGA® FIRST.

003307-150130

Learn more today at

www.zytigahcp.com.

Every day tells a story.

Date: 05/27/15 Customer Code: 028723-150129 File Name: 028723-150129_730460_v1 (pg 3 Right Hand) Size: 7.75" x 10.5" Colors: CMYK Description: Zytiga PRO 302 A size Master Pub: Cancer Therapy Advisor Online Edition (7/1/15 Online Issue) K

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Reference: 1. Ryan CJ, Smith MR, Fizazi K, et al; for the COU-AA-302 Investigators. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2015;16(2):152-160.

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Drug Interactions—Based on in vitro data, ZYTIGA® is a substrate of CYP3A4. In a drug interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%. Avoid concomitant strong CYP3A4 inducers during ZYTIGA® treatment. If a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA® dosing frequency only during the co-administration period [see Dosage and Administration (2.3)]. In a dedicated drug interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone. ZYTIGA® is an inhibitor of the hepatic drug-metabolizing enzymes CYP2D6 and CYP2C8. Avoid co-administration with CYP2D6 substrates with a narrow therapeutic index. If alternative treatments cannot be used, exercise caution and consider a dose reduction of the CYP2D6 substrate drug. In a CYP2C8 drug interaction trial in healthy subjects, the AUC of pioglitazone, a CYP2C8 substrate, was increased by 46% when administered with a single dose of ZYTIGA®. Patients should be monitored closely for signs of toxicity related to a CYP2C8 substrate with a narrow therapeutic index if used concomitantly with ZYTIGA®. Use in Specific Populations—Do not use ZYTIGA® in patients with baseline severe hepatic impairment (Child-Pugh Class C).

ZYTIGA® (abiraterone acetate) Tablets Brief Summary of Prescribing Information. INDICATIONS AND USAGE ZYTIGA is a CYP17 inhibitor indicated in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer. CONTRAINDICATIONS Pregnancy: ZYTIGA can cause fetal harm when administered to a pregnant woman. ZYTIGA is not indicated for use in women. ZYTIGA 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 and the potential risk for pregnancy loss [see Use in Specific Populations]. WARNINGS AND PRECAUTIONS Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess: ZYTIGA may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see Clinical Pharmacology (12.1) in full Prescribing Information]. In the two randomized clinical trials, grade 3 to 4 hypertension occurred in 2% of patients, grade 3 to 4 hypokalemia in 4% of patients, and grade 3 to 4 edema in 1% of patients treated with ZYTIGA [see Adverse Reactions]. Co-administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in the incidence and severity of these adverse reactions. Use caution when treating patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia or fluid retention, e.g., those with heart failure, recent myocardial infarction or ventricular arrhythmia. Use ZYTIGA with caution in patients with a history of cardiovascular disease. The safety of ZYTIGA in patients with left ventricular ejection fraction <50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in Study 2) was not established because these patients were excluded from these randomized clinical trials [see Clinical Studies (14) in full Prescribing Information]. Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment with ZYTIGA. Adrenocortical Insufficiency: Adrenal insufficiency occurred in the two randomized clinical studies in 0.5% of patients taking ZYTIGA and in 0.2% of patients taking placebo. Adrenocortical insufficiency was reported in patients receiving ZYTIGA in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations [see Warnings and Precautions]. Hepatotoxicity: In the two randomized clinical trials, grade 3 or 4 ALT or AST increases (at least 5X ULN) were reported in 4% of patients who received ZYTIGA, typically during the first 3 months after starting treatment. Patients whose baseline ALT or AST were elevated were more likely to experience liver test elevation than those beginning with normal values. Treatment discontinuation due to liver enzyme increases occurred in 1% of patients taking ZYTIGA. No deaths clearly related to ZYTIGA were reported due to hepatotoxicity events. Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA, every two weeks for the first three months of treatment and monthly thereafter. In patients with baseline moderate hepatic impairment receiving a reduced ZYTIGA dose of 250 mg, measure ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every two weeks for the following two months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the ULN, or the bilirubin rises above three times the ULN, interrupt ZYTIGA treatment and closely monitor liver function. Re-treatment with ZYTIGA at a reduced dose level may take place only after return of liver function tests to the patient’s baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN [see Dosage and Administration (2.2) in full Prescribing Information]. The safety of ZYTIGA re-treatment of patients who develop AST or ALT greater than or equal to 20X ULN and/or bilirubin greater than or equal to 10X ULN is unknown. ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: • Hypertension, Hypokalemia, and Fluid Retention due to Mineralocorticoid Excess [see Warnings and Precautions]. • Adrenocortical Insufficiency [see Warnings and Precautions]. • Hepatotoxicity [see Warnings and Precautions].

ZYTIGA® (abiraterone acetate) Tablets Clinical Trial Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Two randomized placebo-controlled, multicenter clinical trials enrolled patients who had metastatic castration-resistant prostate cancer who were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy. In both Study 1 and Study 2 ZYTIGA was administered at a dose of 1,000 mg daily in combination with prednisone 5 mg twice daily in the active treatment arms. Placebo plus prednisone 5 mg twice daily was given to control patients. The most common adverse drug reactions (≥10%) reported in the two randomized clinical trials that occurred more commonly (>2%) in the abiraterone acetate arm were fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion. The most common laboratory abnormalities (>20%) reported in the two randomized clinical trials that occurred more commonly (≥2%) in the abiraterone acetate arm were anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT and hypokalemia. Study 1: Metastatic CRPC Following Chemotherapy: Study 1 enrolled 1195 patients with metastatic CRPC who had received prior docetaxel chemotherapy. Patients were not eligible if AST and/or ALT ≥2.5X ULN in the absence of liver metastases. Patients with liver metastases were excluded if AST and/or ALT >5X ULN. Table 1 shows adverse reactions on the ZYTIGA arm in Study 1 that occurred with a ≥2% absolute increase in frequency compared to placebo or were events of special interest. The median duration of treatment with ZYTIGA was 8 months. Table 1: Adverse Reactions due to ZYTIGA in Study 1 ZYTIGA with Placebo with Prednisone (N=791) Prednisone (N=394) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % Musculoskeletal and connective tissue disorders Joint swelling/ discomfort2 29.5 4.2 23.4 4.1 Muscle discomfort3 26.2 3.0 23.1 2.3 General disorders Edema4 26.7 1.9 18.3 0.8 Vascular disorders Hot flush 19.0 0.3 16.8 0.3 Hypertension 8.5 1.3 6.9 0.3 Gastrointestinal disorders Diarrhea 17.6 0.6 13.5 1.3 Dyspepsia 6.1 0 3.3 0 Infections and infestations Urinary tract infection 11.5 2.1 7.1 0.5 Upper respiratory tract infection 5.4 0 2.5 0 Respiratory, thoracic and mediastinal disorders Cough 10.6 0 7.6 0 Renal and urinary disorders Urinary frequency 7.2 0.3 5.1 0.3 Nocturia 6.2 0 4.1 0 Injury, poisoning and procedural complications Fractures5 5.9 1.4 2.3 0 Cardiac disorders Arrhythmia6 7.2 1.1 4.6 1.0 Chest pain or chest discomfort7 3.8 0.5 2.8 0 Cardiac failure8 2.3 1.9 1.0 0.3

ZYTIGA® (abiraterone acetate) Tablets 1 Adverse events graded according to CTCAE version 3.0 2 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness 3 Includes terms Muscle spasms, Musculoskeletal pain, Myalgia,

Musculoskeletal discomfort, and Musculoskeletal stiffness terms Edema, Edema peripheral, Pitting edema, and Generalized edema 5 Includes all fractures with the exception of pathological fracture 6 Includes terms Arrhythmia, Tachycardia, Atrial ﬁbrillation, Supraventricular tachycardia, Atrial tachycardia, Ventricular tachycardia, Atrial ﬂutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Bradyarrhythmia 7 Includes terms Angina pectoris, Chest pain, and Angina unstable. Myocardial infarction or ischemia occurred more commonly in the placebo arm than in the ZYTIGA arm (1.3% vs. 1.1% respectively). 8 Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased 4 Includes

Table 2 shows laboratory abnormalities of interest from Study 1. Grade 3-4 low serum phosphorus (7%) and low potassium (5%) occurred at a greater than or equal to 5% rate in the ZYTIGA arm. Table 2: Laboratory Abnormalities of Interest in Study 1 Abiraterone (N=791) Placebo (N=394) Laboratory All Grades Grade 3-4 All Grades Grade 3-4 Abnormality (%) (%) (%) (%) Hypertriglyceridemia 62.5 0.4 53.0 0 High AST 30.6 2.1 36.3 1.5 Hypokalemia 28.3 5.3 19.8 1.0 Hypophosphatemia 23.8 7.2 15.7 5.8 High ALT 11.1 1.4 10.4 0.8 High Total Bilirubin 6.6 0.1 4.6 0 Study 2: Metastatic CRPC Prior to Chemotherapy: Study 2 enrolled 1088 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy. Patients were ineligible if AST and/or ALT ≥2.5X ULN and patients were excluded if they had liver metastases. Table 3 shows adverse reactions on the ZYTIGA arm in Study 2 that occurred with a ≥2% absolute increase in frequency compared to placebo. The median duration of treatment with ZYTIGA was 13.8 months. Table 3: Adverse Reactions in ≥5% of Patients on the ZYTIGA Arm in Study 2 ZYTIGA with Placebo with Prednisone (N=542) Prednisone (N=540) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % General disorders Fatigue 39.1 2.2 34.3 1.7 Edema2 25.1 0.4 20.7 1.1 Pyrexia 8.7 0.6 5.9 0.2 Musculoskeletal and connective tissue disorders Joint swelling/ discomfort3 30.3 2.0 25.2 2.0 Groin pain 6.6 0.4 4.1 0.7 Gastrointestinal disorders Constipation 23.1 0.4 19.1 0.6 Diarrhea 21.6 0.9 17.8 0.9 Dyspepsia 11.1 0.0 5.0 0.2 Vascular disorders Hot ﬂush 22.3 0.2 18.1 0.0 Hypertension 21.6 3.9 13.1 3.0 Respiratory, thoracic and mediastinal disorders Cough 17.3 0.0 13.5 0.2 Dyspnea 11.8 2.4 9.6 0.9 Psychiatric disorders Insomnia 13.5 0.2 11.3 0.0 Injury, poisoning and procedural complications Contusion 13.3 0.0 9.1 0.0 Falls 5.9 0.0 3.3 0.0 Infections and infestations Upper respiratory tract infection 12.7 0.0 8.0 0.0 Nasopharyngitis 10.7 0.0 8.1 0.0

ZYTIGA® (abiraterone acetate) Tablets Table 3: Adverse Reactions in ≥5% of Patients on the ZYTIGA Arm in Study 2 (continued) ZYTIGA with Placebo with Prednisone (N=542) Prednisone (N=540) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % Renal and urinary disorders Hematuria 10.3 1.3 5.6 0.6 Skin and subcutaneous tissue disorders Rash 8.1 0.0 3.7 0.0 1 Adverse events graded according to CTCAE version 3.0 2 Includes terms Edema peripheral, Pitting edema, and Generalized edema 3 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness Table 4 shows laboratory abnormalities that occurred in greater than 15% of patients, and more frequently (>5%) in the ZYTIGA arm compared to placebo in Study 2. Grade 3-4 lymphopenia (9%), hyperglycemia (7%) and high alanine aminotransferase (6%) occurred at a greater than 5% rate in the ZYTIGA arm. Table 4: Laboratory Abnormalities in >15% of Patients in the ZYTIGA Arm of Study 2 Abiraterone (N=542) Placebo (N=540) Laboratory Grade 1-4 Grade 3-4 Grade 1-4 Grade 3-4 Abnormality % % % % Hematology Lymphopenia 38.2 8.7 31.7 7.4 Chemistry Hyperglycemia1 56.6 6.5 50.9 5.2 High ALT 41.9 6.1 29.1 0.7 High AST 37.3 3.1 28.7 1.1 Hypernatremia 32.8 0.4 25.0 0.2 Hypokalemia 17.2 2.8 10.2 1.7 1Based on non-fasting blood draws Cardiovascular Adverse Reactions: In the combined data for studies 1 and 2, cardiac failure occurred more commonly in patients treated with ZYTIGA compared to patients on the placebo arm (2.1% versus 0.7%). Grade 3-4 cardiac failure occurred in 1.6% of patients taking ZYTIGA and led to 5 treatment discontinuations and 2 deaths. Grade 3-4 cardiac failure occurred in 0.2% of patients taking placebo. There were no treatment discontinuations and one death due to cardiac failure in the placebo group. In Study 1 and 2, the majority of arrhythmias were grade 1 or 2. There was one death associated with arrhythmia and one patient with sudden death in the ZYTIGA arms and no deaths in the placebo arms. There were 7 (0.5%) deaths due to cardiorespiratory arrest in the ZYTIGA arms and 3 (0.3%) deaths in the placebo arms. Myocardial ischemia or myocardial infarction led to death in 3 patients in the placebo arms and 2 deaths in the ZYTIGA arms. Post Marketing Experience The following additional adverse reactions have been identiﬁed during post approval use of ZYTIGA. 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. Respiratory, Thoracic and Mediastinal Disorders: non-infectious pneumonitis. Musculoskeletal and Connective Tissue Disorders: myopathy, including rhabdomyolysis. DRUG INTERACTIONS Drugs that Inhibit or Induce CYP3A4 Enzymes: Based on in vitro data, ZYTIGA is a substrate of CYP3A4. In a dedicated drug interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%. Avoid concomitant strong CYP3A4 inducers during ZYTIGA treatment. If a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA dosing frequency [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) in full Prescribing Information]. In a dedicated drug interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone [see Clinical Pharmacology (12.3) in full Prescribing Information]. Effects of Abiraterone on Drug Metabolizing Enzymes: ZYTIGA is an inhibitor of the hepatic drug-metabolizing enzymes CYP2D6 and CYP2C8. In

ZYTIGA® (abiraterone acetate) Tablets

a CYP2D6 drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively, when dextromethorphan was given with abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily. Avoid co-administration of abiraterone acetate with substrates of CYP2D6 with a narrow therapeutic index (e.g., thioridazine). If alternative treatments cannot be used, exercise caution and consider a dose reduction of the concomitant CYP2D6 substrate drug [see Clinical Pharmacology (12.3) in full Prescribing Information]. In a CYP2C8 drug-drug interaction trial in healthy subjects, the AUC of pioglitazone (CYP2C8 substrate) was increased by 46% when pioglitazone was given together with a single dose of 1,000 mg abiraterone acetate. Therefore, patients should be monitored closely for signs of toxicity related to a CYP2C8 substrate with a narrow therapeutic index if used concomitantly with ZYTIGA [see Clinical Pharmacology (12.3) in full Prescribing Information].

For patients who develop hepatotoxicity during treatment, interruption of treatment and dosage adjustment may be required [see Dosage and Administration (2.2) in full Prescribing Information, Warnings and Precautions, and Clinical Pharmacology (12.3)] in full Prescribing Information. Patients with Renal Impairment: In a dedicated renal impairment trial, the mean PK parameters were comparable between healthy subjects with normal renal function (N=8) and those with end stage renal disease (ESRD) on hemodialysis (N=8) after a single oral 1,000 mg dose of ZYTIGA. No dosage adjustment is necessary for patients with renal impairment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information]. OVERDOSAGE Human experience of overdose with ZYTIGA is limited. There is no speciﬁc antidote. In the event of an overdose, stop ZYTIGA, undertake general supportive measures, including monitoring for arrhythmias and cardiac failure and assess liver function. Storage and Handling: Store at 20°C to 25°C (68°F to 77°F); excursions permitted in the range from 15°C to 30°C (59°F to 86°F) [see USP controlled room temperature]. Based on its mechanism of action, ZYTIGA may harm a developing fetus. Therefore, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves [see Use in Speciﬁc Populations]. PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information) • Patients should be informed that ZYTIGA and prednisone are used together and that they should not interrupt or stop either of these medications without consulting their physician. • Patients receiving GnRH agonists should be informed that they need to maintain this treatment during the course of treatment with ZYTIGA and prednisone. • Patients should be informed that ZYTIGA should not be taken with food and that no food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. They should be informed that the tablets should be swallowed whole with water without crushing or chewing. Patients should be informed that taking ZYTIGA with food causes increased exposure and this may result in adverse reactions. • Patients should be informed that ZYTIGA is taken once daily and prednisone is taken twice daily according to their physician’s instructions. • Patients should be informed that in the event of a missed daily dose of ZYTIGA or prednisone, they should take their normal dose the following day. If more than one daily dose is skipped, patients should be told to inform their physician. • Patients should be apprised of the common side effects associated with ZYTIGA, including peripheral edema, hypokalemia, hypertension, elevated liver function tests, and urinary tract infection. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION. • Patients should be advised that their liver function will be monitored using blood tests. • Patients should be informed that ZYTIGA may harm a developing fetus; thus, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves. Patients should also be informed that it is not known whether abiraterone or its metabolites are present in semen and they should use a condom if having sex with a pregnant woman. The patient should use a condom and another effective method of birth control if he is having sex with a woman of child-bearing potential. These measures are required during and for one week after treatment with ZYTIGA.

USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category X [see Contraindications].: ZYTIGA can cause fetal harm when administered to a pregnant woman based on its mechanism of action and ﬁndings in animals. While there are no adequate and well-controlled studies with ZYTIGA in pregnant women and ZYTIGA is not indicated for use in women, it is important to know that maternal use of a CYP17 inhibitor could affect development of the fetus. Abiraterone acetate caused developmental toxicity in pregnant rats at exposures that were lower than in patients receiving the recommended dose. ZYTIGA 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 ZYTIGA. In an embryo-fetal developmental toxicity study in rats, abiraterone acetate caused developmental toxicity when administered at oral doses of 10, 30 or 100 mg/kg/day throughout the period of organogenesis (gestational days 6-17). Findings included embryo-fetal lethality (increased post implantation loss and resorptions and decreased number of live fetuses), fetal developmental delay (skeletal effects) and urogenital effects (bilateral ureter dilation) at doses ≥10 mg/kg/day, decreased fetal ano-genital distance at ≥30 mg/kg/day, and decreased fetal body weight at 100 mg/kg/day. Doses ≥10 mg/kg/day caused maternal toxicity. The doses tested in rats resulted in systemic exposures (AUC) approximately 0.03, 0.1 and 0.3 times, respectively, the AUC in patients. Nursing Mothers: ZYTIGA is not indicated for use in women. It is not known if abiraterone acetate 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 ZYTIGA, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother. Pediatric Use: Safety and effectiveness of ZYTIGA in pediatric patients have not been established. Geriatric Use: Of the total number of patients receiving ZYTIGA in Phase 3 trials, 73% of patients were 65 years and over and 30% were 75 years and over. No overall differences in safety or effectiveness were observed between these elderly patients and younger patients. 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. Patients with Hepatic Impairment: The pharmacokinetics of abiraterone were examined in subjects with baseline mild (N=8) or moderate (N=8) hepatic impairment (Child-Pugh Class A and B, respectively) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone after a single oral 1,000 mg dose of ZYTIGA increased by approximately 1.1-fold and 3.6-fold in subjects with mild and moderate baseline hepatic impairment, respectively compared to subjects with normal hepatic function. In another trial, the pharmacokinetics of abiraterone were examined in subjects with baseline severe (N=8) hepatic impairment (Child-Pugh Class C) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone increased by approximately 7-fold and the fraction of free drug increased 2-fold in subjects with severe baseline hepatic impairment compared to subjects with normal hepatic function. No dosage adjustment is necessary for patients with baseline mild hepatic impairment. In patients with baseline moderate hepatic impairment (ChildPugh Class B), reduce the recommended dose of ZYTIGA to 250 mg once daily. Do not use ZYTIGA in patients with baseline severe hepatic impairment (Child-Pugh Class C). If elevations in ALT or AST >5X ULN or total bilirubin >3X ULN occur in patients with baseline moderate hepatic impairment, discontinue ZYTIGA treatment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

Manufactured by: Patheon Inc. Mississauga, Canada Manufactured for: Janssen Biotech, Inc. Horsham, PA 19044 ©Janssen Biotech, Inc. 2012 Revised: May 2015 034443-150514

DRUG MONOGRAPHS

GENITOURINARY CANCER 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

℞

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

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 disease: monitor LVEF at baseline and periodically thereafter; 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

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DRUG MONOGRAPHS

GENITOURINARY CANCER 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, proteinuria, necrotizing fasciitis (discontinue if occurs), others (see full labeling). How supplied: Caps–28

THERACYS Sanofi Pasteur

℞

BCG Live. Live Bacillus Calmette and Guerin (BCG) strain of attenuated Mycobacterium bovis; 81mg per vial; pwd for intravesical administration after reconstitution and dilution; preservativefree. Indications: Treatment and prophylaxis of carcinoma in situ (CIS) of the urinary bladder. Prophylaxis of stage Ta and/or T1 papillary tumors following transurethral resection (TUR). 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)

TICE BCG Merck

℞

BCG Live. Bacillus of Calmette and Guerin (BCG) strain of Mycobacterium bovis live, attenuated culture preparation; 50mg 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 tumor of the urinary bladder. Adults: 1 vial in 50mL preservative-free saline intravesically once per week for 6 weeks (may repeat this regimen once if remission not achieved); then monthly for 6–12 months if needed. Avoid fluid at least 4 hrs before treatment and void immediately before administration. Retain in bladder for 2 hours. Children: Not recommended. Contraindications: Immunosuppressed. Active TB. Febrile illness. UTI. Gross hematuria.

Do not give within 7 days after bladder biopsy, transurethral resection (TUR), or traumatic catheterization. Warnings/Precautions: Not a vaccine for prevention of cancer or TB. Not for IV or SC use. Determine PPD status prior to therapy; rule out active TB if (+). Monitor for signs of systemic BCG infection: flu-like symptoms >72 hrs, fever ≥103°F, persistent LFT abnormalities; prostatitis, epididymitis, orchitis >2 days; treat with at least 2 antimycobacterial drugs (except pyrazinamide). Local irritative toxicities: do not treat with antimycobacterials. Bleeding bladder mucosa, small bladder. Disinfect fluid voided after therapy with bleach. PPD seroconversion may occur with treatment. Pregnancy (Cat.C). Nursing mothers: not recommended. Interactions: Immunosuppressants, myelosuppressants, radiation, antimicrobial therapy may reduce efficacy. Adverse reactions: Urine discoloration, bladder irritation, inflammation (begins after 4 hrs and last up to 72 hrs), malaise, fever, chills, flu-like syndrome, systemic BCG infection, dysuria, urinary frequency, hematuria, cystitis, urgency, nocturia, cramps, pain, incontinence, rigors, arthralgia. How supplied: Vial–1

TORISEL Pfizer

℞

mTOR kinase inhibitor. Temsirolimus 25mg/mL; ethanolic soln for IV infusion after two dilutions (first w. supplied diluent); contains alcohol, polysorbate 80. Indications: Advanced renal cell carcinoma. Adults: 25mg once weekly. Infuse IV over 30–60min, using an infusion pump. Continue until disease progression or unacceptable toxicity occurs. Premedicate with IV antihistamine (eg, diphenydramine). Hold dose if ANC <1000/mm3, platelets <75000/mm3, or NCI CTCAE ≥Grade 3 adverse reaction occurs; may restart at a dose reduced by 5mg/week (no lower than 15mg/week) if adverse reactions resolve to ≤Grade 2. Hepatic impairment: bilirubin >1–1.5×ULN or AST > ULN but bilirubin ≤ ULN: reduce to 15mg/week; >1.5×ULN: contraindicated. See Interactions. Children: Not recommended. Contraindications: Bilirubin >1.5×ULN. Warnings/Precautions: Sirolimus or related allergy. Hemodialysis. Perioperative period (may interfere with wound healing). CNS tumors. Monitor for opportunistic infections; consider prophylaxis for pneumocystis jiroveci pneumonia (PJP) when concomitant corticosteroids, other immunosuppresives required. Monitor for interstitial lung disease (ILD); discontinue if suspected. Monitor CBCs weekly and chemistry panels every 2 weeks, blood glucose, lipids, renal function, and for worsening respiratory or GI symptoms (eg, acute abdomen, blood in stool). Elderly. Pregnancy (Cat.D) (avoid pregnancy during and for 3 months after therapy, male

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DRUG MONOGRAPHS

GENITOURINARY CANCER patients should use appropriate contraception), nursing mothers: not recommended. Interactions: Avoid strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole, grapefruit juice); if used, consider reducing temsirolimus dose to 12.5mg/week (allow 1 week after discontinuing CYP3A4 inhibitor before readjusting temsirolimus dose). Avoid strong CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifampicin, phenobarbital, St. John’s Wort); if used, consider increasing temsirolimus dose to 50mg/week. Avoid live vaccines, close contact with vaccinees. Additive toxicity with sunitinib (rash, gout/ cellulitis), anticoagulants (intracerebral bleeding). Adverse reactions: Rash, asthenia, mucositis, nausea, edema, anorexia, infection, pain, anemia, hyperglycemia, hyperlipemia, hypertriglyceridemia, elevated alkaline phosphatase, elevated serum creatinine, lymphopenia, hypophosphatemia, thrombocytopenia, elevated AST, leukopenia; hypersensitivity/infusion reactions (anaphylaxis, dyspnea, flushing, chest pain), immunosuppression, PJP, ILD, bowel perforation, acute renal failure, abnormal wound healing; others (see full labeling). How supplied: Kit (vial + diluent)–1

TRELSTAR Actavis

℞

GnRH analogue. Triptorelin pamoate 3.75mg, 11.25mg, 22.5mg; pwd for IM inj after reconstitution; contains mannitol. Indications: Palliative treatment of advanced prostate cancer. Adults: Give by IM inj in buttock. 3.75mg every 4 weeks, or 11.25mg every 12 weeks, or 22.5mg every 24 weeks. Children: Not established. Contraindications: Women. Pregnancy (Cat.X). Warnings/Precautions: Must administer under physician supervision. Discontinue if hypersensitivity occurs. Initial transient increase in serum testosterone may result in worsening of symptoms. Spinal cord compression. Renal or hepatic impairment. Metastatic vertebral lesions. Upper or lower urinary tract obstruction. Increased risk of diabetes, MI, sudden cardiac death, stroke; monitor blood glucose and for signs/symptoms of CVD during therapy. Interactions: Avoid hyperprolactinemic drugs. Adverse reactions: Inj site reactions, hot flushes, skeletal pain, fatigue, hypertension, headache, dizziness, diarrhea, vomiting, leg edema, insomnia, impotence, emotional lability,

anemia, pruritus, urinary retention, UTI, erectile dysfunction, testicular atrophy; hyperglycemia. How supplied: Single-dose vial–1 MixJect system–1 (vial + vial adapter + prefilled syringe)

VALSTAR Endo

℞

Anthracycline. Valrubicin 40mg/mL; soln for intravesical instillation after dilution; contains 50% polyoxyl castor oil/50% dehydrated alcohol; preservative-free. Indications: Intravesical therapy of BCGrefractory carcinoma in situ (CIS) of the urinary bladder in patients for whom immediate cystectomy would be associated with unacceptable morbidity or mortality. Adults: Drain bladder before instilliation. 800mg given intravesically via urethral catheter once weekly for 6 weeks. Retain drug for 2 hours before voiding, then void. Children: Not recommended. Contraindications: Concurrent UTI. Small bladder capacity (eg, unable to tolerate a 75mL instillation). Warnings/Precautions: Monitor for disease recurrence or progression with cystoscopy, biopsy, and urine cytology every 3 months; if there is not a complete response of CIS to treatment after 3 months or if CIS recurs, cystectomy must be reconsidered. Severe irritable bladder symptoms. Perforated bladder. Bladder mucosa compromised. Delay administration for at least 2 weeks after transurethral resection and/or fulguration. Maintain adequate hydration. Pregnancy (Cat.C); avoid, both males and females should use effective birth control. Nursing mothers: not recommended. Adverse reactions: Bladder symptoms (eg, urinary frequency, dysuria, urinary urgency, spasm, hematuria, pain, incontinence, cystitis, nocturia, local burning, urethral pain, pelvic pain, UTI). How supplied: Single-use vials–4, 24

VANTAS Endo

℞

GnRH analogue. Histrelin acetate 50mg; SC implant. Indications: Palliative treatment of advanced prostate cancer. 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: 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. Measure serum testosterone, PSA levels periodically. Implant not visible on X-ray. Interactions: May interfere with pituitary gonadotropic and gonadal function tests. Adverse reactions: Hot flashes, initial worsening of signs/symptoms (eg, bone pain, urinary tract obstruction, hematuria), fatigue, local reactions, CNS or antiandrogenic effects, renal impairment, constipation; hyperglycemia, diabetes, cardiovascular disease. How supplied: Kit–1 (w. implant and supplies)

VOTRIENT GlaxoSmithKline

℞

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. Monitor liver tests before starting and at Weeks 3, 5, 7, and 9, thereafter at Months 3 and 4, then periodically. If ALT between 3×ULN and 8×ULN continue therapy with weekly monitoring until ALT returns to Grade 1 or baseline. If ALT >8×ULN interrupt therapy until ALT returns to Grade 1 or baseline; may consider reintroducing at a reduced dose, measure liver tests weekly for 8 weeks; if ALT>3×ULN recurs, permanently discontinue. Permanently discontinue if ALT>3×ULN and bilirubin >2×ULN. Gilbert’s syndrome (see full labeling). History of QT prolongation. Cardiac dysfunction risk: evaluate LVEF at baseline and periodically; monitor for CHF. Monitor ECG, electrolytes (eg, calcium, magnesium, potassium), thyroid. History of hemoptysis,

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DRUG MONOGRAPHS

GENITOURINARY CANCER cerebral, or clinically significant GI hemorrhage in the past 6 months: not recommended. Risk of arterial thrombotic events (within previous 6 months: not recommended). Monitor for VTE, PE, infection, proteinuria (reduce dose if 24-hour urine protein ≥3g), thrombotic microangiopathy, GI perforation or fistula. Monitor BP and manage hypertension promptly. Discontinue if severe and persistent hypertension (despite antihypertensives and dose reduction), if repeat episodes of proteinuria (despite dose reductions), thrombotic microangiopathy, or serious infection occurs. Stop therapy at least 7 days before surgery; discontinue in patients with wound dehiscence. Pregnancy (Cat.D), nursing mothers: not recommended. Interactions: See Adult dosing: Potentiated by strong CYP3A4 inhibitors, grapefruit juice. Avoid concomitant strong Pgp or BCRP inhibitors. Antagonized by strong CYP3A4 inducers. Concomitant drugs with narrow therapeutic windows metabolized by CYP3A4, CYP2D6, or CYP2C8: not recommended. Increased risk of ALT elevations with concomitant simvastatin; caution and monitor closely; follow dosing guidelines or consider alternatives to pazopanib, or discontinuing simvastatin if develops. Separate antacids by several hours. Caution with concomitant drugs that prolong QT interval (eg, antiarrhythmics). Adverse reactions: Diarrhea, hypertension, hair color changes, nausea, anorexia, vomiting, fatigue, decreased weight, decreased appetite, tumor pain, musculoskeletal pain, headache, dysgeusia, dyspnea, skin hypopigmentation; hepatoxicity, QT prolongation, hemorrhagic events, arterial thrombotic events (eg, MI, angina, ischemic stroke, TIA), venous thrombotic events (eg, VTE, PE), GI perforation or fistula, impaired wound healing, hypothyroidism, proteinuria, infection, reversible posterior leukoencephalopathy syndrome (discontinue if occurs). How supplied: Tabs–120

XOFIGO Bayer

℞

Alpha particle-emitting radioactive therapeutic agent. Radium Ra 223 dichloride 1000 kBq/mL (27 microcurie/mL) with a total radioactivity of 6000 kBq/vial (162 microcurie/vial) at the reference date; IV injection. Indications: Treatment of patients with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastatic disease. Adults: See full labeling. Administer by slow IV over 1 min. 50kBq (1.35 microcurie) per kg given at 4 week intervals for 6 injections. Children: <18yrs: not established. Contraindications: Women who are or may become pregnant. Pregnancy (Cat.X). Warnings/Precautions: Not for use in women. Bone marrow suppression. Perform hematologic evaluation at baseline and prior to every dose. Before 1st dose, the ANC should be ≥1.5 ×109/L, platelets ≥100 ×109/L and hemoglobin ≥10g/dL.

Before subsequent doses, the ANC should be ≥1 ×109/L and platelets ≥50 ×109/L; discontinue if no recovery within 6–8 weeks after last dose despite receiving supportive care. Monitor closely if evidence of compromised bone marrow reserve. Discontinue if life-threatening complications occur despite supportive care for bone marrow failure. Monitor oral intake and fluid status carefully. Males (use condoms) and female partners of reproductive potential should use highly effective contraceptive method during and 6 months after completion. Nursing mothers: not recommended. Interactions: Concomitant chemotherapy: not established. Discontinue if concomitant with chemotherapy, other systemic radioisotopes or hemibody external radiotherapy. Adverse reactions: Nausea, diarrhea, vomiting, peripheral edema, anemia, lymphocytopenia, leukopenia, thrombocytopenia, neutropenia. How supplied: Single-use vials (6mL)–1

XTANDI Astellas

℞

Androgen receptor inhibitor. Enzalutamide 40mg; soft gelatin caps. Indications: Treatment of metastatic castrationresistant prostate cancer. Adults: Swallow whole. 160mg once daily. Dose modifications: ≥Grade 3 toxicity or intolerable 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

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

Cisplatin + doxorubicin4,5*

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 SQ. Repeat every 3 weeks for maximum of 7 cycles.

Cisplatin + doxorubicin + paclitaxel4,5†

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 + docetaxel6–8‡

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

Ifosfamide + paclitaxel (Category 1 for carcinosarcoma)9

Days 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 + 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 3–4 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 1.2–1.5mg/m2/day IV. 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. continued

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CANCER TREATMENT REGIMEN

GYNECOLOGIC CANCER Endometrial Carcinoma Treatment Regimens Systemic Therapy for Recurrent, Metastatic, or High-risk Endometrial Carcinoma1 (continued) REGIMEN

DOSING

Hormonal Therapy

Medroxyprogesterone acetate20

Medroxyprogesterone acetate 200mg PO once daily.

Tamoxifen

Tamoxifen 20mg PO twice daily.

Anastrazole

Anastrozole 1mg/day PO for at least 28 days.

Tamoxifen + medroxyprogesterone acetate23

Medroxyprogesterone acetate 80mg PO twice daily for 3 weeks alternating with tamoxifen 20mg orally twice daily. Repeat cycle every 3 weeks.

22§

General treatment notes: • Participation in clinical trial is strongly recommended. • 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. * Patients who have received prior pelvic RT 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 is for endometrioid histologies only (i.e., not for serous adenocarcinoma, clear cell adenocarcinoma, or carcinosarcoma). § Anastrozole has minimal activity in an unselected population of patients with recurrent endometrial cancer.

References 1.

10.

11.

Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology™. Uterine Neoplasms. v 2.2015. Available at: http://www.nccn.org/ professionals/physician_gls/pdf/uterine.pdf. Accessed April February 2, 2015 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. Sorbe B, Andersson H, Boman K, et al. Treatment of primary advanced and recurrent endometrial carcinoma with a combination of carboplatin and paclitaxellong-term follow-up. Int J Gynecol Cancer. 2008;18(4):803–808. 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. 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. 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. 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. 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. 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. 2007:25:526–531. Wolfson AH, Brady MF, Rocereto TF, et al. A gynecologic oncology group randomized trial of whole abdominal irradiation (WAI) vs cisplatin-ifosfamidemesna (CIM) in optimally debulked stage I-IV carcinosarcoma (CS) of the uterus. J Clin Oncol. 2006;24(18S):5001. Thigpen JT, Blessing JA, Lagasse LD. Phase II trial of cisplatin as second-line chemotherapy in patients with advanced or recurrent endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 1989;33:68-70.

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;39:78. 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;12:441–448. 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;20:2360–2364. 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;88:277. 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;21:2110–2114. 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;29:2259–2265. 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;29:3278–3285. 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;111:22–26. 20. Thigpen JT, Brady MF, Alvarez RD, et al. Oral medroxyprogesterone acetate in the treatment of advanced or recurrent endometrial carcinoma: a dose-response study by the Gynecologic Oncology Group. J Clin Oncol. 1999;17:1736–1744. 21. Thigpen T, Brady MF, Homesley HD, et al. Tamoxifen in the treatment of advanced or recurrent endometrial carcinoma: a Gynecologic Oncology Group study. J Clin Oncol. 2001;19:364–367. 22. Rose PG, Brunetto VL, VanLe L, et al. A phase II trial of anastrozole in advanced recurrent or persistent endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 2000;78(2):212–216. 23. 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.

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GYNECOLOGIC CANCER Ovarian 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/Primary Adjuvant Therapy1*, †, ‡ Note: All recommendations are Category 2A unless otherwise indicated.

REGIMEN

DOSING

Stage 1A or 1B (grade 2 , 3, or clear cell) & Stage 1C (grade 1–3) §

Paclitaxel + carboplatin2

Day 1: Paclitaxel 175mg/m2 IV over 3 hours; followed by carboplatin (AUC 5–7.5) IV over 1 hour. Repeat every 3 weeks for 3–6 cycles.

Stage 2–4 (IV/IP regimen)∥,¶ Paclitaxel + cisplatin3

Day 1: Paclitaxel 135mg/m2 continuous IV infusion over 3 or 24 hours. Day 2: Cisplatin 75–100mg/m2 IP, followed by Day 8: Paclitaxel 60mg/m2 IP (maximum BSA 2m2). Repeat every 3 weeks for 6 cycles.

Stage 2–4 (IV regimens)# Paclitaxel + carboplatin (Category 1)4 Day 1: Paclitaxel 175mg/m2 IV over 3 hours; followed by carboplatin (AUC 5–7.5) IV over 1 hour. Repeat every 3 weeks for 6–8 cycles. Dose-dense paclitaxel + carboplatin (Category 1)5

Day 1: Paclitaxel 80mg/m2 IV over 1 hour; plus carboplatin (AUC 6) IV over 1 hour. Day 8 and 15: Paclitaxel 80mg/m2 IV over 1 hour. Repeat every 3 weeks for 6 cycles.

Docetaxel + carboplatin (Category 1)6 Day 1: Docetaxel 60–75mg/m2 IV over 1 hour; followed by carboplatin (AUC 5–6) IV over 1 hour. Repeat every 3 weeks for 6 cycles. Stage 2-4 (bevacizumab-containing IV regimens)** Paclitaxel + carboplatin + bevacizumab (Category 1)7–15

Day 1: Paclitaxel 175 mg/m2 IV over 3 hours; plus carboplatin (AUC 5–6) IV over 1 hour; plus bevacizumab 7.5 mg/kg IV over 30–90 minutes. Repeat every 3 weeks for 5–6 cycles. Continue bevacizumab for up to 12 additional cycles. OR Day 1: Paclitaxel 175 mg/m2 IV over 3 hours; plus carboplatin (AUC 6) IV over 1 hour. Repeat every 3 weeks × 6 cycles. Starting Day 1 of cycle 2: Bevacizumab 15 mg/kg IV over 30–90 minutes every 3 weeks for up to 22 cycles.

Principals of Chemotherapy1 For patients with newly diagnosed ovarian, fallopian tube, or primary peritoneal cancer • If they are eligible for chemotherapy, patients should be informed about the different options that are available—that is, IV chemotherapy, a combination of IP and IV chemotherapy, or a clinical trial—so they can decide which is the most the appropriate option. • Prior to the administration of the combined IP and IV regimen, patients must be apprised of the increased toxicities with the combined regimen when compared to using IV chemotherapy alone (increased myelosuppression, renal toxicities, abdominal pain, neuropathy, GI toxicities, metabolic toxicities, and hepatic toxicities). • Patients considered for the IP cisplatin and IP/IV paclitaxel regimen should have normal renal function prior to starting, a medically appropriate performance status based on the future toxicities of the IP/IV regimen, and no prior evidence of medical problems that could significantly worsen during chemotherapy (e.g., pre-existing neuropathy). • Prior to receiving and after receiving each cycle of IP cisplatin, adequate amounts of IV fluids need to be administered in order to prevent renal toxicity. After each cycle has been completed, patients need to be monitored carefully for myelosuppression, dehydration, electrolyte loss, end-organ toxicities (such as renal and hepatic damage), and all other toxicities. Patients often require postchemotherapy IV fluids in the out-patient setting to prevent or help treat dehydration. • Refer to the original references in the discussion section of the guideline for full toxicity data, doses, schedule, and dose modifications. continued

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GYNECOLOGIC CANCER Ovarian Cancer Treatment Regimens Principals of Chemotherapy1 (continued) For patients who have recurrent ovarian, fallopian tube, or primary peritoneal cancer • Patients should be informed about the following: › Availability of clinical trials, including the risks and benefits of various treatments, which will depend on the number of prior lines of chemotherapy the patient has received, and › The patient’s performance status, end-organ status, and pre-existing toxicities from prior regimens. If appropriate, palliative care should also be discussed as a possible treatment choice. (See NCCN Guidelines for Palliative Care). • Because of prior platinum exposure, myelosuppression occurs more frequently with any myelotoxic agent given in the recurrent setting. • With repeat use of either carboplatin and/or cisplatin, patients are at an increased risk of developing a hypersensitivity reaction (also called an allergic reaction) that could be life-threatening. Thus, patients should be counseled about the risk that a hypersensitivity reaction may occur, educated about the signs and symptoms of hypersensitivity reactions, treated by medical staff who know how to manage hypersensitivity reactions, and treated in a medical setting where appropriate medical equipment is available in case of an allergic reaction. (See NCCN Guidelines for Management of Drug Reactions [OV-C]). • Before any chemotherapy drug is given in the recurrent setting, the clinician should be familiar with the drug’s metabolism (i.e., renal and hepatic) and should make certain that the patient is an appropriate candidate for the drug (e.g., that the patient has adequate renal or hepatic function). • Clinicians should be familiar with toxicity management and appropriate dose reduction. • The schedule, toxicity, and potential benefits of any treatment should be thoroughly discussed with the patient and caregivers. Patient education should also include a discussion of precautions and measures to reduce the severity and duration of complications. • Patents who progress on 2 consecutive therapy regimens without evidence of clinical benefits have diminished likelihood of benefitting from additional therapy. Decisions to offer clinical trials, supportive care only, or additional therapy should be made on a highly individual basis. For elderly patients (>65 years) and/or those with comorbidities • Elderly patients and those with comorbidities may be intolerant to the combination chemotherapy regimens recommended in the NCCN Guidelines. Single-agent platinum agents may be appropriate in selected patients › Algorithms have been developed for predicting chemotherapy toxicity. (See the NCCN Guidelines for Senior Adult Oncology). NOTE: Carboplatin dosing may be revised based on changes in serum creatinine methodology. See the FDA dosing statement at: http://www.fda.gov/ AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm228974.htm. * Patients receiving primary chemotherapy should be monitored as follows: 1) pelvic exams at least every 2–3 cycles, 2) interim CBC with platelets as indicated, 3) chemistry profiles if indicated, 4) CA-125 levels or other tumor markers as clinically indicated prior to each cycle of chemotherapy, 5) radiographic imaging if indicated. † All primary chemotherapy/primary adjuvant therapy regimens (including the combined IV/IP chemotherapy) may be used for epithelial ovarian, fallopian tube, and primary peritoneal cancers. ‡ Stage 1A or 1B (grade 2) can be observed or treated with chemotherapy. § Intraperitoneal (IP) chemotherapy in <1 cm optimally debulked stage 2 and stage 3 patients (category 1 for stage III). ∥ All women undergoing surgery for ovarian cancer should be counseled about the clinical benefit associated with combined IV and IP chemotherapy administration prior to surgery. ¶ A 3-hour infusion of paclitaxel has not been proven to be equivalent to a 24-hour infusion, although it has been reported to be more convenient , easier to tolerate, and less toxic.16 # IV regimens may be considered for neoadjuvant therapy. ** Bevacizumab-containing IV regimens based on the ICON-7 and GOG-218 trials. For additional information regarding the controversy over this regimen, please see the NCCN Ovarian Cancer Guidelines for Anti-Angiogenesis Agents (v 3.2014, page 51).1

References 1.

Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology™. Ovarian Cancer including Fallopian Tube Cancer and Primary Peritoneal Cancer. V.3.2014. Available at: http://www.nccn.org/professionals/ physician_gls/pdf/ovarian.pdf. Accessed January 29, 2015. Ozols RF, Bundy BN, Greer BE, et al. Gynecologic Oncology Group. Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol. 2003;21:3194–3200. Armstrong DK, Bundy B, Wenzel L, et al. Gynecologic Oncology Group. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med. 2006;354:34–43.

Pignata S, Scambia G, Ferrandina G, et al. Carboplatin plus paclitaxel versus carboplatin plus pegylated liposomal doxorubicin as first-line treatment for patients with ovarian cancer: the MITO-2 randomized phase III trial. J Clin Oncol. 2011; 29(27):3628–3635. Katsumata N, Yasuda M, Takahashi F, et al. Japanese Gynecologic Oncology Group. Dose-dense paclitaxel once a week in combination with carboplatin every 3 weeks for advanced ovarian cancer: a phase 3, open-label, randomized controlled trial. Lancet. 2009;374:1331–1338. Vasey PA, Jayson GC, Gordon A, et al. Scottish Gynecological Cancer Trials Group. Phase III randomized trial of docetaxel carboplatin versus paclitaxel-carboplatin as first-line chemotherapy for ovarian carcinoma. J Natl Cancer Inst. 2004;96:1682–1691.

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GYNECOLOGIC CANCER References (continued) 7.

8. 9. 10. 11. 12.

Burger RA, Brady MF, Bookman MA, et al. Phase III trial of bevacizumab (BEV) in the primary treatment of advanced epithelial ovarian cancer (EOC), primary peritoneal cancer (PPC), or fallopian tube cancer (FTC): A Gynecologic Oncology Group study [abstract]. J Clin Oncol. 2010;28(Suppl 18): Abstract LBA1. Burger RA, Brady MF, Bookman MA, et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N EngI J Med. 2011;365:2473–2483. Hall M, Gourley C, McNeish I, et al. Targeted anti-vascular therapies for ovarian cancer: current evidence. Br J Cancer. 2013;108:250–258. Kristensen G, Perren T, Qian W, et al. Result of interim analysis of overall survival in the GCIG ICON7 phase III randomized trial of bevacizumab in women with newly diagnosed ovarian cancer [abstract]. J Clin Oncol. 2011;29(Suppl 18):Abstract LBA5006. Perren TJ, Swart AM, Pfisterer J, et al. A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med 2011;365: 2484–2496. Morgan RJ Jr, Alvarez RD, Armstrong DK, et al. Ovarian cancer, version 3.2012. J Natl Compr Canc Netw 2012:10:1339–1349.

13.

14.

15.

16.

Stark D, Nankivell M, Pujade-Lauraine E, et al. Standard chemotherapy with or without bevacizumab in advanced ovarian cancer: quality-of-life outcomes from the International Collaboration on Ovarian Neoplasms (ICON7) phase 3 randomized trial. Lancet Oncol 2013;14:236–243. Monk BJ, Huang HQ, Burger RA, et al. Patient reported outcomes of a randomized, placebo-controlled trial of bevacizumab in the front-line treatment of ovarian cancer: a Gynecologic Oncology Group Study. Gynecol Oncol 2013;128: 573–578. Friedlander ML, Stockier MR, Butow P, et al. Clinical trials of palliative chemotherapy in platinum-resistant or -refractory ovarian cancer: time to think differently? J Clin Oncol 2013: 31:2362. Barlin JN, Dao F, Bou Zgheib N, et al. Progression-free and overall survival of a modified outpatient regimen of primary intravenous/intraperitoneal paclitaxel and intraperitoneal cisplatin in ovarian, fallopian tube, and primary peritoneal cancer. Gynecol Oncol. 2012;125(3):621–624. (Revised 2/2015) © 2015 by Haymarket Media, Inc.

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DRUG MONOGRAPHS

GYNECOLOGIC CANCER ALKERAN GlaxoSmithKline

℞

Nitrogen mustard derivative. Melphalan 2mg; scored tabs. Indications: For the palliation of non-resectable epithelial ovarian cancer. Adults: 0.2mg/kg per day for 5 days; repeat course every 4–5 weeks. Continue treatment as hematological recovery permits (esp. WBCs and platelets); for other regimens: see literature. Children: Not recommended. Contraindications: Prior resistance to melphalan. Warnings/Precautions: Prior irradiation or chemotherapy. Bone marrow suppression. Azotemia. Monitor platelets, hemoglobin, WBC and differential at start of therapy and prior to each course; discontinue if WBC <3,000cells/ µL or platelets <100,000cells/µL. Moderate to severe renal impairment. Elderly. Pregnancy (Cat.D), nursing mothers: not recommended. Interactions: Radiotherapy potentiates antineoplastic effect. For IV: caution with cyclosporine, cisplatin, BCNU, nalidixic acid. Adverse reactions: Bone marrow suppression, GI upset, hepatic dysfunction, anemia, blood dyscrasias, secondary malignancies (eg, nonlymphocytic leukemia), rash, alopecia, pulmonary fibrosis, interstitial pneumonitis, gonadal toxicity (amenorrhea, infertility); hypersensitivity reactions, cardiac arrest (rare). How supplied: Tabs–50; single-use vial–1 (w. diluent)

AVASTIN Genentech

℞

Angiogenesis inhibitor. Bevacizumab 100mg, 400mg; per vial; soln for IV infusion after dilution; preservative-free. Indications: Persistent, recurrent, or metastatic cervical cancer in combination with paclitaxel and cisplatin, or paclitaxel and topotecan. Platinumresistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer in patients who received no more than 2 prior chemotherapy regimens, in combination with paclitaxel, pegylated liposomal doxorubicin or topotecan. Adults: Give by IV infusion. Infuse 1st dose over 90 mins; if tolerated, infuse 2nd dose over 60 mins, and subsequent doses over 30 mins. Cervical cancer: 15mg/kg every 3 weeks with either paclitaxel/cisplatin, or paclitaxel/topotecan. Epithelial ovarian, fallopian tube or primary peritoneal cancer: 10mg/kg every 2 weeks with either paclitaxel, pegylated liposomal doxorubicin, or topotecan (weekly); 15mg/kg every 3 weeks with topotecan (every 3 weeks). Children: Not established. Warnings/Precautions: Risk of GI perforations, surgery and wound healing complications, and hemorrhage. Do not start therapy before or for at least 28 days after surgery; allow surgical incisions to completely heal (see full labeling). Do not administer if recent history of hemoptysis of ≥ ½-teaspoon of red blood.

Permanently discontinue if GI perforation, tracheoesophageal fistula, any grade 4 fistula, or grade 4 venous thromboembolic event. Discontinue if fistula involving internal organ, wound healing complications, hemorrhage, severe arterial thromboembolic event (ATE), hypertensive crisis or encephalopathy, posterior reversible encephalopathy syndrome, or nephrotic syndrome occurs; suspend therapy if severe hypertension, moderate-to-severe proteinuria (resume when <2g/24hrs), or severe infusion reaction occurs. Avoid in ovarian cancer if evidence of recto-sigmoid involvement by pelvic exam, bowel involvement on CT scan, or symptoms of bowel obstruction. History of arterial thromboembolism. Diabetes. Monitor BP every 2–3 weeks. Monitor proteinuria by dipstick urine analysis; if ≥2+, do further assessment with a 24-hour urine collection. Elderly. Increased risk of ovarian failure; inform females of reproductive potential prior to starting therapy. Pregnancy (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 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

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GYNECOLOGIC CANCER 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, 2, and 3; followed by cisplatin. Dose adjustments, renal impairment: see full labeling. Children: Not established. Contraindications: Severe bone marrow depression. 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. Interactions: Myelosuppression potentiated with platinum agents. Neutropenia potentiated by G-CSF. Adverse reactions: See full labeling. Neutropenia, leukopenia, thrombocytopenia, anemia, nausea, vomiting, diarrhea, anorexia, abdominal pain, stomatitis, headache, dyspnea, cough, pyrexia, alopecia, fatigue; infection, sepsis, interstitial lung disease, neutropenic colitis (may be fatal). How supplied: Single-use vials–1

HYDREA Bristol-Myers Squibb

℞

Substituted urea. Hydroxyurea 500mg; caps. Indications: Recurrent metastatic or inoperable ovarian carcinoma. Adults: See literature. Intermittant therapy for solid tumors: 80mg/kg as single dose every 3rd day. Continuous therapy for solid tumors: 20–30mg/kg/day as single dose. Renal impairment: reduce dose. Children: Not recommended. Contraindications: Marked bone marrow depression. Warnings/Precautions: Previous irradiation therapy or chemotherapy. Correct anemia before starting. Monitor hematologic, renal, hepatic function before and during treatment. Marked renal dysfunction. Myeloproliferative disorders; discontinue if cutaneous vasculitic ulcerations develop and use alternative agents. Elderly. Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended.

Interactions: Avoid concomitant didanosine, with or without stavudine, or other antiretrovirals (may cause pancreatitis [monitor], fatal hepatotoxicity, peripheral neuropathy). Myelosuppressives potentiate antineoplastic effect. May antagonize antigout agents. Increased risk of vasculitic toxicities with interferon therapy. May cause falsely elevated urease, uricase, lactate dehydrogenase. Adverse reactions: Leukopenia, anemia, erythrocytic abnormalities, thrombocytopenia, GI upset, rash, erythema, fever, CNS effects, temporary renal impairment, acute pulmonary reactions, secondary leukemias, skin cancer. Note: Wear disposable gloves when handling caps or bottle. How supplied: Caps–100

LYNPARZA AstraZeneca

℞

Poly (ADP-ribose) polymerase (PARP) inhibitor. Olaparib 50mg; caps. Indications: Monotherapy in patients with deleterious or suspected deleterious germline BRCA-mutated (as detected by an FDA-approved test) advanced ovarian cancer who have been treated with ≥3 prior lines of chemotherapy. Adults: Swallow whole. 400mg twice daily; max 800mg daily. Continue until disease progression or unacceptable toxicity. Dose adjustments for adverse reactions: reduce to 200mg twice daily; may further reduce to 100mg twice daily. If concomitant strong CYP3A inhibitor unavoidable: reduce to 150mg twice daily; or if concomitant moderate CYP3A inhibitor unavoidable: reduce to 200mg twice daily. Children: Not established. Warnings/Precautions: Monitor CBC at baseline and monthly thereafter; do not start therapy until recovery from hematological toxicity due to previous chemotherapy (CTCAE Grade ≤1). Discontinue if myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) is confirmed. Interrupt therapy and evaluate if new or worsening respiratory symptoms occur; discontinue if pneumonitis is confirmed. Hepatic and moderate-to-severe renal impairment: not studied. Pregnancy (Cat.D); avoid. Use effective contraception during therapy and for at least 1 month after last dose. Nursing mothers: not recommended. Interactions: Increased myelosuppressive toxicity with concomitant other myelosuppressive anticancer agents, including DNA damaging agents. Avoid concomitant strong CYP3A inhibitors (eg, itraconazole, telithromycin, clarithromycin, ketoconazole, voriconazole, nefazodone, posaconazole, ritonavir, lopinavir/

ritonavir, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) and moderate CYP3A inhibitors (eg, amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, darunavir/ ritonavir, diltiazem, erythromycin, fluconazole, fosamprenavir, imatinib, verapamil); if unavoidable, reduce dose (see Adults). Avoid grapefruit and Seville oranges. Avoid concomitant strong CYP3A inducers (eg, phenytoin, rifampicin, carbamazepine, St. John’s Wort) and moderate CYP3A inducers (eg, bosentan, efavirenz, etravirine, modafinil, nafcillin); if unavoidable, be aware of potential for decreased efficacy. Adverse reactions: Anemia, nausea, fatigue, asthenia, vomiting, diarrhea, dysgeusia, dyspepsia, headache, decreased appetite, nasopharyngitis/pharyngitis/URI, cough, arthralgia/musculoskeletal pain, myalgia, back pain, dermatitis/rash, abdominal pain/ discomfort; lab abnormalities (see full labeling), MDS/AML, pneumonitis. How supplied: Caps–112

Megestrol acetate (various)

℞

Progestin. Megestrol acetate 20mg, 40mg; scored tabs. Indications: Palliative treatment of advanced endometrial carcinoma. Adults: 40–320mg daily in divided doses. Children: Not applicable. Warnings/Precautions: History of thromboembolic disease. Diabetes. Monitor for adrenal insufficiency. Pregnancy (Cat.D), nursing mothers: not recommended. Interactions: May increase insulin requirements. Decreases indinavir levels. Adverse reactions: Weight gain, thromboembolic events, heart failure, GI upset, edema, breakthrough menstrual bleeding, dyspnea, tumor flare, hyperglycemia, alopecia, hypertension, carpal tunnel syndrome, mood changes, hot flashes, malaise, asthenia, lethargy, sweating, rash. How supplied: Contact supplier.

TREXALL Teva

℞

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DRUG MONOGRAPHS

GYNECOLOGIC CANCER 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)

FDA-APPROVED OVARIAN CANCER TREATMENTS Generic Brand AlkylATINg AgENT

Strength

Form

Usual Dose

altretamine

Hexalen

50mg

caps

260mg/m2 daily in four divided doses for either 14 or 21 consecutive days in a 28-day cycle

carboplatin

—

10mg/mL

soln for IV infusion

Advanced ovarian cancer (previously untreated): 300mg/m2 on Day 1 every 4wks for 6 cycles Recurrent ovarian cancer: 360mg/m2 on Day 1 every 4wks

cisplatin

—

1mg/mL

soln for IV infusion after dilution 100mg/m2 once every 4wks

cyclophosphamide —

25mg, 50mg tabs

1–5mg/kg/day

Cytoxan injection

500mg, 1g, 2g

pwd for inj after reconstitution

40–50mg/kg in divided doses over 2–5 days or 10–15mg/kg every 7–10 days or 3–5mg/kg twice weekly

melphalan

Alkeran

2mg

scored tabs

0.2mg/kg/day for 5 days; repeat every 4–5wks

thiotepa

—

15mg

pwd for IV, intravesical, or intracavitary administration after reconstitution

0.3–0.4mg/kg IV once every 1–4wks

ANTIbIOTICS (CyTOTOxIC) doxorubicin

—

doxorubicin (liposomal)

Doxil

10mg, pwd for IV inj after 20mg, 50mg reconstitution

Monotherapy: 60–75mg/m2 every 21 days Combination therapy: 40–60mg/m2 every 21 to 28 days

2mg/mL

soln for IV inj

2mg/mL

dispersion for IV infusion after dilution

50mg/m2 once every 4wks

ANTIMETAbOlITE gemcitabine

gemzar

200mg, 1g

pwd for IV infusion after reconstitution

1000mg/m2 on Days 1 and 8 of each 21-day cycle

hydroxyurea

Hydrea

500mg

caps

Intermittant therapy: 80mg/kg as single dose every 3rd day Continuous therapy: 20–30mg/kg/day as single dose

soln for IV administration after dilution

Previously untreated ovarian cancer: 175mg/m2 over 3hrs or 135mg/m2 over 24hrs; repeat every 3wks Previously treated ovarian cancer: 135mg/m2 or 175mg/m2 over 3hrs every 3wks

pwd for IV infusion after reconstitution and dilution

1.5mg/m2 daily for 5 consecutive days starting on Day 1 of a 21-day cycle

ANTIMICROTubulE AgENTS paclitaxel

Taxol

6mg/mL

TOPOISOMERASE INHIbITOR topotecan

Hycamtin 4mg

Notes

Not an inclusive list of medications and/or doses. Please see drug monograph at www.eMPR.com and/or contact company for full drug labeling.

(Rev. 7/2013)

52 CANCER THERAPY ADVISOR | MAY/JUNE 2015 | CancerTherapyAdvisor.com

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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 2 hours; 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 1 hr post-infusion. Skin toxicity: see full labeling. Children: Not recommended. Warnings/Precautions: Discontinue if severe infusion reactions or interstitial lung disease occur. Monitor for infusion reactions, cardiopulmonary arrest, pulmonary toxicity, skin inflammation/infection; avoid sun, UV light. Additive cutaneous reactions with irradiation. Cardiovascular diseases (w. irradiation or platinum-based therapy with 5-FU). Monitor electrolytes (eg, magnesium, potassium, calcium) during and after cetuximab therapy. Pregnancy (Cat.C). Nursing mothers: not recommended. Interactions: Increased mucositis (Grade 3–4), radiation recall syndrome, acneiform rash, cardiac events, and electrolyte disturbances with radiation and cisplatin. Adverse reactions: Cutaneous reactions (pruritus, nail changes), acneform rash, headache, diarrhea, infection, asthenia, mucositis, weight loss, xerostomia, dehydration, electrolyte abnormalities; infusion reactions (may be severe: eg, bronchospasm, dyspnea), interstitial lung disease, cardiopulmonary arrest, hypomagnesemia, fever, sepsis, kidney failure, pulmonary embolus; others (see full labeling). How supplied: Single-use vials–1

HYDREA Bristol-Myers Squibb

℞

Substituted urea. Hydroxyurea 500mg; caps. Indications: Adjunct with irradiation therapy in primary squamous cell (epidermoid) carcinomas of the head and neck, excluding the lip. Adults: See literature. 80mg/kg as single dose every 3rd day. Renal impairment: reduce dose. Children: Not recommended. Contraindications: Marked bone marrow depression. Warnings/Precautions: Previous irradiation therapy or chemotherapy. Correct anemia before starting. Monitor hematologic, renal, hepatic function before and during treatment. Marked renal dysfunction. Myeloproliferative disorders; discontinue if cutaneous vasculitic ulcerations develop and use alternative agents. Elderly. Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended. Interactions: Avoid concomitant didanosine, with or without stavudine, or other antiretrovirals (may cause pancreatitis [monitor], fatal hepatotoxicity, peripheral neuropathy). Myelosuppressives potentiate antineoplastic effect. May antagonize antigout agents. Increased risk of vasculitic toxicities with interferon therapy. May cause falsely elevated urease, uricase, lactate dehydrogenase. Adverse reactions: Leukopenia, anemia, erythrocytic abnormalities, thrombocytopenia, GI upset, rash, erythema, fever, CNS effects, temporary renal impairment, acute pulmonary reactions, secondary leukemias, skin cancer. Note: Wear disposable gloves when handling caps or bottle. How supplied: Caps–100

TREXALL Teva

℞

Folic acid antagonist. Methotrexate sodium 5mg, 7.5mg, 10mg, 15mg; scored tabs. Also: Methotrexate injection Bedford ℞ Methotrexate 25mg/mL; soln for IV, IM, intraarterial, or intrathecal administration after dilution; preservative-free. Also: Methotrexate for injection Bedford ℞ Methotrexate 1g/vial; pwd for IV, IM, intra-arterial, or intrathecal administration after dilution; preservative-free. Indications: Epidermoid cancers of the head and neck. Adults: See literature. Children: Not established. Contraindications: Pregnancy (Cat.X). Nursing mothers. Warnings/Precautions: Be fully familiar with this drug’s toxicity before use. Discontinue if malignant lymphomas occur. Obtain baseline

and monitor CBCs with differential, platelet counts, chest X-ray, and hepatic, renal and pulmonary function. During therapy monitor hematology monthly, renal and hepatic function every 1–2 months, more often if increasing dose or predisposed to toxicity (eg, dehydration). Discontinue immediately if blood counts drop significantly. Rule out pregnancy in women of childbearing potential; use effective contraception during therapy and for at least 1 ovulatory cycle afterwards for women and for at least 3 months afterwards for men. Interrupt therapy if vomiting, diarrhea, stomatitis, or pulmonary symptoms occur. Hepatic or renal impairment. Obesity. Diabetes. Peptic ulcer. Ulcerative colitis. Infection. Dehydration. Folate deficiency. Ascites, pleural effusions: evacuate fluid, monitor for toxicity and reduce dose or discontinue if needed. Elderly (use low doses and monitor closely). Debilitated. Interactions: Avoid live virus vaccines. Toxicity increased by NSAIDs, salicylates, phenytoin, sulfonylureas, sulfonamides, probenecid, folic acid antagonists. May be potentiated by penicillins (monitor), tetracyclines, chloramphenicol, non-absorbable broad spectrum antibiotics. May be antagonized by folic acid. May potentiate theophylline, mercaptopurine. Increased risk of soft tissue necrosis and osteonecrosis with radiotherapy. Caution with other hepatotoxic drugs (eg, azathioprine, retinoids, sulfasalazine) and nephrotoxic agents (eg, cisplatin). Adverse reactions: Ulcerative stomatitis, leukopenia, nausea, GI upset, malaise, fatigue, chills, fever, dizziness, infection, myelosuppression, hepatotoxicity, renal toxicity, CNS toxicity, seizures (esp in children); interstitial pneumonitis, tumor lysis syndrome, skin reactions (may be fatal; eg, toxic epidermal necrolysis, Stevens-Johnson syndrome). How supplied: Tabs–30; soln (2mL, 4mL, 8mL, 10mL)–10 (single-use vials); pwd (1 gram)–1 (single-use vial)

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 positive

2-9

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 PCyR2-9 Continue current regimen. If response of BCR-ABL1 transcripts >10% (IS) or less than PCyR on bone marrow cytogenetics9-12 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 800 mg, 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% (IS) or PCyR2-9 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 less than PCyR on bone marrow cytogenetics13 Evaluate patient compliance and drug–drug interactions, consider mutational analysis and bone marrow cytogenetics

12 Month Evaluation1 Complete cytogenetic response2-9

Continue current regimen.

Partial cytogenetic response10 Evaluate patient compliance and drug–drug interactions, consider mutational analysis and bone marrow cytogenetics

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

Minor or no cytogenetic response10 Evaluate patient compliance and drug–drug interactions, consider mutational analysis

Change therapy to alternate TKI (preferred) (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 800 mg, as tolerated (if not candidate for alternate TKI or omacetaxine) and evaluate for HSCT depending on response to TKI therapy.

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CANCER TREATMENT REGIMEN

HEMATOLOGIC CANCER 18 Month Evaluation1 REGIMEN Complete cytogenetic

DOSING Continue previous regimen.

2-9

Partial cytogenetic response Evaluate patient compliance and drug-drug interactions, mutational analysis

Change therapy to alternate TKI (other than imatinib) and repeat bone marrow evaluation at 3 months to document Complete Cytogenetic Response (CCyR) AND Evaluation for HSCT depending on response to TKI therapy.

Cytogenetic relapse14 Evaluate patient compliance and drug-drug interactions, mutational analysis

Advanced Phase1 Accelerated phase15-31

Imatinib 600mg orally daily OR Dasatinib 140mg orally daily (70mg twice daily) OR Nilotinib 400mg orally twice daily OR Bosutinib 500mg 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—lymphoid15-31

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

Blast phase—myeloid15-31

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

References 1.

2. 3.

NCCN Clinical Practice Guidelines in Oncology™. Chronic Myelogenous Leukemia. v 1.2015. Available at: http://www. nccn.org/pro fessionals/physician_gls/pdf/cml. pdf. Accessed October 29, 2014. 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. 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. Hochhaus A, Kim D-W, Shah NP, et al. Four-year (yr) follow-up of patients (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. 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. 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. 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. 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.

10.

11.

12.

13.

14.

15.

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. 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. Jabbour E, Kantarjian HM, Saglio G, et al. Early response with dasatinib or imatinib 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.

continued

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HEMATOLOGIC CANCER Leukemia Treatment Regimens: Chronic Myeloid Leukemia (CML) References (continued) 16.

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. 17. Kantarjian HM, O’Brien S, Cortes JE, et al. Treatment of Philadelphia chromosomepositive, accelerated-phase chronic myelogenous leukemia with imatinib mesylate. Clin Cancer Res. 2002;8:2167–2176. 18. 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. 19. 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 followup. Haematologica. 2008;93:1792–1796. 20. 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. 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 e151.

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 imatinibresistant 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 imatinibresistant 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.

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HEMATOLOGIC CANCER Non-Hodgkin Lymphoma Treatment Regimens: Diffuse Large B-Cell Lymphoma 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 Diffuse Large B-Cell Lymphoma1 Note: All recommendations are Category 2A unless otherwise indicated.

REGIMEN

DOSING

First-Line Therapy R-CHOP (category 1)2–4

Days 1, 22, and 43: Rituximab 375mg/m2 IV 7 days prior to beginning CHOP regimen Day 1: Cyclophosphamide 750mg/m2 IV, doxorubicin 50mg/m2 IV bolus, and vincristine 1.4mg/m2 IV bolus (max dose 2mg) Days 3, 24, and 45: Prednisone 100mg PO 5 days. Repeat each cycle every 3 weeks for 3 cycles. Radiotherapy begins 3 weeks after last cycle of R-CHOP.

Dose-dense R-CHOP 14 (category 3)5,6 Day 1: Cyclophosphamide 750mg/m2 IV, doxorubicin 50mg/m2 IV, and vincristine 2mg IV Days 1-5: Prednisone 100mg PO. Repeat every 2 weeks for 6 cycles. Granulocyte colony-stimulating factor (G-CSF) was given on day 4 or 6. Dose-adjusted EPOCH + rituximab (category 2B)7–9

Day 1: Rituximab 375mg/m2 IV day 1 Days 1–4: Etoposide 50mg/m2 IV, doxorubicin 10mg/m2, and vincristine 0.4mg/m2 Day 5: Cyclophosphamide 750mg/m2 IV Days 1–5: Prednisone 60mg/m2 PO BID. Administer G-CSF 5 mcg/kg SQ daily until an ANC >5 × 109/L above nadir level starting day 6. Repeat cycle every 3 weeks for 6 cycles.

First-Line Therapy for Patients with Poor Left Ventricular Function or Very Frail*† RCEPP10

Days 1 and 8: Cyclophosphamide 600mg/m2 IV Day 1: Etoposide IV 70mg/m2 IV (or days 1–3 if not giving PO etoposide) Days 2 and 3: Etoposide 140 mg/m2 PO (rounded to the nearest 50mg capsule) Days 1–10: Procarbazine 60mg/m2 PO and prednisone 60mg/m2 PO. Repeat every 28 days until disease progression, or unacceptable toxicity.

RCDOP11, 12

Day 1: Cyclophosphamide 750mg/m2 IV, liposomal doxorubicin 30mg/m2 IV, and vincristine 2mg IV Days 1–5: Prednisone 60mg/m2 IV Day 8: Rituximab 375mg/m2 IV for cycle 1; administer on day 0 in subsequent cycles. Repeat cycle every 3 weeks for 6–8 cycles.

RCNOP13–15

Day 1: Rituximab 375mg/m2 IV Day 1: Cyclophosphamide 750mg/m2 IV, mitoxantrone 10mg/m2 IV, and vincristine 1.4mg/m2 IV (max dose 2mg) Days 1–5: Prednisone 50mg/m2 PO. Repeat cycle every 3 weeks for 6 cycles (max 8 cycles).

DA-EPOCH + rituximab16

Day 1: Rituximab 275mg/m2 Days 1–4: Doxorubicin 10mg/m2 IV, etoposide 50mg/m2 IV, and vincristine 0.4mg/m2 IV Day 5: Cyclophosphamide 750mg/m2 IV Days 1–5: Prednisone 60mg/m2 PO. Administer G-SCF on day 6 until ANC exceeds nadir. Repeat cycle every 3 weeks.

RCEOP17

Day 1: Rituximab 375mg/m2 IV Day 1: Cyclophosphamide 750mg/m2 IV, etoposide 50mg/m2 IV, and vincristine 1.4mg/m2 IV (max dose 2mg) Days 1–5: Prednisone 100mg PO Days 2–3: Etoposide 100mg/m2 PO. For limited-stage disease, repeat cycle every 3 weeks for 3–4 cycles; for advanced-stage disease, repeat cycle every 3 weeks for 6 cycles. continued

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HEMATOLOGIC CANCER Non-Hodgkin Lymphoma Treatment Regimens: Diffuse Large B-Cell Lymphoma Systemic Therapy for Diffuse Large B-Cell Lymphoma1 (continued) REGIMEN

DOSING

Patients >80 Years of Age with Comorbidities Day 1: Rituximab 375mg/m2 Day 1: Cyclophosphamide 400mg/m2, doxorubicin 25mg/m2, and vincristine 1mg Days 1–5: Prednisone 40mg/m2. Repeat every 3 weeks for 6 cycles.

R-mini-CHOP18

First-Line Consolidation (optional) High-dose therapy with autologous stem cell rescue in patients with age-adjusted IPI high-risk disease (Category 2B)19

Induced with 5 cycles of CHOP or R-CHOP followed by autotransplantation at the first response to induction therapy with CHOP with or without rituximab for 3 cycles.

High-dose therapy with autologous stem cell rescue in patients with double-hit DLBCL19

Induced with 5 cycles of CHOP or R-CHOP followed by autotransplantation at the first response to induction therapy with CHOP with or without rituximab for 3 cycles.

Concurrent Presentation with CNS Disease Parenchymal1

Systemic methotrexate 3g/m2 or more on day 15 of a 21-day R-CHOP cycle that has been supported by growth factors.

Leptomeningeal

Methotrexate/cytarabine IT. Consider Ommaya reservoir placement and/or systemic methotrexate 3–3.5g/m2.

Second-Line Therapy (for patients with intention to proceed to high-dose therapy with autologous stem cell rescue) DHAP ± rituximab20–22

Days 1–4: Cisplatin 100mg/m2 IV via 24-hour infusion, cytosine 2g/m2 in 2 pulses each given 12 hours apart, and dexamethasone 40mg PO or IV ± rituximab 375mg/m2 IV prior to DHAP. Repeat in 3–4 weeks for 6-10 cycles.

ESHAP ± rituximab23,24

Days 1–4: Etoposide 40–60mg/m2 Days 1–5: Methylprednisolone 250–500mg IV Day 5: Cytarabine 2g/m2 IV over 2–3 hours Days 1–4: Cisplatin 25mg/m2 IV via 24-hour infusion, ± Day 1 or 5: Rituximab 375mg/m2 IV. Repeat every 3–4 weeks for 3 cycles.

GDP ± rituximab25,26

Days 1 and 8: Gemcitabine 1000mg/m2 IV over 30 minutes Days 1–4: Dexamethasone 40mg PO Day 1: Cisplatin 75mg/m2 IV OR carboplatin at AUC = 5 IV over 30 minutes, ± Day 8: Rituximab 375mg/m2 slow IV infusion for CD20-positive disease. Repeat every 3 weeks for up to 6 cycles.

GEMOX ± rituximab27

Day 1: Gemcitabine 1000mg/m2 and oxaliplatin 100mg/m2 ± rituximab 375mg/m2 IV. Repeat every 15 days if ANC >1 × 109/L and platelet count >100 × 109/L; if not, then every 3 weeks.

ICE ± rituximab28–30

Days 1–3: Etoposide 100mg/m2 IV bolus Day 2: Carboplatin AUC = 5 (max dose 800mg) IV bolus and ifosfamide admixed with mesna both at a dose of 5g/m2 via 24-hour continuous IV beginning day 2 Days 5–12 (or days 7–14): Filgrastim 5mcg/kg/day for cycles 1–2, increased to 10mcg/kg/day following cycle 3 until completion of peripheral blood stem cell collection, ± Days 1 and 3: Rituximab 375mg/m2 IV bolus and on cycle 1, give additional dose rituximab 375mg/m2 on Day 2. Repeat every 14 days or when ANC >1000 cells/mcL and platelet count >50000/mcL.

MINE ± rituximab31,32‡

Days 1–3: Mesna 13g/m2 and ifosfamide 1.3g/m2 Day 1: Mitoxantrone 12mg/m2 Days 1–3: Etoposide 65mg/m2, ± Days 1, 6, and 8: Rituximab 400mg/m2 for 3 weeks. Repeat every 3 weeks for 2 cycles.

Second-Line Therapy (non-candidates for high-dose therapy) Bendamustine ± rituximab33–35§

Days 1–2: Bendamustine 120mg/m2, ± Day 1: Rituximab 375mg/m2. Repeat every 28 days for up to 6 cycles.

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HEMATOLOGIC CANCER Systemic Therapy for Diffuse Large B-Cell Lymphoma1 (continued) REGIMEN

DOSING

Second-Line Therapy (non-candidates for high-dose therapy) (continued) Brentuximab vedotin for CD30+ disease (Category 2B)36

Brentuximab vedotin 1.8mg/kg IV over 30 minutes every 3 weeks. Repeat cycle until a maximum of 16 cycles, disease progression, or unacceptable toxicity.

CEPP ± rituximab (PO and IV)10

Days 1 and 8: Cyclophosphamide 600mg/m2 IV Day 1: Etoposide IV 70mg/m2 IV (or on days 1–3 if not giving PO etoposide) Days 2 and 3: Etoposide 140mg/m2 PO (rounded to the nearest 50 mg capsule) Days 1–10: Procarbazine 60mg/m2 PO and prednisone 60mg/m2 PO, ± Day 1: Rituximab 375mg/m2 IV. Repeat every 28 days until disease progression or unacceptable toxicity.

CEOP ± rituximab37

Day 1: Cyclophosphamide 750mg/m2 IV, vincristine 1.4mg/m2 IV, and epirubicin 60mg/m2 IV Days 1–5: Prednisone 100mg/day PO, ± Day 0: Rituximab 375mg/m2 IV. Repeat every 3 weeks for at least 6 cycles.

DA-EPOCH ± rituximab38,39

Days 2–4: Doxorubicin 15mg/m2 via continuous IV infusion, etoposide 65mg/m2 via continuous IV infusion, and vincristine 0.5mg via continuous IV infusion Day 5: Cyclophosphamide 750mg/m2 IV Days 1–14: Prednisone 60mg/m2 PO, ± Day 1: Rituximab 375mg/m2 IV. Repeat every 21 days for 4-6 cycles.

GDP ± rituximab40,41

Days 1 and 8: Gemcitabine 1000mg/m2 IV Days 1–4: Dexamethasone 40mg IV Days 1–3: Cisplatin 25mg/m2 IV Or carboplatin AUC = 5 on day 1, ± Day 1: Rituximab 375mg/m2 IV. Repeat every 21 days for 2–6 cycles (max of 4 cycles if using carboplatin).

GemOx ± rituximab42,43

Days 1 and 8: Gemcitabine 1200mg/m2 30-minute IV infusion Day 2: Oxaliplatin 120mg/m2 2-hour IV infusion, ± Day 1: Rituximab 375mg/m2 IV. Repeat every 21 days for 6 cycles.

Lenalidomide ± rituximab44-46

Days 1–21: Lenalidomide 20mg PO ± rituximab 375mg/m2 IV weekly during cycle 1. Repeat every 28 days until complete response.

Rituximab47

Day 1: Rituximab 375mg/m2 IV during each cycle of chemotherapy for up to 8 infusions.

* Inclusion of any anthracycline or anthracenedione in patients with impaired cardiac functioning should have more frequent cardiac monitoring. † There are limited published data regarding the use of these regimens; however, they are used at NCCN Member Institutions for the first-line treatment of DLBCL for patients with poor left ventricular function. ‡ Used in patients receiving consolidation treatment following CHOP in those achieving complete response or near-complete response. § Preferred for elderly patients.

References 1. 2.

3. 4.

Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Hodgkin’s Lymphomas. v 2.2015. Available at: http://www.nccn.org. Accessed March 5, 2015. Coiffier B, Thieblemont C, Van Den Neste E, et al. Long-term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d’Etudes des Lymphomes de l’Adulte. Blood. 2010;116: 2040–2045. Feugier P, Van Hoof A, Sebban C, et al, Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d’Etudes des Lymphomes de l’Adulte. J Clin Oncol. 2005;23:4117–4126. Pfreundschuh M, Trumper L, Osterborg A, et al. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with goodprognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol. 2006;7:379–391.

7. 8.

Pfreundschuh M, Schubert J, Ziepert M, et al. Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomized controlled trial (RICOVER-60). Lancet Oncol. 2008;9:105–116. Cunningham D, Hawkes EA, Jack A, et al. Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone in patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: a phase 3 comparison of dose intensification with 14-day versus 21-day cycles. Lancet. 2013;381:1817–1826. Purroy N, Lopez A, Vallespi T, et al. Dose-adjusted EPOCH plus rituximab (DA-EPOCH-R) in untreated patients with poor risk large B-cell lymphoma. A phase 2 study conducted by the Spanish PETHEMA Group [Abstract]. Blood. 2009; 114:Abstract 2701. Wilson WH, Dunleavy K, Pittaluga S, et al. Phase II study of dose-adjusted EPOCH and rituximab in untreated diffuse large B-cell lymphoma with analysis of germinal center and post-germinal center biomarkers. J Clin Oncol. 2008;26: 2717–2724.

continued

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HEMATOLOGIC CANCER Non-Hodgkin Lymphoma Treatment Regimens: Diffuse Large B-Cell Lymphoma References (continued) 9. 10. 11.

12. 13. 14.

15.

16.

17.

18.

19.

20. 21.

22. 23. 24.

25.

26.

Wilson WH, Jung SH, Porcu P, et al. A Cancer and Leukemia Group B multi-center study of DA-EPOCH-rituximab in untreated diffuse large B-cell lymphoma with analysis of outcome by molecular subtype. Haematologica. 2012;97: 758–765. Chao NJ, Rosenberg SA, Horning SJ. CEPP(B): An effective and well-tolerated regimen in poor-risk, aggressive non-Hodgkin’s lymphoma. Blood. 1990;76:1293–1298. Martino R, Perea G, Caballero MD, et al. Cyclophosphamide, pegylated liposomal doxorubicin (Caelyx), vincristine and prednisone (CCOP) in elderly patients with diffuse large B- cell lymphoma: results from a prospective phase II study. Haematologica. 2002;87:822–827. Zaja F, Tomadini V, Zaccaria A, et al. CHOP-rituximab with pegylated liposomal doxorubicin for the treatment of elderly patients with diffuse large B-cell lymphoma. Leuk Lymphoma. 2006;47:2174–2180. Bessell EM, Burton A, Haynes AP, et al. A randomized multicentre trial of modified CHOP versus MCOP in patients aged 65 years and over with aggressive nonHodgkin’s lymphoma. Ann Oncol. 2003;14:258–267. Bezwoda W, Rastogi RB, Erazo Valla A, et al. Long-term results of a multicentre randomised,comparative phase III trial of CHOP versus CNOP regimens in patients with intermediate- and high-grade non-Hodgkin’s lymphomas. Novantrone International Study Group. Eur J Cancer. 1995;31:903–911. Sonneveld P, de Ridder M, van der Lelie H, et al. Comparison of doxorubicin and mitoxantrone in the treatment of elderly patients with advanced diffuse nonHodgkin’s lymphoma using CHOP versus CNOP chemotherapy. J Clin Oncol. 1995; 13:2530–2539. Garcia-Suarez J, Banas H, Arribas I, et al. Dose-adjusted EPOCH plus rituximab is an effective regimen in patients with poor-prognostic untreated diffuse large B-cell lymphoma: results from a prospective observational study. British Journal of Haematology. 2006;126:276–285. Moccia AA, Schaff K, Hoskins P, et al. R-CHOP with etoposide substituted for doxorubicin (R-CEOP): excellent outcome in diffuse large B cell lymphoma for patients with a contraindication to anthracyclines. Presented at: 51st American Society of Hematology Annual Meeting and Exposition; December 7, 2009; New Orleans, LA. Blood. 2009;114: Abstract 408. Peyrade F, Jardin F, Thieblemont C, et al. Attenuated immunochemotherapy regimen (R-miniCHOP) in elderly patients older than 80 years with diffuse large B-cell lymphoma: a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2011;12:460–468. Stiff PJ, Unger JM, Cook J, et al. Randomized phase III U.S./Canadian intergroup trial (SWOG S9704) comparing CHOP {+/-} R for eight cycles to CHOP {+/-} R for six cycles followed by autotransplant for patients with high-intermediate (H-Int) or high IPI grade diffuse aggressive non-Hodgkin lymphoma (NHL). J Clin Oncol. 2011;29:8001. Velasquez WS, Cabanillas F, Salvador P, et al. Effective salvage therapy for lymphoma with cisplatin in combination with high-dose Ara-C and dexamethasone (DHAP). Blood. 1988; 71:117–122. Mey UJ, Orlopp KS, Flieger D, et al. Dexamethasone, high-dose cytarabine, and cisplatin in combination with rituximab as salvage treatment for patients with relapsed or refractory aggressive non-Hodgkin’s lymphoma. Cancer Invest. 2006; 24:593–600. Gisselbrecht C, Glass B, Mounier N, et al. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol. 2010;28: 4184–4190. Velasquez WS, McLaughlin P, Tucker S, et al. ESHAP—an effective chemotherapy regimen in refractory and relapsing lymphoma: a 4-year follow-up study. J Clin Oncol. 1994;12:1169–1176. Martin A, Conde E, Arnan M, et al. R-ESHAP as salvage therapy for patients with relapsed or refractory diffuse large B-cell lymphoma: the influence of prior exposure to rituximab on outcome. A GEL/TAMO study. Haematologica. 2008;93: 1829–1836. Crump M, Baetz T, Couban S, et al. Gemcitabine, dexamethasone, and cisplatin in patients with recurrent or refractory aggressive histology B-cell non-Hodgkin lymphoma: a Phase II study by the National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG). Cancer. 2004;101:1835–1842. Gopal AK, Press OW, Shustov AR, et al. Efficacy and safety of gemcitabine, carboplatin, dexamethasone, and rituximab in patients with relapsed/refractory lymphoma: a prospective multi-center phase II study by the Puget Sound Oncology Consortium. Leuk Lymphoma. 2010;51:1523–1529.

27. 28. 29.

30. 31.

32. 33. 34. 35. 36.

37.

38. 39. 40. 41.

42.

43. 44. 45. 46. 47.

Lopez A, Gutierrez A, Palacios A, et al. GEMOX-R regimen is a highly effective salvage regimen in patients with refractory/relapsing diffuse large-cell lymphoma: a phase II study. Eur J Haematol. 2008;80:127–132. Zelenetz AD, Hamlin P, Kewalramani T, et al. Ifosfamide, carboplatin, etoposide (ICE)-based second-line chemotherapy for the management of relapsed and refractory aggressive non-Hodgkin’s lymphoma. Ann Oncol. 2003;14:5–10. Kewalramani T, Zelenetz AD, Nimer SD, et al. Rituximab and ICE (RICE) as second-line therapy prior to autologous stem cell transplantation for r elapsed or primary refractory diffuse large B-cell lymphoma. Blood. 2004;103:3684–3688. Gisselbrecht C, Glass B, Mounier N, et al. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol. 2010;28: 4184–4190. Dincol D, Buyukcelik A, Dogan M, et al. Long-term outcome of mesna, ifosfamide, mitoxantrone, etoposide (MINE) regimen as a consolidation in patients with aggressive non-Hodgkin lymphoma responding to CHOP. Med Oncol. 2010;27: 942–945. Emmanouilides C, Lill M, Telatar M, et al. Mitoxantrone/ifosfamide/etoposide salvage regimen with rituximab for in vivo purging in patients with relapsed lymphoma. Clin Lymphoma. 2002;3:111–116. Weidmann E, Kim SZ, Rost A, et al. Bendamustine is effective in relapsed or refractory aggressive non-Hodgkin’s lymphoma. Ann Oncol. 2002;13:1285–1289. Vacirca J, Tabbara I, Acs P, Shumaker G. Bendamustine + rituximab as treatment for elderly patients with relapsed or refractory diffuse large B-cell lymphoma [abstract]. Blood. 2010;116: Abstract 2806. Ohmachi K, Niitsu N, Uchida T, et al. Multicenter phase II study of bendamustine plus rituximab in patients with relapsed or refractory diffuse large B-cell lymphoma. J Clin Oncol. 2013; 31:2103–2109. Bartlett N, Sharman J, Oki Y, et al. A phase 2 study of brentuximab vedotin in patients with relapsed or refractory CD30-positive non-Hodgkin lymphomas: interim results in patients with DLBCL and other B-cell lymphomas [abstract]. Blood. 2013;122; Abstract:848. Yan L, Yimamu M, Wang X, et al. Addition of rituximab to a CEOP regimen improved the outcome in the treatment of non-germinal center immunophenotype diffuse large B cell lymphoma cells with high Bcl-2 expression. Int J Hematol. 2014:99:79–86. Gutierrez M, Chabner BA, Pearson D, et al. Role of a doxorubicin-containing regimen in relapsed and resistant lymphomas: An 8-year follow-up study of EPOCH. J Clin Oncol. 2000;18: 3633–3642. Jermann M, Jost LM, Taverna C, et al. Rituximab-EPOCH, an effective salvage therapy for relapsed, refractory or transformed B-cell lymphomas: Results of a phase II study. Ann Oncol. 2004;15:511–516. Hou Y, Wang H, Ba Y. Rituximab, gemcitabine, cisplatin, and dexamethasone in patients with refractory or relapsed or aggressive B-cell lymphoma. Med Oncol. 2012;29:2409–2416. Gopal A, Press O, Pagel J. Efficacy and Safety of Gemcitabine (G), Carboplatin ©, Dexamethasone (D), and Rituximab in Patients with Relapsed/Refractory Lymphoma: A Prospective Multi-center Phase II Study of by the Puget Sound Oncology Consortium (PSOC). Leuk Lymphoma. 2010;51:1523–1529. Corazzelli G, Capobianco G, Arcamone M, et al. Long-term results of gemcitabine plus oxaliplatin with and without rituximab as salvage treatment for transplantineligible patients with refractory/relapsing B-cell lymphoma. Cancer Chemother Pharmacol. 2009;64:907–916. El Gnaoui T, Dupuis J, Belhadj K, et al. Rituximab, gemcitabine and oxaliplatin: An effective salvage regimen for patients with relapsed or refractory B-cell lymphoma not candidates for high-dose therapy. Ann Oncol. 2007;18:1363–1368. Witzig TE, Vose JM, Zinzani PL, et al. An international phase II trial of single-agent lenalidomide for relapsed or refractory aggressive B-cell non-Hodgkin’s lymphoma. Ann Oncol. 2011; 22:1622–1627. Wiernik PH, Lossos IS, Tuscano JM, et al. Lenalidomide monotherapy in relapsed or refractory aggressive Non-Hodgkin’s lymphoma. J Clin Oncol. 2008;26:4952–4957. Wang M, Fowler N, Wagner-Bartak N, et al. Oral lenalidomide with rituximab in relapsed or refractory diffuse large cell, follicular, and transformed lymphoma: a phase II clinical trial. Leukemia. 2013. Rituxan® (rituximab) [package insert]. Genentech, Inc. South San Francisco, CA.

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER ADCETRIS Seattle Genetics

℞

CD30-directed antibody-drug conjugate. Brentuximab vedotin 50mg/vial; pwd for IV infusion after reconstitution; preservative-free. Indications: Treatment of Hodgkin lymphoma (HL) after failure of autologous stem cell transplant (ASCT) or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates. Treatment of systemic anaplastic large cell lymphoma (sALCL) after failure of at least one prior multiagent chemotherapy regimen. Adults: Give by IV infusion over 30 minutes. 1.8mg/kg every 3 weeks (if >100kg, calculate dose based on wt. of 100kg); continue until a max of 16 cycles, disease progression or unacceptable toxicity. Peripheral neuropathy: if Grade 2/3: withhold until resolve to ≤Grade 1, then restart with 1.2mg/kg; if Grade 4: discontinue therapy. Neutropenia: Grade 3/4: withhold until resolve to ≤Grade 2; may consider growth factor support; recurrent Grade 4: discontinue or consider reducing dose to 1.2mg/kg. Children: Not established. Contraindications: Concomitant bleomycin. Warnings/Precautions: Risk of JC virus infection. Monitor for progressive multifocal leukoencephalopathy (PML); withhold dose if suspected and discontinue if confirmed. Monitor for neuropathy and delay, change, or discontinue dose accordingly. Monitor for infusion-related reactions; permanently discontinue and treat if anaphylaxis occurs. Monitor CBCs prior to each dose and frequently for Grade 3 or 4 neutropenia; if develops, delay, reduce or discontinue dose. Increased risk of tumor lysis syndrome in rapidly proliferating tumor/high tumor burden patients; monitor closely. Pregnancy (Cat.D); avoid. Nursing mothers: not recommended. Interactions: See Contraindications. Potentiated by strong CYP3A4 inhibitors (eg, ketoconazole); monitor. Antagonized by potent CYP3A4 inducers (eg, rifampin). Adverse reactions: Neutropenia, peripheral sensory neuropathy, fatigue, GI upset, anemia, upper respiratory tract infection, pyrexia, rash, thrombocytopenia, cough; infusion reactions, Stevens-Johnson syndrome (discontinue if occurs), PML (may be fatal). How supplied: Single-use vial–1

ALKERAN GlaxoSmithKline

℞

Nitrogen mustard derivative. Melphalan 2mg; scored tabs. Indications: Palliative treatment for multiple myeloma.

Adults: 6mg once daily for 2–3 weeks; stop for up to 4 weeks, maintenance 2mg per day. Continue treatment as hematological recovery permits (esp. WBCs and platelets); for other regimens: see literature. Children: Not recommended. Also: ALKERAN FOR INJECTION ℞ Melphalan HCl 50mg/vial; pwd for IV infusion after reconstitution and dilution. Indications: Palliative treatment of multiple myeloma when oral therapy is not appropriate. Adults: Give by IV infusion over 15–20 minutes. 16mg/m2 every 2 weeks for a total of 4 doses, then at 4-week intervals. Continue treatment as hematological recovery permits. Renal insufficiency (BUN≥30mg/dL): consider reducing dose by 50%. Children: Not recommended. Contraindications: Prior resistance to melphalan. Warnings/Precautions: Prior irradiation or chemotherapy. Bone marrow suppression. Azotemia. Monitor platelets, hemoglobin, WBC and differential at start of therapy and prior to each course; discontinue if WBC <3,000cells/ µL or platelets <100,000cells/µL. Moderate to severe renal impairment. Elderly. Pregnancy (Cat.D), nursing mothers: not recommended. Interactions: Radiotherapy potentiates antineoplastic effect. For IV: caution with cyclosporine, cisplatin, BCNU, nalidixic acid. Adverse reactions: Bone marrow suppression, GI upset, hepatic dysfunction, anemia, blood dyscrasias, secondary malignancies (eg, nonlymphocytic leukemia), rash, alopecia, pulmonary fibrosis, interstitial pneumonitis, gonadal toxicity (amenorrhea, infertility); hypersensitivity reactions, cardiac arrest (rare). How supplied: Tabs–50; single-use vial–1 (w. diluent)

ARRANON GlaxoSmithKline

℞

Nucleoside analogue. Nelarabine 250mg/vial; soln for IV infusion. Indications: T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL) that is unresponsive or has relapsed after ≥2 chemotherapy regimens. Adults and Children: Contact manufacturer. From the pediatric trial: Patients ≤21 yrs: 650mg/m2 by IV infusion over 1 hour daily for 5 consecutive days; repeat every 21 days. From the adult trial: Patients 16–65yrs: 1500mg/m2 by IV infusion over 2 hours on days 1, 3, and 5; repeat every 21 days. The recommended duration of treatment has not been clearly established. Treatment was generally continued until there

was evidence of disease progression, the patient experienced unacceptable toxicity, the patient became a candidate for bone marrow transplant, or the patient no longer continued to benefit from treatment. See literature. Warnings/Precautions: Discontinue if ≥ Grade 2 neurotoxicity occurs; may delay dosing if other toxicities occur (eg, hematologic toxicity). Prior or concurrent intrathecal chemotherapy or craniospinal irradiation (increased risk of neurotoxicity). Renal or hepatic impairment. Obtain CBCs, platelet counts. Monitor for signs/ symptoms of infection, tumor lysis syndrome. Ensure adequate hydration. Elderly. Pregnancy (Cat.D); use effective contraception. Nursing mothers: not recommended. Interactions: Avoid live vaccines. Concomitant adenosine deaminase inhibitors (eg, pentostatin): not recommended. Adverse reactions: Hematologic disorders (eg, anemia, neutropenia, thrombocytopenia), headache, GI upset, constipation, fatigue, somnolence, dizziness, peripheral neuropathy, seizures, respiratory disorders, pyrexia; increased transaminase levels, bilirubin; decreased potassium, albumin. How supplied: Vials–6

ARZERRA GlaxoSmithKline

℞

CD20-directed cytolytic monoclonal antibody. Ofatumumab 20mg/mL; soln for IV infusion after dilution; preservative-free. Indications: In combination with chlorambucil in previously untreated patients with chronic lymphocytic leukemia (CLL), for whom fludarabine-based therapy is considered inappropriate. CLL refractory to fludarabine and alemtuzumab. Adults: See full labeling. Premedicate with acetaminophen (oral), antihistamine (oral or IV), corticosteroid (IV). Give by IV infusion (use in-line filter; rate varies with dose and during infusion). Previously untreated: initially 300mg on Day 1, then 1 week later by 1000mg on Day 8 (Cycle 1), follow by 1000mg on Day 1 of subsequent 28-day cycles for at least 3 cycles until best response or max 12 cycles. Refractory: initially 300mg once, then 1 week later by 2000mg weekly for 7 doses, followed 4 weeks later by 2000mg every 4 weeks for 4 doses. Children: Not established. Warnings/Precautions: Increased risk of HBV reactivation. Test/treat HBV infection prior to initiating therapy. Monitor for signs of hepatitis or HBV reactivation during and for several months after therapy; discontinue if HBV reactivation occurs. Monitor CBCs at regular intervals during

Please see brief summary of Full Prescribing Information on pages 78–80. ©2014 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved. TRE-40083 October 2014.

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER and after therapy, increase frequency if Grade 3/4 cytopenias develop. Monitor for new onset of or changes in neurological signs/symptoms. Increased risk of tumor lysis syndrome (TLS) in high tumor burden and/or high circulating lymphocytes; consider prophylaxis with anti-hyperuricemics and hydration beginning 12–24hrs prior to infusion. Pregnancy (Cat.C). Nursing mothers. Interactions: Avoid vaccination with live viral vaccines. Adverse reactions: Neutropenia, thrombocytopenia, anemia, pneumonia, pyrexia, cough, fatigue, dyspnea, rash, nausea, diarrhea, bronchitis, upper respiratory tract infections; infusion reactions (eg, bronchospasm; laryngeal, pulmonary, or angioedema; flushing, hyper- or hypotension, syncope, cardiac ischemia, back or abdominal pain, fever, urticaria) (interrupt, adjust infusion rate and monitor; permanently discontinue if anaphylaxis occurs), progressive multifocal leukoencephalopathy (discontinue if suspected and evaluate), infections (eg, sepsis), hepatotoxicity, TLS. How supplied: Single-use vial (5mL)–3; (50mL)–1

BELEODAQ Spectrum

℞

Histone deacetylase inhibitor. Belinostat 500mg; per vial; lyophilized pwd for IV inj after reconstitution and dilution. Indications: Relapsed or refractory peripheral T-cell lymphoma. Adults: Give 1000mg/m2 once daily by IV infusion over 30 mins on Days 1–5 of a 21-day cycle; can repeat cycles every 21 days until disease progression or unacceptable toxicity. Dose modifications: Hematologic toxicities: if ANC nadir <0.5×109/L or platelet count <25×109/L: decrease dose by 25% (750mg/m2); discontinue if recurrent ANC <0.5×109/L or platelet count <25×109/L nadirs after 2 dose reductions; 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

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 rituximabrefractory). Adults: See literature. Pretreat with acetaminophen 650mg and oral diphenhydramine 50mg and thyroid blockers; continue thyroid blockers 2 weeks after therapeutic dose. Give by IV infusion. Dosimetric step: Tositumomab 450mg over 1hr, then Iodine I131 tositumomab (containing 5mCi I131 and 35mg tositumomab) over 20 minutes. Therapeutic step (7–14 days after dosimetric step if biodistribution acceptable): tositumomab 450mg over 1hr, then calculated therapeutic dose of Iodine I131 tositumomab over 20 minutes. Reduce infusion rate by 50% if infusional toxicity occurs; stop if severe; may continue at 50% rate if severe symptoms resolve. Children: Not recommended. Contraindications: Hypersensitivity to murine proteins. Pregnancy (Cat.X). Warnings/Precautions: Use only by physicians trained in radionuclide therapy. Handle and dispose of properly. See literature on patient contact restrictions. Not for initial treatment. >25% lymphoma marrow involvement and/or impaired bone marrow reserve, platelet count <100000cells/mm3, neutrophil count <1500cells/mm3, or intolerant to thyroid blockers: not recommended. High tumor burden. Splenomegaly. Renal impairment. Screen for human anti-mouse antibodies (increases anaphylaxis risk). Obtain CBCs and platelet counts before and for up to 12 weeks after therapy. Monitor TSH (before and annually), serum creatinine (before). Use adequate contraception during and for 12 months after therapy. Elderly. Nursing mothers: not recommended. Interactions: Concomitant other forms of irradiation or chemotherapy: not recommended. Caution with live viral vaccines, anticoagulants, platelet aggregation inhibitors. Adverse reactions: Thrombocytopenia, neutropenia, anemia, headache, asthenia, fever, chills, pain, GI upset, cough, pneumonia, pleural effusion, dehydration, rash, infection, hemorrhage, hypersensitivity reactions (may

be fatal), myelodysplastic syndrome, secondary malignancies, antibody formation. Note: For technical questions call (877) 423-9927. How supplied: Dosimetric pack (tositumomab 2 × 225mg/vial + 1 × 35mg/vial and Iodine I131 tositumomab 1 × 20mL single-use vial)–1; Therapeutic pack (tositumomab 2 × 225mg/vial + 1 × 35mg/vial and Iodine I131 tositumomab 1 or 2 × 20mL single-use vial)–1

BLINCYTO Amgen

℞

Bispecific CD19-directed CD3 T-cell engager. Blinatumomab 35mcg; per vial; lyophilized pwd for IV infusion after reconstitution; preservative-free. Indications: Philadelphia chromosome-negative relapsed or refractory B-cell precursor acute lymphoblastic leukemia. Adults: Strictly follow preparation and administration instructions. Pre-medicate with IV dexamethasone 20mg 1 hour prior to 1st dose of each cycle, prior to a step dose, or when restarting infusion after interruption (≥4 hours). Hospitalization recommended for first 9 days of Cycle 1 and first 2 days of Cycle 2. One single cycle = 4 weeks of continuous IV infusion followed by a 2-week treatment-free interval. ≥18yrs (≥45kg): Give by continuous IV infusion at a rate of 10mL/hr for 24 hours or 5mL/hr for 48 hours. Cycle 1: 9mcg/day on Days 1–7 and 28mcg/day on Days 8–28. Subsequent cycles: 28mcg/day on Days 1–28. Treat up to a total of 5 cycles. Dose adjustments: see full labeling. Children: <18yrs: not established. Warnings/Precautions: Monitor for signs/ symptoms of cytokine release syndrome or neurological toxicities; interrupt or discontinue as recommended (see full labeling). Monitor for infections; give antibiotic prophylaxis as appropriate. Monitor for tumor lysis syndrome; interrupt or discontinue as needed. Obtain lab tests (including WBC, ANC) during infusion; interrupt if prolonged neutropenia occurs. Monitor ALT, AST, GGT, and total bilirubin prior to and during treatment; interrupt if transaminases rise >5×ULN or if bilirubin rises >3×ULN. Risk of leukoencephalopathy, esp. in those with prior treatment with cranial irradiation and antileukemic chemotherapy (including high-dose methotrexate or intrathecal cytarabine). Renal impairment (CrCl <30mL/min) or hemodialysis. Elderly. Pregnancy (Cat.C). Nursing mothers: not recommended. Interactions: Caution with concomitant CYP450 substrates (esp. drugs with narrow therapeutic index); adjust dose as needed. Monitor for toxicity with warfarin. Monitor cyclosporine. Adverse reactions: Pyrexia, headache, peripheral edema, febrile neutropenia, nausea, hypokalemia, tremor, rash, constipation; pneumonia, sepsis, neutropenia, device-related infection, tremor, encephalopathy, confusion, overdose, possible immunogenicity. How supplied: Pack–1 (single-use vial + IV solution stabilizer)

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER 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: 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: 200mg daily. Severe renal impairment (CrCl <30mL/min): 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. 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 literature. Premedicate with phenytoin 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). Obese: base dose on adjusted ideal body weight. Children: See literature. Warnings/Precautions: Myelosuppression. Seizure disorder. Head trauma. Renal or hepatic impairment. Obtain CBCs with differential, platelet count, liver enzymes, bilirubin during treatment and until recovery. Monitor for infection and bleeding. Pregnancy (Cat.D); 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, cardiac tamponade (in pediatric patients with thalassemia); rare: bronchopulmonary dysplasia with pulmonary fibrosis. How supplied: Single-use vials (10mL)–8

CAMPATH Genzyme

℞

Monoclonal antibody, CD52 (recombinant, humanized). Alemtuzumab 30mg/mL; soln; for IV infusion after dilution; preservative-free. Indications: B-cell chronic lymphocytic leukemia (B-CLL). Adults: Premedicate with antihistamine and acetaminophen before 1st dose, and at dose escalations. Give by IV infusion over 2 hrs. Initially 3mg per day until infusion reactions are ≤ grade 2, then increase to 10mg per day until infusion reactions are ≤ grade 2, then to maintenance 30mg/day three times per week (on alternate days); duration of therapy (including escalation): 12 weeks. Do not exceed max single dose 30mg/dose or 90mg/week. Give prophylactic antibiotics and antivirals during treatment and for at least 2 months after completion or until CD4+ counts resolve (whichever occurs later). Dose adjustments for neutropenia and thrombocytopenia: see literature. Retitrate if therapy interrupted for ≥7 days. Children: Not recommended.

Warnings/Precautions: Discontinue dose for autoimmune or recurrent/persistent severe cytopenias (except lymphopenia). Withhold dose for severe cytopenias (except lymphopenia), grade 3 or 4 infusion reactions, serious infections, or during antiviral treatment for cytomegalovirus (CMV) infection or confirmed CMV viremia. Obtain CBCs, platelet counts weekly, assess CD4+ counts after treatment until recovery to ≥200cells/µL. Monitor for infusion reactions; CMV infection (continue for 2 months after therapy ends). Pregnancy (Cat.C). Nursing mothers: not recommended. Interactions: Avoid live virus vaccines (after recent therapy). May interfere with tests using antibodies. Irradiate any blood products given (GVHD may occur). Adverse reactions: See literature; may be fatal. Infusion reactions, cytopenias (eg, neutropenia, lymphopenia, thrombocytopenia, anemia), infections (eg, CMV), GI upset, insomnia, anxiety; others. How supplied: Single-use vials–1, 3

CERUBIDINE Bedford

℞

Anthracycline. Daunorubicin HCl 20mg/vial; lyophilized pwd for IV infusion after reconstitution; contains mannitol. Indications: In combination with other chemotherapy for remission induction in acute nonlymphocytic leukemia (myelogenous, monocytic, erythroid) of adults and for remission induction in acute lymphocytic leukemia of children and adults. Adults: Give by IV infusion. Acute nonlymphocytic leukemia (in combination with cytosine arabinoside): <60yrs: 45mg/m2 daily on days 1, 2 and 3 of the first course and on days 1, 2 of subsequent courses; ≥60yrs: 30mg/m2 daily on days 1, 2 and 3 of the first course and on days 1, 2 of subsequent courses. Acute lymphocytic leukemia (in combination with vincristine, prednisone, L-asparaginase): 45mg/m2 daily on days 1, 2 and 3. Hepatic or renal impairment: reduce dose (see literature). Children: Give by IV infusion. <2yrs or BSA<0.5m2: use weight (mg/kg) to calculate dose. 25mg/m2 on Day 1 every week (in combination with vincristine and prednisone). Warnings/Precautions: Treat if any systemic infections 1st. Pre-existing drug-induced bone marrow suppression. Cardiovascular disease, thoracic irradiation, previous doxorubicin therapy (cumulative doses >550mg/m2): increased risk of cardiotoxicity. Monitor blood counts, cardiac, hepatic and renal function prior to each treatment. Renal or hepatic impairment.

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER 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

Cladribine (various)

℞

Chlorinated purine nucleoside analog. Cladribine 1mg/mL; soln for IV infusion after dilution; preservative-free. Indications: Active hairy cell leukemia. Adults: Give by continuous IV infusion for 7 consecutive days. 0.09mg/kg per day. Children: See full labeling. Warnings/Precautions: Delay or discontinue if neurotoxicity or renal toxicity occurs. Myelosuppression. Active infection. Renal or hepatic insufficiency. Monitor blood counts (esp. during first 4–8 weeks post-dose), renal and hepatic function. Pregnancy (Cat.D), nursing mothers: not recommended. Interactions: Live attenuated vaccines: not recommended. Increased toxicity with myelosuppressive, immunosuppressive, or nephrotoxic agents. Adverse reactions: Severe myelosuppression (eg, neutropenia, anemia, thrombocytopenia), fever, infection, fatigue, nausea, rash, headache, inj site reactions, others; neurotoxicity, nephrotoxicity, tumor lysis syndrome (rare). How supplied: Contact supplier.

CLOLAR Genzyme

℞

Purine nucleoside antimetabolite. Clofarabine 1mg/mL; soln for IV infusion after dilution; preservative-free. Indications: Acute lymphoblastic leukemia (ALL) in patients 1–21 years of age after relapses from, and/or refractoriness to, at least two prior regimens. Adults: Not established. Children: Monitor blood pressure, cardiac, renal, and hepatic function before and during therapy. Give by IV infusion over 2 hours. 1–21yrs: 52mg/m2 daily for 5 consecutive days; repeat approximately every 2–6 weeks following recovery or return to baseline organ function. Provide supportive care (eg, IV fluids, antihyperuricemics, alkalinize urine, steroids, antiemetics, diuretics, albumin) throughout treatment. Renal impairment (CrCl 30–60mL/min): reduce dose by 50%. Dose modifications: see full labeling.

Warnings/Precautions: Obtain CBCs and platelets daily during the 5 days of therapy, then 1–2 times weekly or as needed. Monitor for signs/ symptoms of infection, tumor lysis syndrome, cytokine release (eg, tachypnea, hypotension); if cytokine release progresses to systemic inflammatory response syndrome (SIRS)/capillary leak syndrome and/or if organ dysfunction (grade 3 or 4 hepatic or renal toxicity) occurs, discontinue and treat; may restart at lower dose if organ function recovers and patient is stable. Ensure adequate hydration. Monitor for venous occlusive disease of the liver in patients who previously received hematopoietic stem cell transplant; discontinue if suspected. Pregnancy (Cat.D); use effective contraception. Nursing mothers: not recommended. Interactions: Minimize exposure to drugs with known renal toxicity during treatment. Consider avoiding concomitant drugs known to induce hepatic toxicity. Caution with drugs that affect BP or cardiac function; monitor. Adverse reactions: Nausea, vomiting, diarrhea, headache, rash, pruritus, pyrexia, fatigue, palmarplantar erythrodysesthesia syndrome, anxiety, flushing, mucosal inflammation; bone marrow suppression (eg, febrile neutropenia, anemia, leukopenia, thrombocytopenia), infections, hyperuricemia, hypotension, cardiac events, SIRS/capillary leak syndrome, hemorrhage (may be fatal), enterocolitis (monitor), serious skin reactions (discontinue for exfoliative or bullous rash or if Stevens-Johnson syndrome or toxic epidermal necrolysis suspected). How supplied: Single-use vial (20mL)–1, 4

Cytarabine Bedford

℞

Antimetabolite. Cytarabine 100mg, 500mg, 1g, 2g; per vial; lyophilized pwd for IV, intrathecal, SC inj after reconstitution. Indications: Remission induction in acute nonlymphocytic leukemia of adults and children. Acute lymphocytic leukemia. Chronic myelocytic leukemia (blast phase). Prophylaxis and treatment of meningeal leukemia (intrathecal route). Adults and Children: Induction therapy of acute non-lymphocytic leukemia: 100mg/m2 per day by continuous IV infusion (days 1–7) or 100mg/m2 IV every 12 hours (days 1–7). Acute lymphocytic leukemia and chronic myelocytic leukemia: see literature. Meningeal leukemia: Usual range: 5–75mg/m2 intrathecally; may give once daily for 4 days to once every 4 days; most frequently used dose: 30mg/m2 every 4 days until cerebrospinal fluid findings are normal. Warnings/Precautions: Do not use diluent with benzyl alcohol for intrathecal administration. Pre-existing myelosuppression. Renal or hepatic impairment. Monitor blood counts, renal, hepatic function. Neonates. Pregnancy (Cat.D); avoid use. Nursing mothers. Interactions: May antagonize gentamicin, fluorocytosine. Adverse reactions: Myelosuppression (leukopenia, thrombocytopenia, anemia), GI

upset, anorexia, abdominal pain, oral ulceration, rash, fever, hepatic dysfunction, infection, bleeding; cytarabine syndrome, hyperuricemia, pancreatitis, paralysis (rare), others. How supplied: Vials (100mg, 200mg)–10 1g, 2g–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 × ULN; active or uncontrolled infection): do not restart until toxicity resolved. Children: Not recommended. Warnings/Precautions: Renal or hepatic impairment. Obtain CBC and platelet counts before each dosing cycle and as needed. Monitor hepatic function (do baseline liver chemistries and serum creatinine). Pregnancy (Cat.D); use appropriate contraception (both men and women). Nursing mothers: not recommended. Adverse reactions: Neutropenia, thrombocytopenia, anemia, leukopenia, fatigue, pyrexia, nausea, cough, petechiae, constipation, diarrhea, hyperglycemia. How supplied: Single-use vial–1

DEPOCYT Sigma-Tau

℞

Antimetabolite. Cytarabine 50mg/vial; liposomal suspension for intrathecal administration; preservative-free. Indications: Intrathecal treatment of lymphomatous meningitis. Adults: See literature. Give intrathecally over 1–5 minutes. Administer dexamethasone 4mg twice daily for 5 days with each cycle of treatment. Induction: 50mg every 14 days for 2 doses (weeks 1 and 3). Consolidation: 50mg every 14 days for 3 doses (weeks 5, 7 and 9) followed by 1 additional dose at week 13. Maintenance: 50mg every 28 days for 4 doses (weeks 17, 21, 25 and 29). Reduce dose to 25mg if neurotoxicity develops and discontinue if it persists. Children: Not recommended. Contraindications: Active meningeal infection. Warnings/Precautions: Chemical arachnoiditis; reduce symptoms with dexamethasone. Previous

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER 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

DTIC-DOME Bayer

℞

Alkylating agent. Dacarbazine 200mg/vial; pwd for IV infusion after reconstitution and dilution; contains mannitol. Indications: Metastatic malignant melanoma. Second-line therapy for Hodgkin’s disease, in combination with other agents. Adults: Give by IV infusion. Malignant melanoma: 2–4.5mg/kg/day for 10 days, may repeat every 4 weeks; or 250mg/m2 daily for 5 days, may repeat every 3 weeks. Hodgkin’s disease (in combination with other drugs): 150mg/m2 daily for 5 days, may repeat every 4 weeks; or 375mg/m2 on Day 1, then repeat every 15 days. Children: Not recommended. Warnings/Precautions: Monitor CBCs, platelets; may need to discontinue or suspend therapy if hemopoietic toxicity occurs. Pregnancy (Cat.C). Nursing mothers: not recommended. Adverse reactions: Myelosuppression (eg, leukopenia, thrombocytopenia, anemia), anorexia, nausea, vomiting, flu-like syndrome, alopecia, facial flushing/paresthesia, inj site reactions, anaphylaxis; rare: hepatic necrosis, photosensitivity reactions. How supplied: Vials (20mL)–12

ERWINAZE Jazz

℞

Asparagine-specific enzyme. Asparaginase Erwinia chrysanthemi 10,000 IU; per vial; lyophilized pwd for IM or IV inj after reconstitution. Indications: As a component of a multi-agent chemotherapeutic regimen for the treatment of patients with acute lymphoblastic leukemia (ALL) who have developed hypersensitivity to E. coliderived asparaginase. Adults and Children: Give by IM inj (max 2mL/inj site) or IV (infuse over 1hr). To substitute for a pegaspargase dose: 25,000 IU/m2 three times weekly (M/W/F) for 6 doses for each planned pegaspargase dose. To substitute for a native E. coli asparaginase dose: 25,000 IU/m2 for each scheduled native E. coli asparaginase dose within a treatment. When IV use: consider monitoring nadir serum asparaginase activity (NSAA) levels; switch to IM inj if levels are inadequate. Contraindications: History of serious pancreatitis, thrombosis, hemorrhagic events with prior L-asparaginase therapy. Warnings/Precautions: Have resuscitation equipment available and other agents necessary

to treat anaphylaxis. Discontinue if serious hypersensitivity reactions occur. Monitor for pancreatitis; discontinue if severe or hemorrhagic pancreatitis manifested by abdominal pain >72hrs and amylase elevation ≥2×ULN occurs. Withhold therapy if mild pancreatitis; may resume after resolution. Monitor glucose levels at baseline and during therapy. Discontinue if thrombotic or hemorrhagic event occurs; may resume after 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

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

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER FOLOTYN Allos

℞

Folate analogue inhibitor. Pralatrexate 20mg/mL; soln for IV inj; preservative-free. Indications: Relapsed or refractory peripheral T-cell lymphoma. Adults: Prior to administration: mucositis should be ≤Grade 1, platelets should be ≥100,000/μL for first dose and ≥50,000/μL for subsequent doses, absolute neutrophil count should be ≥1000/ μL. Give by IV push over 3–5min. 30mg/m2 once weekly for 6 weeks in 7-week cycles; may reduce to 20mg/m2 or interrupt treatment to manage toxicity (see literature for adjustment criteria). Continue until disease progression or unacceptable toxicity develops. Supplement with vitamin B12 (1mg IM every 8–10 weeks, starting within 10 weeks before first Folotyn dose) and folic acid (1–1.25mg orally daily, beginning 10 days before starting Folotyn and for 30 days after stopping). Children: Not recommended. Warnings/Precautions: End stage renal disease (including dialysis): avoid, unless benefit justifies potential risk for toxicity. Adjust dose to manage toxicities (eg, hematological, mucositis, hepatic impairment); see literature. Monitor CBC and for mucositis weekly. Monitor serum chemistry, renal and hepatic function before the 1st and 4th dose per cycle. Monitor for dermatological reactions; withhold dose or discontinue if severe. Renal or hepatic impairment. Pregnancy (Cat.D) (may cause fetal harm), nursing mothers: not recommended. Interactions: May be potentiated by probenecid, NSAIDs, trimethoprim/sulfamethoxazole, other renally-excreted drugs. Adverse reactions: Mucositis, thrombocytopenia, neutropenia, anemia, abnormal liver function tests, nausea, fatigue, pyrexia, dehydration, sepsis, dyspnea; dermatological reactions (eg, skin exfoliation, ulceration, toxic epidermal necrolysis), tumor lysis syndrome. How supplied: Single-use vials (1mL, 2mL)–1

GAZYVA Genentech

℞

Cytolytic monoclonal antibody (CD20-directed). Obinutuzumab 25mg/mL; soln for IV infusion after dilution; preservative-free. Indications: Treatment of patients with previously untreated chronic lymphocytic leukemia (CLL), in combination with chlorambucil. Adults: Premedicate (eg, glucocorticoid, APAP, antihistamine) before each infusion. Give by IV infusion for 6 treatment cycles (28 days duration). Cycle 1: 100mg on Day 1 at 25mg/hr over 4 hours; 900mg on Day 2 at 50mg/hr, may increase at 50mg/hr every 30mins (max 400mg/hr); 1000mg on Days 8 and 15 at 100mg/hr, may increase by 100mg/hr increments every 30mins (max 400mg/hr); Cycles 2–6: 1000mg on Day 1 at 100mg/hr, may increase by 100mg/hr increments every

30mins (max 400mg/hr). Infusion rate and premedication adjustments: see full labeling. Children: Not established. Warnings/Precautions: Risk of hepatitis B virus (HBV) reactivation; immediately discontinue and any concomitant chemotherapy if occurs. Screen for HBV infection prior to initiation; if positive evidence, monitor and consider antiviral therapy. Discontinue treatment and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressives if PML develops. Monitor closely for infusion reactions; if Grade 4: discontinue permanently; if Grade 3: interrupt until resolved; if Grade 1 or 2: interrupt or reduce the infusion rate and manage symptoms. Preexisting cardiac or pulmonary conditions: monitor more frequently during and post-infusion period for severe reactions. Risk of TLS in high tumor burden and/or high circulating lymphocyte count (>25 × 109/L): prophylaxis with antihyperuricemics and hydration. Active infection: do not administer. Monitor for bleeding; obtain blood and platelet counts frequently. Risk of neutropenia; give antimicrobial prophylaxis; consider antiviral and antifungal prophylaxis. Hepatic or renal impairment (CrCl <30mL/min). Pregnancy (Cat.C). Nursing mothers: not recommended. Interactions: Concomitant live viral vaccines: not recommended. Consider withholding antihypertensives for 12hrs prior to, during, and for 1hr after infusion until BP is stable. Consider withholding drugs that may increase bleeding risk (eg, platelet inhibitors, anticoagulants) esp. during 1st cycle. Adverse reactions: Infusion reactions, neutropenia, thrombocytopenia, anemia, pyrexia, cough, musculoskeletal disorders. How supplied: Single-use vial (40mL)–1

GLEEVEC Novartis

℞

Kinase inhibitor. Imatinib (as mesylate) 100mg, 400mg; scored tabs. Indications: Philadelphia-chromosome (+) chronic myeloid leukemia (CML): in newlydiagnosed adults and children in chronic phase; in patients in blast crisis, accelerated phase, or chronic phase after failure of interferon-alpha therapy. Adults with relapsed or refractory Ph (+) acute lymphoblastic leukemia (ALL). Children with newly diagnosed Ph+ ALL in combination with chemotherapy. Adults with myelodysplastic/ 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).

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER Adverse reactions: Edema (may be severe), nausea, vomiting, musculoskeletal pain, diarrhea, muscle cramps, rash (may be severe; eg, erythema multiforme, Stevens-Johnson syndrome), fatigue, abdominal pain, dizziness, blurred vision, somnolence, fever, headache, cough, arthralgia/myalgia, dyspnea, hypokalemia, night sweats, anorexia, pruritus, hemorrhage, anemia, neutropenia, thrombocytopenia, weight gain, renal or hepatotoxicity, immunosuppression, hypothyroidism; rare: severe CHF, LV dysfunction. Testing considerations: BCR-Abl t(9;22) in Ph+CML patients How supplied: 100mg–90; 400mg–30

HYDREA Bristol-Myers Squibb

℞

Substituted urea. Hydroxyurea 500mg; caps. Indications: Resistant chronic myelocytic leukemia. Adults: See literature. 20–30mg/kg/day as single dose. Renal impairment: reduce dose. Children: Not recommended. Contraindications: Marked bone marrow depression. Warnings/Precautions: Previous irradiation therapy or chemotherapy. Correct anemia before starting. Monitor hematologic, renal, hepatic function before and during treatment. Marked renal dysfunction. Myeloproliferative disorders; discontinue if cutaneous vasculitic ulcerations develop and use alternative agents. Elderly. Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended. Interactions: Avoid concomitant didanosine, with or without stavudine, or other antiretrovirals (may cause pancreatitis [monitor], fatal hepatotoxicity, peripheral neuropathy). Myelosuppressives potentiate antineoplastic effect. May antagonize antigout agents. Increased risk of vasculitic toxicities with interferon therapy. May cause falsely elevated urease, uricase, lactate dehydrogenase. Adverse reactions: Leukopenia, anemia, erythrocytic abnormalities, thrombocytopenia, GI upset, rash, erythema, fever, CNS effects, temporary renal impairment, acute pulmonary reactions, secondary leukemias, skin cancer. Note: Wear disposable gloves when handling caps or bottle. How supplied: Caps–100

ICLUSIG ARIAD

℞

Kinase inhibitor. Ponatinib 15mg, 45mg; tabs; contains lactose. Indications: Treatment of adults with T315Ipositive chronic, accelerated, or blast phase chronic myeloid leukemia (CML) or T315I-positive

Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). Treatment of adults with chronic, accelerated, or blast phase CML or Ph+ ALL for whom no other tyrosine kinase inhibitor (TKI) therapy is indicated. Adults: Swallow whole. ≥18yrs: initially 45mg once daily; consider reducing dose in chronic and accelerated phase CML if major cytogenic response achieved. Consider discontinuing if no response occurred by 3 months. Concomitant strong CYP3A inhibitors: reduce to 30mg once daily. Dose modification for hematologic and nonhematologic toxicity: see full labeling. Children: <18yrs: not established. Warnings/Precautions: Risk of vascular occlusion (eg, arterial and venous thrombosis, fatal MI, stroke, stenosis of arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures) in patients with or without CV risk factors (including ≤50yrs old, or increasing age, history of ischemia, HTN, diabetes, hyperlipidemia); monitor and interrupt or discontinue if occurs. Monitor for signs/symptoms of heart failure; interrupt or consider discontinuing if develops or worsens. Monitor hepatic function at baseline, then at least monthly or as needed; interrupt, reduce or discontinue as clinically indicated. Moderate-to-severe hepatic impairment: not recommended. Monitor and manage BP elevations; interrupt, reduce dose or discontinue if not controlled. Risk of pancreatitis; check serum lipase every 2 weeks for the first 2 months and then monthly thereafter or as clinically indicated; do not restart until complete resolution and lipase levels <1.5×ULN. Monitor for neuropathy; consider interrupting and evaluate if suspected. Conduct eye exams at baseline and periodically during treatment. Interrupt therapy and evaluate for serious/severe hemorrhage or cardiac arrhythmias. Monitor for fluid retention; interrupt, reduce, or discontinue as indicated. Obtain CBCs every 2 weeks for the first 3 months, then monthly or as indicated. Tumor lysis syndrome; ensure adequate hydration and treat uric levels prior to therapy. Compromised wound healing (withhold for 1 week prior to major surgery) and GI perforation. Elderly. Pregnancy (Cat.D); avoid. Nursing mothers: not recommended. Interactions: Potentiated by strong CYP3A inhibitors (eg, boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole); see Adult dose. Avoid concomitant strong CYP3A inducers (eg, carbamazepine, rifampin, phenytoin, St. John’s Wort), or drugs that elevate gastric pH

(eg, PPIs, H2 blockers, antacids). Caution with concomitant P-gp and ABCG2 substrates. Adverse reactions: Hypertension, rash, abdominal pain, fatigue, headache, dry skin, constipation, arthralgia, nausea, pyrexia, anemia, thrombocytopenia, leukopenia, neutropenia, lymphopenia; vascular occlusion, heart failure, hepatotoxicity, ocular toxicities, hemorrhage, myelosuppression. How supplied: Tabs 15mg–60, 180; 45mg–30, 90

IDAMYCIN Pfizer

℞

Anthracycline. Idarubicin HCl 20mg/vial; lyophilized pwd for IV infusion after reconstitution. ℞ Also: IDAMYCIN PFS Idarubicin 1mg/mL; soln for IV infusion; preservative-free. Indications: Acute myeloid leukemia. Adults: Give by slow IV infusion (over 10–15 minutes). 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 recommended. 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. 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: Single-dose vials (5mL, 10mL, 20mL)–1

IMBRUVICA

℞

Pharmacyclics and Janssen Biotech

Bruton’s tyrosine kinase (BTK) inhibitor. Ibrutinib 140mg; caps. Indications: Mantle cell lymphoma (MCL) in patients who have received at least one prior therapy. Chronic lymphocytic leukemia (CLL) in patients who have received at least one prior therapy. CLL in patients with 17p deletion. Adults: Swallow whole with water. MCL: 560mg once daily. CLL: 420mg once daily. Concomitant moderate CYP3A inhibitors: 140mg once daily. Dose modifications for toxicities: see full labeling. Children: Not established.

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER Warnings/Precautions: Risk of hemorrhage; consider the benefit/risk of withholding treatment for 3–7 days pre-and post-surgery. Monitor for fever and infections; evaluate promptly if occurs. Monitor for myelosuppression; obtain CBCs monthly. Periodically monitor for atrial fibrillation (esp. in those with cardiac risk factors, acute infections, history of atrial fibrillation); do ECG if arrhythmic symptoms or new onset dyspnea develop. Risk of second primary malignancies (eg, skin cancer or other carcinomas). Hepatic or renal impairment. Maintain adequate hydration. Pregnancy (Cat.D); avoid. Nursing mothers: not recommended. Interactions: Concomitant strong CYP3A inhibitors taken chronically (eg, ritonavir, indinavir, nelfinavir, saquinavir, boceprevir, telaprevir, nefazodone): not recommended; for 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. Adverse reactions: Thrombocytopenia, diarrhea, neutropenia, anemia, fatigue, musculoskeletal pain, peripheral edema, upper respiratory tract infection, nausea, bruising, dyspnea, constipation, rash, abdominal pain, vomiting, decreased appetite, pyrexia. How supplied: Caps–90, 120

INTRON A Merck

℞

Interferon alfa-2b, recombinant; 10 million, 18 million, or 50 million IU per vial; pwd; for inj after reconstitution/dilution; preservative-free. ℞ Also: INTRON A SOLN Interferon alfa-2b, recombinant; 10 million IU, 18 million IU, 25 million IU; per vial; for inj; contains m-cresol. Indications: Hairy cell leukemia. Initial treatment of clinically aggressive follicular Non-Hodgkin’s lymphoma in conjunction with anthracyclinecontaining combination chemotherapy. Adults: Use SC route if platelets <50,000/mm3. Hairy cell leukemia: 2 million IU/m2 IM or SC 3 times a week for up to 6 months. Follicular lymphoma: 5 million IU SC 3 times a week for up to 18 months in conjunction with anthracyclinecontaining chemotherapy regimen and following completion of the chemotherapy regimen. See literature for appropriate preparation and route and for dose adjustments. Children: Not recommended. Contraindications: Hepatitis: decompensated liver disease. Autoimmune disorders.

Warnings/Precautions: May cause or exacerbate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, or infectious disorders: monitor closely, discontinue if they worsen. Severe psychiatric disorders (esp. depression). Cardiovascular or pulmonary disease. Severe myelosuppression. Uncontrolled thyroid abnormalities. Diabetes. Coagulation disorders. Maintain adequate hydration. Monitor blood, thyroid, visual and liver function before and during therapy; EKG in cardiovascular disease and cancer patients. Psoriasis. Renal dysfunction. Transplant recipients. Elderly. Debilitated. Pregnancy (Cat.C). Nursing mothers: not recommended. Interactions: Caution with myelosuppressives, and drugs that can exacerbate depression. May potentiate theophylline (may double its levels). Adverse reactions: Flu-like symptoms (fever, headache, myalgia, fatigue); hepatic, hematologic, respiratory, skin, genitourinary system, CNS, cardiovascular, endocrine (esp thyroid), GI, or visual disorders; colitis, hypertriglyceridemia, pancreatitis, infections, injection site reactions; others (see literature). How supplied: Pwd (w. diluent): 10million, 18million, 50million IU/vial–1; Soln (vials): 10million IU/vial–6 (kit w. supplies); Soln (multidose vials): 18million, 25million IU/vial–1

ISTODAX Celgene

℞

Histone deacetylase inhibitor. Romidepsin 10mg/vial; pwd for IV infusion after reconstitution and dilution; contains povidone. Indications: Cutaneous T-cell lymphoma in patients who have received at least one prior systemic therapy. Peripheral T-cell lymphoma in patients who have received at least one prior therapy. Adults: ≥18yrs: Give by IV infusion over 4hrs. 14mg/m2 on days 1, 8, and 15 of a 28-day cycle; 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: Correct electrolyte imbalances (esp. K+, Mg++) before starting. Monitor ECG and electrolytes in congenital long QT syndrome, significant cardiovascular disease. Advanced stage disease and/or high tumor syndrome: monitor closely for tumor lysis syndrome. Moderate to severe hepatic impairment. End-stage renal disease. Monitor CBC with differential. Pregnancy (Cat.D; may cause fetal harm). Nursing mothers: not recommended. Interactions: Caution with other drugs that can cause QT prolongation (monitor). Monitor PT/INR with warfarin. Potentiated by drugs that inhibit P-glycoprotein and CYP3A4; avoid concomitant strong CYP3A4 inhibitors (eg, azole antifungals, protease inhibitors, clarithromycin, 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: Nausea, vomiting, fatigue, infections, anorexia, anemia, thrombocytopenia, ECG T-wave changes, neutropenia, lymphopenia; tumor lysis syndrome. How supplied: Kit–1 (single-use vial + diluent and supplies)

JAKAFI Incyte

℞

Kinase inhibitor. Ruxolitinib 5mg, 10mg, 15mg, 20mg, 25mg; tabs. Indications: Treatment of intermediate or highrisk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis. Treatment of polycythemia vera (PV) in patients with inadequate response to, or intolerant of, hydroxyurea. Adults: Doses may be given by NG tube if unable to swallow tabs. Myelofibrosis: Platelets >200×109/L: initially 20mg twice daily. Platelets 100–200×109/L: initially 15mg twice daily. Platelets 50–<100×109/L: initially 5mg twice daily. May increase doses by 5mg twice daily to a max of 25mg twice daily; do not increase during the first 4 weeks of therapy and not more frequently than every 2 weeks. Discontinue treatment after 6 months if no reduction in spleen size or symptom improvement. Interrupt treatment if platelets <50×109/L or ANC <0.5×109/L. May restart after recovery of platelets or ANC (see full labeling for max allowable restarting doses). Consider dose reductions if platelets decrease but remain ≥50×109/L (see full labeling). Dose modifications for patients starting treatment with platelets 50–<100×109/L: see full labeling. PV: initially 10mg twice daily. May increase doses by 5mg twice daily to a max of 25mg twice daily; do not increase during the first 4 weeks of therapy and not more frequently than every 2 weeks. Consider dose reductions for Hgb and/or platelet decreases (see full labeling). Interrupt treatment if Hgb <8g/dL, platelets <50×109/L, or ANC <1.0×109/L. May restart after recovery of hematologic parameters (see full labeling for max allowable restarting doses). Concomitant strong CYP3A4 inhibitors (see Interactions) or fluconazole ≤200mg (Myelofibrosis): initially 10mg twice daily if platelets ≥100×109/L; if platelets 50–<100×109/L: initially 5mg once daily; (PV): initially 5mg twice daily. Other reductions, hepatic or renal impairment, ESRD: see full labeling. Children: Not established. Warnings/Precautions: Monitor for thrombocytopenia, anemia, neutropenia; manage by reducing dose, interrupt, or transfusion if occur. Obtain CBC and platelets before initiating therapy, every 2–4 weeks until doses are stabilized, and then as clinically indicated. Risk of serious bacterial, mycobacterial, fungal,

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER and viral infections; evaluate and treat if signs/ symptoms occur. Confirm resolution of active infections before starting. May exacerbate myelofibrosis following treatment interruption or discontinuation. Risk of non-melanoma skin cancer; perform periodic skin exams. Avoid abrupt cessation. Renal or hepatic impairment. Pregnancy (Cat.C). Nursing mothers: not recommended. Interactions: Avoid concomitant fluconazole doses >200mg daily. Potentiated by strong CYP3A4 inhibitors (eg, boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole) and mild or moderate CYP3A4 inhibitors (eg, erythromycin). Antagonized by strong CYP3A4 inducers (eg, rifampin). Adverse reactions: Thrombocytopenia, anemia, bruising, dizziness, headache; herpes zoster, tuberculosis (monitor promptly and test for latent infection), progressive multifocal leukoencephalopathy (discontinue if occurs). How supplied: Tabs–60

KYPROLIS Onyx

℞

Proteasome inhibitor. Carfilzomib 60mg/vial; lyophilized pwd for IV inj after reconstitution; preservative-free. Indications: Treatment of patients with multiple myeloma who have received at least two prior therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of the last therapy. Adults: See literature. Premedicate with dexamethasone prior to all Cycle 1 doses, during 1st dose escalation and if infusion reactions occur. Give by IV over 2–10 minutes, on two consecutive days each week for 3 weeks (Days 1, 2, 8, 9, 15, and 16), followed by a 12-day rest period (Days 17–28). In Cycle 1: 20mg/m2 per each dose, if tolerated increase to 27mg/m2 starting in Cycle 2 and subsequent cycles; continue until disease progression or unacceptable toxicity occurs. On dialysis: give dose after session. Toxicity dose modification: see literature. Children: Not established. Warnings/Precautions: Risk of cardiac complications (eg, CHF, MI, pulmonary edema); monitor and manage promptly if occurs. Pulmonary hypertension; if suspected, withold therapy until resolved; may consider restarting after reevaluate. Monitor for dyspnea or tumor lysis syndrome, and manage promptly if occurs; interrupt therapy until resolved. Maintain adequate hydration. Monitor platelets frequently

during therapy. Hepatic impairment (monitor enzymes). Pregnancy (Cat.D); avoid. Nursing mothers: not recommended. Adverse reactions: Fatigue, anemia, nausea, thrombocytopenia, dyspnea, diarrhea, pyrexia; cardiac events, pulmonary HTN, infusion reactions, tumor lysis syndrome, hepatic toxicity/failure. 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)

MATULANE Sigma-Tau

℞

Alkylating agent. Procarbazine (as HCl) 50mg; caps. Indications: Stage III and IV Hodgkin’s disease as part of the MOPP (nitrogen mustard, vincristine, procarbazine, prednisone) regimen. Adults: Initially 2–4mg/kg per day for the first week, then 4–6mg/kg per day until max response is obtained or until WBCs <4,000cells/mm3 or platelets <100,000cells/mm3. Maintain at 1–2mg/kg per day once max response attained. In MOPP regimen: 100mg/m2 daily for 14 days. Children: Individualize. Initially 50mg/m2 per day for the first week, then 100mg/m2 per day until max response is obtained or leukopenia or thrombocytopenia occurs. Maintain at 50mg/m2 per day once max response attained. Contraindications: Inadequate marrow reserve. Warnings/Precautions: Discontinue if CNS effects (eg, paresthesias, neuropathies, confusion), leukopenia, thrombocytopenia, hypersensitivity reactions, stomatitis, diarrhea, hemorrhage or bleeding tendencies occur. Hepatic or renal impairment. Obtain baseline CBCs with differential, hemoglobin, hematocrit,

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER reticulocytes, platelets prior to therapy, then monitor at least every 3–4 days. Do renal and hepatic function tests before starting therapy, then repeated weekly. Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended. Interactions: Avoid sympathomimetics, tricyclic antidepressants (eg, amitriptyline, imipramine), foods with high tyramine content (eg, wine, yogurt, ripe cheese, bananas). CNS depression with barbiturates, antihistamines, narcotics, hypotensive agents, phenothiazines. Disulfiram-like reactions with alcohol. Separate radiation or other myelosuppressives by at least 1 month (allow for bone marrow recovery). Adverse reactions: Leukopenia, anemia, thrombopenia, GI upset, bleeding tendencies, CNS effects, dysphagia, anorexia, abdominal pain, hypotension, tachycardia, syncope, cough, alopecia, dermatitis, pain, others. How supplied: Caps–100

Mitoxantrone HCl (various)

℞

Topoisomerase II inhibitor. Mitoxantrone (as HCl) 2mg/mL; soln for IV infusion after dilution; preservative-free. Indications: Acute nonlymphocytic leukemia (ANLL) in combination with other approved drugs. Adults: Give by IV infusion. See full labeling for cytarabine dose. Induction therapy: 12mg/m2 daily on Days 1–3 + cytarabine on days 1–7; if 2nd induction course needed, give for 2 days + cytarabine for 5 days using same daily dosage levels. Consolidation therapy: 12mg/m2 on Days 1–2 + cytarabine on Days 1–5 for 2 courses (1st course given 6 weeks after the final induction course and the 2nd course given 4 weeks after the 1st course). Children: Not established. Warnings/Precautions: Risk of myelosuppression esp. in high doses (>14mg/m2 daily for 3 days); do not administer if baseline neutrophil count <1500 cell/mm3, except in ANLL. Increased risk of cardiotoxicity with pre-existing cardiovascular disease, prior radiotherapy to mediastinal/pericardial area, or previous anthracycline therapy. Assess cardiac history, physical exam, ECG, and LVEF prior to therapy. Increased risk of secondary acute myeloid leukemia. Hepatic impairment. Monitor CBCs, platelets, liver function tests prior to each course. Monitor for signs of infection. Avoid extravasation. Pregnancy (Cat.D); avoid. Nursing mothers: not recommended. Interactions: Caution with concomitant cardiotoxic drugs. Adverse reactions: Myelosuppression, nausea, vomiting, infection, fever, fatigue, alopecia, dyspnea, hypersensitivity reactions, bluishgreen urine, sclera discoloration, hyperuricemia (monitor), menstrual disorders, amenorrhea, interstitial pneumonitis; cardiotoxicity (eg, CHF). How supplied: Contact supplier.

MUSTARGEN Recordati

℞

Nitrogen mustard. Mechlorethamine HCl 10mg/vial; pwd for IV or intracavitary inj after reconstitution. Indications: Palliative treatment of Hodgkin’s disease (stages III and IV), lymphosarcoma, chronic myelocytic or chronic lymphocytic leukemia, polycythemia vera, mycosis fungoides. Palliative treatment of metastatic carcinoma resulting in effusion. Adults: By IV infusion, per therapeutic course: 0.4mg/kg (lean body weight) as single dose or in divided doses of 0.1–0.2mg/kg per day. See literature for intracavitary (eg, intrapleural) administration. Do not exceed recommended dose. Repeat course only after hematological recovery (eg, every 3 weeks). Children: See literature. Contraindications: Infectious diseases. Warnings/Precautions: Drug is highly toxic; verify potential benefits outweigh risks; avoid inadvertent contact with powder or vapor. Do not use if foci of acute and chronic suppurative inflammation are present. Ensure adequate hydration. Avoid extravasation. Chronic lymphatic leukemia. Bone marrow suppression. Previous X-ray, cytotoxic chemotherapy. Infection. Hemorrhagic tendency. Monitor renal, hepatic and bone marrow function. Elderly. Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended. Adverse reactions: Bone marrow suppression, hyperheparinemia, GI upset (may be severe), anorexia, weakness, thrombosis, thrombophlebitis, hypersensitivity, jaundice, alopecia, vertigo, auditory disturbances, hemolytic anemia, skin reactions, infection, amyloidosis, hyperuricemia, gonad damage. How supplied: Vials–4

MYLERAN GlaxoSmithKline

℞

Alkylating agent. Busulfan 2mg; tabs. Indications: Palliative treatment of chronic myelogenous leukemia. Adults: Remission induction: 4–8mg/day or 60micrograms/kg or 1.8mg/m2, daily. Reserve doses >4mg/day for severe cases. Reduce dose or discontinue at first sign of reduced bone marrow reserve. Discontinue before leukocyte count normalizes; see literature. Normal leukocyte counts usually achieved in 12–20 weeks. If remission <3 months, maintenance therapy of 1–3mg/day may be advisable. Children: Remission induction: 60micrograms/kg or 1.8mg/m2, daily. Reduce dose or discontinue at first sign of reduced bone marrow reserve. Discontinue before leukocyte count normalizes. Normal leukocyte counts usually achieved in 12–20 weeks. See literature. Warnings/Precautions: Confirm diagnosis. Monitor hepatic and bone marrow function. Obtain CBCs and differential weekly; monitor for anemia. Previously compromised bone marrow (irradiation, chemotherapy). Seizure disorder or

risk. Head trauma. Elderly. Pregnancy (Cat.D), nursing mothers: not recommended. Interactions: Myelosuppression increased with other myelosuppressives. Increased pulmonary toxicity with other cytotoxic drugs. Potentiated by itraconazole, cyclophosphamide (see literature). May be antagonized by phenytoin. Hepatotoxicity possible with long-term continuous thioguanine therapy. Caution with drugs that lower seizure threshold. Adverse reactions: See literature. Bone marrow suppression (eg, pancytopenia, anemia, leukopenia, thrombocytopenia, aplastic anemia), pulmonary toxicity, cellular dysplasia, malignant tumors, acute leukemias, cardiac tamponade (esp. in thalassemia), hyperpigmentation, adrenal insufficiency, seizures, hepatic veno-occlusive disease, infection (eg, pneumonia, sepsis), mucositis, myasthenia gravis, gonadal suppression, rash; rare: cataracts, bronchopulmonary dysplasia (discontinue if occurs). How supplied: Tabs–25

ONCASPAR Sigma-Tau

℞

Enzyme. Pegaspargase 750 IU/mL; soln for IV or IM inj; preservative-free. Indications: First-line acute lymphoblastic leukemia (including patients with asparaginase hypersensitivity). Adults and Children: Give by IV inj over 1–2hrs or by IM inj (max 2mL/inj site). 2500 IU/m2 no more frequently than every 14 days. Contraindications: History of pancreatitis, serious hemorrhage, or thrombosis with prior L-asparaginase therapy. Warnings/Precautions: Have resuscitation equipment available and observe patient for 1hr postdose. 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

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER 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; capsules. Indications: Multiple myeloma, in patients who have received at least two prior therapies (including lenalidomide and bortezomib), and have shown disease progression on or within 60 days of completion of the last therapy. Clinical benefit, such as improvement in survival or symptoms, has not been verified. 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; may give with dexamethasone. Dose modification for hematologic and other Grade 3/4 toxicities: see full labeling. Children: <18yrs: not established. Contraindications: Pregnancy (Cat.X): avoid during and for at least 4 weeks after completing therapy. Warnings/Precautions: Females of reproductive potential must commit either to abstain from heterosexual sex or to use two methods of reliable contraception, beginning 4 weeks prior to initiating, during therapy, dose interruptions and for 4 weeks after discontinuation. Obtain two negative pregnancy tests prior to initiating therapy: perform first test within 10–14 days, and second test within 24 hours 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 thromboembolism;

consider anticoagulation prophylaxis. Monitor for hematologic toxicities (esp. neutropenia); obtain CBCs weekly for first 8 weeks and monthly thereafter; may need dose interruption and/or modification. Renal impairment (serum creatinine >3mg/dL) or hepatic impairment (serum bilirubin >2mg/dL and AST/ALT >3x ULN): avoid. Risk of hypersensitivity or second primary malignancies. 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; venous thromboembolism, dizziness, confusion, neuropathy, pneumonia, thrombocytopenia. Note: Available only through Pomalyst REMS program. How supplied: Caps–21, 100

PURINETHOL Teva

℞

Antimetabolite. Mercaptopurine (6-MP) 50mg; scored tabs. Indications: Maintenance therapy of acute lymphatic leukemia as part of a combination regimen. Adults and Children: 1.5–2.5mg/kg per day as a single dose. Concomitant allopurinol: reduce dose of mercaptopurine to 1/3–1/4 of the usual dose. TPMT-deficient, renal or hepatic impairment: reduce dose, see literature. Contraindications: Prior resistance to mercaptopurine. Warnings/Precautions: Not effective in CNS leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, the lymphomas (including Hodgkin’s disease), or solid tumors. Renal impairment. Monitor liver function tests weekly at start of therapy, then monthly thereafter; discontinue if hepatotoxicity occurs. Preexisting liver disease (monitor more frequently). Obtain CBCs with differential, hemoglobin, hematocrit, platelets; discontinue if severe bone marrow suppression occurs. Thiopurine-Smethyltransferase (TPMT) deficient: increased risk of myelosuppression, consider genotypic/ phenotypic testing. Pregnancy (Cat.D); esp. 1st trimester, nursing mothers: not recommended. Interactions: Increased risk of bone marrow suppression with allopurinol, aminosalicylate derivatives (eg, olsalazine, mesalazine, sulphasalazine), trimethoprim-sulfamethoxazole. Antagonizes warfarin. Caution with concomitant hepatotoxic agents.

Adverse reactions: Myelosuppression, hyperuricemia/hyperuricosuria, GI upset, intestinal ulceration, rash, hyperpigmentation, alopecia, oligospermia; hepatotoxicity, infection, immunosuppression. How supplied: Tabs–60

PURIXAN Rare Disease

℞

Antimetabolite. Mercaptopurine (6-MP) 20mg/mL; oral susp; contains fruit extract, aspartame. Indications: Maintenance therapy of acute lymphoblastic leukemia as part of a combination regimen. Adults and Children: Shake bottle vigorously for at least 30 secs. Initially 1.5–2.5mg/kg (50–75mg/m2) per day as a single dose. Monitor subsequent doses to maintain desirable ANC level and adjust for excessive hematological toxicity. Thiopurine-S-methyltransferase (TPMT)-deficient: if homozygous, may require up to a 90% dose reduction; if heterozygous, some may require dose reduction based on toxicities. Renal 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

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER REVLIMID Celgene

℞

Immunomodulator. Lenalidomide 2.5mg, 5mg, 10mg, 15mg, 20mg, 25mg; caps; contains lactose. Indications: In combination with dexamethasone for treatment of patients with multiple myeloma (MM). Treatment of patients with mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib. Limitations of use: not for treating patients with chronic lymphocytic leukemia (CLL) outside of controlled clinical trials. Adults: Swallow whole with water. ≥18yrs: initially 25mg once daily on Days 1–21 of each 28-day cycle until disease progression or unacceptable toxicity. >75yrs: may reduce dexamethasone initial dose. Renal impairment: MCL: Moderate (CrCl 30–60mL/min): 10mg per day; MM: Moderate (CrCl 30–50mL/min): 10mg per day; consider increasing to 15mg after 2 cycles, if tolerant. Severe (CrCl <30mL/min without dialysis): 15mg every 48hrs. ESRD (CrCl <30mL/min with dialysis): 5mg once daily; administer after dialysis (on dialysis days). Autologous stem cell transplantation (ASCT) eligible: refer for hematopoietic cell mobilization within 4 cycles; if non-eligible, continue therapy until disease progression or unacceptable toxicity. Dose adjustments if thrombocytopenia or neutropenia develops: see full labeling. Children: <18yrs: not established. Contraindications: Pregnancy (Cat.X). Warnings/Precautions: Must register patient in Revlimid REMS program; patient must understand toxicity with fetal exposure. Counsel patient on need for contraception; females: use 2 forms of contraception 1 month before, during therapy, during dose interruptions, and 1 month after therapy; males: use condom during and 1 month after therapy; obtain 2 negative pregnancy tests (one within 10–14 days, and then another within 24hrs prior to starting therapy), repeat at least weekly for 1st month then every 4 weeks (regular menstrual cycles) or every 2 weeks (irregular cycles); get informed consent. Do not donate blood during and for 1 month after therapy. Monitor for signs/symptoms of thromboembolic events; base thromboprophylaxis on patient’s risks. For MM: obtain CBCs weekly for the first 2 cycles, on Days 1 and 15 of Cycle 3, and every 28 days thereafter; for MCL: obtain CBCs weekly for the first cycle, every 2 weeks during Cycles 2–4, and then monthly thereafter; both: dose interruption and/or reduction may be needed. May require blood product support and/or growth factors. Renal impairment (monitor). Monitor for tumor lysis syndrome in those with high tumor burden. Monitor liver enzymes; discontinue if elevation occurs. Monitor for second primary malignancies. Lactose intolerance. Maximum 1 month per ℞. Nursing mothers: not recommended. Interactions: Monitor digoxin. Concomitant warfarin; monitor PT, INR. May increase risk of thrombosis with dexamethasone, erythropoietic agents, or estrogen containing therapies.

Adverse reactions: Birth defects, thrombocytopenia, neutropenia, anemia, leukopenia, constipation, diarrhea, nausea, vomiting, pruritus, rash, fatigue, arthralgia, pyrexia, back pain, cough, dizziness, headache, dyspnea, nasopharyngitis, epistaxis, upper respiratory tract infection, tremor, blurred vision, muscle cramp, decreased appetite, peripheral edema; thrombosis/embolism, allergic reactions (discontinue if occurs; do not resume), tumor flare reaction (monitor; esp. in treating MCL), hepatotoxicity. Note: Available only through Revlimid REMS program. Report any suspected fetal exposure to the FDA at (800) FDA-1088 and Celgene at (888) 423-5436. How supplied: Caps 2.5mg, 5mg, 10mg–28, 100; 15mg, 20mg, 25mg–21, 100

RITUXAN Genentech

℞

CD20-directed cytolytic monoclonal antibody. Rituximab 10mg/mL; soln for IV infusion; preservative-free. Indications: Relapsed or refractory, low-grade or follicular, CD20(+), B-cell non-Hodgkin’s lymphoma (NHL). Previously untreated follcular, CD20(+), B-cell NHL in combination with first line chemotherapy and, in patients achieving a complete or partial response to Rituxan in combination with chemotherapy, as singleagent maintenance therapy. Non-progressing (including stable disease), low-grade, CD20(+), B-cell NHL as a single agent after first-line CVP chemotherapy. Previously untreated diffuse large B-cell, CD20(+) NHL (DLBCL) in combination with CHOP or other anthracycline-based chemotherapy regimens. CD20(+) chronic lymphocytic leukemia (CLL) in combination with fludarabine and cyclophosphamide. Limitation of use: not recommended for use in patients with severe, active infections. Adults: Give by IV infusion. Premedicate with an antihistamine and acetaminophen prior to each infusion. First infusion: initially at a rate of 50mg/hr; may increase infusion rate in 50mg/hr increments every 30 mins. Subsequent infusions: initially at a rate of 100mg/hr; may increase infusion rate in 100mg/hr increments every 30 mins. Both: max 400mg/hr if infusion reactions do not occur. Previously untreated follicular NHL and DLBCL patients: if no Grade 3 or 4 infusion related adverse events during Cycle 1, a 90-minute infusion may be given in Cycle 2 with a glucocorticoid-containing chemotherapy regimen (see full labeling). NHL: 375mg/m2 once weekly for 4 or 8 doses. Retreatment therapy: 375mg/m2 once weekly for 4 doses. Previously untreated, follicular, CD20(+), B-cell NHL: 375mg/m2 on Day 1 of each cycle of CVP chemotherapy for up to 8 doses. In patients with complete or partial response, initiate Rituxan maintenance 8 weeks following completion of Rituxan in combination with chemotherapy. Administer Rituxan as a single-agent every 8 weeks for 12

doses. Low-grade, CD20(+), B-cell NHL after CVP chemotherapy: 375mg/m2 once weekly for 4 doses every 6 months for up to 16 doses. Diffuse large B-cell NHL: 375mg/m2 on Day 1 of each cycle for up to 8 infusions. CLL: 375mg/m2 the day prior to FC chemotherapy, then 500mg/m2 on Day 1 of cycles 2–6 (every 28 days). Give PCP and antiherpetic viral prophylaxis during and up to 12 months after CLL therapy. As a component of Zevalin regimen: see full labeling. Children: Not established. Warnings/Precautions: Discontinue if severe infusion or mucocutaneous reactions occur (eg, urticaria, hypotension, angioedema, hypoxia, pulmonary infiltrates, acute respiratory distress syndrome, MI, ventricular fibrillation, cardiogenic shock, paraneoplastic pemphigus, StevensJohnson syndrome, lichenoid or vesiculobullous dermatitis, toxic epidermal necrolysis). Increased risk of HBV reactivation. Test/treat HBV infection prior to initiating therapy. Monitor for signs of hepatitis or HBV reactivation during and for several months after therapy; discontinue if HBV reactivation occurs. Tumor lysis syndrome (esp. with high tumor burden); monitor for renal toxicity, fluid balance, electrolyte abnormalities (correct if occurs); discontinue if SCr rises or oliguria occurs. Monitor for new-onset neurologic manifestations; discontinue if progressive multifocal leukoencephalopathy (PML) develops. Discontinue and treat if serious infections (eg, bacterial, fungal, viral) occur. Pre-existing cardiovascular disease; monitor during and after treatment. Monitor CBCs, platelet counts during 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

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER 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. Concomitant CYP3A4 inhibitors (see Interactions): consider reducing dose. Concomitant CYP3A4 inducers (see Interactions): consider increasing dose. See full labeling for dose adjustments with toxicity. Children: <18yrs: not established. Warnings/Precautions: History of QT prolongation. Proarrhythmic conditions. Cumulative high-dose anthracycline therapy. Monitor for signs/symptoms of cardiac dysfunction; treat appropriately if occur. Hypokalemia, hypomagnesemia; correct electrolyte imbalances before starting therapy. Monitor for pleural effusions. Increased risk of pulmonary arterial hypertension (PAH); evaluate for signs/symptoms of underlying cardiopulmonary disease before and during treatment; permanently discontinue if occurs. Obtain CBCs weekly for the first 2 months, then monthly thereafter. Hepatic impairment. Elderly. Pregnancy (Cat.D; use adequate contraception); nursing mothers: not recommended. Interactions: Avoid potent CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, ritonavir, atazanavir, indinavir, nefazodone, nelfinavir, saquinavir, telithromycin, voriconazole), grapefruit juice. May be antagonized by strong CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital), St. John’s wort: not recommended. Separate dosing of antacids by at least 2hrs; H2 blockers, proton pump inhibitors: not recommended. May potentiate drugs metabolized by CYP3A4 (eg, cyclosporine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, ergot alkaloids). Caution with concomitant anticoagulants or drugs that inhibit platelet function. Caution with antiarrhythmics or other drugs that may lead to QT prolongation. Adverse reactions: Myelosuppression (eg, severe thrombocytopenia, neutropenia, anemia), fluid retention (eg, ascites, edema, pleural and pericardial effusions), diarrhea, headache, dyspnea, musculoskeletal pain, rash, fatigue, nausea, severe hemorrhage (eg, CNS, GI); QT prolongation, cardiac events (eg, cardiomyopathy, CHF, fatal MI, left ventricular dysfunction), PAH. How supplied: Tabs 20mg, 50mg, 70mg–60; 80mg, 100mg, 140mg–30

SYNRIBO Teva

℞

Protein synthesis inhibitor. Omacetaxine mepesuccinate 3.5mg/vial; lyophilized powder for SC injection after reconstitution; contains mannitol; preservative-free. Indications: Treatment of adult patients with chronic or accelerated phase chronic myeloid leukemia (CML) with resistance and/or intolerance to two or more tyrosine kinase inhibitors (TKI). Adults: Induction: 1.25mg/m2 by SC injection twice daily for 14 consecutive days every 28 days, over a 28-day cycle. Repeat cycles every 28 days until hematologic response achieved. Maintenance: 1.25mg/m2 by SC injection twice daily for 7 consecutive days every 28 days, over a 28-day cycle, as long as clinically beneficial. Dose adjustments and modifications: see full labeling. Children: Not established. Warnings/Precautions: Risk of myelosuppression (thrombocytopenia, neutropenia, anemia), hemorrhage (cerebral, GI). Monitor CBCs with platelets weekly during induction, initial maintenance cycles, and every 2 weeks during later cycles. Monitor glucose levels (esp. in diabetics). Avoid in poorly controlled diabetes until glycemic control is established. Elderly. Pregnancy (Cat.D); avoid. Nursing mothers: not recommended. Interactions: Avoid concomitant anticoagulants, aspirin, NSAIDs if platelets <50,000/microliters; may increase risk of bleeding. Adverse reactions: Thrombocytopenia, anemia, neutropenia, diarrhea, nausea, fatigue, asthenia, injection site reaction, pyrexia, infection, lymphopenia; bleeding, hyperglycemia. How supplied: Single-use vial–1

TABLOID GlaxoSmithKline

℞

Antimetabolite. Thioguanine 40mg; tabs; scored. Indications: Remission induction and remission consolidation treatment of acute nonlymphocytic leukemias. Treatment of the chronic phase of chronic myelogenous leukemia (see literature). Adults and Children: See literature. Initially, 2mg/kg per day. If, after 4 weeks, with no improvement, no leukocyte or platelet depression, may increase to 3mg/kg per day. Total daily dose may be given at one time. Contraindications: Allergy to mercaptopurine. Warnings/Precautions: Not recommended for maintenance therapy or long-term continuous treatments; increased risk of liver toxicity (discontinue if occurs). Pre-existing liver disease. Monitor liver function tests weekly at start of therapy, then monthly thereafter. Thiopurine

methyltransferase (TPMT) enzyme deficiency (may need to reduce dose to avoid severe bone marrow suppression); consider testing for TPMT deficiency. Obtain hemoglobin, hematocrit, WBCs with differential, platelets frequently during therapy. Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended. Interactions: Avoid live vaccines (if immunocompromised). Caution with drugs that inhibit TPMT (eg, olsalazine, mesalazine, or sulphasalazine). Adverse reactions: Myelosuppression, hyperuricemia, GI upset, anorexia, stomatitis, hepatotoxicity, elevated liver enzymes, jaundice (discontinue if occurs). How supplied: Tabs–25

TARGRETIN Eisai

℞

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 >3×ULN occurs. Monitor WBC with differential and thyroid function at baseline and during

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER treatment; treat hypothyroidism if needed. Avoid sun and UV light. Nursing mothers: not recommended. Interactions: Concomitant gemfibrozil: not recommended. Levels may be increased by CYP3A4 inhibitors (eg, ketoconazole, itraconazole, erythromycin, grapefruit juice). Levels may be reduced by CYP3A4 inducers (eg, rifampin, phenobarbital, phenytoin). May potentiate antihyperglycemics (eg, insulin, sulfonylureas, thiazolidinediones); monitor. May potentiate or be potentiated by protein-bound drugs. May antagonize tamoxifen, hormonal contraceptives, other CYP3A4 substrates. Limit Vit. A supplements to avoid toxicity. May increase CA125 assay values. Adverse reactions: Lipid abnormalities, headache, hypothyroidism, asthenia, leukopenia, anemia, rash, GI disturbances, peripheral edema, dry skin, exfoliative dermatitis, alopecia, insomnia, fatigue, abnormal liver function tests, pancreatitis, pruritus, photosensitivity. How supplied: Caps–100

TARGRETIN GEL Eisai

℞

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). 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

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HEMATOLOGIC CANCER months; discontinue if symptoms develop. Monitor for signs/symptoms of thromboembolic events, neutropenia, bradycardia, syncope, orthostatic hypotension, tumor lysis syndrome. Reevaluate if ANC <750/mm2; consider withholding if neutropenia persists. Measure HIV viral load after 1st and 3rd months, and every 3 months thereafter. Discontinue if pregnancy or severe skin rash occurs. History of seizure. Avoid contact with non-intact capsule or powder content. Maximum 1 month per ℞. Interactions: Increased sedative effect with barbiturates, alcohol, chlorpromazine, reserpine. Caution with drugs associated with peripheral neuropathy. Avoid drugs (eg, rifampin, carbamazepine, St. John’s wort) that decrease effectiveness of hormonal contraceptives. Increased risk of thromboembolism with concomitant erythropoietic agents, or estrogencontaining therapies in those receiving thalidomide with dexamethasone. Adverse reactions: Fatigue, birth defects, somnolence, skin rash (eg, Stevens-Johnson Syndrome, toxic epidermal necrolysis), headache, bradycardia, peripheral neuropathy, seizures, drowsiness, dizziness, orthostatic hypotension, leukopenia, anorexia, nausea, anxiety, asthenia, tremor, fever, weight loss, dry skin, neutropenia, increased HIV viral load, constipation, confusion, hypocalcemia, edema, dyspnea, thrombosis/ embolism. Note: Available only through STEPS program. Suspected fetal exposure must be reported to the FDA at (800) FDA-1088 and Celgene at (888) 423-5436. How supplied: Blister packs (50mg)–1, 28; (100mg, 150mg, 200mg)–28

TREANDA Teva

℞

Alkylating agent. Bendamustine HCl 90mg/mL; soln for IV infusion after dilution; 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 30 minutes. 100mg/m2 on Days 1 and 2 of a 28-day cycle, up to 6 cycles. Hematologic toxicity (≥Grade 3): reduce dose to 50mg/m2 on Days 1 and 2 of each cycle; if toxicity recurs, reduce dose to 25mg/m2 on Days 1 and 2. Non-hematologic toxicity (clinically significant ≥Grade 3): reduce dose to 50mg/m2 on Days 1 and 2 of each cycle. Subsequent cycles: may consider dose re-escalation. NHL: Give by IV infusion over 60 minutes. 120mg/m2 on Days 1 and 2 of a 21-day

cycle, up to 8 cycles. Hematologic toxicity (Grade 4) or non-hematologic toxicity (≥Grade 3): reduce dose to 90mg/m2 on Days 1 and 2 of each cycle; if toxicity recurs, reduce dose to 60mg/m2 on Days 1 and 2. Delay treatment for Grade 4 hematologic toxicity or clinically significant ≥Grade 2 nonhematologic toxicity. Severe renal impairment (CrCl <40mL/min) or moderate to severe hepatic impairment: not recommended. Children: Not established. Warnings/Precautions: Myelosuppression; monitor leukocytes, platelets, hemoglobin, neutrophils closely; restart treatment based on ANC and platelet count recovery. Renal or hepatic impairment. Monitor for infection, infusion or skin reactions, tumor lysis syndrome. Avoid extravasation. Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended. Interactions: May be potentiated or antagonized by CYP1A2 inhibitors, inducers; consider alternatives. Adverse reactions: Lymphopenia, anemia, leukopenia, thrombocytopenia, neutropenia, pyrexia, nausea, vomiting, diarrhea, asthenia, fatigue, malaise, dry mouth, somnolence, cough, constipation, headache, mucosal inflammation, stomatitis, increased bilirubin, increased AST or ALT; infection, infusion reactions (discontinue if severe), tumor lysis syndrome, skin reactions (if severe or progressive, withhold dose or discontinue), other malignancies (eg, myelodysplastic syndrome, acute myeloid leukemia, bronchial carcinoma). How supplied: Single-use vial (45mg/0.5mL, 180mg/2mL)–1

TREXALL Teva

℞

Folic acid antagonist. Methotrexate sodium 5mg, 7.5mg, 10mg, 15mg; scored tabs. Also: Methotrexate injection Bedford ℞ Methotrexate 25mg/mL; soln for IV, IM, intraarterial, or intrathecal administration after dilution; preservative-free. Also: Methotrexate for injection Bedford ℞ Methotrexate 1g/vial; pwd for IV, IM, intra-arterial, or intrathecal administration after dilution; preservative-free. Indications: Prophylaxis and treatment of meningeal leukemia. Advanced mycosis fungoids (cutaneous T cell lymphoma). Advanced nonHodgkin’s lymphomas. Adults: See literature. Tablet form is often preferred when low doses are being administered. Leukemia: Induction: 3.3mg/m2 + prednisone, given daily; maintenance: give twice weekly either orally or by IM inj for a total weekly dose of 30mg/m2; or 2.5mg/kg IV every 14 days.

Meningeal leukemia (treatment): 12mg/m2 intrathecally (max 15mg) at intervals of 2–5 days; see literature for prophylaxis treatment. Burkitt’s tumor (stage I–II): 10–25mg per day orally for 4–8 days. Lymphosarcomas (stage III): 0.625–2.5mg/kg daily. Mycosis fungoides (cutaneous T cell lymphoma): 5–50mg once weekly. Children: See literature. Contraindications: Pregnancy (Cat.X). Nursing mothers. Warnings/Precautions: Be fully familiar with this drug’s toxicity before use. Discontinue if malignant lymphomas occur. Obtain baseline and monitor CBCs with differential, platelet counts, chest X-ray, and hepatic, renal and pulmonary function. During therapy monitor hematology monthly, renal and hepatic function every 1–2 months, more often if increasing dose or predisposed to toxicity (eg, dehydration). Discontinue immediately if blood counts drop significantly. Rule out pregnancy in women of childbearing potential; use effective contraception during therapy and for at least 1 ovulatory cycle afterwards for women and for at least 3 months afterwards for men. Interrupt therapy if vomiting, diarrhea, stomatitis, or pulmonary symptoms occur. Hepatic or renal impairment. Obesity. Diabetes. Peptic ulcer. Ulcerative colitis. Infection. Dehydration. Folate deficiency. Ascites, pleural effusions: evacuate fluid, monitor for toxicity and reduce dose or discontinue if needed. Elderly (use low doses and monitor closely). Debilitated. Interactions: Avoid live virus vaccines. Toxicity increased by NSAIDs, salicylates, phenytoin, sulfonylureas, sulfonamides, probenecid, folic acid 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

HEMATOLOGIC CANCER 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, wraparound sunglasses and cover exposed skin (or use sunblock: SPF ≥15) for 24hrs after treatment. Basal cell carcinomas (monitor and treat if occur). Pregnancy (Cat.D); nursing mothers: not recommended. Interactions: Increased photosensitivity with anthralin, coal tar, griseofulvin, phenothiazines, nalidixic acid, halogenated salicylanilides, sulfonamides, tetracyclines, thiazides, organic staining dyes. Adverse reactions: Hypotension secondary to changes in extracorporeal volume. How supplied: Vials (10mL)–12

VALCHLOR Actelion

℞

Nitrogen mustard. Mechlorethamine 0.016%; topical gel; contains propylene glycol, isopropyl alcohol. Indications: Treatment of Stage IA and IB mycosis fungoides-type cutaneous T-cell lymphoma in patients who have received prior skin-directed therapy. Adults: Apply a thin film once daily to affected areas of the skin. Apply to completely dry skin ≥4 hours before or 30 minutes after showering or washing. Allow treated areas to completely dry for 5–10 minutes after applying. Wash hands thoroughly after application. Discontinue if any grade of skin ulceration, blistering, or moderatelyto-severe, or severe dermatitis occur; restart at reduced frequency of once every 3 days upon improvement; if reintroduction is tolerated for at least 1 week, can increase to every other day for 1 week and then once daily if tolerated. Children: Not established. Warnings/Precautions: Mucosal (oral, nasal) or eye exposure; blindness and severe irreversible anterior eye injury may occur; immediately irrigate for ≥15 minutes with copious amounts of water. Secondary exposure; avoid direct skin contact with patient. Risk of dermatitis (eg, face, genitalia, anus, and intertriginous skin); monitor for redness, swelling, inflammation, itchiness, blisters,

ulceration, and secondary skin infections. Monitor for nonmelanoma skin cancer during and after treatment. Flammable (avoid fire and flame until gel has dried). Pregnancy (Category D); may cause fetal harm. Nursing mothers: not recommended. Adverse reactions: Dermatitis, pruritus, bacterial skin infection, skin ulceration or blistering, hyperpigmentation. How supplied: Gel–60g

VELCADE Millennium

℞

Proteasome inhibitor. Bortezomib 3.5mg/vial; lyophilized pwd for IV or SC inj after reconstitution; contains mannitol. Indications: Multiple myeloma. Mantle cell lymphoma. Adults: Give as a 3–5 second IV bolus inj or as SC inj into thigh or abdomen (rotate sites). Previously untreated multiple myeloma: Treat for nine 6-week cycles in combination with oral melphalan and oral prednisone. Cycles 1–4: 1.3mg/m2 twice weekly (Days 1, 4, 8, 11, 22, 25, 29, 32); Cycles 5–9: 1.3mg/m2 once weekly (Days 1, 8, 22, 29). Previously untreated mantle cell lymphoma: Treat for six 3-week cycles in combination with IV rituximab, cyclophosphamide, doxorubicin, and oral prednisone. 1.3mg/m2 twice weekly for 2 weeks (Days 1, 4, 8, 11) then 10 day rest period (Days 12–21); if response first documented at Cycle 6, two more cycles are recommended. Relapsed multiple myeloma or mantle cell lymphoma: Standard schedule: 1.3mg/m2 twice weekly for 2 weeks (Days 1, 4, 8, 11) then 10 day rest period (Days 12–21); Extended therapy (if using >8 cycles): may use standard schedule, or maintenance schedule: 1.3mg/m2 once weekly for 4 weeks (Days 1, 8, 15, 22) then 13-day rest period (Days 23–35). Multiple myeloma patients who have previously responded to bortezomib (alone or in combination) and have relapsed at least 6 months after completing prior bortezomib therapy: may retreat starting at last tolerated dose, given twice weekly every 3 weeks (Days 1, 4, 8, 11); max 8 cycles. Allow at least 72hrs between consecutive doses. May be given as a single agent or in combination with dexamethasone. Dose modifications: see full labeling. SC inj may be considered for patients with pre-existing or at high-risk of peripheral neuropathy. Moderate-tosevere hepatic impairment: reduce to 0.7mg/m2 in 1st cycle; may consider dose increase to 1mg/m2 or further decrease to 0.5mg/m2 in subsequent cycles based on tolerance. Children: Not established. Contraindications: Boron or mannitol sensitivity. Intrathecal administration.

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER 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 evaluate if new or worsening cardiopulmonary symptoms develop. Monitor CBC frequently during therapy and platelets prior to each dose; adjust dose/ schedule for thrombocytopenia (see full labeling). Monitor for toxicities. High tumor burden (monitor for tumor lysis syndrome). Pregnancy (Cat.D); avoid. Nursing mothers: not recommended. Interactions: Concomitant strong CYP3A4 inducers (eg, rifampin): not recommended; efficacy may be reduced. Avoid St. John’s Wort. Potentiated by strong CYP3A4 inhibitors (eg, ketoconazole, ritonavir); consider reducing bortezomib dose. Caution with hypotensives and hypoglycemics. Adverse reactions: GI toxicity (eg, nausea, diarrhea, constipation, vomiting; interrupt therapy if severe), thrombocytopenia, neutropenia, anemia, leukopenia, lymphopenia, peripheral neuropathy, fatigue, neuralgia, rash, pyrexia, anorexia, asthenia, herpes reactivation, insomnia, dyspnea, paresthesia, headache, decreased appetite, dizziness, blurred vision, edema, arthralgia, pain, dysesthesia, psychiatric disorders, cough, pruritus, orthostatic hypotension, CHF, decreased LVEF, hepatotoxicity; rare: posterior reversible encephalopathy syndrome (discontinue if occurs). How supplied: Single-dose vial–1

VESANOID Roche

℞

Retinoid. Tretinoin 10mg; soft gelatin caps; contain parabens. Indications: Induction of remission in patients with acute promyelocytic leukemia (APL), FrenchAmerican-British (FAB) classification M3 (including the M3 variant), characterized by the presence of the t(15;17) translocation and/or the presence of the PML/RARα gene who are refractory to, or who have relapsed from, anthracycline chemotherapy, or for whom anthracycline-based chemotherapy is contraindicated. Adults: Use only for induction of remission. 45mg/m2 per day in two divided doses until complete remission is documented. Discontinue 30 days after complete remission or after 90 days of treatment, whichever occurs first. Children: See literature. Warnings/Precautions: Confirm APL diagnosis. Monitor for Retinoic Acid-APL (RA-APL) syndrome, leukocytosis, pseudotumor cerebri, or respiratory compromise. Consider temporarily interrupting therapy if moderate to severe RA-APL syndrome develops. Monitor blood counts, coagulation profile, lipids, liver function; consider temporary withdrawal if tests >5×ULN. Pregnancy (Cat.D); obtain negative pregnancy test 1 week before starting treatment, counsel patient about

need to use 2 effective methods of contraception during, and 1 month after therapy. Nursing mothers: not recommended. Interactions: Do not administer with Vitamin A. May be potentiated or antagonized by CYP450 enzyme inducers or inhibitors. Caution with anti-fibrinolytic agents; and other agents known to cause pseudotumor cerebri/intracranial hypertension. Adverse reactions: Headache, fever, skin/ mucous membrane dryness, bone pain, GI upset, rash, mucositis, pruritus, increased sweating, visual disturbances, alopecia; RA-APL syndrome, leukocytosis, pseudotumor cerebri, hypercholesterolemia/hypertriglyceridemia, others. How supplied: Caps–100

VIDAZA Celgene

℞

Cytidine analogue. Azacitidine 100mg/vial; lyophilized pwd for SC inj after reconstitution or IV inj after reconstitution and dilution; contains mannitol; preservative-free. Indications: Myelodysplastic syndromes (refractory anemias, chronic myelomonocytic leukemia). Adults: Premedicate for nausea & vomiting. Initially 75mg/m2 SC (doses >4mL divide equally into 2 syringes and inject into 2 separate sites) or IV (infuse over 10–40 mins, must complete within 1hr of reconstitution) daily for 7 days; repeat cycle every 4 weeks. May increase to 100mg/m2 after 2 cycles if no response and no toxicity. Treat for at least 4–6 cycles. Adjust subsequent doses on blood counts and toxicities (eg, neutropenia, thrombocytopenia, decreased serum bicarbonate). Children: Not established. Contraindications: Advanced malignant hepatic tumors. Warnings/Precautions: Renal or hepatic impairment. High tumor burden. Obtain CBC counts before each dosing cycle and as needed. Monitor serum bicarbonate and renal and hepatic function (do baseline liver chemistries and serum creatinine). Elderly. Pregnancy (Cat.D); use appropriate contraception (both men and women). Nursing mothers: not recommended. Adverse reactions: Nausea, vomiting, diarrhea, blood dyscrasias (esp. anemia, thrombocytopenia, neutropenia, leukopenia), fever, fatigue, inj site reactions, constipation, ecchymosis, petechiae, rigors, dyspnea, arthralgia, headache, anorexia, renal failure/tubular acidosis, hypokalemia, hepatic coma, others (see full labeling). How supplied: Single-use vial–1

VUMON Bristol-Myers Squibb

℞

Topoisomerase inhibitor. Teniposide 10mg/mL; soln for IV infusion after dilution; contains benzyl alcohol, Cremophor EL (polyoxyethylated castor oil), dehydrated alcohol. Indications: Refractory childhood acute lymphoblastic leukemia.

Adults and Children: See literature. Give as slow IV infusion (at least 30–60 minutes). Patients failing induction therapy with a cytarabine-containing regimen: 165mg/m2 + cytarabine twice weekly for 8 to 9 doses. Refractory to vincristine/prednisone-containing regimen: 250mg/m2 + vincristine weekly for 4 to 8 weeks + oral prednisone for 28 days. Warnings/Precautions: Severe myelosuppression. Monitor for hypersensitivity reactions following infusion; have epinephrine available. Risk of hypotension with rapid IV administration. Hepatic dysfunction. Monitor and obtain CBCs with differential, hemoglobin, platelets, renal and hepatic functions before, during, and after therapy. Down syndrome (use reduced dose). Monitor children with hypoalbuminemia. Avoid extravasation. Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended. Interactions: Potentiated by tolbutamide, sodium salicylate, and sulfamethizole. Concomitant vincristine sulfate may cause neuropathy. Concomitant antiemetics in patients given high doses of teniposide may increase risk of CNS depression, hypotension. Adverse reactions: Myelosuppression (leukopenia, neutropenia, thrombocytopenia, anemia), mucositis, GI upset, infection, alopecia, bleeding, rash, fever, hypotension, CNS depression, hypersensitivity reactions (may be fatal). How supplied: Ampules (5mL)–1

ZEVALIN Spectrum

℞

Radionuclide (B-lymphocyte-restricted differentiation antigen [CD20] inhibitor). Ibritumomab tiuxetan 3.2mg/2mL; soln for IV inj; contains albumin; preservative-free. Indications: B-cell non-Hodgkin’s lymphoma (relapsed or refractory, low grade or follicular). Previously untreated follicular non-Hodgkin’s lymphoma in patients who achieve a partial or complete response to first-line chemotherapy. Adults: See literature. Prepare In-111 Zevalin and Y-90 Zevalin as directed. Initiate Zevalin therapy after recovery of platelets to ≥150000/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 100000–149000cells/mm3, reduce dose to 0.3 mCi/kg. Do not treat if platelets <100000cells/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

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HEMATOLOGIC CANCER marrow reserve (eg, prior myeloablative therapies, platelet count <100000cells/mm3, neutrophil count <1500cells/mm3), or history of failed stem cell collection: not recommended. Monitor for cytopenias and complications (eg, febrile neutropenia, hemorrhage) for up to 3 months after treatment. Obtain CBCs, platelets weekly until levels recover. Avoid extravasation. Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended. Interactions: Caution with anticoagulants, platelet aggregation inhibitors, or live viral vaccines. Separate growth factor treatment by 2 weeks before and after Zevalin therapy. Adverse reactions: Neutropenia, leukopenia, thrombocytopenia, anemia, infections, asthenia, musculoskeletal symptoms, GI upset, abdominal pain, fatigue, nasopharyngitis, cough, dizziness, hemorrhage, altered biodistribution; infusion reactions, severe cutaneous/mucocutaneous reactions: both may be fatal, discontinue if occurs; leukemia and myelodysplastic syndrome. Note: Indium-11 chloride sterile solution must be ordered separately at the time the In-11 Zevalin kit is ordered. Yttrium-90 chloride sterile solution will be shipped directly upon placement of order for Y-90 Zevalin kit. How supplied: In-111 Zevalin kit (ibritumomab tiuxetan 3.2mg/2mL vial + sodium acetate vial + formulation buffer vial + empty reaction vial)–1 Y-90 Zevalin kit (ibritumomab tiuxetan 3.2mg/2mL vial + sodium acetate vial + formulation buffer vial + empty reaction vial)–1

ZOLINZA Merck

℞

Histone deacetylase inhibitor. Vorinostat 100mg; caps. Indications: Refractory cutaneous T-cell lymphoma. Adults: Take with food. Swallow whole. 400mg once daily. If not tolerated, may reduce to 300mg once daily, then to 300mg once daily 5 days/week if needed. Continue until disease progression or not tolerated. Children: <18yrs: not recommended. Warnings/Precautions: Renal or hepatic impairment. Monitor for DVT, pulmonary embolism. Correct electrolyte disturbances before starting therapy. Maintain adequate hydration. Diabetes. Monitor CBC, platelets, blood glucose, serum creatinine, electrolytes (esp. potassium, calcium, magnesium) every 2 weeks for 1st 2 months, then monthly. Pregnancy (Cat.D). Nursing mothers: not recommended. Interactions: Increased risk of thrombocytopenia and GI bleed with other HDAC inhibitors (eg, valproic acid). Concomitant warfarin: monitor PT, INR.

Adverse reactions: GI upset, fatigue, chills; thrombocytopenia, anemia (may need to modify dose or discontinue); anorexia, dysgeusia, pulmonary embolism, DVT, hyperglycemia. How supplied: Caps–120

ZOMETA Novartis

℞

Bisphosphonate. Zoledronic acid 4mg/5mL concentrated soln for IV infusion after dilution; 4mg/100mL ready-to-use soln for IV infusion. Indications: Adjunct in multiple myeloma and bone metastases of solid tumors. Limitation of use: not established for use in hyperparathyroidism or nontumor-related hypercalcemia. Adults: Give by IV infusion over at least 15 minutes. CrCl >60mL/min: 4mg; CrCl 50–60mL/min: 3.5mg; CrCl 40–49mL/min: 3.3mg; CrCl 30–39mL/min: 3mg; CrCl <30mL/min: see full labeling; all: every 3–4 weeks (give oral multivitamin supplement with calcium 500mg + Vit. D 400 IU daily). Children: Not recommended. Warnings/Precautions: Not recommended for use in patients with bone metastases with severe renal impairment. Renal or hepatic insufficiency. Check serum creatinine before each dose: withhold until serum creatinine is within 10% of baseline if serum creatinine increases by 0.5 mg/dL from a normal pre-treatment level, or by 1 mg/dL from an abnormal pre-treatment level, within 2 weeks of next dose. Assure adequate hydration when treating hypercalcemia of malignancy. Correct hypocalcemia before initiating treatment; supplement with calcium and vitamin D. Closely monitor electrolytes (esp. calcium, magnesium, phosphate), CBC/ differential, hematocrit, hemoglobin. Evaluate if thigh or groin pain develops and consider discontinuing if atypical femur fracture is suspected. Aspirin-sensitive asthma. Avoid dental surgery (do preventative dental work before therapy). Elderly. Pregnancy (Cat.D). Nursing mothers: not recommended. Interactions: Avoid concomitant other bisphosphonates. Additive hypocalcemic effect with aminoglycosides, loop diuretics. Caution with other nephrotoxic drugs (eg, thalidomide). Adverse reactions: Nausea, fatigue, anemia, musculoskeletal pain (discontinue if severe), constipation, fever, vomiting, dyspnea, flu-like syndrome, electrolyte disturbances, hypotension, CNS effects, rigors, headache, paresthesia, renal toxicity; jaw osteonecrosis, atypical subtrochanteric, diaphyseal femoral fractures, severe hypocalcemia. How supplied: Single-use vial, ready-to-use bottle–1

ZYDELIG Gilead

℞

Phosphatidylinositol 3-kinase inhibitor. Idelalisib 100mg, 150mg; tabs. Indications: Relapsed chronic lymphocytic leukemia (CLL), in combination with rituximab, in patients for whom rituximab alone would be considered appropriate due to other co-morbidities. Relapsed follicular B-cell nonHodgkin lymphoma (FL) in patients who have received at least 2 prior systemic therapies. Relapsed small lymphocytic lymphoma (SLL) in patients who have received at least 2 prior systemic therapies. Adults: Swallow whole. ≥18yrs: initially 150mg twice daily; continue until disease progression or unacceptable toxicity. Dose modifications: see full labeling. Children: <18yrs: not established. Contraindications: History of serious allergic reactions including anaphylaxis and toxic epidermal necrolysis. Warnings/Precautions: Risk of fatal/ serious hepatotoxicity: monitor ALT/AST every 2 weeks for the first 3 months, every 4 weeks for the next 3 months, then every 1–3 months thereafter; if ALT/AST >3×ULN, monitor weekly until resolved; if ALT/AST >5×ULN, withhold and continue monitoring weekly until resolved. Monitor for diarrhea or colitis; withhold if severe and discontinue if life-threatening. Risk of fatal/ serious pneumonitis; monitor for pulmonary symptoms, interstitial infiltrates, or a decline by >5% in oxygen saturation; if suspected, interrupt or discontinue as indicated. Risk of fatal/serious intestinal perforation; discontinue permanently if occurs. Monitor for severe cutaneous or serious allergic reactions; discontinue if occur. Monitor CBCs at least every 2 weeks for the first 3 months, and at least weekly if neutrophils <1.0Gi/L. Pregnancy (Cat.D); avoid. Use effective contraception during treatment and for at least 1 month after last dose. Nursing mothers: not recommended. Interactions: Avoid concomitant drugs that may cause hepatotoxicity or diarrhea. Avoid concomitant strong CYP3A inducers (eg, rifampin, phenytoin, St. John’s wort, carbamazepine) or CYP3A substrates (eg, oral midazolam). Concomitant strong CYP3A inhibitors (eg, ketoconazole); monitor for idelalisib toxicity. Adverse reactions: Diarrhea, pyrexia, fatigue, nausea, cough, pneumonia, abdominal pain, chills, rash, neutropenia, hypertriglyceridemia, hyperglycemia, ALT/AST elevations. How supplied: Tabs–60

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DRUG MONOGRAPHS

LUNG CANCER ABRAXANE Celgene

℞

Taxane antimicrotubule. Paclitaxel [bound to albumin (human)] 100mg/vial; pwd for IV infusion after reconstitution; solvent-free. Indications: First-line treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC), in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy. Adults: Do not treat if neutrophil count <1,500 cells/mm3 or platelets <100,000 cells/mm3. In combination with carboplatin: 100mg/m2 IV over 30 minutes 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. Monitor for sensory neuropathy, sepsis, or pneumonitis. Hepatic or renal dysfunction. Contains human albumin; remote risk of viral transmission. Use appropriate contraception (men and women). Pregnancy (Cat.D), nursing mothers: not recommended. Interactions: May potentiate or be potentiated by CYP2C8 and/or CYP3A4 inducers (eg, rifampin, carbamazepine, phenytoin, efavirenz, nevirapine) and/or inhibitors (eg, ketoconazole, other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir, nelfinavir). Adverse reactions: Bone marrow suppression (eg, neutropenia, anemia), infections, alopecia, sensory neuropathy (may require dose reduction or interruption), peripheral neuropathy, GI upset, mucositis, fatigue/asthenia, myalgia/arthralgia, abnormal ECG; alkaline phosphatase or AST elevation; dyspnea, edema, hypotension, rash (may be serious); rare: thrombotic events. How supplied: Single-use vial–1

ALIMTA Lilly

℞

Antifolate. Pemetrexed 100mg/vial, 500mg/vial; pwd for IV inj after reconstitution and dilution; preservative-free. Indications: Locally advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC): in combination with cisplatin as initial treatment, or as maintenance in patients whose disease has not progressed after 4 cycles of platinum-based 1st-line chemotherapy; or as a single agent after prior chemotherapy. Malignant pleural mesothelioma (MPM): in combination with cisplatin in patients whose disease is either unresectable or who are otherwise not candidates for curative surgery. Limitations of use: not for the treatment of squamous cell NSCLC. Adults: See full labeling. 500mg/m2 by IV infusion over 10 mins on Day 1 of each 21-day cycle. Adjust

dose if toxicity (esp. myelosuppression) develops. Combination therapy: Give cisplatin beginning 30 mins after pemetrexed infusion. Supplement with oral folic acid and intramuscular vitamin B12 prior to initiating pemetrexed and continue during treatment. Pretreat with corticosteroid the day before, the day of, and day after pemetrexed. Children: Not recommended. Warnings/Precautions: See full labeling. Renal impairment (CrCl <45mL/min): not recommended. Discontinue if Grade 3 or 4 neurotoxicity occurs, or if any Grade 3 or 4 toxicity occurs after two dose reductions. Do not start a treatment cycle unless ANC is ≥1500cells/mm3, platelets ≥100,000cells/mm3 and CrCl ≥45mL/min. Hepatic impairment. Monitor CBCs, platelets, renal and hepatic function. Clinically significant third space fluid: consider draining effusion first. Pregnancy (Cat.D); avoid, use effective contraception. Nursing mothers: not recommended. Interactions: May be potentiated by nephrotoxic agents, drugs eliminated by renal tubular secretion (eg, probenecid). Concomitant NSAIDs: use caution in patients with mild to moderate renal insufficiency (esp. ibuprofen). Adverse reactions: Fatigue, nausea, anorexia, vomiting, stomatitis, pharyngitis, constipation, fever, infection with neutropenia, rash, desquamation, neutropenia, leukopenia, anemia, thrombocytopenia, elevated creatinine, chest pain, neuropathy; rare: renal failure. Testing considerations: TS (thymidylate synthase) expression for response and toxicity How supplied: Single-use vial–1

AVASTIN Genentech

℞

Angiogenesis inhibitor. Bevacizumab 100mg, 400mg; per vial; soln for IV infusion after dilution; preservative-free. Indications: First-line treatment of unresectable, locally advanced, recurrent or metastatic nonsquamous, non-small cell lung cancer (NSCLC), in combination with carboplatin and paclitaxel. Adults: Give by IV infusion. Infuse 1st dose over 90 mins; if tolerated, infuse 2nd dose over 60 mins, and subsequent doses over 30 mins. 15mg/kg every 3 weeks with carboplatin/paclitaxel. Children: Not established. 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 (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 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 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

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DRUG MONOGRAPHS

LUNG CANCER syndrome develops. Pregnancy (Cat.C); avoid; use effective contraception during therapy and for ≥3 months after completion. Nursing mothers: not recommended. Adverse reactions: Hypertension, diarrhea, headache, fatigue, hyponatremia, anemia, intestinal obstruction, neutropenia, epistaxis, stomatitis/mucosal inflammation, rash, arterial thromboembolic events, proteinuria, GI perforation, infusion-related reactions. How supplied: Single-dose vial (10mL, 50mL)–1

Etoposide Capsules (various)

℞

Topoisomerase inhibitor. Etoposide 50mg; contain parabens. Indications: Small cell lung cancer. Adults: Round dose to nearest 50mg increment. Range: 70mg/m2 per day for 4 days to 100mg/m2 per day for 5 days. Repeat course every 3 to 4 weeks after recovery (esp myelosuppression). Renal impairment (CrCl ≤50mL/min): reduce dose (see literature). Consider dose reduction with existing myelosuppression due to previous radiation or chemotherapy. Children: Not recommended. Warnings/Precautions: Monitor blood (esp CBC/differential, platelets, hemoglobin) before each cycle and during therapy; renal function. Withhold dose if platelet count <50,000/mm3 or ANC <500/mm3. Hypoalbuminemia. Elderly. Pregnancy (Cat.D); nursing mothers: not recommended. Interactions: Potentiated by cyclosporine. Additive toxicity with radiation, other cytotoxic therapies. Adverse reactions: GI upset, mucositis, myelosuppression (esp. neutropenia, thrombocytopenia; may be fatal), alopecia, fever, infections, peripheral neurotoxicity; hypersensitivity reactions, acute leukemia (rare); others. How supplied: Contact supplier.

GILOTRIF Boehringer Ingelheim

℞

Tyrosine kinase inhibitor. Afatinib 20mg, 30mg, 40mg; tabs. Indications: First-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitutions as detected by an FDAapproved test. Limitations of use: safety and efficacy of Gilotrif have not been established in patients whose tumors have other EGFR mutations. Adults: Take on an empty stomach at least 1 hour before or 2 hours after a meal. 40mg once daily until disease progression or not tolerated. Concomitant

P-gp inhibitors: reduce afatinib daily dose by 10mg if not tolerated; resume previous dose after discontinuing the P-gp inhibitor. Concomitant P-gp inducers: increase afatinib by 10mg as tolerated; resume previous dose 2–3 days after discontinuing the P-gp inducer. Dose modification: see full labeling. Children: Not established. Warnings/Precautions: Permanently discontinue for life-threatening bullous, blistering, or exfoliative skin lesions, confirmed interstitial lung disease, severe drug-induced hepatic impairment, persistent ulcerative keratitis, symptomatic left ventricular dysfunction, or severe/intolerable adverse reactions (at dose 20mg/day). Withhold for severe or prolonged diarrhea Grade ≥2 lasting for ≥2 consecutive days while taking antidiarrheal, prolonged cutaneous reaction Grade ≥2 (lasting >7 days) or intolerable, renal dysfunction Grade ≥2, or worsening liver function. History of keratitis, ulcerative keratitis, or severe dry eye. Monitor closely in moderate-to-severe renal impairment or severe hepatic impairment; adjust dose if not tolerated. Embryofetal toxicity: females of reproductive potential should use highly effective contraception during treatment and for at least 2 weeks after last afatinib dose. Pregnancy (Cat.D). Nursing mothers: not recommended. Interactions: Potentiated by P-gp inhibitors (eg, ritonavir, cyclosporine A, ketoconazole, itraconazole, erythromycin, verapamil, quinidine, tacrolimus, nelfinavir, saquinavir, amiodarone). Antagonized by P-gp inducer (eg, rifampicin, carbamazepine, phenytoin, phenobarbital, St. John’s wort). Adverse reactions: Diarrhea, rash/dermatitis acneiform, stomatitis, paronychia, dry skin, decreased appetite, pruritus. How supplied: Tabs–30

HYCAMTIN GlaxoSmithKline

℞

Topoisomerase inhibitor. Topotecan (as HCl) 4mg/vial; pwd for IV infusion after reconstitution and dilution; contains mannitol; preservative-free. Indications: Small cell lung cancer sensitive disease after failure of 1st line chemotherapy. Adults: Verify dose using BSA. Usual max dose 4mg IV. Confirm baseline neutrophils >1,500cells/mm3 and platelets >100,000cells/mm3 prior to 1st course of therapy. Give by IV infusion over 30 mins. 1.5mg/m2 daily for 5 consecutive days starting on Day 1 of a 21-day cycle. Dose adjustments, renal impairment: see full labeling. Children: Not established. Also: HYCAMTIN CAPSULES ℞ Topotecan (as HCl) 0.25mg, 1mg; caps. Indications: Relapsed small cell lung cancer with prior complete or partial response and at least 45 days from the end of 1st line chemotherapy.

Adults: Confirm baseline neutrophils ≥1,500cells/mm3 and platelets ≥100,000cells/mm3 prior to 1st course of therapy. Swallow whole. 2.3mg/m2/day once daily for 5 consecutive days; repeat every 21 days. Dose adjustments, renal impairment: see full labeling. Children: Not established. Contraindications: IV: Severe bone marrow depression. 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. Caps: Avoid concomitant P-glycoprotein inhibitors (eg, amiodarone, azithromycin, captopril, carvedilol, clarithromycin, conivaptan, cyclosporine, diltiazem, dronedarone, erythromycin, felodipine, itraconazole, ketoconazole, lopinavir, ritonavir, quercetin, quinidine, ranolazine, ticagrelor, verapamil) and BCRP inhibitors (eg, cyclosporine, eltrombopag). Adverse reactions: See full labeling. Neutropenia, leukopenia, thrombocytopenia, anemia, nausea, vomiting, diarrhea, anorexia, abdominal pain, stomatitis, headache, dyspnea, cough, pyrexia, alopecia, fatigue; infection, sepsis, interstitial lung disease, neutropenic colitis (may be fatal). How supplied: Single-use vials–1; Caps–10

MUSTARGEN Recordati

℞

Nitrogen mustard. Mechlorethamine HCl 10mg/vial; pwd for IV or intracavitary inj after reconstitution. Indications: Palliative treatment of bronchogenic carcinoma. Adults: By IV infusion, per therapeutic course: 0.4mg/kg (lean body weight) as single dose or in divided doses of 0.1–0.2mg/kg per day. See literature for intracavitary (eg, intrapleural) administration. Do not exceed recommended dose. Repeat course only after hematological recovery (eg, every 3 weeks). Children: See literature. Contraindications: Infectious diseases.

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DRUG MONOGRAPHS

LUNG CANCER 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, alopecia, jaw pain, myalgia, arthralgia, rash, severe constipation, paralytic ileus, intestinal obstruction, necrosis, and/or perforation; dyspnea, severe bronchospasm. How supplied: Single-use vial (1mL, 5mL)–1

OPDIVO Bristol-Myers Squibb

℞

Human programmed death receptor-1 (PD-1)blocking antibody. Nivolumab 10mg/mL; per vial; soln for IV infusion after dilution; preservativefree; contains mannitol. Indications: Metastatic squamous non-small cell lung cancer with progression on or after platinum-based chemotherapy. Adults: Give as IV infusion over 60 minutes. 3mg/kg every 2 weeks until disease progression or unacceptable toxicity. Dose modifications: see full labeling. Children: Not established. Warnings/Precautions: See full labeling. Monitor for any immune-mediated adverse reactions; withhold dose and give corticosteroids (at 1–2mg/kg/day prednisone equivalents) based on severity of event. Permanently discontinue for any life-threatening or Grade 4 adverse reaction, Grade 3 or 4 pneumonitis, Grade 4 colitis, AST/ALT >5×ULN or total bilirubin >3×ULN, SCr >6×ULN, recurring severe or Grade 3 adverse reaction, inability to reduce prednisone dose to ≤10mg/day (or equivalent) within 12 weeks, or failure to recover to Grade 0–1 within 12 weeks after last dose. Grade 2 pneumonitis, Grade 2 or 3 colitis, AST/ALT >3–5×ULN or total bilirubin >1.5–3×ULN, SCr >1.5–6×ULN or >1.5X baseline, other severe or Grade 3 adverse reactions; withhold dose, give corticosteroids, and when recovered to Grade 0–1 or resolved, consider re-initiation. Monitor for abnormal liver tests, elevated serum creatinine, and thyroid function prior to and during treatment; give replacement therapy for hypothyroidism. Pregnancy: avoid. Use effective contraception during and for ≥5 months after last dose. Lactation: discontinue nursing. Adverse reactions: Fatigue, dyspnea, musculoskeletal pain, decreased appetite, cough, nausea, constipation; any immune-mediated reactions. How supplied: Single-use vial (4mL, 10mL)–1

PHOTOFRIN Pinnacle Biologics

℞

Photosensitizing agent. Porfimer (as sodium) 75mg/vial; pwd for IV inj after reconstitution; preservative-free. Indications: Reduction of obstruction and palliation in patients with completely or partially obstructing endobronchial non-small-cell lung cancer (NSCLC). Treatment of microinvasive endobronchial NSCLC in patients for whom surgery and radiotherapy is not indicated. Adults: See literature. Give by slow IV inj over 3–5 minutes. 2mg/kg then illumination with laser light 40–50 hours following injection. 2nd course may be given at a minimum of 30 days after initial therapy; max 3 courses (separated by ≥30 days). Children: Not recommended. Contraindications: Porphyria. Existing tracheoesophageal or bronchoesophageal fistula. Tumors eroding into a major blood vessel. Emergency treatment of patients with severe acute respiratory distress caused by an obstructing endobronchial lesion. Esophageal or gastric varices. Esophageal ulcers >1cm in diameter.

Warnings/Precautions: Avoid direct sunlight or bright indoor light; wear dark sunglasses when outdoors. Increased risk of fatal massive hemoptysis with large, centrally located tumors, cavitating tumors, extensive tumor extrinsic to the bronchus. Caution with endobronchial tumors in locations where treatment-induced inflammation could obstruct airway. Avoid extravasation. Pregnancy (Cat.C; use adequate contraception), nursing mothers: not recommended. Interactions: Increased risk of photosensitivity reactions with other photosensitizing agents (eg, tetracyclines, sulfonamides, phenothiazines, sulfonylurea hypoglycemic agents, thiazide diuretics, griseofulvin, fluoroquinolones). May be antagonized by dimethyl sulfoxide, β-carotene, ethanol, formate, mannitol, allopurinol, calcium channel blockers, prostaglandin synthesis inhibitors, drugs that decreased clotting, vasoconstriction or platelet aggregation (eg, thromboxane A2 inhibitors), glucocorticoid hormones. Separate radiotherapy by 2–4 weeks. Adverse reactions: Photosensitivity reactions (eg, erythema, swelling, itching, burning sensation, feeling hot, blisters), fluid imbalance, chest pain, fever, pain, abdominal pain, GI upset, constipation, mucositis, ocular sensitivity, dyspnea, pleural effusion, anemia, fistula formation, fatal massive hemoptysis, others. How supplied: Vial–1

TARCEVA Astellas and Genentech

℞

Kinase inhibitor. Erlotinib (as HCl) 25mg, 100mg, 150mg; tabs. Indications: First-line treatment in patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test. Maintenance treatment of patients with locally advanced or metastatic NSCLC whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. Treatment of locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen. Limitations of use: Do not use in combination with platinumbased chemotherapy. Not evaluated as first-line treatment in patients with metastatic NSCLC whose tumors have EGFR mutations other than exon 19 deletions or exon 21 (L858R) substitution. Adults: Take on empty stomach. 150mg once daily. Use until disease progression or unacceptable toxicity occurs. Diarrhea unresponsive to loperamide, severe skin reactions, strong CYP3A4 inhibitors (see Interactions), hepatic impairment: reduce in 50mg decrements. Concomitant CYP3A4 inducers (see Interactions): increase in 50mg increments at 2-week intervals; max 450mg (see full labeling). Concurrent cigarette smoking: increase in 50mg increments at 2-week intervals; max 300mg (see full labeling); upon cessation, reduce to 150mg or 100mg daily. Children: Not established. Warnings/Precautions: Discontinue if interstitial lung disease, severe hepatic toxicity, GI perforation, severe bullous, blistering or

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DRUG MONOGRAPHS

LUNG CANCER exfoliating skin conditions, or corneal perforation or severe ulceration occurs. Withhold or consider discontinuing therapy if severe renal failure due to dehydration, or acute/worsening ocular disorders occur. Monitor LFTs periodically; withhold in patients without history of hepatic impairment for total bilirubin >3×ULN or transaminases >5×ULN, or in patients with history of hepatic impairment or biliary obstruction for doubling of bilirubin or tripling of transaminases over baseline. Discontinue if abnormal LFTs do not improve or resolve within 3 weeks. Withhold for persistent severe diarrhea unresponsive to loperamide, severe rash, or grade 3–4 keratitis. Monitor renal function, serum electrolytes, pulmonary function, INR, prothrombin time. History of peptic ulcers or diverticular disease. Pregnancy (Cat.D); use effective contraception during therapy and at least 2 weeks after the last dose. Nursing mothers: not recommended. Interactions: Potentiated by CYP3A4 inhibitors (eg, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, voriconazole, grapefruit) and CYP1A2 inhibitors (eg, ciprofloxacin); avoid if possible. Plasma levels decreased by CYP3A4 inducers (eg, rifampin, rifabutin, rifapentine, phenytoin, carbamazepine, phenobarbital, St. John’s wort), proton pump inhibitors or H2 blockers (take erlotinib 10hrs after and at least 2hrs before next dose), and smoking; avoid if possible. Increased risk of GI perforation with concomitant anti-angiogenic agents, steroids, NSAIDs, taxane-based chemotherapy. Monitor for bleeding with oral anticoagulants, NSAIDs. Adverse reactions: Rash, diarrhea, nausea, vomiting, anorexia, fatigue, elevated LFTs, unexplained pulmonary symptoms (eg, dyspnea, cough, fever; discontinue and follow-up if occurs), stomatitis, infection; rare: GI perforation (may be fatal), ocular disorders (eg, conjunctivitis, keratitis, corneal ulceration/perforation), MI/ischemia, hemolytic anemia, cerebrovascular accidents, interstitial lung disease; hepatic or renal failure and hepatorenal syndrome (may be fatal); bullous, blistering and exfoliative skin conditions (eg, StevensJohnson syndrome, toxic epidermal necrolysis). Testing considerations: K-RAS mutation analysis, EGFR amplification analysis How supplied: Tabs–30

TREXALL Teva

℞

℞ 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. Adults: Swallow whole. 250mg twice daily until disease progression or intolerance. Dose modification and/or dose reduction to 200mg twice daily may be required based on Grade 3 or 4 severity, then to 250mg once daily, or permanently discontinue if intolerable. Severe renal impairment (CrCl <30mL/min) not requiring dialysis: 250mg once daily. Dose reduction for hematologic and non-hematologic toxicities: see full labeling. Children: Not established. Warnings/Precautions: Confirm ALK-positive NSCLC with an FDA-approved test before treating. Monitor ALT and total bilirubin every 2 weeks during first 2 months, then monthly, and more frequently for elevated transaminases; temporarily suspend, reduce dose, or permanently discontinue as clinically indicated. Monitor CBCs with differential monthly and more frequently if Grade 3 or 4 abnormalities, fever or infection occurs. Risk of severe pneumonitis: monitor for pulmonary symptoms; permanently discontinue if occurs. Congenital long QT syndrome; avoid. History of or predisposition for QTc prolongation (eg, CHF, bradyarrhythmias, electrolyte abnormalities, concomitant drugs that prolong QT interval): consider monitoring ECG, electrolytes periodically. Torsade de pointes, ventricular tachycardia, serious arrhythmia: permanently discontinue if QTc >500ms or ≥60ms change from baseline. Monitor hr and BP regularly; discontinue if life-threatening bradycardia occurs. Hepatic impairment. Severe renal impairment. Pregnancy (Cat.D); avoid. Use adequate contraception during therapy and at least 90 days after completion. Nursing mothers: not recommended. Interactions: Avoid concomitant strong CYP3A inhibitors (eg, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, voriconazole), grapefruit juice, or strong CYP3A inducers (eg, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, St. John’s Wort). Avoid concomitant CYP3A substrates with narrow therapeutic indices (eg, alfentanil, cyclosporine, ergots, fentanyl, pimozide, quinidine, sirolimus, tacrolimus); if needed, reduce doses. Avoid concomitant agents known to cause bradycardia (eg, beta-blockers, non-dihydropyridine calcium channel blockers, clonidine, digoxin); adjust dose or discontinue. Caution with moderate CYP3A

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DRUG MONOGRAPHS

LUNG CANCER inhibitors. Dose reduction may be needed with coadministered drugs metabolized by CYP3A. Adverse reactions: Vision disorder, nausea, diarrhea, vomiting, constipation, edema, fatigue, Grade 3–4 events: ALT increased, neutropenia; elevated total bilirubin, pneumonitis (may be fatal), QT prolongation, bradycardia, hepatotoxicity (may be fatal). How supplied: Caps–60

ZYKADIA Novartis

℞

Tyrosine kinase inhibitor. Ceritinib 150mg; hard gel caps. Indications: Treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic nonsmall cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib. Not established for improvement in survival or disease-related symptoms. Adults: Take on an empty stomach (at least 2 hours before or after a meal). 750mg once daily until disease progression or unacceptable toxicity.

Discontinue if 300mg once daily not tolerated. Moderate-to-severe hepatic impairment: not established. Dose modifications: see full labeling. Children: Not established. Warnings/Precautions: Monitor for severe or persistent GI toxicity; if occurs, withhold until improved; resume at reduced dose. Monitor ALT/AST and total bilirubin once monthly, and more frequently if elevated transaminases develop; withhold then reduce dose, or permanently discontinue as clinically indicated. Congenital long QT syndrome; avoid. CHF, bradyarrhythmias, electrolyte abnormalities; monitor ECG, electrolytes periodically. Permanently discontinue if QTc prolongation in combination with Torsade de pointes or polymorphic ventricular tachycardia or serious arrhythmia develop. Monitor hr and BP regularly; serum glucose and pulmonary symptoms as clinically indicated. Permanently discontinue if treatment-related interstitial lung disease (ILD)/pneumonitis, uncontrolled hyperglycemia, or life-threatening bradycardia occur. Pregnancy (Cat.D). Females of reproductive

potential should use effective contraception during treatment and for at least 2 weeks after completion. Nursing mothers: not recommended. Interactions: Avoid concomitant strong CYP3A4 inhibitors (eg, ritonavir, macrolides, ketoconazole, nefazodone), grapefruit juice; if unavoidable, reduce ceritinib dose by 1/3. Avoid concomitant strong CYP3A4 inducers (eg, carbamazepine, phenytoin, rifampin, St. John’s Wort). Avoid concomitant CYP3A substrates (eg, alfentanil, cyclosporine, ergots, fentanyl, pimozide, quinidine, sirolimus, tacrolimus) or CYP2C9 substrates (eg, phenytoin, warfarin) with narrow therapeutic indices; if unavoidable, reduce doses of these drugs. Avoid concomitant agents known to cause bradycardia (eg, beta-blockers, nondihydropyridine CCBs, clonidine, digoxin). Adverse reactions: Diarrhea, nausea, vomiting, abdominal pain, constipation, elevated transaminases, fatigue, decreased appetite; bradycardia, hepatotoxicity, ILD/pneumonitis, QTc prolongation, hyperglycemia. How supplied: Caps–70

FDA-APPROVED NON-SMALL CELL LUNG CANCER (NSCLC) TREATMENTS Generic Brand Strength ANGIOGENESIS INHIBITOR

Form

Usual Dose

bevacizumab

Avastin

100mg, 400mg

soln for IV infusion after dilution

ramucirumab

Cyramza

10mg/mL

soln for IV infusion after dilution

15mg/kg once every 3wks with carboplatin/ paclitaxel 10mg/kg on Day 1 of a 21-day cycle prior to docetaxel; continue until disease progression or unacceptable toxicity

pwd for IV infusion after reconstitution

ANTIMETABOLITES gemcitabine

Gemzar

200mg, 1g

methotrexate

—

25mg/mL

pemetrexed

Trexall Alimta

1000mg/m2 on Days 1, 8, and 15 of each 28 day cycle; or 1250mg/m2 on Days 1 and 8 of each 21 day cycle See drug entry and manufacturer’s literature

soln for IV, IM, intra-arterial, or intrathecal administration after dilution 1g pwd for IV, IM, intra-arterial, or intrathecal administration after dilution 5mg, 7.5mg, 10mg, 15mg scored tabs 100mg, 500mg pwd for IV inj after reconstitution 500mg/m2 on Day 1 of each 21-day cycle and dilution

ANTIMICROTUBULE AGENTS docetaxel paclitaxel

Taxotere Taxol

40mg/mL 6mg/mL

paclitaxel [bound to Abraxane 100mg/vial albumin (human)] vinorelbine Navelbine 10mg/mL

soln for IV infusion after dilution soln for IV infusion after dilution

75mg/m2 once every 3wks 135mg/m2 IV plus cisplatin every 3wks

pwd for IV infusion after reconstitution soln for IV inj after dilution

100mg/m2 on Days 1, 8, and 15 of each 21day cycle Monotherapy: 30mg/m2 once weekly Combination therapy: 25mg/m2 once weekly given every 4wks; or 30mg/m2 once weekly given on Days 1 and 29, then every 6wks

PHOTOSENSITIZING AGENT porfimer

Photofrin 75mg

pwd for IV inj after reconstitution 2mg/kg then illumination with laser light 40–50hrs following injection

TYROSINE KINASE INHIBITORS afatinib ceritinib

Gilotrif Zykadia

20mg, 30mg, 40mg 150mg

tabs hard gel caps

crizotinib erlotinib

Xalkori Tarceva

200mg, 250mg 25mg, 100mg, 150mg

caps tabs

40mg once daily on empty stomach 750mg once daily until disease progression or unacceptable toxicity 250mg twice daily 150mg once daily

Notes

Not an inclusive list of medications, official indications, and/or dosing details. Please see drug monograph at www.eMPR.com and/or contact company for full (Rev. 1/2015) drug labeling.

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DRUG MONOGRAPHS

SARCOMA DOXIL Janssen Biotech

℞

Anthracycline. Doxorubicin HCl (liposomal) 2mg/mL; dispersion for IV infusion after dilution; preservative-free. Indications: AIDS-related Kaposi’s sarcoma refractory to combination chemotherapy. Adults: Give by IV infusion at initial rate of 1mg/min; may increase rate to complete infusion over 1hr if no infusion reactions occur; may premedicate with antiemetics. 20mg/m2 once every 3 weeks. Hepatic dysfunction (serum bilirubin ≥1.2mg/dL), hand-foot syndrome, hematologic toxicity (esp. ANC, platelets), or stomatitis: reduce dose. Consider total anthracycline and anthracenedione doses and irradiation when calculating total cumulative dose. See full labeling. Children: Not established. Warnings/Precautions: Not substitutable on a mg/mg basis with other doxorubicin products. Cardiotoxicity, acute infusion-related reactions, myelosuppression may occur. Have resuscitative/ antiallergic equipment and expertise available. Hepatic impairment. Monitor blood (esp. CBC + platelets), hepatic (esp. SGOT/SGPT, alkaline phosphatase), and cardiac function (esp. myocardial biopsy). Monitor periodically for secondary oral cancers with long-term use. Avoid extravasation. Pregnancy (Cat.D); avoid. Nursing mothers: not recommended. Interactions: Caution with cyclosporine, phenobarbital, phenytoin, streptozocin, digoxin, myelosuppressants, others. Previous mediastinal irradiation, cyclophosphamide, other cardiotoxic drugs: monitor for cardiotoxicity and hepatotoxicity. Adverse reactions: Asthenia, fatigue, fever, anorexia, nausea, vomiting, stomatitis, diarrhea,

constipation, hand and foot syndrome, rash, neutropenia, thrombocytopenia, anemia; infusion reactions, cardiovascular events (eg, cardiomyopathy, CHF, acute LV failure), recall of skin reaction from prior radiation therapy, toxoplasmosis, urine discoloration (red/orange). How supplied: Single-use vials (10mL, 25mL)–1

INTRON A Merck

℞

Interferon alfa-2b, recombinant; 10 million, 18 million, or 50 million IU per vial; pwd; for inj after reconstitution/dilution; preservative-free. Also: INTRON A SOLN ℞ Interferon alfa-2b, recombinant; 10 million IU, 18 million IU, 25 million IU; per vial; for inj; contains m-cresol. Indications: AIDS-related Kaposi’s sarcoma. Adults: Use appropriate preparation and route: see literature. Use SC route if platelets <50,000/mm3. 30 million IU/m2 IM or SC three times weekly; continue until rapid disease progression or maximal response achieved after 16 weeks; reduce dose by ½ or suspend therapy if severe adverse reactions occur; discontinue if persists. Children: Not recommended. Contraindications: Hepatitis: decompensated liver disease. Autoimmune disorders. Warnings/Precautions: May cause or exacerbate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, or infectious disorders: monitor closely, discontinue if they worsen. Severe psychiatric disorders (esp. depression). Cardiovascular or pulmonary disease. Severe myelosuppression. Uncontrolled thyroid abnormalities. Diabetes. Coagulation disorders. Maintain adequate hydration. Monitor blood, thyroid, visual and liver function before and during

therapy; EKG in cardiovascular disease and cancer patients. Psoriasis. Renal dysfunction. Transplant recipients. Elderly. Debilitated. Pregnancy (Cat.C). Nursing mothers: not recommended. Interactions: Caution with myelosuppressives, and drugs that can exacerbate depression. May potentiate theophylline (may double its levels). Adverse reactions: Flu-like symptoms (fever, headache, myalgia, fatigue); hepatic, hematologic, respiratory, skin, genitourinary system, CNS, cardiovascular, endocrine (esp thyroid), GI, or visual disorders; colitis, hypertriglyceridemia, pancreatitis, infections, injection site reactions; others (see literature). How supplied: Pwd (w. diluent): 10million, 18million, 50million IU/vial–1; Soln (vials): 10million IU/vial–6 (kit w. supplies); Soln (multidose vials): 18million, 25million IU/vial–1

PANRETIN Eisai

℞

Retinoid. Alitretinoin 0.1%; gel. Indications: Cutaneous lesions of AIDS-related Kaposi’s sarcoma (KS). Adults: Apply twice daily to lesions (avoid mucous membranes and normal skin); do not occlude; may increase to 3-4 times daily as tolerated. Reduce frequency or suspend treatment if local toxicity occurs. Children: Not recommended. Warnings/Precautions: Not for use when systemic KS therapy required. Avoid sun, UV light. Flammable. Pregnancy (Cat.D), nursing mothers: not recommended. Interactions: Increases DEET toxicity (avoid). Adverse reactions: Photosensitivity, rash, pruritus, pain, exfoliative dermatitis, paresthesia, edema. How supplied: Gel–60g

DOSAGES FOR THE ELDERLY Special caution is advised when prescribing drugs for elderly patients. Keep the following points in mind when prescribing drugs for patients of approximately 60 years or older:

1. Renal Function: Glomerular filtration rate, renal tubular secretion and blood flow tend to decrease with advancing age, while the incidence of renal pathology increases. 2. Drug Sensitivity: Elderly patients may show unusual sensitivity or paradoxical reactions to a number of drugs. Refer to the complete prescribing information. 3. Drug Distribution: The ratio of fat to lean body weight may increase in the elderly, which affects the volume of distribution of fat-soluble drugs. Plasma albumin concentrations may be decreased in the elderly. This potentiates plasma-protein bound drugs and increases the potential for drug interactions caused by plasma-protein displacement. 4. Polypharmacy: It is important to determine the patient’s current medication use, including nonprescription products, before adding any medication to determine any possible interactions. 5. Hepatic Function: Reduced function of metabolic enzymes in the liver may occur in the elderly.

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DRUG MONOGRAPHS

SKIN CANCER EFUDEX Valeant

℞

Antimetabolite. Fluorouracil 2%, 5%; soln. ℞ Also: EFUDEX CREAM Fluorouracil 5%. Indications: Multiple actinic or solar keratoses. Superficial basal cell carcinoma when conventional therapy is impractical (5% only); see literature. Adults: Keratoses: Apply twice daily until erosion occurs (usually 2–4 wks). Basal cell carcinoma (5% only): Apply twice daily, usually for 3–6 weeks (obliteration may take 10–12 weeks). Children: Not recommended. Contraindications: Dihydropyrimidine dehydrogenase (DPD) deficiency. Pregnancy (Cat.X). Warnings/Precautions: Apply cautiously near eyes, nose, mouth. Avoid mucous membranes, occlusion, ulcerated/inflamed skin, exposure to UV light. Wash hands after application if fingers were used. Notify patients of expected skin reaction. Biopsy unresponsive lesions. Nursing mothers: not recommended. Adverse reactions: Pain or burning at application site, pruritus, irritation, hyperpigmentation. How supplied: Soln–10mL (w. drop dispenser); Crm–25g

ERIVEDGE Genentech

℞

Hedgehog pathway inhibitor. Vismodegib 150mg; caps. Indications: Treatment of adults with metastatic basal cell carcinoma, or locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation. Adults: Swallow whole. 150mg once daily, until disease progression or unacceptable toxicity. Children: Not established. Warnings/Precautions: Risk of embryo-fetal death and severe birth defects in pregnant women. Verify pregnancy status 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 at least 7 months after last dose. Pregnancy (Cat.D). Nursing mothers: not recommended. Interactions: May be potentiated by P-gp inhibitors (eg, clarithromycin, erythromycin, azithromycin). May be antagonized by drugs that affect gastric pH (eg, proton pump inhibitors, H2-receptor antagonists, antacids). Adverse reactions: Muscle spasms, alopecia, dysgeusia, weight loss, fatigue, GI upset, decreased appetite, constipation, arthralgias, ageusia. Note: Report immediately exposure to Erivedge during pregnancy by contacting the Genentech Adverse Event Line at (888) 835-2555. How supplied: Caps–28

GLEEVEC Novartis

℞

Kinase inhibitor. Imatinib (as mesylate) 100mg, 400mg; scored tabs. Indications: Adults with aggressive systemic mastocytosis (ASM) without the D816V c-Kit mutation or with c-Kit mutational status unknown. Adults with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans (DFSP). Adults: Take with food and water. May disperse tab in water or apple juice and take promptly. ≥18yrs: ASM without D816V c-Kit mutation or status unknown: 400mg once daily. ASM associated with eosinophilia: initially 100mg once daily; may increase to 400mg once daily if insufficient response. If severe non-hematologic reactions develop: interrupt dose; resume at a lower dose in hepatic dysfunction. Severe hepatic impairment: reduce dose by 25%. Renal or hematologic reactions: see full labeling. Avoid concomitant strong CYP3A4 inducers (eg, rifampin): if needed, increase imatinib dose by at least 50%. Children: Not recommended. Warnings/Precautions: Hepatic or renal impairment. Monitor weight and for fluid retention regularly; CBCs weekly for 1st month, bi-weekly for 2nd month, then periodically (eg, every 2–3 months); liver function at baseline then monthly or as needed; GI symptoms at baseline. Cardiovascular disease or risk factors; monitor. Immunosuppression and potential toxicities (liver, kidney, cardiac) from long-term use. Monitor for tumor lysis syndrome; correct clinically significant dehydration and treat high uric acid levels before initiating therapy. Monitor growth in children. Possible cardiogenic shock/LV dysfunction in conditions with high eosinophil levels (eg, HES/CEL, MDS/MPD, ASM); consider concomitant systemic steroid prophylaxis (1–2mg/kg) for 1 or 2 wks if abnormal ECG or serum troponin. Monitor TSH levels in thyroidectomy patients undergoing levothyroxine replacement. Pregnancy (Cat.D); avoid. Use highly effective contraception during treatment. Nursing mothers: not recommended. Interactions: Avoid grapefruit juice. Potentiated by CYP3A4 inhibitors (eg, azole antifungals, protease inhibitors, nefazodone, clarithromycin, telithromycin). Antagonized by strong CYP3A4 inducers (eg, dexamethasone, fosphenytoin, phenytoin, phenobarbital, carbamazepine, oxcarbamazepine, primidone, St. John’s wort, rifampin, rifabutin, rifampicin); consider alternatives. May potentiate drugs metabolized by CYP3A4 (eg, benzodiazepines, dihydropyridine calcium channel blockers, cyclosporine, ergots, alfentanil, fentanyl, pimozide, quinidine, certain statins, sirolimus, tacrolimus), CYP2D6, or CYP2C9 (use heparin instead of warfarin). Adverse reactions: Edema (may be severe), nausea, vomiting, musculoskeletal pain, diarrhea, muscle cramps, rash (may be severe; eg, erythema multiforme, Stevens-Johnson

syndrome), fatigue, abdominal pain, dizziness, blurred vision, somnolence, fever, headache, cough, arthralgia/myalgia, dyspnea, hypokalemia, night sweats, anorexia, pruritus, hemorrhage, anemia, neutropenia, thrombocytopenia, weight gain, renal or hepatotoxicity, immunosuppression, hypothyroidism; rare: severe CHF, LV dysfunction. How supplied: 100mg–90; 400mg–30

HYDREA Bristol-Myers Squibb

℞

Substituted urea. Hydroxyurea 500mg; caps. Indications: Melanoma. Adults: See literature. Intermittant therapy for solid tumors: 80mg/kg as single dose every 3rd day. Continuous therapy for solid tumors: 20–30mg/kg/day as single dose. Renal impairment: reduce dose. Children: Not recommended. Contraindications: Marked bone marrow depression. Warnings/Precautions: Previous irradiation therapy or chemotherapy. Correct anemia before starting. Monitor hematologic, renal, hepatic function before and during treatment. Marked renal dysfunction. Myeloproliferative disorders; discontinue if cutaneous vasculitic ulcerations develop and use alternative agents. Elderly. Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended. Interactions: Avoid concomitant didanosine, with or without stavudine, or other antiretrovirals (may cause pancreatitis [monitor], fatal hepatotoxicity, peripheral neuropathy). Myelosuppressives potentiate antineoplastic effect. May antagonize antigout agents. Increased risk of vasculitic toxicities with interferon therapy. May cause falsely elevated urease, uricase, lactate dehydrogenase. Adverse reactions: Leukopenia, anemia, erythrocytic abnormalities, thrombocytopenia, GI upset, rash, erythema, fever, CNS effects, temporary renal impairment, acute pulmonary reactions, secondary leukemias, skin cancer. Note: Wear disposable gloves when handling caps or bottle. How supplied: Caps–100

INTRON A Merck

℞

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DRUG MONOGRAPHS

SKIN CANCER Warnings/Precautions: May cause or exacerbate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, or infectious disorders: monitor closely, discontinue if they worsen. Severe psychiatric disorders (esp. depression). Cardiovascular or pulmonary disease. Severe myelosuppression. Uncontrolled thyroid abnormalities. Diabetes. Coagulation disorders. Maintain adequate hydration. Monitor blood, thyroid, visual and liver function before and during therapy; EKG in cardiovascular disease and cancer patients. Psoriasis. Renal dysfunction. Transplant recipients. Elderly. Debilitated. Pregnancy (Cat.C). Nursing mothers: not recommended. Interactions: Caution with myelosuppressives, and drugs that can exacerbate depression. May potentiate theophylline (may double its levels). Adverse reactions: Flu-like symptoms (fever, headache, myalgia, fatigue); hepatic, hematologic, respiratory, skin, genitourinary system, CNS, cardiovascular, endocrine (esp thyroid), GI, or visual disorders; colitis, hypertriglyceridemia, pancreatitis, infections, injection site reactions; others (see literature). How supplied: Pwd (w. diluent): 10million, 18million, 50million IU/vial–1; Soln (vials): 10million IU/vial–6 (kit w. supplies); Soln (multidose vials): 18million, 25million IU/vial–1

KEYTRUDA Merck

℞

Human programmed death receptor-1 (PD-1)blocking antibody. Pembrolizumab 50mg; per vial; lyophilized pwd for IV infusion after reconstitution; preservative-free. Indications: Treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. Adults: Give as IV infusion over 30mins. 2mg/kg every 3 weeks until disease progression or unacceptable toxicity. Dose modifications: see full labeling. Administer corticosteroids for most Grade ≥2 related immune-mediated reactions. Children: Not established. Warnings/Precautions: Monitor for signs/ symptoms of pneumonitis; withhold dose if Grade 2 pneumonitis; permanently discontinue if Grade 3 or 4 develops. Monitor for signs/ symptoms of colitis; withhold dose if Grade 2 or 3 colitis; permanently discontinue if Grade 4 develops. Monitor for changes in liver function; withhold dose or discontinue based on severity of elevated liver enzymes. Monitor for hypophysitis; withhold dose if Grade 2 hypophysitis; withhold or discontinue if Grade 3; permanently discontinue if Grade 4 develops. Monitor for changes in renal

function; withhold dose if Grade 2 nephritis; permanently discontinue if Grade 3 or 4 develops. Monitor thyroid function at treatment initiation, during, and as clinically indicated; withhold if Grade 3 hyperthyroidism; permanently discontinue if Grade 4 develops. Permanently discontinue if any severe or Grade 3 immunemediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction. Use highly effective contraception during treatment and for at least 4 months after the last dose. Pregnancy (Cat.D), nursing mothers: not recommended. Adverse reactions: Fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, arthralgia, diarrhea, sepsis; renal failure, dyspnea, pneumonia, cellulitis. How supplied: Single-use vial–1

MEKINIST GlaxoSmithKline

℞

Kinase inhibitor. Trametinib 0.5mg, 1mg, 2mg; tabs. Indications: As monotherapy or in combination with dabrafenib for the treatment of unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDAapproved test. Limitation of use: as a single agent is not indicated for the treatment of patients who have received prior BRAF-inhibitor therapy. Adults: Confirm presence of BRAF V600E or V600K mutation prior to initiation. Take at least 1hr before or 2hrs after a meal. Monotherapy or in combination with dabrafenib: 2mg once daily; continue until disease progression or unacceptable toxicity occurs. In combination therapy: take at same time each day either with the AM or PM dose of dabrafenib. Dose modifications: see full labeling. Children: Not established. Warnings/Precautions: See full labeling for dabrafenib prior to starting combination therapy. Risk of cardiomyopathy; assess LVEF prior to initiation, after one month, and then at every 2–3 month intervals during treatment; withhold if absolute LVEF decreases by 10% from pre-treatment values and is less than the lower limit of normal; permanently discontinue if symptomatic cardiomyopathy or persistent asymptomatic LVEF dysfunction is unresolved within 4 weeks. Perform eye exam at any time for visual disturbances and compare to baseline. Retinal pigment epithelial detachment; withhold if diagnosed; if resolved within 3 weeks, may resume at reduced dose. Withhold if new or progressive pulmonary symptoms or findings develop. Permanently discontinue if retinal vein occlusion, interstitial lung disease, or pneumonitis

occurs. Monitor for skin toxicities and secondary infections. Embryo-fetal toxicity. Females of reproductive potential should use highly effective contraception during and for 4 months after treatment. Pregnancy (Cat.D). Nursing mothers: not recommended. Adverse reactions: Rash, diarrhea, lymphedema; combination with dabrafenib: pyrexia, chills, fatigue, rash, nausea, vomiting, constipation, abdominal pain, peripheral edema, cough, headache, arthralgia, night sweats, decreased appetite, myalgia; hemorrhage, thromboembolic events. How supplied: Tabs–30

OPDIVO Bristol-Myers Squibb

℞

Human programmed death receptor-1 (PD-1)blocking antibody. Nivolumab 10mg/mL; per vial; soln for IV infusion after dilution; preservativefree; contains mannitol. Indications: Unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. Adults: Give as IV infusion over 60 minutes. 3mg/kg every 2 weeks until disease progression or unacceptable toxicity. Dose modifications: see full labeling. Children: Not established. Warnings/Precautions: See full labeling. Monitor for any immune-mediated adverse reactions; withhold dose and give corticosteroids (at 1–2mg/kg/day prednisone equivalents) based on severity of event. Permanently discontinue for any life-threatening or Grade 4 adverse reaction, Grade 3 or 4 pneumonitis, Grade 4 colitis, AST/ALT >5×ULN or total bilirubin >3×ULN, SCr >6×ULN, recurring severe or Grade 3 adverse reaction, inability to reduce prednisone dose to ≤10mg/day (or equivalent) within 12 weeks, or failure to recover to Grade 0–1 within 12 weeks after last dose. Grade 2 pneumonitis, Grade 2 or 3 colitis, AST/ALT >3–5×ULN or total bilirubin >1.5–3×ULN, SCr >1.5–6×ULN or >1.5X baseline, other severe or Grade 3 adverse reactions; withhold dose, give corticosteroids, and when recovered to Grade 0–1 or resolved, consider re-initiation. Monitor for abnormal liver tests, elevated serum creatinine, and thyroid function prior to and during treatment; give replacement therapy for hypothyroidism. Pregnancy: avoid. Use effective contraception during and for ≥5 months after last dose. Lactation: discontinue nursing. Adverse reactions: Rash, pruritus; any immunemediated reactions. How supplied: Single-use vial (4mL, 10mL)–1

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DRUG MONOGRAPHS

SKIN CANCER 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 ℞

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)

Alpha interferon. Peginterferon alfa-2b 296mcg, 444mcg, 888mcg; per vial; lyophilized pwd for SC inj after reconstitution. Indications: Adjuvant treatment of melanoma with microscopic or gross nodal involvement within 84 days of definitive surgical resection including complete lymphadenectomy. Adults: Give by SC inj. Rotate inj sites. Premedicate with acetaminophen. ≥18yrs: 6mcg/kg/week for 8 doses, followed by 3mcg/kg/week for up to 5yrs. Renal impairment (moderate): initially 4.5mcg/kg/week for 8 doses, followed by 2.25mcg/kg/week for up to 5yrs; (severe or ESRD on dialysis): initially 3mcg/kg/ week for 8 doses, followed by 1.5mcg/kg/week for up to 5yrs. Withhold dose if ANC <0.5×109/L, platelets <50×109/L, ECOG PS ≥2, or for nonhematologic toxicity ≥ Grade 3. Resume at reduced dose (see full labeling) when: ANC ≥0.5×109/L, platelets ≥50×109/L, ECOG PS 0–1, and non-hematologic toxicity has completely resolved or improved to Grade 1. Children: <18yrs: not established. Contraindications: Anaphylaxis to peginterferon alfa-2b or interferon alfa-2b. Autoimmune hepatitis. Hepatic decompensation (Child-Pugh score >6 [Class B and C]). Warnings/Precautions: Increased risk of serious depression, suicidal ideation, and other neuropsychiatric disorders. Permanently discontinue for: persistent severe or worsening neuropsychiatric disorders (eg, depression, psychosis, encephalopathy); new onset ventricular arrhythmia or cardiovascular decompensation; new or worsening retinopathy; Grade 4 non-hematologic toxicity; severe (Grade 3) hepatic injury or hepatic decompensation; hypothyroidism, hyperthyroidism, or diabetes mellitus that cannot be effectively managed; or if unable to tolerate a dose of 1mcg/kg/week. Monitor for signs/symptoms of depression/ psychosis every 3 weeks during first 8 weeks, then every 6 months, continue for at least 6 months after last dose. Perform eye exam in patients with retinopathy and those with vision changes during therapy. Monitor hepatic function with serum bilirubin, ALT/AST, alkaline phosphate, and LDH at 2 and 8 weeks, and 2 and 3 months following initiation, then every 6 months. Obtain TSH levels within 4 weeks prior to initiation, at 3 and 6 months following initiation, then every 6 months. Moderate-to-severe renal impairment (monitor). Pregnancy (Cat.C). Nursing mothers: not recommended. Interactions: Potentiates CYP1A2 (eg, caffeine) or CYP2D6 (eg, desipramine) substrates.

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 non-hormonal contraception during and for 4 weeks after treatment. Pregnancy (Cat.D). Nursing mothers: not recommended. Interactions: Concomitant strong inhibitors (eg, ketoconazole, nefazodone, clarithromycin, gemfibrozil) or inducers (eg, rifampin, phenytoin, carbamazepine, phenobarbital, St John’s wort) of CYP3A4 or CYP2C8: not recommended; if unavoidable, monitor closely. Drugs that affect gastric pH (eg, PPIs, H2-blockers, antacids) may decrease dabrafenib exposure. May antagonize effects of CYP3A4, CYP2B6, CYP2C8, CYP2C9, CYP2C19, UGT, transporters, or other substrates (eg, midazolam, warfarin, dexamethasone, hormonal contraceptives). Adverse reactions: Hyperkeratosis, headache, pyrexia, arthralgia, papilloma, alopecia, palmar-plantar erythrodysesthesia syndrome; combination with trametinib: chills, fatigue,

SYLATRON Merck

TAFINLAR GlaxoSmithKline

℞

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DRUG MONOGRAPHS

SKIN CANCER 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

hemorrhagic manifestations; 4) severe motor or sensory neuropathy, Guillain-Barre syndrome, or myasthenia gravis; 5) severe immune-mediated reactions involving any organ system; 6) immunemediated ocular disease that is unresponsive to topical immunosuppressive therapy. Monitor for enterocolitis, dermatitis, neuropathy, endocrinopathy; perform LFTs and thyroid tests at baseline and before each dose. Moderate or severe hepatic impairment. Pregnancy (Cat.C). Nursing mothers: not recommended. Adverse reactions: Fatigue, diarrhea, pruritus, rash, colitis; immune-mediated adverse reactions (may be severe and fatal). How supplied: Single-use vial (50mg, 200mg)–1

℞

Cytotoxic T-lymphocyte antigen 4 (CTLA-4)blocking antibody. Ipilimumab 5mg/mL; soln for IV infusion; preservative-free. Indications: Treatment of unresectable or metastatic melanoma. Adults: Give by IV infusion over 90 mins. 3mg/kg every 3 weeks for a total of 4 doses. Withhold dose for moderate immune-mediated reactions or symptomatic endocrinopathy. Complete/partial resolution of adverse reaction and receiving <7.5mg prednisone or equivalent per day: may resume treatment. Permanently discontinue and initiate systemic high-dose corticosteroids for severe adverse reactions. Children: Not established. Warnings/Precautions: Permanently discontinue if: persistent moderate adverse reactions or inability to reduce corticosteroid dose to 7.5mg prednisone or equivalent per day; failure to complete full treatment course within 16 weeks from first dose; severe or life-threatening reactions, including: 1) colitis with abdominal pain, fever, ileus, or peritoneal signs; increase in stool frequency and incontinence, need for IV hydration for >24hrs, GI hemorrhage/perforation; 2) AST or ALT >5X ULN or total bilirubin >3X ULN; 3) Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or

ZELBORAF Genentech

℞

Kinase inhibitor. Vemurafenib 240mg; tabs. Indications: Treatment of unresectable or metastatic melanoma with BRAFV600E mutation as detected by an FDA-approved test. Limitation of use: not for treatment of wild-type BRAF melanoma. Adults: Swallow whole. ≥18yrs: 960mg every 12hrs; until disease progression or unacceptable toxicity occurs. Dose modifications for adverse reactions or QTc prolongation: see full labeling. Dose reductions <480mg twice daily: not recommended. Children: <18yrs: not established. Warnings/Precautions: Confirm BRAFV600E mutation-positive melanoma with FDA-approved test before initiating. Risk of cutaneous squamous cell carcinoma (cuSCC): ≥65yrs, prior skin cancer, chronic sun exposure; if occurs, do excision and evaluate. Perform dermatologic evaluation before therapy, every 2 months

during, and consider monitoring 6 months after discontinuation. Monitor for signs/symptoms of new non-cutaneous SCC and other malignancies. Long QT syndrome or QTc >500ms, uncorrectable electrolyte abnormalities, or concomitant drugs that prolong the QT interval: not recommended. Prior to and following initiation or after dose adjustment for QTc prolongation, evaluate ECG and electrolytes after 15 days, monthly during the 1st 3 months, then every 3 months thereafter, or more as clinically indicated. Severe hepatic or renal impairment. Monitor liver enzymes, bilirubin before initiating and monthly during treatment, or as needed. Monitor for ophthalmologic reactions routinely. Avoid sun exposure. Pregnancy (Cat.D); avoid. Use adequate contraception during therapy and for at least 2 months after discontinuation. Nursing mothers: not recommended. Interactions: Avoid concomitant strong CYP3A4 inhibitors (eg, azole antifungals, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir) or strong CYP3A4 inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital); consider alternatives. Concomitant CYP1A2 substrates with narrow therapeutic indices: not recommended; if unavoidable, consider dose reduction of substrates and monitor. Increased transaminase and bilirubin with concomitant ipilimumab. Adverse reactions: Arthralgia, rash, alopecia, fatigue, photosensitivity, nausea, pruritus, skin papilloma; severe hypersensitivity or dermatologic reactions (permanently discontinue if occurs), uveitis, blurry vision, photophobia, other malignancies. How supplied: Tabs–120

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%

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

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DRUG MONOGRAPHS

ASSOCIATED HEMATOLOGICAL DISORDERS Anemias

ANADROL-50 Meda

CIII

Androgen. Oxymetholone 50mg; scored tabs. Indications: Anemia caused by deficient red cell production. Acquired aplastic anemia, congenital anemia, myelofibrosis, and hypoplastic anemias due to myelotoxic drugs. Adults and Children: Individualized. 1–5mg/kg per day for at least 3–6 months; may attempt to lower dose or discontinue after remission. Congenital aplastic anemia: may need continued maintenance dose. Contraindications: Male breast or prostate carcinoma. Breast cancer in females with hypercalcemia. Nephrosis or the nephrotic phase of nephritis. Severe hepatic dysfunction. Pregnancy (Cat.X). Warnings/Precautions: Not a replacement for other supportive treatments (eg, transfusion; iron, folic acid, Vit. B12, Vit. B6 replacement). Discontinue if jaundice, abnormal liver function, hypercalcemia, or edema occurs. Cardiac, hepatic, or renal dysfunction. Monitor hepatic function, blood, and bone age. Elderly. Young children. Nursing mothers: not recommended. Interactions: May potentiate oral anticoagulants. May alter insulin needs. Adverse reactions: Peliosis hepatis, premature epiphyseal closure in adolescents, edema, hepatic carcinoma, prostatic hypertrophy or carcinoma, gynecomastia, priapism, oligospermia, nausea, jaundice, hirsutism, virilization, male pattern baldness, acne, polycythemia, headache, CNS excitation, insomnia, altered libido, fluid and electrolyte disturbances, suppression of clotting factors, increased serum cholesterol. How supplied: Tabs–100

ARANESP Amgen

℞

Erythropoiesis stimulating protein. Darbepoetin alfa 25mcg/mL, 40mcg/mL, 60mcg/mL, 100mcg/mL, 150mcg/0.75mL, 200mcg/mL, 300mcg/mL, 500mcg/mL; for IV or SC inj; preservative-free; contains albumin (human) or polysorbate 80. ℞ Also: ARANESP SINGLEJECT Darbepoetin alfa 25mcg/0.42mL, 40mcg/0.4mL, 60mcg/0.3mL, 100mcg/0.5mL, 150mcg/0.3mL, 200mcg/0.4mL, 300mcg/0.6mL, 500mcg/mL; per prefilled syringe; for IV or SC inj; preservative-free; contains albumin (human) or polysorbate 80. Indications: Anemia of chronic renal failure (CRF), including patients on and not on dialysis. Chemotherapy-induced anemia in patients with non-myeloid malignancies. Adults: CRF (not currently on epoetin alfa): initially 0.45mcg/kg SC or IV once weekly; alternatively for CRF (not on dialysis): 0.75mcg/kg SC once every 2 weeks. Cancer: initially 2.25mcg/kg SC once weekly or 500mcg

SC once every 3 weeks. Discontinue after completion of chemotherapy course. Adjust dose to maintain hemoglobin level (target 10–12g/dL; max 12g/dL) sufficient to avoid red blood cell transfusion; see literature. Converting from epoetin alfa, and for dose adjustment: see literature. Children: Not recommended. Contraindications: Uncontrolled hypertension. Do not use in patients with pure red cell aplasia due to erythropoietin antibodies. Warnings/Precautions: See literature. Evaluate serum iron, ferritin, transferrin saturation before and during therapy; most patients will need iron supplementation. Monitor hemoglobin weekly for 4 weeks after start and dose changes, until stabilized, then periodically; reduce dose if hemoglobin increases >1g/dL in any 2-week period; withhold dose if hemoglobin exceeds 12g/dL. Monitor BP (reduce or withhold dose if hypertension occurs), folate, Vit. B12, renal function, electrolytes, fluid balance, and for premonitory neurological symptoms. Seizure, cardiovascular, or hematologic disorders. Infection, inflammation, malignancy, occult blood loss, severe albumin toxicity, bone marrow fibrosis may reduce effectiveness; consider other etiologies in treatment failures. Adjust dialysis ℞ as needed. Latex allergy. Pregnancy (Cat.C). Nursing mothers. Adverse reactions: Infection, hyper- or hypotension, myalgia, headache, GI upset, dyspnea, edema, arthralgia, limb or back pain, arrhythmia/cardiac arrest, cough, fatigue, chest pain, dizziness, pruritus, clotted vascular access, CHF, flu-like symptoms, local reactions, asthenia, seizure, iron deficiency. Increased risk of death, cardiovascular or thrombotic events if hemoglobin >12g/dL. May stimulate tumor growth, shorten time to tumor progression or overall survival if hemoglobin ≥12g/dL. Cancer patients also: pneumonia, dehydration. How supplied: Single-dose vials (25, 40, 60, 100, 150mcg)–4; Single-dose vial (200, 300mcg)–1; Single-dose prefilled syringes (25, 40, 60, 100, 150mcg)–4; Single-dose prefilled syringes (200, 300, 500mcg)–1

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, lightheadedness, 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

ATGAM Pfizer

BIFERARx Meda

℞

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).

BIFERA Meda

OTC

Iron (as polysaccharide iron complex [PIC] 22mg + heme iron polypeptide [HIP] as Proferrin bovine source 6mg) 28mg; gluten-free tabs. Indications: Iron supplement. Iron deficiency. Adults: 1 tab once daily. Children: Not recommended. Contraindications: Hemochromatosis. Hemosiderosis. Warnings/Precautions: May mask pernicious anemia. Monitor hemoglobin, hematocrit, ferritin levels periodically. Pregnancy. Nursing mothers. Adverse reactions: Allergic sensitization. How supplied: Tabs–30 ℞

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

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DRUG MONOGRAPHS

ASSOCIATED HEMATOLOGICAL DISORDERS Cyanocobalamin injection

℞

(various)

Vitamin. Cyanocobalamin 1000mcg/mL; soln for IM or SC inj; contains benzyl alcohol. Indications: Vit. B12 deficiencies due to malabsorption. Pernicious anemia. Vit. B12 absorption test (Schilling test). Adults: Give by IM or deep SC inj. Pernicious anemia: 100mcg daily for 6–7 days; then 100mcg every other day for 7 doses; then every 3–4 days for 2–3 weeks; then 100mcg monthly for life. Deficiencies due to malabsorption: if severe, may need to treat like pernicious anemia; use oral preparations for chronic treatment. Schilling test: 1000mcg. Children: See literature. Contraindications: Sensitivity to cobalt. Warnings/Precautions: Hereditary optic nerve atrophy (Leber’s disease). Severe megaloblastic anemia (intense treatment may lead to hypokalemia and death). Monitor potassium for first 48 hours; replace if needed. Obtain hematocrit, reticulocyte count, Vit. B12, folate, and iron levels before and during treatment. Reevaluate periodically. Premature infants. Renal impairment (possible aluminum toxicity). Folic acid use may mask B12 deficiency. Pregnancy (Cat.C). Interactions: Antibiotics, methotrexate, pyrimethamine interfere with Vit. B12 diagnostic tests. Colchicine, para-aminosalicylic acid, heavy alcohol intake for >2 weeks may produce malabsorption of Vit. B12. Adverse reactions: Pulmonary edema, CHF, vascular thrombosis, polycythemia vera, transient diarrhea, itching, transitory exanthema; anaphylactic shock (may be fatal; do test dose if hypersensitivity suspected). How supplied: Contact supplier.

DEXFERRUM American Regent

℞

Hematinic. Iron (as dextran complex) 50mg/mL; soln for IV inj. Indications: Iron deficiency where oral therapy is unsatisfactory or impossible. Adults and Children: <4months: not recommended. Give by IV inj. Administer 0.5mL test dose first; if no signs/symptoms of anaphylactic-type reactions, may give full therapeutic dose. ≥4months: Iron deficiency anemia: determine total dose based on hemoglobin and body weight (see literature). Iron replacement for blood loss: Replacement iron (in mg) = blood loss (in mL) × hematocrit. Max daily doses: <5kg: 0.5mL (25mg), <10kg: 1mL (50mg), ≥10kg: 2mL (100mg).

Contraindications: Anemia not associated with iron deficiency. Warnings/Precautions: Monitor for signs/ symptoms of anaphylactic-type reactions, esp. in patients with history of allergies, asthma; have epinephrine available. Hepatic impairment. Avoid during acute phase of infectious kidney disease. Cardiovascular disease. Avoid large IV doses: higher incidence of adverse events. Iron overload more likely with hemoglobinopathies or refractory anemias. Rheumatoid arthritis. Neonates. Pregnancy (Cat.C). Nursing mothers. Interactions: Concomitant ACE inhibitors may increase the risk for anaphylactic-type reactions. May falsely elevate serum bilirubin and decrease serum calcium. Adverse reactions: See literature. Anaphylactic reactions (may be fatal, even in patients who tolerated test dose), cardiovascular events, pruritus, GI upset, arthralgia, arthritis, inj site reactions, others. How supplied: Single-dose vials (1mL, 2mL)–10

DROXIA Bristol-Myers Squibb

℞

Substituted urea. Hydroxyurea 200mg, 300mg, 400mg; caps. Indications: To reduce the frequency of painful crises and to reduce the need for blood transfusions in adults with sickle cell anemia with recurrent moderate-to-severe painful crises. Adults: Base dose on ideal or actual weight, whichever is less. Initially 15mg/kg/day as a single dose. May increase dose by 5mg/kg/day every 12 weeks to maximum tolerated dose or 35mg/kg/day achieved; do not increase dose if blood counts are between acceptable range and toxic. If blood counts toxic, discontinue until hematologic recovery, see literature for dosage adjustments. Renal impairment (CrCl <60mL/min or ESRD): initially 7.5mg/kg per day; give dose following dialysis. Children: Not recommended. Warnings/Precautions: Markedly depressed bone marrow function: not recommended. Monitor hematologic, renal, and liver function before and during therapy. Renal dysfunction. Macrocytosis may mask folic acid deficiency; prophylactic folic acid is recommended. Myeloproliferative disorders; discontinue if cutaneous vasculitic ulcerations develop. Pregnancy (Cat.D); avoid use. Nursing mother: not recommended. Interactions: Avoid concomitant didanosine, with or without stavudine, or other antiretrovirals (may cause pancreatitis [monitor], fatal hepatotoxicity, peripheral neuropathy). May

antagonize antigout agents. Increased risk of vasculitic toxicities with interferon therapy. May cause falsely elevated urease, uricase, lactate dehydrogenase. Adverse reactions: Neutropenia, thrombocytopenia, anemia, low reticulocyte count, hair loss, rash, fever, GI upset, weight gain, bleeding, parvovirus B-19 infection, melanonychia, erythema, CNS effects, temporary renal impairment, acute pulmonary reactions, secondary leukemias, skin cancer. Note: Wear disposable gloves when handling caps or bottle. How supplied: Caps–60

EPOGEN Amgen

℞

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DRUG MONOGRAPHS

ASSOCIATED HEMATOLOGICAL DISORDERS 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 (all)–10; Multidose 2mL vials (10000 Units/mL)–10; Multidose 1mL vials (20000 Units/mL)–10

FEOSOL Meda

OTC

Iron 65mg (as sulfate 200mg); tabs. OTC Also: FEOSOL CAPLETS Iron 50mg (as carbonyl). OTC Also: FEOSOL ELIXIR Iron 44mg/5mL (as sulfate 220mg/5mL); alcohol 5%. Indications: Iron deficiency and iron deficiency anemia. Adults: 1 tab or 1 caplet or 5mL daily. Children: Individualize. May mix with water or fruit juice. Contraindications: Hemochromatosis. Hemosiderosis.

Warnings/Precautions: Monitor hemoglobin, hematocrit, reticulocyte count periodically. Elderly. Interactions: Inhibits tetracycline absorption. Adverse reactions: Nausea, abdominal discomfort and pain, constipation, diarrhea, masks occult bleeding, black stools, tooth discoloration (elixir). How supplied: Tabs, caplets–30, 60; Elixir–16oz

FER-IN-SOL DROPS

OTC

Mead Johnson Nutrition Iron 15mg/1mL (as sulfate 75mg/1mL); contains sulfites, alcohol; gluten-free. Indications: Iron deficiency and iron deficiency anemias. Adults and Children: May give directly into the mouth or mix with formula, fruit juice, cereal or other foods. <4yrs: 1mL daily. ≥4yrs: not recommended. Contraindications: Hemochromatosis. Hemosiderosis. Warnings/Precautions: Monitor hemoglobin, hematocrit, reticulocyte count periodically. Elderly. Interactions: Inhibits tetracycline absorption. Adverse reactions: Nausea, abdominal discomfort and pain, constipation, masks occult bleeding, black stools, stains teeth and dentures. How supplied: Drops–50mL (w. calibrated dropper)

FERAHEME AMAG

℞

Hematinic. Elemental iron 30mg/mL (as ferumoxytol 510mg/17mL); colloidal iron for IV inj; contains mannitol 44mg/mL; preservativefree. Indications: Iron deficiency anemia in adult patients with chronic kidney disease. Adults: Give undiluted by IV injection at a rate up to 1mL/sec (30mg/sec). Initially 510mg, then an additional 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: Not recommended. Warnings/Precautions: Iron overload: do not administer. Monitor for severe hypotension, and for hypersensitivity for at least 30 minutes after each injection. Evaluate hemoglobin, ferritin, iron, transferrin saturation at least 1 month after 2nd injection. Have equipment/personnel available to treat hypersensitivity reactions. 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 literature). Adverse reactions: Diarrhea, nausea, hypotension (may be significant), dizziness, constipation, peripheral edema; infusion reactions, anaphylactoid reactions (may be fatal), other hypersensitivity reactions (eg, rash, pruritus, urticaria, wheeze). How supplied: Single-use vials (17mL)–1, 10

FERGON Bayer Consumer

OTC

Iron 27mg (as gluconate 240mg); tabs. Indications: Iron deficiency anemias. Adults: 1 tab daily. Children: Not recommended. Contraindications: Hemochromatosis. Hemosiderosis. Warnings/Precautions: Monitor hemoglobin, hematocrit, reticulocyte count periodically. Elderly. Interactions: Inhibits tetracycline absorption. Adverse reactions: Nausea, abdominal discomfort and pain, constipation, diarrhea, masks occult bleeding, black stools. How supplied: Tabs–100

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

FERRETTS Pharmics

OTC

Iron 106mg (as fumarate); scored tabs; phosphorus- and gluten-free. Indications: Iron deficiency and iron deficiency anemia. Adults: 1 tablet daily. Children: Not recommended. Contraindications: Hemochromatosis. Hemosiderosis. Warnings/Precautions: Monitor hemoglobin, hematocrit, reticulocyte count periodically. Elderly. Interactions: Inhibits tetracycline absorption. Adverse reactions: GI upset, abdominal discomfort, constipation, masks occult bleeding, black stools. How supplied: Tabs–60

FERRLECIT Sanofi Aventis

℞

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DRUG MONOGRAPHS

ASSOCIATED HEMATOLOGICAL DISORDERS 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

FERRO-SEQUELS IVC

OTC

Iron (as fumarate) 50mg; timed-rel caplets; contains docusate sodium. Indications: Iron deficiency and iron deficiency anemias. Adults: 1 caplet daily or as needed. Children: Not recommended. Contraindications: Hemochromatosis. Hemosiderosis. Warnings/Precautions: Monitor hemoglobin, hematocrit, reticulocyte count periodically. Elderly. Interactions: Inhibits tetracycline absorption. Adverse reactions: Nausea, abdominal discomfort and pain, constipation, diarrhea, masks occult bleeding, black stools. How supplied: Caplets–100

Folic acid (various)

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.

ICAR-C Hawthorn

Iron (as carbonyl) 100mg, Vit. C 250mg; tabs. ℞ Also: ICAR-C PLUS Iron (as carbonyl) 100mg, Vit. B12 25mcg, folic acid 1mg, Vit. C 250mg; tabs. OTC Also: ICAR PEDIATRIC SUSP Iron (as carbonyl) 15mg/1.25mL; grape flavor; sugar- and alcohol-free. Indications: Iron deficiency and iron deficiency anemia. Adults: 1 tab once daily. Children: Use Ped Susp. 15mg (of iron) once daily. Contraindications: Hemochromatosis. Hemosiderosis. Warnings/Precautions: Folic acid may mask pernicious anemia. Monitor hemoglobin, hematocrit, reticulocyte count periodically. Elderly. Interactions: Inhibits tetracycline absorption. Aluminum- or magnesium-containing antacids inhibit iron absorption. Adverse reactions: Nausea, abdominal discomfort and pain, constipation, diarrhea, masks occult bleeding, black stools. How supplied: Tabs–100 Ped Susp–4oz (w. dosing syringe)

INFED Actavis ℞

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.

OTC

℞

Hematinic. Iron (as dextran complex) 50mg/mL; soln for IV or IM inj. Indications: Iron deficiency where oral therapy is unsatisfactory or impossible. Adults and Children: Give by IV or by deep IM (into upper outer quadrant of buttock only) inj. Administer 0.5mL test dose first; if no signs/ symptoms of anaphylactic-type reactions, may give full therapeutic dose. Iron deficiency anemia: determine total dose based on hemoglobin and body weight (see literature). Iron replacement for blood loss: Replacement iron (in mg) = blood loss (in mL) × hematocrit. Max daily doses: <5kg: 0.5mL (25mg), <10kg: 1mL (50mg), ≥10kg: 2mL (100mg). Contraindications: Anemias not associated with iron deficiency.

Warnings/Precautions: Monitor for signs/ symptoms of anaphylactic-type reactions, esp. in patients with history of drug allergies, asthma; have epinephrine available. Avoid large IV doses: higher incidence of adverse events. Severe hepatic impairment. Avoid during acute phase of infectious kidney disease. Dialysis. Cardiovascular disease. May reactivate quiescent rheumatoid arthritis. Neonates (avoid during first 4 months). Pregnancy (Cat.C). Nursing mothers. Interactions: Concomitant ACE inhibitors may increase the risk for anaphylactic-type reactions. May falsely elevate serum bilirubin or decrease serum calcium levels. Adverse reactions: See literature. Anaphylactic reactions (may be fatal; even if test dose was tolerated), cardiovascular events, pruritus, GI upset, arthralgia, arthritis, inj site reactions, others; possible IM inj site tumors, sepsis in neonates. How supplied: Vials (2mL)–10

INJECTAFER American Regent

℞

Hematinic. Iron (as ferric carboxymaltose) 50mg/mL; soln for IV inj or infusion; preservativefree. Indications: Iron deficiency anemia in adults who have intolerance or insufficient response to oral iron; or have non-dialysis-dependent chronic kidney disease. 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

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DRUG MONOGRAPHS

ASSOCIATED HEMATOLOGICAL DISORDERS Leucovorin Teva

℞

Folic acid derivative. Leucovorin calcium 100mg/vial, 350mg/vial; lyophilized pwd for IV or IM inj after reconstitution; preservative-free. Indications: Megalobastic anemia due to folic acid deficiency when oral therapy is not feasible. Adults: Up to 1mg daily. Children: See literature. Contraindications: Pernicious anemia and other megaloblastic anemias due to Vit. B12 deficiency. Warnings/Precautions: Do not administer intrathecally. CNS metastases. Monitor CBCs with differential, platelets, electrolytes, liver function tests prior to each treatment, then periodically. Elderly. Debilitated. Pregnancy (Cat.C). Nursing mothers. Interactions: Potentiates toxicity of 5-fluorouracil; use lower 5-fluorouracil dose. May antagonize phenobarbital, phenytoin, and primidone. Caution with trimethoprim-sulfamethoxazole. Adverse reactions: Leukopenia, thrombocytopenia, infection, GI upset, stomatitis, constipation, lethargy, malaise, fatigue, alopecia, dermatitis, anorexia; seizures, syncope. How supplied: Single-use vials–1

LUPRON DEPOT 3.75mg

℞

AbbVie

GnRH analogue. Leuprolide acetate 3.75mg; depot susp for IM inj; preservative-free. Indications: Presurgical treatment of patients with anemia due to uterine leiomyomata (fibroids), with iron therapy if iron therapy alone is inadequate. Adults: ≥18 years: 3.75mg IM once per month for up to 3 months. Children: <18 years: not applicable. Also: LUPRON DEPOT-3 MONTH 11.25mg ℞ Leuprolide acetate 11.25mg; depot susp for IM inj; preservative-free. Adults: ≥18 years: 11.25mg IM once every 3 months (1 injection). Do not split doses. Children: <18 years: not applicable. Contraindications: Undiagnosed abnormal vaginal bleeding. Pregnancy (Cat.X). Nursing mothers. Warnings/Precautions: Exclude pregnancy before starting; use nonhormonal contraception during therapy; discontinue if pregnancy occurs. Risk factors for decreased bone mineral density (eg, chronic alcohol, tobacco, anticonvulsants, corticosteroids). Missing successive doses may cause breakthrough bleeding or ovulation. Elderly. Adverse reactions: Hot flashes, headache, vaginitis, depression, emotional lability, pain, decreased libido, breast changes, amenorrhea, mastodynia, joint disorder, asthenia, GI upset, edema, bone density loss, local reactions, acne, memory disorders, others; rarely: anaphylaxis, asthma, increased serum transaminases or lipids. How supplied: Kit–1 (single-dose syringe w. diluent, supplies)

NASCOBAL Strativa

℞

Cyanocobalamin 500mcg/spray; soln for nasal spray; contains benzalkonium chloride. Indications: Maintenance of normal hematologic status in pernicious anemia patients who are in remission after intramuscular Vit. B12 therapy and who have no nervous system involvement. Supplementation for other Vit. B12 deficiencies. Adults: Hematological parameters must be within normal range before beginning therapy. Allow at least 1hr before or after hot foods or liquids. Initial dose: One spray (500mcg) in one nostril once weekly. Monitor response, may increase dose if serum B12 levels decline. Children: Not recommended. Warnings/Precautions: Confirm diagnosis. May need supplemental folate. Risk of hypokalemia or sudden death in severe megablastic anemia. Leber’s disease. Defer dose if nasal congestion, rhinitis, or upper respiratory infections occur. Reevaluate if low levels of Vit. B12 persist despite treatment. Do not use for Schilling Test. Infection, uremia, and iron or folic acid deficiency may reduce response. Increased risk of stomach carcinoma in those with pernicious anemia; perform tests when indicated. May unmask polycythemia vera. Monitor B12 blood levels 1 month after starting therapy, 1 month after any dose increase, and regularly at 3–6 month intervals. Monitor serum potassium, platelet counts. Pregnancy (Cat.C). Interactions: Antibiotics, methotrexate, pyrimethamine may interfere with lab tests. Colchicine, chronic heavy alcohol use may impair Vit. B12 absorption. Reduced response with bone marrow suppressants (eg, chloramphenicol). Adverse reactions: Headache, nausea, rhinitis. How supplied: Single-use nasal spray (0.125mL)–4

NULECIT Actavis

℞

Hematinic. Iron (as sodium ferric gluconate complex in sucrose) 12.5mg/mL; soln for IV inj or infusion; contains benzyl alcohol. Indications: Iron deficiency anemia in patients on chronic hemodialysis receiving epoetin therapy. Adults: Give by IV infusion (diluted) or slow IV inj (undiluted). 125mg infused over 1 hour or by slow IV inj (at a rate of up to 12.5mg/min). Minimum cumulative dose: 1g given over 8 sequential dialysis sessions; usual max: 125mg/dose. Children: <6yrs: not recommended. Give by IV infusion (diluted) over 1 hour. ≥6yrs: 1.5mg/kg per dose at 8 sequential dialysis sessions; max: 125mg/dose. Contraindications: Anemias not caused by iron deficiency. Iron overload. Warnings/Precautions: Hemoglobinopathies. Refractory anemias. Avoid in neonates. Pregnancy (Cat.B). Nursing mothers. Interactions: May reduce absorption of concomitant oral iron preparations. Adverse reactions: Hypotension, hypertension, GI upset, chest pain, back pain, abdominal pain,

pruritus, inj site reaction, cramps, headache, dizziness, syncope, fatigue, fever, dyspnea, tachycardia; rare: hypersensitivity reactions. How supplied: Vials (5mL)–10

PROCRIT Janssen Biotech

℞

Erythropoietin (human, recombinant). Epoetin alfa 2000 Units, 3000 Units, 4000 Units, 10000 Units, 40000 Units; per mL; soln for IV or SC inj; contains albumin (human); preservative-free. ℞ Also: PROCRIT MULTIDOSE Epoetin alfa 10000 Units, 20000 Units; per mL; soln for IV or SC inj; contains albumin (human) and benzyl alcohol. Indications: Anemia in chronic renal failure (CRF). Anemia related to zidovudine in HIVinfected patients. Chemotherapy-induced anemia in patients with non-myeloid malignancies (serum erythropoietin ≤200 mUnits/mL). To reduce need for allogeneic blood transfusions in anemic (hemoglobin >10 to ≤13g/dL) patients scheduled for elective, noncardiac, nonvascular surgery. Adults: Individualize (see literature for titration). CRF: initially 50–100 Units/kg 3 times per week IV (dialysis or non dialysis) or SC (non dialysis); usual max (non dialysis) 150 Units/kg 3 times per week; (dialysis) 200 Units/kg 3 times per week; target hemoglobin: 10–12g/dL. Zidovudinetreated HIV patients: if serum erythropoietin ≤500 mUnits/mL and zidovudine dose ≤4.2g/wk: initially 100 Units/kg IV or SC 3 times per week for 8 weeks; usual max 300 Units/kg 3 times per week. Chemotherapy-induced: initially 150 Units/kg SC 3 times per week; may increase to 300 Units/kg 3 times per week after 8 weeks. Or, initially 40000 Units SC once weekly; may increase to 60000 Units once weekly after 4 weeks. Discontinue after completion of chemotherapy course. Surgery: If ≥21 days until surgery: 600 Units/kg once weekly SC at 21, 14 and 7 days before surgery, and a 4th dose on day of surgery. If <21 days until surgery: 300 Units/kg per day SC for 10 days before, on day of, and for 4 days after surgery. All: adjust dose to maintain the lowest hemoglobin level (target max 12g/dL) sufficient to avoid red blood cell transfusion; see literature. Children: Individualize (see literature for monitoring). CRF (dialysis): <1 month: not recommended. ≥1 month of age: initially 50 Units/kg three times per week IV or SC. Target hemoglobin: 10–12g/dL. Chemotherapy-induced: ≥5yrs: 600 Units/kg IV weekly (max 40,000 Units); may increase to 900 Units/kg IV weekly (max 60,000 Units) after 4 weeks. Discontinue after completion of chemotherapy course. Other uses: see literature. Contraindications: Uncontrolled hypertension. Warnings/Precautions: See literature. Evaluate serum iron, ferritin, transferrin saturation before therapy; all patients will need iron supplementation. Monitor hemoglobin (measure twice weekly for 2–6 weeks after any dosage adjustment; reduce dose if hemoglobin increases

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DRUG MONOGRAPHS

ASSOCIATED HEMATOLOGICAL DISORDERS >1g/dL in any 2-week period; withhold dose if hemoglobin exceeds 12g/dL), blood pressure, renal function, iron levels, clotting times, serum chemistry, CBC, and for premonitory neurological symptoms. Seizure disorders. Cardiovascular or hematologic disorders. Hypertension (esp. in renal failure). Porphyria. Concurrent infection, inflammation, increased zidovudine dose, or other factors may reduce effectiveness. Perisurgery: consider DVT prophylaxis. Consider other etiologies in treatment failures. Adjust anticoagulant dose in dialysis patients. Menses may resume. Pregnancy (Cat.C). Nursing mothers. Adverse reactions: Iron deficiency, hypertension, headache, arthralgia, GI disturbances, edema, local reaction, rash, paresthesia, dizziness, clotted vascular access (A-V shunt), pyrexia, respiratory congestion, seizures. Increased risk of death, cardiovascular or thrombotic events if hemoglobin >12g/dL. May stimulate tumor growth, shorten time to tumor progression or overall survival if hemoglobin ≥12g/dL. Children: also abdominal pain, upper respiratory infection, cough, pharyngitis, constipation. How supplied: Single-use 1mL vials (2000 Units/mL, 3000 Units/mL, 4000 Units/mL, 10000 Units/mL)–6, 25; Single-use 1mL vials (40000 Units/mL)–4; Multidose 2mL vials (10000 Units/mL)–4, 6; Multidose 1mL vials (20000 Units/mL)–4, 6

PROMACTA GlaxoSmithKline

℞

Thrombopoietin receptor agonist. Eltrombopag (as olamine) 12.5mg, 25mg, 50mg, 75mg; tabs. Indications: Severe aplastic anemia in adults who have had insufficient response to immunosuppressive therapy. Adults: Take on empty stomach. Initially 50mg once daily. Hepatic impairment or East Asian ancestry: initially 25mg once daily. Titrate dose by 50mg every 2 weeks as needed to maintain platelet count ≥50×109/L; max 150mg daily. Monitoring, dose adjustment, and discontinuation: see full labeling. Children: Not established. Warnings/Precautions: Increased risk of hepatic decompensation in chronic hepatitis C, when concomitant with interferon and ribavirin; discontinue Promacta if antiviral therapy is discontinued. Monitor liver function prior to initiation, every 2 weeks during dose adjustments, and monthly after stabilized (see full labeling); discontinue if ALT ≥3×ULN and is progressive or persistent for ≥4 weeks, or if occurs with increased bilirubin, or evidence of hepatic injury/ decompensation; reinitiate therapy if benefit outweighs risk; if restarted, monitor carefully.

Increased risk of thromboembolism; do not use to normalize platelet counts. Do baseline eye exam; monitor for cataracts. Renal impairment. Pregnancy (Cat.C). Nursing mothers: not recommended. Interactions: Do not take within 4hrs of food/ drugs containing polyvalent cations (eg, Fe+2, Ca+2, Al+3, Mg+2, Se+2, Zn+2). Potentiate substrates of OATP1B1 (eg, most statins, bosentan, ezetimibe, glyburide, olmesartan, valsartan, repaglinide, rifampin) or BCRP (eg, imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone, sulfasalazine, topotecan); monitor and consider reducing their doses. Antagonized by lopinavir/ ritonavir. Adverse reactions: Nausea, diarrhea, fatigue, cough, headache, pain, dyspnea, pyrexia, dizziness, febrile neutropenia, ecchymosis, muscle spasms, arthralgia, rhinorrhea; elevated hepatic enzymes, hepatotoxicity, hemorrhage, thrombotic complications from excessive increases in platelet counts, 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, 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

SLOW FE Novartis Consumer

OTC

Iron 50mg (as sulfate 160mg); sust-rel tabs. Indications: Iron deficiency and iron deficiency anemias. Adults: Swallow whole. 1–2 tabs daily; max 4 daily. Children: Swallow whole. <6 yrs: not recommended. ≥6 yrs: 1 tab daily. Also: SLOW FE PLUS FOLIC ACID OTC Iron, elemental 50mg (as ferrous sulfate 160mg), folic acid 0.4mg; sust-rel tabs. Adults: Swallow whole. 1–2 tabs daily. Children: Not recommended. Contraindications: Hemochromatosis. Hemosiderosis. Warnings/Precautions: Hepatitis. Pancreatitis. Peptic ulcer or GI inflammation. Achlorhydria. Monitor hematocrit. Folic acid may mask pernicious anemia. Repeated blood transfusions. Elderly. Interactions: Inhibits tetracycline absorption. Adverse reactions: Nausea, abdominal discomfort and pain, constipation, diarrhea, masks occult bleeding, black stools. How supplied: Slow Fe–30, 60, 90; Plus folic acid–20

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DRUG MONOGRAPHS

ASSOCIATED HEMATOLOGICAL DISORDERS 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 complement-mediated 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: <10yrs: not recommended. Contraindications: Hemochromatosis. Hemosiderosis. Warnings/Precautions: For pernicious anemia, parenteral cyanocobalamin is preferred. Resistance to exogenous intrinsic factor may develop. Folic acid may mask pernicious anemia. Monitor blood parameters. Hepatitis. Pancreatitis. Peptic ulcer or GI inflammation. Achlorhydria. Repeated blood transfusions. Pregnancy (Cat.C). Nursing mothers. Elderly. Interactions: Inhibits tetracycline absorption. Adverse reactions: Nausea, abdominal discomfort and pain, constipation, diarrhea, masks occult bleeding, black stools, rash. How supplied: Caps–60, 100

VENOFER American Regent

℞

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

Bleeding disorders

ADVATE Baxter

℞

Clotting factor. Antihemophilic Factor VIII (recombinant) 250 IU, 500 IU, 1000 IU, 1500 IU, 2000 IU, 3000 IU; per vial; pwd for IV inj after reconstitution; albumin- and preservative-free. Indications: In patients with Hemophilia A: to control and prevent hemorrhagic episodes, for perioperative management, and routine prophylaxis to prevent or reduce the frequency of hemorrhagic episodes. Adults and Children: Dosage Required (IU) = Body Weight (kg) × Desired % Factor VIII Increase × 0.5. Infuse over ≤5 minutes (max infusion rate 10mL/min); monitor pulse; if increased significantly, reduce infusion rate or hold. Hemorrhage: Mild: obtain 20–40% FVIII increase; give every 12–24hrs for 1–3 days until resolved. Moderate: obtain 30–60% FVIII increase; give every 12–24hrs for 3 days or until pain or disability resolved. Major: obtain 60–100% FVIII increase; give every 8–24hrs until resolved. Perioperative: Minor: obtain 60–100% FVIII increase; give single bolus infusion within 1 hour of surgery, then every 12–24hrs as needed to control bleeding; Major: pre- and Post-op: obtain 80–120% FVIII increase; give pre-op and maintenance bolus infusion, then repeat every 8–24hrs based on healing. Routine prophylaxis: give 20–40 IU/kg every other day (3–4 times weekly). Or, alternatively, an every 3rd day dosing regimen may be followed. Adjust based on response. 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. Labor & delivery. Pregnancy (Cat.C). Nursing mothers. Adverse reactions: Headache, arthralgia, pyrexia, cough, nasopharyngitis, pharyngolaryngeal pain; antibody formation, hypersensitivity reactions. How supplied: Single-dose vial–1 (w. diluent, Baxject II needleless transfer device)

ALPHANATE Grifols Biologicals

℞

Clotting factor. Antihemophilic Factor VIII/von Willebrand Factor Complex (human) 250 IU, 500 IU, 1000 IU, 1500 IU; per vial; lyophilized pwd for IV inj after reconstitution; contains albumin. Indications: Prevention and control of bleeding in Hemophilia A or acquired Factor VIII deficiency. Surgical and/or invasive procedures in von Willebrand disease (VWD) when desmopressin is ineffective or contraindicated. Adults: Dosage Required (IU) = Body Weight (kg) × Desired % Factor VIII Increase × 0.5. Individualize. Give by IV inj; max infusion rate ≤10mL/min. Hemorrhage: Minor: 15 FVIII IU/kg twice daily for 1–2 days. Moderate: 25 FVIII IU/kg twice daily for 2–7 days. Severe: 40–50 FVIII

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ASSOCIATED HEMATOLOGICAL DISORDERS IU/kg twice daily for at least 3–5 days, then 25 FVIII IU/kg twice daily until healed (up to 10 days). Surgery: 40–50 FVIII IU/kg prior to surgery then 25–50 FVIII IU/kg twice daily for 7–10 days or until healed. Von Willebrand: pre-op dose: 60 VWF:RCof IU/kg, then 40–60 VWF:RCof IU/kg every 8–12hrs if needed; may reduce dose after 3rd post-op day; treat until healed. Others: see literature. Children: Give by IV inj; max infusion rate ≤10mL/min. Von Willebrand: initially 75 VWF:RCof IU/kg, then 50–75 VWF:RCof IU/kg every 8–12hrs if needed; may reduce dose after 3rd post-op day; treat until healed. Warnings/Precautions: Not for those with severe VWD undergoing major surgery. Contains human plasma; monitor for possible infection transmission. Blood groups A, B or AB; large and/or frequent dosing may result in hemolytic anemia. Monitor for development of Factor VIII inhibitors. Pregnancy (Cat.C). Adverse reactions: Urticaria, fever, chills, GI upset, headache, somnolence, lethargy, inj site reactions, pruritus, pharyngitis, paresthesia, facial edema, rash; antibody formation, infection, thromboembolic events (in VWD patients), hemolytic anemia (rare). Note: Report all infections suspected to be transmitted by Alphanate to (888) GRIFOLS. How supplied: Single-dose vial–1 (w. diluent, supplies)

ALPHANINE SD Grifols Biologicals ℞ Clotting factor. Coagulation Factor IX (human) 250 IU, 500 IU, 1000 IU, 1500 IU; per vial; lyophilized concentrate for IV infusion after reconstitution; contains non-therapeutic Factor II, Factor VII, Factor X. Indications: Prevention and control of bleeding in Hemophilia B. Adults: Dosage Required (IU) = Body Weight (kg) × Desired Factor IX increase × 1 IU/kg. Individualize. Max infusion rate: 10mL/min. Mild hemorrhage: increase FIX 20–30% (20–30 IU/kg twice daily) for 1–2 days or until resolved. Moderate hemorrhage: increase FIX 25–50% (25–50 IU/kg twice daily) for 2–7 days. Major hemorrhage: increase FIX 50% (30–50 IU/kg twice daily) for 3–5 days then maintain at 20% (20 IU/kg twice daily) for up to 10 days. Surgery: Pre-op: increase FIX 50–100% (50–100 IU/kg twice daily), then maintain at 50–100% for 7–10 days or until healed. Children: See literature. Warnings/Precautions: Not for treating Factor II, VII, or X deficiencies; Hemophilia A with Factor VIII inhibitors, or reversal of coumarin-induced hemorrhage. Contains human plasma; monitor for transmission of infectious diseases. Previously

untreated patients: closely monitor for signs of anaphylaxis between days 10 and 20 of exposure. Immune tolerance induction. Major deletion mutations in Factor IX gene. Liver disease. Surgery. Pregnancy (Cat.C). Adverse reactions: Chills, nausea, inj site reactions; hypersensitivity reactions, thrombosis, disseminated intravascular coagulation. Note: Report all infections suspected to be transmitted by AlphaNine SD to (888) 675-2762. How supplied: Single-use vials–1 (w. diluent, supplies)

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 long-term 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

BEBULIN VH Baxter

℞

Clotting factor. Coagulation Factor IX Complex (human) 500–700 IU; per vial; freeze-dried concentrate for IV infusion after reconstitution; contains Factors II, VII, X and heparin. Indications: Prevention and control of bleeding in Hemophilia B.

Adults and Children: Dosage Required (IU) = Body Weight (kg) × Desired Factor IX increase × 1.2 IU/kg. Max infusion rate: 2mL/min. Bleeding: minor: 20% increase (25–35 IU/kg) for 1 dose. Moderate: 40% increase (40–55 IU/kg) once, give 2nd dose after 24hrs (continue until resolved). Major: ≥60% increase (60–70 IU/kg) once daily for 2–3 days or until healed. Surgery: Give loading dose 1hr prior to surgery. May repeat dose every 12hrs initially then every 24hrs in late post-op period. Minor: Initially 40–60% (50–60 IU/kg), then 20–40% (25–55 IU/kg) for 1–2 weeks. Major: Initially ≥60% increase (70–95 IU/kg) then 20–60% (35–75 IU/kg) for 1–2 weeks, then 20% (25–35 IU/kg) until healed. Prophylaxis: 20–30 IU/kg 1–2 times weekly. Warnings/Precautions: Not for treating factor deficiencies other than Factor IX deficiency. Contains human plasma; monitor for possible infection transmission. Thromboembolic disorders; risk increased during post-op period; avoid FIX increases >60%; monitor for thrombosis, disseminated intravascular coagulation (DIC). Surgery. Pregnancy (Cat.C). Adverse reactions: Hypersensitivity reactions, thrombosis, DIC. Note: Report all infections suspected to be transmitted by Bebulin VH to (800) 423-2862. How supplied: Single-use vials–1 (w. diluent, needles)

BENEFIX Pfizer

℞

Clotting factor. Coagulation Factor IX (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 bleeding in hemophilia B. Peri-operative management in patients with hemophilia B. Adults: Dosage Required (IU) = Body Weight (kg) × Desired Factor IX increase × 1.3 IU/kg. Give by IV infusion over several minutes. If inhibitor present or low Factor IX recovery, may need higher doses. Minor hemorrhage: 20–30% increase every 12–24hrs for 1–2 days. Moderate: 25–50% increase every 12–24hrs for 2–7 days until resolved. Major: 50–100% increase every 12–24 hrs for 7–10 days. Children: <15yrs: See literature. Dose (IU) = body weight (kg) × % FIX increase × 1.4 IU/kg. Contraindications: Hamster protein hypersensitivity. Warnings/Precautions: Not for Hemophilia A with FVIII inhibitors or other factor deficiencies, reversal of coumarin-induced anticoagulation or for low levels of liver-dependant coagulation factors. Fibrinolysis, disseminated intravascular

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ASSOCIATED HEMATOLOGICAL DISORDERS coagulation (DIC), liver disease, neonates, or during post-op period; increased risk of thromboembolic events. Monitor for Factor IX inhibitors and deletion mutations of Factor IX gene; increased risk of anaphylaxis. Immune tolerance induction. Latex allergy. Pregnancy (Cat.C). Adverse reactions: Headache, fever, chills, flushing, GI upset, lethargy, taste perversion, hypoxia, inj site reactions, dizziness, allergic rhinitis; hypersensitivity reactions, inhibitor development, thrombosis. How supplied: Single-use vials–1 (w. diluent, supplies)

CARIMUNE NF CSL Behring

℞

Immune globulin. Immune globulin (human) 3g, 6g, 12g; per vial; pwd for IV infusion after reconstitution; contains sucrose and NaCl; preservative-free. Indications: Immune thrombocytopenic purpura (ITP). Adults and Children: Induction: give by IV infusion at a rate of 0.5mg/kg/min for first 30mins, if tolerated may increase to 1mg/kg/min up to max 3mg/kg/min in a stepwise manner. 0.4g/kg on 2–5 consecutive days. Use of 6% immunoglobulin solution is recommended. Acute childhood ITP: discontinue therapy after second day of 5 day course if platelet count response to first two doses is 30–50000/μL. Maintenance: If platelet count falls to <30000/μL and/or clinically significant bleed: give 0.4g/kg as a single infusion, may increase to 0.8–1g/kg as single infusion if inadequate response. Risk of renal dysfunction/failure or thrombosis: max infusion rate <2mg/kg/min. Contraindications: IgA-deficiency with antibodies against IgA. Previous severe reaction to human immune globulin. Warnings/Precautions: Advanced age, prolonged immobilization, hypercoagulable conditions, history of venous or arterial thrombosis, use of estrogens, indwelling central vascular catheters, hyperviscosity, cardiovascular risk factors: increased risk of thrombosis. Monitor for signs/symptoms of thrombosis and assess blood viscosity in patients at risk for hyperviscosity. Pre-existing renal insufficiency, diabetes, >65yrs, hypovolemia, sepsis, paraproteinemia: increased risk of renal dysfunction or acute renal failure. Correct volume depletion; assess renal function, BUN, serum creatinine, urine output before and during therapy; discontinue if renal function deteriorates. Monitor for aseptic meningitis, hemolysis and delayed hemolytic anemia. Monitor for pulmonary dysfunction; perform test for anti-neutrophil antibodies if transfusionrelated acute lung injury (TRALI) suspected. Contains human plasma; monitor for possible infection transmission. Have epinephrine inj available. Elderly. Pregnancy (Cat.C). Interactions: Concomitant nephrotoxic drugs: increased risk of renal toxicity. May affect response to live virus vaccines.

Adverse reactions: Headache, arthralgia, myalgia, transient skin reactions, infusion reactions (eg, flushing, chills, fever), renal toxicities; aseptic meningitis syndrome (esp. high dose 2g/kg), TRALI, thrombosis. How supplied: Single-use vial–1

CORIFACT CSL Behring

℞

Clotting factor. Factor XIII concentrate (human); 1000–1600 units; per vial; powder for IV injection after reconstitution; preservative-free. Indications: Routine prophylactic treatment and peri-operative management of surgical bleeding in patients with congenital Factor XIII (FXIII) deficiency. Adults and Children: Give by slow IV injection at a rate of ≤4mL/min. Initially 40units/kg. Adjust ±5units/kg to maintain 5–20% trough FXIII activity levels using Berichrom Activity Assay: One trough level of <5%: increase by 5units/kg; trough level of 5–20%: no change; two trough levels of >20%: decrease by 5units/kg; one trough level of >25%: decrease by 5units/kg. Routine prophylaxis: give every 28 days. Peri-operative management: individualized based on patient’s FXIII activity level, surgery type, and clinical response; dose adjustment: see full labeling. Warnings/Precautions: Contains human plasma; monitor for possible infection transmission. Long-term therapy: consider appropriate vaccination (hepatitis A and B virus). Monitor FXIII activity levels during and after surgery. Monitor for development of inhibitory antibodies, thromboembolic events. Pregnancy (Cat.C). Nursing mothers. Adverse reactions: Joint inflammation, hypersensitivity, rash, pruritus, erythema, hematoma, arthralgia, headache, elevated thrombin-antithrombin levels, increased blood lactate dehydrogenase; acute ischemia, neutralizing antibodies. How supplied: Single-use vial–1

CYKLOKAPRON Pfizer

℞

Plasminogen activation inhibitor. Tranexamic acid 100mg/mL; soln for IV inj. Indications: Short-term use in hemophilia to reduce or prevent hemorrhage, and reduce the need for replacement therapy during and following tooth extraction. Adults and Children: Give by IV inj. Max injection rate: 1mL/min. Pre-extraction: 10mg/kg; Post-op: 10mg/kg 3–4 times daily for 2–8 days. Renal impairment: serum creatinine 1.36–2.83mg/dL: 10mg/kg twice daily; 2.83–5.66mg/dL: 10mg/kg once daily; >5.66mg/dL: 10mg/kg every 48hrs or 5mg/kg every 24 hours. Contraindications: Acquired defective color vision. Subarachnoid hemorrhage. Active intravascular clotting. Warnings/Precautions: Therapy longer than several days: do ophthalmologic exam (before

and during); discontinue if visual changes occur. Renal insufficiency; reduce dose. History of thromboembolic disease. Disseminated intravascular coagulation. Upper urinary tract bleeding. Pregnancy (Cat.B). Nursing mothers. Interactions: Avoid concomitant Factor IX complex concentrates or Anti-inhibitor Coagulant concentrates; increased risk of thrombosis. Do not mix with solutions containing penicillin. Adverse reactions: GI upset, giddiness, hypotension, visual abnormalities; rare: thromboembolic events. How supplied: Amps (10mL)–10

ETHAMOLIN QOL Medical

℞

Sclerosing agent. Ethanolamine oleate 50mg/mL; soln for IV inj; contains benzyl alcohol 2%. Indications: For the treatment of esophageal varices that have recently bled, to prevent rebleeding. Adults: Usual IV dose: 1.5–5mL per varix. Max dose per treatment session: 20mL. Child Class C or concomitant cardiopulmonary disease: give less than the recommended max dose. To obliterate the varix, may give injections at the time of the acute bleeding episode and then after one week, six weeks, three months, and six months as indicated. Children: Not recommended. Warnings/Precautions: Should be performed by physician familiar with technique. Submucosal inj: not recommended. Cardiorespiratory disease; monitor. Child Class C (more likely to develop esophageal ulceration). Elderly, critically ill (increased risk of fatal aspiration pneumonia). Pregnancy (Cat.C). Nursing mothers. Adverse reactions: Pleural effusion/ infiltration, esophageal ulcer, pyrexia, retrosternal pain, esophageal stricture, pneumonia, rare: anaphylactic reaction (may be fatal), acute renal failure. How supplied: Ampules (2mL)–10

FEIBA Baxter

℞

Clotting factor. Anti-inhibitor Coagulant Complex (AICC) 500 units, 1000 units, 2500 units; per vial; lyophilized pwd for IV infusion after reconstitution; contains Factors II, IX, X (non-activated); Factor VII (activated); Factor VIII inhibitor bypassing activity; Prothrombin Complex Factors; heparin-free. Indications: To control and prevent bleeding episodes, perioperative management, or as routine prophylaxis to prevent or reduce the 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

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ASSOCIATED HEMATOLOGICAL DISORDERS

℞

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. Preexisting 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 antineutrophil 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

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.

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

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

HELIXATE FS CSL Behring

℞

hemorrhage or minor surgery: 15–30 IU/kg; may repeat 1 dose at 12–24hrs if needed. Major/ life-threatening hemorrhage, fractures or head trauma: initially 40–50 IU/kg, then 20–25 IU/kg every 8–12hrs. Major surgery: pre-op dose: 50 IU/kg (verify ∼100% activity prior to surgery); may repeat after 6–12hrs initially, and for 10–14 days until completely healed. Contraindications: Mouse or hamster protein sensitivity. Warnings/Precautions: Not for treating von Willebrand’s disease. Confirm Factor VIII deficiency prior to treatment. Monitor for development of Factor VIII inhibitors. Pregnancy (Cat.C). Nursing mothers. Adverse reactions: Inj site reactions, dizziness, rash, dysgeusia, increased BP, pruritus, depersonalization, GI upset, rhinitis; antibody formation, hypersensitivity reactions. How supplied: Single-use bottle–1 (w. diluent)

HEMOFIL M Baxter

℞

Clotting factor. Antihemophilic Factor VIII (human) 220–400 IU, 401–800 IU, 801–1700 IU, 1701–2000 IU; per bottle; dried concentrate for IV infusion after reconstitution; contains albumin. Indications: Prevention and control of hemorrhagic episodes in Hemophilia A. Adults and Children: Dosage Required (IU) = Body Weight (kg) × Desired % Factor VIII Increase × 0.5. Individualize. Infuse at rate of up to 10mL/min. Monitor pulse rate; if increased significantly, reduce infusion rate or hold. Hemorrhage: Mild: obtain 20–40% FVIII increase; give every 12–24hrs for 1–3 days until resolved. Moderate: obtain 30–60% FVIII increase; give every 12–24hrs for 3 days or until pain or disability resolved. Life-threatening: obtain 60–100% FVIII increase; give every 8–24hrs until resolved. Surgery: Minor: obtain 60–80% FVIII increase; give single infusion plus oral antifibrinolytic therapy within 1 hour; Major: pre- and Post-op: obtain 80–100% FVIII increase; repeat every 8–24hrs based on healing. Contraindications: Mouse protein sensitivity. Warnings/Precautions: Not for von Willebrand’s disease. Confirm Factor VIII deficiency prior to treatment. Contains human plasma; monitor for possible infection transmission. Monitor for development of Factor VIII inhibitors. Latex allergy. Pregnancy (Cat.C). Adverse reactions: Allergic reactions, nausea, fever, chills, urticaria, antibody formation. Note: Report all infections suspected to be transmitted by Hemofil M to (800) 423-2862. How supplied: Single-dose bottle–1 (w. diluent, needles)

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ASSOCIATED HEMATOLOGICAL DISORDERS HUMATE-P CSL Behring

℞

Clotting factors. Antihemophilic Factor VIII/Von Willebrand Factor Complex (human) 250 IU FVIII + 600 IU VWF, 500 IU FVIII + 1200 IU VWF, 1000 IU FVIII + 2400 IU VWF; per vial; lyophilized pwd for IV infusion after reconstitution; contains albumin. Indications: Treatment and prevention of bleeding in adults with Hemophilia A. Treatment of spontaneous and trauma-induced bleeding, and prevention of excessive bleeding during and after surgery in adults and children with von Willebrand disease (VWD). Adults: Max injection rate: 4mL/min. Hemophilia A: Minor bleed: 15 IU FVIII/kg (obtain 30% FVIII increase) once; if needed, may give ½ dose once or twice daily for 1–2 days. Moderate bleed: initially 25 IU FVIII/kg (obtain 50% FVIII increase), then 15 IU FVIII/kg (maintain 30% FVIII increase) every 8–12hrs for 1–2 days, then repeat dose for 1–2 times daily for a total of 7 days or until healed. Severe bleed: initially 40–50 IU FVIII/kg, then 20–25 IU FVIII/kg every 8hrs (maintain 80–100% FVIII increase) for 7 days, then repeat dose for 1–2 times daily for additional 7 days (maintain 30–50% FVIII increase). VWD: Type 1 (Mild): major bleed: initially 40–60 IU/kg, then 40–50 IU/kg every 8–12hrs for 3 days, then once daily for a total of 7 days. Type 1 (Moderate or severe): minor bleed: 40–50 IU/kg for 1–2 doses; major bleed: initially 50–75 IU/kg, then 40–60 IU/kg every 8–12hrs for 3 days, then once daily for a total of 7 days. Types 2 and 3: minor bleed: 40–50 IU/kg for 1–2 doses; major bleed: initially 60–80 IU/kg, then 40–60 IU/kg every 8–12hrs for 3 days, then once daily for a total of 7 days. For dosing in surgery: see literature. Children: Max injection rate: 4mL/min. VWD: Type 1 (Mild): major bleed: initially 40–60 IU/kg, then 40–50 IU/kg every 8–12hrs for 3 days, then once daily for a total of 7 days. Type 1 (Moderate or severe): minor bleed: 40–50 IU/kg for 1–2 doses; major bleed: initially 50–75 IU/kg, then 40–60 IU/kg every 8–12hrs for 3 days, then once daily for a total of 7 days. Types 2 and 3: minor bleed: 40–50 IU/kg for 1–2 doses; major bleed: initially 60–80 IU/kg, then 40–60 IU/kg every 8–12hrs for 3 days, then once daily for a total of 7 days. For dosing in surgery: see literature. Contraindications: Previous anaphylactic or severe systemic response to antihemophilic factor or von Willebrand factor preparations. Warnings/Precautions: Confirm Factor VIII or von Willebrand factor deficiency prior to treatment. Increased risk of thromboembolic events in VWD. Contains human plasma; monitor for possible infection transmission. Large or frequent doses: monitor hematocrit for signs of hemolytic anemia. Monitor for development of inhibitors. Pregnancy (Cat.C). Adverse reactions: Allergic reaction, GI upset, inj site reactions, mild vasodilation, pruritus,

paresthesia, peripheral edema, antibody formation; anaphylaxis, thrombosis. Note: Report all infections suspected to be transmitted by Humate-P to (800) 504–5434. How supplied: Single-use vials–1 (w. diluent, supplies)

KCENTRA CSL Behring

℞

Clotting factor. Prothrombin complex concentrate (human) 500 units, 1000 units; per vial; lyophilized pwd for IV infusion after reconstitution; contains non-activated coagulation Factors II, VII, IX, X, antithrombotic Proteins C and S; also, heparin, human albumin, antithrombin III; preservative-free; latex-free. Indications: Urgent reversal of acquired coagulation factor deficiency induced by Vitamin K antagonist (VKA) therapy in adults with acute major bleeding or need for an urgent surgery/ invasive procedure. Adults: See full labeling. Administer concomitant Vitamin K. Individualize dosing based on patient’s baseline INR and weight. Potency (units) is defined by Factor IX content. Give by IV Infusion at a rate of 0.12mL/kg/min (∼3 units/kg/min); max rate of 8.4mL/min (∼210 units/min). ≤100kg: Pre-treatment INR: (2–<4): 25 units of Factor IX/kg; max 2500 units; (4–6): 35 units of Factor IX/kg; max 3500 units; (>6): 50 units of Factor IX/kg; max 5000 units. >100kg: do not exceed max dose. Repeat dosing: not recommended. Children: Not established. Contraindications: Severe hypersensitivity to heparin, Factors II, VII, IX, X, Proteins C and S, antithrombin III, human albumin. Disseminated intravascular coagulation (DIC). Known heparininduced thrombocytopenia (HIT). Warnings/Precautions: Risk of arterial and venous thromboembolic complications (may be fatal). History of thromboembolic events within the previous 3 months. Monitor for signs/ symptoms of thromboembolic events during and after infusion. Discontinue immediately if hypersensitivity reactions occur. Measure INR before, during, and after each treatment. Contains human plasma; monitor for possible infection transmission. Pregnancy (Cat.C). Nursing mothers. Adverse reactions: Headache, nausea, vomiting, hypotension, anemia; hypersensitivity, thromboembolic events (eg, stroke, PE, DVT). Note: Report all infections suspected to be transmitted by Kcentra to (866) 915-6958. How supplied: Kit (500 units, 1000 units)–1 (single-use vial + diluent, supplies)

KOATE-DVI Grifols Biologicals

℞

Clotting factor. Antihemophilic Factor VIII (human) 250 IU, 500 IU, 1000 IU; per bottle; dried concentrate for IV infusion after reconstitution; contains albumin. Indications: Prevention and control of hemorrhagic episodes or in order to perform

emergency or elective surgery in Hemophilia A patients. Adults: Dosage Required (IU) = Body Weight (kg) × Desired % Factor VIII Increase × 0.5. Individualize. Infuse over 5–10 minutes if tolerated. Use filter needle. Hemorrhage: Mild: 10 IU/kg as single dose. Moderate: 15–25 IU/kg, then 10–15 IU/kg every 8–12hrs if needed. Severe: initially 40–50 IU/kg, then 20–25 IU/kg every 8–12hrs. Major surgery: pre-op dose: 50 IU/kg, then verify Factor VIII level achieved prior to surgery; may repeat every 6–12hrs initially and for 10–14 days until healing complete. Children: Not recommended. Warnings/Precautions: Not for von Willebrand’s disease. Confirm Factor VIII deficiency prior to treatment. Contains human plasma; monitor for possible infection transmission. Large or frequent doses: monitor hematocrit for signs of progressive anemia. Monitor for development of Factor VIII inhibitors. Pregnancy (Cat.C). Adverse reactions: Allergic reactions, tingling sensations, blurred vision, headache, GI upset, jittery feeling, antibody formation. How supplied: Single-dose bottle–1 (w. diluent)

KOGENATE FS Bayer

℞

Clotting factor. Antihemophilic Factor VIII (recombinant) 250 IU, 500 IU, 1000 IU, 2000 IU, 3000 IU; per vial; lyophilized pwd for IV infusion after reconstitution; contains sucrose; preservative-free. Indications: Prevention and control of hemorrhagic episodes in Hemophilia A. Surgical prophylaxis in Hemophilia A. Routine prophylaxis to reduce frequency of hemorrhagic episodes and joint damage in children with Hemophilia A with no pre-existing joint damage. Adults and Children: Dosage Required (IU) = Body Weight (kg) × Desired % Factor VIII Increase × 0.5. Individualize. Infuse over 1–15mins if tolerated. Minor hemorrhage: 10–20 IU/kg; may repeat dose if needed. Moderate hemorrhage or minor surgery: 15–30 IU/kg; may repeat dose every 12–24hrs until resolved. Major hemorrhage, fractures or head trauma: initially 40–50 IU/kg, then 20–25 IU/kg every 8–12hrs until resolved. Major surgery: Pre-op: 50 IU/kg (verify 100% activity prior to surgery); repeat if needed after 6–12hrs initially, and for 10–14 days until completely healed. Routine prophylaxis in children: 25 IU/kg every other day. 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. Labor & delivery. Pregnancy (Cat.C). Nursing mothers. Adverse reactions: Inj site reactions, dizziness, rash, BP increase, pruritus, hypersensitivity

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ASSOCIATED HEMATOLOGICAL DISORDERS reactions, antibody formation, central venous line-associated infections. How supplied: Kit–1 (vial w. diluent and BIO-SET system)

MONOCLATE-P CSL Behring

℞

Clotting factor. Antihemophilic Factor VIII:C (human) 250 IU, 500IU, 1000 IU, 1500 IU; per vial; lyophilized concentrate for IV infusion after reconstitution; contains albumin. Indications: Treatment and surgical prophylaxis for Hemophilia A. Adults and Children: Dosage Required (IU) = Body Weight (kg) × Desired % Factor VIII Increase × 0.5. Individualize. Infusion rate: 2mL/min if tolerated. Mild hemorrhages: single infusion to attain 30% FVIII increase. Moderate hemorrhage or minor surgery: initially 15–25 IU/kg, then 10–15 IU/kg every 8–12hrs if needed. Severe hemorrhage: initially 40–50 IU/kg, then 20–25 IU/kg every 8–12hrs. Major surgery: give first dose 1 hour pre-op to attain 80–100% FVIII increase, then give a ½ dose 5 hours after first dose; maintain daily at ≥30% FVIII increase for 10–14 days post-op. Contraindications: Mouse protein sensitivity. Warnings/Precautions: Not for von Willebrand’s disease. Confirm Factor VIII deficiency prior to treatment. Contains human plasma; monitor for possible infection transmission. Large or frequent dosing: monitor hematocrit for signs of progressive anemia. Monitor for development of Factor VIII inhibitors. Pregnancy (Cat.C). Adverse reactions: Allergic reactions, chills, GI upset, inj site reactions, antibody formation. Note: Report any infections suspected to be transmitted by Monoclate-P to (800) 504-5434. How supplied: Single-dose vial–1 (w. diluent, supplies)

MONONINE CSL Behring

℞

Clotting factor. Coagulation Factor IX (human) 500 IU, 1000 IU; per vial; lyophilized pwd for IV infusion after reconstitution. Indications: Prevention and control of bleeding in Hemophilia B. Adults and Children: Dosage Required (IU) = Body Weight (kg) × Desired Factor IX increase × 1 IU/kg. Individualize. Infuse at a rate of 2mL/min. Minor spontaneous hemorrhage, prophylaxis: increase FIX 15–25%; give up to 20–30 IU/kg once; may repeat in 24hrs if needed. Major trauma, surgery: increase FIX 25–50%; give up to 75 IU/kg every 18–30hrs for up to 10 days; adjust

based on FIX levels. FIX inhibitors: may use higher doses. Contraindications: Mouse protein sensitivity. Warnings/Precautions: Not for Hemophilia A or other factor deficiencies, reversal of coumarin-induced anticoagulation or for bleeding due to low levels of liver-dependant coagulation factors. Fibrinolysis, disseminated intravascular coagulation (DIC), liver disease, neonates, or during post-op period; increased risk of thromboembolic events. Immune tolerance induction. Contains human plasma; monitor for possible infection transmission. Monitor for Factor IX inhibitors and deletion mutations of Factor IX gene; increased risk of hypersensitivity reactions. Pregnancy (Cat.C). Adverse reactions: Headache, fever, chills, flushing, GI upset, tingling, lethargy, inj site reaction, elevated ALT, inhibitor development; hypersensitivity reactions, thrombosis. Note: Report all infections suspected to be transmitted by Mononine to (800) 504-5434. How supplied: Single-dose vial–1 (w. diluent, supplies)

NEUMEGA Pfizer

℞

Thrombopoietic growth factor (Interleukin-11). Oprelvekin 5mg/vial; lyophilized pwd for SC inj after reconstitution; preservative-free. Indications: Prevention of severe thrombocytopenia. To reduce platelet transfusions following myelosuppressive chemotherapy in adults with non-myeloid malignancies who are at high risk of severe thrombocytopenia. Adults: Initiate 6–24hrs after chemotherapy completion. Give by SC inj into abdomen, thigh, or hip; also upper arm if not self-injecting. 50micrograms/kg once daily until post-nadir platelet count is ≥50,000/microliter; max 21 days. Discontinue ≥2days prior to next chemotherapy cycle. Severe renal impairment: CrCl <30mL/min: 25micrograms/kg. May give for ≤6 cycles following chemotherapy. Children: Not recommended. Warnings/Precautions: Not for use after myeloablative chemotherapy. Monitor fluid balance and electrolytes; increased risk of serious fluid retention with CHF, renal impairment, chronic diuretic or aggressive hydration therapy. Consider draining pre-existing fluid collections (eg, pericardial effusion, ascites). Obtain CBCs before and during therapy; monitor platelet counts. Pre-existing papilledema or tumors involving the CNS. History of stroke, transient ischemic attack, or atrial arrhythmias.

Effectiveness unknown with chemotherapy regimens >5 days duration or with regimens associated with delayed myelosuppression (eg, nitrosoureas, mitomycin-C). Pregnancy (Cat.C). Nursing mothers: not recommended. Adverse reactions: Edema, dyspnea, tachycardia, conjunctival injection, palpitations, atrial arrhythmias, pleural effusions, neutropenic fever, syncope, atrial fibrillation, fever, pneumonia, CHF, pulmonary edema, dilutional anemia, blurred vision, paresthesia, dehydration, skin discoloration, exfoliative dermatitis, eye hemorrhage, stroke, papilledema, hypersensitivity reactions (permanently discontinue if occur). How supplied: Single-use vials–7 (w. diluent)

NITROPRESS Hospira

℞

Vasodilator. Sodium nitroprusside 25mg/mL; soln for IV infusion after dilution. Indications: To produce controlled hypotension to reduce surgical bleeding. Adults and Children: Use infusion pump only. Monitor BP closely. Initially 0.3microgram/kg/ min; may increase infusion rate every few minutes until desired effect; max 10microgram/kg/min and no more than 10 minutes. Titrate infusion rate (see literature). Contraindications: Compensatory hypertension due to aortic coarctation or arteriovenous shunting. Inadequate cerebral circulation or moribund patients requiring emergency surgery. Congenital (Lebers) optic atrophy. Tobacco amblyopia. Acute CHF associated with reduced peripheral vascular resistance. Warnings/Precautions: Use only when available equipment and personnel allow BP to be continuously monitored. Cyanide toxicity possible (esp. at infusion rates >2micrograms/kg/min); monitor acid-base disturbances and venous oxygen concentration. Elevated intracranial pressure. Correct pre-existing anemia and hypovolemia, esp. during anesthesia. Poor surigical risk. Hepatic impairment. Elderly. Pregnancy (Cat.C). Nursing mothers: not recommended. Interactions: Hypotensive effect potentiated by ganglionic blocking agents, negative inotropic agents, and inhaled anesthetics. Adverse reactions: Excessive hypotension, cyanide toxicity, methemoglobinemia, abdominal pain, apprehension, diaphoresis, dizziness, headache, muscle twitch, nausea, palpitations, restlessness, rash, hypothyroidism, ileus, flushing, infusion site reactions. How supplied: Single-dose vials (2mL)–100

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ASSOCIATED HEMATOLOGICAL DISORDERS NOVOSEVEN RT Novo Nordisk

℞

Clotting factors. Recombinant Coagulation Factor VIIa (rFVIIa) Room Temperature Stable 1mg, 2mg, 5mg, 8mg; per vial; lyophilized pwd for IV inj after reconstitution; preservative-free. Indications: Treatment of bleeding and perioperative management in adults and children with Hemophilia A and B with inhibitors, congenital Factor VII deficiency, and Glanzmann’s thrombasthenia refractory to platelet transfusions, with or without antibodies to platelets. Treatment of bleeding and peri-operative management in adults with acquired hemophilia. Adults and Children: See full labeling. Give by IV bolus only. Individualize; base treatment schedule modification on hemostasis evaluation. Hemophilia A or B with inhibitors: Bleeding: 90mcg/kg every 2hrs, adjust until hemostasis is achieved; post-hemostatic dosing: continue at 3–6hrs intervals for severe bleeds. Peri-operative: initially 90mcg/kg prior to surgery, repeat at 2hr intervals during surgery; minor (post-surgical dosing): every 2hrs for 48hrs, then every 2–6hrs until healed; major (post-surgical dosing): every 2hrs for 5 days, then every 4hrs until healed. Congenital Factor VII deficiency: Bleeding: 15–30mcg/kg every 4–6hrs until hemostasis is achieved; Peri-operative: 15–30mcg/kg prior to surgery, repeat every 4–6hrs during surgery and until hemostasis is achieved. Glanzmann’s thrombasthenia: Bleeding: 90mcg/kg every 2–6hrs until hemostasis is achieved; Perioperative: initially 90mcg/kg prior to surgery, repeat every 2hrs during surgery, then every 2–6hrs post-surgical. Acquired hemophilia: Bleeding: 70–90mcg/kg every 2–3hrs until hemostasis is achieved; Peri-operative: 70–90mcg/kg prior to surgery, repeat every 2–3hrs during surgery and until hemostasis is achieved. Warnings/Precautions: Risk of serious arterial and venous thromboembolic events. Disseminated intravascular coagulation (DIC), advanced atherosclerotic disease, crush injury, septicemia, uncontrolled post-partum hemorrhage, history of coronary heart disease, hepatic disease, post-op immobilization, elderly, neonates; increased risk of developing thrombotic events. Monitor for signs/symptoms of coagulation activation or thrombosis; discontinue or reduce dose if occur. Monitor prothrombin time and FVII coagulant activity before and after dosing in FVII deficiency. Perform analysis for antibodies if factor VIIa activity fails to reach expected level. Mouse, hamster, or bovine protein hypersensitivity. Pregnancy (Cat.C). Nursing mothers: not recommended. Interactions: Avoid concomitant activated or non-activated prothrombin complex concentrates; may increase risk of thrombotic events. Do not mix with infusion solutions. Concomitant Coagulation Factor XIII may cause thrombosis.

Adverse reactions: Thrombotic events, fever, fibrinogen plasma decreased, hypertension, headache, nausea, dyspnea; pain, thrombophlebitis, pulmonary embolism, decreased therapeutic response, cerebrovascular disorder, angina pectoris, abnormal hepatic function, DIC, hypersensitivity reactions (discontinue and treat if occur). How supplied: Single-use vial–1 (w. diluent); MixPro–1 (single-use vial + pre-filled diluent syringe + vial adapter)

NPLATE Amgen

℞

Thrombopoietin receptor agonist. Romiplostim (recombinant) 250mcg, 500mcg; per vial; lyophilized pwd for SC inj after reconstitution; contains sucrose and mannitol; preservative-free. Indications: Thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic purpura (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Adults: Give by SC inj. To reduce risk of bleeding: use lowest effective dose to achieve and maintain platelets ≥50×109/L. ≥18yrs: initially: 1mcg/kg weekly; may increase by 1mcg/kg if platelets <50×109/L; max: 10mcg/kg weekly. May reduce by 1mcg/kg if platelets >200×109/L for 2 consecutive weeks. Do not dose if platelets >400×109/L; resume Nplate at a dose reduced by 1mcg/kg when platelets fall to <200×109/L. Discontinue if platelets have not increased after 4 weeks at max dose. Children: <18yrs: not recommended. Warnings/Precautions: Not for normalization of platelet counts or to treat thrombocytopenia due to MDS or any cause of thrombocytopenia other than chronic ITP. Risk of bone marrow fibrosis with cytopenias. Worsened thrombocytopenia after discontinuation. Monitor CBCs, platelets, and peripheral blood smears before and weekly during dose adjustments then monthly after achieving stable dose; and weekly for 2 weeks after discontinuation of therapy. Monitor after initial response for formation of neutralizing antibodies. Risk of hematologic malignancies (esp. myelodysplastic syndrome). Renal or hepatic impairment. Elderly. Pregnancy (Cat.C). Nursing mothers. Interactions: May increase bleeding risk with anticoagulants or antiplatelet agents. Adverse reactions: Arthralgia, dizziness, insomnia, myalgia, pain in extremity, abdominal pain, shoulder pain, dyspepsia, paresthesia, headaches; bone marrow reticulin deposition, worsening thrombocytopenia, risk of bleeding, thrombotic/thromboembolic complications, antibody formation. How supplied: Single-use vial–1

PRIVIGEN CSL Behring Immune globulin. Immune globulin (human) 0.1g/mL; soln for IV infusion; contains L-proline; sucrose-, preservative-, and latex-free.

℞

Indications: Chronic immune thrombocytopenic purpura (ITP). Adults and Children: <15yrs: not established. ≥15yrs: Give by IV infusion at an initial rate of 0.5mg/kg/min, if tolerated may increase to 4mg/kg/min. Renal dysfunction, thrombosis risk: give at the minimum infusion rate practicable. Usual dose: 1g/kg once daily for 2 consecutive days for a total dose of 2g/kg. Increased risk of thrombosis, hemolysis, acute renal injury, or volume overload: consider carefully the relative risks and benefits before prescribing high dose regimen (2g/kg). Contraindications: IgA-deficiency with antibodies against IgA and history of hypersensitivity. Hyperprolinemia. Previous severe reaction to human immune globulin. Warnings/Precautions: Advanced age, prolonged immobilization, hypercoagulable conditions, history of venous or arterial thrombosis, use of estrogens, indwelling central vascular catheters, hyperviscosity, cardiovascular risk factors: increased risk of thrombosis. Monitor for signs/symptoms of thrombosis and assess blood viscosity in patients at risk for hyperviscosity. Pre-existing renal insufficiency, diabetes, >65yrs, obese, hypovolemia: increased risk of renal dysfunction and acute renal failure. Correct volume depletion; assess renal function, BUN, serum creatinine, urine output before and during therapy; discontinue if renal function deteriorates. Monitor for aseptic meningitis, hemolysis, delayed hemolytic anemia, transfusionrelated 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

PROFILNINE SD Grifols Biologicals ℞ Clotting factor. Coagulation Factor IX complex (human) 500 IU, 1000 IU, 1500 IU; per vial; lyophilized concentrate for IV infusion after reconstitution; contains Factor X, Factor II, Factor VII; preservative-free. Indications: Prevention and control of bleeding in Hemophilia B. Adults: Dosage Required (IU) = Body Weight (kg) × Desired Factor IX increase × 1 IU/kg. Individualize. Max infusion rate: 10mL/min. Mild

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ASSOCIATED HEMATOLOGICAL DISORDERS to moderate hemorrhage: give single dose to increase Factor IX 20–30%. Serious hemorrhage: give daily infusions to increase Factor IX 30–50%. Surgery: increase Factor IX by 30–50% for at least 1 week Post-op. Dental extraction: increase Factor IX to 50% immediately prior to procedure; may give additional doses if bleeding recurs. Children: See literature. Warnings/Precautions: Not for treating Factor VII deficiency. Contains human plasma; monitor for possible infection transmission. Liver disease, prolonged treatment duration or if undergoing surgery: increased risk of disseminated intravascular coagulation (DIC) and thrombosis. Pregnancy (Cat.C). Adverse reactions: Urticaria, fever, chills, GI upset, headache, somnolence, lethargy, flushing, tingling; hypersensitivity reactions, thrombosis, DIC. Note: Report all infections suspected to be transmitted by Profilnine SD to (888) 675-2762. How supplied: Single-use vials–1 (w. diluent, supplies)

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 ≥50×109/L; max 75mg once daily. Chronic hepatitis C-associated thrombocytopenia: initially 25mg once daily. Titrate dose by 25mg every 2 weeks as needed to achieve target platelet counts; max 100mg/day. Monitoring, dose adjustment, and discontinuation: see full labeling. Children: Not established. Warnings/Precautions: Increased risk of hepatic decompensation in chronic hepatitis C,

when concomitant with interferon and ribavirin; discontinue Promacta if antiviral therapy is discontinued. Monitor liver function prior to initiation, every 2 weeks during dose adjustments, and monthly after stabilized (see full labeling); discontinue if ALT ≥3×ULN and is progressive or persistent for ≥4 weeks, or if occurs with increased bilirubin, or evidence of hepatic injury/ decompensation; reinitiate therapy if benefit outweighs risk; if restarted, monitor carefully. Increased risk of thromboembolism; do not use to normalize platelet counts. Do baseline eye exam; monitor for cataracts. Renal impairment. Pregnancy (Cat.C). Nursing mothers: not recommended. Interactions: Do not take within 4hrs of food/ drugs containing polyvalent cations (eg, Fe+2, Ca+2, Al+3, Mg+2, Se+2, Zn+2). Potentiate substrates of OATP1B1 (eg, most statins, bosentan, ezetimibe, glyburide, olmesartan, valsartan, repaglinide, rifampin) or BCRP (eg, imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone, sulfasalazine, topotecan); monitor and consider reducing their doses. Antagonized by lopinavir/ ritonavir. Adverse reactions: Nausea, diarrhea, vomiting, infections, increased ALT/AST, myalgia, pain, pharyngitis, paresthesia, rash, anemia, pyrexia, fatigue, headache, decreased appetite, asthenia, insomnia, cough, pruritus, chills, alopecia, peripheral edema; hepatotoxicity, hemorrhage, thrombotic complications from excessive increases in platelet counts, cataracts. How supplied: Tabs–30

RECOMBINATE Baxter

℞

Clotting factor. Antihemophilic Factor VIII (recombinant) 250 IU, 500 IU, 1000 IU; per bottle; lyophilized pwd for IV infusion after reconstitution; contains albumin; preservative-free. Indications: Prevention and control of hemorrhagic episodes and perioperative management in Hemophilia A. Adults and Children: Dosage Required (IU) = Body Weight (kg) × Desired % Factor VIII Increase × 0.5. Infuse at rate of up to 10mL/min. Monitor pulse rate; if increased significantly, reduce infusion rate or hold. Hemorrhage: Mild: obtain 20–40% FVIII increase; give every 12–24hrs for 1–3 days until resolved. Moderate: obtain 30–60% FVIII increase; give every 12–24hrs for 3 days or until pain or disability resolved. Life-threatening: obtain 60–100% FVIII increase; give every 8–24hrs until resolved. Surgery: Minor: obtain 60–80% FVIII increase; give single infusion plus oral antifibrinolytic therapy within 1 hour; Major: pre- and Post-op: obtain 80–100% FVIII increase; repeat every 8–24hrs based on healing.

Contraindications: Mouse, hamster, or bovine protein sensitivity. Warnings/Precautions: Not for von Willebrand’s disease. Confirm Factor VIII deficiency prior to treatment. Monitor for development of Factor VIII inhibitors. Latex allergy. Pregnancy (Cat.C). Adverse reactions: Allergic reactions, nausea, fever, chills, urticaria, antibody formation. How supplied: Single-dose bottle–1 (w. diluent)

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;

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ASSOCIATED HEMATOLOGICAL DISORDERS 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

RIXUBIS Baxter

℞

Clotting factor. Coagulation Factor IX (recombinant) 250 IU, 500 IU, 1000 IU, 2000 IU, 3000 IU; per vial; lyophilized pwd for IV infusion after reconstitution; preservative-free. Indications: Control and prevention of bleeding episodes, perioperative management, and routine prophylaxis in hemophilia B. Adults: Empirical finding: 1 IU/kg increases circulating activity of FIX by 0.9 IU/dL. Initial dose = body weight (kg) × desired FIX increase (% or IU/dL) × reciprocal of observed recovery (IU/dL per IU/kg). Incremental recovery in previously treated patients (PTPs): Dose (IU) = body weight (kg) × desired FIX increase (% or IU/dL) × 1.1 dL/kg. Individualize. Give by IV bolus infusion only. Max infusion rate 10mL/min. Control/ prevention of bleeding: Minor: 20–30% required every 12–24hrs for at least 1 day until healing achieved. Moderate: 25–50% required every 12–24hrs for 2–7 days until bleeding stops and healing achieved. Major: 50–100% required every 12–24hrs for 7–10 days until bleeding stops and healing achieved. Peri-op management: Minor surgery: 30–60% required every 24hrs for at least 1 day until healing achieved. Major surgery: 80–100% required every 8–24hrs for 7–10 days until bleeding stops and healing achieved. Routine prophylaxis in PTPs: 40–60 IU/kg twice weekly; titration may be necessary based on patient’s age, bleeding pattern, physical activity. Children: Empirical finding: 1 IU/kg increases circulating activity of FIX by 0.7 IU/dL. Initial dose = body weight (kg) × desired FIX increase (% or IU/dL) × reciprocal of observed recovery (IU/dL per IU/kg). Incremental recovery in previously treated patients (PTPs): Dose (IU) = body weight (kg) × desired FIX increase (% or IU/dL) × 1.4 dL/kg. Individualize. Give by IV bolus infusion only. Max infusion rate 10mL/min. Control/ prevention of bleeding: Minor: 20–30% required every 12–24hrs for at least 1 day until healing achieved. Moderate: 25–50% required every 12–24hrs for 2–7 days until bleeding stops and healing achieved. Major: 50–100% required every 12–24hrs for 7–10 days until bleeding stops and healing achieved. Peri-op management: Minor surgery: 30–60% required every 24hrs for at least 1 day until healing achieved. Major surgery: 80–100% required every 8–24hrs for 7–10 days until bleeding stops and healing achieved. Routine prophylaxis in PTPs: 60–80 IU/kg twice weekly; titration may be necessary based on patient’s age, bleeding pattern, physical activity.

Contraindications: Hamster protein hypersensitivity. Disseminated intravascular coagulation (DIC). Signs of fibrinolysis. Warnings/Precautions: Not for induction of immune tolerance in patients with hemophilia B; risk of nephrotic syndrome. Evaluate regularly for development of Factor IX inhibitors; measure Factor IX inhibitor concentration if expected activity plasma levels are not attained, or if bleeding is not controlled with an expected dose. Potential risk for thromboembolic complications; monitor for signs of thrombotic and consumptive coagulopathy, in patients with liver disease, signs of fibrinolysis, peri- and post-operatively, or at risk for thrombotic events or DIC. Pregnancy (Cat.C). Nursing mothers. Adverse reactions: Dysgeusia, extremity pain, positive test for furin antibody; hypersensitivity reactions (discontinue if occur). How supplied: Single-use vials–1 (w. diluent, supplies)

STIMATE CSL Behring

℞

Antidiuretic hormone. Desmopressin acetate 150mcg/spray; soln for nasal spray. Indications: To maintain hemostasis or to stop bleeding in Hemophilia A and mild-to-moderate Type I von Willebrand Disease (VWD), each with Factor VIII levels >5%. Adults and Children: <11months: not recommended. Give test dose prior to initiating therapy. >11months: <50kg: 1 spray in one nostril (150mcg). ≥50kg: 1 spray per nostril (300mcg). May repeat dose based on clinical response. Pre-op: give 2hrs prior to procedure. Repeated administration before 48 hrs associated with tachyphylaxis. Warnings/Precautions: Not for treating Type IIb VWD, or severe VWD with abnormal molecular form of Factor VIII antigen. Adjust fluid intake downward (esp in children and elderly) to reduce risk of water intoxication, hyponatremia. Monitor fluid intake, plasma osmolality. Fluid and electrolyte imbalances (eg, cystic fibrosis). Coronary artery disease. Hypertension. Predisposition to thrombosis. Unreliable absorption if altered nasal mucosa (eg, scarring, edema); discontinue until resolved. Pregnancy (Cat.B). Nursing mothers. Interactions: Caution with other pressor agents (monitor). Adverse reactions: Headache, nausea, abdominal cramps, vulval pain, facial flushing, local reactions, sore throat, water intoxication, hyponatremia; rare: BP changes, severe allergic reactions, thrombotic events. How supplied: Spray Pump–2.5mL (25 sprays)

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

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ASSOCIATED HEMATOLOGICAL DISORDERS capillaries and small venules. Adjunct for surgical hemostasis with absorbable gelatin sponge. Adults: For topical use only. See literature. Profuse bleeding (eg, abraided surfaces of liver or spleen): 1000 IU/mL. General use (eg, plastic surgery, dental extractions, skin grafting): 100 IU/mL. May dilute to prepare intermediate strengths, if needed. Oozing surfaces: may use dry form. Children: Not recommended. Warnings/Precautions: Not for injection or use in large blood vessels. Antibody formation: do not re-expose, abnormalities in hemostasis (eg, severe bleeding or thrombosis) more likely with repeated use. Pregnancy (Cat.C). Nursing mothers. Adverse reactions: Hypersensitivity reactions, antibody formation. How supplied: Vials–1 (w. diluent) Pump Spray Kit (20000 IU)–1 (w. diluent) Syringe Spray Kit (20000 IU)–1 (w. diluent) Epistaxis Kit (5000 IU)–1 (w. diluent)

WILATE Octapharma

℞

Coagulation factor complex. Von Willebrand Factor/Factor VIII Complex (human); 450 IU VWF:RCo and 450 IU FVIII activities per 5mL; 900 IU VWF:RCo and 900 IU FVIII activities per 10mL; pwd; for IV injection after reconstitution; preservative-free; solvent-detergent treated. Indications: Bleeding episodes (spontaneous and trauma induced) in patients with severe von Willebrand disease, and patients with mild to moderate von Willebrand disease for whom desmopressin is ineffective or contraindicated. Adults and Children: <5yrs: contact manufacturer. Give by IV injection at 2–4mL/min. ≥5yrs: Minor bleed: 20–40 IU/kg once, then 20–30 IU/kg every 12–24 hours. Major bleed: 40–60 IU/kg once, then 20–40 IU/kg every 12–24 hours. Monitor and adjust according to VWF:RCo and FVIII activity, and location of bleed; usual treatment duration is 3 days (minor hemorrhage) and 5–7 days (major hemorrhage). See literature for activity level goals. Warnings/Precautions: Not for prophylaxis of spontaneous bleeding, prevention of surgical bleeding, or hemophilia A. Treatment should be supervised by physician trained in coagulopathies. Risk of thrombotic events with sustained excessive FVIII levels; monitor. Ineffectiveness may indicate antibody formation; discontinue if confirmed. Risk of transmission of blood-borne diseases; consider vaccination against hepatitis A and B. Monitor pulse during injection; slow or stop infusion if marked increase in heart rate occurs. Pregnancy (Cat.C). Nursing mothers.

Adverse reactions: Urticaria, dizziness, hypersensitivity reactions, antibody formation. How supplied: Kit–1 (w. diluent, supplies)

WINRHO SDF

℞

Emergent BioSolutions

Rho(D) immune globulin intravenous human 600IU (120mcg), 1500IU (300mcg), 2500IU (500mcg), 5000IU (1000mcg), 15000IU (3000mcg); per vial; lyophilized pwd or soln; for IV or IM inj after reconstitution; 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)

Immune-mediated blood disorders

BAYRHO-D FULL DOSE Bayer ℞ Rho(D) immune globulin human 300mcg; for IM inj; solvent/detergent treated. Indications: Preventing Rho(D) sensitization in nonsensitized Rho(D) negative or Du negative patients to the Rho(D) factor, following pregnancy or accidental transfusion. Adults: Each vial or syringe (approx. 300mcg) prevents sensitization to a volume of up to 15mL of Rh positive red blood cells. Administer IM at 28 weeks of gestation, within 72 hours of an Rh incompatible delivery, miscarriage, abortion, or transfusion accident. Children: Not recommended. ℞ Also: BAYRHO-D MINI-DOSE Rho(D) immune globulin human 50mcg; for IM inj. Indications: Prevention of Rho(D) sensitization following termination of pregnancies up to 12 weeks gestation. Adults: Each syringe (approx. 50mcg) prevents sensitization to 2.5mL of Rh positive red blood cells. Give IM up to 12 weeks’ gestation, within 3 hours of an Rh incompatible delivery, miscarriage, or abortion. Children: Not recommended. Contraindications: Rho(D) positive patients. Pregnancy (Cat.C).

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ASSOCIATED HEMATOLOGICAL DISORDERS Warnings/Precautions: Live vaccines. Have epinephrine available. Adverse reactions: Local reactions. How supplied: Full Dose (single-dose syringes and vials)–1, 10; Mini-Dose (single-dose syringes)–10

HYPERRHO S/D FULL DOSE ℞ Grifols Biologicals

Immune globulin. Rho(D) immune globulin human 1500 IU; per syringe; soln for IM inj; preservativefree; latex-free. Indications: Prevention of isoimmunization in non-sensitized Rho(D) negative women during pregnancy and in appropriate obstetrical conditions, unless the fetus or father is known to be Rho(D) negative. Prevention of isoimmunization in Rho(D) negative individuals transfused with Rho(D) positive blood products. Adults: See literature. Give IM only. Pregnancy (28 weeks gestation), postpartum prophylaxis (within 72 hours), obstetric complications, invasive procedures during pregnancy: 1500IU. Incompatible transfusions (within 72 hours): volume of red blood cells transfused divided by 15mL provides the number of syringes to be administered; if the dose is a fraction, round to next higher whole number of syringes. Children: Not recommended. ℞ Also: HYPERRHO S/D MINI-DOSE Rho(D) immune globulin human; 250 IU; per syringe; soln for IM inj.; preservative-free; latex-free. Indications: Prevention of isoimmunization of Rho(D) negative women during spontaneous or induced abortion of ≤12 weeks’ gestation when mother is not sensitized to Rho(D) antigen and father is not known to be Rho(D) negative. Adults: Postabortion or miscarriage of up to 12 weeks gestation: 1 syringe IM within 3hrs of spontaneous or induced abortion or within 72hrs following termination of pregnancy. Children: Not recommended. Contraindications: Neonates. Warnings/Precautions: Contains human plasma; monitor for possible infection transmission. IgA deficiency. Pregnancy (Cat.C). Interactions: Avoid live vaccines within 3 months. Adverse reactions: Local or infusion reactions. Note: Report all infections suspected to be transmitted by HyperRHO S/D to (800) 520-2807. How supplied: Full dose (Single-dose prefilled syringe)–1; Mini dose (Single-dose prefilled syringe)–10

RHOGAM Kedrion

℞

Rho(D) immune globulin human 300mcg; for IM inj. Indications: Preventing Rho(D) sensitization in nonsensitized Rho(D) negative or Du negative patients to the Rho(D) factor, following pregnancy or accidental transfusion. Adults: Each vial or syringe (approx. 300mcg) prevents sensitization to a volume of up to 15mL of Rh positive red blood cells. Administer IM at

28 weeks of gestation, within 72 hours of an Rh incompatible delivery, miscarriage, abortion, or transfusion accident. Children: See literature. Contraindications: Rho(D) positive patients. Warnings/Precautions: Pregnancy (Cat.C). Adverse reactions: Local reactions. How supplied: Single-dose syringes–5, 25

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: Suppression of Rh isoimmunization in non-sensitized Rho (D) negative women during pregnancy and in appropriate obstetrical conditions, unless the fetus or father is known to be Rho (D) negative. Suppression of Rh isoimmunization in Rho (D) negative individuals transfused with Rho (D) positive blood products. Adults: See full labeling. Pregnancy (28–30 weeks gestation), postpartum prevention (within 72hrs), obstetric complications, invasive procedures during pregnancy: 1500 IU (300mcg). Incompatible transfusions (within 72hrs): 100 IU (20mcg) per 2mL transfused blood or per 1mL erythrocyte concentrate. 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

WINRHO SDF

℞

Emergent BioSolutions Rho(D) immune globulin intravenous human 600IU (120mcg), 1500IU (300mcg), 2500IU (500mcg), 5000IU (1000mcg), 15000IU (3000mcg); per vial; lyophilized pwd or soln; for IV or IM inj after reconstitution; preservative-free. Indications: Suppression of Rh isoimmunization in nonsensitized Rho(D) negative women in appropriate obstetrical conditions, unless the fetus or father is known to be Rho(D) negative. Suppression of Rh isoimmunization in Rho(D) negative females after accidental transfusion of Rho(D) positive blood products. Adults: Pregnancy: 1500IU at 28 weeks gestation; if given early in pregnancy, repeat every 12 weeks. Post-delivery: 600IU as soon as possible (preferably within 72 hrs, up to 28 days) of an Rh incompatible delivery. Amniocentesis or other manipulation late in pregnancy (after 34 weeks gestation), abortion: 600IU as soon as possible (within 72 hrs). Chorionic villus sampling, amniocentesis (before 34 weeks

gestation), threatened abortion: 1500IU as soon as possible, repeat every 12 weeks during pregnancy. Transfusion: IV route: 3000IU (600micrograms) every 8 hours; or IM route: 6000IU (1200micrograms) every 12 hours; for both: total dose based on exposure (see literature); give within 72 hours. Children: See literature. Do not give to infant for maternal Rh incompatability. Contraindications: Rho(D) positive patients. IgA deficiency. Allergy to blood products. Treatment of immune globulin deficiency syndromes. Warnings/Precautions: Rho(D) negative patients who are Rh immunized. Thrombocytopenia. Pregnancy (Cat.C). Interactions: Do not give live vaccines within 3 months. Adverse reactions: Local or infusion reactions, fever; 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

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

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ASSOCIATED HEMATOLOGICAL DISORDERS sickle cell crisis develops. Hepatic or moderateto-severe renal impairment. Pregnancy (Cat.C). Nursing mothers. Interactions: Caution with drugs that may potentiate release of neutrophils (eg, lithium). May cause transient positive changes in boneimaging test results. Adverse reactions: Bone pain; splenic rupture (may be fatal), acute respiratory distress syndrome, serious allergic reactions, sickle cell crisis, potential for tumor growth stimulatory effects on malignant cells. How supplied: Single-use prefilled syringe (0.5mL, 0.8mL)–1, 10 (w. safety needle guard)

LEUKINE Genzyme

℞

Granulocyte-macrophage colony stimulating factor (recombinant). Sargramostim (recombinant human granulocyte-macrophage colony stimulating factor, or rhu GM-CSF) 250mcg; per vial; pwd for SC inj or IV infusion after reconstitution; preservative-free. Indications: To speed neutrophil recovery and reduce infections after induction chemotherapy in treatment of acute myelogenous leukemia (AML) in patients >55 years of age. To mobilize hematopoietic progenitor cells into peripheral blood for collection by leukapheresis. To speed myeloid recovery in non-Hodgkin’s lymphoma, acute lymphoblastic leukemia (ALL), and Hodgkin’s disease in autologous bone marrow transplantation (BMT). To speed myeloid recovery in allogeneic BMT. Patients with BMT failure or engraftment delay. Adults: See literature for timing and duration of dosing, and for repeat courses of therapy. Individualize. Neutrophil recovery: 250mcg/m2 per day IV over 4 hrs. Mobilization or post peripheral blood progenitor cell transplantation: 250mcg/ m2 per day IV over 24 hrs or SC once daily. Myeloid recovery after BMT: 250mcg/m2 per day IV over 2 hrs. BMT failure or engraftment delay: 250mcg/ m2 per day IV over 2 hrs for 14 days. Children: See literature. Contraindications: Excessive leukemic myeloid blasts in bone marrow or peripheral blood (≥10%). Allergy to GM-CMF or yeastderived products. Concomitant (within 24 hrs) chemotherapy or radiotherapy. Warnings/Precautions: Fluid retention, pleural or pericardial effusions. Pulmonary infiltrates. Respiratory disease or symptoms. Hypoxia. Reduce infusion rate by ½ if dyspnea occurs; discontinue if dyspnea worsens. Cardiac disease. CHF. Renal or hepatic dysfunction (monitor before and every other week during therapy). Monitor

CBC and differential twice weekly. Reduce dose by ½ or discontinue if absolute neutrophil count exceeds 20,000cells/mm3 or if platelet count exceeds 500,000cells/mm3. Myeloid malignancies. Monitor body weight and hydration. Pregnancy (Cat.C). Nursing mothers. Interactions: Caution with lithium, corticosteroids, others that may enhance myeloproliferative effects. May be antagonized by radiotherapy, myelotoxic drugs. Adverse reactions: Flu-like symptoms, GI disturbances, edema, dyspnea, pharyngitis, rash, joint or bone or chest pain, eye hemorrhage, hypomagnesemia, anxiety, headache, pleural +/or pericardial effusion, arthralgia, myalgia, others. How supplied: Vials–5

NEULASTA Amgen

℞

Granulocyte colony stimulating factor. Pegfilgrastim (polyethylene glycol/filgrastim conjugate) 6mg/0.6mL soln; SC inj; 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. Adults: Do not give between 14 days before and 24 hours after chemotherapy. Adolescents <45 kg: not recommended. ≥45 kg: 6mg SC once per chemotherapy cycle. Children: Not recommended. Contraindications: Do not use for peripheral blood progenitor cell (PBPC) mobilization. Hypersensitivity to E. coli-derived products. Warnings/Precautions: Monitor CBC and platelets before and during therapy. Monitor for splenomegaly/splenic rupture and for adult respiratory distress syndrome (ARDS); suspend until ARDS resolves if fever or lung infiltrates occur. Sickle cell disease (may cause sickle cell crisis). Myeloid malignancies. Myelodysplasia. Pregnancy (Cat.C). Nursing mothers. Interactions: Caution with drugs that cause delayed myelosuppression (eg, nitrosoureas, mitomycin C), or increase release of neutrophils (eg, lithium), antimetabolites (eg, 5-FU), and radiation therapy. Adverse reactions: Bone pain, anaphylaxis, ARDS; splenic rupture (rare). How supplied: Prefilled syringe–1

NEUPOGEN Amgen

℞

Granulocyte colony stimulating factor. Filgrastim 600mcg/mL prefilled syringe; for SC or IV infusion; preservative-free.

℞ Also: NEUPOGEN VIALS Filgrastim 300mcg/mL; for SC or IV infusion; preservative-free. Indications: See full labeling. To decrease incidence of infection in patients with nonmyeloid malignancies receiving certain myelosuppressive anti-cancer drugs. To reduce time to neutrophil recovery and fever duration after induction and consolidation chemotherapy treatment of adults with AML. To reduce duration of neutropenia and related sequelae in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by 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 adult respiratory distress syndrome (ARDS); suspend until ARDS resolves if fever or lung infiltrates occur. Confirm diagnosis and do appropriate pretreatment hematological workup in SCN. Preexisting cardiac or hyperplastic skin conditions. Sickle cell disease (may cause sickle cell crisis). Avoid simultaneous chemo- and radiation therapy. Pregnancy (Cat.C). Nursing mothers. Interactions: Caution with mitomycin C, and with concomitant (same day) drugs that decrease platelets, or increase release of neutrophils (eg, lithium), or cause delayed myelosuppression, or with myelosuppressive doses of antimetabolites (eg, nitrosoureas, 5-FU). Adverse reactions: Bone pain, cutaneous vasculitis, splenomegaly, others (see literature). How supplied: Prefilled syringes (0.5mL, 0.8mL)–10; Vials (1mL, 1.6mL)–10

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DRUG MONOGRAPHS

ASSOCIATED HEMATOLOGICAL DISORDERS Miscellaneous hematological agents

CINRYZE ViroPharma

℞

C1 inhibitor. C1 inhibitor (human) 500 Units/vial; lyophilized pwd for IV infusion after reconstitution; preservative-free. Indications: Routine prophylaxis against angioedema attacks in adolescent and adult patients with hereditary angioedema. Adults: Give by IV infusion at a rate of 1mL/min (10mins). 1000 Units every 3–4 days. Children: Not recommended. Warnings/Precautions: Contains human plasma; monitor for possible infection transmission. Have epinephrine available to treat hypersensitivity reactions. Monitor patients with known risk factors for thrombotic events. Labor & delivery. Pregnancy (Cat.C). Nursing mothers. Adverse reactions: Upper respiratory tract infection, sinusitis, rash, headache; thrombotic events, hypersensitivity reactions (may be severe); discontinue if occurs. Note: To report infections that may have been transmitted by Cinryze, call CinryzeSolutions at (877) 945-1000. How supplied: Single-use vial–1

EXJADE Novartis

℞

Iron chelating agent. Deferasirox 125mg, 250mg, 500mg; tabs for oral susp. Indications: Chronic iron overload due to blood transfusions in patients ≥2yrs of age. Chronic iron overload in patients ≥10yrs of age with nontransfusion dependent thalassemia 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. Non-transfusion dependent thalassemia syndromes: <10yrs: not established. ≥10yrs: 10mg/kg once daily; if baseline LIC>15mg Fe/g dw, consider increasing dose to 20mg/kg after 4 weeks. Suspend therapy if serum ferritin <300mcg/L and obtain LIC to determine whether it has fallen to <3mg Fe/g dw. After 6 months, if LIC remains >7mg Fe/g dw, increase

dose to max 20mg/kg/day. If after 6 months, LIC is 3–7mg Fe/g dw, continue with max 10mg/kg/day. When LIC is <3mg Fe/g dw, interrupt treatment and continue to monitor LIC. Restart when LIC rises again to >5mg Fe/g dw. Adjustments based on serum creatinine: see full labeling. Hepatic impairment: moderate: reduce dose by 50%; severe: avoid. Contraindications: CrCl <40mL/min or serum creatinine >2x age-appropriate ULN. Poor performance status. High risk myelodysplastic syndromes.Advanced malignancies. Platelets <50×109/L. Warnings/Precautions: May cause renal or hepatic failure, GI hemorrhage; may be fatal. 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 non-transfusion dependent thalassemia 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 concomitant 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. Other concomitant iron chelation therapy: not recommended. Adverse reactions: GI upset, 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 tablets. Indications: Treatment of transfusional iron overload due to thalassemia syndromes when current chelation therapy is inadequate. 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 recommended. Warnings/Precautions: Not established for use in treating other chronic anemias. 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). History of QT prolongation (eg, those with CHF, bradycardia, diuretic use, cardiac hypertrophy, hypokalemia, hypomagnesemia). 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. Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended. Interactions: Avoid concomitant use with other drugs associated with neutropenia or agranulocytosis. Allow at least 4-hour interval with antacids or mineral supplements containing polyvalent cations (eg, iron, aluminum, zinc). Concomitant UGT 1A6 inhibitors: closely monitor and may need dose adjustments or interruptions. Adverse reactions: Chromaturia, GI upset, abdominal pain, increased ALT, arthralgia, neutropenia; agranulocytosis, possible Torsades de Pointes. 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.

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ASSOCIATED HEMATOLOGICAL DISORDERS 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 Dyax

℞

Plasma kallikrein inhibitor. Ecallantide 10mg/mL; soln for SC inj; preservative-free. Indications: Treatment of acute attacks of hereditary angioedema. Adults: Give 30mg SC in three 10mg (1mL) inj into abdomen, thigh, or upper arm. May give additional 30mg within 24hrs if attack persists. Children: <12yrs: not established. Warnings/Precautions: Have medical support available to manage anaphylaxis and hereditary angioedema. Monitor closely for hypersensitivity reactions. Labor & delivery. Pregnancy (Cat.C). Nursing mothers. Adverse reactions: Headache, nausea, diarrhea, pyrexia, inj site reactions, nasopharyngitis, fatigue, upper respiratory tract infection, pruritus, upper abdominal pain; anaphylaxis, antibody formation. How supplied: Single-use vials–3

MOZOBIL Genzyme

℞

Hematopoietic stem cell mobilizer. Plerixafor 20mg/mL; soln for SC inj; preservative-free. Indications: In combination with granulocyte colony stimulating factor (G-CSF): To mobilize hematopoietic stem cells to the peripheral blood for collection and autologous transplantation in patients with non-Hodgkin’s lymphoma or multiple myeloma. Adults: Start after 4 days’ treatment with G-CSF. Give approximately 11hrs before starting apheresis. Repeat up to 4 consecutive days. Base dose on actual body weight. 0.24mg/kg SC; max 40mg/day. Renal impairment (CrCl≤50mL/min): 0.16mg/kg; max 27mg/day. Children: Not established. Warnings/Precautions: Not for use in leukemia. May cause mobilization of tumor cells. Monitor blood and platelet counts (esp. neutrophils). Monitor for splenic rupture (eg, left upper quadrant/scapular or shoulder pain). Monitor for signs/symptoms of hypersensitivity during and after administration for at least 30mins. Pregnancy (Cat.D); avoid. Nursing mothers: not recommended. Interactions: May be potentiated by drugs that reduce renal function or compete for active tubular secretion. Adverse reactions: Diarrhea, nausea, fatigue, injection site reactions, headache, arthralgia, dizziness, vomiting; anaphylactic shock, hypersensitivity reactions (may be serious), tumor cell mobilization, increased circulating neutrophils, decreased platelet counts, enlarged spleen, vasovagal reaction may occur. How supplied: Single-use vials (1.2mL)–1

HEMATOLOGICAL REFERENCE VALUES Analyte

Reference value Conventional units SI units

Antithrombin III • Antigenic • Functional

22–39mg/dL 80–130%

220–390mg/L 0.8–1.30 U/L

Bleeding time

2.0–9.5min

Erythrocyte count • Male • Female

4.50–5.90 × 106/mm3 4.00–5.20 × 106/mm3

4.50–5.90 × 1012/L 4.00–5.20 × 1012/L

Erythrocyte sedimentation rate • Male • Female

0–17mm/hr 1–25mm/hr

Ferritin • Male • Female

30–300ng/mL 10–200ng/mL

30–300μg/L 10–200μg/L

Fibrinogen

150–400mg/dL

1.50–4.00g/L

Folate (folic acid) • Normal • Borderline deficient • Deficient • Excess

3.1–17.5ng/mL 2.2–3.0ng/mL <2.2ng/mL >17.5ng/mL

7.0–39.7nmol/L 5.0–6.8nmol/L <5.0nmol/L >39.7nmol/L

Folic acid

150–450ng/mL/cells

340–1020nmol/L/cells

Hematocrit • Male • Female

41.0–53.0% 36.0–46.0%

0.41–0.53 0.36–0.46

Hemoglobin • Plasma • Whole blood, male • Whole blood, female

1–5mg/dL 13.5–17.5g/dL 12.0–16.0g/dL

0.01–0.05g/L 8.4–10.9mmol/L 7.4–9.9mmol/L

Hemoglobin electrophoresis • Hemoglobin A • Hemoglobin A1c • Hemoglobin A2 • Hemoglobin F • Hemoglobins other than A, A2, or F

95–98% 3.8–6.4% 1.5–3.5% 0–2.0% Absent

0.95–0.98 0.038–0.064Hg fraction 0.015–0.035 0–0.02 Absent

Iron (hematology and coagulation values)

30–160μg/dL

5.4–28.7μmol/L

Iron-binding capacity (hematology and coagulation values)

228–428μg/dL

40.8–76.7μmol/L

Iron (clinical chemistry values)

50–150μg/dL

9–27μmol/L

Iron-binding capacity (clinical chemistry values)

250–370μg/dL

45–66μmol/L

Leukocyte count (WBC)

4.5–11.0 × 103/mm3

4.5–11 × 109/L

Mean corpuscular hemoglobin (MCH)

26.0–34.0pg/cell

Mean corpuscular hemoglobin concentration (MCHC)

31.0–37.0g/dL

310–370g/L

Mean corpuscular volume (MCV)

80–100μm3

80–100fl

Partial-thromboplastin time (activated)

22.1–35.1sec

Platelet count

150–350 × 103/mm3

150–350 × 109/L

Prothrombin time

11.1–13.1sec

Reticulocyte count

0.5–2.5% red cells

0.005–0.025 red cells

Transferrin

230–390mg/dL

2.3–3.9g/L

Vitamin B12 • Normal • Borderline • Deficient

>250pg/mL 125–250pg/mL <125pg/mL

>185pmol/L 92–185pmol/L <92pmol/L

References National Institutes of Health. Third report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). September 2002. Available at: www.nhlbi. (Rev. 8/2012) nih.gov/guidelines/cholesterol/index.htm. Accessed August 2012.

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DRUG MONOGRAPHS

ASSOCIATED HEMATOLOGICAL DISORDERS ANTICOAGULANT DOSING CONVERSIONS Conversion of DABIGATRAN ETEXILATE Switching from DABIGATRAN to WARFARIN • Adjust starting time of warfarin based on CrCl as follows: ° CrCl >50mL/min: Start warfarin 3 days before discontinuing dabigatran ° CrCl 30–50mL/min: Start warfarin 2 days before discontinuing dabigatran ° CrCl 15–30mL/min: Start warfarin 1 day before discontinuing dabigatran ° CrCl <15mL/min: No recommendations can be made • Since dabigatran can increase INR, the INR will better reflect warfarin’s effect only after dabigatran has been stopped for at least 2 days Switching from DABIGATRAN to PARENTERAL ANTICOAGULANT • Currently receiving dabigatran: ° Wait 12hrs (CrCl ≥30mL/min) or 24hrs (CrCl <30mL/min) after the last dose of dabigatran before initiating treatment with a parenteral anticoagulant

Conversion of APIXABAN Switching from APIXABAN to WARFARIN • Apixiban affects INR levels, so the INR measurement during co-administration with warfarin may not be useful for determing the appropriate dose of warfarin ° Discontinue apixaban and start both a parenteral anticoagulant and warfarin at the time the next dose of apixaban would have been taken, then discontinue the parenteral anticoagulant when INR reaches an acceptable range Switching between APIXABAN and ANTICOAGULANTS other than WARFARIN • Discontinue one being taken and begin the other at the next scheduled dose

Conversion of RIVAROXABAN Switching from RIVAROXABAN to WARFARIN • Rivaroxaban affects INR levels, so INR measurements during co-administration with warfarin may not be useful for determining the appropriate dose of warfarin ° Discontinue rivaroxaban and start both a parenteral anticoagulant and warfarin at the time the next dose of rivaroxaban would have been taken Switching from RIVAROXABAN to ANTICOAGULANTS other than WARFARIN • Currently taking rivaroxaban and transitioning to an anticoagulant with rapid onset: ° Discontinue rivaroxaban and give 1st dose of the other anticoagulant (oral or parenteral) at the time the next dose of rivaroxaban would have been taken Switching from ANTICOAGULANTS other than WARFARIN to RIVAROXABAN • Currently receiving an anticoagulant other than warfarin: ° Start rivaroxaban 0–2hrs prior to the next scheduled evening dose of the drug (eg, low molecular weight heparin or non-warfarin oral anticoagulant and omit administration of the other anticoagulant ° Start rivaroxaban at the same time a continuous infusion of unfractionated heparin is discontinued

Conversion of HEPARIN Switching from HEPARIN to WARFARIN • Dose warfarin with the usual initial amount (eg, 2–5mg PO or IV daily) and determine PT/INR at the usual intervals • Overlap warfarin with full dose heparin therapy for 4–5 days until warfarin has produced the desired therapeutic response as determined by PT/INR. Heparin may be discontinued at that time without tapering. • The interference with heparin anticoagulation is of minimal clinical significance during initial therapy with warfarin • Patients receiving both heparin and warfarin should have blood for PT/INR determination drawn at least: ° 5hrs after the last IV bolus dose of heparin, or ° 4hrs after cessation of a continuous IV infusion of heparin, or ° 24hrs after the last subcutaneous heparin injection Switching from HEPARIN/PARENTERAL ANTICOAGULANT to DABIGATRAN • Currently receiving a parenteral anticoagulant: ° Start dabigatran 0–2hrs before the next scheduled dose of the parenteral drug would have been given, or ° Start dabigatran at the time of discontinuation of a continuously administered parenteral drug (eg, IV unfractionated heparin)

Conversion of WARFARIN Switching from WARFARIN to DABIGATRAN • Discontinue warfarin and start dabigatran when INR is <2.0 Switching from WARFARIN to APIXABAN • Discontinue warfarin and start apixaban when INR is <2.0 Switching from WARFARIN to RIVAROXABAN • Discontinue warfarin and start rivaroxaban as soon as INR is <3.0 to avoid periods of inadequate anticoagulation

Notes

Please see drug monograph at www.eMPR.com and/or contact company for full drug labeling.

(Rev. 11/2013)

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ALPHABETICAL INDEX A Abiraterone Zytiga Abraxane (inj) cancer, breast cancer, pancreatic non-small cell lung cancer Actinic keratoses Adcetris (inj) Ado-trastuzumab Kadcyla Advate (inj) Afatinib Gilotrif Afinitor cancer, breast cancer, pancreatic cancer, renal progressive neuroendocrine tumors of pancreatic origin (pNET) subependymal giant cell astrocytoma (SEGA) Aldesleukin Proleukin (inj) Alemtuzumab Campath (inj) Alimta (inj) Alitretinoin Panretin (ext) Alkeran cancer, ovarian multiple myeloma Alphanate (inj) AlphaNine SD (inj) 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 Advate (inj) Alphanate (inj)* Helixate FS (inj) Hemofil M (inj) Humate-P (inj)* Koate-DVI (inj) Kogenate FS (inj)

44 5 18 84 90 61 8 100 85 3, 5, 18, 37 3, 5, 18, 37 3, 5, 18, 37 3, 5, 18, 37 3, 5, 18, 37 41, 92 63 84 89 50, 61 50, 61 100 101 50 101 101 94 3 5 94–100 115–116 102 94 100 100 103 103 104 104 104

Brand name–bold type Generic name–light type

Monoclate-P (inj) 105 Recombinate (inj) 107 ReFacto (inj) 107 Xyntha (inj) 109 Aplastic anemia 94 Aranesp (inj) 94 Arimidex 5 Aromasin 5 Arranon 61 Arsenic trioxide Trisenox (inj) 81 Arzerra (inj) 61 Asparaginase Erwinia chrysanthemi Erwinaze (inj) 65 Atgam (inj) 94 Atypical hemolytic uremic syndrome 100 Avastin (inj) cancer, cervical 3, 32, 37, 50, 84 cancer, colorectal 3, 32, 37, 50, 84 cancer, ovarian 3, 32, 50, 84 cancer, renal 3, 32, 37, 50, 84 glioblastoma 3, 32, 37, 50, 84 non-small cell lung cancer 3, 32, 37, 50, 84 Axitinib Inlyta 39 Azacitidine Vidaza (inj) 82

B Barrett’s esophagus 34, 86 Basal cell carcinoma 90 BayRho-D (inj) 109 BCG, live TheraCys (inj) 42 Tice BCG (inj) 42 Bebulin VH (inj) 101 Beleodaq (inj) 62 Belinostat Beleodaq (inj) 62 Bendamustine Treanda (inj) 75 BeneFIX (inj) 101 Bevacizumab Avastin (inj) 3, 32, 37, 50, 84 Bexarotene Targretin 73 Targretin (ext) 74 Bexxar 62 Bicalutamide Casodex 37 Bifera 94 BiferaRx 94 Bleeding 101–102, 104, 107–108 Blinatumomab Blincyto (inj) 62 Blincyto (inj) 62

Medical condition–red type

Bone metastases Bortezomib Velcade (inj) Bosulif Bosutinib Bosulif Brentuximab vedotin Adcetris (inj) Busulfan Busulfex (inj) Myleran Busulfex (inj)

1, 83 81 63 63 61 63 70 63

C C1 inhibitor Cinryze (inj) Cabazitaxel Jevtana (inj) Cabozantinib Cometriq Campath (inj) Cancer, adrenal cortex Cancer, bladder Cancer, breast

115 39 19 63 20 42–43 1, 3, 5–19, 33–34, 36–38, 51, 53, 75, 87 3, 32, 37, 50, 84–85

Cancer, cervical Cancer, colorectal 3, 6, 17, 19, 32–37, 50, 53, 84 Cancer, endometrial 8, 51 Cancer, esophageal 34, 86 Cancer, GI 7, 32, 34 Cancer, head and neck 1, 16, 32, 51, 53, 67, 75, 87, 90 Cancer, liver 34, 40 Cancer, lung 1, 16, 50–51, 53, 70, 75, 84–87 Cancer, ovarian 3, 32, 47–51, 53, 61, 65, 67, 84–85, 89–90 Cancer, pancreatic 3, 5–6, 18–20, 29–31, 33, 35, 37, 41, 86 Cancer, prostate 6, 37–41, 43–44 Cancer, renal 3, 5, 18, 32, 34, 37, 39–43, 50, 84, 92 Cancer, sarcoma 1 Cancer, stomach 6, 19, 33 Cancer, testicular 38 Cancer, thyroid 18–21, 34, 40 Capecitabine Xeloda 17, 36 Caprelsa 18 Carfilzomib Kyprolis (inj) 69 Carimune NF (inj) 102 Casodex 37 Ceritinib Zykadia 88

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Brand name–bold type Generic name–light type

Cerubidine (inj) 63 Cetuximab Erbitux (inj) 32, 53 Chlorambucil Leukeran 69 Chorioadenoma destruens 1, 16, 51, 53, 75, 87 Choriocarcinoma, gestational 1, 16, 51, 53, 75, 87 Chronic kidney disease 97 Cinryze (inj) 115 Cladribine (inj) 64 Clofarabine Clolar (inj) 64 Clolar (inj) 64 Coagulation Factor IX AlphaNine SD (inj) 101 BeneFIX (inj) 101 Mononine (inj) 105 Rixubis (inj) 108 Coagulation Factor IX complex Bebulin VH (inj) 101 Profilnine SD (inj) 106 Coagulation Factor VIIa NovoSeven RT (inj) 106 Colorectal cancer 33 Cometriq 19 Congenital Factor VII deficiency 106 Congenital Factor VIII deficiency 100, 107 Congenital Factor XIII deficiency 102 Congenital fibrinogen deficiency 108 Corifact (inj) 102 Crizotinib Xalkori 87 Cyanocobalamin Cyanocobalamin (inj) 95 Nascobal (nasal) 98 Cyklokapron (inj) 102 Cyramza (inj) cancer, GI 32 cancer, lung 84 Cytarabine Cytarabine 64 DepoCyt (inj) 64

D Dabrafenib Tafinlar Dacarbazine DTIC-Dome (inj) Dacogen (inj)

92 65 64

Medical condition–red type

ALPHABETICAL INDEX

Darbepoetin alfa Aranesp (inj) 94 Dasatinib Sprycel 72 Daunorubicin Cerubidine (inj) 63 Decitabine Dacogen (inj) 64 Deferasirox Exjade 115 Deferiprone Ferriprox 115 Degarelix Firmagon (inj) 38 Delatestryl 6 Delestrogen (inj) 37 Denileukin diftitox Ontak (inj) 70 Denosumab Xgeva (inj) 1 DepoCyt (inj) 64 Dermatofibrosarcoma protuberans 33, 66, 90 Desmopressin Stimate (nasal) 108 DexFerrum (inj) 95 Docusate sodium Ferralet 90* 96 Ferro-Sequels* 97 Doxil (inj) cancer, ovarian 50, 65, 89 Kaposi’s sarcoma 50, 65, 89 multiple myeloma 50, 65, 89 Doxorubicin, liposomal Doxil (inj) 50, 65, 89 Droxia 95 DTIC-Dome (inj) 65

E Ecallantide Kalbitor (inj) Eculizumab Soliris (inj) Efudex (ext) Eligard Eloxatin (inj) Eltrombopag Promacta Emcyt Enzalutamide Xtandi

Epoetin alfa Epogen (inj) Procrit (inj) Epogen (inj) Erbitux (inj) cancer, colorectal cancer, head and neck Eribulin Halaven 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) Etoposide Everolimus Afinitor Evista Exemestane Aromasin Exjade

116

F

100 90 38 32

Factor VIII complex Wilate (inj)* Factor XIII Corifact (inj) Faslodex (inj) Feiba (inj) Femara Feosol Fer-In-Sol

99, 107 38 44

95 98 95 32, 53 32, 53 7 90 20, 86 65 74 102 6, 38 6, 38 6, 38 37 38 15, 40 40 102 102 85 3, 5, 18, 37 6 5 115

109 102 6 102 6 96 96

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ALPHABETICAL INDEX Feraheme (inj) Fergon Ferralet 90 Ferretts Ferric carboxymaltose Injectafer Ferriprox Ferrlecit (inj) Ferro-Sequels Fibrinogen RiaSTAP (inj) Filgrastim Neupogen (inj) Firazyr (inj) Firmagon (inj) Fludara (inj) Fludarabine Fludara (inj) Fluorouracil cancer, breast cancer, colorectal cancer, pancreatic cancer, stomach Fluorouracil Efudex (ext) Fluorouracil Flutamide Folic acid BiferaRx* Ferralet 90* Folic acid Trinsicon* Folotyn (inj) Fulvestrant Faslodex (inj) Fusilev (inj)

96 96 96 96 97 115 96 97 108 111 115 38 65 65 6, 19, 33 6, 19, 33 6, 19, 33 6, 19, 33 90 6, 19, 33 38 94 96 97 100 66 6 33

G Gamunex-C (inj) 103 Gazyva (inj) 66 GI stromal tumors 20, 33, 35, 41, 66, 90 Gilotrif 85 Glanzmann’s thrombasthenia 106 Gleevec dermatofibrosarcoma protuberans 33, 66, 90 GI stromal tumors 33, 66, 90 hypereosinophilic syndrome 33, 66, 90 leukemia, acute myeloid 33, 66, 90 leukemia, chronic eosinophilic 33, 66, 90 leukemia, chronic myelogenous 33, 66, 90 mastocytosis 33, 66, 90 myelodysplastic syndromes 33, 66, 90 Glioblastoma 3, 32, 37, 50, 84 Granix (inj) 110

Brand name–bold type Generic name–light type

H Halaven 7 Helixate FS (inj) 103 Hematopoietic stem cell mobilizer 116 Hemofil M (inj) 103 Hemophilia 102 Hemophilia A 100, 103–109 Hemophilia B 101, 105–106, 108 Herceptin (inj) cancer, breast 7, 34 cancer, GI 7, 34 Hexalen 50 Histrelin Vantas 43 Hodgkin lymphoma 61 Hodgkin’s disease 65, 69–70, 85 Humate-P (inj) 104 Hycamtin cancer, cervical 50, 85 cancer, lung 50, 85 cancer, ovarian 50, 85 Hydatidiform mole 1, 16, 51, 53, 75, 87 Hydrea cancer, head and neck 51, 53, 67, 90 cancer, ovarian 51, 53, 67, 90 leukemia, chronic myelocytic 51, 53, 67, 90 melanoma 51, 53, 67, 90 Hydroxyurea Droxia 95 Hydrea 51, 53, 67, 90 Hypercalcemia 83 Hypereosinophilic syndrome 33, 66, 90 HyperRHO S/D Full Dose (inj) 110 Hypogonadism 6

I Ibrance 8 Ibritumomab Zevalin (inj) 82 Ibrutinib Imbruvica 67 ICAR-C 97 Icatibant Firazyr (inj) 115 Iclusig 67 Idamycin (inj) 67 Idarubicin Idamycin (inj) 67 Idelalisib Zydelig 83 Idiopathic thrombocytopenic purpura 102–103, 106, 108–109 Ifex (inj) 38

Medical condition–red type

Ifosfamide Ifex (inj) 38 Imatinib Gleevec 33, 66, 90 Imbruvica 67 Immune globulin Carimune NF (inj) 102 Gamunex-C (inj) 103 Privigen (inj) 106 Immunomodulators 109–111 INFeD (inj) 97 Injectafer 97 Inlyta 39 Interferon alfa-2b Intron A (inj) 68, 89, 90 Intron A (inj) Kaposi’s sarcoma 68, 89, 90 leukemia, hairy cell 68, 89, 90 lymphoma, follicular 68, 89, 90 melanoma 68, 89, 90 Iodine I 131 Tositumomab Bexxar* 62 Ipilimumab Yervoy (inj) 93 Iron ICAR-C 97 Iron deficiency anemia 97 Iron fumarate Ferretts 96 Ferro-Sequels* 97 Trinsicon* 100 Iron gluconate Fergon 96 Ferrlecit (inj) 96 Nulecit (inj) 98 Iron sulfate Feosol 96 Fer-In-Sol 96 Slow Fe 99 Iron (as carbonyl) Ferralet 90* 96 Iron (as dextran complex) DexFerrum (inj) 95 INFeD (inj) 97 Iron (as ferumoxytol) Feraheme (inj) 96 Iron (as polysaccharide iron complex + heme iron polypeptide) Bifera 94 BiferaRx* 94 Iron (as sucrose) Venofer (inj) 100 Istodax 68 Ixabepilone Ixempra (inj) 8 Ixempra (inj) 8

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Brand name–bold type Generic name–light type

J Jakafi Jevtana (inj)

68 39

K Kadcyla Kalbitor (inj) Kaposi’s sarcoma KCentra (inj) Keytruda (inj) Koate-DVI (inj) Kogenate FS (inj) Kyprolis (inj)

8 116 50, 65, 68, 89–90 104 91 104 104 69

L Lapatinib Tykerb 16 Lenalidomide Revlimid 72, 99 Lenvatinib Lenvima 19 Lenvima 19 Letrozole Femara 6 Leucovorin anemia 98 cancer, colorectal 34 Leukemia 69–70, 85 Leukemia, acute lymphoblastic 62, 64–65, 67, 69–72, 82 Leukemia, acute lymphocytic 63–64, 71 Leukemia, acute myeloid 33, 66–67, 90 Leukemia, acute nonlymphocytic 63–64, 70, 73 Leukemia, acute promyelocytic 81–82 Leukemia, B-cell chronic lymphocytic 63, 65 Leukemia, chronic eosinophilic 33, 66, 90 Leukemia, chronic lymphocytic 61, 66–67, 72, 75–80, 83 Leukemia, chronic myelocytic 51, 53, 64, 67, 90 Leukemia, chronic myelogenous 33, 63, 66, 70, 72–74, 90 Leukemia, chronic myeloid 54–56, 67 Leukemia, hairy cell 64, 68, 89–90

Medical condition–red type

ALPHABETICAL INDEX

Leukemia, meningeal 64 Leukemia, T-cell acute lymphoblastic 61 Leukeran 69 Leukine (inj) 111 Leuprolide Eligard 38 Leuprolide acetate (inj) 39 Lupron Depot 3.75mg (inj) 98 Lupron Depot 7.5mg (inj) 39 Leuprolide acetate (inj) 39 Levoleucovorin Fusilev (inj) 33 Lupron Depot 3.75mg (inj) 98 Lupron Depot 7.5mg (inj) 39 Lymphocyte immune globulin Atgam (inj)* 94 Lymphoma, cutaneous T-cell 68, 70, 73–74, 81, 83 Lymphoma, follicular 68, 83, 89–90 Lymphoma, malignant 69 Lymphoma, mantle cell 67, 81 Lymphoma, peripheral T-cell 62, 68 Lymphoma, small lymphocytic 83 Lymphoma, T-cell 66 Lymphoma, T-cell lymphoblastic 61 Lymphomatous meningitis 64 Lymphosarcoma 70, 85 LYNPARZA 51 Lysodren 20

Mercaptopurine Purinethol 71 Purixan 71 Methotrexate Trexall 1, 16, 51, 53, 75, 87 Methoxsalen Uvadex 81 Mitotane Lysodren 20 Mitoxantrone HCl (inj) cancer, prostate 40 leukemia, acute nonlymphocytic 70 Monoclate-P (inj) 105 Mononine (inj) 105 Mozobil (inj) 116 Multiple myeloma 50, 61, 65, 69, 71–72, 74, 81, 83, 89 Mustargen (inj) cancer, lung 70, 85 Hodgkin’s disease 70, 85 leukemia 70, 85 lymphosarcoma 70, 85 mycosis fungoides 70, 85 polycythemia vera 70, 85 Mycosis fungoides 1, 16, 51, 53, 70, 75, 85, 87 Mycosis fungoides-type cutaneous T-cell lymphoma 81 Myelodysplastic syndromes 33, 64, 66, 82, 90 Myleran 70

M

N

Malignant pleural mesothelioma 84 Mantle cell lymphoma 72 Marqibo (inj) 69 Mastocytosis 33, 66, 90 Matulane 69 Mechlorethamine Mustargen (inj) 70, 85 Valchlor (ext) 81 Megestrol acetate cancer, breast 8, 51 cancer, endometrial 8, 51 Mekinist 91 Melanoma 51, 53, 65, 67–68, 89–93 Melanoma, metastatic 41, 92 Melphalan Alkeran 50, 61 Menest 40

Nascobal (nasal) Navelbine (inj) Nelarabine Arranon Neoplasms Neulasta (inj) Neumega (inj) Neupogen (inj) Neuroendocrine tumors Neutropenia Nexavar cancer, liver cancer, renal cancer, thyroid Nilandron Nilotinib Tasigna

98 86 61 38, 40, 42–43 111 105 111 20, 35, 41 110–114 34, 40 34, 40 20, 34, 40 40 74

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ALPHABETICAL INDEX Nilutamide Nilandron 40 Nitropress (inj) 105 Nivolumab Opdivo (inj) 86, 91 Non-Hodgkin’s lymphoma 1, 16, 51, 53, 57–60, 62, 72, 75, 82, 87 Non-small cell lung cancer 3, 20, 32, 34, 37, 50, 84–88 NovoSeven RT (inj) 106 Nplate (inj) 106 Nulecit (inj) 98

O Obinutuzumab Gazyva (inj) Ofatumumab Arzerra (inj) Olaparib LYNPARZA Omacetaxine mepesuccinate Synribo (inj) Oncaspar (inj) Ontak (inj) Opdivo (inj) cancer, lung melanoma Oprelvekin Neumega (inj) Oxaliplatin Eloxatin (inj) Oxymetholone Anadrol-50

66 61 51 73 70 70 86 91 105 32 94

P Paclitaxel, protein-bound Abraxane (inj) 5, 18, 84 Palbociclib Ibrance 8 Panitumumab Vectibix (inj) 35 Panretin (ext) 89 Paroxysmal nocturnal hemoglobinuria 100 Pazopanib Votrient 1, 43 Pegaspargase Oncaspar (inj) 70 Pegfilgrastim Neulasta (inj) 111 Peginterferon alfa-2b Sylatron (inj) 92 Pembrolizumab Keytruda (inj) 91 Pemetrexed Alimta (inj) 84

Brand name–bold type Generic name–light type

Perjeta (inj) 15 Pertuzumab Perjeta (inj) 15 Photofrin (inj) barrett’s esophagus 34, 86 cancer, esophageal 34, 86 non-small cell lung cancer 34, 86 Plerixafor Mozobil (inj) 116 Poisoning/overdose 115 Polycythemia vera 68, 70, 85 Pomalidomide Pomalyst 71 Pomalyst 71 Ponatinib Iclusig 67 Porfimer Photofrin (inj) 34, 86 Pralatrexate Folotyn (inj) 66 Premarin cancer, breast 15 cancer, prostate 40 Privigen (inj) 106 Procarbazine Matulane 69 Procrit (inj) 98 Profilnine SD (inj) 106 Progressive neuroendocrine tumors of pancreatic origin (pNET) 3, 5, 18, 37 Proleukin (inj) cancer, renal 41, 92 melanoma, metastatic 41, 92 Promacta anemia 99 thrombocytopenia 107 Prothrombin complex concentrate (human) KCentra (inj) 104 Provenge (inj) 41 Purinethol 71 Purixan 71

R Radium Ra 223 dichloride Xofigo (inj) Raloxifene Evista Ramucirumab Cyramza (inj) Recombinate (inj) Recothrom ReFacto (inj) Regorafenib Stivarga Revlimid anemia

44 6 32, 84 107 107 107 35 99

Medical condition–red type

mantle cell lymphoma multiple myeloma Rh Isoimmunization RhoGam (inj) Rhophylac (inj) idiopathic thrombocytopenic purpura Rh Isoimmunization Rho(D) immune globulin BayRho-D (inj) HyperRHO S/D Full Dose (inj) RhoGam (inj) Rhophylac (inj) WinRho SDF (inj) RiaSTAP (inj) Rituxan (inj) Rituximab Rituxan (inj) Rixubis (inj) Romidepsin Istodax Romiplostim Nplate (inj) Ruxolitinib Jakafi

72 72 110 110

108 110 109 110 110 108, 110 109, 110 108 72 72 108 68 106 68

S Sargramostim Leukine (inj) 111 Sickle cell anemia 95 Sipuleucel-T Provenge (inj) 41 Skeletal-related events 1 Slow Fe 99 Small cell lung cancer 85 Sodium nitroprusside Nitropress (inj) 105 Soliris (inj) 100 Soltamox 15 Sorafenib Nexavar 20, 34, 40 Sprycel 72 Stimate (nasal) 108 Stivarga 35 Subependymal giant cell astrocytoma (SEGA) 3, 5, 18, 37 Sunitinib Sutent 20, 35, 41 Superficial basal cell carcinoma 90 Surgical bleed 105 Sutent cancer, pancreatic 20, 35, 41 GI stromal tumors 20, 35, 41 neuroendocrine tumors 20, 35, 41 Sylatron (inj) 92 Synribo (inj) 73

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Brand name–bold type Generic name–light type

Systemic anaplastic large cell lymphoma

T Tabloid Tafinlar 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 Thrombin Recothrom Thrombin-JMI Thrombin-JMI Thrombocytopenia Thyrogen (inj) Thyrotropin alfa Thyrogen (inj) Tice BCG (inj) Topotecan Hycamtin Torisel (inj) Tositumomab Bexxar* Trametinib Mekinist Tranexamic acid Cyklokapron (inj)

73 92 15 16 20, 86 20, 86 73 74 74 110 3 3 42 82

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 Trinsicon Triptorelin Trelstar (inj) Trisenox (inj) Tykerb

Uvadex

74 74 42

V

107 108 108 105–107 21 21 42 50, 85 42 62 91 102

7, 34 75 43 82 1, 16, 51, 53, 75, 87 1, 16, 51, 53, 75, 87 1, 16, 51, 53, 75, 87 1, 16, 51, 53, 75, 87 1, 16, 51, 53, 75, 87 1, 16, 51, 53, 75, 87 1, 16, 51, 53, 75, 87 1, 16, 51, 53, 75, 87 100 43 81 16

U

ALPHABETICAL INDEX

Medical condition–red type

Valchlor (ext) Valrubicin Valstar Valstar Vandetanib Caprelsa Vantas Vectibix (inj) Velcade (inj) Vemurafenib Zelboraf Venofer (inj) Vesanoid Vidaza (inj) Vincristine sulfate liposome Marqibo (inj) Vinorelbine Navelbine (inj) Vismodegib Erivedge

81 43 43 18 43 35 81 93 100 82 82 69 86 90

VKA reversal Von Willebrand disease Von Willebrand Factor Alphanate (inj)* Humate-P (inj)* Wilate (inj)* Vorinostat Zolinza Votrient cancer, renal cancer, sarcoma Vumon (inj)

104 100, 104, 108–109 100 104 109 83 43 1 82

W Wilate (inj) WinRho SDF (inj) idiopathic thrombocytopenic purpura Rh Isoimmunization

109

109 110

X Xalkori Xeloda cancer, breast cancer, colorectal Xgeva (inj) Xofigo (inj) Xtandi Xyntha (inj)

87 17, 36 17, 36 1 44 44 109

Y Yervoy (inj)

Z Zaltrap (inj) Zelboraf Zevalin (inj) Ziv-aflibercept Zaltrap (inj) Zoledronic acid Zometa Zolinza Zometa Zydelig Zykadia Zytiga

36 93 82 36 83 83 83 83 88 44

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MANUFACTURERS INDEX AbbVie (800) 633-9110 Actavis (800) 432-8534 (732) 465-3600 Actelion Pharmaceuticals (866) 228-3546 Alexion Pharmaceuticals, Inc. (203) 272-2596 Allos Therapeutics (888) 255-6788 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 Corp, Consumer Care Div. (800) 331-4536 (973) 254-5000 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 Covis Pharmaceuticals, Inc. (919) 535-3049 CSL Behring, LLC (800) 504-5434 (800) 683-1288 DARA BioSciences, Inc. (919) 872-5578 Dendreon (877) 256-4545 Dyax Corp. (888) 452-5248

Eisai Pharmaceuticals (888) 422-4743 (201) 692-1100 Emergent BioSolutions Inc. (800) 768-2304 Endo Pharmaceuticals (800) 462-3636 (610) 558-9800 Exelixis, Inc. (650) 837-7000 Ferring Pharmaceuticals, Inc. (888) 337-7464 Genentech, Inc. (800) 821-8590 (650) 225-1000 Genzyme Corporation (800) 745-4447 (617) 252-7500 Gilead Sciences, Inc. (800) 445-3235 (650) 574-3000 GlaxoSmithKline (888) 825-5249 Grifols Biologicals, Inc. (888) 474-3657 Hawthorn Pharmaceuticals (888) 455-5253 Hospira (800) 615-0187 Incyte Corporation (855) 463-3463 International Vitamin Corporation (888) 698-5032 Janssen Biotech, Inc. (800) 526-7736 Jazz Pharmaceuticals plc (650) 496-3777 JHP Pharmaceuticals (866) 923-2547 Kedrion Biopharma (855) 353-7466 Lilly, Eli and Company (800) 545-5979 (317) 276-2000 Mead Johnson Nutrition (812) 429-5000 (812) 429-6399 Meda Pharmaceuticals (888) 455-8383 Merck & Co., Inc. (800) 672-6372 (800) 609-4618 Millennium Pharmaceuticals, Inc. (866) 835-2233 Mission Pharmacal Company (210) 696-8400 (800) 292-7364 Novartis Consumer Health (800) 452-0051 Novartis Pharmaceuticals Corp (800) 693-9993 (973) 503-8300 Novo Nordisk (800) 727-6500 (609) 987-5800

Octapharma (888) 429-4535 Onyx Pharmaceuticals (650) 266-0000 Otsuka America Pharmaceutical, Inc. (800) 441-6763 (301) 990-0030 Pfizer Inc. (800) 438-1985 (212) 573-2323 Pharmacyclics and Janssen Biotech (877) 877-3536 Pharmics Inc. (800) 456-4138 (801) 966-4138 Pierre Fabre Pharmaceuticals, Inc. (973) 355-8000 Pinnacle Biologics (847) 283-7690 Prometheus Labs, Inc. (888) 423-5227 QOL Medical, LLC (866) 469-3773 Rare Disease Therapeutics, Inc. (615) 399-0700 Recordati Rare Diseases, Inc. (908) 236-0888 Regeneron and Sanofi Aventis (800) 981-2491 Roche Laboratories (800) 526-6367 (973) 235-5000 Sanofi Aventis (800) 446-6267 (800) 633-1610 Sanofi Pasteur, Inc. (800) 822-2463 Seattle Genetics, Inc. (855) 473-2436 Shire US, Inc. (800) 536-7878 (859) 282-2100 Sigma-Tau Pharmaceuticals, Inc. (800) 447- 0169 Spectrum Pharmaceuticals, Inc. (877) 387-4538 Strativa Pharmaceuticals (201) 802-4000 Teva Pharmaceuticals (215) 591-3000 Therakos, Inc. (877) 865-6850 (610) 280-1000 UCB Inc. (800) 234-5535 (585) 475-9000 Valeant Pharmaceuticals, Inc (877) 361-2719 ViroPharma (610) 458-7300 Warner Chilcott Laboratories (800) 521-8813 (973) 442-3200 ZymoGenetics, Inc. (800) 775-6686 (206) 442-6600

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