Cancer Therapy Advisor November/December 2015 Issue

NOVEMBER/DECEMBER 2015 | VOL 2, ISSUE 2

CancerTherapyAdvisor.com

CancerTherapyAdvisor

A16 CME ACTIVITY

Post-ASCO 2015 QualityFocused Suggested Options for PracticeSM A review of options for patients with neoadjuvant HER2+ breast cancer in the community setting.

FEATURING Cancer Therapy Regimens and Oncology Drug Monographs from

1 Bone Cancer



3 Brain Cancer

 14 Breast Cancer  25 Endocrine Cancer

A28 VIEWPOINT

 31 Gastrointestinal Cancer

Will Lower Dose Regorafenib Be Safer for Patients with Colorectal Cancer?

47 Genitourinary Cancer

 55 Gynecologic Cancer 59 Head and Neck Cancer

NOVEMBER/DECEMBER 2015 | VOL 2, ISSUE 2

A30 IN THE CLINIC

60 Hematologic Cancer

Diagnosing Upper Gastrointestinal Bleeding Secondary to Malignancy

78 Lung Cancer 84 Sarcoma 85 Skin Cancer

A31 VIEWPOINT

89 Associated Hematological

ADT Not Linked With Greater Risk of Cardiac Death in Patients With Prostate Cancer

Disorders



Regimen included

A26 FEATURE The First Basket Study Delivers on Promise of Precision Medicine for Underrepresented Patients

CTA_Cover_1215.indd 1

10/28/15 5:29 PM

B:17.375 in LT:17 in ST:15.5 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

9.6

CYRAMZA + paclitaxel (8.5, 10.8)

MONTHS

OS PROBABILITY

0.8

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

2

4

6

8

10

12

14

16

18

20

22

24

26

28

TIME FROM RANDOMIZATION (MONTHS) Number at Risk

CYRAMZA 330 + paclitaxel Placebo 335 + paclitaxel

308

267

228

185

148

116

78

60

41

24

13

6

1

0

294

241

180

143

109

81

64

47

30

22

13

5

2

0

• 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

Warnings and Precautions Hemorrhage • CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events.

In study 1, which evaluated CYRAMZA as a single agent in advanced gastric cancer, the incidence of severe bleeding was 3.4% for CYRAMZA and 2.6% for placebo. In study 2, which evaluated CYRAMZA plus paclitaxel, the incidence of severe bleeding was 4.3% for CYRAMZA plus paclitaxel and 2.4% for placebo plus paclitaxel. Patients with gastric cancer receiving nonsteroid anti-inflammatory drugs (NSAIDs) were excluded from enrollment in studies 1 and 2; therefore, the risk of gastric hemorrhage in CYRAMZA-treated patients with gastric tumors receiving NSAIDs is unknown. Permanently discontinue CYRAMZA in patients who experience severe bleeding.

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

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

of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue CYRAMZA for grade 3 or 4 IRRs. Gastrointestinal Perforations • CYRAMZA is an antiangiogenic therapy that can increase the risk of gastrointestinal perforation, a potentially fatal event. Four of 570 patients (0.7%) who received CYRAMZA as a single agent in clinical trials experienced gastrointestinal perforation. In study 2, the incidence of gastrointestinal perforations was also increased in patients who received CYRAMZA plus paclitaxel (1.2%) as compared to patients who received placebo plus paclitaxel (0.3%). Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.

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

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

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

Proteinuria Including Nephrotic Syndrome • Monitor proteinuria by urine dipstick and/or urinary protein creatinine ratio for the development of worsening of proteinuria during CYRAMZA therapy.

Withhold CYRAMZA for urine protein levels that are ≥2 g over 24 hours.

Reinitiate CYRAMZA at a reduced dose once the urine protein level returns to <2 g over 24 hours. Permanently discontinue CYRAMZA for urine protein levels >3 g over 24 hours or in the setting of nephrotic syndrome.

VISIT WWW.CYRAMZAHCP.COM FOR MORE INFORMATION, INCLUDING CYRAMZA MONOTHERAPY TRIAL DATA Thyroid Dysfunction • Monitor thyroid function during treatment with CYRAMZA. Embryofetal Toxicity • Based on its mechanism of action, CYRAMZA can cause fetal harm when administered to pregnant women. Animal models link angiogenesis, VEGF, and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with CYRAMZA and for at least 3 months after the last dose of CYRAMZA.

Most Common Adverse Reactions—Single Agent • The most commonly reported adverse reactions (all grades; grade 3/4) occurring in ≥5% of patients receiving CYRAMZA and ≥2% higher than placebo in study 1 were hypertension (16% vs 8%; 8% vs 3%), diarrhea (14% vs 9%; 1% vs 2%), headache (9% vs 3%; 0% vs 0%), and hyponatremia (6% vs 2%; 3% vs 1%).

• The most common serious adverse events with CYRAMZA in study 1 were anemia (3.8%) and intestinal obstruction (2.1%). Red blood cell transfusions were given to 11% of CYRAMZA-treated patients vs 8.7% of patients who received placebo.

• Clinically relevant adverse reactions reported in ≥1% and <5% of CYRAMZA-treated patients in study 1 were: neutropenia (4.7% vs 0.9%), epistaxis (4.7% vs 0.9%), rash (4.2% vs 1.7%), intestinal obstruction (2.1% vs 0%), and arterial thromboembolic events (1.7% vs 0%).

• Across clinical trials of CYRAMZA administered as a single agent, clinically relevant adverse reactions (including grade ≥3) reported in 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 JOB#: 30455-2

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

Use in Specific Populations • Pregnancy: Based on its mechanism of action, CYRAMZA can cause fetal harm. Animal models link angiogenesis, VEGF, and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no available data on CYRAMZA use in pregnant women to inform any drug-associated risks.

No animal studies have been conducted to evaluate the effect of ramucirumab on reproduction and fetal development. Advise females of reproductive potential of the potential risk for maintaining pregnancy, risk to the fetus, and risk to newborn and infant development, and to use effective contraception during CYRAMZA therapy and for at least 3 months following the last dose of CYRAMZA. • Lactation: Because of the potential risk for serious adverse reactions in nursing infants from ramucirumab, advise women that breastfeeding is not recommended during treatment with CYRAMZA. • Females of Reproductive Potential: Advise females of reproductive potential that based on animal data CYRAMZA may impair fertility.

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

RB-G HCP ISI 17SEP2015 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.

PP-RB-US-0347

10/2015 PRINTED IN USA

ARTIST: MC COLLECT DATE:

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

AD

M03 CP M

ACD

© Lilly USA, LLC 2015. All rights reserved.

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

FINISH SIZE: 17” wide x 11” high “A size”

LOCATION: Mechanicals

ED

• 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).

AE

inserv

B:11.5 in LT:11 in ST:10.75 in 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:17.375 in LT:17 in ST:15.5 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

9.6

CYRAMZA + paclitaxel (8.5, 10.8)

MONTHS

OS PROBABILITY

0.8

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

2

4

6

8

10

12

14

16

18

20

22

24

26

28

TIME FROM RANDOMIZATION (MONTHS) Number at Risk

CYRAMZA 330 + paclitaxel Placebo 335 + paclitaxel

308

267

228

185

148

116

78

60

41

24

13

6

1

0

294

241

180

143

109

81

64

47

30

22

13

5

2

0

• 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

Warnings and Precautions Hemorrhage • CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events.

In study 1, which evaluated CYRAMZA as a single agent in advanced gastric cancer, the incidence of severe bleeding was 3.4% for CYRAMZA and 2.6% for placebo. In study 2, which evaluated CYRAMZA plus paclitaxel, the incidence of severe bleeding was 4.3% for CYRAMZA plus paclitaxel and 2.4% for placebo plus paclitaxel. Patients with gastric cancer receiving nonsteroid anti-inflammatory drugs (NSAIDs) were excluded from enrollment in studies 1 and 2; therefore, the risk of gastric hemorrhage in CYRAMZA-treated patients with gastric tumors receiving NSAIDs is unknown. Permanently discontinue CYRAMZA in patients who experience severe bleeding.

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

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

of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue CYRAMZA for grade 3 or 4 IRRs. Gastrointestinal Perforations • CYRAMZA is an antiangiogenic therapy that can increase the risk of gastrointestinal perforation, a potentially fatal event. Four of 570 patients (0.7%) who received CYRAMZA as a single agent in clinical trials experienced gastrointestinal perforation. In study 2, the incidence of gastrointestinal perforations was also increased in patients who received CYRAMZA plus paclitaxel (1.2%) as compared to patients who received placebo plus paclitaxel (0.3%). Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.

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

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

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

Proteinuria Including Nephrotic Syndrome • Monitor proteinuria by urine dipstick and/or urinary protein creatinine ratio for the development of worsening of proteinuria during CYRAMZA therapy.

Withhold CYRAMZA for urine protein levels that are ≥2 g over 24 hours.

Reinitiate CYRAMZA at a reduced dose once the urine protein level returns to <2 g over 24 hours. Permanently discontinue CYRAMZA for urine protein levels >3 g over 24 hours or in the setting of nephrotic syndrome.

VISIT WWW.CYRAMZAHCP.COM FOR MORE INFORMATION, INCLUDING CYRAMZA MONOTHERAPY TRIAL DATA Thyroid Dysfunction • Monitor thyroid function during treatment with CYRAMZA. Embryofetal Toxicity • Based on its mechanism of action, CYRAMZA can cause fetal harm when administered to pregnant women. Animal models link angiogenesis, VEGF, and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with CYRAMZA and for at least 3 months after the last dose of CYRAMZA.

Most Common Adverse Reactions—Single Agent • The most commonly reported adverse reactions (all grades; grade 3/4) occurring in ≥5% of patients receiving CYRAMZA and ≥2% higher than placebo in study 1 were hypertension (16% vs 8%; 8% vs 3%), diarrhea (14% vs 9%; 1% vs 2%), headache (9% vs 3%; 0% vs 0%), and hyponatremia (6% vs 2%; 3% vs 1%).

• The most common serious adverse events with CYRAMZA in study 1 were anemia (3.8%) and intestinal obstruction (2.1%). Red blood cell transfusions were given to 11% of CYRAMZA-treated patients vs 8.7% of patients who received placebo.

• Clinically relevant adverse reactions reported in ≥1% and <5% of CYRAMZA-treated patients in study 1 were: neutropenia (4.7% vs 0.9%), epistaxis (4.7% vs 0.9%), rash (4.2% vs 1.7%), intestinal obstruction (2.1% vs 0%), and arterial thromboembolic events (1.7% vs 0%).

• Across clinical trials of CYRAMZA administered as a single agent, clinically relevant adverse reactions (including grade ≥3) reported in 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 JOB#: 30455-2

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

Use in Specific Populations • Pregnancy: Based on its mechanism of action, CYRAMZA can cause fetal harm. Animal models link angiogenesis, VEGF, and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no available data on CYRAMZA use in pregnant women to inform any drug-associated risks.

No animal studies have been conducted to evaluate the effect of ramucirumab on reproduction and fetal development. Advise females of reproductive potential of the potential risk for maintaining pregnancy, risk to the fetus, and risk to newborn and infant development, and to use effective contraception during CYRAMZA therapy and for at least 3 months following the last dose of CYRAMZA. • Lactation: Because of the potential risk for serious adverse reactions in nursing infants from ramucirumab, advise women that breastfeeding is not recommended during treatment with CYRAMZA. • Females of Reproductive Potential: Advise females of reproductive potential that based on animal data CYRAMZA may impair fertility.

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

RB-G HCP ISI 17SEP2015 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.

PP-RB-US-0347

10/2015 PRINTED IN USA

ARTIST: MC COLLECT DATE:

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

AD

M03 CP M

ACD

© Lilly USA, LLC 2015. All rights reserved.

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

FINISH SIZE: 17” wide x 11” high “A size”

LOCATION: Mechanicals

ED

• 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).

AE

inserv

B:11.5 in LT:11 in ST:10.75 in 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.

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

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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

11

1

5

1

17

1

6

0

31

0

7

0

25

15

6

3

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

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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.

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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

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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.

Eli Lilly and Company, Indianapolis, IN 46285, USA Copyright © 2015, Eli Lilly and Company. All rights reserved.

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

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A7 LATEST NEWS

A31

Headlines in Oncology Research and Practice

ADT Not Linked With Greater Risk of Cardiac Death in Patients With Prostate Cancer

A9 IN THE PIPELINE

JIM DALEY

The Latest on Oncology Drugs

A10

FEATURED PRODUCTS The Latest on Oncology Drugs

A32 REGIMEN & MONOGRAPH INDEX 1-106 CANCER THERAPY REGIMENS & DRUG MONOGRAPHS Highlighted topics () contain both treatment regimens and drug monographs.

A16 CME ACTIVITY MediBrief: Post-ASCO 2015 QualityFocused Suggested Options for PracticeSM for Neoadjuvant HER2+ Breast Cancer in the Community Setting

A26

VIEWPOINT

FEATURE The First Basket Study Delivers on Promise of Precision Medicine for Underrepresented Patients DEBRA HUGHES

1 Bone Cancer

 3 Brain Cancer

 14 Breast Cancer

 25 Endocrine Cancer

 31 Gastrointestinal Cancer

47 Genitourinary Cancer

 55 Gynecologic Cancer

59 Head and Neck Cancer 60 Hematologic Cancer

A28 VIEWPOINT Will Lower Dose Regorafenib Be Safer for Patients With Colorectal Cancer?

JASON HOFFMAN, PharmD, RPh

78 Lung Cancer 84 Sarcoma 85 Skin Cancer 89 Associated Hematological Disorders

A30 IN THE CLINIC Diagnosing Upper Gastrointestinal Bleeding Secondary to Malignancy C. ANDREW KISTLER, MD, PharmD, RPh

108 ALPHABETICAL INDEX 114 MANUFACTURERS INDEX

Cancer Therapy Advisor (ISSN 2375-558X), November/December 2015, Volume 2, Number 2. 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.

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EDITORIAL & BUSINESS STAFF

EDITORIAL ADVISORY BOARD

Managing Editor, Haymarket Oncology

Barbara Ann Burtness, MD

Lauren Burke

Senior Manager, Drug Information Anissa Lee, RPh

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Yale Cancer Center  New Haven, CT

Steven J. Cohen, MD Fox Chase Cancer Center  Philadelphia, PA

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Production Manager

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Fox Chase Cancer Center  Philadelphia, PA

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A6 CANCER THERAPY ADVISOR | NOVEMBER/DECEMBER 2015 | CancerTherapyAdvisor.com

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LATEST NEWS

In a recent study published in the Journal of the National Cancer Institute researchers evaluated whether capecitabine could be substituted for continuous infusion fluorouracil (5-FU) for the treatment of patients with stage 2 or 3 rectal cancer with curative intent during neoadjuvant radiotherapy.

The phase 3 trial enrolled 1,608 patients with clinical stage 2 or 3 rectal cancer undergoing preoperative radiotherapy.

Participants were randomly assigned to receive continuous infusion 5-FU or capecitabine with or without oxaliplatin.

Results showed no statistically significant differences in 5-year disease-free survival, 3-year local-regional tumor event rates, or 5-year overall survival between regimens comparing 5-FU with capecitabine. Researchers also found no statistically significant differences between regimens with oxaliplatin and those without oxaliplatin. Oxaliplatin was significantly associated with increased overall and grade 3 to 4 diarrhea.

The findings suggest that oxaliplatin does not improve efficacy and increases toxicity in this patient population, and capecitabine combined with radiotherapy produces similar outcomes to those achieved with continuous infusion 5-FU.

Eltrombopag up to 300 mg Safe for Thombocytopenia in MDS, Acute Leukemia Eltrombopag at doses up to 300 mg daily had an acceptable safety profile for the treatment of thrombocytopenia in patients with advanced myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML), a recent study published in the journal The Lancet Hematology has shown.

For the international, placebo-controlled, double-blind, phase 1/2 trial, researchers enrolled 98 patients who had relapsed or refractory disease or were ineligible for standard therapy, had platelet counts <30 Ă&#x2014; 109 platelets/L, had 10% to 50% bone marrow blasts, or were dependent on platelet transfusions.

Participants were randomly assigned to receive eltrombopag once daily at a dose ranging from 50 mg to 300 mg or placebo.

Results showed that 98% of patients in the eltrombopag group experienced adverse events compared with 94% in the placebo group.

The most common adverse events in the eltrombopag treatment arm were pyrexia, nausea, diarrhea, fatigue, decreased appetite, and pneumonia. Grade 3 or higher drug-related adverse events were higher in the placebo group and grade 3 or higher hemorrhage occurred in 26% of patients who received placebo compared with 16% given eltrombopag.

Accelerated Partial Breast Not Inferior to Whole-breast Irradiation Following Surgery Accelerated partial breast irradiation (APBI) using sole interstitial multicatheter brachytherapy in patients with early breast cancer was not inferior to adjuvant whole-breast irradiation, according to results of a phase 3 randomized non-inferiority trial reported in The Lancet.

Investigators looked at 5-year local control, disease-free survival, and overall survival to compare APBI with whole-breast irradiation in patients with stage 0, 1, and 2a breast cancer who had undergone breast-conserving surgery.

Between April 2004 and July 2009, a total of 1,184 patients in seven European countries were randomly assigned to receive either APBI (633 patients) or whole-breast irradiation (551 patients). A follow-up 5 years later showed that 9 patients treated with APBI and 5 patients treated with whole-breast irradiation had a local recurrence. The cumulative recurrence rate was 1.44% (95% CI, 0.51-2.38) with APBI and 0.92% with whole-breast irradiation (95% CI, 0.12-1.73)

Survival Benefit Associated With Chemoradiotherapy in Older Patients Chemoradiotherapy (CRT) may provide additional overall survival (OS) benefit in older patients with limited-stage small-cell lung cancer, in comparison to chemotherapy (CT) alone, according an article published in the Journal of Clinical Oncology.

Investigators identified 8,637 patients from the National Cancer Data Base who were 70 years or older, diagnosed with limited-stage small-cell lung cancer, and treated with CT (3,775; 43.7%) or CRT (4,862; 56.3%) from 2003 to 2011. The likelihood of receiving CRT decreased with increasing age, stage 3 disease, female sex, and comorbidities (all P < .01).

Š THINKSTOCK

Capecitabine Established as Standard of Care in Pre-Op Rectal Cancer Setting

CancerTherapyAdvisor.com | NOVEMBER/DECEMBER 2015 | CANCER THERAPY ADVISOR A7

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LATEST NEWS

In RCC, Second-line Therapy May Improve Overall Survival Patients with renal cell carcinoma (RCC) who receive second-line therapy may have longer overall survival, according to treatment patterns in the United Kingdom published in Annals of Oncology.

Researchers studied data from 514 UK adults with RCC as part of the RECCORD registry, a real-world UK database that anonymously assessed for demographics, treatments, and outcomes across cancer centers in England, Scotland, and Wales.

Patients were included if they were treated for metastatic RCC with systemic anticancer treatment from March 2009 to November 2012, and were measured for overall survival, time to disease progression, and toxicity.

Most patients received first-line treatment with sunitinib, while first-line use of pazopanib increased as the study progressed. Median overall survival was found to be 23.9 months, which was similar to that reported for clinical trials of targeted RCC therapies.

The researchers found that 15.8% of patients received second-line treatment, half of whom were given everolimus.

Overall survival was found to be significantly longer for those who received second-line treatment after disease progression compared to those who did not.

TKIs Result in Excellent Clinical Outcomes in Chronic Phase CML In the era of tyrosine kinase inhibitors (TKIs), patients with chronic myeloid leukemia in chronic phase (CML-CP) who survived for a certain number of years maintained excellent clinical outcomes, a study published in the journal Cancer has shown.

Researchers sought to estimate the probability of survival in patients who have already survived for 1 additional year after 12 months of TKI therapy. They analyzed cumulative response and survival data from 483 patients with a median follow-up of 99.4 months included in six frontline TKI clinical trials and calculated the conditional probability for failure-free survival, transformation-free survival, event-free survival, and overall survival according to patients’ responses within 1 year of TKI therapy initiation.

Results showed that conditional probabilities of failure-free survival, transformation-free survival, event-free survival, and overall survival for 1 additional year for patients alive after TKI treatment ranged from 92.0% to 99.1%, 98.5% to 100%, 96.2% to 99.6%, and 96.8% to 99.7%, respectively.

Researchers found that conditional probabilities of transformation-free survival, event-free survival, and overall survival for 1 additional year remained at greater than 95%, while conditional failure-free survival did not improve with a deeper response each year.

KRAS Status Does Not Seem to Affect Erlotinib Treatment Outcomes KRAS mutational status does not seem to influence the outcome of maintenance treatment with erlotinib in patients with metastatic colorectal cancer (mCRC), according to a study published in Annals of Oncology.

For the study, researchers enrolled 233 treatment-naïve patients (median age: 64 years) with mCRC. Patients received 18 weeks of induction chemotherapy with XELOX/FOLFOX or XELIRI/ FOLFIRI plus bevacizumab and the 138 without disease progression were then eligible for maintenance therapy.

KRAS wild-type patients were randomly assigned to receive bevacizumab with or without erlotinib, while KRAS mutated patients were randomly assigned to receive bevacizumab or metronomic capecitabine.

Results showed that median progression-free survival was not significantly different between KRAS wild type patients that received bevacizumab alone and those that received bevacizumab plus erlotinib (HR, 1.03; 95% CI, 0.70–1.50; P = .867).

In regard to safety, KRAS wild type patients, particularly those who also received erlotinib, experienced more frequent grade 3 and 4 toxicities during maintenance therapy.

© THINKSTOCK

In univariable and multivariable analyses, CRT administration increased survival (median OS, 15.6 vs 9.3 months; 3-year OS, 22.0% vs 6.3%; log-rank P < .001; Cox P < .001).

OS benefit with CRT was also observed in a matched cohort of 6,856 patients (hazard ratio, 0.52; 95% CI, 0.5-0.55; P < .001).

In a subset analysis with patients alive for 4 months after diagnosis, a survival advantage was displayed with concurrent CRT in comparison to sequential CRT (median OS, 17.0 vs 15.4 months; log-rank P=.01). The authors concluded that the survival benefit associated with CRT warrants its preference in older patients who are anticipated to tolerate toxicities.

A8 CANCER THERAPY ADVISOR | NOVEMBER/DECEMBER 2015 | CancerTherapyAdvisor.com

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IN THE PIPELINE New ALL Drug Granted Breakthrough Therapy Designation Pfizer announced that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy designation to the investigational antibody-drug conjugate (ADC) inotuzumab ozogamicin for the treatment of acute lymphoblastic leukemia (ALL).

The designation was based on the results of the phase 3 INO-VATE ALL trial, which compared inotuzumab ozogamicin to standard of care chemotherapy in 326 adult patients with relapsed or refractory CD22-positive ALL. Topline results from the trial were announced in April 2015 and also presented at the 20th Congress of the European Hematology Association (EHA).

Inotuzumab ozogamicin is an investigational antibody-drug conjugate (ADC) comprised of a monoclonal antibody (mAb) targeting CD22, a cell surface antigen expressed on approximately 90% of B-cell malignancies, linked to a cytotoxic agent.

For more information call (800) 438–1985 or visit Pfizer.com.

Abemaciclib Granted Breakthrough Tx for Advanced Breast Cancer Lilly announced that the U,S, Food and Drug Administration (FDA) has granted Breakthrough Therapy designation to abemaciclib for patients with refractory hormone receptor-positive (HR+) advanced or metastatic breast cancer.

The designation is based on data from the breast cancer cohort expansion of the phase 1 trial, JPBA, which studied the efficacy and safety of abemaciclib in women with advanced or metastatic

breast cancer who received a median of 7 prior systemic treatments Abemaciclib is currently being studied in a clinical development program that includes a phase 2 trial, MONARCH 1, to evaluate its use as monotherapy in women with HR+, human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer, and 2 phase 3 trials: MONARCH 2, to evaluate the combination of abemaciclib and fulvestrant in postmenopausal women with HR+, HER2- advanced or metastatic breast cancer, and MONARCH 3, to evaluate the combination of abemaciclib and a nonsteroidal aromatase inhibitor in patients with HR+, HER2locoregionally recurrent or metastatic breast cancer.

Abemacicl ib ( LY2835219) is a cyclin-dependent kinase (CDK) 4 and 6 inhibitor.

For more information call (800) 545-5979 or visit Lilly.com.

FDA Grants Avelumab Fast Track Status for Aggressive Skin Cancer Pfizer and Merck announced that the U.S. Food and Drug Administration (FDA) has granted avelumab Fast Track designation for the treatment of metastatic Merkel cell carcinoma (MCC), a rare and aggressive type of skin cancer.

The designation is based on data from the phase 2 multicenter study, JAVELIN Merkel 200, which assesses the safety and efficacy of avelumab in patients with metastatic MCC who have progressed after at least 1 prior chemotherapy regimen. The primary endpoint is objective response rate, and secondary endpoints include duration of response, progression-free survival, overall survival, and safety.

Avelumab (MSB0010718C) is an investigational fully human antiPD-L1 IgG1 monoclonal antibody. It was granted Orphan Drug designation by the FDA for the treatment of MCC on September 21, 2015.

For more information call (800) 438–1985 or visit Pfizer.com.

Guadecitabine Granted Orphan Drug Status for MDS or AML Astex Pharmaceuticals announced that the U.S. Food and Drug Administration (FDA) has granted Orphan Drug designation to guadecitabine (SGI-110) for the potential treatment of myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML).

Guadecitabine has been evaluated in multiple phase 1 and phase 2 trials, including the recently completed phase 1/2 study which investigated over 400 patients with MDS or AML in four different patient populations: treatment naïve and relapsed/refractory AML and MDS. The trial demonstrated that guadecitabine was clinically active and well tolerated in all 4 patient groups.

Currently, the ASTRAL-1 study, a large, global, randomized trial, is evaluating guadecitabine in 800 treatment-naïve A ML patients who are unsuitable for intensive induction chemotherapy. The trial compares guadecitabine with physician’s choice of low-dose cytarabine, decitabine, or azacitidine.

Guadecitabine is a novel next-generation, small molecule DNA hypomethylating agent formulated as a single, small volume, subcutaneous injection designed to deliver longer exposure to the active moiety, decitabine.

For more information visit Astx.com.

CancerTherapyAdvisor.com | NOVEMBER/DECEMBER 2015 | CANCER THERAPY ADVISOR A9

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FEATURED PRODUCT Pharmacology: Sonidegib inhibits the Hedgehog pathway by binding to and inhibiting Smoothened, a transmembrane protein involved in Hedgehog signal transduction.

Odomzo

Rx

Company: Novartis Pharmacologic class: Hedgehog pathway inhibitor Active ingredients: Sonidegib 200mg; caps.

Indication: Treatment of adults with locally advanced basal cell carcinoma (BCC) that has recurred following surgery or radiation therapy, or those who are not candidates for surgery or radiation therapy.

Iressa

Rx

Company: AstraZeneca Pharmacologic class: Tyrosine kinase inhibitor Active ingredients: Gefitinib 250mg; tablets.

Indications: First-line treatment of metastatic non-small cell lung cancer (NSCLC) with EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test. Limitations of use: not established in metastatic NSCLC with EGFR mutations other than exon 19 deletions or exon 21 substitution mutations.

Clinical trials: The safety and efficacy of Odomzo were evaluated in a single, multicenter, double-blind, multiple cohort trial conducted in patients with locally advanced basal cell carcinoma (laBCC) (n=194) or metastatic basal cell carcinoma (mBCC) (n=36). Patients were randomized (2:1) to receive either Odomzo 800mg or 200mg once daily until disease progression or intolerable toxicity. Randomization was stratified by stage of disease (locally advanced or metastatic), laBCC disease histology (aggressive vs. non-aggressive), and geographic region.

Pharmacology: Gefitinib exerts its action by reversibly inhibiting the kinase activity of wild-type and certain EGFR activating mutations (exon 19 deletion or exon 21 L858R substitution mutation), preventing autophosphorylation of the receptorâ&#x20AC;&#x2122;s tyrosine kinase residues, thereby inhibiting further downstream signalling and blocking EGFR-dependent proliferation.

Clinical trials: The efficacy and safety of Iressa were demonstrated in two multicenter, open-label clinical trials. Study 1 involved a total of 106 treatment-naive patients with metastatic EGFR mutation positive NSCLC, who received Iressa 250mg once daily until disease progression or intolerable toxicity. The major efficacy outcome measure was objective response rate (ORR) according to RECIST v1.1 as evaluated by both a

The major efficacy outcome measure of the trial was objective response rate (ORR) as determined by blinded central review according to modified Response Evaluation Criteria in Solid Tumors (mRECIST) for laBCC patients or RECIST version 1.1 for mBCC patients. Duration of response (DOR), determined by blinded central review, was a key secondary outcome measure.

A total of 66 patients with laBCC random ized to receive Odomzo 200mg daily were followed for at least 12 months unless discontinued earlier. At endpoint, the ORR was 58% (95% CI: 45, 70), consisting of 3 (5%) complete responses and 35 (53%) partial responses. Among the 38 patients with an objective response, 7 (18%) experienced subsequent disease

Blinded Independent Central Review (BICR) and investigators. Duration of response (DOR) was an additional outcome measure. The median duration of treatment was 8.0 months. Study 2 was conducted in 1217 patients with metastatic NSCLC adenocarcinoma histology receiving first-line treatment who were randomized (1:1) to receive Iressa 250mg once daily or up to 6 cycles of carboplatin/paclitaxel. Results of Study 1 were supported by an exploratory analysis of a subset of 186 patients from Study 2. The efficacy outcomes included progression-free survival (PFS) and ORR as assessed by BICR. The median duration of treatment for Iressa-treated patients was 9.8 months.

In Study 1, Iressa resulted in an ORR of 50% (95% CI: 41, 59) and median DOR of 6.0 months based on BICR assessment and in an ORR of 70% (95% CI: 61, 78)

A10 CANCER THERAPY ADVISOR | NOVEMBER/DECEMBER 2015 | CancerTherapyAdvisor.com

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FEATURED PRODUCT progression with 4 out of 7 patients having maintained a response of 6 months or longer. The remaining 31 patients (82%) have ongoing responses ranging from 1.9+ to 18.6+ months and the median duration of response has not been reached.

A total of 128 patients randomized to Odomzo 800mg daily had laBCC. Twelve of these patients had a diagnosis of Gorlin Syndrome. There was no evidence of better antitumor activity (ORR) among patients with laBCC randomized to receive Odomzo 800mg daily and followed for at least 12 months unless discontinued earlier.

For more clinical trial data, see full labeling.

For more information view the concise drug monograph on page 84.

and median DOR of 8.3 months based on investigator assessment. Response rates were similar in patients whose tumors had EGFR exon 19 deletions and exon 21 (L858R) substitution mutations.

In Study 2, the hazard ratio for PFS favored the Iressa-treated patients [HR of 0.54 (95% CI: 0.38, 0.79)] with a median PFS of 10.9 months for the Iressa-treated patients and 7.4 months for the carboplatin/paclitaxel-treated patients based on BICR assessment. In addition, the ORR was 67% (95% CI: 56, 77) and 41% (95% CI: 31, 51), respectively. The median duration of response was 9.6 months for Iressa-treated patients and 5.5 months for carboplatin/paclitaxel-treated patients.

For more clinical trial data, see full labeling.

For more information view the concise drug monograph on page 77.

Adcetris

Rx

Company: Seattle Genetics Pharmacologic class: CD30-directed antibody-drug conjugate Active ingredients: Brentuximab vedotin 50mg/vial; lyophilized powder for IV infusion after reconstitution; preservative-free.

Indication: Treatment of patients with classical Hodgkin lymphoma (HL) after failure of autologous hematopoietic stem cell transplant (auto-HSCT) or after failure of ≥2 prior multi-agent chemotherapy regimens in patients who are not autoHSCT candidates or are at high risk of relapse or progression as post-autoHSCT consolidation. Treatment of patients with systemic anaplastic large cell lymphoma (sALCL) after failure of ≥1 prior multi-agent chemotherapy regimen.

Pharmacology: The anticancer activity of Adcetris is due to the binding of the antibody-drug conjugate to CD30expressing cells, followed by internalization of the ADC-CD30 complex, and the release of monomethyl auristatin E (MMAE), a microtubule disrupting agent, via proteolytic cleavage.

Clinical trials: The efficacy of Adcetris in patients with classical HL who relapsed after autologous hematopoietic stem cell

transplantation (auto-HSCT) was evaluated in one open-label, single-arm, multicenter trial (Study 1, N=102). Patients were treated with Adcetris 1.8mg/kg IV over 30 minutes every 3 weeks. An independent review facility (IRF) performed efficacy evaluations which included overall response rate (ORR = complete remission [CR] + partial remission [PR]) and duration of response as defined by clinical and radiographic measures. Adcetris resulted in an ORR of 73% (32% CR, 40% PR), with median duration of response of 6.7 months (range 1.3–21.9+ months).

Study 2, an open-label, single-arm, multicenter trial evaluated the efficacy of Adcetris treatment in patients with relapsed sALCL (N=58). Patients were administered with Adcetris 1.8mg/ kg IV over 30 minutes every 3 weeks.

Efficacy evaluations included ORR (CR + PR) and duration of response. Adcetris treatment resulted in an ORR of 86% (57% CR, 29% PR), with a median duration of response of 12.6 months (range 0.1–15.9+ months).

Study 3 was a randomized, double-blind, placebo-controlled trial that evaluated the efficacy of Adcetris treatment in patients with classical HL at high risk of relapse or disease progression post-auto-HSCT (N=329). Patients were randomized 1:1 to receive placebo or Adcetris 1.8mg/kg IV over 30 minutes every 3 weeks for up to 16 cycles, beginning 30–45 days post-autoHSCT. The primary endpoint was progression-free survival (PFS) determined

by IRF with a median PFS follow-up time of 22 months (range, 0–49 months). The study demonstrated a statistically significant improvement in IRF-assessed PFS and increase in median PFS in the Adcetris arm vs. placebo arm.

For more clinical trial data, see full labeling.

For more information view the concise drug monograph on page 59.

CancerTherapyAdvisor.com | NOVEMBER/DECEMBER 2015 | CANCER THERAPY ADVISOR A11

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A first-in-class option recommended by the NCCN Clinical Practice Guidelines in Oncology for Breast Cancer*

Doubled mPFS with first-line IBRANCE + letrozole vs letrozole alone1 Compelling 10-month improvement in mPFS (HR=0.488; 95% CI: 0.319–0.748)1 100

HR=0.488 (95% CI: 0.319-0.748)

90

JOINING FORCES In PALOMA-1, first-line IBRANCE® (palbociclib) + letrozole doubled median progressionfree survival (mPFS) A RECOMMENDED National Comprehensive TREATMENT OPTION Cancer Network® (NCCN®) palbociclib (IBRANCE) + LETROZOLE FOR THE FIRST-LINE TREATMENT OF POSTMENOPAUSAL WOMEN WITH ER+/HER2- METASTATIC BREAST CANCER

PFS probability (%)

80

PALOMA-1 was a randomized 1:1, open-label, multicenter Phase II study designed to evaluate the efficacy and safety of IBRANCE 125 mg (once daily for 3 weeks on, 1 week off) in combination with letrozole 2.5 mg (once daily continuously) compared with letrozole alone in the first-line treatment of postmenopausal women with ER-positive, HER2-negative advanced breast cancer who had not received previous systemic treatment for their metastatic disease (N=165).1,2

20.2 months

70 60

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

50

10.2 months

40

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

30 20 10

HR=hazard ratio; CI=confidence interval.

0 0

4

8

12

16

84 81

67 48

24

28

32

36

40

21 6

13 3

8 3

5 1

1

Months

Number of patients at risk IBR+LET LET

20

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 (IBRANCE + letrozole n=65; letrozole alone n=66) 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.

To learn more about this NCCN®-recommended treatment option, visit IBRANCEimpact.com 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.

*Referenced with permission from NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines)®: Breast Cancer V.3.2015. © National Comprehensive Cancer Network, Inc. 2015. All rights reserved. To view the most recent and complete version of the guideline, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®. NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.

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. Lancet Oncol. 2015;16(1):25-35.

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.

A first-in-class option recommended by the NCCN Clinical Practice Guidelines in Oncology for Breast Cancer*

Doubled mPFS with first-line IBRANCE + letrozole vs letrozole alone1 Compelling 10-month improvement in mPFS (HR=0.488; 95% CI: 0.319–0.748)1 100

HR=0.488 (95% CI: 0.319-0.748)

90

JOINING FORCES In PALOMA-1, first-line IBRANCE® (palbociclib) + letrozole doubled median progressionfree survival (mPFS) A RECOMMENDED National Comprehensive TREATMENT OPTION Cancer Network® (NCCN®) palbociclib (IBRANCE) + LETROZOLE FOR THE FIRST-LINE TREATMENT OF POSTMENOPAUSAL WOMEN WITH ER+/HER2- METASTATIC BREAST CANCER

PFS probability (%)

80

PALOMA-1 was a randomized 1:1, open-label, multicenter Phase II study designed to evaluate the efficacy and safety of IBRANCE 125 mg (once daily for 3 weeks on, 1 week off) in combination with letrozole 2.5 mg (once daily continuously) compared with letrozole alone in the first-line treatment of postmenopausal women with ER-positive, HER2-negative advanced breast cancer who had not received previous systemic treatment for their metastatic disease (N=165).1,2

20.2 months

70 60

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

50

10.2 months

40

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

30 20 10

HR=hazard ratio; CI=confidence interval.

0 0

4

8

12

16

84 81

67 48

24

28

32

36

40

21 6

13 3

8 3

5 1

1

Months

Number of patients at risk IBR+LET LET

20

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 (IBRANCE + letrozole n=65; letrozole alone n=66) 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.

To learn more about this NCCN®-recommended treatment option, visit IBRANCEimpact.com 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.

*Referenced with permission from NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines)®: Breast Cancer V.3.2015. © National Comprehensive Cancer Network, Inc. 2015. All rights reserved. To view the most recent and complete version of the guideline, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®. NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.

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. Lancet Oncol. 2015;16(1):25-35.

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.

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

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

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

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

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

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

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

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

Brief Summary of Prescribing Information

Dose Modification and Management – Non-Hematologic Toxicities

IBRANCE® (palbociclib) capsules Initial US Approval: 2015

CTCAE Grade

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

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

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

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

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

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

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

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

Dose Modification and Managementa – Hematologic Toxicities CTCAE Grade

Dose Modifications

Grade 1 or 2

No dose adjustment is required.

Grade 3b

No dose adjustment is required.

Consider repeating complete blood count monitoring one week later.

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

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

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

Resume at next lower dose.

Grade 4b

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

Resume at next lower dose.

Grading according to CTCAE Version 4.0.

ANC=absolute neutrophil count; CTCAE=Common Terminology Criteria for Adverse Events. a M onitor 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 Except lymphopenia (unless associated with clinical events, e.g., opportunistic infections).

Dose Modifications

Grade 1 or 2

No dose adjustment is required.

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

Withhold until symptoms resolve to: • Grade ≤1; • Grade

≤2 (if not considered a safety risk for the patient) Resume at the next lower dose.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

• IBRANCE may interact with grapefruit. Patients should not consume grapefruit products while on treatment with IBRANCE. • Inform 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].

• 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.

• 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.

IBR767308-01

© 2015 Pfizer Inc.

All rights reserved.

October 2015

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

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

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

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

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

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

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

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

Brief Summary of Prescribing Information

Dose Modification and Management – Non-Hematologic Toxicities

IBRANCE® (palbociclib) capsules Initial US Approval: 2015

CTCAE Grade

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

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

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

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

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

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

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

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

Dose Modification and Managementa – Hematologic Toxicities CTCAE Grade

Dose Modifications

Grade 1 or 2

No dose adjustment is required.

Grade 3b

No dose adjustment is required.

Consider repeating complete blood count monitoring one week later.

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

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

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

Resume at next lower dose.

Grade 4b

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

Resume at next lower dose.

Grading according to CTCAE Version 4.0.

ANC=absolute neutrophil count; CTCAE=Common Terminology Criteria for Adverse Events. a M onitor 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 Except lymphopenia (unless associated with clinical events, e.g., opportunistic infections).

Dose Modifications

Grade 1 or 2

No dose adjustment is required.

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

Withhold until symptoms resolve to: • Grade ≤1; • Grade

≤2 (if not considered a safety risk for the patient) Resume at the next lower dose.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

• IBRANCE may interact with grapefruit. Patients should not consume grapefruit products while on treatment with IBRANCE. • Inform 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].

• 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.

• 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.

IBR767308-01

© 2015 Pfizer Inc.

All rights reserved.

October 2015

CME ACTIVITY

EDUCATIONAL OBJECTIVES: After completing this activity, the participant should be better able to: • Discuss the potential predictors of response to neoadjuvant HER2+ breast cancer • Identify populations who would benefit from neoadjuvant HER2+ breast cancer treatment, but may be missed due to unanticipated events • Explain how to improve the management of current and emerging neoadjuvant treatment related adverse events TO COMPLETE THE ACTIVITY, PRE-TEST, POST-TEST, EVALUATION FORM, AND CLAIM YOUR CERTIFICATE: Go to myCME.com/postasco

ACCREDITED PROVIDER This activity is provided by Global Education Group.

Chirag Bhagat, PharmD, has nothing to disclose.

COMMERCIAL SUPPORTER This activity is supported by an educational grant from Genentech.

Amanda Glazar, PhD, has nothing to disclose.

Release Date: November 1, 2015

ACCREDITATION STATEMENT Global Education Group is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

Expiration Date: November 1, 2016 INTENDED AUDIENCE For reasons that are greatly related to quality care and the changing healthcare environment, the primary target audience for this activity is not only the U.S.-based community oncologists and oncology surgeons, but also the U.S-based allied health professionals who treat patients with HER2+ breast cancer. While the activity will be ACCME-accredited only, it will also be appropriately designed, adult-learning wise, for the supportive care team such as the advanced practice nurse and oncology-specialized pharmacist who treat patients with HER2+ breast cancer, and may be unable to attend ASCO due to geographic or business restraints.

FEE AND REFUND/CANCELLATION POLICY There is no fee for this educational activity.

CONFLICT OF INTEREST DISCLOSURE POLICY Global Education Group (Global) requires instructors, planners, managers and other individuals and their spouse/life partner who are in a position to control the content of this activity to disclose any real or apparent conflict of interest they may have as related to the content of this activity. All identified conflicts of interest are thoroughly vetted by Global for fair balance, scientific objectivity of studies mentioned in the materials or used as the basis for content, and appropriateness of patient care recommendations.

ACCREDITED PROVIDER DISCLOSURE The planners and managers reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME activity:

Andrea Funk has nothing to disclose.

Ashley Marostica, RN, MSN, has nothing to disclose.

DESIGNATION STATEMENT Global Education Group designates this enduring activity for a maximum of 1.00 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

DISCLOSURE OF UNLABELED USE The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of any organization associated with this activity. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings. This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. Global Education Group (Global) does not recommend the use of any agent outside of the labeled indications.

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

For information about the accreditation of this program, please contact Global at 303-395-1782 or inquire@globaleducationgroup.com.

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CME ACTIVITY

Abstract Review MediBrief: Post-ASCO 2015 Quality-Focused Suggested Options for PracticeSM for Neoadjuvant HER2+ Breast Cancer in the Community Setting Abstract 505:

Cross-section of cancer cell in the breast overproducing HER2 genes, leading to an excessive number of HER2 receptors.

Studies in breast cancer have shown improved efficacy of pertuzumab, a novel anti-HER2 antibody, when combi ned w it h t he est abl ished HER2-directed antibody trastuzumab. Previously, investigators of the NeoSphere (Neoadjuvant Study of Pertuzumab and Trastuzumab in an Early Regimen Evaluation) trial evaluated the combination of pertuzumab or trastuzumab, or both, with docetaxel and the combination of pertuzumab and trastuzumab without chemotherapy in the neoadjuvant setting.1 In this analysis, investigators Gianni and colleagues present the findings from a five-year analysis of the NeoSphere trial evaluating four cycles of neoadjuvant docetaxel and/or trastuzumab and/or pertuzumab.2 NeoSphere is a multicentre, openlabel, phase 2 study of treatment-naive women with locally advanced, inflammatory, or early HER2-positive breast cancer. 417 women were randomly assigned (1:1:1:1) centrally and stratified by operable, locally advanced, and inflammatory breast cancer, and by hormone receptor expression to receive four neoadjuvant cycles of: trastuzumab

Š CAROL AND MIKE WERNER / SCIENCE SOURCE

Five-Year Analysis Of The Phase II Neosphere Trial Evaluating Four Cycles Of Neoadjuvant Docetaxel (D) And/Or Trastuzumab (T) And/Or Pertuzumab (P).

(8 mg/kg loading dose, followed by 6 mg/kg every 3 weeks) + docetaxel (75 mg/ m2, escalating, if tolerated, to 100 mg/m2 every 3 weeks; group A) or pertuzumab (loading dose 840 mg, followed by 420 mg every 3 weeks) and trastuzumab + docetaxel (group B) or pertuzumab and trastuzumab (group C) or pertuzumab + docetaxel (group D) (Figure 1).

In the main analysis1, the primary endpoint was comparison of pathologic complete response rate (pCR) in the breast (bpCR) and the secondary

endpoints included progression-free survival (PFS), disease-free survival (DFS), and safety profi le. The addition of pertuzumab to trastuzumab + docetaxel led to a statistically significant and clinically meaningful 16.8% increase [95% CI, 3.5â&#x20AC;&#x201C;30.1; P = .0141] in pathologic complete response rate (pCR) in the breast (bpCR, ypT0/is); and a 17.8% increase in total pCR in the breast and axilla (tpCR, ypT0/is, ypN0).

Furthermore, the primary analysis suggested that the results were much better

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CME ACTIVITY FIGURE 1. NeoSphere study design and objectives TD (n=107) trastuzumab (8 6 mg/kg) docetaxel (75 100 mg/m2

Chemo-naive & primary tumors >2 cm (N=417)

PTD (n=107) pertuzumab (840 420 mg) trastuzumab (8 6 mg/kg) docetaxel (75 100mg/m2) PT (n=107) pertuzumab (840 420 mg) trastuzumab (8 6 mg/kg)

Surgery

Patients with operable or locally advanced/ inflammatory HER2-positive BC

PD (n=96) pertuzumab (840 420 mg) docetaxel (75 100mg/m2)

• Primary endpoint: Comparison of bpCR rates TD vs PTD TD vs PT PTD vs PD • Secondary endpoints: PFS DFS Safety • Exploration analyses: PFS by hormone receptor status PFS-tpCR association

Study dosing: q3w × 4

FIGURE 2. NeoSphere study design: the adjuvant part of the trial FEC q3w ×3 trastuzumab q3w cycles 5-17

Surgery

FEC q3w ×3 trastuzumab q3w cycles 5-17 docetaxel q3w ×4 FEC q3w ×3 trastuzumab q3w cycles 5-17 FEC q3w ×3 trastuzumab q3w cycles 5-21

when the tumors were ER-negative rather than ER-positive.

After surgery in the adjuvant portion of the trial, all treatment groups received an identical chemotherapy backbone and identical adjuvant trastuzumab until the end of 1-year (Figure 2).

Five years after randomization of the last patient in the NeoSphere trial, a pre-planned descriptive intent-totreat (ITT) analysis was conducted to assess DFS and PFS. DFS was defi ned as the time from the date of surgery to the first documentation of progressive disease or death. PFS was defined as the time from randomization to the first documentation of progressive disease, disease recurrence, or death (equivalent to the commonly used defi nition of

event-free survival3). Cardiac function was followed up by visit and LVEF monitoring every 6 months for 2 years.

The patient characteristics were well balanced in all arms of the study (Table 1). In the ITT population, the median age was 50, 50, 49, and 49 for Group A, B, C, and D, respectively.

Also, there was almost an even split between tumors with hormone receptor (HR)-positive and negative status.

Considering the adjuvant portion, the safeties of the treatments in the trial were good. The safety was mostly influenced by the chemotherapy given, which was particularly clear in Group C (pertuzumab and trastuzumab) without chemotherapy in the neoadjuvant portion.

In the adjuvant portion, this is the arm

that received docetaxel (Figure 2) after surgery that resulted in higher incidence of neutropenia, granulocytopenia, and other toxicities that are associated with chemotherapy (Table 2). The cardiac safety after the surgery was very good with all LVDs and LVEF declines recovered except one asymptomatic LVD event, which developed during follow-up (pertuzumab and trastuzumab group) and was ongoing at final analysis.

Kaplan-Meier survival curves showed that Group B (pertuzumab + trastuzumab + docetaxel) obtained the highest 5-year PFS (Figure 3) and DFS (Figure 4) rates compared to all other groups.

5-year PFS was 86% (95% CI: 77-91) for pertuzumab + trastuzumab + docetaxel group compared to 81% (95% CI: 71-87), 73% (95% CI: 64-81), and 73% (95% CI: 63-81) for Group A (TD), C (PT), and D (PD), respectively (Figure 3).

5-year DFS was 84% (95% CI: 72-91) for pertuzumab + trastuzumab + docetaxel group compared to 81% (95% CI: 72-88), 80% (95% CI: 70-86), and 75% (95% CI: 64-83) for Group A (TD), C (PT), and D (PD), respectively (Figure 4).

Across all four-treatment arms pooled in the study, patients who achieved tpCR were more likely to be alive and disease-free at 5-years [PFS HR=0.54; 95% CI, 0.29–1.00 (Figure 5); DFS HR=0.68; 95% CI, 0.36–1.26].

The 5-year PFS for t pCR i n HR-negative tumors was 84% vs. 72% of patients that did not achieve tpCR in HR-negative tumors (HR 0.65; 95% CI: 0.32-1.30). Similarly, 5-year PFS for patients with HR-positive tumors favored those who achieved tpCR compared to those who did not (HR 0.66: 95% CI: 0.15-2.79).

In summary, the findings demonstrate the combination of neoadjuvant pertuzumab and trastuzumab + docetaxel improved long-term outcomes as defined by 5-year survival rates. These results are

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CME ACTIVITY consistent with the primary analysis of pCR suggesting a benefit of pertuzumab added to trastuzumab + docetaxel that persists over time regardless of use of identical adjuvant therapy in the pertuzumab + trastuzumab + docetaxel and trastuzumab + docetaxel arms. Also, improvement was observed to be greater for patients with HR-negative disease. Overall patients who achieved tpCR had a reduced risk of a PFS or DFS and no new or long-term safety concerns, and no additional cardiotoxicity was reported with the addition of pertuzumab to trastuzumab and docetaxel.

These findings further support the association between pCR and improvements in long-term outcomes, as well as an early indicator of benefit in future neoadjuvant studies of HER2-targeted agent.

Suggested Options for Practice

• Pooled analysis from all four-treatment arms in the NeoSphere study suggests that it is critical for patients to achieve tpCR since these patients are more likely to be alive and disease-free at 5-years.

• Moving forward, PFS and DFS are in line with the results of the primary endpoint of pCR and suggest a persisting benefit of neoadjuvant pertuzumab added to trastuzumab and docetaxel, despite the use of identical adjuvant treatment. Furthermore, there are no new long-term safety concerns for this treatment strategy.

Abstract 524: Adaptively Randomized Trial Of Neoadjuvant Chemotherapy With Or Without The Akt Inhibitor Mk-2206: Graduation Results From The I-Spy 2 Trial.

Pathological complete response (pCR) to neoadjuvant chemotherapy is a predictor of long-term outcome and may be utilized to test the potential benefit of novel targeted treatment strategies when added to standard chemotherapy.

Investigational agent MK-2206 is a selective allosteric inhibitor of Akt1, Akt2, and less so Akt3. MK-2206 does not bind to the active site of Akt, and consequently does not compete with either ATP or peptide substrate for binding to Akt. In this analysis, investigators Tripathy et al. report the efficacy results for neoadjuvant chemotherapy with or without the AKT inhibitor MK-2206 from the I-SPY 2 trial (Investigation of Serial Studies to

TABLE 1. Patient baseline characteristics: ITT population TD (n=107)

PTD (n=107)

PT (n=107)

PD (n=96)

50 (32-74)

50 (28-77)

49 (22-80)

49 (27-70)

94.3 5.7

89.7 10.3

86.0 14.0

83.3 16.7

Median age, years (range) ECOG PS, % 0 1 HR-positive (ER-and/or PR-positive), %

46.7

46.7

47.7

47.9

HR-negative (ER-and PR-negative), %

53.3

53.3

51.9

52.1

Operable, %

59.8

60.7

60.7

62.5

Locally advanced, %

33.6

29.9

32.7

32.3

Inflammatory, %

6.5

9.3

6.5

5.2

TABLE 2. Tolerability of neoadjuvant and adjuvant treatment: 10 common grade ≥3 AEs (safety population) Patients, n(%) Neutropenia and granulocytopenia

Neoadjuvant Adjuvant TD PTD PT PD TD PTD PT PD (n=107) (n=107) (n=108) (n=94) (n=103) (n=102) (n=94) (n=88) 62 (57.9) 49 (45.8)

1(0.9)

54 (57.4) 24 (23.3) 25 (24.5) 45 (47.9) 21 (23.9)

Febrile neutropenia

8 (7.5)

9 (8.4)

0

7 (7.4)

3 (2.9)

3 (2.9)

5 (5.3)

Diarrhea

4 (3.7)

6 (5.6)

0

4 (4.3)

0

1 (1.0)

3 (3.2)

1 (1.1)

Asthenia

0

2 (1.9)

0

2 (2.1)

1 (1.0)

0

3 (3.2)

1 (1.1)

2 (1.9)

2 (1.9)

0

1 (1.1)

-

-

-

-

0

1(0.9)

2 (1.9)

0

-

-

-

-

Rash Drug Hypersensitivity

The Akt serine/threonine-specific protein kinase plays a key role in growth factor receptor-initiated signaling and activates mTOR and downstream effectors (Figure 6).

Predict Your Therapeutic Response with Imaging and Molecular Analysis 2).5 I-SPY 2 is a randomized, neoadjuvant, Phase III study to test agents and combinations added to standard chemotherapy.

Women with invasive breast cancer ≥2.5 cm on exam or ≥2 cm on imaging were adaptively randomized to 12 weekly paclitaxel (and trastuzumab if HER2+) cycles (control) or in combination with one of several experimental agents followed by doxorubicin/cyclophosphamide (AC) x 4, with serial biomarkers (biopsies, blood draw and MRI scans) (Figure 7).

Patients are stratified to 8 subsets based on hormone-receptor (HR), HER2, and MammaPrint gene profiling score [hi-1

ALT increase

10 (11.4)

3 (2.8)

0

0

1 (1.1)

-

-

-

-

Vomiting

-

-

-

-

3 (2.9)

0

1 (1.1)

2 (2.3)

Nausea

-

-

-

-

2 (1.9)

1 (1.0)

1 (1.1)

0

Radiation skin injury

-

-

-

-

2 (1.9)

2 (2.0)

2 (2.1)

0

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CME ACTIVITY

PFS, %

FIGURE 3. PFS: All arms of therapy (ITT population) 100 90 80 70 60 50 40 30 20 10 0

5-year PFS, % (95% CI)

0

12

TD n=107

PTD n=107

PT n=107

PD n=96

81 (71-87)

86 (77-91)

73 (64-81)

73 (63-81)

24

36

48

TD PTD PT PD

60

Months

PFS, %

FIGURE 4. DFS: All arms of therapy (ITT population) 100 90 80 70 60 50 40 30 20 10 0

5-year DFS, % (95% CI)

0

12

TD n=107

PTD n=107

PT n=107

PD n=96

81 (72-88)

84 (72-91)

80 (70-86)

75 (64-83)

24

36

48

TD PTD PT PD

60

Months

PFS, %

FIGURE 5. PFS by tpCR: All treatment arms combined (ITT population) 100 90 80 70 60 50 40 30 20 10 0

tpCR No tpCR No tpCR n=323 5-year PFS, % (95% CI) HR (95% CI)

0

12

tpCR n=94

76 (71-81) 85 (76-81) 0.54 (0.29-1.00)

24

36

Months

48

60

vs. hi-2(MP+)], with combinations of subsets defining 10 agent signatures. In all 8 subsets, the efficacy of MK-2206 135 mg daily by mouth was evaluated. The primary endpoint was pCR (no residual invasive disease in breast or nodes) and evaluable patients received any taxane with or without investigational therapy.

Patients who progressed, changed to non-protocol therapy or left the treating institution were evaluable and counted as not having pCR. Patients who withdrew consent prior to surgery (without progression or change to non-protocol treatment) were considered non-evaluable for pCR. Adaptive assignment to the experimental arms was based on current Bayesian probabilities of superiority over control.

Graduation by signature is based on Bayesian predictive probability â&#x2030;Ľ85% for success in a 2-arm, N=300, Phase 3, randomized 1:1 trial with pCR endpoint. Futility stopping occurs when the probability of success is <10% in all 10 signatures.

A total of 153 women with invasive breast cancer were enrolled in the study.

Of the 153 patients, 94 (34 with trastuzumab) were randomized to MK-2206 and 59 (11 with trastuzumab) in the control arm. In the MK-2206 arm, 7 patients withdrew consent with no evidence of progression and were deemed non-evaluable. 2 patients received no therapy and were non-evaluable for toxicity or pCR in the control arm.

MK-2206 graduated in the first 3 signatures (HR-/HER2+, HR-, and HER2+; Table 3). Accrual ended with 93 patients assigned to that arm and when 56 patients had been concurrently randomized to control. Final posterior and predictive probabilities are shown for all 10 signatures (Table 3).

The Bayesian pCR probability distributions are shown below (Figure 8) for the highlighted 3 signatures (HR-/ HER2+, HR-, HER2+) from Table 3.

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DRUG MONOGRAPHS

BONE CANCER Methotrexate injection

℞

Bedford

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

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

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

Children: See literature.

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

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

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

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

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

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

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

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

VOTRIENT GlaxoSmithKline

℞

Tyrosine kinase inhibitor. Pazopanib 200mg; tabs.

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

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

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

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

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

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

Monitor for VTE, PE, infection, proteinuria (reduce dose if 24-hour urine protein ≥3g), thrombotic microangiopathy, GI perforation or fistula.

Monitor BP and manage hypertension promptly.

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

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

Antagonized by strong CYP3A4 inducers.

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

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

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

How supplied: Tabs—120

XGEVA Amgen

℞

Osteoclast inhibitor (RANKL inhibitor).

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

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

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

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

Contraindications: Pre-existing hypocalcemia.

Warnings/Precautions: Correct hypocalcemia before starting; ensure adequate daily calcium, magnesium, and Vit.D intake, esp. in renal impairment (CrCl <30mL/min). Monitor calcium (esp. 1st weeks of initiating), phosphorus,

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DRUG MONOGRAPHS

BONE CANCER magnesium levels and Vit.D intake in susceptible patients (eg, severe renal impairment, receiving dialysis). Risk of osteonecrosis of the jaw in diabetes, gingival infections. Perform oral exam and preventive dentistry before and regularly during therapy. Maintain good oral hygiene. Avoid invasive dental procedures during treatment; consider temporary discontinuation if procedure is necessary. Evaluate for atypical fractures if thigh/groin pain develops; consider withholding

therapy until risk/benefit assessment. Pregnancy (Cat.D); use highly effective contraception during therapy, and for at least 5 months after last dose.

Nursing mothers: not recommended (may impair mammary gland development/lactation).

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

systemic corticosteroids; increased risk of osteonecrosis of the jaw.

Adverse reactions: Fatigue, asthenia, hypophosphatemia, nausea, arthralgia, headache, back pain, pain in extremity, dyspnea, decreased appetite, peripheral edema, vomiting, anemia, constipation, diarrhea; osteonecrosis of the jaw, hypocalcemia (may be fatal), 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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CANCER TREATMENT REGIMEN

BRAIN CANCER Brain 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.

Systemic Therapy for Adult Low-Grade Infiltrative Supratentorial Astrocytoma/Oligodendroglioma1 Note: All recommendations are Category 2A unless otherwise indicated.

REGIMEN

DOSING

Adjuvant Treatment Combination PCV (lomustine + procarbazine + vincristine) (Category 1)2

Day 1: Lomustine 110mg/m2 orally.

Days 8–21: Procarbazine 60mg/m2 orally once daily.

Days 8 and 29: Vincristine 1.4mg/m2 (maximum 2mg) IV. Repeat every 6 weeks.

Temozolomide3–5

Days 1–49: Temozolomide 75mg/m2 orally.

Repeat cycle every 11 weeks (7 weeks on/4 weeks off) for 6 cycles.

OR For children/adolescents: Temozolomide monthly 5-day courses at doses of 200mg/m2/day (patients with no prior craniospinal irradiation [CSI]) or 180mg/m2/day (prior CSI).

OR Days 1–21: Temozolomide 75mg/m2/day.

Repeat cycle every 28 days.

Recurrent or Progressive, Low Grade Disease Temozolomide3,6*

Days 1–49: Temozolomide 75mg/m2 orally.

Repeat cycle every 11 weeks (7 weeks on/4 weeks off) for 6 cycles.

OR Days 1–5: Temozolomide 150mg/m2 to 200mg/m2; when patients progress during conventional temozolomide treatment, change temozolomide to a 50mg/m2 daily regimen.

Repeat cycle every 28 days.

Combination PCV regimens (lomustine + procarbazine + vincristine)7

Day 1: Lomustine 110mg/m2 orally.

Days 8–21: Procarbazine 60mg/m2 orally once daily.

Days 8 and 29: Vincristine 1.4mg/m2 (maximum 2mg) IV. Repeat every 6 weeks.

Platinum-based regimen: Carboplatin8

Day 1: Carboplatin 350mg/m2.

Days 1–3: Teniposide 50mg/m2.

Repeat cycle every 4 weeks.

Platinum-based regimen: Carboplatin9

Carboplatin 560mg/m2 IV at 4-week intervals; continued until disease progression, unacceptable toxicity, or for 12 additional courses after achieving maximal response.

Platinum-based regimen: Cisplatin10

Days 1–3: Cisplatin 25mg/m2/day IV + etoposide 100mg/m2/day IV. Repeat cycle every 4 weeks for first 3 cycles, then repeat every 5 weeks for next 3 cycles, then repeat every 6 weeks for the last 3 cycles; total 10 cycles over approximately 10–11 months (total dose 750mg/m2 cisplatin and 3,000mg/m2 etoposide).

Lomustine11

Lomustine 130mg/m2 orally every 6 weeks.

Carmustine12

Carmustine 150–200mg/m2 IV as a single dose or divided over 2 days given every 6 weeks OR 75–100mg/m2/day IV for 2 days every 6 weeks. continued

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BRAIN CANCER Brain Cancer Treatment Regimens Systemic Therapy for Anaplastic Gliomas1 REGIMEN

DOSING

Adjuvant Treatment Temozolomide13,14

Day 1-5: Temozolomide 200mg/m2/day orally.

Repeat cycle every 4 weeks until disease progression or for up to 24 cycles.

PCV with deferred RT13

Day 1: Lomustine 110mg/m2 orally.

Days 8–21: Procarbazine 60mg/m2 orally once daily.

Days 8 and 29: Vincristine 1.4mg/m2 (maximum 2mg) IV. Repeat every 6 weeks.

Concurrent temozolomide (with RT)15

2 Gy given 5 days/week for 6 weeks plus continuous daily oral temozolomide (75mg/m2/day, 7 days per week from the first to the last day of radiotherapy), followed by 6 cycles of adjuvant temozolomide 150–200mg/m2/day for 5 days.

Repeat cycle every 28 days.

Temozolomide4,6,16

Temozolomide 50mg/m2 daily for up to 1 year or until disease progression.

OR For children/adolescents: Temozolomide monthly 5-day courses at doses of 200mg/m2/day (patients with no prior CSI) or 180mg/m2/day (prior CSI).

OR Days 1–5: Temozolomide 150mg/m2 to 200mg/m2 5 days of each 28-day cycle; when patients progress during conventional temozolomide treatment, change temozolomide to a 50mg/m2 daily regimen.

OR Days 1–5: Temozolomide 150mg/m2 to 200mg/m2.

Repeat cycle every 28 days.

Lomustine or carmustine11,12,17

Day 1: Lomustine 100–130mg/m2/day orally.

Repeat cycle every 6 weeks.

OR Carmustine 150–200mg/m2 IV as a single dose or divided over 2 days given every 6 weeks OR 75–100mg/m2/day IV for 2 days every 6 weeks.

Combination PCV regimens (lomustine + procarbazine + vincristine)7

Day 1: Lomustine 110mg/m2 orally.

Days 8–21: Procarbazine 60mg/m2 orally once daily.

Days 8 and 29: Vincristine 1.4mg/m2 (maximum 2mg) IV. Repeat every 6 weeks.

Bevacizumab18–20†

Day 1: Bevacizumab 10mg/kg IV. Repeat cycle every 14 days.

Bevacizumab + irinotecan21,22‡

Day 1: Bevacizumab 10mg/kg IV plus irinotecan 125mg/m2.

Repeat cycle every 2 weeks.

OR Bevacizumab 10mg/mg2 IV plus irinotecan 340mg/m2 IV in patients receiving enzyme-inducing antiepileptic drugs (EIAED).

Repeat cycle every 14 days.

Bevacizumab + nitrosurea23

Days 1 and 15: Bevacizumab 10mg/kg IV. Days 1 and 8: Fotemustine 75mg/m2 IV. Followed after a 3-week interval by a maintenance phase of bevacizumab 10mg/kg IV plus fotemustine 75mg/m2 IV. Repeat cycle every 3 weeks.

Bevacizumab + carboplatin (Category 2B)24,25

Day 1: Bevacizumab 10mg/kg IV plus carboplatin AUC 4–6mg •min/mL, depending on the patient’s prior treatment history and bone marrow reserves; cycle 2 doses of carboplatin (every 28 days) and 3 doses of bevacizumab (every 14 days) and lasted 6 weeks.

Irinotecan26,27

Day 1: Irinotecan 350mg/m2 IV to patients on non-enzyme-inducing antiepileptic drugs (NEIAED) or 600mg/m2 to patients on EIAED. Repeat cycle every 21 days.

OR Day 1: Irinotecan 350mg/m2 IV. Repeat cycle every 21 days.

Platinum-based regimen: Carboplatin8

Day 1: Carboplatin 350mg/m2.

Days 1–3: Teniposide 50mg/m2.

Repeat cycle every 4 weeks.

Platinum-based regimen: Carboplatin9

Carboplatin 560mg/m2 IV at 4-week intervals; continued until disease progression, unacceptable toxicity, or for 12 additional courses after achieving maximal response.

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BRAIN CANCER Systemic Therapy for Anaplastic Gliomas1 (continued) REGIMEN

DOSING

Adjuvant Treatment (continued) Platinum-based regimen: Cisplatin10

Days 1–3: Cisplatin 25mg/m2/day IV + etoposide 100mg/m2/day IV. Repeat cycle every 4 weeks for first 3 cycles, then repeat every 5 weeks for next 3 cycles, then repeat every 6 weeks for the last 3 cycles; total 10 cycles over approximately 10–11 months (total dose 750mg/m2 cisplatin and 3,000mg/m2 etoposide).

Cyclophosphamide (Category 2B)28,29

Days 1–2: Cyclophosphamide 750mg/m2 IV. Repeat cycle every 28 days.

Etoposide30

Etoposide 50mg/day given until the neutrophil count dropped to < 1.0 × 109/L or the platelets fell to < 75 × 109/L and resumed when the counts rose to normal levels.

Systemic Therapy for Anaplastic Oligoastrocytoma1 Adjuvant Treatment Radiotherapy + PCV for 1p19q co-deleted (category 1)31

59.6 4 Gy of RT, followed by 6 cycles of standard PCV: Day 1: Lomustine 110mg/m2 orally.

Days 8–21: Procarbazine 60mg/m2 orally once daily.

Days 8 and 29: Vincristine 1.4mg/m2 (maximum 2mg) IV. Repeat every 6 weeks.

Systemic Therapy for Glioblastoma1 Adjuvant Treatment Concurrent temozolomide (with RT)15

2 Gy given 5 days/week for 6 weeks plus continuous daily oral temozolomide (75mg/m2/day, 7 days per week from the first to the last day of radiotherapy), followed by 6 cycles of adjuvant temozolomide 150–200mg/m2/day for 5 days.

Repeat cycle every 28 days.

Post-RT temozolomide32

Days 1–5: Temozolomide 150–200mg/m2/day orally for 5 days.

Repeat cycle every 28 days.

Temozolomide + standard RT33

Days 1–5: Temozolomide 200mg/m2, orally plus: Standard RT: 60.0 Gy administered in 2.0 Gy fractions over 6 weeks.

Recurrence Therapy Bevacizumab34–36†

Day 1: Bevacizumab 10mg/kg IV. Repeat cycle every 14 days.

Bevacizumab + irinotecan22,34–36‡

Day 1: Bevacizumab 10mg/kg IV. Repeat cycle every 14 days.

After tumor progression, immediately treat with bevacizumab 10mg/kg IV plus irinotecan 340mg/m2 or 125mg/m2 IV every 14 days, depending on use of EIAEDs.

Bevacizumab + nitrosurea23‡

Days 1 and 15: Bevacizumab 10mg/kg IV Days 1 and 8: Fotemustine 75mg/m2 IV Followed after a 3-week interval by a maintenance phase of bevacizumab 10mg/kg IV plus fotemustine 75mg/m2 IV. Repeat cycle every 3 weeks.

Bevacizumab + carboplatin (Category 2B)24,25‡

Day 1: Bevacizumab 10mg/kg IV plus carboplatin AUC 4–6mg • min/mL, depending on the patient’s prior treatment history and bone marrow reserves; cycle 2 doses of carboplatin (every 28 days) and 3 doses of bevacizumab (every 14 days) for 6 weeks.

Temozolomide6,32,37

Days 1–5: Temozolomide 150mg/m2 to 200mg/m2; when patients progress during conventional temozolomide treatment, change temozolomide to a 50mg/m2 daily regimen.

Repeat cycle every 28 days.

OR 2 Gy given 5 days/week for 6 weeks plus continuous daily oral temozolomide (75mg/m2/day, 7 days per week from the first to the last day of radiotherapy), followed by 6 cycles of adjuvant temozolomide 150–200mg/m2/day for 5 days.

Repeat cycle every 28 days.

OR Chemotherapy-naive patients: Days 1–5: Temozolomide 200mg/m2/day.

Chemotherapy-experienced patients: Days 1–5: Temozolomide 150mg/m2/day, increasing to 200mg/m2/day in the absence of grade 3/4 toxicity.

Repeat cycle every 28 days. continued

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BRAIN CANCER Brain Cancer Treatment Regimens Systemic Therapy for Glioblastoma1 (continued) REGIMEN

DOSING

Recurrence Therapy (continued) Lomustine or carmustine11,12,17

Day 1: Lomustine 100–130mg/m2/day orally.

Repeat cycle every 6 weeks.

OR Carmustine 150–200mg/m2 IV as a single dose or divided over 2 days given every 6 weeks OR 75–100mg/m2/day IV for 2 days every 6 weeks.

Combination PCV regimens (lomustine + procarbazine + vincristine)7

Day 1: Lomustine 110mg/m2 orally Days 8–21: Procarbazine 60mg/m2 orally once daily Days 8 and 29: Vincristine 1.4mg/m2 (maximum 2mg) IV. Repeat every 6 weeks.

Cyclophosphamide (category 2B)28

Days 1–2: Cyclophosphamide 750mg/m2 IV. Repeat cycle every 28 days.

Platinum-based regimen: Carboplatin8

Day 1: Carboplatin 350mg/m2 Days 1–3: Teniposide 50mg/m2.

Repeat cycle every 4 weeks.

Platinum-based regimen: Carboplatin9

Carboplatin 560mg/m2 IV at 4-week intervals; continued until disease progression, unacceptable toxicity, or for 12 additional courses after achieving maximal response.

Platinum-based regimen: Cisplatin10

Days 1–3: Cisplatin 25mg/m2/day IV + etoposide 100mg/m2/day IV. Repeat cycle every 4 weeks for first 3 cycles, then repeat every 5 weeks for next 3 cycles, then repeat every 6 weeks for the last 3 cycles; total 10 cycles over approximately 10–11 months (total dose 750mg/m2 cisplatin and 3,000mg/m2 etoposide).

Systemic Therapy for Intracranial and Spinal Ependymoma (Excluding Supependymoma)1 Recurrence Therapy Platinum-based regimen: Carboplatin8

Day 1: Carboplatin 350mg/m2 Days 1–3: Teniposide 50mg/m2.

Repeat cycle every 4 weeks.

Platinum-based regimen: Carboplatin9

Carboplatin 560mg/m2 IV at 4-week intervals; continued until disease progression, unacceptable toxicity, or for 12 additional courses after achieving maximal response.

Platinum-based regimen: Cisplatin10

Days 1–3: Cisplatin 25mg/m2/day IV + etoposide 100mg/m2/day IV. Repeat cycle every 4 weeks for first 3 cycles, then repeat every 5 weeks for next 3 cycles, then repeat every 6 weeks for the last 3 cycles; total 10 cycles over approximately 10–11 months (total dose 750mg/m2 cisplatin and 3,000mg/m2 etoposide).

Etoposide30

Etoposide 50mg/day given until the neutrophil count dropped to <1.0 × 109/L or the platelets fell to <75 × 109/L and resumed when the counts rose to normal levels.

Bevacizumab34–37†

Day 1: Bevacizumab 10mg/kg IV. Repeat cycle every 14 days.

Temozolomide3–5

Days 1–49: Temozolomide 75mg/m2 orally.

Repeat cycle every 11 weeks (7 weeks on/4 weeks off) for 6 cycles.

OR Days 1–21: Temozolomide 75mg/m2/day.

Repeat cycle every 28 days.

Systemic Therapy for Adult Medulloblastoma and Supratentorial Primitive Neuroectodermal Tumor (PNET)1 Adjuvant Treatment Weekly vincristine during craniospinal radiation therapy followed by either of the following regimens. Note that omission of vincristine during radiation therapy phase of therapy or dose modification may be required for adults because they do not tolerate this regimen as well. Data supporting the use of vincristine has been found in pediatric trials only. Patients should be closely monitored for neurologic toxicity with periodic exams.

Vincristine + cisplatin + lomustine38

During craniospinal radiotherapy (RT): Day 1: Lomustine 75mg/m2 orally.

Day 2: Cisplatin 75mg/m2 IV. Days 2, 8 and 15: Vincristine 1.5mg/m2 IV bolus, max 2mg bolus; up to max 8 doses.

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BRAIN CANCER Systemic Therapy for Adult Medulloblastoma and Supratentorial Primitive Neuroectodermal Tumor (PNET)1 (continued) REGIMEN

DOSING

Adjuvant Treatment (continued) Vincristine + cisplatin + cyclophosphamide39

Day 1: Cisplatin 75mg/m2 IV. Days 2, 8 and 15: Vincristine 1.5mg/m2 IV bolus, max 2mg bolus.

Days 22, 23: Cyclophosphamide 1,000mg/m2 IV.

Recurrence Therapy No prior chemotherapy: Consider high-dose chemotherapy with autologous stem cell reinfusion in patients who achieve a complete remission with conventional doses of salvage chemotherapy or have no residual disease after re-resection.35 Carboplatin + thiotepa + etoposide39

Days −8 to −6: Carboplatin AUC 7mg • min/mL IV, maximum 500mg/m2/day).

Days −5 to −3: Thiotepa 300mg/m2/day IV plus etoposide 250mg/m2/day I. Day 0: Autologous stem cell rescue (ASCR).

Prior chemotherapy: Consider high-dose chemotherapy with autologous stem cell reinfusion in patients who achieve a complete remission with conventional doses of salvage chemotherapy or have no residual disease after re-resection.35 Temozolomide3

Temozolomide 75mg/m2 orally in 11-week cycles of 7 weeks on followed by 4 weeks off.

Oral etoposide40,41

Days 1–21: Etoposide 50mg daily.

Repeat cycle every 4 weeks.

Primary CNS Lymphoma1 Primary Treatment High dose methotrexate + chemotherapy42–44

High dose methotrexate combined with the following plus radiation therapy: Weeks 1, 3, 5, 7, and 9: MTX 2.5g/m2 + vincristine 1.4mg/m2 with a cap of 2.8mg (2m2).

Weeks 1, 5, and 9: Procarbazine 100mg/m2/day orally for 7 days.

Weeks, 2, 4, 6, 8, and 10: Methotrexate 12mg intraventicularly.

Weeks 1, 3, 5, 7, and 9: Leucovorin 20mg every 6 hours orally for 12 doses.

Weeks, 2, 4, 6, 8, and 10: Leucovorin 10mg orally twice daily for 8 doses.

Weeks 11–15: Whole-brain RT in 1.80-Gy fractions for a total dose of 45 Gy. Weeks 16 and 19: Cytarabine 3mg/m2/day IV for 2 days.

Repeat for 5 cycles.

OR Day 1: MTX 3.5g/m2.

Days 2–3: Cytarabine 2g/m2 IV twice a day.

OR Day 1: MTX 4gm/m2 IV, followed by leucovorin 20–25mg IV every 6 hours starting 24 hours after MTX for 72 hours or until serum MTX level <1 × 10–8mg/dL. Increase leucovorin to 40mg every 4 hours if MTX level >1 × 10–5mg/dL at 48 hours or >1 × 10–8mg/dL at 72 hours.

Days 3–5: Ifosfamide 1.5gm/m2 IV + mesna 400mg IV before ifosfamide, then 4 hours and 8 hours after.

High dose methotrexate (MTX 2.5–4.0mg/m2) + chemotherapy ± monoclonal antibody45

Day 1: Rituximab 500mg/m2 IV. Day 2: MTX 3.5mg/m2 IV plus vincristine 1.4mg/m2.

Procarbazine 100mg/m2/day was administered for 7 days with odd-numbered cycles.

High dose methotrexate (MTX 8.0mg/m2) + chemotherapy ± monoclonal antibody46–47

High dose methotrexate combined with the following plus radiation therapy deferred radiation therapy: Induction therapy MTX 8g/m2 IV administered every 2 weeks until complete response achieved or max of 8 cycles reached.

Consolidation MTX 8g/m2 IV administered every 2 weeks for 2 cycles.

Maintenance therapy MTX 8g/m2 IV administered every 4 weeks for 11 cycles.

Plus Day 1: Rituximab 375mg/m2 IV. Repeat cycle every 4 weeks for 4 cycles.

OR Induction therapy Day 1: Rituximab 375mg/m2 IV, followed by Days 1–5: Temozolomide 150–200mg/m2 orally daily, after rituximab infusion.

Repeat cycle every 4 weeks for 4 cycles.

Maintenance therapy Days 1–5: Temozolomide 150–200mg/m2 orally daily.

Repeat cycle every 4 weeks for 8 cycles. continued

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BRAIN CANCER Brain Cancer Treatment Regimens Primary CNS Lymphoma REGIMEN

1

(continued)

DOSING

Primary Treatment (continued) Consider urgent glucarpidase (carboypeptidase G2) for prolonged MTX clearance due to MTX-induced renal toxicity48

Glucarpidase, one 50U/kg dose IV, 2 doses 24 hours apart, or 3 doses every 4 hours; thymidine 8 g/m2/day IV administered as continuous IV infusion for ≥48 hours after the last dose of glucarpidase; leucovorin 1g/m2 IV every 6 hours before administration of glucarpidase and at a dose of 250mg/m2 IV every 6 hours for 48 hours after administration of the last dose of glucarpidase.

Recurrent or Progressive Disease Consider high-dose chemotherapy with autologous stem cell reinfusion in patients who achieve a complete remission with conventional doses of salvage chemotherapy or have no residual disease after re-resection.35 Re-treat with high-dose methotrexate46

Induction therapy MTX 8g/m2 IV administered every 2 weeks until complete response achieved or max of 8 cycles reached.

Consolidation MTX 8g/m2 IV administered every 2 weeks for 2 cycles.

Maintenance therapy MTX 8g/m2 IV administered every 4 weeks for 11 cycles.

Rituximab ± temozolomide49

Induction therapy Day 1: Rituximab 375mg/m2 IV, ± Days 1–5: Temozolomide 150–200mg/m2 orally daily, administered after rituximab infusion.

Repeat cycle every 4 weeks for 4 cycles.

Maintenance therapy Days 1–5: Temozolomide 150–200mg/m2 orally daily, administered after rituximab infusion.

Repeat cycle every 4 weeks for 8 cycles.

Topotecan50

Days 1–5: Topotecan 1.5mg/m2 IV. Repeat cycle every 21 days.

High-dose cytarabine51

Cytarabine 3g/m2 IV.

Dexamethasone + high-dose cytarabine + cisplatin52

Day 1: Cisplatin 100mg/m2 continuous IV infusion over 24 hours, followed by 2 pulses each of cytarabine at a dose of 2g/m2 given 12 hours apart.

Days 1–4: Dexamethasone 40mg PO or IV. Repeat cycle every 3–4 weeks for 6–10 courses.

Pemetrexed53

Pemetrexed 900mg/m2 IV every 21 days for 6 weeks.

Meningioma1 Interferon-alfa (Category 2B)54

α-IFN 106 units/m2 SC every other day for 4 weeks.

Repeat cycle every 4 weeks.

Somatostatin analog55

Sandostatin LAR Depot 10–30mg IM every 4 weeks.

Sunitinib (Category 2B)56

Days 1–28: Sunitinib 50mg orally daily.

Repeat cycle every 42 days.

Systemic Therapy for Limited (1–3) Metastatic or Multiple (>3) Metastatic Lesions1 Recurrent disease—Treatment as per the regimens of the primary tumor (‡ Bevacizumab + chemotherapy can be considered for patients who have failed monotherapy with bevacizumab) Carmustine wafer57

8 wafers (7.7mg) for a total of 61.6mg implanted intracranially.

High-dose methotrexate (MTX; breast Breast: MTX 3.5g/m2 IV. Lymphoma: Treatment based on weekly high-dose MTX 3.5g/m2 and weekly intra-CSF cytarabine; oral procarbazine and lymphoma)58,59 100mg/m2 days 2–15 was added to patients whose bone marrow reserve could tolerate this drug.

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CANCER TREATMENT REGIMEN

BRAIN CANCER Systemic Therapy for Limited (1–3) Metastatic or Multiple (>3) Metastatic Lesions1 (continued) REGIMEN

DOSING

Capecitabine ± lapatinib, cisplatin, etoposide60–68

Days 1–14: Lapatinib 1,250mg orally plus capecitabine 1,000mg/m2 orally twice per day.

Repeat cycle every 21 days.

OR Days 1–14: Capecitabine 2,000mg/m2/day in 2 divided doses for 14 days, followed by a 7-day rest and lapatinib 1,250mg once daily continuously.

OR Day 1: Cisplatin 100mg/m2 IV. Days 4, 6, and 8: Etoposide 100mg/m2.

Repeat cycle every 21 days.

OR Day 1: Cisplatin 100mg/m2 IV. Days 1, 3, and 5 OR Days 4, 6, and 8: Etoposide 100mg/m2 IV. Repeat cycle every 21 days.

OR (breast) Capecitabine orally starting at a dose of 1,800mg/m2/day (up to 2,000mg/m2/day) in 2 divided doses, and temozolomide given orally once daily at a starting dose of 75mg/m2/day. Concomitant daily doses given on days 1–5 and days 8–12, with cycles repeated every 21 days until disease progression.

OR (breast) Days 1–14: Capecitabine 2,000mg/m2/day orally once daily.

Repeat cycle every 21 days.

OR (breast) Days 1–21: Capecitabine 2,400mg/m2/day orally once daily.

Repeat cycle every 28 days.

Ipilimumab (melanoma)69

Day 1: Ipilimumab 10mg/kg IV. Repeat cycle every 21 days for a maximum 4 cycles.

Individuals who were clinically stable at week 24 were eligible to receive ipilimumab 10mg/kg every 12 weeks.

BRAF inhibitors (melanoma): Dabrafenib70

Dabrafenib 150mg orally twice daily.

BRAF inhibitors (melanoma): Vemurafenib71

Vemurafenib 960mg orally twice daily.

Topotecan (small cell lung)50

Days 1–5: Topotecan 1.5mg/m2 IV over 30 minutes.

Repeat cycle every 21 days.

Systemic Therapy for Leptomeningeal Metastases1 Organ-specific Systemic Chemotherapy; Emphasizing Drugs with Good CNS Penetration Intra-CSF chemotherapy: Liposomal (slow-release) cytarabine (lymphoma/leukemias)72,73

Induction Liposomal cytarabine 50mg intrathecally once every 14 days for 2 doses.

Maintenance Liposomal cytarabine 50mg every 14 days for 2 doses, followed by 50mg every 28 days for 2 doses.

OR Induction Liposomal cytarabine 50mg intraventricularly every 14 days for 3 doses plus rituximab 25mg intraventricularly twice per week for 8 doses.

Maintenance Liposomal cytarabine 50mg intraventricularly once weekly plus rituximab 25mg intraventricularly twice weekly for 4 weeks.

Repeat cycle every 4 weeks until disease progression.

Intra-CSF chemotherapy: topotecan74

Topotecan 400 μg intraventrically twice weekly for 6 weeks.

Intra-CSF chemotherapy: etoposide

Induction Days 1–5: Etoposide 0.5mg/day intra-CSF every other week for 8 weeks.

Maintenance Days 1–5: Etoposide 0.5mg/day every 4 weeks.

75

Intra-CSF chemotherapy: trastuzumab76

Cumulative dose of intrathecal trastuzumab given in clinical studies was 1,040mg (SD 697.9, median 1,215, range 55–1,675).

Intra-CSF chemotherapy: Interferon-alfa (category 2B)77

IFN-α 1 × 106 IU subcutaneously every other day 3 times per week for 4 weeks by induction. continued

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CANCER TREATMENT REGIMEN

BRAIN CANCER Brain Cancer Treatment Regimens Systemic Therapy for Leptomeningeal Metastases1 (continued) REGIMEN

DOSING

Organ-specific Systemic Chemotherapy; Emphasizing Drugs with Good CNS Penetration (continued) High-dose methotrexate for lymphoma and breast58

Breast: MTX 3.5g/m2 IV.

Erlotinib (Category 2B)78

Weekly pulse erlotinib for EGFR exon 19 or exon 21 L858R mutation non-small cell lung cancer; trial demonstrates that a new schedule of erlotnib administration may overcome acquired resistance to erlotinib. Pulsatile high-dose erlotinib was found to be effective against brain metastases in patients who had progressed while on treatment with standard-dose erlotinib.

Pulsatile high-dose erlotinib 1,500mg (median dose with range of 900–1,500mg) once weekly.

Systemic Therapy for Metastatic Spine Tumors1 Use regimen for disease specific site. * For patients not previously treated † Patients who have good performance status but evidence of radiographic progression may benefit from continuation of bevacizumab to prevent rapid neurologic deterioration ‡ Bevacizumab + chemotherapy can be considered for patients who have failed monotherapy with bevacizumab

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BRAIN CANCER References (continued) 32. Malmström A, Grønberg BH, Marosi C, et al ; Nordic Clinical Brain Tumour Study Group (NCBTSG). Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomised, phase 3 trial. Lancet Oncol. 2012; 13:916–926.

33. Cloughesy TF, Prados MD, Wen PY. A phase II randomized non- comparative clinical trial of the effect of bevacizumab alone or in combination with irinotecan on 6 month progression free survival (PFS6) in recurrent treatment-refractory glioblastoma (GBM) [abstract]. J Clin Oncol. 2008;26(suppl 15):2010b.

34. Friedman HS, Prados MD, Wen PY, et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol. 2009;27:4733–4740.

35. Kreisl TN, Kim L, Moore K, et al. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma.

J Clin Oncol. 2009;27:740–745.

36. Yung WK, Prados MD, Yaya-Tur R, et al. Multicenter phase II trial of temozolomide in patients with anaplastic astrocytoma or anaplastic oligoastrocytoma at first relapse. Temodal Brain Tumor Group. J Clin Oncol. 1999;17:2762–2771.

37. Packer RJ, Gajjar A, Vezina G, et al. Phase III study of craniospinal radiation therapy followed by adjuvant chemotherapy for newly diagnosed average-risk medulloblastoma. J Clin Oncol. 2006;24:4202–4208.

38. Dunkel IJ, Gardner SL, Garvin JH Jr, Goldman S, Shi W, Finlay JL. High-dose carboplatin, thiotepa, and etoposide with autologous stem cell rescue for patients with previously irradiated recurrent medulloblastoma. Neuro Oncol. 2010; 12:297–303.

39. Ashley DM, Meier L, Kerby T, et al. Response of recurrent medulloblastoma to lowdose oral etoposide. J Clin Oncol. 1996;14:1922–1927.

40. Chamberlain MC, Kormanik PA. Chronic oral VP-16 for recurrent medulloblastoma.

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41. DeAngelis LM, Seiferheld W, Schold SC, Fisher B, Schultz CJ; Radiation Therapy Oncology Group Study 93-10. Combination chemotherapy and radiotherapy for primary central nervous system lymphoma: Radiation Therapy Oncology Group Study 93-10. J Clin Oncol. 2002;20:4643–4648.

42. Ferreri AJ, Reni M, Foppoli M, et al; International Extranodal Lymphoma Study Group (IELSG). High-dose cytarabine plus high-dose methotrexate versus highdose methotrexate alone in patients with primary CNS lymphoma: a randomised phase 2 trial. Lancet. 2009;374:1512–1520.

43. Thiel E, Korfel A, Martus P, et al. High-dose methotrexate with or without whole brain radiotherapy for primary CNS lymphoma (G-PCNSL-SG-1): a phase 3, randomised, non-inferiority trial. Lancet Oncol. 2010;11:1036–1047.

44. Shah GD, Yahalom J, Correa DD, et al. Combined immunochemotherapy with reduced whole-brain radiotherapy for newly diagnosed primary CNS lymphoma.

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45. Batchelor T, Carson K, O’Neill A, Grossman SA, Alavi J, New P, Hochberg F, Priet R. Treatment of primary CNS lymphoma with methotrexate and deferred radiotherapy: a report of NABTT 96–07. J Clin Oncol. 2003;21:1044–1049.

46. Chamberlain MC, Johnson SK. High-dose methotrexate and rituximab with deferred radiotherapy for newly diagnosed primary B-cell CNS lymphoma. Neuro Oncol. 2010;12: 736–744.

47. Wieduwilt MJ, Valles F, Issa S, et al. Immunotherapy with intensive consolidation for primary central nervous system lymphoma: a pilot study and prognostic assessment by diffusion-weighted MRI. Clin Cancer Res. 2012 Jan 6. [Epub ahead of print] 48. Widemann BC, Balis FM, Kim A, et al. Glucarpidase, leucovorin, and thymidine for high-dose methotrexate-induced renal dysfunction: clinical and pharmacologic factors affecting outcome. J Clin Oncol. 2010;28:3979–3986.

49. Enting RH, Demopoulos A, DeAngelis LM, Abrey LE. Salvage therapy for primary CNS lymphoma with a combination of rituximab and temozolomide. Neurology.

2004;63:901–903.

50. Topotecan (Hycamtin) [prescribing information]. Research Triangle Park, NC: GlaxoSmithKline. 2015.

51. De Angelis L, Kreis W, Chan K, et al. Pharmacokinetics of ara-C and ara-U in plasma and CSF after high-dose administration of cytosine arabinoside. Cancer Chemother Pharmacol. 1992; 29:173–177.

52. McLaughlin P, Velasquez WS, Redman JR, et al. Chemotherapy with dexamethasone, high-dose cytarabine, and cisplatin for parenchymal brain lymphoma. J Natl Cancer Inst. 1988;80: 1408–1412.

53. Raizer JJ, Rademaker A, Evens AM, et al. Pemetrexed in the treatment of relapsed/ refractory primary central nervous system lymphoma. Cancer.

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54. Chamberlain MC, Glantz MJ. Interferon-alpha for recurrent World Health Organization grade 1 intracranial meningiomas. Cancer. 2008;113:2146–2151.

55. Chamberlain MC, Glantz MJ, Fadul CE. Recurrent meningioma: salvage therapy with long-acting somatostatin analogue. Neurology. 2007;69:969–973.

56. Kaley TJ, Wen P, Schiff D, et al. Phase II trial of sunitinib for recurrent and progressive atypical and anaplastic meningioma. Neuro-Oncology. 2014;17:116–121.

57. Ewend MG, Brem S, Gilbert M, et al. Treatment of single brain metastasis with resection, intracavity carmustine polymer wafers, and radiation therapy is safe and provides excellent local control. Clin Cancer Res. 2007;13:3637–3641.

58. Lassman AB, Abrey LE, Shah GD, et al. Systemic high-dose intravenous methotrexate for central nervous system metastases. J Neurooncol. 2006;78:255–260.

59. Bokstein F, Lossos A, Lossos IS, et al. Central nervous system relapse of systemic non-Hodgkin’s lymphoma: Results of treatment based on high-dose methotrexate combination chemotherapy. Leuk Lymphoma. 2002;43:587–593.

60. Metro G, Foglietta J, Russillo M, et al. Clinical outcome of patients with brain metastases from HER2-positive breast cancer treated with lapatinib and capecitabine. Ann Oncol. 2011;22:625–630.

61. Sutherland S, Ashley S, Miles D, et al. Treatment of HER2-positive metastatic breast cancer with lapatinib and capecitabine in the lapatinib expanded access programme, including efficacy in brain metastases--the UK experience. Br J Cancer. 2010; 102:995–1002.

62. Cocconi G, Lottici R, Gisagni G et al, Combination therapy with platinum and etoposide in brain metastases from breast carcinoma. Cancer Invest. 1990;8:327–334.

63. Franciosi V, Cocconi G, Michiara M, et al. Front-line chemotherapy with cisplatin and etoposide for patients with brain metastases from breast carcinoma, nonsmall cell lung carcinoma, or malignant melanoma. Cancer. 1999;85:1599–1605.

64. Rivera E, Meyers C, Groves M, et al. Phase I study of capecitabine in combination with temozolomide in the treatment of patients with brain metastases from breast carcinoma. Cancer. 2006;107:1348–1354.

65. Fabi A, Vidiri A, Ferretti G, et al. Dramatic regression of multiple brain metastases from breast cancer with Capecitabine: another arrow at the bow? Cancer Invest.

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66. Siegelmann-Danieli N, Stein M, Bar-Ziv J. Complete response of brain metastases originating in breast cancer to capecitabine therapy. Isr Med Assoc J. 2003;5:833–834.

67. Wang MLH, Yung AWK, Royce ME, et al. Capecitabine for 5-fluorouracil-resistant brain metastases from breast cancer. Am J Clin Oncol. 2001;24:421–424.

68. Hikino H, Yamada T, Johbara K, et al. Potential role of chemo-radiation with oral capecitabine in a breast cancer patient with central nervous system relapse.

Breast. 2006;15:97–99.

69. Margolin K, Ernstoff MS, Hamid O, et al. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol. 2012;13:459–465.

70. Long GV, Trefzer U, Davies MA, et al. Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;13:1087–1095.

71. Dummer R, Goldinger SM, Turtschi CP, et al. Vemurafenib in patients with BRAF(V600) mutation-positive melanoma with symptomatic brain metastases: final results of an open-label pilot study. Eur J Cancer. 2014;50:611–621.

72. Jaeckle KA, Phuphanich S, Bent MJ, et al Intrathecal treatment of neoplastic meningitis due to breast cancer with a slow-release formulation of cytarabine. Br J Cancer. 2001; 84:157–163.

73. Chamberlain MC, Johnston S, Van Horn A, Glantz MJ. Recurrent lymphomatous meningitis treated with intra-CSF rituximab and liposomal ara-C. J Neurooncol.

2009;91: 271–277.

74. Groves MD, Glantz MJ, Chamberlain MC, et al. A multicenter phase II trial of intrathecal topotecan in patients with meningeal malignancies. Neuro Oncol. 2008;10:208-215.

75. Chamberlain MC, Tsao-Wei DD, Groshen S. Phase II trial of intracerebrospinal fluid etoposide in the treatment of neoplastic meningitis. Cancer. 2006;106:2021–2027.

76. Zagouri F, Sergentanis TN, Bartsch R, et al. Intrathecal administration of trastuzumab for the treatment of meningeal carcinomatosis in HER2-positive metastatic breast cancer: a systematic review and pooled analysis. Breast Cancer Res Treat. 2013;139:13–22.

77. Chamberlain MC. A phase II trial of intra-cerebrospinal fluid alpha interferon in the treatment of neoplastic meningitis. Cancer. 2002; 94:2675–2680.

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(Revised 9/2015) © 2015 by Haymarket Media, Inc.

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DRUG MONOGRAPHS

BRAIN CANCER AFINITOR Novartis

℞

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

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

Adults and Children: <1yr: not recommended.

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

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

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

Contraindications: Allergy to other rapamycin derivatives.

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

Monitor for signs of wound-related complications. Peri-surgical period. Hepatic impairment (see Adult dose). Monitor CBCs, renal function, lipids, and blood glucose prior to starting and periodically thereafter. Avoid close contact with those who have received live vaccines. Pediatrics: complete childhood vaccination series according to ACIP guidelines prior to initiation. Elderly. Women of childbearing potential should use effective method of contraception during and up to 8 weeks after treatment. Pregnancy (Cat.D), nursing mothers: not recommended.

Interactions: Avoid live vaccines. Potentiated by strong CYP3A4/PgP inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole), grapefruit or grapefruit juice; avoid. Caution with moderate CYP3A4/PgP inhibitors (eg,

amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem); reduce everolimus dose if used. Antagonized by strong CYP3A4/PgP inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital), St. John’s Wort; avoid.

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

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

AVASTIN Genentech

℞

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

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

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

10mg/kg every 2 weeks.

Children: Not established.

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

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

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

Elderly. Increased risk of ovarian failure; inform females of reproductive potential prior to starting therapy. Pregnancy: may cause fetal harm;

use effective contraception during and for 6 months after last dose. Nursing mothers: not recommended.

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

How supplied: Single-use vial—1

TEMODAR Merck

℞

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

Indications: Newly diagnosed glioblastoma multiforme. Refractory anaplastic astrocytoma.

Adults: See full labeling for monitoring and dose adjustment guidelines. IV: Infuse over 90 mins. Oral caps: Swallow whole with water; take on empty stomach at bedtime to reduce nausea, pretreat with antiemetics. Glioma: Concomitant phase, for newly diagnosed: 75mg/m2 daily for 42 days with focal radiotherapy; Maintenance phase, Cycle 1: 150mg/m2 once daily for 5 consecutive days, then 23 days off; for Cycles 2 through 6: increase to 200mg/m2 once daily for 5 consecutive days if tolerated, then 23 days off. Anaplastic astrocytoma: 150mg/m2 once daily for 5 consecutive days per 28-day treatment cycle; increase dose in subsequent cycles to 200mg/m2 if tolerated; continue until disease progression, discontinue if minimum dose not tolerated.

Children: Not established.

Contraindications: Hypersensitivity to dacarbazine.

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

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

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

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DRUG MONOGRAPHS

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

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

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

UNITUXIN United Therapeutics

℞

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

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

Adults: Not applicable.

Children: Confirm adequate hematologic, respiratory, hepatic, and renal function prior to each course. Hydrate and premedicate with antihistamines, analgesics (eg, IV opioids), and antipyretics prior to each dose: see full

labeling. Give via IV infusion over 10–20 hours for 4 consecutive days; max 5 cycles. Initial rate: 0.875mg/m2/hr for 30mins; may gradually increase as tolerated up to max 1.75mg/m2/hr.

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

Warnings/Precautions: Risk of serious infusion reactions; monitor during and at least 4 hours after completion of each infusion; interrupt or discontinue if severe or prolonged infusion reactions occur. Have resuscitative medications and equipment available. Risk of neuropathy.

Permanently discontinue if life-threatening infusion reactions, Grade 3 pain unresponsive to max supportive measures, Grade 4 sensory neuropathy or Grade 3 sensory neuropathy that interferes with daily activities for more than 2 weeks, Grade 2 peripheral motor neuropathy, recurrent signs of eye disorders or vision loss, signs of atypical hemolytic uremic syndrome occurs. Interrupt or discontinue if severe capillary leak syndrome, symptomatic hypotension, systolic BP less than lower limit of normal for age or decreased by >15% compared to baseline develops. Monitor for systemic infection; temporarily discontinue until resolves. Monitor BP, peripheral blood counts during therapy, and serum electrolytes daily. Renal or hepatic impairment. Pregnancy; avoid. Use effective contraception during therapy and for at least 2

months after last dose. Nursing mothers: not recommended.

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

How supplied: Single-use vial (5mL)—1

SEE LITERATURE Consult the manufacturer’s labeling for full prescribing information.

ADVERSE REACTIONS Those adverse reactions listed within product monographs represent the potential for adverse effects based upon the active ingredient(s) and/or the drug class. It is not meant to be an inclusive list of responses.

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

1. Renal Function: Glomerular filtration rate, renal tubular secretion and blood flow tend to decrease with advancing age, while the incidence of renal pathology increases.

2. Drug Sensitivity: Elderly patients may show unusual sensitivity or paradoxical reactions to a number of drugs. Refer to the complete prescribing information.

3. Drug Distribution: The ratio of fat to lean body weight may increase in the elderly, which affects the volume of distribution of fat-soluble drugs. Plasma albumin concentrations may be decreased in the elderly. This potentiates plasma-protein bound drugs and increases the potential for drug interactions caused by plasma-protein displacement.

4. Polypharmacy: It is important to determine the patient’s current medication use, including nonprescription products, before adding any medication to determine any possible interactions.

5. Hepatic Function: Reduced function of metabolic enzymes in the liver may occur in the elderly.

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CANCER TREATMENT REGIMEN

BREAST CANCER Breast Cancer (Recurrent or Metastatic) Treatment Regimens Clinical Trials: The NCCN recommends cancer patient participation in clinical trials as the gold standard for treatment.

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

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

Preferred Single Agents1 Note: All recommendations are Category 2A unless otherwise indicated.

REGIMEN

DOSING

Doxorubicin2,3

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

OR Day 1: Doxorubicin 20mg/m2 IV. Repeat cycle weekly.

Pegylated liposomal doxorubicin4

Day 1: Liposomal doxorubicin 50mg/m2 IV. Repeat cycleevery 28 days

Paclitaxel5,6

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

OR Day 1: 80mg/m2 IV. Repeat cycle weekly.

Capecitabine7

Days 1–14: Capecitabine 1,000–1,250mg/m2 PO twice daily.

Repeat cycle every 28 days.

Gemcitabine8

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

Vinorelbine9

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

Eribulin10

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

Other Single Agents1 Cyclophosphamide11

Days 1–21: Cyclophosphamide 50mg PO daily.

Repeat cycle every 28 days.

Carboplatin12

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

Docetaxel13,14,15

Day 1: Docetaxel 60–100mg/m2 IV. Repeat cycle every 21 days.

OR Day 1: Docetaxel 40mg/m2 IV. Repeat cycle weekly for 6 weeks followed by a 2-week rest, then repeat.

Albumin-bound paclitaxel16,17

Days 1, 8, and 15: Albumin-bound paclitaxel 100mg/m2 or 150mg/m2 IV. Repeat cycle every 28 days.

OR Day 1: Albumin-bound paclitaxel 260mg/m2 IV. Repeat cycle every 21 days.

Cisplatin18

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

Epirubicin19

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

Ixabepilone20

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

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CANCER TREATMENT REGIMEN

BREAST CANCER Chemotherapy Combinations1 REGIMEN

DOSING

CAF21

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

FAC22

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

Day 1: Cyclophosphamide 500mg/m2 IV. Repeat cycle every 21 days for 6 cycles.

FEC23

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

AC24

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

EC25

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

CMF26

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

Docetaxel + capecitabine26

Day 1: Docetaxel 75mg/m2 IV. Days 1–14: Capecitabine 950mg/m2 PO twice daily.

Repeat cycle every 21 days.

GT28

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

Repeat cycle every 21 days.

Gemcitabine + carboplatin29

Days 1 and 8: Gemcitabine 1,000mg/m2.

Days 1 and 8: Carboplatin AUC 2 IV. Repeat cycle every 21 days.

Paclitaxel + bevacizumab30

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

Repeat cycle every 28 days.

Preferred First-Line Agents for HER2-Positive Disease1 General treatment note: All trastuzumab-containing regimens require cardiac monitoring at baseline and at Months 3, 6, and 9.1 Pertuzumab + trastuzumab + docetaxel (Category 1)31

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

Pertuzumab + trastuzumab + weekly paclitaxel32

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

Other First-Line Agents For HER2-Positlve Disease1 Paclitaxel + carboplatin + trastuzumab33,34

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

OR Day 1: Trastuzumab 8mg/kg IV followed by 6mg/kg IV every 21 days. continued

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CANCER TREATMENT REGIMEN

BREAST CANCER Breast Cancer (Recurrent or Metastatic) Treatment Regimens Other First-Line Agents For HER2-Positlve Disease1 (continued) REGIMEN

DOSING

Weekly paclitaxel + carboplatin + trastuzumab33,35

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

OR Day 1: Trastuzumab 8mg/kg IV followed by 6mg/kg IV every 21 days.

Trastuzumab + paclitaxel33,36,37

Day 1: Paclitaxel 175mg/m2 IV cycled every 21 days.

OR Day 1: Paclitaxel 80–90mg/m2 IV weekly, plus Day 1: Trastuzumab 4mg/kg IV followed by 2mg/kg IV weekly.

OR Day 1: Trastuzumab 8mg/kg IV followed by 6mg/kg IV every 21 days.

Trastuzumab + docetaxel33,38,39

Day 1: Docetaxel 80–100mg/m2 IV cycled every 21 days.

OR Days 1, 8, and 15: Docetaxel 35mg/m2 IV weekly, plus Day 1: Trastuzumab 4mg/kg IV followed by 2mg/kg IV weekly.

OR Day 1: Trastuzumab 8mg/kg IV followed by 6mg/kg IV every 21 days.

Trastuzumab + vinorelbine33,40,41

Day 1: Vinorelbine 25mg/m2 IV weekly.

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

OR Day 1: Trastuzumab 8mg/kg IV followed by 6mg/kg IV every 21 days.

Trastuzumab + capecitabine33,42

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

OR Day 1: Trastuzumab 8mg/kg IV followed by 6mg/kg IV every 21 days.

Preferred Agents for Trastuzumab-Exposed HER2-Positive Disease1 Ado-trastuzumab emtansine (T-DM1)44

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

Other Agents for Trastuzumab-Exposed HER2-Positlve Disease1 Lapatinib + capecitabine45

Days 1–21: Lapatinib 1,250mg PO daily.

Days 1–14: Capecitabine 1,000mg/m2 PO twice daily cycled every 21 days.

Trastuzumab + capecitabine46

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

OR Day 1: Trastuzumab 8mg/kg IV followed by 6mg/kg IV every 21 days.

Trastuzumab + lapatinib47

Lapatinib 1,000mg PO daily, plus Day 1: Trastuzumab 4mg/kg IV followed by 2mg/kg IV weekly.

OR Day 1: Trastuzumab 8mg/kg IV followed by 6mg/kg IV every 21 days.

References 1.

2.

3.

Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer V.3.2015. Available at: http:// www.nccn.org. Accessed August 28,2015.

Chan S, Friedrichs K, Noel D, et al. Prospective randomized trial of docetaxel versus doxorubicin in patients with metastatic breast cancer. J Clin Oncol.

1999;17:2341–2354.

Gundersen S, Kvinnsland S, Klepp O, et al. Weekly adriamycin versus VAC in advanced breast cancer. A randomized trial. Eur J Cancer Clin Oncol.

1986;22:1431–1434.

4.

5.

6.

O’Brien ME, Wigler N, Inbar M, et al. Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCI (CAELYX/DoxiI) versus conventional doxorubicin for first-line treatment of metastatic breast cancer. Ann Oncol. 2004;15:440–449.

Seidman AD, Tiersten A, Hudis C, et al. Phase II trial of paclitaxel by 3-hour infusion as initial and salvage chemotherapy for metastatic breast cancer. J Clin Oncol.

1995;13:2575–2581.

Perez EA, Vogel CL, Irwin DH, et al. Multicenter phase II trial of weekly paclitaxel in women with metastatic breast cancer. J Clin Oncol. 2001;19:4216–4223.

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CANCER TREATMENT REGIMEN

BREAST CANCER References (continued) 7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

Bajetta E, Procopio G, Celio L, et al. Safety and efficacy of two different doses of capecitabine in the treatment of advanced breast cancer in older women.

J Clin Oncol. 2005;23:2155–2161.

Seidman AD. Gemcitabine as single-agent therapy in the management of advanced breast cancer. Oncology. (Williston Park) 2001;15:11–14.

Zelek L, Barthier S, Riofrio M, et al. Weekly vinorelbine is an effective palliative regimen after failure with anthracyclines and taxanes in metastatic breast carcinoma. Cancer. 2001; 92:2267–2272.

Cortes J, O’Shaughnessy J, Loesch O, et al. Eribulin monotherapy versus treatment of physicians choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomized study. Lancet. 2011;377:914–923.

Licchetta A, Correale P, Migali C, et al. Oral metronomic chemo- hormonal-therapy of metastatic breast cancer with cyclophosphamide and megestrol acetate.

J Chemother. 2010;22(3):201–204.

Isakoff S J, Goss PE, Mayer EL, et al. TBCRCOO9: A multi-center phase II study of cisplatin or carboplatin for metastatic triple-negative breast cancer and evaluation of p631p73 as a biomarker of response [abstract). J Clin Oncol. 2011;29 (15_suppl): Abstract 1025.

Burriss HA 3rd. Single-agent docetaxel (Taxotere) in randomized phase Ill trials.

Semin Oncol. 1999;26:1–6.

Harvey V, Mouridsen H, Semiglazov V, et al: Phase Ill trial comparing three doses of docetaxel for second-line treatment of advanced breast cancer. J Clin Oncol.

2006;24(31): 4963–4970.

Burstein HJ, Manola J, Younger J, et al. Docetaxel administered on a weekly basis for metastatic breast cancer. J Clin Oncol. 2000;18:1212–1219.

Gradishar W, Tjulandin S. Davidson N, et al. Phase Ill trial of nanoparticle albuminbound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol. 2005;23:7794–7803.

Gradishar W, Dimitry K, Sergey C, et al: Significantly longer progression-free survival with nab-paclitaxel compared with docetaxel as first-line therapy for metastatic breast cancer. J Clin Oncol. 2009;27(22):3611–3619.

Silver DR, Richardson AL, EkIund AC, et al. Efficacy of neoadjuvant cisplatin in triple-negative breast cancer. J Clin Oncol. 2010;28(7):1145–1153.

Bastholt L, Dalmark M, Gjedde SB, et al. Dose-response relationship of epirubicin in the treatment of postmenopausal patients with metastatic breast cancer a randomized study of epirubicin at four different dose levels performed by the Danish Breast Cancer Cooperative Group. J Clin Oncol. 1996;14:1146–1155.

Perez E, Lerzo G, Pivot X, et al. Efficacy and safety of ixabepilone (BMS-247550) in a phase II study of patients with advanced breast cancer resistant to an anthracycline, a taxane, and capecitabine. J Clin Oncol. 2007;25(23):3407–3414.

Bull JM, Tormey DC, Li SH, et al. A randomized comparative trial of adriamycin versus methotrexate in combination drug therapy. Cancer. 1978;41:1649–1657.

Hortobagyi GN, Gutterman JU, Blumenschein GR, et al: Combination chemoimmunotherapy of metastatic breast cancer with 5-fluorouracil, adriamycin, cyclophosphamide, and BCG.Cancer. 1979;43:1225–33.

Ackland SR, Anton A, Breithach GR, et al. Dose-intensive epirubicin-based chemotherapy is superior to an intensive intravenous cyclophosphamide, methotrexate, and fluorouracil regimen in metastatic breast cancer a randomized multinational study. J Clin Oncol. 2001;19:943–953.

Nabholtz JM, Falkson C, Campos O, et al: Docetaxel and doxorubicin compared with doxorubicin and cyclophosphamide as first-line chemotherapy for metastatic breast cancer results of a randomized, multicenter, phase Ill trial. J Clin Oncol. 2003;21(6):968–975.

Langley RE, Carmichel J, Jones AL, et al. Phase Ill trial of epirubicin plus paclitaxel compared with epirubicin plus cyclophosphamide as first-line chemotherapy for metastatic breast cancer United Kingdom Cancer Research Institute. J Clin Oncol.

2005;23:8322–8330.

Bonadonna G, Brusamolino E, Valagussa P, et al. Combination chemotherapy as an adjuvant treatment in operable breast cancer. N Engl J Med. 1976;294:405–410.

O’Shaughnessy J, Miles D, Vukelja S, et al. Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer phase Ill thai results. J Clin Oncol. 2002;20:2812–2823.

Albain KS, Nag S, Calderillo-Ruiz G, et al Gemcitabine plus paclitaxel versus paclitaxel monotherapy in patients with metastatic breast cancer and prior anthracycline treatment. J Clin Oncol. 2008;26(24):3950–3957.

29. O’Shaughnessy J, Schwartzberg LS, Danso MA, et al. A randomized phase ill study of iniparib (BSI-201) in combination with gemcitabine/carboplatin (GIC) in metastatic triple-negative breast cancer (TNBC). [abstract]. J Clin Oncol. 2011; 29(Suppl_15):Abstract 1007.

30. Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizurriab versus paclitaxel alone for metastatic breast cancer. N EngI J Med. 2007;357:2666–2676.

31. Baselga J, Cones J, Kim SB, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N EngI J Med. 2012;366:109–119.

32. Datko F, D’Andrea G, Dickler M, et al. Phase II study of pertuzumab, trastuzumab, and weekly paclitaxel in patients with metastatic HER2-overexpressing metastatic breast cancer [abstract]. Cancer Research. 2012;72: Abstract P5-18–20.

33. Leyland-Jones B, Gelmon K, Ayoub JP, et al. Pharmacokinetics, safety, and efficacy of trastuzumab administered every three weeks in combination with paclitaxel.

J Clin Oncol. 2003;21: 3965–3971.

34. Robert N, Leyland-Jones B, Asmar L, et al. Randomized phase III study of trastuzumab, paclitaxel, and carboplatin compared with trastuzumab and paclitaxel in women with HER-2-overexpressing metastatic breast cancer. J Clin Oncol. 2006;24: 2786–2792.

35. Perez EA, Suman VJ, Rowland KM, et al. Two concurrent phase II trials of paclitaxel/ carboplatin/trastuzumab (weekly or every-3-week schedule) as first-line therapy in women with HER2-overexpressing metastatic breast cancer: NCCTG study 983252. Clin Breast Cancer. 2005;6:425–432.

36. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2.

N EngI J Med. 2001; 344:783–792.

37. Seidman A, Berry DA, Cirrincione C, et al. Randomized phase Ill trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol 9840. J Clin Oncol. 2008;26:1642–1649.

38. Marty M, Cognetti F, Maraninchi O, et al. Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 study group. J Clin Oncol.

2005;23:4265–4274.

39. Esteva FJ, Valero V, Booser O, et al. Phase II study of weekly docetaxel and trastuzumab for patients with HER-2-overexpressing metastatic breast cancer.

J Clin Oncol. 2002;20: 1800–1808.

40. Burstein HJ, Keshaviah A, Baron AD, et al. Trastuzumab plus vinorelbine or taxane chemotherapy for HER2-overexpressing metastatic breast cancer the trastuzumab and vinorelbine or taxane study. Cancer. 2007;110:965–972.

41. Andersson M, Lidbrink E, Bjerre K, et al. Phase III randomized study comparing docetaxel plus trastuzumab with vinorelbine plus trastuzumab as first-line therapy for metastatic or locally advanced human epidermal growth factor receptor 2-positive breast cancer: the HERNATA study. J Clin Oncol.

2011;29: 264–271.

42. von Minckwitz G, du Bois A, Schmidt M, et al. Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer a German breast group 26/breast international group 03-05 study. J Clin Oncol.

2009;27:1999–2006.

43. Cobleigh MA, Vogel CL, Tripathy D, et al. Multinational study of the efficacy and safety of humanized anti-l-IER2 ruonodonal antibody in women who have HER2overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol. 1999;17:2639–2648.

44. Verma S, Miles O, Gianni L, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer (supplementary appendix available online]. N EngI J Med. 2012;367:1783–1791.

45. Geyer C, Forster J, Undquist O, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 2006:355:2733–2743.

46. Bartsch R, Wenzel C, Altorjai G, et al. Capecitabine and trastuzumab in heavily pretreated metastatic breast cancer. J Clin Oncol. 2007;25:3853–3858.

47. Blackwell KL, Burstein H, Storniolo AM, et al. Randomized study of lapatinib alone or in combination with trastuzumab in women with ErbB2-positive. Trastuzumabrefractory metastatic breast cancer. J Clin Oncol. 2010;28(7):1124–1130.

(Revised 9/2015) © 2015 by Haymarket Media, Inc.

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DRUG MONOGRAPHS

BREAST CANCER ABRAXANE Celgene

℞

Taxane antimicrotubule. Paclitaxel [bound to albumin (human)] 100mg/vial; pwd for IV infusion after reconstitution; solvent-free.

Indications: Treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy (prior therapy should have included an anthracycline unless clinically contraindicated).

Adults: Do not treat if neutrophil count <1,500 cells/mm3 or platelets <100,000 cells/mm3.

260mg/m2 by IV infusion over 30 mins every 3 weeks. If severe neutropenia (neutrophil <500 cells/mm3 for ≥1week) or severe sensory neuropathy occurs: reduce subsequent doses to 220mg/m2; reduce to 180mg/m2 if severe neutropenia or sensory neuropathy recurs. If grade 3 sensory neuropathy occurs, suspend use until resolution to grade 1 or 2; reduce subsequent doses. Hepatic impairment: see full labeling. Avoid extravasation.

Children: Not evaluated.

Contraindications: Baseline neutrophil count <1,500 cells/mm3. Prior severe hypersensitivity reaction (do not rechallenge).

Warnings/Precautions: Do not substitute for, or with, other paclitaxel products (due to formulation differences). Do frequent complete blood cell counts. Hepatic impairment (total bilirubin >5×ULN or AST >10×ULN): not recommended. Monitor for sensory neuropathy, sepsis, or pneumonitis. Renal dysfunction.

Contains human albumin; remote risk of viral transmission. Use appropriate contraception (men and women). Pregnancy (Cat.D), nursing mothers: not recommended.

Interactions: May potentiate or be potentiated

by CYP2C8 and/or CYP3A4 inducers (eg, rifampin, carbamazepine, phenytoin, efavirenz, nevirapine) and/or inhibitors (eg, ketoconazole, other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir, nelfinavir).

Adverse reactions: Bone marrow suppression (eg, neutropenia, anemia), infections, alopecia, sensory neuropathy (may require dose reduction or interruption), peripheral neuropathy, GI upset, mucositis, fatigue/ asthenia, myalgia/arthralgia, abnormal ECG; alkaline phosphatase or AST elevation; dyspnea, edema, hypotension, rash (may be serious); rare: thrombotic events.

How supplied: Single-use vial—1

AFINITOR Novartis mTOR kinase inhibitor. Everolimus 2.5mg, 5mg, 7.5mg, 10mg; tabs.

Indications: Postmenopausal women with advanced hormone receptor-positive, HER2negative breast cancer (advanced HR+ BC) in combination with exemestane after failure of treatment with letrozole or anastrozole.

℞

Adults: Swallow tabs whole with water. Take at the same time each day either consistently with or without food. 10mg once daily. Mild hepatic impairment (Child-Pugh class A): 7.5mg daily, may reduce to 5mg if not tolerated. Moderate hepatic impairment (Child-Pugh class B): 5mg daily, may be reduce to 2.5mg if not tolerated.

Severe hepatic impairment (Child-Pugh class C): max 2.5mg daily if benefits outweigh risk.

Concomitant moderate CYP3A4/PgP inhibitors: reduce to 2.5mg once daily; may consider increasing to 5mg if tolerated. If moderate inhibitor is discontinued, allow 2–3 days washout period before increasing everolimus dose; return to dose used prior to initiating the moderate inhibitor. Concomitant strong CYP3A4/PgP inducers: consider doubling the daily dose by increments of 5mg or less.

If strong inducer is discontinued, consider washout period of 3–5 days before returning to the dose used prior to initiating the strong inducer. Continue therapy until disease progression or unacceptable toxicity occurs.

Dose modifications for adverse reactions, or others: see full labeling.

Children: Not recommended.

Contraindications: Allergy to other rapamycin derivatives.

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

Monitor for signs of wound-related complications.

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

Pediatrics: complete childhood vaccination series according to ACIP guidelines prior to initiation. Elderly. 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.

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.

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DRUG MONOGRAPHS

BREAST CANCER Interactions: Antagonized by strong CYP3A4 inducers (eg, rifampicin, phenytoin, carbamazepine, phenobarbital, St. John’s wort).

Adverse reactions: Hot flashes, fatigue, arthralgia, headache, insomnia, increased sweating, nausea, increased appetite; reductions in bone mineral density.

How supplied: Tabs—30

DELATESTRYL Endo

CIII

Androgen. Testosterone enanthate 200mg/mL; IM inj; in sesame oil; contains chlorobutanol.

Indications: Testosterone replacement therapy in adult males with congenital or acquired primary hypogonadism or hypogonadotropic hypogonadism. To stimulate puberty in males with delayed puberty. Limitations of use: not established in men with age-related hypogonadism.

Adults: Give by deep IM inj into gluteal muscle.

200–400mg once every 2–4 weeks. Max 400mg/month. Monitor closely.

Children: Not established.

Contraindications: Male breast or prostate cancer. Pregnancy (Cat.X).

Warnings/Precautions: Discontinue if jaundice, abnormal liver function, hypercalcemia, or edema occurs. Monitor liver function, hemoglobin, hematocrit, cholesterol, urine, serum calcium. Preexisting cardiac, hepatic, or renal dysfunction. History of MI or coronary artery disease. Monitor for venous thromboembolism; discontinue if suspected. Elderly. Nursing mothers: not recommended.

Interactions: May potentiate oral anticoagulants, oxyphenbutazone. May alter insulin requirements. Increased risk of edema with ACTH, corticosteroids. May affect thyroid levels.

Adverse reactions: Amenorrhea, menstrual irregularities, inhibition of gonadotropin secretion, virilization; others: inj site reactions, peliosis hepatis, edema, hepatic carcinoma, nausea, jaundice, hirsutism, acne, polycythemia, headache, anxiety, depression, paresthesia, altered libido, fluid and electrolyte disturbances, suppression of clotting factors, increased serum cholesterol.

How supplied: Multidose vial (5mL)—1

ESTRACE Warner Chilcott

℞

Estrogen. Estradiol 0.5mg, 1mg, 2mg+; scored tabs; +contains tartrazine.

Indications: Palliative treatment of metastatic breast cancer in select patients (see literature).

Adults: 10mg 3 times daily for at least 3 months.

Children: Not applicable.

Contraindications: Thrombophlebitis.

Thromboembolic disorders. Cerebrovascular disorders. Abnormal undiagnosed genital bleeding. Estrogen-depended neoplasias. Liver dysfunction or disease. Pregnancy (Cat.X).

Warnings/Precautions: Asthma (2mg tabs).

Hepatic dysfunction. Conditions aggravated by fluid retention. Cardiovascular disorders, arterial vascular disease, and risks factors (eg, hypertension, diabetes, obesity, SLE). Familial hyperlipoprotenemia. Monitor BP. Discontinue if jaundice occurs and before prolonged immobilization (eg, surgery). Nursing mothers.

Adverse reactions: See literature. GI upset, headache, hypertension, edema, hypercalcemia, gallbladder or thromboembolic disease, gynecomastia, impotence, impaired glucose tolerance.

How supplied: Tabs—100

EVISTA Lilly

℞

Selective estrogen receptor modulator (SERM).

Raloxifene HCl 60mg; tabs.

Indications: Reduction in risk of invasive breast cancer in postmenopausal women: with osteoporosis and/or at high risk for invasive breast cancer.

Adults: 60mg once daily.

Children: Not recommended.

Contraindications: Active or history of venous thromboembolic events. Nursing mothers.

Pregnancy (Cat.X). Women who may become pregnant.

Warnings/Precautions: Not for use in premenopausal women. Concomitant systemic estrogen therapy: not recommended. Discontinue 72 hours before, and during prolonged immobilization; resume when fully ambulatory.

Coronary heart disease or risk of coronary event (increased risk of death due to stroke). Hepatic dysfunction. Moderate to severe renal impairment.

Interactions: May antagonize warfarin; monitor.

Avoid concomitant cholestyramine, other anion exchange resins. Caution with other highly 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

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DRUG MONOGRAPHS

BREAST CANCER Fluorouracil (various)

℞

Antimetabolite. Fluorouracil 50mg/mL; soln for IV inj.

Indications: Palliative management of carcinoma of the breast.

Adults: Give by IV inj. 12mg/kg once daily for 4 successive days; max 800mg/day. If no toxicity is observed, 6mg/kg are given on the 6th, 8th, 10th, and 12th days unless toxicity occurs. Maintenance therapy: repeat dosage of 1st course every 30 days after the last day of the previous course of treatment; or give a maintenance dose of 10–15mg/kg per week as a single dose; max: 1g/ week. Poor risk patients: see literature for dose adjustments.

Children: Not recommended.

Contraindications: Poor nutritional state.

Depressed bone marrow function. Potentially serious infections.

Warnings/Precautions: Narrow margin of safety; monitor for toxicity. Consider hospitalization for 1st course. History of 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 7 months after therapy.

Nursing mothers: not recommended.

Interactions: Increased cardiomyopathy with anthracycline-containing chemotherapy.

Increased toxicity with other myelosuppressives.

Potentiated by paclitaxel.

Adverse reactions: Fever, diarrhea, nausea, chills, infections, increased cough, headache, CHF, insomnia, fatigue, dyspnea, rash, neutropenia, anemia, stomatitis, mucosal inflammation, nasopharyngitis, dysgeusia, myalgia, thrombosis/embolism; severe infusion reactions, febrile neutropenia/exacerbation of chemotherapy-induced neutropenia, pulmonary toxicity (eg, interstitial pneumonitis), cardiomyopathy (eg, left ventricular myocardial dysfunction); pregnant women: possible oligohydramnios (monitor).

Note: Enroll pregnant women with breast cancer who are using trastuzumab in the MotHER-the Herceptin Pregnancy Registry (800) 690-6720.

Testing considerations: HER2 protein overexpression How supplied: Vial—1 (w. diluent)

IBRANCE Pfizer

℞

Kinase inhibitor. Palbociclib 75mg, 100mg, 125mg; capsules.

Indications: In combination with letrozole, for the treatment of postmenopausal women 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

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DRUG MONOGRAPHS

BREAST CANCER with letrozole 2.5mg once daily continuously throughout the 28-day cycle. Dose modification for adverse reactions: First reduction: 100mg/day; Second dose reduction: 75mg/day; discontinue if <75mg/day required. Dose modification for hematologic or non-hematologic toxicities: see full labeling. Concomitant strong CYP3A inhibitors: avoid and consider alternative drug; if use necessary, reduce palbociclib dose to 75mg.

Children: Not evaluated.

Warnings/Precautions: Monitor CBC prior to initiation and at start of each cycle, as well as Day 14 of first 2 cycles, and as clinically indicated. Interrupt, reduce dose, or delay starting treatment cycles if Grade 3 or 4 neutropenia develops. Monitor for signs/ symptoms of infection and pulmonary embolism; treat appropriately if develop.

Moderate or severe hepatic impairment.

Severe renal impairment. Pregnancy: avoid.

Use effective contraception during therapy and for at least 2 weeks after last dose. Lactation: discontinue nursing.

Interactions: Avoid concomitant strong CYP3A inhibitors (eg, clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, verapamil, voriconazole), grapefruit or grapefruit juice; if unavoidable, reduce dose (see Adults). Avoid concomitant strong CYP3A inducers (eg, phenytoin, rifampin, carbamazepine, St. John’s wort) or moderate CYP3A inducers (eg, bosentan, efavirenz, etravirine, modafinil, nafcillin).

May potentiate midazolam or other CYP3A substrates with narrow therapeutic index (eg, alfentanil, cyclosporine, dihydroergotamine, ergotamine, everolimus, fentanyl, pimozide, quinidine, sirolimus, tacrolimus); reduce dose of these drugs.

Adverse reactions: Neutropenia, leukopenia, fatigue, anemia, upper respiratory infection, nausea, stomatitis, alopecia, diarrhea, thrombocytopenia, decreased appetite, vomiting, asthenia, peripheral neuropathy, epistaxis.

How supplied: Caps—21

IXEMPRA Bristol-Myers Squibb

℞

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

Indications: Metastatic or locally advanced breast cancer: In combination with capecitabine after failure of an anthracycline and a taxane; and

as monotherapy after failure of an anthracycline, a taxane, and capecitabine.

Adults: Pretreat with both H1 and H2 blockers 1hr before infusion; and with steroid if previous hypersensitivity reaction occurred. 40mg/m2

by IV infusion over 3hrs, once every 3wks. Use max body surface area (BSA) of 2.2m2 to calculate dose if BSA >2.2m2. Moderate hepatic impairment (as monotherapy): initially 20mg/m2 per dose; max 30mg/m2 per dose (see literature).

Neuropathy, myelosuppression, concomitant strong CYP3A4 inhibitors: reduce dose.

Concomitant strong CYP3A4 inducers: consider gradual dose increases. See literature.

Children: Not recommended.

Contraindications: Baseline neutrophils <1500cells/mm3 or platelets <100,000cells/mm3. AST or ALT >2.5×ULN or bilirubin >1×ULN (in combination with capecitabine).

Warnings/Precautions: Monitor CBC and liver function at baseline, then periodically. Hepatic impairment (ALT or AST >10×ULN or bilirubin >3×ULN: not recommended; ALT or AST >5×ULN: limited data, use caution). Diabetes. Neuropathy.

Cardiac disease (discontinue if cardiac ischemia or cardiac dysfunction occurs). Monitor for signs/ symptoms of neuropathy, neutropenia. Pregnancy (Cat.D), nursing mothers: not recommended.

Interactions: Potentiated by strong CYP3A4 inhibitors (eg, azole antifungals, protease inhibitors, certain macrolides, nefazodone, grapefruit juice); avoid. Caution with mild or moderate CYP3A4 inhibitors; consider alternative agents. Antagonized by strong CYP3A4 inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, dexamethasone, phenobarbital); avoid.

Avoid St. John’s wort.

Adverse reactions: Peripheral sensory neuropathy, fatigue, asthenia, myalgia, arthralgia, alopecia, GI upset, stomatitis, mucositis, musculoskeletal pain, palmarplantar erythrodysesthesia syndrome, anorexia, abdominal pain, nail disorder, constipation; myelosuppression (neutropenia, leukopenia, anemia, thrombocytopenia); hypersensitivity reactions; others.

How supplied: Kit—1 vial (w. diluent)

KADCYLA Genentech

℞

HER2-targeted antibody-drug conjugate. Adotrastuzumab emtansine 100mg, 160mg; per vial; powder; for IV infusion after reconstitution.

Indications: Treatment in patients with HER2positive (+), metastatic breast cancer (MBC) who previously received trastuzumab and a taxane, separately or in combination. Patients should

have either: received prior therapy for metastatic disease or developed disease recurrence during or within 6 months of completing adjuvant therapy.

Adults: Give by IV infusion only over 90 minutes 3.6mg/kg max every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity.

Subsequent infusions may be given over 30 minutes if previously tolerated. Monitor closely for possible SC infiltration during infusion. Dose modifications: see full labeling.

Children: Not established.

Warnings/Precautions: Do not substitute for or with trastuzumab. Hepatotoxicity; monitor serum transaminases and bilirubin prior to starting and to each dose; reduce dose or discontinue if occurs. Permanently discontinue if serum transaminases >3×ULN and with total bilirubin >2×ULN. Risk of left ventricular dysfunction. Assess LVEF prior to initiation and every 3 months during treatment; interrupt and discontinue as appropriate. Risk of embryo-fetal toxicity. Permanently discontinue if interstitial lung disease or pneumonitis occurs.

Monitor for signs/symptoms of extravasation, infusion-related or hypersensitivity reactions; if significant, slow or interrupt infusion; discontinue if life-threatening. Monitor platelets at baseline and prior to each dose; if platelets <50,000/mm3, delay dose until recovery to ≥75,000/mm3; if platelets <25,000/mm3, delay until recovery to ≥75,000/mm3 and reduce dose.

If thrombocytopenia occurs <100,000/mm3 and concomitant anticoagulants, monitor closely.

Monitor for neurotoxicity; withhold temporarily if Grade 3 or 4 peripheral neuropathy occurs.

Test for HER2 protein overexpression or gene amplification using FDA-approved tests by labs with demonstrated proficiency. Pregnancy (Cat.D); use adequate contraception during and for 7 months after last dose. Nursing mothers: not recommended.

Interactions: Avoid concomitant strong CYP3A4 inhibitors (eg, azole antifungals, clarithromycin, atazanavir, indinavir, ritonavir, nefazodone, nelfinavir, saquinavir, telithromycin); if unavoidable, consider delaying therapy. Caution with concomitant anticoagulation or antiplatelet therapy; monitor closely.

Adverse reactions: Fatigue, nausea, musculoskeletal pain, hemorrhage, thrombocytopenia, headache; increased transaminases, constipation, epistaxis.

Note: Enroll pregnant women who were exposed to Kadcyla in the MotHER Pregnancy Registry (800) 690-6720.

How supplied: Single-use vial—1

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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; verify pregnancy status prior to initiation. Pretreatment LVEF value of ≤50%, history of CHF, decreases in LVEF to <50% during prior trastuzumab therapy, uncontrolled hypertension, recent MI, serious cardiac arrythmia requiring treatment or a cumulative prior anthracycline exposure to >360mg/m2 of doxorubicin or its equivalent: not studied.

Assess LVEF at baseline and at regular intervals (eg, every 3 months in metastatic setting, and every 6 weeks in the neoadjuvant setting) during treatment; if LVEF is <45%, or is 45% to 49% with a ≥10% absolute decrease below the pretreatment value, withhold (pertuzumab + trastuzumab) and repeat LVEF within 3 weeks; discontinue if LVEF has not improved. Monitor for signs/symptoms of infusion reactions; slow or interrupt infusion and treat if occurs; discontinue if severe. Test and confirm for HER2 protein overexpression using FDA-approved tests by labs with demonstrated proficiency. Pregnancy (Cat.D); use adequate contraception during and at least 7 months after therapy. Nursing mothers: not recommended.

Adverse reactions: Diarrhea, alopecia, neutropenia, nausea, fatigue, rash, peripheral neuropathy; hypersensitivity (monitor), decreases in LVEF; pregnant women: possible oligohydramnios (monitor).

Note: Encourage women who are exposed to Perjeta during pregnancy to enroll in the MotHER Pregnancy Registry: (800) 690-6720.

How supplied: Single-use vial—1

PREMARIN Pfizer

℞

Estrogen. Conjugated estrogens 0.3mg, 0.45mg, 0.625mg, 0.9mg, 1.25mg; tabs.

Indications: Treatment of breast cancer (for palliation only) in appropriately selected women and men with metastatic disease.

Adults: 10mg 3 times daily for at least 3 months.

Children: Not applicable.

Contraindications: Known, suspected, or history of breast cancer, except in appropriately selected patients being treated for metastatic disease. Known or suspected estrogen-dependent neoplasia. Undiagnosed abnormal genital bleeding. Pulmonary embolism/DVT (active or history of). Arterial thromboembolism (eg, stroke, MI; active or history of). Liver dysfunction or disease. Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders. Known or suspected pregnancy (Cat.X).

Warnings/Precautions: Not for prevention of cardiovascular disease. Use for shortest duration consistent with treatment goals and risks. Reevaluate periodically. Patients with an intact uterus should almost always receive a progestin with systemic estrogens to avoid endometrial hyperplasia. Discontinue if cardiovascular events occur or are suspected; if jaundice occurs; and during immobilization or at least 4–6 weeks before surgery associated with thromboembolism. Hepatic dysfunction.

Conditions aggravated by fluid retention.

Gallbladder disease. Bone disease associated with hypercalcemia. Hereditary angioedema.

Do initial complete physical and repeat annually (include BP, mammogram, PAP smear). Adolescents. Nursing mothers: not recommended.

Adverse reactions: See literature. Increased risk of cardiovascular events, estrogendependent carcinoma, gallbladder disease, thromboembolic disorders, hepatic tumors.

GI upset, breakthrough bleeding, edema, weight changes, mastodynia, hypertension, depression, anaphylactic reactions, angioedema, intolerance to contact lenses.

How supplied: Tabs 0.3mg, 0.625mg, 1.25mg— 100, 1000; 0.45mg, 0.9mg—100

SOLTAMOX ORAL

SOLUTION DARA BioSciences

℞

Antiestrogen. Tamoxifen (as citrate) 10mg/5mL; licorice and aniseed flavors; sugar-free; contains alcohol.

Indications: Treatment of metastatic breast cancer in men and women. Axillary node-positive breast cancer in postmenopausal women after

surgery + irradiation. Axillary node-negative breast cancer in women after surgery + irradiation. Reduction in risk of invasive breast cancer in women with ductal carcinoma in situ (DCIS) after surgery + radiation. Reduction in breast cancer incidence in high-risk women.

Adults: Treatment: 20–40mg/day; give doses >20mg in divided doses (AM and PM). Reduction of incidence in high-risk women or DCIS: 20mg once daily for 5 years.

Children: Not recommended.

Contraindications: For reduction in incidence in high-risk women and women with DCIS: concomitant coumarin anticoagulants, history of deep vein thrombosis or pulmonary embolism.

Warnings/Precautions: See literature. Do gynecological exam at least annually. DCIS and risk reduction: consider increased risk of uterine cancer (endometrial adenocarcinoma, uterine sarcoma), stroke and pulmonary embolism. Women with advanced disease: discontinue if severe hypercalcemia occurs.

Monitor blood, lipids, liver function, for thromboembolism symptoms (eg, leg swelling, unexplained shortness of breath), and for uterine changes/cancer (eg, pelvic pain or pressure); promptly investigate any abnormal vaginal bleeding. Breast cancer treatment: history of thromboembolic events. Pregnancy (Cat.D); avoid. Premenopausal: use effective non-hormonal contraception during and within 2 months of discontinuing therapy; begin therapy during menses or, if irregular menses, obtain (−) B-hCG pregnancy test first. Nursing mothers: not recommended.

Interactions: See Contraindications. May potentiate oral anticoagulants; if co-administered, monitor PT. Concomitant anastrozole: not recommended. Antagonizes letrozole. Plasma levels reduced by CYP3A4 inducers (eg, rifampin, aminoglutethimide). Cytotoxic drugs increase risk of thrombotic events. Potentiated by bromocriptine.

Adverse reactions: Hot flashes, vaginal discharge, altered menses, oligomenorrhea, nausea, cough, edema, fatigue, abdominal cramps, bone and tumor pain (in advanced disease), local disease flare, hypercalcemia, thrombotic events, ovarian cysts, uterine fibroids or cancer (endometrial adenocarcinoma, uterine sarcoma), endometrial or visual changes, liver abnormalities, hypertriglyceridemia, blood dyscrasias, hair loss.

How supplied: Soln—150mL

Tamoxifen (various)

℞

Antiestrogen. Tamoxifen (as citrate) 10mg, 20mg; tabs.

Indications: Treatment of metastatic breast cancer in men and women. Axillary node-positive breast cancer in postmenopausal women after surgery + irradiation. Axillary node-negative breast cancer in women after surgery + irradiation. Reduction in risk of invasive breast

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DRUG MONOGRAPHS

BREAST CANCER cancer in women with ductal carcinoma in situ (DCIS) after surgery + radiation. Reduction in breast cancer incidence in high-risk women.

Adults: Treatment: 20–40mg/day; give doses >20mg in divided doses (AM and PM). Reduction of incidence in high-risk women or DCIS: 20mg once daily for 5 years.

Children: McCune-Albright Syndrome, precocious puberty: see literature.

Contraindications: For risk reduction: concomitant coumarin anticoagulants, history of deep vein thrombosis or pulmonary embolism, planned pregnancy. Pregnancy (Cat.D). Nursing mothers.

Warnings/Precautions: See literature. Do gynecological exam at least annually. DCIS and risk reduction: consider increased risk of uterine cancer (endometrial adenocarcinoma, uterine sarcoma) and thrombotic events.

Women with advanced disease: discontinue if severe hypercalcemia occurs. Monitor blood, lipids, liver function, for thromboembolism symptoms (eg, leg swelling, unexplained shortness of breath), and for uterine changes/ cancer (eg, pelvic pain or pressure); promptly investigate any abnormal vaginal bleeding. Breast cancer treatment: history of thromboembolic events. Premenopausal: use effective nonhormonal contraception during and within 2 months of discontinuing therapy; begin therapy during menses or, if irregular menses, obtain (−) B-hCG pregnancy test first.

Interactions: May potentiate oral anticoagulants (see Contraindications). Antagonizes anastrozole (avoid concomitant use); letrozole. Plasma levels reduced by CYP3A4 inducers (eg, rifampin).

Cytotoxic drugs increase risk of thrombotic events. Potentiated by bromocriptine.

Adverse reactions: Hot flashes, vaginal discharge, altered menses, rash, headache, nausea, cough, edema, fatigue, abdominal cramps, bone and tumor pain (in advanced disease), local disease flare, hypercalcemia, thrombotic events, ovarian cysts, uterine fibroids or cancer (endometrial adenocarcinoma, uterine sarcoma), endometrial or visual changes, jaundice, hypertriglyceridemia, blood dyscrasias, hair loss.

How supplied: Contact supplier.

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

Oncology Nurse Advisor provides important clinical information, including a CE activity in each issue.

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DRUG MONOGRAPHS

BREAST CANCER decrease in LVEF occurs, or if LVEF falls below institution’s lower limit of normal; may restart after at least 2 weeks at reduced dose if asymptomatic and LVEF recovers. Conditions that impair left ventricular function, or risk factors for QT prolongation (eg, hypokalemia, hypomagnesemia, congenital long QT syndrome, concomitant antiarrhythmics, cumulative high dose anthracyclines); correct electrolyte disturbances before starting. Monitor for interstitial lung disease or pneumonitis; discontinue if pulmonary symptoms ≥grade 3 (NCI CTCAE). Monitor liver function tests before, every 4–6 weeks during therapy and as indicated; discontinue if hepatotoxicity occurs; do not retreat. Severe hepatic impairment: consider dose reduction. Diarrhea: promptly treat with anti-diarrheal agents; if severe, may require fluids, electrolytes, antibiotics and therapy interruption/discontinuation. Monitor ECG. Pregnancy (Cat.D); avoid. Nursing mothers: not recommended.

Interactions: Avoid potent CYP3A4 inhibitors (eg, ketoconazole), grapefruit; reduce dose if unavoidable. Avoid potent CYP3A4 inducers (eg, carbamazepine); slowly titrate dose up if unavoidable. May affect drugs that are affected by p-glycoprotein, CYP2C8, CYP3A4.

Adverse reactions: Diarrhea (may be severe), nausea, vomiting, hand/foot syndrome, rash, fatigue; decreased LVEF, QT prolongation, interstitial lung disease, pneumonitis, hepatotoxicity (may be fatal).

Testing considerations: HER2 protein overexpression How supplied: Tabs—150

XELODA Genentech

℞

Fluoropyrimidine. Capecitabine (prodrug of 5-fluorouracil) 150mg, 500mg; tabs.

Indications: Metastatic breast cancer resistant to both paclitaxel and an anthracyclinecontaining chemotherapy regimen or resistant to paclitaxel when further anthracycline therapy is not indicated (eg, prior cumulative doses of 400mg/m2 of doxorubicin or its equivalents).

With docetaxel for metastatic breast cancer after failure of prior anthracycline-containing regimen.

Adults: See full labeling. Give cyclically (2 weeks on, 1 week off). Swallow whole. Take with water within 30 minutes after AM & PM meals. ≥18yrs: 1250mg/m2 twice daily. Combination therapy: give with docetaxel 75mg/m2 IV infused over 1 hour every 3 weeks. Interrupt, adjust dose, and/or treat symptoms if toxicity occurs (eg, hyperbilirubinemia, diarrhea, nausea, vomiting, hand-and-foot syndrome, stomatitis) (see full labeling); do not increase dose afterwards.

Renal impairment (CrCl 51–80mL/min): monitor carefully; (CrCl 30–50mL/min): reduce capecitabine dose to 75% of starting dose (ie, 950mg/m2 twice daily).

Children: <18yrs: not established.

Contraindications: Severe renal impairment (CrCl <30mL/min).

Warnings/Precautions: Hepatic or renal dysfunction. Monitor and correct dehydration at initiation. Coronary artery disease. Interrupt therapy if severe diarrhea occurs; give antidiarrheals until resolves or reduces to Grade 1. Dihydropyrimidine dehydrogenase deficiency.

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

Interactions: Increased anticoagulant effect with warfarin; monitor PT/INR frequently.

Potentiated by leucovorin. Monitor phenytoin and other CYP2C9 substrates.

Adverse reactions: Diarrhea, hand-andfoot syndrome, nausea, vomiting, abdominal pain, fatigue/weakness, hyperbilirubinemia; lymphopenia, necrotizing enterocolitis, stomatitis, dermatitis, anorexia, cardiotoxicity, blood dyscrasias, paresthesias, eye irritation, edema, myalgia, dehydration, alopecia; severe mucocutaneous reactions (eg, SJS, TEN); permanently discontinue if occurs.

Testing considerations: TS (thymidylate synthase), MSI (microsatellite instability), DPD (dihydropyrimidine dehydrogenase) How supplied: Tabs 150mg—60; 500mg—120

DOSAGE Recommended adult dosage and, where appropriate, the dosage for children. Doses are given for children <12 years of age unless stated otherwise.

Assume the adult dosage for children ≥12 years. Dosages for children are presented in ascending age order.

FDA PREGNANCY CATEGORIES When pregnancy appears as a contraindication or precaution to the use of a drug, it is usually qualified by a category as assigned by the FDA.

A: Adequate and well-controlled studies in pregnant women have failed to show a risk to the fetus in the first trimester of pregnancy and there is no evidence of risk in later trimesters.

B: Animal studies have failed to show a risk to the fetus and there are no adequate and wellcontrolled studies in pregnant women; or animal studies have shown an adverse effect but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus during the first trimester of pregnancy and there is no evidence of a risk in later trimesters.

C: Animal studies have shown an adverse effect on the fetus, there are no adequate and well-controlled studies in humans, and the potential benefits may outweigh the risks; or there are no animal studies and no adequate and well-controlled studies in humans.

D: Positive evidence of human fetal risk but the benefits may outweigh the risks.

X: Animal or human studies have shown fetal abnormalities or toxicity, or both, and the risks clearly outweigh any possible benefits.

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CANCER TREATMENT REGIMEN

ENDOCRINE CANCER Thyroid 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.

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

Papillary Carcinoma Total thyroidectomy or lobectomy plus isthmusectomy (category 2B).

Post-surgical therapy may include radioiodine treatment, external beam radiation therapy, or adjuvant radioiodine ablation.

For bone metastases, bisphosphonate or denosumab therapy may be considered.

Follicular Carcinoma Total thyroidectomy if invasive cancer, metastatic cancer, or patient preference, or lobectomy/isthmusectomy.

Post-surgical therapy may include radioiodine treatment, external beam radiation therapy, embolization of metastasis, adjuvant radioiodine ablation, clinical trial for progressive disease, small molecule kinase inhibitor (sorafenib, axitinib, pazopanib, sunitinib, or vandetanib), or systemic therapy if trial not available.

For bone metastases, options above and bisphosphonate or denosumab therapy may be considered.

Hürthle Carcinoma Total thyroidectomy if invasive cancer, metastatic disease, or patient preference.

Post-surgical therapy may include radioiodine treatment, adjuvant radioiodine ablation, or external beam radiation therapy.

For bone metastases, bisphosphonate or denosumab therapy may be considered.

For clinically progressive or symptomatic disease, consider surgical resection +/− external beam radiation therapy of metastasis, clinical trial for non-radioiodine-sensitive tumors, small molecular kinase inhibitor (lenvatinib, sorafenib, axitinib, pazopanib, sunitinib, or vandetanib), or systemic therapy.

Medullary Carcinoma Total thyroidectomy with therapeutic or adjuvant external beam radiation therapy.

Locoregional: • Surgical resection +/− external beam radiation therapy • Consider external beam radiation therapy • For unresectable disease that is symptomatic or structurally progressive, consider vandetanib 300mg orally once daily2 or cabozantinib 140mg orally once daily (max 180mg daily)3 until disease progression (Category 1)4,5 Symptomatic distant metastases: • Clinical trial is preferred • Vandetanib or cabozantinib (Category 1)3-5 • Small molecular kinase inhibitor (sorafenib, axitinib, pazopanib, or sunitinib) if vandetinib or cabozantinib are not available, appropriate, or if disease progresses3-7 • Dacarbazine (DTIC)-based chemotherapy8 • External beam radiation therapy for focal symptoms • For bone metastases, bisphosphonate or denosumab therapy may be considered.

Asymptomatic, distant metastases • Observation or resection, ablation if structurally progressive disease Anaplastic Carcinoma Locally resectable or unresectable local tumor +/− distant disease—clinical trial preferred.

Consider external beam radiotherapy and/or concurrent chemotherapy. (Concurrent chemoradiation regimens: paclitaxel/carboplatin, paclitaxel, cisplatin or doxorubicin9; Chemotherapy regimens: paclitaxel/carboplatin, paclitaxel10 or doxorubicin11.) continued

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CANCER TREATMENT REGIMEN

ENDOCRINE CANCER Thyroid Carcinoma Treatment Regimens Treatment of Metastatic Disease Not Amenable to RAI Therapy For progressive and/or symptomatic, radioactive iodine-refractory papillary, follicular, or Hürthle carcinoma, consider lenvatinib 24mg PO once daily or sorafenib 400mg PO twice daily.12,13

References 1.

2.

3.

4.

5.

6.

Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Thyroid Carcinoma V.2.2015. Available at: http://www. nccn.org. Accessed August 17, 2015.

Caprelsa [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals, LP. 2011.

Cometriq [package insert]. San Francisco, CA: Exelixis Inc. 2012.

Schoffski, et al. An international, double-blind, randomized, placebo-controlled phase III trial (EXAM) of cabozantinib (XL 184) in medullary thyroid carcinoma (MTC) patients (pts) with documented RECIST progression at baseline [abstract].

J Clin Oncol. 2012;30(Supl 15):Abstract 5508.

Traynor K. Cabozantinib approved for advanced medullary thyroid cancer. Am J Health Syst Pharm. 2013;70(2):88.

Ravaud A, et al. Efficacy of sunitinib in advanced medullary thyroid carcinoma: intermediate results of phase II THYSU. Oncologist. 2010;15(2):212–213.

7.

8.

9.

10.

11.

Sherman SI. Advances in chemotherapy of differentiated epithelial and medullary thyroid cancers. J Clin Endocrinol Metab. 2009;94(5):1493–1499.

Nocera M, et al. Treatment of advanced medullary thyroid cancer with an alternating combination of doxorubicin-streptozocin and 5 FU-dacarbazine. Groupe d’Etude des Tumeurs à Calcitonine (GETC). Br J Cancer. 2000;83(6):715–718.

Smallridge RC, et al. American thyroid association guidelines for management of patients with anaplastic thyroid cancer. Thyroid. 2012;22(11):1104–1139.

Ain KB, et al. Treatment of anaplastic thyroid carcinoma with paclitaxel: phase 2 trial using ninety-six-hour infusion. Collaborative Anaplastic Thyroid Cancer Health Intervention Trials (CATCHIT) Group. Thyroid.

2000;10(7):587–594.

Shimaoka K, et al. A randomized trial of doxorubicin versus doxorubicin plus cisplatin in patients with advanced thyroid carcinoma. Cancer. 1985;56(9):2155–2160.

(Revised 8/2015) © 2015 by Haymarket Media, Inc.

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26 CANCER THERAPY ADVISOR | NOVEMBER/DECEMBER 2015 | CancerTherapyAdvisor.com

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DRUG MONOGRAPHS

ENDOCRINE CANCER ABRAXANE Celgene

℞

Taxane antimicrotubule. Paclitaxel [bound to albumin (human)] 100mg/vial; pwd for IV infusion after reconstitution; solvent-free.

Indications: First-line treatment of metastatic adenocarcinoma of the pancreas, in combination with gemcitabine.

Adults: Do not treat if neutrophil count <1,500 cells/mm3 or platelets <100,000 cells/mm3.

125mg/m2 IV over 30–40 mins on Days 1, 8, and 15 of each 28-day cycle. Moderate to severe hepatic impairment (total bilirubin >1.5): not recommended. Dose reductions for hematologic and neurologic adverse reactions: see full labeling. Avoid extravasation.

Children: Not evaluated.

Contraindications: Baseline neutrophil count <1,500 cells/mm3. Prior severe hypersensitivity reaction (do not rechallenge).

Warnings/Precautions: Do not substitute for, or with, other paclitaxel products (due to formulation differences). Do frequent complete blood cell counts. Hepatic impairment (total bilirubin >5×ULN or AST >10×ULN): not recommended. Monitor for sensory neuropathy, sepsis, or pneumonitis. Renal dysfunction.

Contains human albumin; remote risk of viral transmission. Use appropriate contraception (men and women). Pregnancy (Cat.D), nursing mothers: not recommended.

Interactions: May potentiate or be potentiated

by CYP2C8 and/or CYP3A4 inducers (eg, rifampin, carbamazepine, phenytoin, efavirenz, nevirapine) and/or inhibitors (eg, ketoconazole, other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir, nelfinavir).

Adverse reactions: Bone marrow suppression (eg, neutropenia, anemia), infections, alopecia, sensory neuropathy (may require dose reduction or interruption), peripheral neuropathy, GI upset, mucositis, fatigue/ asthenia, myalgia/arthralgia, abnormal ECG; alkaline phosphatase or AST elevation; dyspnea, edema, hypotension, rash (may be serious); rare: thrombotic events.

How supplied: Single-use vial—1

AFINITOR Novartis

℞

mTOR kinase inhibitor. Everolimus 2.5mg, 5mg, 7.5mg, 10mg; tabs.

Indications: Progressive neuroendocrine tumors of pancreatic origin (PNET) in adults with unresectable, locally advanced or metastatic disease. Not for treating functional carcinoid tumors.

Adults: Swallow tabs whole with water. Take at the same time each day either consistently with or without food. 10mg once daily. Mild hepatic impairment (Child-Pugh class A): 7.5mg daily, may reduce to 5mg if not tolerated. Moderate hepatic impairment (Child-Pugh class B): 5mg daily, may be reduce to 2.5mg if not tolerated.

Severe hepatic impairment (Child-Pugh class C): max 2.5mg daily if benefits outweigh risk.

Concomitant moderate CYP3A4/PgP inhibitors: reduce to 2.5mg once daily; may consider increasing to 5mg if tolerated. If moderate inhibitor is discontinued, allow 2–3 days washout period before increasing everolimus dose; return to dose used prior to initiating the moderate inhibitor. Concomitant strong CYP3A4/PgP inducers: consider doubling the daily dose by increments of 5mg or less. If strong inducer is discontinued, consider washout period of 3–5 days before returning to the dose used prior to initiating the strong inducer. Continue therapy until disease progression or unacceptable toxicity occurs.

Dose modifications for adverse reactions, or others: see full labeling.

Children: Not recommended.

Contraindications: Allergy to other rapamycin derivatives.

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

Monitor for signs of wound-related complications. Peri-surgical period. Hepatic impairment (see Adult dose). Monitor CBCs, renal function, lipids, and blood glucose prior to starting and periodically thereafter. Avoid close contact with those who have received live vaccines. Pediatrics: complete childhood vaccination series according to ACIP guidelines prior to initiation. Elderly. Women of childbearing potential should use effective method of contraception during and up to 8 weeks after treatment. Pregnancy (Cat.D), nursing mothers: not recommended.

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

carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital), St. John’s Wort; avoid.

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

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

CAPRELSA AstraZeneca

℞

Kinase inhibitor. Vandetanib 100mg, 300mg, tabs.

Indications: Symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease.

Adults: Do not crush tabs. May disperse tabs in 2oz noncarbonated water for oral or NGT administration; avoid contact of dispersion with skin, mucous membranes. 300mg once daily.

Renal impairment (CrCl<50mL/min): initially 200mg once daily. Dose adjustments for adverse reactions: see full labeling. Do not take a missed dose within 12hrs of the next dose.

Children: Not established.

Contraindications: Congenital long QT syndrome.

Warnings/Precautions: Hypocalcemia, hypokalemia, hypomagnesemia, QTcF interval >450msec, history of torsades de pointes, bradyarrhythmias, uncompensated heart failure, recent hemoptysis: not recommended.

Ventricular arrhythmias. Recent MI. Monitor electrolytes (esp. K+, Ca++, Mg++), TSH, and ECG for QT prolongation at baseline, 2–4 weeks and 8–12 weeks after starting, then every 3 months, and after dose reductions or dose interruptions >2 weeks; reduce dose as needed. Correct electrolyte disturbances before starting.

Maintain serum K+ at least 4mEq/mL. Hepatic impairment (Child-Pugh B or C): not recommended. Interrupt therapy and follow-up if acute or worsening pulmonary symptoms, QTcF >500msec, or CTCAE Grade ≥3 toxicity occurs. Monitor for heart failure; consider discontinuing if occurs. Discontinue if confirmed interstitial lung disease, severe

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DRUG MONOGRAPHS

ENDOCRINE CANCER ischemic cerebrovascular event, hemorrhage, uncontrolled hypertension, or posterior leukoencephalopathy symptoms (RPLS) occur. Avoid sun, UV light. Elderly. Pregnancy (Cat.D) (may cause fetal harm; use appropriate effective contraception during and for 4 months after stopping therapy), nursing mothers: not recommended.

Interactions: Avoid strong CYP3A4 inducers (eg, rifampicin, St. John’s Wort). Avoid other drugs that can prolong QT interval (eg, amiodarone, disopyramide, procainamide, sotalol, dofetilide, chloroquine, clarithromycin, dolasetron, granisetron, haloperidol, pimozide, methadone, moxifloxacin).

Potentiates OCT2 transporters (eg, metformin), digoxin; monitor.

Adverse reactions: Diarrhea/colitis (suspend if severe), rash, acneiform dermatitis, nausea, hypertension, headache, upper respiratory tract infections, decreased appetite, abdominal pain, hypocalcemia, hypoglycemia, increased ALT; QT prolongation, torsades de pointes, sudden death, severe skin reactions (eg, Stevens-Johnson syndrome; discontinue if occurs).

Note: Prescribers and pharmacies must enroll in the Caprelsa REMS program by calling (800) 2369933 or visit www.caprelsarems.com.

How supplied: Tabs—30

COMETRIQ Exelixis

℞

Kinase inhibitor. Cabozantinib 20mg, 80mg; caps.

Indications: Treatment of progressive, metastatic medullary thyroid cancer (MTC).

Adults: Swallow whole. 140mg daily. Do not eat at least 2 hours before or 1 hour after dose.

Continue until disease progression or unacceptable toxicity. Withhold for Grade 4 hematologic adverse reactions, ≥Grade 3 nonhematologic 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 lifethreatening fistula, or severe and persistent neurologic symptoms occur. Withhold if Grade 3 hypertension persists despite therapy, Grade 3 cardiac dysfunction or hemorrhage, ≥Grade 3 liver impairment or QT prolongation, Grade 3 or 4 renal failure/impairment, ≥2g of proteinuria/24hrs, or reversible posterior leukoencephalopathy syndrome (RPLS) occurs. Monitor for signs/symptoms of cardiac decompensation. Monitor liver function prior to treatment, every 2 weeks for the first 2 months, then at least monthly during treatment. Monitor for proteinuria prior to, and periodically during treatment. Dehydration. Hypovolemia. Congenital long QT syndrome, CHF, bradyarrhythmias, or those taking Class Ia or III antiarrhythmic drugs; monitor ECGs. Monitor and correct electrolyte abnormalities. Monitor blood calcium levels at least monthly; replace as needed during treatment. Monitor thyroid stimulating hormone levels monthly; adjust replacement therapy as needed. Pregnancy: avoid. Use effective contraception during treatment and for at least 2 weeks after treatment completion. Lactation: discontinue nursing.

Adverse reactions: Hypertension, fatigue, diarrhea, arthralgia/myalgia, decreased appetite, weight decreased, nausea, stomatitis,

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DRUG MONOGRAPHS

ENDOCRINE CANCER headache, vomiting, proteinuria, palmar-plantar erythrodysesthesia syndrome, abdominal pain, dysphonia.

How supplied: Blister cards—6

NEXAVAR Bayer and Onyx

SOMATULINE DEPOT Ipsen

℞

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

℞

Somatostatin analogue. Lanreotide 60mg, 90mg, 120mg; prolonged-release soln for SC inj.

Indications: Treatment of unresectable, well- or moderately-differentiated, locally advanced or metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs) to improve progression-free survival.

Adults: Give by deep SC inj into the superior external quadrant of the buttock. Rotate inj site.

120mg every 4 weeks.

Children: Not established.

Warnings/Precautions: Diabetes.

Hypothyroidism. Cardiovascular disease.

Hepatic or severe renal impairment. Monitor thyroid function, gallbladder, glucose.

Pregnancy (Cat.C). Nursing mothers: not recommended.

Interactions: Potentiates bromocriptine, CYP450 substrates (eg, quinidine, terfenadine), bradycardia-inducing drugs (eg, β-blockers); adjust doses. Antagonizes cyclosporine; adjust dose. May need to adjust antidiabetic agents.

Adverse reactions: Diarrhea, cholelithiasis, abdominal pain, nausea, inj site reactions; gallbladder sludge, gallstones, hyperglycemia, hypoglycemia, sinus bradycardia, hypertension, anemia; rare: hypothyroidism.

How supplied: Single-use pre-filled syringe—1

SUTENT Pfizer

℞

Multikinase inhibitor. Sunitinib (as malate) 12.5mg, 25mg, 37.5mg, 50mg; gelatin caps.

Indications: Progressive, well-differentiated pancreatic neuroendocrine tumors (pNET) in patients with unresectable locally advanced or metastatic disease.

Adults: 37.5mg once daily continuously without a scheduled off-treatment period. May adjust dose in increments or decrements of 12.5mg.

Concomitant strong CYP3A4 inhibitors (see Interactions): may reduce dose to 25mg daily.

Concomitant strong CYP3A4 inducers (see Interactions): may increase to max 62.5mg daily.

Children: Not established.

Warnings/Precautions: Hepatotoxicity; may be severe or fatal. Monitor liver function tests before starting, during each cycle of treatment and as clinically needed; interrupt if Grade 3 or 4 hepatic adverse events occur and discontinue if no resolution; if severe liver function changes or signs/symptoms of failure, do not restart.

Cardiovascular events: monitor for CHF during therapy, and LVEF at baseline and periodically; interrupt or reduce dose if LVEF <50% and

>20% below baseline; discontinue if CHF occurs.

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

Monitor for proteinuria; perform baseline and periodic urinalyses; interrupt and reduce dose if 24-hr urine protein ≥3g; discontinue if nephrotic syndrome or repeat urine protein ≥3g persists.

Undergoing major surgery. Stress (monitor for adrenal insufficiency). Discontinue if severe cutaneous reactions (eg, erythema multiforme, SJS, TEN) develop; do not restart if diagnosis suspected. ESRD on dialysis. Severe hepatic impairment. Pregnancy (Cat.D; avoid). Nursing mothers: not recommended.

Interactions: May be potentiated by strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole), grapefruit; consider reducing dose or use alternate drug. May be antagonized by CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital); consider increasing dose or use alternate drug. Concomitant St. John’s wort: not recommended. Caution with concomitant antiarrhythmics.

Adverse reactions: Fatigue, asthenia, fever, diarrhea, nausea, vomiting, mucositis/stomatitis, dyspepsia, abdominal pain, constipation, hypertension, peripheral edema, rash, handfoot syndrome, skin discoloration, dry skin, hair color changes, altered taste, headache, back pain, arthralgia, extremity pain, cough, dyspnea, anorexia, bleeding; hepatotoxicity, left ventricular dysfunction, QT prolongation, osteonecrosis of the jaw, tumor lysis syndrome, thyroid dysfunction, impaired wound healing, hypoglycemia, thrombotic microangiopathy (discontinue if develops), proteinuria, necrotizing fasciitis (discontinue if occurs), others (see full labeling).

How supplied: Caps—28

Access Cancer Therapy Advisor treatment regimens in a user-friendly format.

CancerTherapyAdvisor.com/TreatmentRegimens.

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DRUG MONOGRAPHS

ENDOCRINE CANCER TARCEVA Astellas and Genentech

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,

℞

Kinase inhibitor. Erlotinib (as HCl) 25mg, 100mg, 150mg; tabs.

Indications: In combination with gemcitabine: first-line treatment of locally advanced, unresectable or metastatic pancreatic cancer.

Adults: Take on empty stomach. 100mg once daily + gemcitabine (see full labeling). Use until disease progression or unacceptable toxicity occurs. Diarrhea unresponsive to loperamide, severe skin reactions, strong CYP3A4 inhibitors (see Interactions), hepatic impairment: reduce in 50mg decrements.

Concomitant CYP3A4 inducers (see Interactions): increase in 50mg increments at 2-week intervals; max 450mg (see full labeling).

Concurrent cigarette smoking: increase in 50mg increments at 2-week intervals; max 300mg (see full labeling); upon cessation, reduce to 150mg or 100mg daily.

Children: Not established.

Warnings/Precautions: Discontinue if interstitial lung disease, severe hepatic toxicity, GI perforation, severe bullous, blistering or exfoliating skin conditions, or corneal perforation or severe ulceration occurs. Withhold or consider discontinuing therapy if severe renal failure due to dehydration, or acute/ worsening ocular disorders occur. Monitor LFTs periodically; withhold in patients without history of hepatic impairment for total bilirubin >3×ULN or transaminases >5×ULN, or in patients with history of hepatic impairment or biliary obstruction for doubling of bilirubin or tripling of transaminases over baseline.

Discontinue if abnormal LFTs do not improve or resolve within 3 weeks. Withhold for persistent

Stevens-Johnson syndrome, toxic epidermal necrolysis).

Testing considerations: K-RAS mutation analysis, EGFR amplification analysis How supplied: Tabs—30

HYPERSENSITIVITY to

a drug or its class is assumed to be a contraindication in all product monographs, although not explicitly stated.

SEE LITERATURE Consult the manufacturer’s labeling for full prescribing information.

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.

CARE OF DRUGS Patients should be advised that all drug preparations require careful storage.

LIVER FUNCTION ASSESSMENT Child-Pugh Score is used to assess residual liver function and injury severity in cirrhosis patients.

CHILD-PUGH SCORES Criteria

1 point

2 points

3 points

Total serum bilirubin (mg/dL)

<2

2–3

>3

Serum albumin (g/dL)

>3.5

2.8–3.5

<2.8

INR

<1.70

1.71–2.20

>2.20

Ascites

No ascites

Ascites controlled

Ascites not controlled

Encephalopathy

No encephalopathy

Encephalopathy controlled

Encephalopathy not controlled

INTERPRETATION OF CHILD-PUGH SCORES Class A

Class B

Class C

Points

5–6

7–9

10–15

Life expectancy

15–20 years

Candidate for liver transplant

1–3 years

Perioperative mortality

10%

30%

82%

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CANCER TREATMENT REGIMEN

GASTROINTESTINAL CANCER Colon 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.

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

REGIMEN

DOSING

mFOLFOX6

Day 1: Oxaliplatin 85mg/m2 IV over 2 hours.

Day 1: Leucovorin 400mg/m2* IV over 2 hours.

Days 1–3: 5-FU 400mg/m2 IV bolus on day 1, then 1,200mg/m2/day × 2 days (total 2,400mg/m2 over 46–48 hours)† IV continuous infusion.

Repeat cycle every 2 weeks.

mFOLFOX6 + bevacizumab3,5

Day 1: Oxaliplatin 85mg/m2 IV over 2 hours.

Day 1: Leucovorin 400mg/m2* IV over 2 hours.

Days 1–3: 5-FU 400mg/m2 IV bolus on day 1, then 1,200mg/m2/day × 2 days (total 2,400mg/m2 over 46–48 hours)† IV continuous infusion.

Day 1: Bevacizumab 5mg/kg IV. Repeat cycle every 2 weeks.

mFOLFOX6 + panitumumab3,6

Day 1: Oxaliplatin 85mg/m2 IV over 2 hours.

Day 1: Leucovorin 400mg/m2* IV over 2 hours.

Days 1–3: 5-FU 400mg/m2 IV bolus on day 1, then 1,200mg/m2/day × 2 days (total 2,400mg/m2 over 46–48 hours)† IV continuous infusion.

Day 1: Panitumumab 6mg/kg IV over 60 minutes.

Repeat cycle every 2 weeks.

FOLFOX + cetuximab3,7

Day 1: Oxaliplatin 85mg/m2 IV over 2 hours.

Day 1: Leucovorin 400mg/m2* IV over 2 hours.

Days 1–3: 5-FU 400mg/m2 IV bolus on day 1, then 1,200mg/m2/day × 2 days (total 2,400mg/m2 over 46–48 hours)† IV continuous infusion.

Repeat cycle every 2 weeks, plus Cetuximab 400mg/m2 IV over 2 hours for the first infusion, then 250mg/m2 IV over 60 minutes weekly.

OR Day 1: Cetuximab 500mg/m2 IV over 2 hours every 2 weeks.

CapeOX2

Day 1: Oxaliplatin 130mg/m2 IV over 2 hours.

Days 1–14: Capecitabine 850–1,000mg/m2‡ twice daily PO. Repeat cycle every 3 weeks.

CapeOX + bevacizumab2,8

Day 1: Oxaliplatin 130mg/m2 IV over 2 hours.

Days 1–14: Capecitabine 850–1,000mg/m2‡ PO twice daily.

Day 1: Bevacizumab 7.5mg/kg IV. Repeat cycle every 3 weeks.

FOLFIRI9

Day 1: Irinotecan 180mg/m2 IV over 30–90 minutes.

Day 1: Leucovorin 400mg/m2* IV infusion to match duration of irinotecan infusion.

Days 1–3: 5-FU 400mg/m2 IV bolus day 1, then 1,200mg/m2/day × 2 days (total 2,400mg/m2 over 46–48 hours)† continuous infusion.

Repeat cycle every 2 weeks.

FOLFIRI + bevacizumab9,10

Day 1: Irinotecan 180mg/m2 IV over 30–90 minutes.

Day 1: Leucovorin 400mg/m2* IV infusion to match duration of irinotecan infusion.

Days 1–3: 5-FU 400mg/m2 IV bolus day 1, then 1,200mg/m2/day × 2 days (total 2,400mg/m2 over 46–48 hours)† IV continuous infusion.

Day 1: Bevacizumab 5mg/kg IV. Repeat cycle every 2 weeks.

2-4

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CANCER TREATMENT REGIMEN

GASTROINTESTINAL CANCER Advanced or Metastatic Disease1 (continued) REGIMEN

DOSING

FOLFIRI + cetuximab

Day 1: Irinotecan 180mg/m2 IV over 30–90 minutes.

Day 1: Leucovorin 400mg/m2* IV infusion to match duration of irinotecan infusion.

Days 1–3: 5-FU 400mg/m2 IV bolus day 1, then 1,200mg/m2/day × 2 days (total 2,400mg/m2 over 46–48 hours)† IV continuous infusion, plus Days 1 and 8: Cetuximab 400mg/m2 IV over 2 hours first infusion, then 250mg/m2 IV over 60 minutes.10 OR Day 1: Cetuximab 500mg/m2 IV over 2 hours.

Repeat cycle every 2 weeks.

FOLFIRI + panitumumab9,13

Day 1: Irinotecan 180mg/m2 IV over 30–90 minutes.

Day 1: Leucovorin 400mg/m2* IV infusion to match duration of irinotecan infusion.

Days 1–3: 5-FU 400mg/m2 IV bolus day 1, then 1,200mg/m2/day × 2 days (total 2,400mg/m2 over 46–48 hours)† IV continuous infusion.

Day 1: Panitumumab 6mg/kg IV over 60 minutes.

Repeat cycle every 2 weeks.

FOLFIRI + ziv-aflibercept14

Day 1: Irinotecan 180mg/m2 IV over 30–90 minutes.

Day 1: Leucovorin 400mg/m2* IV infusion to match duration of irinotecan infusion.

Days 1–3: 5-FU 400mg/m2 IV bolus day 1, then 1,200mg/m2/day × 2 days (total 2,400mg/m2 over 46–48 hours)† continuous infusion.

Day 1: Ziv-aflibercept 4mg/kg IV over 1 hour.

Repeat cycle every 2 weeks.

FOLFIRI + ramucirumab15

Day 1: Irinotecan 180mg/m2 IV over 30–90 minutes.

Day 1: Leucovorin 400mg/m2* IV infusion to match duration of irinotecan infusion.

Days 1–3: 5-FU 400mg/m2 IV bolus day 1, then 1,200mg/m2/day × 2 day (total 2,400mg/m2 over 46–48 hours)† IV continuous infusion.

Day 1: Ramucirumab 8mg/kg IV over 60 minutes.

Repeat cycle every 2 weeks.

Capecitabine16

Days 1–14: 850–1,250mg/m2 PO twice daily.

Repeat cycle every 3 weeks.

Capecitabine + bevacizumab8,16

Days 1–14: Capecitabine 850–1,250mg/m2 PO twice daily.

Day 1: Bevacizumab 7.5mg/kg IV. Repeat cycle every 3 weeks.

Bolus or infusional 5-FU/leucovorin Roswell Park regimen17

Days 1, 8, 15, 22, 29, and 36: Leucovorin 500mg/m2 IV over 2 hours.

Days 1, 8, 15, 22, 29, and 36: 5-FU 500mg/m2 IV bolus 1 hour after start of leucovorin.

Repeat cycle every 8 weeks.

Simplified biweekly infusional 5-FU/ LV (sLV5FU2)9

Day 1: Leucovorin 400mg/m2* IV over 2 hours.

Days 1–3: 5-FU bolus 400mg/m2 and then 1,200mg/m2/day × 2 days (total 2,400mg/m2 over 46–48 hours)† continuous infusion.

Repeat cycle every 2 weeks.

Weekly infusional LV5FU218,19

Day 1: Leucovorin 20mg/m2 IV over 2 hours.

Day 1: 5-FU 500mg/m2 IV bolus injection 1 hour after the start of leucovorin.

Day 1: 5-FU 2,600mg/m2 by 24-hour infusion plus leucovorin 500mg/m2 Repeat cycle every week.

IROX20

Day 1: Oxaliplatin 85mg/m2 IV over 2 hours, followed by irinotecan 200mg/m2 IV over 30 or 90 minutes.

Repeat cycle every 3 weeks.

FOLFOXIRI ± bevacizumab21,22

Day 1: Irinotecan 165mg/m2 IV, plus oxaliplatin 85mg/m2 IV. Day 1: Leucovorin 400mg/m2* Days 1–3: Fluorouracil 1,600mg/m2/day × 2 days (total 3,200mg/m2 over 48 hours)† continuous infusion starting on day 1, ± Day 1: Bevacizumab 5mg/kg IV. Repeat cycle every 2 weeks.

Irinotecan23,24

Days 1 and 8: Irinotecan 125mg/m2 IV over 30–90 minutes.

Repeat cycle every 3 weeks.

OR Day 1: Irinotecan 300–350mg/m2 IV over 30–90 minutes.

Repeat cycle every 3 weeks.

Cetuximab (KRAS/NRAS WT gene only) + irinotecan12,25

Cetuximab 400mg/m2 first infusion, then 250mg/m2 IV weekly OR cetuximab 500mg/m2 IV every 2 weeks, ± Irinotecan 300–350mg/m2 IV every 3 weeks OR irinotecan 180mg/m2 IV every 2 weeks OR irinotecan 125mg/m2 on days 1 and 8 and repeat every 3 weeks.

Cetuximab (KRAS/NRAS WT gene only)12

Day 1: Cetuximab 400mg/m2 first infusion, then 250mg/m2 IV weekly23 OR 500mg/m2 IV over 2 hours.

Repeat cycle every 2 weeks.

9,12

continued

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CANCER TREATMENT REGIMEN

GASTROINTESTINAL CANCER Colon Cancer Treatment Regimens Advanced or Metastatic Disease1 (continued) REGIMEN

DOSING

Panitumumab (KRAS/NRAS WT gene only)

Panitumumab 6mg/kg IV over 60 minutes every 2 weeks.

Regorafenib27

Days 1–21: Regorafenib 160mg PO daily.

Repeat cycle every 28 days.

Adjuvant Chemotherapy Regimens1 Principals of Adjuvant Therapy1 FOLFOX is superior to 5-FU/leucovorin for patients with stage III colon cancer.28,29 Capecitabine/oxaliplatin is superior to bolus 5-FU/ leucovorin for patients with stage III colon cancer. FLOX is an alternative to FOLFOX or CapeOx but FOLFOX or CapeOx are preferred.30 Capecitabine appears to be equivalent to bolus 5-FU/leucovorin in patients with stage III colon cancer.31 A survival benefit has not been demonstrated for the addition of oxaliplatin to 5-FU/leucovorin in stage II colon cancer.32 FOLFOX is reasonable for high-risk stage II patients and is not indicated for good- or average-risk patients with stage II colon cancer.

A benefit for the addition of oxaliplatin to 5-FU/leucovorin in patients age 70 and older has not been proven.32 Bevacizumab, cetuximab, panitumumab, or irinotecan should not be used in the adjuvant setting for patients with stage II or III colon cancer outside the setting of a clinical trial. mFOLFOX633-35

Day 1: Oxaliplatin 85mg/m2 IV over 2 hours.

Day 1: Leucovorin 400mg/m2* IV over 2 hours.

Days 1–3: 5-FU 400mg/m2 IV bolus on day 1, then 1,200mg/m2/day × 2 days. (total 2,400mg/m2 over 46–48 hours)† continuous infusion.

Repeat cycle every 2 weeks.

FLOX36

5-FU 500mg/m2 IV bolus weekly × 6 + leucovorin 500mg/m2 IV weekly × 6, each 8-week cycle × 3 with oxaliplatin 85mg/m2 IV administered on weeks 1, 3, and 5 of each 8-week cycle × 3.

Capecitabine37

Days 1–14: 1,250mg/m2 twice daily PO. Repeat cycle every 3 weeks for 24 weeks.

CapeOx38

Day 1: Oxaliplatin 130mg/m2 over 2 hours, day 1.

Days 1–14: Capecitabine 1,000mg/m2 twice daily PO. Repeat cycle every 3 weeks for 24 weeks.

5-FU/leucovorin39,40

Leucovorin 500mg/m2 given as a 2-hour infusion and repeated weekly × 6 weeks, plus 5-FU 500mg/m2 given IV bolus 1 hour after the start of leucovorin and repeated weekly × 6 weeks.

Repeat cycle every 8 weeks for 4 cycles.

OR Simplified biweekly infusional 5-FU/LV (sLV5FU2) Leucovorin 400mg/m2* IV over 2 hours on day 1, followed by 5-FU bolus 400mg/m2 and then 1,200mg/m2/day × 2 days (total 2,400mg/m2 over 46-48 hours)† continuous infusion.

Repeat cycle every 2 weeks.

* Leucovorin 400mg/m2 is the equivalent of levoleucovorin 200mg/m2. † NCCN recommends limiting chemotherapy orders to 24-hour units (i.e., 1,200mg/m2/day NOT 2,400mg/m2 over 48 hours) to minimize medication errors. ‡ The majority of safety and efficacy data for this regimen have been developed in Europe, where a capecitabine starting dose of 1,000mg/m2 twice daily for 14 days, repeated every 21 days, is standard. Evidence suggests that North American patients may experience greater toxicity with capecitabine (as well as with other fluoropyrimidines) than European patients, and may require a lower dose of capecitabine. The relative efficacy of CapeOx with lower starting doses of capecitabine has not been addressed in large-scale randomized trials.

References 1.

2.

3.

Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Colon Cancer V.3.2015. Available at: http://www. nccn.org. Accessed August 28, 2015. deGramont A, Figer A, Seymour M, et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced rectal cancer. J Clin Oncol.

2000;18:2938–2947.

Cheeseman SL, Joel SP, Chester JD, et al. A “modified deGramont” regimen of fluorouracil, alone and with oxaliplatin, for advanced colorectal cancer.

Br J Cancer. 2002;87:393–399. Available at: http://www.ncbi.nlm.nih.gov/ pubmed/12177775.

4.

5.

6.

Maindrault-Goebel F, deGramont A, Louvet C, et al. Evaluation of oxaliplatin dose intensity in bimonthly leucovorin and 48-hour 5-fluorouracil continuous infusion regimens (FOLFOX) in pretreated metastatic colorectal cancer. Ann Oncol. 2000; 11:1477–1483.

Emmanouilides C, Sfakiotaki G, Androulakis N, et al. Front-line bevacizumab in combination with oxaliplatin, leucovorin and 5-fluorouracil (FOLFOX) in patients with metastatic colorectal cancer: a multicenter phase II study. BMC Cancer.

2007;7:91.

Douillard JY, Siena S, Cassidy J, et al. Randomized, phase Ill trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4

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CANCER TREATMENT REGIMEN

GASTROINTESTINAL CANCER References (continued) alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol. 2010;28: 4697–4705.

7. Venook AP, Niedzwiecki D, Lenz H-J, et al. CALGB/SWOG 80405: Phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab or cetuximab for patients with KRAS wild-type untreated metastatic adenocarcinoma of the colon or rectum [abstract]. ASCO Meeting Abstracts 2014;32:LBA3.

8. Saltz LB, Clarke S, Diaz-Rubio E, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase Ill study. J Clin Oncol. 2008;26:2013–2019.

Available at: http://www.ncbi.nlm.nih.gov/pubmed/18421054.

9. Andre T, Louvet C, Maindrault-Goebel F, et al. CPT-11 (irinotecan) addition to bimonthly, high-dose leucovorin and bolus and continuous-infusion 5-fluorouracil (FOLFIRI) for pretreated metastatic colorectal cancer. Eur J Cancer.

1999;35(9): 1343–1347.

10. Fuchs CS, Marshall J, Mitchell E, et al. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol.

2007;25: 4779–4786. Available at: http://www.ncbi.nlm.nih.gov/pubmed/ 17947725.

11. Cunningham D, Humblet Y, Siena 5, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N EngI J Med. 2004;351: 337–345.

12. Martin-Martorell P, Rosellô S, Rodriguez-Braun E, et al. Biweekly cetuximab and irinotecan in advanced colorectal cancer patients progressing after at least one previous line of chemotherapy: results of a phase II single institution trial.

Br J Cancer. 2008;99:455–458.

13. Peeters M, Price TJ, Cervantes A, et al. Randomized phase Ill study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Gun Oncol. 2010;28:4706–4713. Available at: http://www.ncbi.nlm.nih. gov/pubmed/20921462.

14. Van Cutsem E, Tabernero J, Lakomy R, et al. Addition of Aflibercept to Fluorouracil, Leucovorin, and Irinotecan Improves Survival in a Phase Ill Randomized Trial in Patients With Metastatic Colorectal Cancer Previously Treated With an Oxaliplatin-Based Regimen. J Clin Oncol. 2012;30:3499–3506.

Available at: http://www.ncbi.nlm.nih.gov/pubmed/22949147.

15. Tabernero J, Yoshino T, Cohn AL, et al. Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomized, double-blind, multicentre, phase 3 study. Lancet Oncol.

2015;16:499-508.

16. Van Cutsem E, Twelves C, Cassidy J, et al. Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase Ill study. J Clin Oncol.

2001;19:4097–4106.

17. Wolmark N. Rockette H, Fisher B, et al. The benefit of leucovorin-modulated fluorouracil as postoperative adjuvant therapy for primary colon cancer: results from National Surgical Adjuvant Breast and Bowel Protocol C-03. J Clin Oncol.

1993;11: 1879–1887.

18. Jäger E, Heike M, Bernhard H, et al. Weekly high-dose leucovorin versus low-dose leucovorin combined with fluorouracil in advanced colorectal cancer: results of a randomized multicenter trial. J Clin Oncol.

1996;14:2274–2279.

19. Douillard JY, Cunningham D, Roth AD, et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomized trial. Lancet. 2000;355:1041–1047.

20. Haller DG, Rothenberg ML, Wong AO, et al. Oxaliplatin plus irinotecan compared with irinotecan alone as second-line treatment after single agent fluoropyrimidine therapy for metastatic colorectal carcinoma. J Clin Oncol.

2008;26: 4544–4550.

21. Falcone A, Ricci S, Brunetti I, et al. Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: The Gruppo Oncologico Nord Ovest. J Clin Oncol.

2007; 25(13):1670–1676.

22. Loupakis F, Cremolini C, Masi G, et al. FOLFOXIRI plus bevacizumab (bev) versus FOLFIRI plus bev as first-line treatment of metastatic colorectal cancer (MCRC): results of the phase III randomized TRIBE trial. J Clin Oncol. 2013;31(Suppl 4) Abstract 336.

23. Cunningham D, Pyrhonen S, James R, et al. Randomized trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet. 1998;352:1413–1418.

24. Fuchs CS, Moore MR, Harker G, et al. Phase Ill comparison of two irinotecan dosing regimens in second-line therapy of metastatic colorectal cancer. J Clin Oncol.

2003;21:807–814.

25. Van Cutsem E, Tejpar S, Vanbeckevoort D, et al. Intrapatient Cetuximab Dose Escalation in Metastatic Colorectal Cancer According to the Grade of Early Skin Reactions: The Randomized EVEREST Study. J Clin Oncol. 2012;30:2861–2868.

Available at: http://www.ncbi.nlm.nih.gov/pubmed/22753904.

26. Van Custem E, Peeters M, Siena S, et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol.

2007;25:1658–1664.

27. Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381:303–312.

Available at: http://www.ncbi.nlm.nih.gov/pubmed/23177514.

28. Andre T, Boni C, Mounedji-Boudiaf L, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004;350:2343-51.

29. Andre T, Boni C, Navarro M, et al. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trail. J Clin Oncol. 2009;27:3109-16. Epub 2009 May 18.

30. Kuebler JP, Wieand HS, O’Connell MJ, et al. Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: results from NSABP C-07. J Clin Oncol. 2007;25:2198-2204.

31. Twelves C, Wong A, Nowacki MP, et al. Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med. 2005;352(26):2696-704.

32. Tournigand C, André T, Bonnetain F, et al. Adjuvant therapy with fluorouracil and oxaliplatin in stage II and elderly (between ages 70 and 75 years) with colon cancer: a subgroup analyses of the Multicenter International Study of oxaliplatin, fluorouracil, and leucovorin in the adjuvant treatment of colon cancer trial. J Clin Oncol. 2012;published online ahead of print on August 20, 2012.

33. Andre T, Boni C, Mounedji-Boudiaf L, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N EngI J Med. 2004;350:2343–2351.

34. Cheeseman SL, Joel SP, Chester JD, et al. A “modified deGramont” regimen of fluorouracil, alone and with oxaliplatin, for advanced colorectal cancer. Br J Cancer. 2002;87:393–399. Available at: http://www.ncbi.nlm.nih.gov/ pubmed/12177775.

35. Maindrault-Goebel F, deGramont A, Louvet C, et al. Evaluation of oxaliplatin dose intensity in bimonthly leucovorin and 48-hour 5-fluorouracil continuous infusion regimens (FOLFOX) in pretreated metastatic colorectal cancer. Annals of Oncology. 2000;11:1477–1483.

36. Kuebler JP, Wieand HS, O’Connell MJ, et al. Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: results from NSABP C-07. J Clin Oncol. 2007:25:2198–2204.

37. Twelves C, Wong A, Nowacki MP, et al. Capecitabine as adjuvant treatment for stage III colon cancer. N Eng J Med. 2005; 352:2696–2704.

38. Schmoll HJ, Cartwright T, Tabernero J, et al. Phase III trial of capecitabine plus oxaliplatin as adjuvant therapy for stage III colon cancer: a planned safety analysis in 1,864 patients. J Clin Oncol. 2007;25:102–109. Hailer DG, Tabernero J, Maroun J, et al. Capecitabine Plus Oxaliplatin Compared With Fluorouracil and Folinic Acid As Adjuvant Therapy for Stage Ill Colon Cancer. J Clin Oncol 2011;29:1465–1471.

Available at: http://www.ncbi.nlm.nih.gov/pubmed/21383294.

39. Haller DG, Catalano PJ, Macdonald JS Mayer RJ. Phase III study of fluorouracil, leucovorin and levamisole in high risk stage II and III colon cancer: final report of Intergroup 0089. J Clin Oncol. 2005:23:8671–8678.

40. Andre T, Louvet C, Maindrault-Goebel F, et al. CPT-11 (irinotecan) addition to bimonthly, high-dose leucovorin and bolus and continuous-infusion 5-fluorouracil (FOLFIRI) for pretreated metastatic colorectal cancer. Eur J Cancer.

(Revised 9/2015) © 2015 by Haymarket Media, Inc

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DRUG MONOGRAPHS

GASTROINTESTINAL CANCER AVASTIN Genentech

℞

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

Indications: Metastatic colorectal carcinoma, in combination with 5-FU-based chemotherapy for first- or second-line treatment; or in combination with fluoropyrimidine-irinotecanor fluoropyrimidine-oxaliplatin-based therapy for second-line treatment in patients who have progressed on a first-line Avastin-containing regimen. Limitation of use: not for adjuvant treatment of colon cancer.

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

5mg/kg (when used with bolus-IFL) or 10mg/kg (when used with FOLFOX-4) once every 2 weeks until disease progression detected; 5mg/kg every 2 weeks or 7.5mg/kg every 3 weeks (when used with fluoropyrimidineirinotecan- 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-tosevere proteinuria (resume when <2g/24hrs), or severe infusion reaction occurs. Avoid in ovarian cancer if evidence of recto-sigmoid involvement by pelvic exam, bowel involvement on CT scan, or symptoms of bowel obstruction.

History of arterial thromboembolism. Diabetes.

Monitor BP every 2–3 weeks. Monitor proteinuria by dipstick urine analysis; if ≥2+, do further assessment with a 24-hour urine collection.

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

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

How supplied: Single-use vial—1

CYRAMZA Lilly

℞

Human IgG1 monoclonal antibody. Ramucirumab 10mg/mL; per vial; soln for IV infusion after dilution; preservative-free.

Indications: As a single agent, or in combination with paclitaxel, for treatment of advanced or metastatic, gastric or gastro-esophageal junction adenocarcinoma with disease progression on or after prior fluoropyrimidineor platinum-containing chemotherapy. In combination with FOLFIRI (irinotecan, folinic acid, and 5-fluorouracil), for the treatment of metastatic colorectal cancer (mCRC) with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine.

Adults: Give by IV infusion over 60 mins.

Premedicate with IV histamine H1-antagonist (eg, diphenhydramine) prior to each infusion; or with dexamethasone and acetaminophen in those who have experienced Grade 1 or 2 infusion reaction. Gastric cancer: 8mg/kg every 2 weeks.

When given in combination: administer prior to paclitaxel. mCRC: 8mg/kg every 2 weeks prior to FOLFIRI. Continue until disease progression or unacceptable toxicity. Dose modifications: see full labeling.

Children: Not established.

Warnings/Precautions: Increased risk of hemorrhage; permanently discontinue if severe bleeding occurs. Control hypertension prior to initiating. Monitor blood pressure every 2 weeks or more frequently as indicated; if severe hypertension develops, temporarily suspend until medically controlled. Monitor for infusion-related reactions during therapy.

Have emergency resuscitative equipment available. Permanently discontinue if severe arterial thromboembolic events, severe uncontrolled hypertension (despite antihypertensives), hypertensive crisis or encephalopathy, Grade 3 or 4 infusion-related reactions, urine protein >3g/24hrs, nephrotic

syndrome, or GI perforation occurs. Impaired wound healing: withhold Cyramza prior to surgery. Clinical deterioration in patients with Child-Pugh B or C cirrhosis (eg, new or worsening encephalopathy, ascites, hepatorenal syndrome). Discontinue if reversible posterior leukoencephalopathy syndrome develops.

Monitor proteinuria by urine dipstick and/or urinary protein creatinine ratio. Monitor thyroid function. Pregnancy: avoid. Use effective contraception during therapy and for ≥3 months after last ramucirumab dose. Nursing mothers: not recommended.

Adverse reactions: Hypertension, diarrhea, headache, fatigue, asthenia, hyponatremia, anemia, intestinal obstruction, neutropenia, epistaxis, stomatitis/mucosal inflammation, rash, decreased appetite; arterial thromboembolic events, proteinuria, GI perforation, infusionrelated 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,

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

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DRUG MONOGRAPHS

GASTROINTESTINAL CANCER anemia, GI upset, increased liver enzymes, emesis, fatigue, stomatitis; hypersensitivity reactions (monitor), pulmonary fibrosis (may be fatal), hepatotoxicity.

Testing considerations: ERCC1 overexpression How supplied: Single-use vials (50mg, 100mg, 200mg)—1

ERBITUX Bristol-Myers Squibb

℞

Epidermal growth factor receptor blocker.

Cetuximab 100mg/vial, 200mg/vial; soln for IV infusion; preservative-free.

Indications: K-Ras (wild-type), EGFRexpressing metastatic colorectal cancer: for use in combination with FOLFIRI (irinotecan, 5-fluorouracil, leucovorin) for first-line treatment,

or in combination with irinotecan (if refractory to irinotecan-based chemotherapy), or as a single agent (after failure of both irinotecan- and oxaliplatin-based regimens or if irinotecanintolerant). Limitation of use: not indicated for Ras mutant colorectal cancer that harbor somatic mutations in exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146) or when Ras mutation test results are unknown.

Adults: Pretreat with H1 blocker. Give by IV infusion (use filter); max rate: 10mg/min.

Initial dose: 400mg/m2 once over 2hrs; then 250mg/m2 once weekly over 1 hour until disease progression or unacceptable toxicity.

Complete administration 1hr prior to FOLFIRI. Permanently reduce infusion rate by 50% if

Grade 1 or 2 and non-serious Grade 3 infusion reaction occurs; permanently discontinue if Grade 3 or 4 serious reaction occurs. Monitor patient during and for 1hr post-infusion. Skin toxicity: see full labeling.

Children: Not established.

Warnings/Precautions: Confirm EGFR expression status and absence of Ras mutation for colorectal cancer prior to initiation.

Discontinue if severe infusion reactions or interstitial lung disease occur. Monitor for infusion reactions, cardiopulmonary arrest, pulmonary toxicity, dermatologic toxicities/ infection; avoid sun, UV light. Additive cutaneous reactions with irradiation. Cardiovascular diseases (w. irradiation or platinum-based therapy with 5-FU). Monitor electrolytes (eg,

FDA-APPROVED COLORECTAL CANCER TREATMENTS Generic Brand ALKYLATING AGENTS

Strength

Form

oxaliplatin

5mg/mL

soln for IV infusion Day 1: 85mg/m2 + leucovorin, followed by 5–FU. after dilution Day 2: Leucovorin followed by 5–FU. Give by IV infusion every 2wks for a total of 6mos (eg, 12 cycles).

Eloxatin

Usual Dose

ANTIMETABOLITES capecitabine

Xeloda

150mg, 500mg tabs

1250mg/m2 twice daily for 2wks on and 1wk off, for a total of 8 cycles

fluorouracil

—

50mg/mL

12mg/kg once daily for 4 successive days; max 800mg/day. If no toxicity, then 6mg/kg on days 6, 8, 10, 12; stop after day 12. Discontinue if toxicity occurs.

soln for IV inj

FOLIC ACID DERIVATIVE leucovorin

—

levoleucovorin Fusilev

100mg, 350mg lyophilized pwd for IV or IM inj reconstitution

200mg/m2 by slow IV inj over a minimum of 3min followed by 5-fluorouracil (370mg/m2); or 20mg/m2 IV followed by 5-fluorouracil (425mg/m2); both regimens: daily for 5 days, may be repeated at 4-week intervals for 2 courses and then repeated at 4–5-week intervals

lyophilized powder 100mg/m2 by slow IV inj over a minimum of 3min, followed by 5-FU at for IV inj after 370mg/m2 by IV inj; or 10mg/m2 by IV inj followed by 5-FU at 425mg/m2 reconstitution

by IV inj. Administer 5-FU separately to avoid precipitate formation. Treat daily for 5wks; may repeat at 4-week intervals for 2 courses, then at 4–5175mg/17.5mL, soln for IV inj week intervals.

250mg/25mL 50mg/vial

FUSION PROTEIN ziv-aflibercept Zaltrap

25mg/mL

soln for IV infusion 4mg/kg as an IV infusion over 1hr every 2wks; continue until disease after dilution progression or unacceptable toxicity.

MONOCLONAL ANTIBODIES bevacizumab

Avastin

100mg, 400mg soln for IV infusion 5mg/kg (with bolus–IFL) or 10mg/kg (with FOLFOX–4) once every 14 days after dilution until disease progression detected; 5mg/kg every 2wks or 7.5mg/kg every 3wks (when used with fluoropyrimidine-irinotecan- or fluoropyrimidineoxaliplatin-based therapy). 1st infusion over 90min, 2nd infusion over 60min, subsequent infusion over 30min.

cetuximab

Erbitux

100mg, 200mg soln for IV infusion Loading dose: 400mg/m2 once over 2hrs; then 250mg/m2 once weekly over 1hr

panitumumab Vectibix

20mg/mL

soln for IV infusion 6mg/kg as IV inf over 60min once every 14 days. Doses >1000mg: infuse after dilution over 90min.

TOPOISOMERASE INHIBITORS irinotecan

Camptosar 20mg/mL

soln for IV infusion Combination therapy (with 5-FU and leucovorin): 125mg/m2 on days 1, 8, 15, after dilution 22; or, 180mg/m2 on days 1, 15, 29; both: give every 6wks.

Monotherapy: 125mg/m2 on days 1, 8, 15, 22, then 2-week rest; or, 350mg/m2 once every 3wks.

Notes

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

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DRUG MONOGRAPHS

GASTROINTESTINAL CANCER 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,

Download the Oncology Nurse Advisor app for convenient access to clinical information and updates relevant to the oncology nursing community.

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DRUG MONOGRAPHS

GASTROINTESTINAL CANCER night sweats, anorexia, pruritus, hemorrhage, anemia, neutropenia, thrombocytopenia, weight gain, renal or hepatotoxicity, immunosuppression, hypothyroidism; rare: severe CHF, LV dysfunction.

How supplied: 100mg—90; 400mg—30

HERCEPTIN Genentech

℞

Human epidermal growth factor receptor (HER2) inhibitor. Trastuzumab 440mg/vial; lyophilized pwd for IV infusion after reconstitution and dilution; preservative-free.

Indications: HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma, in combination with cisplatin and capecitabine or 5-fluorouracil, in patients who have not received prior treatment.

Adults: Do not substitute for or with adotrastuzumab emtasine. Give as IV infusion.

Initially 8mg/kg over 90 mins, followed by

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.

6mg/kg over 30–90 mins every 3 weeks until disease progression. Infusion reactions or cardiomyopathy: see full labeling.

Children: Not established.

Warnings/Precautions: Increased risk of cardiomyopathy. Conduct cardiac assessment (eg, history, physical exam, LVEF) at baseline, every 3 months during and after therapy or every 6 months for ≥2yrs after therapy (if adjuvant); repeat LVEF at 4 week intervals if dose is withheld due to significant left ventricular cardiac dysfunction. Interrupt therapy if dyspnea or significant hypotension occurs; consider discontinuing permanently if severe infusion reactions, CHF, pulmonary toxicity, or significant left ventricular myocardial dysfunction develops. Symptomatic intrinsic lung disease.

Extensive tumor involvement of the lungs. Test for HER2 protein overexpression and HER2 gene amplification using FDA-approved tests for specific tumor type (breast or gastric/ gastroesophageal adenocarcinoma). Elderly.

Pregnancy (Cat.D); use adequate contraception during and at least 7 months after therapy.

Nursing mothers: not recommended.

Interactions: Increased cardiomyopathy with anthracycline-containing chemotherapy.

Increased toxicity with other myelosuppressives.

Potentiated by paclitaxel.

Adverse reactions: Diarrhea, fatigue, anemia, stomatitis, weight loss, upper respiratory tract infections, fever, thrombocytopenia, mucosal inflammation, nasopharyngitis, dysgeusia, infections; severe infusion reactions, febrile neutropenia/exacerbation of chemotherapyinduced neutropenia, pulmonary toxicity (eg, interstitial pneumonitis), cardiomyopathy (eg, left ventricular myocardial dysfunction); pregnant women: possible oligohydramnios (monitor).

Testing considerations: HER2 protein overexpression How supplied: Vial—1 (w. diluent)

Leucovorin Teva

℞

Folic acid derivative. Leucovorin calcium 100mg/vial, 350mg/vial; lyophilized pwd for IV or IM inj after reconstitution; preservative-free.

Indications: Palliative treatment of advanced colorectal cancer in combination with 5-fluorouracil.

Adults: Max IV infusion rate: 160mg/min.

200mg/m2 by slow IV inj over a minimum of 3 minutes, followed by 5-fluorouracil (370mg/m2); or 20mg/m2 IV followed by 5-fluorouracil (425mg/m2); both regimens: daily for 5 days, may be repeated at 4-week intervals for 2 courses and then repeated at 4–5 week intervals (if completely recovered from toxic effects of previous course).

Children: See literature.

Contraindications: Pernicious anemia and other megaloblastic anemias due to Vit. B12 deficiency.

Warnings/Precautions: Do not administer intrathecally. CNS metastases. Monitor CBCs with differential, platelets, electrolytes, liver function tests prior to each treatment, then periodically.

Elderly. Debilitated. Pregnancy (Cat.C). Nursing mothers.

Interactions: Potentiates toxicity of 5-fluorouracil; use lower 5-fluorouracil dose.

May antagonize phenobarbital, phenytoin, and primidone. Caution with 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

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DRUG MONOGRAPHS

GASTROINTESTINAL CANCER STIVARGA Bayer

℞

Kinase inhibitor. Regorafenib 40mg; tabs.

Indications: Treatment of patients with metastatic colorectal cancer who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecanbased chemotherapy, an anti-VEGF therapy, and, if KRAS wild type, an anti-EGFR therapy. Treatment of patients with locally advanced, unresectable or metastatic gastrointestinal stromal tumor (GIST) who have been previously treated with imatinib mesylate or sunitinib malate.

Adults: Swallow whole with water after a lowfat meal (contains <600 calories and <30% fat). 160mg once daily for the first 21 days of each 28-day cycle; until disease progression or unacceptable toxicity. Dose modifications: see full prescribing information.

Children: <18yrs: not established.

Warnings/Precautions: Risk of severe hepatotoxicity (may be fatal). Monitor hepatic function before starting and at least every 2 weeks during first 2 months of treatment; interrupt and reduce or discontinue if hepatotoxicity or hepatocellular necrosis occurs. Severe hepatic impairment: not recommended. Increased risk of hemorrhage; permanently discontinue if severe or life-threatening. Interrupt and reduce or permanently discontinue if dermatological toxicity occurs (eg, hand-foot skin reaction [a.k.a. palmar-plantar erythrodysesthesia], rash). Ensure BP is controlled before starting; monitor weekly for the first 6 weeks then every cycle or as clinically indicated; withhold if severe or uncontrolled. Myocardial ischemia/ infarction: withhold if new or acute onset develops; resume when resolved. Discontinue if reversible posterior leukoencephalopathy syndrome (RPLS) or GI perforation/fistula develops. Wound healing complications: stop treatment at least 2 weeks before surgery; discontinue if wound dehiscence occurs. Fetal toxicity. Pregnancy (Cat.D); use effective contraception during treatment and up to 2 months after completion. Nursing mothers: not recommended.

Interactions: Avoid concomitant strong CYP3A4 inducers (eg, rifampin, phenytoin, carbamazepine, phenobarbital, St. John’s Wort). Avoid concomitant strong CYP3A4 inhibitors (eg, clarithromycin, grapefruit juice, itraconazole, ketoconazole, posaconazole, telithromycin, voriconazole).

Monitor INR levels with concomitant warfarin.

Adverse reactions: Asthenia/fatigue, decreased appetite and food intake, hand-foot skin reaction, diarrhea, mucositis, weight loss, infection, hypertension, dysphonia, GI and abdominal pain, rash, fever, nausea; hepatotoxicity, hemorrhage, GI perforation, cardiac ischemia/infarction, RPLS. How supplied: Tabs—84 (3 × 28)

SUTENT Pfizer

℞

Multikinase inhibitor. Sunitinib (as malate) 12.5mg, 25mg, 37.5mg, 50mg; gelatin caps.

Indications: Gastrointestinal stromal tumor (GIST) after disease progression on or intolerance to imatinib mesylate.

Adults: 50mg once daily for 4 weeks, then 2 weeks off (see full labeling). May adjust dose in increments or decrements of 12.5mg. Concomitant strong CYP3A4 inhibitors (see Interactions): may reduce dose to 37.5mg daily. Concomitant strong CYP3A4 inducers (see Interactions): may increase to max 87.5mg daily.

Children: Not established.

Warnings/Precautions: Hepatotoxicity; may be severe or fatal. Monitor liver function tests before starting, during each cycle of treatment and as clinically needed; interrupt if Grade 3 or 4 hepatic adverse events occur and discontinue if no resolution; if severe liver function changes or signs/ symptoms of failure, do not restart. Cardiovascular events: monitor for CHF during therapy, and LVEF at baseline and periodically; interrupt or reduce dose if LVEF <50% and >20% below baseline; discontinue if CHF occurs. History of QT prolongation or proarrythmic conditions (eg, bradycardia, electrolyte disturbances); perform periodic ECG, monitor electrolytes. Monitor BP. Suspend therapy if severe hypertension, seizures, or pancreatitis develops. Obtain CBCs, platelets, serum chemistries at start of each cycle. Concomitant exposure to risk factors (eg, IV bisphosphonates therapy or dental disease) may increase the risk of osteonecrosis of the jaw; avoid or consider preventive dentistry prior to treatment. Risk of tumor lysis syndrome: monitor closely in RCC and GIST patients with high tumor burden. Monitor for thyroid dysfunction; obtain baseline levels prior to treatment. Monitor blood glucose levels during and after treatment discontinuation. Monitor for proteinuria; perform baseline and periodic urinalyses; interrupt and reduce dose if 24-hr urine protein ≥3g; discontinue if nephrotic syndrome or repeat urine protein ≥3g persists. Undergoing major surgery. Stress (monitor for adrenal insufficiency).

Discontinue if severe cutaneous reactions (eg, erythema multiforme, SJS, TEN) develop; do not restart if diagnosis suspected. ESRD on dialysis.

Severe hepatic impairment. Pregnancy (Cat.D; avoid). Nursing mothers: not recommended.

Interactions: May be potentiated by strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole), grapefruit; consider reducing dose or use alternate drug. May be antagonized by CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin,

phenobarbital); consider increasing dose or use alternate drug. Concomitant St. John’s wort: not recommended. Caution with concomitant antiarrhythmics.

Adverse reactions: Fatigue, asthenia, fever, diarrhea, nausea, vomiting, mucositis/stomatitis, dyspepsia, abdominal pain, constipation, hypertension, peripheral edema, rash, handfoot syndrome, skin discoloration, dry skin, hair color changes, altered taste, headache, back pain, arthralgia, extremity pain, cough, dyspnea, anorexia, bleeding; hepatotoxicity, left ventricular dysfunction, QT prolongation, osteonecrosis of the jaw, tumor lysis syndrome, thyroid dysfunction, impaired wound healing, hypoglycemia, thrombotic microangiopathy (discontinue if develops), proteinuria, necrotizing fasciitis (discontinue if occurs), others (see full labeling).

How supplied: Caps—28

VECTIBIX Amgen

℞

Human epidermal growth factor receptor (EGFR) inhibitor. Panitumumab 20mg/mL; soln for IV infusion after dilution; preservative-free.

Indications: First-line treatment of wild-type KRAS metastatic colorectal carcinoma (mCRC) in combination with FOLFOX, or as monotherapy following disease progression after prior fluoropyrimidine-, oxaliplatin-, and irinotecancontaining chemotherapy as determined by an FDA-approved test. Limitation of use: not for treating KRAS-mutant mCRC or for whom KRAS mutation status is unknown.

Adults: 6mg/kg by IV infusion over 60 mins once every 14 days. If 1st infusion is tolerated, give subsequent infusions over 30–60 mins.

Doses >1000mg: infuse over 90 mins. Dose modifications: see full labeling.

Children: Not established.

Warnings/Precautions: Confirm absence of a KRAS mutation using an FDA-approved test prior to initiation. Withhold or discontinue therapy for dermatologic or soft tissue toxicity associated with severe inflammatory or infectious complications; monitor. Discontinue if severe infusion reactions develop. Interrupt therapy if acute onset or worsening of pulmonary symptoms; discontinue if interstitial lung disease (ILD) is confirmed. Limit sun exposure. Monitor electrolytes (eg, magnesium, calcium) prior to initiation, during, and for 8 weeks after completing therapy. Monitor for ocular toxicities (eg, keratitis); interrupt or discontinue if occur. May impair fertility in women; use effective contraception during treatment and for 6 months following last dose. Pregnancy (Cat.C). Nursing mothers: not recommended; discontinue during therapy and for 2 months after last dose.

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DRUG MONOGRAPHS

GASTROINTESTINAL CANCER Interactions: Concomitant bevacizumab and chemotherapy: increased mortality and toxicity may occur.

Adverse reactions: Skin rash, paronychia, fatigue, nausea, diarrhea; hypomagnesemia, hypocalcemia, hypokalemia, dermatologic toxicities with possible infection (may be fatal), infusion reactions, immunogenicity, ILD, pulmonary fibrosis, keratitis, photosensitivity, possible acute renal failure w. chemotherapy.

Testing considerations: EGFR amplification analysis, K-RAS mutation analysis.

How supplied: Single-use vial (5mL, 10mL, 20mL)—1

XELODA Genentech

Warnings/Precautions: Hepatic or renal dysfunction. Monitor and correct dehydration at initiation. Coronary artery disease. Interrupt therapy if severe diarrhea occurs; give antidiarrheals until resolves or reduces to Grade 1. Dihydropyrimidine dehydrogenase deficiency.

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

Interactions: Increased anticoagulant effect with warfarin; monitor PT/INR frequently.

Potentiated by leucovorin. Monitor phenytoin and other CYP2C9 substrates.

Adverse reactions: Diarrhea, hand-andfoot syndrome, nausea, vomiting, abdominal pain, fatigue/weakness, hyperbilirubinemia; lymphopenia, necrotizing enterocolitis, stomatitis, dermatitis, anorexia, cardiotoxicity, blood dyscrasias, paresthesias, eye irritation, edema, myalgia, dehydration, alopecia; severe mucocutaneous reactions (eg, SJS, TEN); permanently discontinue if occurs.

Testing considerations: TS (thymidylate synthase), MSI (microsatellite instability), DPD (dihydropyrimidine dehydrogenase) How supplied: Tabs 150mg—60; 500mg—120

℞

Fluoropyrimidine. Capecitabine (prodrug of 5-fluorouracil) 150mg, 500mg; tabs.

Indications: First-line treatment of metastatic colorectal carcinoma when fluoropyrimidine therapy alone is preferred. Adjuvant treatment of Dukes’ C colon cancer after complete resection of the primary tumor when fluoropyrimidine therapy alone is preferred.

Adults: See full labeling. Give cyclically (2 weeks on, 1 week off). Swallow whole. Take with water within 30 minutes after AM & PM meals. ≥18yrs: 1250mg/m2 twice daily. Continue for a total of 8 cycles. Interrupt, adjust dose, and/or treat symptoms if toxicity occurs (eg, hyperbilirubinemia, diarrhea, nausea, vomiting, hand-and-foot syndrome, stomatitis) (see full labeling); do not increase dose afterwards. Renal impairment (CrCl 51–80mL/min): monitor carefully; (CrCl 30–50mL/min): reduce capecitabine dose to 75% of starting dose (ie, 950mg/m2 twice daily).

Children: <18yrs: not established.

Contraindications: Severe renal impairment (CrCl <30mL/min).

ZALTRAP Sanofi US and Regeneron

℞

Fusion protein. Ziv-aflibercept 25mg/mL; soln for IV infusion after dilution; preservative-free.

Indications: In combination with 5-fluorouracil, leucovorin, irinotecan (FOLFIRI) for patients with metastatic colorectal cancer (mCRC) that is resistant to or has progressed following an oxaliplatin-containing regimen.

Adults: Start ziv-aflibercept prior to any component of the FOLFIRI regimen on treatment day. Give 4mg/kg as an IV infusion over 1hr every 2 weeks; continue until disease progression or unacceptable toxicity. For recurrent or severe

hypertension, suspend until controlled. Upon resumption, permanently reduce to 2mg/kg. For recurrent proteinuria, suspend until proteinuria <2g per 24hrs, then permanently reduce to 2mg/kg.

Children: Not established.

Warnings/Precautions: Increased risk of hemorrhage; monitor for signs/symptoms. Do not start in patients with severe hemorrhage; discontinue if develops. Monitor for GI perforation, fistula formation, compromised wound healing; discontinue if occurs. Suspend therapy at least 4 weeks prior to elective surgery; do not resume for at least 4 weeks following major surgery and until wound is fully healed. Monitor BP every 2 weeks and treat appropriately if hypertension occurs; temporarily suspend until controlled; discontinue if hypertensive crisis/encephalopathy occurs. Discontinue if arterial thromboembolic events (eg, transient ischemic attack, cerebrovascular accident, angina pectoris) occur.

Monitor for proteinuria; suspend if proteinuria ≥2g per 24hrs; discontinue if nephrotic syndrome or thrombotic microangiopathy occurs. Monitor CBC with differential at baseline and prior to start of each cycle; delay until neutrophils ≥1.5×109/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

LIVER FUNCTION ASSESSMENT Child-Pugh Score is used to assess residual liver function and injury severity in cirrhosis patients.

CHILD-PUGH SCORES Criteria

1 point

2 points

3 points

Total serum bilirubin (mg/dL)

<2

2–3

>3

Serum albumin (g/dL)

>3.5

2.8–3.5

<2.8

INR

<1.70

1.71–2.20

>2.20

Ascites

No ascites

Ascites controlled

Ascites not controlled

Encephalopathy

No encephalopathy

Encephalopathy controlled

Encephalopathy not controlled

Class A

Class B

Class C

Points

5–6

7–9

10–15

Life expectancy

15–20 years

Candidate for liver transplant

1–3 years

Perioperative mortality

10%

30%

82%

INTERPRETATION OF CHILD-PUGH SCORES

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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

Read the latest oncology headlines, including practice-changing research and practical commentary from experts by visiting CancerTherapyAdvisor.com.

CancerTherapyAdvisor.com | NOVEMBER/DECEMBER 2015 | CANCER THERAPY ADVISOR 47

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DRUG MONOGRAPHS

GENITOURINARY CANCER vascular disease, and risks factors (eg, hypertension, diabetes, obesity, SLE). Familial hyperlipoprotenemia. Monitor BP. Discontinue if jaundice occurs and before prolonged immobilization (eg, surgery).

Adverse reactions: See literature. GI upset, headache, hypertension, edema, hypercalcemia, gallbladder or thromboembolic disease, gynecomastia, impotence, impaired glucose tolerance.

How supplied: Multi-dose vials (5mL)—1

ELIGARD 7.5mg 1-MONTH

℞

Tolmar

GnRH analogue. Leuprolide acetate 7.5mg per inj; ext-rel susp; for SC inj.

Also: ELIGARD 22.5mg 3-MONTH ℞ Sanofi Aventis Leuprolide acetate 22.5mg per inj; ext-rel susp; for SC inj.

Also: ELIGARD 30mg 4-MONTH ℞ Sanofi Aventis Leuprolide acetate 30mg per inj; ext-rel susp; for SC inj.

Also: ELIGARD 45mg 6-MONTH ℞ Sanofi Aventis Leuprolide acetate 45mg per inj; ext-rel susp; for SC inj.

Indications: Palliative treatment of advanced prostate cancer.

Adults: Allow product to reach room temperature before using; inject within 30 minutes of mixing.

Use correct formulation. 7.5mg SC once per month; or 22.5mg SC once every 3 months; or 30mg SC once every 4 months; or 45mg SC once every 6 months. Rotate inj site.

Children: Not established.

Contraindications: Women. Pregnancy (Cat.X).

Warnings/Precautions: May worsen metastatic vertebral lesions and/or urinary tract obstruction; monitor closely during first few weeks. Increased risk of diabetes, MI, sudden cardiac death, stroke; monitor blood glucose, HbA1c, and for signs/symptoms of CVD during therapy. Risk of QT prolongation in patients with congenital long QT syndrome, CHF, or frequent electrolyte abnormalities. Correct and monitor electrolyte abnormalities; consider monitoring ECGs. Monitor serum testosterone, PSA periodically. Nursing mothers: not recommended.

Interactions: Caution with concomitant drugs known to prolong the QT interval. May interfere with pituitary-gonadal diagnostic tests.

Adverse reactions: Malaise, fatigue, hot flashes/sweats, testicular atrophy, gynecomastia, local reactions, pain, spinal cord compression, decreased bone density; transient worsening of signs/symptoms (eg, bone pain, neuropathy, hematuria, bladder outlet obstruction); rare: pituitary apoplexy.

How supplied: Single-use kit—1 (with sterile or sterile safety needle)

EMCYT Pfizer

℞

Estramustine phosphate sodium (prodrug of estradiol) 140mg; caps.

Indications: Palliative of metastatic, progressive prostate cancer.

Adults: Take 1 hour before or 2 hours after meals.

14mg/kg in 3 or 4 divided doses; reevaluate after 30 to 90 days. Continue as long as favorable response maintained.

Children: Not applicable.

Contraindications: Active thrombophlebitis or thromboembolic disorders (except when tumor mass caused by thromboembolic phenomenon). Allergy to estradiol, nitrogen mustard.

Warnings/Precautions: History of thrombophlebitis, thrombosis, thromboembolic disorders. Cerebro- or cardiovascular disease.

Diabetes. Hypertension. Conditions aggravated by fluid retention. Renal or hepatic dysfunction.

Monitor bilirubin and hepatic enzymes during and for 2 months after treatment is discontinued. Metabolic bone diseases associated with hypercalcemia. Use effective contraception.

Interactions: Absorption impaired by calcium.

Adverse reactions: Edema, dyspnea, leg cramps; nausea, diarrhea, GI upset; pruritus, dry skin, easy bruising; breast tenderness and enlargement; lethargy, emotional lability, insomnia; leucopenia; abnormal bilirubin, LDH, SGOT. Thrombosis, MI. How supplied: Caps—100

ESTRACE Warner Chilcott

℞

Estrogen. Estradiol 0.5mg, 1mg, 2mg+; scored tabs; +contains tartrazine.

Indications: Palliative treatment of androgendependent advanced prostate cancer.

Adults: 1–2mg 3 times daily.

Children: Not applicable.

Contraindications: Thrombophlebitis.

Thromboembolic disorders. Cerebrovascular disorders. Abnormal undiagnosed genital bleeding. Estrogen-depended neoplasias.

Liver dysfunction or disease. Pregnancy (Cat.X).

Warnings/Precautions: Asthma (2mg tabs).

Hepatic dysfunction. Conditions aggravated by fluid retention. Cardiovascular disorders, arterial vascular disease, and risks factors (eg, hypertension, diabetes, obesity, SLE).

Familial hyperlipoprotenemia. Monitor BP. Discontinue if jaundice occurs and before prolonged immobilization (eg, surgery). Nursing mothers.

Adverse reactions: See literature. GI upset, headache, hypertension, edema, hypercalcemia, gallbladder or thromboembolic disease, gynecomastia, impotence, impaired glucose tolerance.

How supplied: Tabs—100

FIRMAGON Ferring

℞

GnRH receptor antagonist. Degarelix 80mg/vial, 120mg/vial; pwd for SC inj after reconstitution.

Indications: Advanced prostate cancer.

Adults: Give by SC inj in abdomen once every 28 days; avoid waist and rib areas. Two 120mg injections once, then one 80mg inj once every 28 days.

Children: Not established.

Contraindications: Pregnancy (Cat.X).

Warnings/Precautions: Congenital long QT syndrome. CHF. Correct electrolyte abnormalities. Monitor electrolytes and ECG periodically. Monitor serum PSA. Discontinue if serious hypersensitivity reaction occurs; do not rechallenge. Moderate or severe renal impairment (CrCl <50mL/min). Severe hepatic impairment.

Nursing mothers: not recommended.

Interactions: Caution with concomitant drugs known to prolong the QT interval.

Adverse reactions: Inj site reactions (eg, pain, erythema, swelling, induration), hot flashes, increased weight, fatigue, increased transaminases, increased gammaglutamyltransferase; QT prolongation.

How supplied: Treatment Initiation pack (120mg/vial)—2 (w. supplies); Treatment Maintenance pack (80mg/vial)—1 (w. supplies)

Flutamide (various)

℞

Antiandrogen. Flutamide 125mg; caps.

Indications: In combination with LHRH agonists (GnRH analogues) in locally confined stage B2–C and stage D2 metastatic prostate carcinoma.

Adults: 250mg every 8 hrs.

Children: Not applicable.

Contraindications: Severe hepatic impairment.

ALT ≥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;

48 CANCER THERAPY ADVISOR | NOVEMBER/DECEMBER 2015 | CancerTherapyAdvisor.com

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For men with mCRPC who have progressed on ADT

Z Y T I G A® & P R E D N I S O N E

LET’S

DO

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

IMPORTANT SAFETY INFORMATION 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.

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

Please see additional Important Safety Information on the next pages.

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

Date: 10/13/15 Customer Code: 037771-150729 Group 360 Job #: 740851 File Name: 037771-150729_740851_v1 (p1 Right hand start) Brand: Zytiga Size: 7.75" x 10.5" Colors: CMYK Description: Lets Do This Pub: Cancer Therapy Advisor (11/1/15 ONLINE Issue) K

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STRONG

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For men with mCRPC who have progressed on ADT

ZYTIGA® & PREDNISONE: (abiraterone acetate)

In the final analysis of the pivotal phase 3 trial*…

ZYTIGA® + prednisone achieved a median OS of almost 3 years (34.7 months) after a median 4 years (49 months) of follow-up† months improvement in median  4.4 overall survival—34.7 months with

Median

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—at the prespecified rPFS analysis, 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

4 Years



(49 months)

of follow-up

034441-150514

© Janssen Biotech, Inc. 2015 8/15 037771-150729

Date: 10/13/15 Customer Code: 037771-150729 Group 360 Job #: 740851 File Name: 037771-150729_740851_v1 (p2 Left side) Brand: Zytiga Size: 7.75" x 10.5" Colors: CMYK Description: Lets Do This Pub: Cancer Therapy Advisor (11/1/15 ONLINE Issue) K

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

Janssen Biotech, Inc.

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IMPORTANT SAFETY INFORMATION 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.

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).

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Let’s do this 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 analyses1 in women who are or may become pregnant; warnings and Contraindicated precautions include mineralocorticoid excess, adrenocortical insufficiency, and hepatotoxicity

most common adverse reactions (≥10%) are fatigue, joint swelling or The discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension,

hyperglycemia, elevated AST, hypophosphatemia, elevated ALT, and hypokalemia

OS = overall survival; rPFS = radiographic progression-free survival. *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 rPFS. Select exclusion criteria included aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≥2.5X ULN, liver metastases, moderate or severe pain, opiate use for cancer pain, prior ketoconazole treatment for prostate cancer, a history of adrenal gland or pituitary disorders, 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.

II At the prespecified rPFS analysis, 150 (28%) of patients treated with ZYTIGA® + prednisone and 251 (46%) of patients treated with placebo + prednisone had radiographic progression.

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.

STRONG T O G E T H E R

Learn more today at www.zytigahcp.com

Date: 10/13/15 Customer Code: 037771-150729 Group 360 Job #: 740851 File Name: 037771-150729_740851_v1 (p3 Right side) Brand: Zytiga Size: 7.75" x 10.5" Colors: CMYK Description: Lets Do This Pub: Cancer Therapy Advisor (11/1/15 ONLINE Issue) K

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most common laboratory abnormalities (>20%) are anemia, elevated alkaline The phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia,

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dyspnea, urinary tract infection, and contusion

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

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 repeat every 3 weeks or after hematological recovery (platelets ≥100000/µL, WBC ≥4000/µL).

Children: Not recommended.

Contraindications: Severe bone marrow depression.

Warnings/Precautions: Discontinue if neurologic effects (eg, somnolence, confusion, hallucinations) occur. Do urinalysis before each dose, postpone dose if hematuria occurs. Give mesna and at least 2L fluids daily. Do hematologic profile before each dose; discontinue if WBCs <2000/µL or platelets <50000/µL. May interfere with wound healing. Impaired hepatic, renal, or hematopoetic function. Prior radiation therapy or other cytotoxic agents. Ensure adequate hydration. Pregnancy (Cat.D). Nursing mothers: not recommended.

Interactions: Increased risk of myelosuppression with other chemotherapy agents.

Adverse reactions: Alopecia, GI upset, hematuria, CNS toxicity, infection, renal or liver dysfunction, phlebitis, fever, urotoxicity (eg, hemorrhagic cystitis), leukopenia, thrombocytopenia.

How supplied: Single-dose vials—1

INLYTA Pfizer

℞

Kinase inhibitor. Axitinib 1mg, 5mg; tabs.

Indications: Treatment of advanced renal cell carcinoma (RCC) after failure of one prior systemic therapy.

Adults: Take 12hrs apart. Swallow whole with a glass of water. Initially 5mg twice daily. If tolerated for at least two consecutive weeks with no adverse reactions >Grade 2, normotensive, and not receiving antihypertensives, may increase dose to 7mg twice daily, then 10mg twice daily.

May reduce dose from 5mg twice daily to 3mg twice daily, then 2mg twice daily if additional dose reduction required. Concomitant strong CYP3A4/5 inhibitors: avoid; if warranted, decrease Inlyta dose by approximately ½. If strong CYP3A4/5 inhibitor discontinued, return Inlyta dose (after 3–5 half-lives of the inhibitor) to that used prior to CYP3A4/5 inhibitor initiation.

Moderate hepatic impairment: decrease dose by approximately ½.

Children: Not studied.

Warnings/Precautions: Control and monitor BP prior to and during therapy; discontinue if severe and persistent hypertension (despite antihypertensive therapy and dose reduction).

Risk of thromboembolic events. Untreated brain metastasis, recent active GI bleed: not recommended. Interrupt therapy if bleeding requires medical intervention. Monitor for

signs/symptoms of cardiac failure during therapy; permanently discontinue if occurs.

GI perforation and fistula formation; monitor.

Monitor thyroid, liver function (ALT, AST, bilirubin), and for proteinuria before starting therapy, then periodically. Reduce dose or temporarily interrupt for moderate-to-severe proteinuria.

Risk of reversible posterior leukoencephalopathy syndrome (discontinue if occurs). Stop treatment at least 24hrs prior to scheduled surgery.

Severe hepatic impairment. End-stage renal disease. Pregnancy (Cat.D); avoid. Use adequate contraception during therapy. Nursing mothers: not recommended.

Interactions: See Adult dose. Avoid strong CYP3A4/5 inhibitors (eg, grapefruit juice, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole), CYP3A4/5 inducers (eg, rifampin, dexamethasone, phenytoin, carbamazepine, rifabutin, rifapentin, phenobarbital, St. John’s wort), moderate CYP3A4/5 inducers (eg, bosentan, efavirenz, etravirine, modafinil, nafcillin).

Adverse reactions: Diarrhea, nausea, vomiting, hypertension, fatigue, decreased appetite, dysphonia, palmar-plantar erythrodysesthesia (hand-foot) syndrome, weight decreased, asthenia, constipation.

How supplied: Tabs 1mg—180; 5mg—60

JEVTANA Sanofi Aventis

℞

Antimicrotubule agent. Cabazitaxel 60mg/1.5mL; soln for IV infusion after dilution; contains polysorbate 80, diluent contains ethanol.

Indications: In combination with prednisone, hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing regimen.

Adults: Pretreat with IV antihistamine, corticosteroid, and H2 blocker 30 mins before each dose (see full labeling) and with antiemetic (IV or oral as needed). 25mg/m2

by IV infusion over 1hr every 3 weeks, with oral prednisone 10mg/day during treatment. Do not treat if neutrophil count ≤1,500 cells/mm3.

Prolonged grade ≥3 neutropenia (>1 week), febrile neutropenia, grade ≥3 diarrhea, grade 2 peripheral neuropathy: delay treatment and/or reduce dose to 20mg/m2 (see full labeling).

Discontinue if grade ≥3 peripheral neuropathy or if any reactions persist after dosing at 20mg/m2.

Hepatic impairment: (mild): reduce starting dose to 20mg/m2; (moderate): reduce to 15mg/m2. If concomitant a strong CYP3A inhibitor necessary, consider a 25% cabazitaxel dose reduction.

Children: Not established.

Contraindications: Baseline neutrophil count ≤1,500cells/mm3. Allergy to polysorbate 80.

Severe hepatic impairment (total bilirubin >3×ULN).

Warnings/Precautions: Increased risk of neutropenia complications; consider G-CSF prophylaxis. Do CBC weekly in 1st cycle and before each subsequent cycle. Patients with hemoglobin <10g/dL. Discontinue if hypersensitivity reactions occur. Increased risk of GI disorders in patients with neutropenia, age, or history of pelvic radiotherapy, adhesions, ulceration, and GI bleeding. Evaluate and treat if serious GI toxicity occurs; treatment delay or discontinuation may be needed. Hepatic impairment (monitor).

ESRD (CrCl <15mL/min). Elderly (increased susceptibility to adverse reactions); monitor closely. Pregnancy (Cat.D); avoid. Nursing mothers: not recommended.

Interactions: Potentiated by strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole); avoid. Antagonized by strong CYP3A4 inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital).

Increased GI toxicity with concomitant steroids, NSAIDs, antiplatelets, anticoagulants.

Adverse reactions: Bone marrow suppression (esp. neutropenia, anemia, leukopenia, thrombocytopenia), diarrhea (may be fatal), fatigue, nausea, vomiting, constipation, asthenia, abdominal pain, hematuria, back pain, anorexia, peripheral neuropathy, pyrexia, dyspnea, dysgeusia, cough, arthralgia, alopecia; febrile neutropenia, renal failure, hypersensitivity reactions (eg, rash, hypotension, bronchospasm).

How supplied: Kit (single-use vial + diluent)—1

LUPRON DEPOT 7.5mg AbbVie ℞ GnRH analogue. Leuprolide acetate 7.5mg; depot susp for IM inj.

Indications: Palliative treatment of advanced prostatic carcinoma.

Adults: 7.5mg IM once a month. Rotate inj site.

Children: Not applicable.

Also: LUPRON DEPOT-6 MONTH 45mg ℞ Leuprolide acetate 45mg; depot susp for IM inj.

Adults: 45mg as single IM inj every 6 months (24 weeks). Do not split doses.

Children: Not applicable.

Also: LUPRON DEPOT-3 MONTH 22.5mg ℞ Leuprolide acetate 22.5mg; depot susp for IM inj.

Adults: 22.5mg IM inj every 3 months (84 days).

Do not split doses.

Children: Not applicable.

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DRUG MONOGRAPHS

GENITOURINARY CANCER ℞ Also: LUPRON DEPOT-4 MONTH 30mg Leuprolide acetate 30mg; depot susp for IM inj; preservative-free.

Adults: 30mg as single IM inj every 4 months (16 weeks). Do not split doses.

Children: Not applicable.

Contraindications: Pregnancy (Cat.X).

Warnings/Precautions: Metastatic vertebral lesions. Urinary obstruction. Monitor serum testosterone, PSA, acid phosphatase. Increased risk of diabetes, MI, sudden cardiac death, stroke; monitor blood glucose, HbA1c, and for signs/ symptoms of CVD during therapy. History of seizures. Risk of QT prolongation: long-term androgen deprivation therapy, congenital long QT syndrome, electrolyte abnormalities, or CHF. Correct and monitor electrolyte abnormalities; consider monitoring ECGs. Instruct patient on correct self administration. Nursing mothers: not recommended.

Interactions: Concomitant antiarrhythmics may prolong the QT interval.

Adverse reactions: Hot flashes/sweats, inj site reaction, initial worsening of signs/symptoms (eg, bone pain, urinary tract obstruction, hematuria), edema, GI disorders, pain, cardiovascular events, CNS and antiandrogenic effects, asthenia, testicular atrophy, urinary disorders, spinal cord compression; hyperglycemia, anaphylactoid, photosensitivity.

How supplied: Depot kit—1 (prefilled dualchamber syringe w. supplies)

MENEST Pfizer

℞

Estrogen. Esterified estrogens 0.3mg, 0.625mg, 1.25mg, 2.5mg; tabs.

Indications: Palliative treatment of androgendependent advanced prostate cancer.

Adults: 1.25–2.5mg 3 times daily.

Children: Not applicable.

Contraindications: Thrombophlebitis.

Thromboembolic disorders. Cerebrovascular or coronary artery disease. Pregnancy (Cat.X).

Warnings/Precautions: Hepatic dysfunction.

Gallbladder disease. Conditions aggravated by fluid retention. Familial hyperlipoproteinemia.

Discontinue if jaundice occurs. Nursing mothers.

Adverse reactions: See literature. Migraine, depression, edema, weight changes, hypertension, GI upset, gynecomastia, impotence.

How supplied: Tabs 2.5mg—50 0.3mg, 0.625mg, 1.25mg—100

NEXAVAR Bayer and Onyx

℞

Multikinase inhibitor. Sorafenib 200mg; tabs.

Indications: Advanced renal cell carcinoma.

Adults: Take on an empty stomach. 400mg twice daily. If toxicity occurs, may reduce dose to 400mg once daily; if further dose reduction required, may reduce dose to 400mg every other day (see full labeling). Concomitant strong CYP3A4 inducers: consider increasing dose, monitor for toxicity.

Children: Not established.

Contraindications: Concomitant carboplatin/ paclitaxel in patients with squamous cell lung cancer.

Warnings/Precautions: Avoid in congenital long QT syndrome. Monitor patients with CHF, bradyarrhythmias, drugs known to prolong the QT interval, electrolyte abnormalities. Discontinue if severe dermatologic toxicity, hypertension, GI perforation, hemorrhage, cardiac ischemia, MI occurs. Suspend therapy before major surgery.

Monitor BP weekly during the first 6 weeks and thereafter. Monitor hepatic function regularly; discontinue if transaminases significantly elevated. Severe hepatic impairment (Child-Pugh C) or on dialysis. Use effective contraception during and for 2 weeks after stopping treatment.

Pregnancy (Cat.D), nursing mothers: not recommended.

Interactions: See Contraindications. Avoid strong CYP3A4 inducers (eg, St. John’s Wort, dexamethasone, phenytoin, carbamazepine, rifabutin, rifampin, phenobarbital) and neomycin; may decrease sorafenib levels. May potentiate warfarin (monitor PT & INR), other drugs metabolized by UGT1A1 or UGT1A9 pathway, or substrates of CYP2B6, CYP2C8, CYP2C9, P-gp.

Concomitant Class Ia and III antiarrhythmics; may prolong QT interval.

Adverse reactions: Dermatologic toxicity (eg, rash, hand-foot skin reaction, alopecia, pruritus, dry skin, Stevens-Johnson syndrome, toxic epidermal necrolysis), fatigue, weight loss, diarrhea, anorexia, abdominal pain, hypertension, hemorrhage, electrolyte abnormalities; druginduced hepatitis, QT prolongation.

How supplied: Tabs—120

PREMARIN Pfizer

℞

Estrogen. Conjugated estrogens 0.3mg, 0.45mg, 0.625mg, 0.9mg, 1.25mg; tabs.

Indications: Treatment of advanced androgendependent carcinoma of the prostate (for palliation only).

Adults: 1.25mg–2.5mg 3 times daily.

Children: Not applicable.

Contraindications: Known, suspected, or history of breast cancer, except in appropriately selected patients being treated for metastatic disease. Known or suspected estrogen-dependent neoplasia. Undiagnosed abnormal genital bleeding. Pulmonary embolism/DVT (active or history of). Arterial thromboembolism (eg, stroke, MI; active or history of). Liver dysfunction or disease. Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders. Known or suspected pregnancy (Cat.X).

Warnings/Precautions: Not for prevention of cardiovascular disease. Use for shortest duration consistent with treatment goals and risks. Reevaluate periodically. Patients with an intact uterus should almost always receive a progestin with systemic estrogens to avoid endometrial hyperplasia. Discontinue if cardiovascular events occur or are suspected;

if jaundice occurs; and during immobilization or at least 4–6 weeks before surgery associated with thromboembolism. Hepatic dysfunction.

Conditions aggravated by fluid retention.

Gallbladder disease. Bone disease associated with hypercalcemia. Hereditary angioedema. Do initial complete physical and repeat annually (include BP, mammogram, PAP smear). Adolescents.

Nursing mothers: not recommended.

Adverse reactions: See literature. Increased risk of cardiovascular events, estrogen-dependent carcinoma, gallbladder disease, thromboembolic disorders, hepatic tumors. GI upset, breakthrough bleeding, edema, weight changes, mastodynia, hypertension, depression, anaphylactic reactions, angioedema, intolerance to contact lenses.

How supplied: Tabs 0.3mg, 0.625mg, 1.25mg— 100, 1000; 0.45mg, 0.9mg—100

PROLEUKIN Prometheus

℞

Interleukin-2, recombinant. Aldesleukin 22 million IU/vial; pwd for IV infusion after reconstitution and dilution; contains mannitol; preservative-free.

Indications: Metastatic renal cell carcinoma.

Adults: ≥18yrs: 600,000 IU/kg (0.037mg/kg) every 8 hours by IV infusion over 15 minutes for a max of 14 doses, followed by 9 days rest, then repeat for another 14 doses (max 28 doses/ course), as tolerated. Retreatment and dose adjustments: see literature.

Children: <18yrs: not established.

Contraindications: Abnormal thallium stress test or pulmonary function tests. Organ allografts.

Previous drug related toxicity (eg, sustained ventricular tachycardia [≥5 beats], uncontrolled or unresponsive arrhythmias, chest pain with ECG changes consistent with angina, or MI, cardiac tamponade, intubation >72hrs, renal failure requiring dialysis >72hrs, coma or toxic psychosis >48hrs, repetitive or difficult seizures, bowel ischemia or perforation, GI bleeding requiring surgery).

Warnings/Precautions: See literature.

History of cardiac or pulmonary disease. Renal, hepatic, or CNS impairment. Seizure disorder.

Bacterial infections (treat prior to starting therapy; esp. patients with indwelling central lines). Withhold dose if organ perfusion is not maintained, urine output is reduced, systolic BP <90mmHg, CHF, cardiac ischemia or arrhythmias occur; or if moderate-to-severe lethargy or somnolence (continuing may result in coma) develops. Evaluate and treat CNS metastases; obtain negative scan before starting treatment.

Do thallium stress test; monitor vital signs, weight, fluid intake and output daily. Correct hypovolemia or fluid accumulations if occur.

Obtain CBCs, differential and platelets, blood chemistries (electrolytes, renal and hepatic function tests), chest X-rays, serum creatinine (should be ≤1.5mg/dL before starting therapy), pulmonary function tests, arterial blood gases.

Monitor for capillary leak syndrome, mental status changes, thyroid changes, diabetes onset.

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DRUG MONOGRAPHS

GENITOURINARY CANCER Elderly. Pregnancy (Cat.C). Nursing mothers: not recommended.

Interactions: Psychotropics may increase CNS toxicity. Increased toxicity with other nephrotoxic, hepatotoxic, myelotoxic, or cardiotoxic drugs. Hypersensitivity reactions with other antineoplastics. Myocardial injury and rhabdomyolysis risk increased with interferonalfa. Antagonized by glucocorticoids (avoid). β-blockers and other antihypertensives may potentiate hypotension. Delayed reactions to iodinated contrast media. May increase risk of allograft rejection.

Adverse reactions: Hypotension, GI upset, oliguria, flu-like syndrome, respiratory disorders (eg, dyspnea), CNS effects (eg, confusion, somnolence), rash, metabolic and nutritional disorders (eg, bilirubinemia, increased creatinine), hyperglycemia, thyroid disorder, thrombocytopenia, anemia, impaired neutrophil function, capillary leak syndrome, cardiotoxicity, exacerbation of autoimmune and inflammatory disease, eosinophilia, possible antibody formation; others.

How supplied: Single-use vials—1

PROVENGE Dendreon

℞

Autologous cellular immunotherapy. Sipuleucel-T (autologous CD54+ cells activated with PAP-GMCSF); minimum 50 million cells/dose; suspension for IV infusion.

Indications: Asymptomatic or minimally symptomatic metastatic castrate-resistant (hormone-refractory) prostate cancer.

Adults: Autologous use only. Obtain product release from manufacturer, match patient identity on product and Cell Product Disposition form, check expiration date and time on product before infusing. Premedicate 30 minutes before infusion with acetaminophen and antihistamine. Give three doses at 2-week intervals. For each dose: give entire contents of bag by IV infusion over 60 minutes; do not use filter; do not use if clumps do not disperse with gentle mixing. Observe patient for at least 30 minutes after infusion. May interrupt or slow infusion if acute transfusion reaction occurs; do not restart if product at room temp for >3 hours.

Children: Not applicable.

Warnings/Precautions: Cardiac or pulmonary conditions. Each dose requires a standard leukapheresis procedure about 3 days before infusion. If scheduled infusion is missed, do an additional leukapheresis procedure if treatment course is to be continued. Risk of disease transmission. Pregnancy, lactation: not applicable.

Interactions: May be antagonized by concomitant chemotherapy or immunosuppressive therapy.

Adverse reactions: Infusion reactions (eg, chills, fever, respiratory events, GI upset, hypertension, tachycardia), fatigue, back pain, joint ache, headache.

Note: If product sterility tests indicate microbial contamination, manufacturer will contact physician (tests are incomplete at time of infusion).

How supplied: Patient-specific bag (250mL)—1

SUTENT Pfizer

℞

Multikinase inhibitor. Sunitinib (as malate) 12.5mg, 25mg, 37.5mg, 50mg; gelatin caps.

Indications: Advanced renal cell carcinoma (RCC).

Adults: 50mg once daily for 4 weeks, then 2 weeks off (see full labeling). May adjust dose in increments or decrements of 12.5mg.

Concomitant strong CYP3A4 inhibitors (see Interactions): may reduce dose to 37.5mg daily.

Concomitant strong CYP3A4 inducers (see Interactions): may increase to max 87.5mg daily.

Children: Not established.

Warnings/Precautions: Hepatotoxicity; may be severe or fatal. Monitor liver function tests before starting, during each cycle of treatment and as clinically needed; interrupt if Grade 3 or 4 hepatic adverse events occur and discontinue if no resolution; if severe liver function changes or signs/symptoms of failure, do not restart.

Cardiovascular events: monitor for CHF during therapy, and LVEF at baseline and periodically; interrupt or reduce dose if LVEF <50% and >20% below baseline; discontinue if CHF occurs. History of QT prolongation or proarrythmic conditions (eg, bradycardia, electrolyte disturbances); perform periodic ECG, monitor electrolytes. Monitor BP. Suspend therapy if severe hypertension, seizures, or pancreatitis develops. Obtain CBCs, platelets, serum chemistries at start of each cycle.

Concomitant exposure to risk factors (eg, IV bisphosphonates therapy or dental disease) may increase the risk of osteonecrosis of the jaw; avoid or consider preventive dentistry prior to treatment. Risk of tumor lysis syndrome: monitor closely in RCC and GIST patients with high tumor burden. Monitor for thyroid dysfunction; obtain baseline levels prior to treatment.

Monitor blood glucose levels during and after treatment discontinuation. Monitor for proteinuria; perform baseline and periodic urinalyses; interrupt and reduce dose if 24-hr urine protein ≥3g; discontinue if nephrotic

syndrome or repeat urine protein ≥3g persists.

Undergoing major surgery. Stress (monitor for adrenal insufficiency). Discontinue if severe cutaneous reactions (eg, erythema multiforme, SJS, TEN) develop; do not restart if diagnosis suspected. ESRD on dialysis. Severe hepatic impairment. Pregnancy (Cat.D; avoid). Nursing mothers: not recommended.

Interactions: May be potentiated by strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole), grapefruit; consider reducing dose or use alternate drug. May be antagonized by CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital); consider increasing dose or use alternate drug. Concomitant St. John’s wort: not recommended. Caution with concomitant antiarrhythmics.

Adverse reactions: Fatigue, asthenia, fever, diarrhea, nausea, vomiting, mucositis/stomatitis, dyspepsia, abdominal pain, constipation, hypertension, peripheral edema, rash, handfoot syndrome, skin discoloration, dry skin, hair color changes, altered taste, headache, back pain, arthralgia, extremity pain, cough, dyspnea, anorexia, bleeding; hepatotoxicity, left ventricular dysfunction, QT prolongation, osteonecrosis of the jaw, tumor lysis syndrome, thyroid dysfunction, impaired wound healing, hypoglycemia, thrombotic microangiopathy (discontinue if develops), proteinuria, necrotizing fasciitis (discontinue if occurs), others (see full labeling).

How supplied: Caps—28

THERACYS Sanofi Pasteur

℞

BCG Live. Live Bacillus Calmette and Guerin (BCG) strain of attenuated Mycobacterium bovis; 81mg per vial; pwd for intravesical administration after reconstitution and dilution; preservativefree.

Indications: Treatment and prophylaxis of carcinoma in situ (CIS) of the urinary bladder.

Prophylaxis of stage Ta and/or T1 papillary tumors following transurethral resection (TUR).

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

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DRUG MONOGRAPHS

GENITOURINARY CANCER 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) ℞

immunosuppresives required. Monitor for interstitial lung disease (ILD); discontinue if suspected. Monitor CBCs weekly and chemistry panels every 2 weeks, blood glucose, lipids, renal function, and for worsening respiratory or GI symptoms (eg, acute abdomen, blood in stool).

Elderly. Pregnancy (Cat.D) (avoid pregnancy during and for 3 months after therapy, male patients should use appropriate contraception), nursing mothers: not recommended.

Interactions: Avoid strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole, grapefruit juice); if used, consider reducing temsirolimus dose to 12.5mg/week (allow 1 week after discontinuing CYP3A4 inhibitor before readjusting temsirolimus dose). Avoid strong CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifampicin, phenobarbital, St. John’s Wort); if used, consider increasing temsirolimus dose to 50mg/week.

Avoid live vaccines, close contact with vaccinees.

Additive toxicity with sunitinib (rash, gout/ cellulitis), anticoagulants (intracerebral bleeding).

Adverse reactions: Rash, asthenia, mucositis, nausea, edema, anorexia, infection, pain, anemia, hyperglycemia, hyperlipemia, hypertriglyceridemia, elevated alkaline phosphatase, elevated serum creatinine, lymphopenia, hypophosphatemia, thrombocytopenia, elevated AST, leukopenia; hypersensitivity/infusion reactions (anaphylaxis, dyspnea, flushing, chest pain), immunosuppression, PJP, ILD, bowel perforation, acute renal failure, abnormal wound healing; others (see full labeling).

How supplied: Kit (vial + diluent)—1

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

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

TORISEL Pfizer

TRELSTAR Actavis

℞

edema, insomnia, impotence, emotional lability, anemia, pruritus, urinary retention, UTI, erectile dysfunction, testicular atrophy; hyperglycemia.

How supplied: Single-dose vial—1 MixJect system—1 (vial + vial adapter + prefilled syringe)

VALSTAR Endo

℞

Anthracycline. Valrubicin 40mg/mL; soln for intravesical instillation after dilution; contains 50% polyoxyl castor oil/50% dehydrated alcohol; preservative-free.

Indications: Intravesical therapy of BCGrefractory carcinoma in situ (CIS) of the urinary bladder in patients for whom immediate cystectomy would be associated with unacceptable morbidity or mortality.

Adults: Drain bladder before instilliation. 800mg given intravesically via urethral catheter once weekly for 6 weeks. Retain drug for 2 hours before voiding, then void.

Children: Not recommended.

Contraindications: Concurrent UTI. Small bladder capacity (eg, unable to tolerate a 75mL instillation).

Warnings/Precautions: Monitor for disease recurrence or progression with cystoscopy, biopsy, and urine cytology every 3 months; if there is not a complete response of CIS to treatment after 3 months or if CIS recurs, cystectomy must be reconsidered. Severe irritable bladder symptoms. Perforated bladder. Bladder mucosa compromised.

Delay administration for at least 2 weeks after transurethral resection and/or fulguration.

Maintain adequate hydration. Pregnancy (Cat.C); avoid, both males and females should use effective birth control. Nursing mothers: not recommended.

Adverse reactions: Bladder symptoms (eg, urinary frequency, dysuria, urinary urgency, spasm, hematuria, pain, incontinence, cystitis, nocturia, local burning, urethral pain, pelvic pain, UTI).

How supplied: Single-use vials—4, 24

VANTAS Endo

℞

GnRH analogue. Histrelin acetate 50mg; SC implant.

Indications: Palliative treatment of advanced prostate cancer.

Adults: Insert 1 implant SC in the inner aspect of the upper arm. Remove after 12 months; may replace.

Children: Not applicable.

Contraindications: Pregnancy (Cat.X). Nursing mothers. Not for use in women or children.

Warnings/Precautions: Initial transient increase in serum testosterone may result in worsening signs/symptoms (eg, bone pain, neuropathy, hematuria). Metastatic vertebral lesions, urinary tract obstruction (monitor closely in 1st few weeks). Avoid wetting inserted arm for

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DRUG MONOGRAPHS

GENITOURINARY CANCER 24hrs and heavy lifting or strenuous exertion for 1st week. Increased risk of developing diabetes; monitor blood glucose and HbA1c periodically; treat if occurs. Increased risk of developing MI, sudden cardiac death, stroke; monitor for signs/ symptoms of cardiovascular disease. May prolong QT/QTc interval in patients with congenital long QT syndrome, CHF, electrolyte abnormalities; monitor ECGs. If electrolyte abnormalities occur, correct and monitor. Measure serum testosterone, PSA levels periodically. Implant not visible on X-ray.

Interactions: May interfere with pituitary gonadotropic and gonadal function tests. Caution with concomitant drugs known to prolong the QT interval.

Adverse reactions: Hot flashes, fatigue, implant site reactions, testicular atrophy, renal impairment; hyperglycemia, diabetes, cardiovascular disease.

How supplied: Kit—1 (w. implant and supplies)

VOTRIENT GlaxoSmithKline

℞

Tyrosine kinase inhibitor. Pazopanib 200mg; tabs.

Indications: Advanced renal cell carcinoma.

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

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

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

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

Warnings/Precautions: Not indicated for use in combination with other cancer agents. Risk of severe and fatal hepatotoxicity (esp. ≥65yrs old). Monitor liver tests before starting and at Weeks 3, 5, 7, and 9, thereafter at Months 3 and 4, then periodically. If ALT between 3×ULN and 8×ULN continue therapy with weekly monitoring until ALT returns to Grade 1 or baseline. If ALT >8×ULN interrupt therapy until ALT returns to Grade 1 or baseline; may consider reintroducing at a reduced dose, measure liver tests weekly for 8 weeks; if ALT>3×ULN recurs, permanently discontinue. Permanently discontinue if ALT>3×ULN and bilirubin >2×ULN. Gilbert’s syndrome (see full labeling). History of QT

prolongation. Cardiac dysfunction risk: evaluate LVEF at baseline and periodically; monitor for CHF. Monitor ECG, electrolytes (eg, calcium, magnesium, potassium), thyroid function. History of hemoptysis, cerebral, or clinically significant GI hemorrhage in the past 6 months: not recommended. Risk of arterial thrombotic events (within previous 6 months: not recommended).

Monitor for VTE, PE, infection, proteinuria (reduce dose if 24-hour urine protein ≥3g), thrombotic microangiopathy, GI perforation or fistula.

Monitor BP and manage hypertension promptly.

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

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

Antagonized by strong CYP3A4 inducers.

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

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

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

How supplied: Tabs—120

XOFIGO Bayer Alpha particle-emitting radioactive therapeutic agent. Radium Ra 223 dichloride 1000 kBq/mL (27 microcurie/mL) with a total radioactivity of 6000 kBq/vial (162 microcurie/vial) at the reference date; IV injection.

Indications: Treatment of patients with castration-resistant prostate cancer,

℞

symptomatic bone metastases and no known visceral metastatic disease.

Adults: See full labeling. Administer by slow IV over 1 min. 50kBq (1.35 microcurie) per kg given at 4 week intervals for 6 injections.

Children: <18yrs: not established.

Contraindications: Women who are or may become pregnant. Pregnancy (Cat.X).

Warnings/Precautions: Not for use in women.

Bone marrow suppression. Perform hematologic evaluation at baseline and prior to every dose.

Before 1st dose, the ANC should be ≥1.5 ×109/L, platelets ≥100 ×109/L and hemoglobin ≥10g/dL. Before subsequent doses, the ANC should be ≥1 ×109/L and platelets ≥50 ×109/L; discontinue if no recovery within 6–8 weeks after last dose despite receiving supportive care. Monitor closely if evidence of compromised bone marrow reserve.

Discontinue if life-threatening complications occur despite supportive care for bone marrow failure. Monitor oral intake and fluid status carefully. Males (use condoms) and female partners of reproductive potential should use highly effective contraceptive method during and 6 months after completion. Nursing mothers: not recommended.

Interactions: Concomitant chemotherapy: not established. Discontinue if concomitant with chemotherapy, other systemic radioisotopes or hemibody external radiotherapy.

Adverse reactions: Nausea, diarrhea, vomiting, peripheral edema, anemia, lymphocytopenia, leukopenia, thrombocytopenia, neutropenia.

How supplied: Single-use vials (6mL)—1

XTANDI Astellas

℞

Androgen receptor inhibitor. Enzalutamide 40mg; soft gelatin caps.

Indications: Treatment of metastatic castrationresistant prostate cancer.

Adults: Swallow whole. 160mg once daily. Dose modifications: ≥Grade 3 toxicity or intolerable 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.

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DRUG MONOGRAPHS

GENITOURINARY CANCER 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.

21

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.

2.

3.

4.

5.

6.

7.

8.

9.

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.

(Revised 2/2015) © 2015 by Haymarket Media, Inc.

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DRUG MONOGRAPHS

GYNECOLOGIC CANCER AVASTIN Genentech

℞

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

Indications: Persistent, recurrent, or metastatic cervical cancer in combination with paclitaxel and cisplatin, or paclitaxel and topotecan. Platinumresistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer in patients who received no more than 2 prior chemotherapy regimens, in combination with paclitaxel, pegylated liposomal doxorubicin or topotecan.

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

Cervical cancer: 15mg/kg every 3 weeks with either paclitaxel/cisplatin, or paclitaxel/topotecan.

Epithelial ovarian, fallopian tube or primary peritoneal cancer: 10mg/kg every 2 weeks with either paclitaxel, pegylated liposomal doxorubicin, or topotecan (weekly); 15mg/kg every 3 weeks with topotecan (every 3 weeks).

Children: Not established.

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

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

Discontinue if fistula involving internal organ, wound healing complications, hemorrhage, severe arterial thromboembolic event (ATE), hypertensive crisis or encephalopathy, posterior reversible encephalopathy syndrome, or nephrotic syndrome occurs; suspend therapy if severe hypertension, moderate-to-severe proteinuria (resume when <2g/24hrs), or severe infusion reaction occurs. Avoid in ovarian cancer if evidence of recto-sigmoid involvement by pelvic exam, bowel involvement on CT scan, or symptoms of bowel obstruction. History of arterial thromboembolism. Diabetes. Monitor BP every 2–3 weeks. Monitor proteinuria by dipstick urine analysis; if ≥2+, do further assessment with a 24-hour urine collection. Elderly. Increased risk of ovarian failure; inform females of reproductive potential prior to starting therapy. Pregnancy: may cause fetal harm; use effective contraception during and for 6 months after last dose. Nursing mothers: not recommended.

Adverse reactions: Epistaxis, headache, hypertension, rhinitis, proteinuria, taste

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

How supplied: Single-use vial—1

DOXIL Janssen Biotech

HEXALEN Eisai

℞

Anthracycline. Doxorubicin HCl (liposomal) 2mg/mL; dispersion for IV infusion after dilution; preservative-free.

Indications: Ovarian cancer refractory to platinum-based chemotherapy.

Adults: Give by IV infusion at initial rate of 1mg/min; may increase rate to complete infusion over 1hr if no infusion reactions occur; may premedicate with antiemetics. 50mg/m2 once every 4 weeks; continue for at least 4 cycles as tolerated. Hepatic dysfunction (serum bilirubin ≥1.2mg/dL), hand-foot syndrome, hematologic toxicity (esp. ANC, platelets), or stomatitis: reduce dose. Consider total anthracycline and anthracenedione doses and irradiation when calculating total cumulative dose. See full labeling.

Children: Not established.

Warnings/Precautions: Not substitutable on a mg/mg basis with other doxorubicin products.

Cardiotoxicity, acute infusion-related reactions, myelosuppression may occur. Have resuscitative/ antiallergic equipment and expertise available.

Hepatic impairment. Monitor blood (esp. CBC + platelets), hepatic (esp. SGOT/SGPT, alkaline phosphatase), and cardiac function (esp. myocardial biopsy). Monitor periodically for secondary oral cancers with long-term use. Avoid extravasation. Pregnancy (Cat.D); avoid. Nursing mothers: not recommended.

Interactions: Caution with cyclosporine, phenobarbital, phenytoin, streptozocin, digoxin, myelosuppressants, others. Previous mediastinal irradiation, cyclophosphamide, other cardiotoxic drugs: monitor for cardiotoxicity and hepatotoxicity.

Adverse reactions: Asthenia, fatigue, fever, anorexia, nausea, vomiting, stomatitis, diarrhea, constipation, hand and foot syndrome, rash, neutropenia, thrombocytopenia, anemia; infusion reactions, cardiovascular events (eg, cardiomyopathy, CHF, acute LV failure), recall of skin reaction from prior radiation therapy, toxoplasmosis, urine discoloration (red/orange).

How supplied: Single-use vials (10mL, 25mL)—1

℞

S-triazine derivative. Altretamine 50mg; caps.

Indications: Palliative treatment of persistent or recurrent ovarian cancer following first-line therapy with a cisplatin and/or alkylating agentbased combination.

Adults: 260mg/m2 daily in four divided doses (after meals and at bedtime), for either 14 or 21 consecutive days in a 28-day cycle. Discontinue for >14 days if GI intolerance is unresponsive to treatment, WBC count <2000/mm3 or granulocyte count <1000/mm3, platelet count <75000/mm3, or progressive neurotoxicity occurs. Restart at 200mg/m2 daily. Discontinue indefinitely if neurologic symptoms fail to stabilize.

Children: Not recommended.

Contraindications: Severe myelosuppression or neurologic toxicity, except cisplatin-related neuropathy.

Warnings/Precautions: Monitor for myelosuppression (do monthly CBCs) and neurotoxicity. Pregnancy (Cat.D). Nursing mothers: not recommended.

Interactions: Avoid pyridoxine. Severe orthostatic hypotension with MAOIs. Adverse reactions: Nausea, vomiting, peripheral neuropathy, CNS symptoms (eg, mood disorders, ataxia, dizziness), myelosuppression, renal dysfunction, increased alkaline phosphatase.

How supplied: Caps—100

HYCAMTIN GlaxoSmithKline

℞

Topoisomerase inhibitor. Topotecan (as HCl) 4mg/vial; pwd for IV infusion after reconstitution and dilution; contains mannitol; preservative-free.

Indications: Metastatic carcinoma of the ovary after failure of initial or subsequent chemotherapy. Stage IV-B, recurrent or persistent carcinoma of the cervix in combination with cisplatin.

Adults: Verify dose using BSA. Usual max dose 4mg IV. Confirm baseline neutrophils >1,500cells/mm3 and platelets >100,000cells/mm3 prior to 1st course of therapy.

Give by IV infusion over 30 mins. Ovarian cancer: 1.5mg/m2 daily for 5 consecutive days starting on Day 1 of a 21-day cycle. Cervical cancer: 0.75mg/m2 on Days 1 (with cisplatin), 2, and 3, repeated every 21 days. Dose adjustments, renal impairment: see full labeling.

Children: Not established.

Warnings/Precautions: Monitor peripheral blood cell counts during therapy; hold subsequent doses until neutrophils >1,000cells/mm3, platelets >100,000cells/mm3, and hemoglobin ≥9g/dL. History of interstitial lung disease,

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DRUG MONOGRAPHS

GYNECOLOGIC CANCER 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; administer ≥24hrs after last topotecan dose.

Adverse reactions: See full labeling. Neutropenia, leukopenia, thrombocytopenia, anemia, nausea, vomiting, diarrhea, anorexia, abdominal pain, stomatitis, headache, dyspnea, cough, pyrexia, alopecia, fatigue; infection, sepsis, interstitial lung disease, neutropenic colitis (may be fatal).

How supplied: Single-use vials—1

HYDREA Bristol-Myers Squibb

℞

Substituted urea. Hydroxyurea 500mg; caps.

Indications: Recurrent metastatic or inoperable ovarian carcinoma.

Adults: See literature. Intermittant therapy for solid tumors: 80mg/kg as single dose every 3rd day. Continuous therapy for solid tumors: 20–30mg/kg/day as single dose. Renal impairment: reduce dose.

Children: Not recommended.

Contraindications: Marked bone marrow depression.

Warnings/Precautions: Previous irradiation therapy or chemotherapy. Correct anemia before starting. Monitor hematologic, renal, hepatic function before and during treatment. Marked renal dysfunction. Myeloproliferative disorders; discontinue if cutaneous vasculitic ulcerations develop and use alternative agents. Elderly.

Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended.

Interactions: Avoid concomitant didanosine, with or without stavudine, or other antiretrovirals (may cause pancreatitis [monitor], fatal hepatotoxicity, peripheral neuropathy). Myelosuppressives potentiate antineoplastic effect. May antagonize antigout agents. Increased risk of vasculitic toxicities with interferon therapy. May cause falsely elevated urease, uricase, lactate dehydrogenase.

Adverse reactions: Leukopenia, anemia, erythrocytic abnormalities, thrombocytopenia, GI upset, rash, erythema, fever, CNS effects, temporary renal impairment, acute pulmonary reactions, secondary leukemias, skin cancer.

Note: Wear disposable gloves when handling caps or bottle.

How supplied: Caps—100

LYNPARZA AstraZeneca Poly (ADP-ribose) polymerase (PARP) inhibitor.

Olaparib 50mg; caps.

Indications: Monotherapy in patients with deleterious or suspected deleterious germline

℞

BRCA-mutated (as detected by an FDA-approved test) advanced ovarian cancer who have been treated with ≥3 prior lines of chemotherapy.

Adults: Swallow whole. 400mg twice daily; max 800mg daily. Continue until disease progression or unacceptable toxicity. Dose adjustments for adverse reactions: reduce to 200mg twice daily; may further reduce to 100mg twice daily. If concomitant strong CYP3A inhibitor unavoidable: reduce to 150mg twice daily; or if concomitant moderate CYP3A inhibitor unavoidable: reduce to 200mg twice daily.

Children: Not established.

Warnings/Precautions: Monitor CBC at baseline and monthly thereafter; do not start therapy until recovery from hematological toxicity due to previous chemotherapy (CTCAE Grade ≤1). Discontinue if myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) is confirmed. Interrupt therapy and evaluate if new or worsening respiratory symptoms occur; discontinue if pneumonitis is confirmed. Hepatic and moderate-to-severe renal impairment: not studied. Pregnancy (Cat.D); avoid. Use effective contraception during therapy and for at least 1 month after last dose. Nursing mothers: not recommended.

Interactions: Increased myelosuppressive toxicity with concomitant other myelosuppressive anticancer agents, including DNA damaging agents. Avoid concomitant strong CYP3A inhibitors (eg, itraconazole, telithromycin, clarithromycin, ketoconazole, voriconazole, nefazodone, posaconazole, ritonavir, lopinavir/ ritonavir, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) and moderate CYP3A inhibitors (eg, amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, darunavir/ ritonavir, diltiazem, erythromycin, fluconazole, fosamprenavir, imatinib, verapamil); if unavoidable, reduce dose (see Adults). Avoid grapefruit and Seville oranges. Avoid concomitant strong CYP3A inducers (eg, phenytoin, rifampicin, carbamazepine, St. John’s Wort) and moderate CYP3A inducers (eg, bosentan, efavirenz, etravirine, modafinil, nafcillin); if unavoidable, be aware of potential for decreased efficacy.

Adverse reactions: Anemia, nausea, fatigue, asthenia, vomiting, diarrhea, dysgeusia, dyspepsia, headache, decreased appetite, nasopharyngitis/pharyngitis/URI, cough, arthralgia/musculoskeletal pain, myalgia, back pain, dermatitis/rash, abdominal pain/ discomfort; lab abnormalities (see full labeling), MDS/AML, pneumonitis.

How supplied: Caps—112

TREXALL Teva

℞

Folic acid antagonist. Methotrexate sodium 5mg, 7.5mg, 10mg, 15mg; scored tabs. ℞ Also: Methotrexate injection Bedford Methotrexate 25mg/mL; soln for IV, IM, intraarterial, or intrathecal administration after dilution; preservative-free.

℞ Also: Methotrexate for injection Bedford Methotrexate 1g/vial; pwd for IV, IM, intra-arterial, or intrathecal administration after dilution; preservative-free.

Indications: Gestational choriocarcinoma.

Chorioadenoma destruens. Hydatidiform mole.

Adults: See literature. Tablet form is often preferred when low doses are being administered.

Choriocarcinoma and similar trophoblastic diseases: 15–30mg orally or by IM inj daily for 5 days; usually repeated 3–5 times as required with a rest period of ≥1 week between courses.

Children: Not applicable.

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

Warnings/Precautions: Be fully familiar with this drug’s toxicity before use. Discontinue if malignant lymphomas occur. Obtain baseline and monitor CBCs with differential, platelet counts, chest X-ray, and hepatic, renal and pulmonary function. During therapy monitor hematology monthly, renal and hepatic function every 1–2 months, more often if increasing dose or predisposed to toxicity (eg, dehydration). Discontinue immediately if blood counts drop significantly. Rule out pregnancy in women of childbearing potential; use effective contraception during therapy and for at least 1 ovulatory cycle afterwards for women and for at least 3 months afterwards for men. Interrupt therapy if vomiting, diarrhea, stomatitis, or pulmonary symptoms occur.

Hepatic or renal impairment. Obesity. Diabetes.

Peptic ulcer. Ulcerative colitis. Infection.

Dehydration. Folate deficiency. Ascites, pleural effusions: evacuate fluid, monitor for toxicity and reduce dose or discontinue if needed.

Elderly (use low doses and monitor closely).

Debilitated.

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

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

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

How supplied: Tabs—30; soln (2mL, 4mL, 8mL, 10mL)—10 (single-use vials); pwd (1 gram)—1 (single-use vial)

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DRUG MONOGRAPHS

HEAD AND NECK CANCER ERBITUX Bristol-Myers Squibb

℞

Epidermal growth factor receptor blocker.

Cetuximab 100mg/vial, 200mg/vial; soln for IV infusion; preservative-free.

Indications: In combination with radiation therapy for treating locally or regionally advanced squamous cell carcinoma of the head and neck (SCCHN). In combination with platinum-based therapy with 5-fluorouracil (5-FU) for first-line treatment of recurrent locoregional disease or metastatic SCCHN. As a single agent for recurrent or metastatic SCCHN after failure of prior platinum-based therapy.

Adults: Pretreat with H1 blocker. Give by IV infusion (use filter); max rate: 10mg/min.

Initial dose: 400mg/m2 once over 2hrs; then 250mg/m2 once weekly over 1 hour. Combination therapy: Give initial dose 1 week prior to initiation of radiation therapy. Complete administration 1 hour prior to platinum-based therapy with 5-FU. Give subsequent weekly dose for duration of radiation therapy (6–7 weeks) or until disease progression or unacceptable toxicity.

Permanently reduce infusion rate by 50% if Grade 1 or 2 and non-serious Grade 3 infusion reaction occurs; permanently discontinue if Grade 3 or 4 serious reaction occurs. Monitor patient during and for 1hr post-infusion. Skin toxicity: see full labeling.

Children: Not established.

Warnings/Precautions: Discontinue if severe infusion reactions or interstitial lung disease occur. Monitor for infusion reactions, cardiopulmonary arrest, pulmonary toxicity, dermatologic toxicities/infection; avoid sun, UV light. Additive cutaneous reactions with irradiation. Cardiovascular diseases (w. irradiation or platinum-based therapy with 5-FU). Monitor electrolytes (eg, magnesium, potassium, calcium) during and after cetuximab therapy. Pregnancy (Cat.C). Nursing mothers: not recommended.

Interactions: Increased mucositis (Grade 3–4), radiation recall syndrome, acneiform rash, cardiac events, and electrolyte disturbances with radiation and cisplatin.

Adverse reactions: Cutaneous reactions (pruritus, nail changes), acneform rash, headache, diarrhea, infection, asthenia, mucositis, weight loss, xerostomia, dehydration, electrolyte abnormalities; infusion reactions (may be severe: eg, bronchospasm, dyspnea), interstitial lung disease, cardiopulmonary arrest, hypomagnesemia, fever, sepsis, kidney failure, pulmonary embolus; others (see full labeling).

How supplied: Single-use vials—1

HYDREA Bristol-Myers Squibb

℞

Substituted urea. Hydroxyurea 500mg; caps.

Indications: Adjunct with irradiation therapy in primary squamous cell (epidermoid) carcinomas of the head and neck, excluding the lip.

Adults: See literature. 80mg/kg as single dose every 3rd day. Renal impairment: reduce dose.

Children: Not recommended.

Contraindications: Marked bone marrow depression.

Warnings/Precautions: Previous irradiation therapy or chemotherapy. Correct anemia before starting. Monitor hematologic, renal, hepatic function before and during treatment. Marked renal dysfunction. Myeloproliferative disorders; discontinue if cutaneous vasculitic ulcerations develop and use alternative agents. Elderly.

Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended.

Interactions: Avoid concomitant didanosine, with or without stavudine, or other antiretrovirals (may cause pancreatitis [monitor], fatal hepatotoxicity, peripheral neuropathy).

Myelosuppressives potentiate antineoplastic effect. May antagonize antigout agents. Increased risk of vasculitic toxicities with interferon therapy.

May cause falsely elevated urease, uricase, lactate dehydrogenase.

Adverse reactions: Leukopenia, anemia, erythrocytic abnormalities, thrombocytopenia, GI upset, rash, erythema, fever, CNS effects, temporary renal impairment, acute pulmonary reactions, secondary leukemias, skin cancer.

Note: Wear disposable gloves when handling caps or bottle.

How supplied: Caps—100

TREXALL Teva

℞

Folic acid antagonist. Methotrexate sodium 5mg, 7.5mg, 10mg, 15mg; scored tabs.

Also: Methotrexate injection Bedford ℞ Methotrexate 25mg/mL; soln for IV, IM, intraarterial, or intrathecal administration after dilution; preservative-free.

Also: Methotrexate for injection Bedford ℞ Methotrexate 1g/vial; pwd for IV, IM, intra-arterial, or intrathecal administration after dilution; preservative-free.

Indications: Epidermoid cancers of the head and neck.

Adults: See literature.

Children: Not established.

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

Warnings/Precautions: Be fully familiar with this drug’s toxicity before use. Discontinue if

malignant lymphomas occur. Obtain baseline and monitor CBCs with differential, platelet counts, chest X-ray, and hepatic, renal and pulmonary function. During therapy monitor hematology monthly, renal and hepatic function every 1–2 months, more often if increasing dose or predisposed to toxicity (eg, dehydration).

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

Diabetes. Peptic ulcer. Ulcerative colitis. Infection.

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

Interactions: Avoid live virus vaccines. Toxicity increased by NSAIDs, salicylates, phenytoin, sulfonylureas, sulfonamides, probenecid, folic acid antagonists. May be potentiated by penicillins (monitor), tetracyclines, chloramphenicol, nonabsorbable broad spectrum antibiotics. May be antagonized by folic acid. May potentiate theophylline, mercaptopurine. Increased risk of soft tissue necrosis and osteonecrosis with radiotherapy. Caution with other hepatotoxic drugs (eg, azathioprine, retinoids, sulfasalazine) and nephrotoxic agents (eg, cisplatin).

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

How supplied: Tabs—30; soln (2mL, 4mL, 8mL, 10mL)—10 (single-use vials); pwd (1 gram)—1 (single-use vial)

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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DRUG MONOGRAPHS

HEMATOLOGIC CANCER ADCETRIS Seattle Genetics

℞

CD30-directed antibody-drug conjugate.

Brentuximab vedotin 50mg/vial; lyophilized pwd for IV infusion after reconstitution; preservative-free.

Indications: Treatment of patients with classical Hodgkin lymphoma (HL) after failure of autologous hematopoietic stem cell transplant (auto-HSCT) or after failure of ≥2 prior multiagent chemotherapy regimens in patients who are not auto-HSCT candidates or are at high risk of relapse or progression as post-autoHSCT consolidation. Treatment of patients with systemic anaplastic large cell lymphoma (sALCL) after failure of ≥1 prior multi-agent chemotherapy regimen.

Adults: Give by IV infusion over 30 minutes.

1.8mg/kg up to max 180mg/dose every 3 weeks; continue until disease progression or unacceptable toxicity. Post-auto-HSCT consolidation: initiate within 4–6 weeks postauto-HSCT or upon recovery from auto-HSCT; max 16 cycles. Mild hepatic impairment: initially 1.2mg/kg up to 120mg. Peripheral neuropathy: if Grade 2/3: withhold until resolve to ≤Grade 1, then restart with 1.2mg/kg; if Grade 4: discontinue therapy. Neutropenia: Grade 3/4: withhold until resolve to ≤Grade 2; may consider G-CSF prophylaxis for subsequent cycles; recurrent Grade 4: consider discontinue or dose reduction to 1.2mg/kg. Patients with prior infusion-related reaction: premedicate with APAP, antihistamine, and corticosteroid for subsequent doses.

Children: Not established.

Contraindications: Concomitant bleomycin.

Warnings/Precautions: Risk of JC virus infection. Monitor for progressive multifocal leukoencephalopathy (PML); withhold dose if suspected and discontinue if confirmed.

Monitor for neuropathy; delay, change dose, or discontinue if new or worsening symptoms occur. Monitor for infusion-related reactions; permanently discontinue and treat if anaphylaxis occurs. Monitor CBCs prior to each dose and frequently for fever or Grade 3 or 4 neutropenia; delay, reduce, discontinue dose or consider G-CSF prophylaxis if develops. Increased risk of tumor lysis syndrome in rapidly proliferating tumor/ high tumor burden patients; monitor closely.

Monitor for emergence of bacterial, fungal, or viral infections. Monitor for pulmonary toxicity; if symptoms occur, withhold dose during evaluation and until improvement. Monitor liver enzymes and bilirubin; delay, change dose, or discontinue if hepatotoxicity occurs. Severe renal impairment or moderate or severe hepatic impairment: avoid.

Discontinue if serious skin reactions (eg, SJS, TEN) occur. Pregnancy (Cat.D); avoid. Nursing mothers: not recommended.

Interactions: See Contraindications. Potentiated by strong CYP3A4 inhibitors or P-gp inhibitors; monitor closely. Antagonized by potent CYP3A4 inducers.

Adverse reactions: Neutropenia, peripheral sensory neuropathy, fatigue, nausea, anemia, upper respiratory tract infection, diarrhea, pyrexia, rash, thrombocytopenia, cough, vomiting.

How supplied: Single-use vial—1

ARRANON GlaxoSmithKline

℞

Nucleoside analogue. Nelarabine 250mg/vial; soln for IV infusion.

Indications: T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL) that is unresponsive or has relapsed after ≥2 chemotherapy regimens.

Adults and Children: Contact manufacturer.

From the pediatric trial: Patients ≤21 yrs: 650mg/m2 by IV infusion over 1 hour daily for 5 consecutive days; repeat every 21 days. From the adult trial: Patients 16–65yrs: 1500mg/m2

by IV infusion over 2 hours on days 1, 3, and 5; repeat every 21 days. The recommended duration of treatment has not been clearly established.

Treatment was generally continued until there was evidence of disease progression, the patient experienced unacceptable toxicity, the patient became a candidate for bone marrow transplant, or the patient no longer continued to benefit from treatment. See literature.

Warnings/Precautions: Discontinue if ≥ Grade 2 neurotoxicity occurs; may delay dosing if other toxicities occur (eg, hematologic toxicity).

Prior or concurrent intrathecal chemotherapy or craniospinal irradiation (increased risk of neurotoxicity). Renal or hepatic impairment.

Obtain CBCs, platelet counts. Monitor for signs/ symptoms of infection, tumor lysis syndrome.

Ensure adequate hydration. Elderly. Pregnancy (Cat.D); use effective contraception. Nursing mothers: not recommended.

Interactions: Avoid live vaccines. Concomitant adenosine deaminase inhibitors (eg, pentostatin): not recommended.

Adverse reactions: Hematologic disorders (eg, anemia, neutropenia, thrombocytopenia), headache, GI upset, constipation, fatigue, somnolence, dizziness, peripheral neuropathy, seizures, respiratory disorders, pyrexia; increased transaminase levels, bilirubin; decreased potassium, albumin.

How supplied: Vials—6

ARZERRA 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 and after therapy, increase frequency if Grade 3/4 cytopenias develop. Monitor for new onset of or changes in neurological signs/symptoms.

Increased risk of tumor lysis syndrome (TLS) in high tumor burden and/or high circulating lymphocytes; consider prophylaxis with anti-hyperuricemics and hydration beginning 12–24hrs prior to infusion. Pregnancy (Cat.C).

Nursing mothers.

Interactions: Avoid vaccination with live viral vaccines.

Adverse reactions: Neutropenia, thrombocytopenia, anemia, pneumonia, pyrexia, cough, fatigue, dyspnea, rash, nausea, diarrhea, bronchitis, upper respiratory tract infections; infusion reactions (eg, bronchospasm; laryngeal, pulmonary, or angioedema; flushing, hyper- or hypotension, syncope, cardiac ischemia, back or abdominal pain, fever, urticaria) (interrupt, adjust infusion rate and monitor; permanently discontinue if anaphylaxis occurs), progressive multifocal leukoencephalopathy (discontinue if suspected and evaluate), infections (eg, sepsis), hepatotoxicity, TLS. How supplied: Single-use vial (5mL)—3; (50mL)—1

BELEODAQ Spectrum

℞

Histone deacetylase inhibitor. Belinostat 500mg; per vial; lyophilized pwd for IV inj after reconstitution and dilution.

Indications: Relapsed or refractory peripheral T-cell lymphoma.

Adults: Give 1000mg/m2 once daily by IV infusion over 30 mins on Days 1–5 of a 21-day cycle; can repeat cycles every 21 days until disease progression or unacceptable toxicity. Dose modifications: Hematologic toxicities: if ANC nadir <0.5×109/L or platelet count <25×109/L: decrease dose by 25% (750mg/m2); discontinue if recurrent ANC <0.5×109/L or platelet count <25×109/L nadirs after 2 dose reductions; Nonhematologic toxicities: if any CTCAE Grade 3/4 reaction: decrease dose by 25% (750mg/m2); discontinue if recurrent CTCAE Grade 3/4 reaction after 2 dose reductions. Patients with homozygous UGT1A1*28 allele: initially 750mg/m2.

Children: Not established.

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER 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; preservativefree.

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

neurological toxicities; interrupt or discontinue as recommended (see full labeling). Monitor for infections; give antibiotic prophylaxis as appropriate. Monitor for tumor lysis syndrome; interrupt or discontinue as needed. Obtain lab tests (including WBC, ANC) during infusion; interrupt if prolonged neutropenia occurs.

Monitor ALT, AST, GGT, and total bilirubin prior to and during treatment; interrupt if transaminases rise >5×ULN or if bilirubin rises >3×ULN. Risk of leukoencephalopathy, esp. in those with prior treatment with cranial irradiation and antileukemic chemotherapy (including high-dose methotrexate or intrathecal cytarabine). Renal impairment (CrCl <30mL/min) or hemodialysis.

Elderly. Pregnancy (Cat.C). Nursing mothers: not recommended.

Interactions: Caution with concomitant CYP450 substrates (esp. drugs with narrow therapeutic index); adjust dose as needed. Monitor for toxicity with warfarin. Monitor cyclosporine.

Adverse reactions: Pyrexia, headache, peripheral edema, febrile neutropenia, nausea, hypokalemia, tremor, rash, constipation; pneumonia, sepsis, neutropenia, device-related infection, tremor, encephalopathy, confusion, overdose, possible immunogenicity.

How supplied: Pack—1 (single-use vial + IV solution stabilizer)

BOSULIF Pfizer ℞

Bispecific CD19-directed CD3 T-cell engager.

Blinatumomab 35mcg; per vial; lyophilized pwd for IV infusion after reconstitution; preservativefree.

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

℞

Tyrosine kinase inhibitor. Bosutinib 100mg, 500mg; tabs.

Indications: Treatment of chronic, accelerated, or blast phase Philadelphia chromosomepositive (Ph+) chronic myelogenous leukemia (CML) with resistance or intolerance to prior therapy.

Adults: Initially 500mg once daily with food.

Continue until disease progression or patient intolerance. Consider dose escalation to 600mg once daily in patients who do not reach complete hematological response (CHR) by Week 8 or a complete cytogenetic response (CCyR) by Week 12, who did not have Grade 3 or higher adverse reactions. Adjust dose for hematologic and non-hematologic toxicity: see full labeling.

Hepatic impairment: initially 200mg daily. Renal impairment (CrCl 30–50mL/min): initially 400mg daily; (CrCl <30mL/min): initially 300mg daily.

Children: <18yrs: not established.

Warnings/Precautions: Monitor and manage GI toxicity, fluid retention; withhold, reduce dose, or discontinue as necessary. Perform CBC weekly for first month, then monthly; hepatic enzyme tests monthly for first three months

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER (more frequently if transaminase elevations occur); withhold, reduce dose, or discontinue as necessary. Monitor renal function at baseline and during therapy; consider adjusting dose if renal impairment occurs. Pregnancy (Cat.D); avoid.

Nursing mothers: not recommended.

Interactions: Potentiated by concomitant strong or moderate CYP3A and/or P-gp inhibitors (eg, ritonavir, indinavir, nelfinavir, saquinavir, ketoconazole, boceprevir, telaprevir, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin, nefazodone, conivaptan, fluconazole, darunavir, erythromycin, diltiazem, atazanavir, aprepitant, amprenavir, fosamprenavir, crizotinib, imatinib, verapamil, grapefruit products, ciprofloxacin); avoid.

Antagonized by concomitant strong or moderate CYP3A inducers (eg, rifampin, phenytoin, carbamazepine, St. John’s Wort, rifabutin, phenobarbital, bosentan, nafcillin, efavirenz, modafinil, etravirine); avoid. Antagonized by proton pump inhibitors (eg, lansoprazole); consider short-acting antacids or H2 blockers instead; separate dosing by more than 2hrs. May potentiate drugs that are P-gp substrates (eg, digoxin).

Adverse reactions: Diarrhea, nausea, thrombocytopenia, vomiting, abdominal pain, rash, anemia, pyrexia, fatigue; fluid retention (monitor), hepatic toxicity.

How supplied: Tabs 100mg—120; 500mg—30

BUSULFEX Otsuka

℞

Alkylating agent. Busulfan 6mg/mL; soln for IV administration after dilution.

Indications: In combination with cyclophosphamide, as a conditioning regimen prior to allogeneic hematopoietic progenitor cell transplantation for chronic myelogenous leukemia.

Adults: See full labeling. Premedicate with anticonvulsants and antiemetics. Give by IV infusion over 2 hours. 0.8mg/kg of ideal body weight or actual body weight, whichever is lower, every 6 hours for 4 days (total of 16 doses). Give cyclophosphamide after the 16th dose of busulfan (Days -3 and -2). Give hematopoietic progenitor cells on Day 0. Obese: base dose on adjusted ideal body weight.

Children: See full labeling.

Warnings/Precautions: Risk of severe and prolonged myelosuppression; requires hematopoietic progenitor cell transplantation.

Seizure disorder. Head trauma. Renal or hepatic impairment. Monitor CBCs with differential, platelet counts, liver enzymes, bilirubin during treatment and until recovery. Monitor for infection and bleeding. Use effective contraception during and after treatment. Pregnancy; avoid use.

Nursing mothers: not recommended.

Interactions: Potentiated by itraconazole and acetaminophen. May be antagonized by phenytoin. Caution with potentially epileptogenic drugs.

Adverse reactions: Myelosuppression (eg, granulocytopenia, thrombocytopenia, anemia), GI upset, stomatitis, anorexia, abdominal pain, dyspepsia, fever, headache, asthenia, chills, pain, tachycardia, hypertension, edema, dyspnea, dizziness, depression, elevated creatinine, hypomagnesemia, hyperglycemia, hypokalemia, hypocalcemia, hyperbilirubinemia, insomnia, anxiety, rhinitis, rash; seizures (with higher doses), hepatic veno-occlusive disease (with high AUC), cardiac tamponade (in pediatric patients with thalassemia), cellular dysplasia; rare: bronchopulmonary dysplasia with pulmonary fibrosis.

How supplied: Single-use vials (10mL)—8

CAMPATH Genzyme

℞

Monoclonal antibody, CD52 (recombinant, humanized). Alemtuzumab 30mg/mL; soln; for IV infusion after dilution; preservative-free.

Indications: B-cell chronic lymphocytic leukemia (B-CLL).

Adults: Premedicate with antihistamine and acetaminophen before 1st dose, and at dose escalations. Give by IV infusion over 2 hrs.

Initially 3mg per day until infusion reactions are ≤ grade 2, then increase to 10mg per day until infusion reactions are ≤ grade 2, then to maintenance 30mg/day three times per week (on alternate days); duration of therapy (including escalation): 12 weeks. Do not exceed max single dose 30mg/dose or 90mg/week.

Give prophylactic antibiotics and antivirals during treatment and for at least 2 months after completion or until CD4+ counts resolve (whichever occurs later). Dose adjustments for neutropenia and thrombocytopenia: see literature. Retitrate if therapy interrupted for ≥7 days.

Children: Not recommended.

Warnings/Precautions: Discontinue dose for autoimmune or recurrent/persistent severe cytopenias (except lymphopenia). Withhold dose for severe cytopenias (except lymphopenia), grade 3 or 4 infusion reactions, serious infections, or during antiviral treatment for cytomegalovirus (CMV) infection or confirmed CMV viremia. Obtain CBCs, platelet counts weekly, assess CD4+ counts after treatment until recovery to ≥200cells/µL. Monitor for infusion reactions; CMV infection (continue for 2 months after therapy ends).

Pregnancy (Cat.C). Nursing mothers: not recommended.

Interactions: Avoid live virus vaccines (after recent therapy). May interfere with tests using antibodies. Irradiate any blood products given (GVHD may occur).

Adverse reactions: See literature; may be fatal.

Infusion reactions, cytopenias (eg, neutropenia, lymphopenia, thrombocytopenia, anemia), infections (eg, CMV), GI upset, insomnia, anxiety; others.

How supplied: Single-use vials—1, 3

CERUBIDINE Bedford

℞

Anthracycline. Daunorubicin HCl 20mg/vial; lyophilized pwd for IV infusion after reconstitution; contains mannitol.

Indications: In combination with other chemotherapy for remission induction in acute nonlymphocytic leukemia (myelogenous, monocytic, erythroid) of adults and for remission induction in acute lymphocytic leukemia of children and adults.

Adults: Give by IV infusion. Acute nonlymphocytic leukemia (in combination with cytosine arabinoside): <60yrs: 45mg/m2 daily on days 1, 2 and 3 of the first course and on days 1, 2 of subsequent courses; ≥60yrs: 30mg/m2 daily on days 1, 2 and 3 of the first course and on days 1, 2 of subsequent courses. Acute lymphocytic leukemia (in combination with vincristine, prednisone, L-asparaginase): 45mg/m2 daily on days 1, 2 and 3. Hepatic or renal impairment: reduce dose (see literature).

Children: Give by IV infusion. <2yrs or BSA<0.5m2: use weight (mg/kg) to calculate dose. 25mg/m2 on day 1 every week (in combination with vincristine and prednisone).

Warnings/Precautions: Treat if any systemic infections 1st. Pre-existing drug-induced bone marrow suppression. Cardiovascular disease, thoracic irradiation, previous doxorubicin therapy (cumulative doses >550mg/m2): increased risk of cardiotoxicity. Monitor blood counts, cardiac, hepatic and renal function prior to each treatment. Renal or hepatic impairment.

Hyperuricemia; monitor blood uric acid levels and give allopurinol prophylatically. Avoid extravasation. Children. Elderly. Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended.

Interactions: Do not use if previously received max cumulative doxorubicin dose; or if concomitant with cyclophosphamide: increased cardiotoxicity. Concomitant myelosuppressives: consider dose reduction. Increased risk of liver toxicity with hepatotoxic agents (eg, high-dose methotrexate).

Adverse reactions: Myelosuppression, cardiotoxicity, alopecia, rash, inj site reactions, GI upset, mucositis, abdominal pain, hyperuricemia; rare: anaphylaxis.

How supplied: Single-dose vials—10

CLOLAR Genzyme

℞

Purine nucleoside antimetabolite. Clofarabine 1mg/mL; soln for IV infusion after dilution; preservative-free.

Indications: Acute lymphoblastic leukemia (ALL) in patients 1–21 years of age after relapses from, and/or refractoriness to, at least two prior regimens.

Adults: Not established.

Children: Monitor blood pressure, cardiac, renal, and hepatic function before and during

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER 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, palmar-plantar erythrodysesthesia syndrome, anxiety, flushing, mucosal inflammation; bone marrow suppression (eg, febrile neutropenia, anemia, leukopenia, thrombocytopenia), infections, hyperuricemia, hypotension, cardiac events, SIRS/capillary leak syndrome, hemorrhage (may be fatal), enterocolitis (monitor), serious skin reactions (discontinue for exfoliative or bullous rash or if StevensJohnson syndrome or toxic epidermal necrolysis suspected).

How supplied: Single-use vial (20mL)—1, 4

DACOGEN Otsuka

℞

Nucleoside analogue. Decitabine 50mg/vial; lyophilized pwd for IV infusion after reconstitution and dilution.

Indications: Myelodysplastic syndromes (MDS) including previously treated and untreated, de novo and secondary MDS of all FrenchAmerican-British subtypes and Intermediate-1, Intermediate-2, and High-risk International Prognostic Scoring System groups.

Adults: May premedicate with antiemetics. Treat for a minimum of 4 cycles; may take longer for a complete or partial response. Regimen 1: Give by continuous IV infusion over 3 hours. 15mg/m2 every 8 hours for 3 days; repeat every 6 weeks.

Regimen 2: Give by continuous IV infusion over 1 hour. 20mg/m2 once daily for 5 days; repeat every 4 weeks. Both: dose adjustment based on hematology values: see literature. Nonhematologic toxicities (eg, serum creatinine ≥2mg/dL; SGPT, total bilirubin ≥ 2 × ULN; active or uncontrolled infection): do not restart until toxicity resolved.

Children: Not recommended.

Warnings/Precautions: Renal or hepatic impairment. Obtain CBC and platelet counts before each dosing cycle and as needed. Monitor hepatic function (do baseline liver chemistries and serum creatinine). Pregnancy (Cat.D); use appropriate contraception (both men and women). Nursing mothers: not recommended.

Adverse reactions: Neutropenia, thrombocytopenia, anemia, leukopenia, fatigue, pyrexia, nausea, cough, petechiae, constipation, diarrhea, hyperglycemia.

How supplied: Single-use vial—1

DEPOCYT Sigma-Tau

℞

Antimetabolite. Cytarabine 50mg/vial; liposomal suspension for intrathecal administration; preservative-free.

Indications: Intrathecal treatment of lymphomatous meningitis.

Adults: See literature. Give intrathecally over 1–5 minutes. Administer dexamethasone 4mg twice daily for 5 days with each cycle of treatment. Induction: 50mg every 14 days for 2 doses (weeks 1 and 3). Consolidation: 50mg every 14 days for 3 doses (weeks 5, 7 and 9) followed by 1 additional dose at week 13.

Maintenance: 50mg every 28 days for 4 doses (weeks 17, 21, 25 and 29). Reduce dose to 25mg if neurotoxicity develops and discontinue if it persists.

Children: Not recommended.

Contraindications: Active meningeal infection.

Warnings/Precautions: Chemical arachnoiditis; reduce symptoms with dexamethasone. Previous irradiation, cytotoxic chemotherapy. Monitor blood counts and for development of neurotoxicity. Renal and hepatic impairment. Pregnancy (Cat.D); avoid use.

Nursing mothers: not recommended.

Interactions: Increased risk of neurotoxicity with concomitant cranial/spinal irradiation or other intrathecal antineoplastics.

Adverse reactions: See literature. Arachnoiditis, GI upset, headache, fever, neurological toxicity (myelopathy), hydrocephalus, elevated CSF protein and WBC, weakness, back pain, insomnia, blurred vision, anaphylactic reactions; others.

How supplied: Single-use vials (5mL)—1

DOXIL Janssen Biotech

℞

Anthracycline. Doxorubicin HCl (liposomal) 2mg/mL; dispersion for IV infusion after dilution; preservative-free.

Indications: Multiple myeloma, in combination with bortezomib, in patients not previously treated with bortezomib and who have received at least one prior therapy.

Adults: Give by IV infusion at initial rate of 1mg/min; may increase rate to complete infusion over 1hr if no infusion reactions occur; may premedicate with antiemetics. 30mg/m2 on day 4 of each cycle following bortezomib (see full labeling for bortezomib dose); may treat for up to 8 cycles. Hepatic dysfunction (serum bilirubin ≥1.2mg/dL), hand-foot syndrome, hematologic toxicity (esp. ANC, platelets), or stomatitis: reduce dose. Consider total anthracycline and anthracenedione doses and irradiation when calculating total cumulative dose. See full labeling.

Children: Not established.

Warnings/Precautions: Not substitutable on a mg/mg basis with other doxorubicin products.

Cardiotoxicity, acute infusion-related reactions, myelosuppression may occur. Have resuscitative/ antiallergic equipment and expertise available.

Hepatic impairment. Monitor blood (esp. CBC + platelets), hepatic (esp. SGOT/SGPT, alkaline phosphatase), and cardiac function (esp. myocardial biopsy). Monitor periodically for secondary oral cancers with long-term use. Avoid extravasation. Pregnancy (Cat.D); avoid. Nursing mothers: not recommended.

Interactions: Caution with cyclosporine, phenobarbital, phenytoin, streptozocin, digoxin, myelosuppressants, others. Previous mediastinal irradiation, cyclophosphamide, other cardiotoxic drugs: monitor for cardiotoxicity and hepatotoxicity.

Adverse reactions: Asthenia, fatigue, fever, anorexia, nausea, vomiting, stomatitis, diarrhea, constipation, hand and foot syndrome, rash, neutropenia, thrombocytopenia, anemia; infusion reactions, cardiovascular events (eg, cardiomyopathy, CHF, acute LV failure), recall of skin reaction from prior radiation therapy, toxoplasmosis, urine discoloration (red/orange).

How supplied: Single-use vials (10mL, 25mL)—1

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER 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

FARYDAK Novartis

℞

Histone deacetylase inhibitor. Panobinostat 10mg, 15mg, 20mg; caps.

Indications: Multiple myeloma, in patients who have received at least two prior therapies (including bortezomib and an immunomodulatory agent), in combination with bortezomib and dexamethasone.

Adults: Swallow whole with water. Take at same time on scheduled days. Initially 20mg once every other day for 3 doses/wk in Weeks 1 and 2 of each 21-day cycle for up to 8 cycles. Consider 8 more cycles for patients with clinical benefit if no severe or significant toxicity; max 16 cycles (48 wks).

Give with bortezomib inj and oral dexamethasone per scheduled day. Hepatic impairment: mild: initially 15mg; moderate: initially 10mg; severe: avoid. Concomitant strong CYP3A inhibitors: initially 10mg. Dose adjustments and modifications for toxicity: see full labeling.

Children: Not established.

Warnings/Precautions: Risk of severe diarrhea and cardiac toxicities. Monitor hydration and electrolytes at baseline, weekly during therapy, or more as indicated. Initiate antidiarrheals at onset of diarrhea; interrupt dose if 4–6 stools/day.

Do not initiate if history of recent MI or unstable angina, QTcF >450msec, significant baseline ST-segment or T-wave abnormalities, active infections. Perform ECG prior to initiation and repeat during treatment as indicated. Correct electrolyte abnormalities prior to initiation and monitor; interrupt if QTcF ≥480msec; discontinue if QT prolongation does not resolve.

Serious hemorrhage. Obtain CBC prior to initiation; monitor weekly during therapy or more as indicated. Monitor for infections; treat and consider interruption or discontinuation if diagnosed. Monitor liver function prior to and during treatment; consider dose adjustments if abnormal tests observed. ESRD or dialysis: not studied. Elderly: monitor for toxicity more frequently (esp. GI, myelosuppression, cardiac).

Pregnancy: avoid. Obtain pregnancy test prior to and during treatment. Use effective contraception during and for ≥1 month after last dose; males: use condoms during and for ≥3 months after last dose. Nursing mothers: not recommended.

Interactions: Potentiated by strong CYP3A inhibitors (eg, boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, others); see Adults. Avoid star fruit, pomegranate or grapefruit juice. Avoid concomitant strong CYP3A inducers. Avoid concomitant sensitive CYP2D6 substrates (eg, atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, tolterodine, venlafaxine) or substrates with narrow therapeutic index (eg, thioridazine, pimozide); if unavoidable, monitor frequently. Concomitant antiarrhythmics or QT prolonging drugs: not recommended. Antiemetics that prolong QT interval (eg, dolasetron, ondansetron, tropisetron): monitor ECG frequently.

Adverse reactions: Diarrhea, fatigue, nausea, peripheral edema, decreased appetite, pyrexia, vomiting, electrolyte imbalance, increased creatinine, thrombocytopenia, lymphopenia, leukopenia, neutropenia, anemia.

How supplied: Blister packs—6

FLUDARA Genzyme

℞

Antimetabolite. Fludarabine phosphate 50mg/vial; lyophilized pwd for IV infusion after reconstitution and dilution; preservative-free; contains mannitol.

Indications: B-cell chronic lymphocytic leukemia (CLL) in patients who have not responded to or whose disease progressed during treatment with at least 1 alkylating-agent containing regimen.

Adults: Give by IV infusion over 30 minutes.

25mg/m2 daily for 5 days every 28 days. Renal dysfunction (CrCl 30–70mL/min): reduce dose by 20%; CrCl <30mL/min: not recommended. Give

for 3 cycles after the max response. Reduce or delay dose if toxicity occurs.

Children: Not recommended.

Warnings/Precautions: Myelosuppression.

Evaluate and monitor for hemolysis. Monitor blood (esp CBC, platelets). Use irradiated blood products if transfusions are required. May need to prophylax for tumor lysis syndrome with large tumors. Renal insufficiency. Delay or stop therapy if neurotoxicity occurs. Elderly.

Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended.

Interactions: Severe pulmonary toxicity with pentostatin (not recommended).

Adverse reactions: Myelosuppression (severe/cumulative), bone marrow hypoplasia, autoimmune hemolytic anemia (fatal/ severe), infection, fever, chills, GI upset, malaise, fatigue, CNS effects (eg, weakness, agitation, confusion, visual disturbances, coma, peripheral neuropathy), pneumonia, pulmonary hypersensitivity (eg, dyspnea, interstitial pulmonary infiltrate), stomatitis, GI bleeding, edema, tumor lysis syndrome, rash, hemorrhagic cystitis (rare); others.

How supplied: Single-dose vials—5

GAZYVA Genentech

℞

Cytolytic monoclonal antibody (CD20-directed).

Obinutuzumab 25mg/mL; soln for IV infusion after dilution; preservative-free.

Indications: Treatment of patients with previously untreated chronic lymphocytic leukemia (CLL), in combination with chlorambucil.

Adults: Premedicate (eg, glucocorticoid, APAP, antihistamine) before each infusion.

Give by IV infusion for 6 treatment cycles (28 days duration). Cycle 1: 100mg on Day 1 at 25mg/hr over 4 hours; 900mg on Day 2 at 50mg/hr, may increase at 50mg/hr every 30mins (max 400mg/hr); 1000mg on Days 8 and 15 at 100mg/hr, may increase by 100mg/hr increments every 30mins (max 400mg/hr); Cycles 2–6: 1000mg on Day 1 at 100mg/hr, may increase by 100mg/hr increments every 30mins (max 400mg/hr). Infusion rate and premedication adjustments: see full labeling.

Children: Not established.

Warnings/Precautions: Risk of hepatitis B virus (HBV) reactivation; immediately discontinue and any concomitant chemotherapy if occurs.

Screen for HBV infection prior to initiation; if positive evidence, monitor and consider antiviral therapy. Discontinue treatment and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressives if PML develops. Monitor closely for infusion reactions; if Grade 4: discontinue permanently; if Grade 3: interrupt until resolved; if Grade 1 or 2: interrupt or reduce the infusion rate and manage symptoms. Preexisting cardiac or pulmonary conditions: monitor more frequently during and post-infusion period for severe reactions. Risk of TLS in high tumor burden and/or high circulating

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER 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).

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.

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

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER Adults: Swallow whole. ≥18yrs: initially 45mg once daily; consider reducing dose in chronic and accelerated phase CML if major cytogenic response achieved. Consider discontinuing if no response occurred by 3 months. Concomitant strong CYP3A inhibitors: reduce to 30mg once daily. Dose modification for hematologic and nonhematologic toxicity: see full labeling.

Children: <18yrs: not established.

Warnings/Precautions: Risk of vascular occlusion (eg, arterial and venous thrombosis, fatal MI, stroke, stenosis of arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures) in patients with or without CV risk factors (including ≤50yrs old, or increasing age, history of ischemia, HTN, diabetes, hyperlipidemia); monitor and interrupt or discontinue if occurs. Monitor for signs/symptoms of heart failure; interrupt or consider discontinuing if develops or worsens.

Monitor hepatic function at baseline, then at least monthly or as needed; interrupt, reduce or discontinue as clinically indicated. Moderate-tosevere hepatic impairment: not recommended.

Monitor and manage BP elevations; interrupt, reduce dose or discontinue if not controlled. Risk of pancreatitis; check serum lipase every 2 weeks for the first 2 months and then monthly thereafter or as clinically indicated; do not restart until complete resolution and lipase levels <1.5×ULN. Monitor for neuropathy; consider interrupting and evaluate if suspected. Conduct eye exams at baseline and periodically during treatment.

Interrupt therapy and evaluate for serious/severe hemorrhage or cardiac arrhythmias. Monitor for fluid retention; interrupt, reduce, or discontinue as indicated. Obtain CBCs every 2 weeks for the first 3 months, then monthly or as indicated.

Tumor lysis syndrome; ensure adequate hydration and treat uric levels prior to therapy.

Compromised wound healing (withhold for 1 week prior to major surgery) and GI perforation. Elderly.

Pregnancy (Cat.D); avoid. Nursing mothers: not recommended.

Interactions: Potentiated by strong CYP3A inhibitors (eg, boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole); see Adult dose. Avoid concomitant strong CYP3A inducers (eg, carbamazepine, rifampin, phenytoin, St. John’s Wort), or drugs that elevate gastric pH (eg, PPIs, H2 blockers, antacids). Caution with concomitant P-gp and ABCG2 substrates.

Adverse reactions: Hypertension, rash, abdominal pain, fatigue, headache, dry skin, constipation, arthralgia, nausea, pyrexia, anemia, thrombocytopenia, leukopenia, neutropenia, lymphopenia; vascular occlusion, heart failure, hepatotoxicity, ocular toxicities, hemorrhage, myelosuppression.

How supplied: Tabs 15mg—60, 180; 45mg— 30, 90

IDAMYCIN Pfizer

℞

Anthracycline. Idarubicin HCl 20mg/vial; lyophilized pwd for IV infusion after reconstitution. ℞ Also: IDAMYCIN PFS Idarubicin 1mg/mL; soln for IV infusion; preservative-free.

Indications: Acute myeloid leukemia.

Adults: Give by slow IV infusion (over 10–15 mins). 12mg/m2 daily for 3 days (in combination with cytarabine). May give 2nd course if needed; if toxicity develops after 1st course, delay until resolved; reduce dose by 25%. Hepatic and renal impairment: consider reduce dose.

Children: Not established.

Warnings/Precautions: Pre-existing bone marrow suppression. Cardiovascular disease.

Thoracic irradiation. Previous anthracycline therapy at high cumulative doses. Renal or hepatic impairment. Monitor CBCs, cardiac, renal and hepatic function prior to and during treatment. Avoid extravasation. Elderly.

Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended.

Interactions: Concomitant drugs that suppress cardiac contractility or cardiotoxic drugs (eg, trastuzumab, cyclophosphamide, paclitaxel): not recommended; avoid use for 5 half-lives after discontinuing cardiotoxic drug.

Adverse reactions: Myelosuppression, GI upset, mucositis, abdominal pain, alopecia, rash, inj site reactions, hepatotoxicity, renal toxicity, cardiotoxicity (eg, CHF, arrhythmias, chest pain, MI, asymptomatic declines in LVEF), hyperuricemia.

How supplied: Single-dose vials—1; PFS: Singledose vials (5mL, 10mL, 20mL)—1

IMBRUVICA

℞

Pharmacyclics and Janssen Biotech

Bruton’s tyrosine kinase (BTK) inhibitor. Ibrutinib 140mg; caps.

Indications: Mantle cell lymphoma (MCL) in patients who have received at least one prior therapy. Chronic lymphocytic leukemia (CLL) in patients who have received at least one prior therapy. CLL in patients with 17p deletion.

Waldenstrom’s macroglobulinemia (WM).

Adults: Swallow whole with water. MCL: 560mg once daily. CLL and WM: 420mg once daily.

Concomitant moderate CYP3A inhibitors: 140mg once daily. Mild hepatic impairment (Child-Pugh Class A): 140mg once daily. Dose modifications for toxicities: see full labeling.

Children: Not established.

Warnings/Precautions: Risk of hemorrhage; consider the benefit/risk of withholding treatment for 3–7 days pre-and post-surgery.

Monitor for fever and infections; evaluate promptly if occurs. Monitor for myelosuppression; obtain CBCs monthly. Periodically monitor for atrial fibrillation (esp. in those with cardiac risk factors, acute infections, history of atrial

fibrillation); do ECG if arrhythmic symptoms or new onset dyspnea develop. Risk of second primary malignancies (eg, skin cancer or other carcinomas). Monitor for tumor lysis syndrome in patients at risk (eg, high tumor burden). Moderate or severe hepatic impairment: not recommended.

Maintain adequate hydration. Pregnancy (Cat.D); avoid. Nursing mothers: not recommended.

Interactions: Concomitant strong CYP3A inhibitors taken chronically (eg, ritonavir, indinavir, nelfinavir, saquinavir, boceprevir, telaprevir, nefazodone): not recommended; for shortterm (≤7days) use of strong CYP3A inhibitors (eg, ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin); consider interrupting ibrutinib therapy. If concomitant moderate CYP3A inhibitors must be used (eg, fluconazole, darunavir, erythromycin, diltiazem, atazanavir, aprepitant, amprenavir, fosamprevir, crizotinib, imatinib, verapamil, ciprofloxacin): reduce ibrutinib dose (see Adults). Avoid grapefruit and Seville oranges during treatment. Avoid concomitant strong CYP3A inducers (eg, carbamazepine, rifampin, phenytoin, St. John’s Wort); consider alternatives.

Increased risk of hemorrhage with concomitant antiplatelets or anticoagulants.

Adverse reactions: Thrombocytopenia, diarrhea, neutropenia, anemia, fatigue, musculoskeletal pain, peripheral edema, upper respiratory tract infection, nausea, bruising, dyspnea, constipation, rash, abdominal pain, vomiting, decreased appetite, pyrexia.

How supplied: Caps—90, 120

INTRON A Merck

℞

Alpha interferon. Interferon alfa-2b, recombinant; 10 million, 18 million, or 50 million IU per vial; pwd; for inj after reconstitution/dilution; preservativefree; contains albumin. ℞ Also: INTRON A SOLN Interferon alfa-2b, recombinant; 10 million IU, 18 million IU, 25 million IU; per vial; for inj; contains m-cresol.

Indications: 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: Decompensated liver disease. Autoimmune hepatitis.

Warnings/Precautions: May cause or exacerbate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, or infectious disorders: monitor closely, discontinue

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER if they worsen. Severe psychiatric disorders (esp. depression). Cardiovascular or pulmonary disease. Severe myelosuppression; discontinue if neutrophil count <0.5 X109/L or platelets 25×109/L. Permanently discontinue if severe (Grade 3) hepatic injury or decompensation (Child-Pugh score >6 [Class B and C]) develop.

Thyroid abnormalities; discontinue if uncontrolled by medication. Diabetes. Coagulation disorders.

Maintain adequate hydration. Monitor blood, thyroid, visual and liver function before and during therapy; EKG in cardiovascular disease and cancer patients. Psoriasis. Renal dysfunction.

Transplant recipients. Elderly. Debilitated.

Pregnancy (Cat.C). Nursing mothers: not recommended.

Interactions: Caution with myelosuppressives, and drugs that can exacerbate depression. May potentiate theophylline (may double its levels).

Adverse reactions: Flu-like symptoms (fever, headache, myalgia, fatigue); hepatic, hematologic, respiratory, skin, genitourinary system, CNS, cardiovascular, endocrine (esp. thyroid), GI, or visual disorders; colitis, hypertriglyceridemia, pancreatitis, infections, injection site reactions, dental and periodontal disorders; others (see full labeling).

How supplied: Pwd (w. diluent): 10million, 18million, 50million IU/vial—1; Soln (multidose vials): 18million, 25million IU/vial—1

ISTODAX Celgene

℞

Histone deacetylase inhibitor. Romidepsin 10mg/vial; pwd for IV infusion after reconstitution and dilution; contains povidone.

Indications: Cutaneous T-cell lymphoma in patients who have received at least one prior systemic therapy. Peripheral T-cell lymphoma in patients who have received at least one prior therapy.

Adults: ≥18yrs: Give by IV infusion over 4hrs.

14mg/m2 on days 1, 8, and 15 of a 28-day cycle; repeat cycle every 28 days; continue as tolerated and as beneficial. May interrupt, reduce dose to 10mg/m2, or discontinue based on toxicities (see full labeling).

Children: <18yrs: not established.

Warnings/Precautions: Increased risk of serious infections (eg, pneumonia, sepsis, Epstein Barr, HBV). Prior history of hep B infection; consider monitoring for reactivation and give antiviral prophylaxis. Correct electrolyte imbalances (esp. K+, Mg++) before starting.

Monitor ECG and electrolytes in congenital long QT syndrome, significant cardiovascular disease. Advanced stage disease and/or high tumor syndrome: monitor closely for tumor

lysis syndrome. Moderate-to-severe hepatic impairment. End-stage renal disease. Monitor CBC with differential. Pregnancy (Cat.D; may cause fetal harm). Nursing mothers: not recommended.

Interactions: Caution with other drugs that can cause QT prolongation (monitor). Monitor PT/INR with warfarin. Potentiated by drugs that inhibit P-gp and CYP3A4; avoid concomitant strong CYP3A4 inhibitors (eg, azole antifungals, protease inhibitors, clarithromycin, telithromycin, nefazodone). Caution with moderate CYP3A4 inhibitors. Avoid concomitant rifampin. May be antagonized by other strong CYP3A4 inducers (eg, dexamethasone, carbamazepine, phenytoin, phenobarbital, rifabutin, rifapentine, St. John’s Wort); avoid when possible.

Adverse reactions: Neutropenia, lymphopenia, thrombocytopenia, anemia, nausea, vomiting, fatigue, infections, anorexia, ECG T-wave changes; tumor lysis syndrome.

How supplied: Kit—1 (single-use vial + diluent and supplies)

JAKAFI Incyte

℞

Kinase inhibitor. Ruxolitinib 5mg, 10mg, 15mg, 20mg, 25mg; tabs.

Indications: Treatment of intermediate or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis. Treatment of polycythemia vera (PV) in patients with inadequate response to, or intolerant of, hydroxyurea.

Adults: Doses may be given by NG tube if unable to swallow tabs. Myelofibrosis: Platelets >200×109/L: initially 20mg twice daily. Platelets 100–200×109/L: initially 15mg twice daily.

Platelets 50–<100×109/L: initially 5mg twice daily. May increase doses by 5mg twice daily to a max of 25mg twice daily; do not increase during the first 4 weeks of therapy and not more frequently than every 2 weeks. Discontinue treatment after 6 months if no reduction in spleen size or symptom improvement.

Interrupt treatment if platelets <50×109/L or ANC <0.5×109/L. May restart after recovery of platelets or ANC (see full labeling for max allowable restarting doses). Consider dose reductions if platelets decrease but remain ≥50×109/L (see full labeling). Dose modifications for patients starting treatment with platelets 50–<100×109/L: see full labeling. PV: initially 10mg twice daily. May increase doses by 5mg twice daily to a max of 25mg twice daily; do not increase during the first 4 weeks of therapy

and not more frequently than every 2 weeks.

Consider dose reductions for Hgb and/or platelet decreases (see full labeling). Interrupt treatment if Hgb <8g/dL, platelets <50×109/L, or ANC <1.0×109/L. May restart after recovery of hematologic parameters (see full labeling for max allowable restarting doses). Concomitant strong CYP3A4 inhibitors (see Interactions) or fluconazole ≤200mg (Myelofibrosis): initially 10mg twice daily if platelets ≥100×109/L; if platelets 50–<100×109/L: initially 5mg once daily; (PV): initially 5mg twice daily. Other reductions, hepatic or renal impairment, ESRD: see full labeling.

Children: Not established.

Warnings/Precautions: Monitor for thrombocytopenia, anemia, neutropenia; manage by reducing dose, interrupt, or transfusion if occur. Obtain CBC and platelets before initiating therapy, every 2–4 weeks until doses are stabilized, and then as clinically indicated.

Risk of serious bacterial, mycobacterial, fungal, and viral infections; evaluate and treat if signs/ symptoms occur. Confirm resolution of active infections before starting. May exacerbate myelofibrosis following treatment interruption or discontinuation. Risk of non-melanoma skin cancer; perform periodic skin exams. Avoid abrupt cessation. Renal or hepatic impairment.

Pregnancy (Cat.C). Nursing mothers: not recommended.

Interactions: Avoid concomitant fluconazole doses >200mg daily. Potentiated by strong CYP3A4 inhibitors (eg, boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole) and mild or moderate CYP3A4 inhibitors (eg, erythromycin). Antagonized by strong CYP3A4 inducers (eg, rifampin).

Adverse reactions: Thrombocytopenia, anemia, bruising, dizziness, headache; herpes zoster, tuberculosis (monitor promptly and test for latent infection), progressive multifocal leukoencephalopathy (discontinue if occurs).

How supplied: Tabs—60

KYPROLIS Onyx

℞

Proteasome inhibitor. Carfilzomib 60mg/vial; lyophilized pwd for IV inj after reconstitution; preservative-free.

Indications: As monotherapy for treatment of patients with multiple myeloma who have received at least two prior therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression

Access Cancer Therapy Advisor treatment regimens in a user-friendly format.

CancerTherapyAdvisor.com/TreatmentRegimens.

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER on or within 60 days of completion of the last therapy. In combination with lenalidomide and dexamethasone for treatment of patients with relapsed multiple myeloma who have received 1–3 prior therapies.

Adults: See full labeling. Premedicate with dexamethasone for monotherapy prior to all Cycle 1 doses, during subsequent cycles, and if infusion reactions occur. Give by IV over 10 mins, on two consecutive days each week for 3 weeks (Days 1, 2, 8, 9, 15, and 16), followed by a 12-day rest period (Days 17–28). In Cycle 1: 20mg/m2 per each dose on Days 1 and 2, if tolerated increase to 27mg/m2 on Day 8 and subsequent cycles. From Cycle 13, omit the Day 8 and 9 doses. In combination therapy: discontinue after Cycle 18; see full labeling for lenalidomide and dexamethasone dosing. Both therapies: continue until disease progression or unacceptable toxicity occurs. On dialysis: give dose after session.

Toxicity dose modification: see full labeling.

Children: Not established.

Warnings/Precautions: Risk of cardiac complications (eg, CHF, MI, pulmonary edema); monitor and manage promptly if occurs.

Pulmonary hypertension; if suspected, withold therapy until resolved; may consider restarting after reevaluate. Discontinue if pulmonary toxicity occurs. Monitor for dyspnea or tumor lysis syndrome, and manage promptly if occurs; interrupt therapy until resolved. Maintain adequate hydration. Monitor for volume overload.

Monitor platelets frequently during therapy.

Monitor for thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/ HUS); discontinue and evaluate if suspected.

Discontinue and evaluate if posterior reversible encephalopathy syndrome (PRES) is suspected. Monitor BP, renal function regularly; reduce or withhold dose as needed. Hepatic impairment (monitor enzymes). Consider thromboprophylaxis for combination therapy.

Consider antiviral prophylaxis for monotherapy.

Elderly (≥75yrs). Pregnancy; avoid. Use effective contraception during and for ≥2 weeks after therapy completion. Nursing mothers.

Adverse reactions: Fatigue, anemia, nausea, thrombocytopenia, dyspnea, diarrhea, pyrexia, decreased platelets, headache, decreased hemoglobin, cough, edema peripheral; cardiac events, pulmonary HTN, acute kidney injury, infusion reactions, tumor lysis syndrome, hepatic toxicity/failure, TTP/HUS, PRES. How supplied: Single-use vial—1

LEUKERAN GlaxoSmithKline

℞

Alkylating agent. Chlorambucil 2mg; tabs.

Indications: Palliative treatment of chronic lymphatic (lymphocytic) leukemia and malignant lymphomas (including lymphosarcoma, giant follicular lymphoma, and Hodgkin’s disease).

Adults: See literature. 0.1–0.2mg/kg per day for 3–6 weeks. Reduce dose if leukocyte or platelet counts fall below normal values and discontinue

if more severe depression occurs. Do not give full dose within 4 weeks of radio- or chemotherapy.

Children: Not recommended.

Warnings/Precautions: Compromised bone marrow function. History of seizure disorder or head trauma. Monitor blood weekly (during first 3–6 weeks, do WBC count 3–4 days after each weekly CBC). Discontinue if skin reactions occur.

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

Interactions: Avoid live vaccines.

Myelosuppressives, radiotherapy potentiate antineoplastic effect. Caution with drugs that lower seizure threshold.

Adverse reactions: Bone marrow suppression, seizures, fever, rash, hypersensitivity, urticaria, azoospermia, amenorrhea, sterility, hepato- and pulmonary toxicity, secondary malignancies, GI upset.

How supplied: Tabs—50

MARQIBO Spectrum

℞

Vinca alkaloid. Vincristine sulfate liposome injection; after preparation, each vial contains 0.16mg/mL; for IV infusion.

Indications: Philadelphia chromosome-negative (Ph–) acute lymphoblastic leukemia (ALL) in second or greater relapse or has progressed following ≥2 anti-leukemia therapies.

Adults: 2.25mg/m2 IV over 1hr once every 7 days.

Dose modifications for peripheral neuropathy: see full labeling.

Children: Not established.

Contraindications: Demyelinating conditions, including Charcot-Marie-Tooth syndrome.

Intrathecal administration (death has occurred).

Warnings/Precautions: For IV use only; fatal if given by other routes. Discontinue and treat if extravasation is suspected. Preexisting neuromuscular disorders. Monitor for symptoms of neuropathy before and during therapy; if occurs or worsens, delay, reduce or discontinue dose. Monitor CBCs prior to each dose; if Grade 3 or 4 myelosuppression develops, consider dose modification or reduction. Monitor for tumor lysis syndrome; manage if occurs. Institute a prophylactic bowel regimen to mitigate potential constipation, bowel obstruction, and/or paralytic ileus; consider dietary fiber intake, hydration, stool softeners. Monitor liver function tests; if hepatotoxicity occurs, reduce or interrupt dosing. Elderly. Pregnancy (Cat.D); avoid. Nursing mothers: not recommended.

Interactions: Drugs known to interact with non-liposomal vincristine sulfate (eg, phenytoin: increased seizure risk). Avoid concomitant strong CYP3A inhibitors (eg, ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin) or strong CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, St. John’s Wort). Avoid concomitant potent P-gp inhibitors or inducers.

Adverse reactions: Constipation, nausea, pyrexia, fatigue (may be severe; adjust dose or discontinue), peripheral neuropathy, febrile neutropenia, diarrhea, anemia, decreased appetite, insomnia.

How supplied: Kit—1, 3 (vials + supplies)

MUSTARGEN Recordati

℞

Nitrogen mustard. Mechlorethamine HCl 10mg/vial; pwd for IV or intracavitary inj after reconstitution.

Indications: Palliative treatment of Hodgkin’s disease (stages III and IV), lymphosarcoma, chronic myelocytic or chronic lymphocytic leukemia, polycythemia vera, mycosis fungoides.

Palliative treatment of metastatic carcinoma resulting in effusion.

Adults: By IV infusion, per therapeutic course: 0.4mg/kg (lean body weight) as single dose or in divided doses of 0.1–0.2mg/kg per day.

See literature for intracavitary (eg, intrapleural) administration. Do not exceed recommended dose. Repeat course only after hematological recovery (eg, every 3 weeks).

Children: See literature.

Contraindications: Infectious diseases.

Warnings/Precautions: Drug is highly toxic; verify potential benefits outweigh risks; avoid inadvertent contact with powder or vapor. Do not use if foci of acute and chronic suppurative inflammation are present. Ensure adequate hydration. Avoid extravasation. Chronic lymphatic leukemia. Bone marrow suppression. Previous X-ray, cytotoxic chemotherapy. Infection.

Hemorrhagic tendency. Monitor renal, hepatic and bone marrow function. Elderly. Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended.

Adverse reactions: Bone marrow suppression, hyperheparinemia, GI upset (may be severe), anorexia, weakness, thrombosis, thrombophlebitis, hypersensitivity, jaundice, alopecia, vertigo, auditory disturbances, hemolytic anemia, skin reactions, infection, amyloidosis, hyperuricemia, gonad damage.

How supplied: Vials—4

MYLERAN GlaxoSmithKline

℞

Alkylating agent. Busulfan 2mg; tabs.

Indications: Palliative treatment of chronic myelogenous leukemia.

Adults: Remission induction: 4–8mg/day or 60micrograms/kg or 1.8mg/m2, daily. Reserve doses >4mg/day for severe cases. Reduce dose or discontinue at first sign of reduced bone marrow reserve. Discontinue before leukocyte count normalizes; see literature. Normal leukocyte counts usually achieved in 12–20 weeks. If remission <3 months, maintenance therapy of 1–3mg/day may be advisable.

Children: Remission induction: 60micrograms/kg or 1.8mg/m2, daily. Reduce dose or discontinue at first sign of reduced bone

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER marrow reserve. Discontinue before leukocyte count normalizes. Normal leukocyte counts usually achieved in 12–20 weeks. See literature.

Warnings/Precautions: Confirm diagnosis.

Monitor hepatic and bone marrow function.

Obtain CBCs and differential weekly; monitor for anemia. Previously compromised bone marrow (irradiation, chemotherapy). Seizure disorder or risk. Head trauma. Elderly. Pregnancy (Cat.D), nursing mothers: not recommended.

Interactions: Myelosuppression increased with other myelosuppressives. Increased pulmonary toxicity with other cytotoxic drugs. Potentiated by itraconazole, cyclophosphamide (see literature).

May be antagonized by phenytoin. Hepatotoxicity possible with long-term continuous thioguanine therapy. Caution with drugs that lower seizure threshold.

Adverse reactions: See literature. Bone marrow suppression (eg, pancytopenia, anemia, leukopenia, thrombocytopenia, aplastic anemia), pulmonary toxicity, cellular dysplasia, malignant tumors, acute leukemias, cardiac tamponade (esp. in thalassemia), hyperpigmentation, adrenal insufficiency, seizures, hepatic veno-occlusive disease, infection (eg, pneumonia, sepsis), mucositis, myasthenia gravis, gonadal suppression, rash; rare: cataracts, bronchopulmonary dysplasia (discontinue if occurs).

How supplied: Tabs—25

ONCASPAR Sigma-Tau

℞

Enzyme. Pegaspargase 750 IU/mL; soln for IV or IM inj; preservative-free.

Indications: First-line acute lymphoblastic leukemia (including patients with asparaginase hypersensitivity).

Adults and Children: Give by IV inj over 1–2hrs or by IM inj (max 2mL/inj site). 2500 IU/m2 no more frequently than every 14 days.

Contraindications: History of pancreatitis, serious hemorrhage, or thrombosis with prior L-asparaginase therapy.

Warnings/Precautions: Have resuscitation equipment available and observe patient for 1hr post-dose. Monitor coagulation parameters.

Discontinue if serious allergic reactions, thrombotic events, or pancreatitis occurs.

Monitor for hepatotoxicity and abnormal liver function. Pregnancy (Cat.C). Nursing mothers: not recommended.

Adverse reactions: Allergic reactions (including anaphylaxis), hyperglycemia, pancreatitis, CNS thrombosis, coagulopathy, hyperbilirubinemia, hepatotoxicity, elevated transaminases, hyperlipidemia.

How supplied: Single-use vial (5mL)—1

ONTAK Eisai

℞

Interleukin 2-diphtheria toxin fusion protein.

Denileukin diftitox 150mcg/mL; soln for IV infusion after thawing and dilution.

Indications: Persistent or recurrent cutaneous T-cell lymphoma in which malignant cells express the CD25 component of the IL-2 receptor.

Adults: Premedicate with an antihistamine or acetaminophen prior to each infusion. Give by IV infusion over 30–60 minutes. 9 or 18mcg/kg per day for 5 consecutive days every 21 days for 8 cycles.

Children: Not recommended.

Warnings/Precautions: Ensure CD25 expression before starting therapy. Have resuscitative equipment available during administration. Permanently discontinue if serious infusion reactions occur. Monitor for signs/symptoms of capillary leak syndrome (hypotension, edema, hypoalbuminemia) and weight gain. Monitor serum albumin levels prior to each treatment course; withhold treatment if serum albumin <3g/dL. Pregnancy (Cat.C).

Nursing mothers: not recommended.

Adverse reactions: Fever, fatigue, rigors, GI upset, headache, edema, cough, dyspnea, pruritus, rash, hypotension, back pain, myalgia, chest pain, tachycardia, hypoalbuminemia, asthenia, elevated transaminases; capillary leak syndrome (may be fatal), serious infusion reactions, visual impairment (monitor).

Testing considerations: CD25 expression How supplied: Single-use vials (2mL)—6

POMALYST Celgene

℞

Immunomodulator. Pomalidomide 1mg, 2mg, 3mg, 4mg; caps.

Indications: In combination with dexamethasone for multiple myeloma, in patients who have received at least two prior therapies (including lenalidomide and a proteasome inhibitor), and have shown disease progression on or within 60 days of completion of the last therapy.

Adults: Swallow whole; may be taken with water.

Take without food. 4mg once daily on Days 1–21 of repeated 28-day cycles until disease progression; give with dexamethasone. Concomitant strong CYP1A2 inhibitors in presence of strong CYP3A4 and P-gp inhibitors: reduce Pomalyst dose by 50%. Dose modification for hematologic and other Grade 3/4 toxicities: see full labeling.

Children: <18yrs: not established.

Contraindications: Pregnancy (Cat.X): avoid during and for at least 4 weeks after completing therapy.

Warnings/Precautions: Females of reproductive potential must commit either to abstain from heterosexual sex or to use two methods of reliable contraception, beginning 4 weeks prior to initiating, during therapy, dose interruptions and for 4 weeks after discontinuation. Obtain two negative pregnancy tests prior to initiating therapy: perform first test within 10–14 days, and second test within 24hrs prior to prescribing, and then weekly during first month, then monthly thereafter in women with regular menstrual cycles or every 2 weeks if irregular cycles. Males: must use latex or synthetic condom during therapy and up to 28 days after discontinuing, even after successful vasectomy; do not donate sperm. Patients must not donate blood during therapy and for 1 month after discontinuation. Venous and arterial thromboembolism; consider anticoagulation prophylaxis. Monitor for hematologic toxicities (esp. neutropenia); obtain CBCs weekly for first 8 weeks and monthly thereafter; may need dose interruption and/or modification. Renal impairment (serum creatinine >3mg/dL) or hepatic impairment (serum bilirubin >2mg/dL and AST/ALT >3×ULN): avoid. Monitor LFTs monthly; discontinue and evaluate if elevated liver enzymes occur; consider using lower dose when restarting. Risk of second primary malignancies.

High tumor burden (monitor). Discontinue if angioedema, skin exfoliation, bullae, or other severe dermatologic reactions occur; do not restart. Nursing mothers: not recommended.

Interactions: May be potentiated by strong CYP1A2, CYP3A (eg, ketoconazole), or P-gp inhibitors; avoid. May be antagonized by strong CYP1A2, CYP3A (eg, rifampin), or P-gp inducers; avoid. Smoking may reduce efficacy.

Adverse reactions: Fatigue, asthenia, neutropenia, anemia, constipation, nausea, diarrhea, dyspnea, upper-respiratory tract infections, back pain, pyrexia; thromboembolism, dizziness, confusion, neuropathy, pneumonia, thrombocytopenia, tumor lysis syndrome.

Note: Available only through Pomalyst REMS program.

How supplied: Caps—21, 100

PURINETHOL Teva

℞

Antimetabolite. Mercaptopurine (6-MP) 50mg; scored tabs.

Indications: Maintenance therapy of acute lymphatic leukemia as part of a combination regimen.

Adults and Children: 1.5–2.5mg/kg per day as a single dose. Concomitant allopurinol: reduce dose of mercaptopurine to 1/3–1/4 of

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

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER 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

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

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER 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 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

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER established. Elderly. Pregnancy (Cat.D); avoid.

Nursing mothers: not recommended.

Interactions: Avoid concomitant anticoagulants, aspirin, NSAIDs if platelets <50,000/microliters; may increase risk of bleeding.

Adverse reactions: Thrombocytopenia, anemia, neutropenia, diarrhea, nausea, fatigue, asthenia, injection site reaction, pyrexia, infection, lymphopenia; bleeding, hyperglycemia.

How supplied: Single-use vial—1

TABLOID GlaxoSmithKline

℞

Antimetabolite. Thioguanine 40mg; tabs; scored.

Indications: Remission induction and remission consolidation treatment of acute nonlymphocytic leukemias. Treatment of the chronic phase of chronic myelogenous leukemia (see literature).

Adults and Children: See literature. Initially, 2mg/kg per day. If, after 4 weeks, with no improvement, no leukocyte or platelet depression, may increase to 3mg/kg per day. Total daily dose may be given at one time.

Contraindications: Allergy to mercaptopurine.

Warnings/Precautions: Not recommended for maintenance therapy or long-term continuous treatments; increased risk of liver toxicity (discontinue if occurs). Pre-existing liver disease.

Monitor liver function tests weekly at start of therapy, then monthly thereafter. Thiopurine methyltransferase (TPMT) enzyme deficiency (may need to reduce dose to avoid severe bone marrow suppression); consider testing for TPMT deficiency. Obtain hemoglobin, hematocrit, WBCs with differential, platelets frequently during therapy. Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended.

Interactions: Avoid live vaccines (if immunocompromised). Caution with drugs that inhibit TPMT (eg, olsalazine, mesalazine, or sulphasalazine).

Adverse reactions: Myelosuppression, hyperuricemia, GI upset, anorexia, stomatitis, hepatotoxicity, elevated liver enzymes, jaundice (discontinue if occurs).

How supplied: Tabs—25

TARGRETIN Valeant

℞

Retinoid. Bexarotene 75mg; caps.

Indications: Cutaneous manifestations of cutaneous T-cell lymphoma in patients who are refractory to at least one prior systemic therapy.

Adults: Take with food. Initially 300mg/m2 once daily; may increase after 8 weeks to 400mg/m2 once daily if no tumor response and if well tolerated; monitor carefully. If toxicity occurs, reduce to 200mg/m2 then 100mg/m2 once daily, or suspend therapy.

Children: Not recommended.

Contraindications: Pregnancy (Cat.X).

Warnings/Precautions: Be fully familiar with this drug’s toxicity before use. Pancreatitis or risk of pancreatitis (eg, history of pancreatitis, uncontrolled hyperlipidemia, excess alcohol

consumption, uncontrolled diabetes, biliary tract disease, drugs that can cause pancreatitis).

Counsel patients monthly about need for contraception. Women of childbearing potential: obtain reliable negative pregnancy test within 1 week of start; repeat monthly. Start therapy on 2nd or 3rd day of normal menstrual period. Use two effective forms of contraception 1 month prior to, during, and for 1 month after therapy.

Max 1 month/℞. Men with partners who are or may become pregnant: use condoms during and for at least 1 month after therapy. Monitor lipids before treatment, weekly until stable, then every 8 weeks; try to keep triglycerides <400mg/dL; treat hyperlipidemia, or reduce or suspend bexarotene if needed. Hepatic or renal insufficiency. Monitor liver function at baseline, 1, 2, and 4 weeks after start, then (if stable) at least every 8 weeks during therapy; consider suspending or discontinuing treatment if SGOT/ AST, SGPT/ALT, or bilirubin >3×ULN occurs.

Monitor WBC with differential and thyroid function at baseline and during treatment; treat hypothyroidism if needed. Avoid sun and UV light.

Nursing mothers: not recommended.

Interactions: Concomitant gemfibrozil: not recommended. Levels may be increased

by CYP3A4 inhibitors (eg, ketoconazole, itraconazole, erythromycin, grapefruit juice).

Levels may be reduced by CYP3A4 inducers (eg, rifampin, phenobarbital, phenytoin). May potentiate antihyperglycemics (eg, insulin, sulfonylureas, thiazolidinediones); monitor. May potentiate or be potentiated by protein-bound drugs. May antagonize tamoxifen, hormonal contraceptives, other CYP3A4 substrates. Limit Vit. A supplements to avoid toxicity. May increase CA125 assay values.

Adverse reactions: Lipid abnormalities, headache, hypothyroidism, asthenia, leukopenia, anemia, rash, GI disturbances, peripheral edema, dry skin, exfoliative dermatitis, alopecia, insomnia, fatigue, abnormal liver function tests, pancreatitis, pruritus, photosensitivity.

How supplied: Caps—100

TARGRETIN GEL Valeant

℞

Retinoid. Bexarotene 1%; gel.

Indications: Cutaneous lesions in patients with CTCL (Stage IA and IB) who have refractory or persistent disease after other therapies or who have not tolerated other therapies.

Adults: Apply once every other day for the 1st week; then increase frequency at weekly intervals to once daily, then twice daily, then 3 times daily, then 4 times daily based on lesion tolerance.

Usual dosing frequency: 2–4 times daily; may reduce if application site toxicity occurs. Allow gel to dry. Do not occlude.

Children: Not recommended.

Contraindications: Pregnancy (Cat.X).

Warnings/Precautions: Be fully familiar with this drug’s toxicity before use. Counsel patients monthly about need for contraception. Women

of childbearing potential: obtain reliable negative pregnancy test within 1 week of start; repeat monthly. Start therapy on 2nd or 3rd day of normal menstrual period. Use two effective forms of contraception 1 month prior to, during, and for 1 month after therapy. Max 1 month/℞. Men with partners who are or may become pregnant: use condoms during and for at least 1 month after therapy. Hepatic or renal insufficiency.

Discontinue temporarily if severe irritation occurs.

Avoid sun, UV light, and mucosal membranes.

Nursing mothers: not recommended.

Interactions: Avoid concomitant products that contain DEET. May be potentiated by CYP3A4 inhibitors (eg, ketoconazole, itraconazole, erythromycin, grapefruit juice). Caution with gemfibrozil. Limit Vit. A supplements to avoid toxicity.

Adverse reactions: Application site reactions (eg, rash, pruritus, skin disorders, pain, contact dermatitis).

How supplied: Gel—60g

TASIGNA Novartis

℞

Kinase inhibitor. Nilotinib (as HCl monohydrate) 150mg, 200mg; caps; contains lactose.

Indications: Newly diagnosed adults with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase.

Chronic and accelerated phase Ph+ CML in adults resistant or intolerant to imatinib.

Adults: Take on an empty stomach. Swallow whole with water; if unable, may disperse capsule contents in 1 tsp of applesauce, then take immediately (within 15 mins). Newly diagnosed Ph+ CML: 300mg every 12hrs. Hepatic impairment (mild, moderate, severe): initially 200mg twice daily, followed by dose increase to 300mg twice daily if tolerated. Resistant or intolerant Ph+ CML: 400mg every 12hrs. Hepatic impairment (mild or moderate): initially 300mg twice daily, followed by dose increase to 400mg twice daily if tolerated; severe: initially 200mg twice daily, followed by sequential dose increase to 300mg twice daily, and then 400mg twice daily if tolerated. May give concomitant hematopoietic growth factors, hydroxyurea, or anagrelide if clinically indicated. See full labeling for dose adjustments in QT prolongation, hematological and non-hematological toxicities, concomitant strong CYP3A4 inhibitors and inducers.

Children: Not established.

Contraindications: Hypokalemia.

Hypomagnesemia. Long QT syndrome.

Warnings/Precautions: Prolongs QT interval, sudden deaths have been reported; correct electrolyte abnormalities before starting; monitor. Monitor ECG at baseline, after 7 days, then periodically and after dose changes.

Cardiovascular status should be evaluated; monitor cardiovascular risk factors and actively manage during therapy. Hereditary galactose intolerance, severe lactase deficiency, glucosegalactose malabsorption: not recommended.

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER 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 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

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER (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)

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 moderately-to-severe, or severe dermatitis occur; restart at reduced frequency of once every 3 days upon improvement; if reintroduction is tolerated for at least 1 week, can increase to

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER every other day for 1 week and then once daily if tolerated.

Children: Not established.

Warnings/Precautions: Mucosal (oral, nasal) or eye exposure; blindness and severe irreversible anterior eye injury may occur; immediately irrigate for ≥15 minutes with copious amounts of water. Secondary exposure; avoid direct skin contact with patient. Risk of dermatitis (eg, face, genitalia, anus, and intertriginous skin); monitor for redness, swelling, inflammation, itchiness, blisters, ulceration, and secondary skin infections.

Monitor for nonmelanoma skin cancer during and after treatment. Flammable (avoid fire and flame until gel has dried). Pregnancy (Category D); may cause fetal harm. Nursing mothers: not recommended.

Adverse reactions: Dermatitis, pruritus, bacterial skin infection, skin ulceration or blistering, hyperpigmentation.

How supplied: Gel—60g

VELCADE Millennium

℞

Proteasome inhibitor. Bortezomib 3.5mg/vial; lyophilized pwd for IV or SC inj after reconstitution; contains mannitol.

Indications: Multiple myeloma. Mantle cell lymphoma.

Adults: Give as a 3–5 second IV bolus inj or as SC inj into thigh or abdomen (rotate sites).

Previously untreated multiple myeloma: Treat for nine 6-week cycles in combination with oral melphalan and oral prednisone. Cycles 1–4: 1.3mg/m2 twice weekly (Days 1, 4, 8, 11, 22, 25, 29, 32); Cycles 5–9: 1.3mg/m2 once weekly (Days 1, 8, 22, 29). Previously untreated mantle cell lymphoma: Treat for six 3-week cycles in combination with IV rituximab, cyclophosphamide, doxorubicin, and oral prednisone. 1.3mg/m2 twice weekly for 2 weeks (Days 1, 4, 8, 11) then 10 day rest period (Days 12–21); if response first documented at Cycle 6, two more cycles are recommended. Relapsed multiple myeloma or mantle cell lymphoma: Standard schedule: 1.3mg/m2 twice weekly for 2 weeks (Days 1, 4, 8, 11) then 10 day rest period (Days 12–21); Extended therapy (if using >8 cycles): may use standard schedule, or maintenance schedule: 1.3mg/m2 once weekly for 4 weeks (Days 1, 8, 15, 22) then 13-day rest period (Days 23–35). Multiple myeloma patients who have previously responded to bortezomib (alone or in combination) and have relapsed at least 6 months after completing prior bortezomib therapy: may retreat starting at last tolerated dose, given twice weekly every 3 weeks (Days 1, 4, 8, 11); max 8 cycles. Allow at least 72hrs between

consecutive doses. May be given as a single agent or in combination with dexamethasone.

Dose modifications: see full labeling. SC inj may be considered for patients with pre-existing or at high-risk of peripheral neuropathy. Moderate-tosevere hepatic impairment: reduce to 0.7mg/m2 in 1st cycle; may consider dose increase to 1mg/m2 or further decrease to 0.5mg/m2 in subsequent cycles based on tolerance.

Children: Not established.

Contraindications: Boron or mannitol sensitivity. Intrathecal administration.

Warnings/Precautions: Hepatic impairment.

Pre-existing severe neuropathy; treat only after careful risk-benefit assessment. Monitor for development or worsening of peripheral neuropathy; consider dose and/or schedule 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),

℞

French-American-British (FAB) classification M3 (including the M3 variant), characterized by the presence of the t(15;17) translocation and/or the presence of the PML/RARα gene who are refractory to, or who have relapsed from, anthracycline chemotherapy, or for whom anthracycline-based chemotherapy is contraindicated.

Adults: Use only for induction of remission.

45mg/m2 per day in two divided doses until complete remission is documented. Discontinue 30 days after complete remission or after 90 days of treatment, whichever occurs first.

Children: See literature.

Warnings/Precautions: Confirm APL diagnosis. Monitor for Retinoic Acid-APL (RA-APL) syndrome, leukocytosis, pseudotumor cerebri, or respiratory compromise. Consider temporarily interrupting therapy if moderate to severe RA-APL syndrome develops. Monitor blood counts, coagulation profile, lipids, liver function; consider temporary withdrawal if tests >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

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER no toxicity. Treat for at least 4–6 cycles. Adjust subsequent doses on blood counts and toxicities (eg, neutropenia, thrombocytopenia, decreased serum bicarbonate).

Children: Not established.

Contraindications: Advanced malignant hepatic tumors.

Warnings/Precautions: Renal or hepatic impairment. High tumor burden. Obtain CBC counts before each dosing cycle and as needed.

Monitor serum bicarbonate and renal and hepatic function (do baseline liver chemistries and serum creatinine). Elderly. Pregnancy (Cat.D); use appropriate contraception (both men and women). Nursing mothers: not recommended.

Adverse reactions: Nausea, vomiting, diarrhea, blood dyscrasias (esp. anemia, thrombocytopenia, neutropenia, leukopenia), fever, fatigue, inj site reactions, constipation, ecchymosis, petechiae, rigors, dyspnea, arthralgia, headache, anorexia, renal failure/ tubular acidosis, hypokalemia, hepatic coma, others (see full labeling).

How supplied: Single-use vial—1

VUMON Bristol-Myers Squibb

℞

Topoisomerase inhibitor. Teniposide 10mg/mL; soln for IV infusion after dilution; contains benzyl alcohol, Cremophor EL (polyoxyethylated castor oil), dehydrated alcohol.

Indications: Refractory childhood acute lymphoblastic leukemia.

Adults and Children: See literature. Give as slow IV infusion (at least 30–60 minutes).

Patients failing induction therapy with a cytarabine-containing regimen: 165mg/m2 + cytarabine twice weekly for 8 to 9 doses.

Refractory to vincristine/prednisone-containing regimen: 250mg/m2 + vincristine weekly for 4 to 8 weeks + oral prednisone for 28 days.

Warnings/Precautions: Severe myelosuppression. Monitor for hypersensitivity reactions following infusion; have epinephrine available. Risk of hypotension with rapid IV administration. Hepatic dysfunction. Monitor and obtain CBCs with differential, hemoglobin, platelets, renal and hepatic functions before, during, and after therapy. Down syndrome (use reduced dose). Monitor children with hypoalbuminemia.

Avoid extravasation. Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended.

Interactions: Potentiated by tolbutamide, sodium salicylate, and sulfamethizole.

Concomitant vincristine sulfate may cause neuropathy. Concomitant antiemetics in patients given high doses of teniposide may increase risk of CNS depression, hypotension.

Adverse reactions: Myelosuppression (leukopenia, neutropenia, thrombocytopenia, anemia), mucositis, GI upset, infection, alopecia, bleeding, rash, fever, hypotension, CNS depression, hypersensitivity reactions (may be fatal).

How supplied: Ampules (5mL)—1

ZEVALIN Spectrum

℞

Radionuclide (B-lymphocyte-restricted differentiation antigen [CD20] inhibitor).

Ibritumomab tiuxetan 3.2mg/2mL; soln for IV inj; contains albumin; preservative-free.

Indications: B-cell non-Hodgkin’s lymphoma (relapsed or refractory, low grade or follicular).

Previously untreated follicular non-Hodgkin’s lymphoma in patients who achieve a partial or complete response to first-line chemotherapy.

Adults: See literature. Prepare In-111 Zevalin and Y-90 Zevalin as directed. Initiate Zevalin therapy after recovery of platelets to ≥150,000/mm3 at least 6 weeks, but no more than 12 weeks, after the last dose of first-line chemotherapy.

Administered in two steps. Step 1: Single infusion of rituximab followed by a fixed dose of 5mCi (1.6mg total antibody dose) of In-111 Zevalin given as a 10-minute IV push. Step 2 (7–9 days after Step 1): Second rituximab infusion followed by 0.4mCi/kg of Y-90 Zevalin given as a 10-minute IV push; if platelet count 100,000–149,000cells/mm3, reduce dose to 0.3 mCi/kg. Do not treat if platelets <100,000cells/mm3. Max Y-90 Zevalin dose: 32mCi. Children: Not recommended.

Contraindications: Hypersensitivity to murine proteins.

Warnings/Precautions: See literature. Use only if trained in radionuclide therapy. Do not treat patients with altered biodistribution. ≥25% lymphoma marrow involvement and/or impaired bone marrow reserve (eg, prior myeloablative therapies, platelet count <100,000cells/mm3, neutrophil count <1,500cells/mm3), or history of failed stem cell collection: not recommended.

Monitor for cytopenias and complications (eg, febrile neutropenia, hemorrhage) for up to 3 months after treatment. Obtain CBCs, platelets weekly until levels recover. Avoid extravasation.

Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended.

Interactions: Caution with anticoagulants, platelet aggregation inhibitors, or live viral vaccines. Separate growth factor treatment by 2 weeks before and after Zevalin therapy.

Adverse reactions: Neutropenia, leukopenia, thrombocytopenia, anemia, infections, asthenia, musculoskeletal symptoms, GI upset, abdominal pain, fatigue, nasopharyngitis, cough, dizziness, hemorrhage, altered biodistribution; infusion reactions, severe cutaneous/mucocutaneous reactions: both may be fatal, discontinue if occurs; leukemia and myelodysplastic syndrome.

Note: Indium-11 chloride sterile solution must be ordered separately at the time the In-11 Zevalin kit is ordered. Yttrium-90 chloride sterile solution will be shipped directly upon placement of order for Y-90 Zevalin kit.

How supplied: In-111 Zevalin kit (ibritumomab tiuxetan 3.2mg/2mL vial + sodium acetate vial + formulation buffer vial + empty reaction vial)—1 Y-90 Zevalin kit (ibritumomab tiuxetan 3.2mg/2mL vial + sodium acetate vial + formulation buffer vial + empty reaction vial)—1

ZOLINZA Merck

℞

Histone deacetylase inhibitor. Vorinostat 100mg; caps.

Indications: Refractory cutaneous T-cell lymphoma.

Adults: Take with food. Swallow whole. 400mg once daily. If not tolerated, may reduce to 300mg once daily, then to 300mg once daily 5 days/week if needed. Continue until disease progression or not tolerated.

Children: <18yrs: not recommended.

Warnings/Precautions: Renal or hepatic impairment. Monitor for DVT, pulmonary embolism. Correct electrolyte disturbances before starting therapy. Maintain adequate hydration. Diabetes. Monitor CBC, platelets, blood glucose, serum creatinine, electrolytes (esp. potassium, calcium, magnesium) every 2 weeks for 1st 2 months, then monthly.

Pregnancy (Cat.D). Nursing mothers: not recommended.

Interactions: Increased risk of thrombocytopenia and GI bleed with other HDAC inhibitors (eg, valproic acid). Concomitant warfarin: monitor PT, INR. Adverse reactions: GI upset, fatigue, chills; thrombocytopenia, anemia (may need to modify dose or discontinue); anorexia, dysgeusia, pulmonary embolism, DVT, hyperglycemia.

How supplied: Caps—120

ZOMETA Novartis

℞

Bisphosphonate. Zoledronic acid 4mg/5mL concentrated soln for IV infusion after dilution; 4mg/100mL ready-to-use soln for IV infusion.

Indications: Hypercalcemia of malignancy.

Limitations of use: not established for use in hyperparathyroidism or nontumor-related hypercalcemia.

Adults: Give by IV infusion over at least 15 minutes. CrCl >60mL/min: 4mg; CrCl 50–60mL/min: 3.5mg; CrCl 40–49mL/min: 3.3mg; CrCl 30–39mL/min: 3mg; CrCl <30mL/min: see full labeling; all: every 3–4 weeks (give oral multivitamin supplement with calcium 500mg + Vit. D 400 IU daily).

Children: Not 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

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER 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, calcitonin.

Adverse reactions: Nausea, fatigue, anemia, musculoskeletal pain (discontinue if severe), constipation, fever, vomiting, dyspnea, flu-like syndrome, electrolyte disturbances, hypotension, CNS effects, rigors, headache, paresthesia, renal toxicity; osteonecrosis of the jaw, atypical subtrochanteric, diaphyseal femoral fractures, severe hypocalcemia.

How supplied: Single-use vial, ready-to-use bottle—1

ZYDELIG Gilead

℞

Phosphatidylinositol 3-kinase inhibitor. Idelalisib 100mg, 150mg; tabs.

Indications: Relapsed chronic lymphocytic leukemia (CLL), in combination with rituximab,

in patients for whom rituximab alone would be considered appropriate due to other co-morbidities. Relapsed follicular B-cell 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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Publishers Alliance CancerTherapyAdvisor.com | NOVEMBER/DECEMBER 2015 | CANCER THERAPY ADVISOR 77

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DRUG MONOGRAPHS

LUNG CANCER ABRAXANE Celgene

℞

Taxane antimicrotubule. Paclitaxel [bound to albumin (human)] 100mg/vial; pwd for IV infusion after reconstitution; solvent-free.

Indications: First-line treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC), in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy.

Adults: Do not treat if neutrophil count <1,500 cells/mm3 or platelets <100,000 cells/mm3. In combination with carboplatin: 100mg/m2 IV over 30 mins on Days 1, 8, and 15 of each 21-day cycle.

Dose reductions for hematologic and neurologic adverse reactions, hepatic impairment: see full labeling. Avoid extravasation.

Children: Not evaluated.

Contraindications: Baseline neutrophil count <1,500 cells/mm3. Prior severe hypersensitivity reaction (do not rechallenge).

Warnings/Precautions: Do not substitute for, or with, other paclitaxel products (due to formulation differences). Do frequent complete blood cell counts. Hepatic impairment (total bilirubin >5×ULN or AST >10×ULN): not recommended. Monitor for sensory neuropathy, sepsis, or pneumonitis.

Renal dysfunction. Contains human albumin; remote risk of viral transmission. Use appropriate contraception (men and women). Pregnancy (Cat.D), nursing mothers: not recommended.

Interactions: May potentiate or be potentiated

by CYP2C8 and/or CYP3A4 inducers (eg, rifampin, carbamazepine, phenytoin, efavirenz, nevirapine) and/or inhibitors (eg, ketoconazole, other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir, nelfinavir).

Adverse reactions: Bone marrow suppression (eg, neutropenia, anemia), infections, alopecia, sensory neuropathy (may require dose reduction or interruption), peripheral neuropathy, GI upset, mucositis, fatigue/asthenia, myalgia/arthralgia, abnormal ECG; alkaline phosphatase or AST elevation; dyspnea, edema, hypotension, rash (may be serious); rare: thrombotic events.

How supplied: Single-use vial—1

ALIMTA Lilly

℞

Antifolate. Pemetrexed 100mg/vial, 500mg/vial; pwd for IV inj after reconstitution and dilution; preservative-free.

Indications: Locally advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC): in combination with cisplatin as initial treatment, or as maintenance in patients whose disease has not progressed after 4 cycles of platinum-based 1st-line chemotherapy; or as a single agent after prior chemotherapy. Malignant pleural mesothelioma (MPM): in combination with cisplatin in patients whose disease is either unresectable or who are otherwise not candidates for curative surgery. Limitations of use: not for the treatment of squamous cell NSCLC.

Adults: See full labeling. 500mg/m2 by IV infusion over 10 mins on Day 1 of each 21-day cycle. Adjust dose if toxicity (esp. myelosuppression) develops.

Combination therapy: Give cisplatin beginning 30 mins after pemetrexed infusion. Supplement with oral folic acid and intramuscular vitamin B12 prior to initiating pemetrexed and continue during treatment. Pretreat with corticosteroid the day before, the day of, and day after pemetrexed.

Children: Not recommended.

Warnings/Precautions: See full labeling. Renal impairment (CrCl <45mL/min): not recommended.

Discontinue if Grade 3 or 4 neurotoxicity occurs, or if any Grade 3 or 4 toxicity occurs after two dose reductions. Do not start a treatment cycle unless ANC is ≥1500cells/mm3, platelets ≥100,000cells/mm3 and CrCl ≥45mL/min. Hepatic impairment. Monitor CBCs, platelets, renal and hepatic function. Clinically significant third space fluid: consider draining effusion first. Pregnancy (Cat.D); avoid, use effective contraception.

Nursing mothers: not recommended.

Interactions: May be potentiated by nephrotoxic agents, drugs eliminated by renal tubular secretion (eg, probenecid). Concomitant NSAIDs: use caution in patients with mild to moderate renal insufficiency (esp. ibuprofen).

Adverse reactions: Fatigue, nausea, anorexia, vomiting, stomatitis, pharyngitis, constipation, fever, infection with neutropenia, rash, desquamation, neutropenia, leukopenia, anemia, thrombocytopenia, elevated creatinine, chest pain, neuropathy; rare: renal failure.

Testing considerations: TS (thymidylate synthase) expression for response and toxicity How supplied: Single-use vial—1

AVASTIN Genentech

℞

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: may cause fetal harm; use effective contraception during and for 6 months after last dose. Nursing mothers: not recommended.

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

How supplied: Single-use vial—1

CYRAMZA Lilly

℞

Human IgG1 monoclonal antibody. Ramucirumab 10mg/mL; per vial; soln for IV infusion after dilution; preservative-free.

Indications: In combination with docetaxel, for treatment of metastatic non-small cell lung cancer (NSCLC) with disease progression on or after platinum-based chemotherapy; patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to initiation.

Adults: Give by IV infusion over 60 mins.

Premedicate with IV histamine H1-antagonist (eg, diphenhydramine) prior to each infusion; 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

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DRUG MONOGRAPHS

LUNG CANCER healing: withhold Cyramza prior to surgery. Clinical deterioration in patients with Child-Pugh B or C cirrhosis (eg, new or worsening encephalopathy, ascites, hepatorenal syndrome). Discontinue if reversible posterior leukoencephalopathy syndrome develops. Monitor proteinuria by urine dipstick and/or urinary protein creatinine ratio.

Monitor thyroid function. Pregnancy: avoid. Use effective contraception during therapy and for ≥3 months after last ramucirumab dose. Nursing mothers: not recommended.

Adverse reactions: Hypertension, diarrhea, headache, fatigue, asthenia, hyponatremia, anemia, intestinal obstruction, neutropenia, epistaxis, stomatitis/mucosal inflammation, rash, decreased appetite; arterial thromboembolic events, proteinuria, GI perforation, infusionrelated reactions.

How supplied: Single-dose vial (10mL, 50mL)—1

GILOTRIF Boehringer Ingelheim

℞

Tyrosine kinase inhibitor. Afatinib 20mg, 30mg, 40mg; tabs.

Indications: First-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitutions as detected by an FDAapproved test. Limitations of use: safety and efficacy of Gilotrif have not been established in patients whose tumors have other EGFR mutations.

Adults: Take on an empty stomach at least 1 hour before or 2 hours after a meal. 40mg once daily until disease progression or not tolerated.

Concomitant P-gp inhibitors: reduce afatinib daily dose by 10mg if not tolerated; resume previous dose after discontinuing the P-gp inhibitor.

Concomitant P-gp inducers: increase afatinib by 10mg as tolerated; resume previous dose 2–3 days after discontinuing the P-gp inducer.

Dose modification: see full labeling.

Children: Not established.

Warnings/Precautions: Permanently discontinue for life-threatening bullous, blistering, or exfoliative skin lesions, confirmed interstitial lung disease, severe drug-induced hepatic impairment, persistent ulcerative keratitis, symptomatic left ventricular dysfunction, or severe/intolerable adverse reactions (at dose 20mg/day). Withhold for severe or prolonged diarrhea Grade ≥2 lasting for ≥2 consecutive days while taking antidiarrheal, prolonged cutaneous reaction Grade ≥2 (lasting >7 days) or intolerable, renal dysfunction Grade ≥2, or worsening liver function. History of keratitis, ulcerative keratitis, or severe dry eye. Monitor closely in moderate-to-severe renal impairment

or severe hepatic impairment; adjust dose if not tolerated. Embryofetal toxicity: females of reproductive potential should use highly effective contraception during treatment and for at least 2 weeks after last afatinib dose. Pregnancy (Cat.D). Nursing mothers: not recommended.

Interactions: Potentiated by P-gp inhibitors (eg, ritonavir, cyclosporine A, ketoconazole, itraconazole, erythromycin, verapamil, quinidine, tacrolimus, nelfinavir, saquinavir, amiodarone). Antagonized

by P-gp inducer (eg, rifampicin, carbamazepine, phenytoin, phenobarbital, St. John’s wort).

Adverse reactions: Diarrhea, rash/dermatitis acneiform, stomatitis, paronychia, dry skin, decreased appetite, pruritus.

How supplied: Tabs—30

HYCAMTIN GlaxoSmithKline

℞

Topoisomerase inhibitor. Topotecan (as HCl) 4mg/vial; pwd for IV infusion after reconstitution and dilution; contains mannitol; preservative-free.

Indications: Small cell lung cancer sensitive disease after failure of 1st line chemotherapy.

Adults: Verify dose using BSA. Usual max dose 4mg IV. Confirm baseline neutrophils >1,500cells/mm3 and platelets >100,000cells/mm3 prior to 1st course of therapy. Give by IV infusion over 30 mins. 1.5mg/m2 daily for 5 consecutive days starting on Day 1 of a 21-day cycle. Dose adjustments, renal impairment: see full labeling.

Children: Not established.

Also: HYCAMTIN CAPSULES ℞ Topotecan (as HCl) 0.25mg, 1mg; caps.

Indications: Relapsed small cell lung cancer with prior complete or partial response and at least 45 days from the end of 1st line chemotherapy.

Adults: Confirm baseline neutrophils ≥1,500cells/mm3 and platelets ≥100,000cells/mm3 prior to 1st course of therapy.

Swallow whole. 2.3mg/m2/day once daily for 5 consecutive days; repeat every 21 days. Dose adjustments, renal impairment: see full labeling.

Children: Not established.

Warnings/Precautions: Monitor peripheral blood cell counts during therapy; hold subsequent doses until neutrophils >1,000cells/mm3, platelets >100,000cells/mm3, and hemoglobin ≥9g/dL. History of interstitial lung disease, pulmonary fibrosis, lung cancer, thoracic exposure to radiation, use of pneumotoxic drugs and/or colony stimulating factors: increased risk of interstitial lung disease; monitor, discontinue if occurs. Moderate to severe renal impairment.

Caps: severe diarrhea; may need to reduce dose.

IV: avoid extravasation. Elderly. Use effective contraception during and for ≥1 month after last dose (in females), or during and for ≥3 months (in

males with female partners). Pregnancy (Cat.D).

Nursing mothers: not recommended.

Interactions: IV: Myelosuppression potentiated with platinum agents. Neutropenia potentiated

by G-CSF; administer ≥24hrs after last topotecan dose. Caps: Avoid concomitant P-glycoprotein inhibitors (eg, amiodarone, azithromycin, captopril, carvedilol, clarithromycin, conivaptan, cyclosporine, diltiazem, dronedarone, erythromycin, felodipine, itraconazole, ketoconazole, lopinavir, ritonavir, quercetin, quinidine, ranolazine, ticagrelor, verapamil) and BCRP inhibitors (eg, cyclosporine, eltrombopag).

Adverse reactions: See full labeling.

Neutropenia, leukopenia, thrombocytopenia, anemia, nausea, vomiting, diarrhea, anorexia, abdominal pain, stomatitis, headache, dyspnea, cough, pyrexia, alopecia, fatigue; infection, sepsis, interstitial lung disease, neutropenic colitis (may be fatal).

How supplied: Single-use vials—1; Caps—10

IRESSA AstraZeneca

℞

Tyrosine kinase inhibitor. Gefitinib 250mg; tabs.

Indications: First-line treatment of metastatic non-small cell lung cancer (NSCLC) with EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test.

Limitations of use: not established in metastatic NSCLC with EGFR mutations other than exon 19 deletions or exon 21 substitution mutations.

Adults: May disperse tabs in water; drink immediately or give via NG tube. Give 250mg once daily until disease progression or unacceptable toxicity occurs. Dose modifications for adverse reactions: see full labeling.

Concomitant strong CYP3A4 inducers: increase to 500mg daily; resume at 250mg seven days after discontinuation of the CYP3A4 inducer.

Children: Not established.

Warnings/Precautions: Permanently discontinue if confirmed interstitial lung disease (ILD), severe hepatic impairment, GI perforation, or persistent ulcerative keratitis occurs. Withhold for up to 14 days if acute onset or worsening pulmonary symptoms, NCI CTCAE Grade ≥2 ALT and/or AST elevations, Grade ≥3 diarrhea or skin reactions, or severe or worsening ocular disorders (including keratitis) occurs. Interrupt or discontinue therapy if severe bullous and exfoliative skin disorders develop. Obtain periodic LFTs. Moderate and severe hepatic impairment; monitor. Use effective contraception during treatment and for at least 2 weeks after completion. Pregnancy, nursing mothers: not recommended.

Interactions: Potentiated by strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole); monitor.

Visit the CTA Resource Centers at CancerTherapyAdvisor.com/Topics to view news, treatment regimens,patient fact sheets, and slideshows about a variety of cancer types.

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DRUG MONOGRAPHS

LUNG CANCER Antagonized by strong CYP3A4 inducers (eg, rifampicin, phenytoin, tricyclics); see Adults. May be antagonized by drugs that increase gastric pH (eg, H2-blockers, antacids); take gefitinib 6 hours after or 6 hours before an H2-blocker or antacid.

Avoid concomitant PPIs; if necessary, take gefitinib 12 hours after last dose or 12 hours before next PPI dose. May potentiate warfarin; monitor INR. Adverse reactions: Skin reactions, diarrhea, vomiting, decreased appetite, stomatitis; ILD, hepatotoxicity, GI perforation, ocular disorders.

Testing considerations: EGFR mutation analysis.

How supplied: Tabs—30

MUSTARGEN Recordati

℞

Nitrogen mustard. Mechlorethamine HCl 10mg/vial; pwd for IV or intracavitary inj after reconstitution.

Indications: Palliative treatment of bronchogenic carcinoma.

Adults: By IV infusion, per therapeutic course: 0.4mg/kg (lean body weight) as single dose or in divided doses of 0.1–0.2mg/kg per day. See literature for intracavitary (eg, intrapleural) administration. Do not exceed recommended dose. Repeat course only after hematological recovery (eg, every 3 weeks).

Children: See literature.

Contraindications: Infectious diseases.

Warnings/Precautions: Drug is highly toxic; verify potential benefits outweigh risks; avoid inadvertent contact with powder or vapor. Do not use if foci of acute and chronic suppurative inflammation are present. Ensure adequate hydration. Avoid extravasation. Chronic lymphatic leukemia. Bone marrow suppression. Previous X-ray, cytotoxic chemotherapy. Infection.

Hemorrhagic tendency. Monitor renal, hepatic and bone marrow function. Elderly. Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended.

Adverse reactions: Bone marrow suppression, hyperheparinemia, GI upset (may be severe), anorexia, weakness, thrombosis, thrombophlebitis, hypersensitivity, jaundice, alopecia, vertigo, auditory disturbances, hemolytic anemia, skin reactions, infection, amyloidosis, hyperuricemia, gonad damage.

How supplied: Vials—4

NAVELBINE Pierre Fabre

℞

Antimicrotubule agent. Vinorelbine (as tartrate) 10mg/mL; soln for IV inj after dilution; preservative-free.

Indications: First-line treatment of ambulatory patients with unresectable, advanced non-small cell lung cancer (NSCLC), as a single agent or in combination with cisplatin. In Stage III NSCLC, use in combination with cisplatin.

Adults: See literature. Give by IV inj over 6–10 minutes. Monotherapy: 30mg/m2 once weekly.

Combination therapy: 25mg/m2 once weekly with cisplatin given every 4 weeks; or 30mg/m2 once weekly with cisplatin given on Days 1 and 29, then every 6 weeks. Dose adjustment for toxicities, hepatic impairment: see literature.

Children: Not recommended.

Contraindications: Pretreatment granulocyte counts <1000 cells/mm3.

Warnings/Precautions: IV use only; fatal if given intrathecally. Discontinue if neurotoxicity ≥grade 2. Pre-existing pulmonary dysfunction or neuropathy. Prior irradiation or chemotherapy. Cardiovascular disease. Monitor for myelosuppression, infection, and/or fever; obtain CBCs with differentials prior to each dose.

Avoid contamination of the eyes or injecting into an extremity with poor circulation (thrombosis possible). Hepatic injury or impairment. Avoid extravasation. Pregnancy (Cat.D), nursing mothers: not recommended.

Interactions: May be potentiated by CYP3A inhibitors. Acute pulmonary reactions possible with mitomycin. Increased risk of granulocytopenia with cisplatin. May increase risk of neurotoxicity with paclitaxel. Prior or concomitant radiation therapy; may result in radiosensitizing effects.

Adverse reactions: Myelosuppression (esp. granulocytopenia), inj site reactions, elevated liver enzymes, chest pain, fatigue, GI upset, alopecia, jaw pain, myalgia, arthralgia, rash, severe constipation, paralytic ileus, intestinal obstruction, necrosis, and/or perforation; dyspnea, severe bronchospasm.

How supplied: Single-use vial (1mL, 5mL)—1

OPDIVO Bristol-Myers Squibb

℞

Human programmed death receptor-1 (PD-1)blocking antibody. Nivolumab 10mg/mL; per vial; soln for IV infusion after dilution; preservativefree; contains mannitol.

Indications: Metastatic squamous non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy.

Adults: Give as IV infusion over 60 minutes.

3mg/kg every 2 weeks until disease progression or unacceptable toxicity. Dose modifications: see full labeling.

Children: Not established.

Warnings/Precautions: See full labeling.

Monitor for any immune-mediated adverse reactions; withhold dose and give corticosteroids (at 1–2mg/kg/day prednisone equivalents) based on severity of event. Permanently discontinue for any life-threatening or Grade 4 adverse reaction, Grade 3 or 4 pneumonitis, Grade 4 colitis, AST/ALT >5×ULN or total bilirubin >3×ULN, SCr >6×ULN, recurring severe or Grade 3 adverse reaction, inability to reduce prednisone dose to ≤10mg/day (or equivalent) within 12 weeks, or failure to recover to Grade 0–1 within 12 weeks after last dose. Grade 2 pneumonitis, Grade 2 or 3 colitis, AST/ALT >3–5×ULN or total bilirubin >1.5–3×ULN, SCr >1.5–6×ULN or >1.5X baseline, other severe or Grade 3 adverse reactions; withhold dose, give corticosteroids, and when recovered to Grade 0–1 or resolved, consider re-initiation.

Monitor for abnormal liver tests, elevated serum creatinine, and thyroid function prior to and during treatment; give replacement therapy for

hypothyroidism. Pregnancy: avoid. Use effective contraception during and for ≥5 months after last dose. Nursing mothers: not recommended.

Adverse reactions: Fatigue, dyspnea, musculoskeletal pain, decreased appetite, cough, nausea, constipation; any immune-mediated reactions.

How supplied: Single-use vial (4mL, 10mL)—1

TARCEVA Astellas and Genentech

℞

Kinase inhibitor. Erlotinib (as HCl) 25mg, 100mg, 150mg; tabs.

Indications: First-line treatment in patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test. Maintenance treatment of patients with locally advanced or metastatic NSCLC whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. Treatment of locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen. Limitations of use: Do not use in combination with platinumbased chemotherapy. Not evaluated as first-line treatment in patients with metastatic NSCLC whose tumors have EGFR mutations other than exon 19 deletions or exon 21 (L858R) substitution.

Adults: Take on empty stomach. 150mg once daily. Use until disease progression or unacceptable toxicity occurs. Diarrhea unresponsive to loperamide, severe skin reactions, strong CYP3A4 inhibitors (see Interactions), hepatic impairment: reduce in 50mg decrements.

Concomitant CYP3A4 inducers (see Interactions): increase in 50mg increments at 2-week intervals; max 450mg (see full labeling). Concurrent cigarette smoking: increase in 50mg increments at 2-week intervals; max 300mg (see full labeling); upon cessation, reduce to 150mg or 100mg daily.

Children: Not established.

Warnings/Precautions: Discontinue if interstitial lung disease, severe hepatic toxicity, GI perforation, severe bullous, blistering or exfoliating skin conditions, or corneal perforation or severe ulceration occurs. Withhold or consider discontinuing therapy if severe renal failure due to dehydration, or acute/worsening ocular disorders occur. Monitor LFTs periodically; withhold in patients without history of hepatic impairment for total bilirubin >3×ULN or transaminases >5×ULN, or in patients with history of hepatic impairment or biliary obstruction for doubling of bilirubin or tripling of transaminases over baseline.

Discontinue if abnormal LFTs do not improve or resolve within 3 weeks. Withhold for persistent severe diarrhea unresponsive to loperamide, severe rash, or grade 3–4 keratitis. Monitor renal function, serum electrolytes, pulmonary function, INR, prothrombin time. History of peptic ulcers or diverticular disease. Pregnancy (Cat.D); use effective contraception during therapy and at least 2 weeks after the last dose. Nursing mothers: not recommended.

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DRUG MONOGRAPHS

LUNG CANCER Interactions: Potentiated by CYP3A4 inhibitors (eg, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, voriconazole, grapefruit) and CYP1A2 inhibitors (eg, ciprofloxacin); avoid if possible. Plasma levels decreased by CYP3A4 inducers (eg, rifampin, rifabutin, rifapentine, phenytoin, carbamazepine, phenobarbital, St. John’s wort), proton pump inhibitors or H2 blockers (take erlotinib 10hrs after and at least 2hrs before next dose), and smoking; avoid if possible. Increased risk of GI perforation with concomitant anti-angiogenic agents, steroids, NSAIDs, taxane-based chemotherapy. Monitor for bleeding with oral anticoagulants, NSAIDs. Adverse reactions: Rash, diarrhea, nausea, vomiting, anorexia, fatigue, elevated LFTs, unexplained pulmonary symptoms (eg, dyspnea, cough, fever; discontinue and follow-up if occurs), stomatitis, infection; rare: GI perforation (may be fatal), ocular disorders (eg, conjunctivitis, keratitis, corneal ulceration/perforation), MI/ ischemia, hemolytic anemia, cerebrovascular accidents, interstitial lung disease; hepatic or renal failure and hepatorenal syndrome (may be fatal); bullous, blistering and exfoliative skin conditions (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis).

Testing considerations: K-RAS mutation analysis, EGFR amplification analysis How supplied: Tabs—30

TREXALL Teva

℞

Folic acid antagonist. Methotrexate sodium 5mg, 7.5mg, 10mg, 15mg; scored tabs. ℞ Also: Methotrexate injection Bedford Methotrexate 25mg/mL; soln for IV, IM, intraarterial, or intrathecal administration after dilution; preservative-free. ℞ Also: Methotrexate for injection Bedford Methotrexate 1g/vial; pwd for IV, IM, intra-arterial, or intrathecal administration after dilution; preservative-free.

Indications: Lung cancer (squamous cell and small cell types).

Adults: See literature.

Children: Not established.

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

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

Discontinue immediately if blood counts drop significantly. Rule out pregnancy in women of childbearing potential; use effective contraception during therapy and for at least 1 ovulatory cycle afterwards for women and for

at least 3 months afterwards for men. Interrupt therapy if vomiting, diarrhea, stomatitis, or pulmonary symptoms occur. Hepatic or renal impairment. Obesity. Diabetes. Peptic ulcer.

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

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

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

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

How supplied: Tabs—30; soln (2mL, 4mL, 8mL, 10mL)—10 (single-use vials); pwd (1 gram)—1 (single-use vial)

XALKORI Pfizer

℞

Tyrosine kinase inhibitor. Crizotinib 200mg, 250mg; hard gel caps.

Indications: Treatment of metastatic non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test.

Adults: Swallow whole. 250mg twice daily until disease progression or intolerance. Dose modification and/or dose reduction to 200mg twice daily may be required based on Grade 3 or 4 severity, then to 250mg once daily, or permanently discontinue if intolerable. Severe renal impairment (CrCl <30mL/min) not requiring dialysis: 250mg once daily. Dose reduction for hematologic and non-hematologic toxicities: see full labeling.

Children: Not established.

Warnings/Precautions: Confirm ALK-positive NSCLC with an FDA-approved test before treating. Monitor ALT and total bilirubin every 2 weeks during first 2 months, then monthly, and more frequently for elevated transaminases; temporarily suspend, reduce dose, or permanently discontinue as clinically indicated.

Monitor CBCs with differential monthly and more frequently if Grade 3 or 4 abnormalities, fever or infection occurs. Risk of severe pneumonitis: monitor for pulmonary symptoms; permanently discontinue if occurs. Congenital long QT

syndrome; avoid. History of or predisposition for QTc prolongation (eg, CHF, bradyarrhythmias, electrolyte abnormalities, concomitant drugs that prolong QT interval): consider monitoring ECG, electrolytes periodically. Torsade de pointes, ventricular tachycardia, serious arrhythmia: permanently discontinue if QTc >500ms or ≥60ms change from baseline. Monitor HR and BP regularly; discontinue if life-threatening bradycardia occurs. Hepatic impairment. Severe renal impairment. Pregnancy (Cat.D); avoid. Use adequate contraception during therapy and at least 90 days after completion. Nursing mothers: not recommended.

Interactions: Avoid concomitant strong CYP3A inhibitors (eg, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, voriconazole), grapefruit juice, or strong CYP3A inducers (eg, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, St. John’s Wort). Avoid concomitant CYP3A substrates with narrow therapeutic indices (eg, alfentanil, cyclosporine, ergots, fentanyl, pimozide, quinidine, sirolimus, tacrolimus); if needed, reduce doses. Avoid concomitant agents known to cause bradycardia (eg, beta-blockers, non-dihydropyridine calcium channel blockers, clonidine, digoxin); adjust dose or discontinue.

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

How supplied: Caps—60

ZYKADIA Novartis

℞

Tyrosine kinase inhibitor. Ceritinib 150mg; hard gel caps.

Indications: Treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib. Not established for improvement in survival or disease-related symptoms.

Adults: Take on an empty stomach (at least 2 hours before or after a meal). 750mg once daily until disease progression or unacceptable toxicity.

Discontinue if 300mg once daily not tolerated.

Moderate-to-severe hepatic impairment: not established. Dose modifications: see full labeling.

If concomitant use of strong CYP3A4 inhibitors unavoidable: reduce ceritinib dose by 1/3.

Children: Not established.

Warnings/Precautions: Monitor for severe or persistent GI toxicity; if occurs, withhold until improved; resume at reduced dose.

Monitor ALT/AST and total bilirubin once monthly, and more frequently if elevated transaminases develop; withhold then reduce

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DRUG MONOGRAPHS

LUNG CANCER treatment-related interstitial lung disease (ILD)/ pneumonitis, uncontrolled hyperglycemia, or life-threatening bradycardia occur. Pregnancy (Cat.D). Females of reproductive potential should use effective contraception during treatment and for at least 2 weeks after completion. Nursing mothers: not recommended.

Interactions: See Adults. Potentiated by strong CYP3A4 inhibitors (eg, ritonavir, macrolides, ketoconazole, nefazodone), grapefruit juice; avoid.

Avoid concomitant strong CYP3A4 inducers (eg, carbamazepine, phenytoin, rifampin, St. John’s Wort). Avoid concomitant CYP3A substrates

dose, or permanently discontinue as clinically indicated. Congenital long QT syndrome; avoid.

Patients with CHF, bradyarrhythmias, electrolyte abnormalities, or those who are taking drugs known to prolong the QTc interval; monitor ECG, electrolytes periodically. Permanently discontinue if QTc prolongation in combination with Torsade de pointes or polymorphic ventricular tachycardia or serious arrhythmia develop. Monitor HR and BP regularly; fasting serum glucose, lipase, amylase prior to initiation and periodically thereafter. Monitor for pulmonary symptoms as clinically indicated. Permanently discontinue if

(eg, alfentanil, cyclosporine, ergots, fentanyl, pimozide, quinidine, sirolimus, tacrolimus) or CYP2C9 substrates (eg, phenytoin, warfarin) with narrow therapeutic indices; if unavoidable, reduce doses of these drugs. Avoid concomitant agents known to cause bradycardia (eg, beta-blockers, non-dihydropyridine CCBs, clonidine, digoxin).

Adverse reactions: Diarrhea, nausea, vomiting, abdominal pain, constipation, elevated transaminases, fatigue, decreased appetite; bradycardia, hepatotoxicity, ILD/pneumonitis, QTc prolongation, hyperglycemia, pancreatitis.

How supplied: Caps—70

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

Strength

Form

Usual Dose

100mg, 400mg

soln for IV infusion after dilution

15mg/kg once every 3wks with carboplatin/paclitaxel

ramucirumab

10mg/mL

soln for IV infusion after dilution

10mg/kg on Day 1 of a 21-day cycle prior to docetaxel; continue until disease progression or unacceptable toxicity

ANTIMETABOLITES gemcitabine Gemzar

200mg, 1g

pwd for IV infusion after reconstitution

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

methotrexate

25mg/mL

soln for IV, IM, intra-arterial, or intrathecal administration after dilution

See drug entry and manufacturer’s literature

1g

pwd for IV, IM, intra-arterial, or intrathecal administration after dilution

pemetrexed

Cyramza

—

Trexall

5mg, 7.5mg, 10mg, 15mg scored tabs

Alimta

100mg, 500mg

pwd for IV inj after reconstitution 500mg/m2 on Day 1 of each 21-day cycle and dilution

ANTIMICROTUBULE AGENTS docetaxel Taxotere 40mg/mL

soln for IV infusion after dilution

75mg/m2 once every 3wks

paclitaxel

soln for IV infusion after dilution

135mg/m2 IV plus cisplatin every 3wks

paclitaxel [bound to Abraxane 100mg/vial albumin (human)]

pwd for IV infusion after reconstitution

100mg/m2 on Days 1, 8, and 15 of each 21-day cycle

vinorelbine

soln for IV inj after dilution

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

soln for IV infusion after dilution

3mg/kg every 2wks until disease progression or unacceptable toxicity

Taxol

6mg/mL

Navelbine 10mg/mL

PD-1 BLOCKING ANTIBODY nivolumab Opdivo

10mg/mL

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 20mg, 30mg, 40mg Gilotrif

tabs

40mg once daily on empty stomach

ceritinib

Zykadia

150mg

hard gel caps

750mg once daily until disease progression or unacceptable toxicity

crizotinib

Xalkori

200mg, 250mg

caps

250mg twice daily

erlotinib

Tarceva

25mg, 100mg, 150mg

tabs

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 drug labeling.

(Rev. 5/2015)

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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

℞

Alpha interferon. Interferon alfa-2b, recombinant; 10 million, 18 million, or 50 million IU per vial; pwd; for inj after reconstitution/dilution; preservativefree; contains albumin. ℞ Also: INTRON A SOLN Interferon alfa-2b, recombinant; 10 million IU, 18 million IU, 25 million IU; per vial; for inj; contains m-cresol.

Indications: AIDS-related Kaposi’s sarcoma.

Adults: Use appropriate preparation and route: see full labeling. Use SC route if platelets <50,000/mm3.

30 million IU/m2 IM or SC three times weekly; continue until rapid disease progression or maximal response achieved after 16 weeks; reduce dose by ½ or suspend therapy if severe adverse reactions occur; discontinue if persists.

Children: Not recommended.

Contraindications: Decompensated liver disease. Autoimmune hepatitis.

Warnings/Precautions: May cause or exacerbate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, or infectious disorders: monitor closely, discontinue if they worsen.

Severe psychiatric disorders (esp. depression).

Cardiovascular or pulmonary disease. Severe myelosuppression; discontinue if neutrophil count <0.5 X109/L or platelets 25×109/L. Permanently discontinue if severe (Grade 3) hepatic injury or decompensation (Child-Pugh score >6 [Class B and C]) develop. Thyroid abnormalities; discontinue if uncontrolled by medication. Diabetes. Coagulation

disorders. Maintain adequate hydration. Monitor blood, thyroid, visual and liver function before and during therapy; EKG in cardiovascular disease and cancer patients. Psoriasis. Renal dysfunction.

Transplant recipients. Elderly. Debilitated. Pregnancy (Cat.C). Nursing mothers: not recommended.

Interactions: Caution with myelosuppressives, and drugs that can exacerbate depression. May potentiate theophylline (may double its levels).

Adverse reactions: Flu-like symptoms (fever, headache, myalgia, fatigue); hepatic, hematologic, respiratory, skin, genitourinary system, CNS, cardiovascular, endocrine (esp. thyroid), GI, or visual disorders; colitis, hypertriglyceridemia, pancreatitis, infections, injection site reactions, dental and periodontal disorders; others (see full labeling).

How supplied: Pwd (w. diluent): 10million, 18million, 50million IU/vial—1; Soln (multidose vials): 18million, 25million IU/vial—1

PANRETIN Eisai

℞

Retinoid. Alitretinoin 0.1%; gel.

Indications: Cutaneous lesions of AIDS-related Kaposi’s sarcoma (KS).

Adults: Apply twice daily to lesions (avoid mucous membranes and normal skin); do not occlude; may increase to 3–4 times daily as tolerated. Reduce frequency or suspend treatment if local toxicity occurs.

Children: Not recommended.

Warnings/Precautions: Not for use when systemic KS therapy required. Avoid sun, UV light.

Flammable. Pregnancy (Cat.D), nursing mothers: not recommended.

Interactions: Increases DEET toxicity (avoid).

Adverse reactions: Photosensitivity, rash, pruritus, pain, exfoliative dermatitis, paresthesia, edema.

How supplied: Gel—60g

FDA PREGNANCY CATEGORIES When pregnancy appears as a contraindication or precaution to the use of a drug, it is usually qualified by a category as assigned by the FDA.

A: Adequate and well-controlled studies in pregnant women have failed to show a risk to the fetus in the first trimester of pregnancy and there is no evidence of risk in later trimesters.

B: Animal studies have failed to show a risk to the fetus and there are no adequate and well-controlled studies in pregnant women; or animal studies have shown an adverse effect but adequate and wellcontrolled studies in pregnant women have failed to demonstrate a risk to the fetus during the first trimester of pregnancy and there is no evidence of a risk in later trimesters.

C: Animal studies have shown an adverse effect on the fetus, there are no adequate and well-controlled studies in humans, and the potential benefits may outweigh the risks; or there are no animal studies and no adequate and well-controlled studies in humans.

D: Positive evidence of human fetal risk but the benefits may outweigh the risks.

X: Animal or human studies have shown fetal abnormalities or toxicity, or both, and the risks clearly outweigh any possible benefits.

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DRUG MONOGRAPHS

SKIN CANCER EFUDEX Valeant

℞

Antimetabolite. Fluorouracil 2%, 5%; soln.

Also: EFUDEX CREAM ℞ Fluorouracil 5%.

Indications: Multiple actinic or solar keratoses.

Superficial basal cell carcinoma when conventional therapy is impractical (5% only); see literature.

Adults: Keratoses: Apply twice daily until erosion occurs (usually 2–4 wks). Basal cell carcinoma (5% only): Apply twice daily, usually for 3–6 weeks (obliteration may take 10–12 weeks).

Children: Not recommended.

Contraindications: Dihydropyrimidine dehydrogenase (DPD) deficiency. Pregnancy (Cat.X).

Warnings/Precautions: Apply cautiously near eyes, nose, mouth. Avoid mucous membranes, occlusion, ulcerated/inflamed skin, exposure to UV light. Wash hands after application if fingers were used. Notify patients of expected skin reaction. Biopsy unresponsive lesions. Nursing mothers: not recommended.

Adverse reactions: Pain or burning at application site, pruritus, irritation, hyperpigmentation.

How supplied: Soln—10mL (w. drop dispenser); Crm—25g

ERIVEDGE Genentech

℞

Hedgehog pathway inhibitor. Vismodegib 150mg; caps.

Indications: Treatment of adults with metastatic basal cell carcinoma, or locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation.

Adults: Swallow whole. 150mg once daily, until disease progression or unacceptable toxicity.

Children: Not established.

Warnings/Precautions: Risk of embryo-fetal death and severe birth defects in pregnant women.

Verify pregnancy status within 7 days prior to initiation of therapy. Counsel patients (males and females) on the need for contraception during and after treatment. Advise patients not to donate blood or blood products while on therapy and for 7 months after last dose. Advise male patients not to donate semen during and for 3 months after final dose. Nursing mothers: not recommended during and for 7 months after final dose.

Interactions: May be potentiated by P-gp inhibitors (eg, clarithromycin, erythromycin, azithromycin). May be antagonized by drugs that affect gastric pH (eg, proton pump inhibitors, H2-receptor antagonists, antacids).

Adverse reactions: Muscle spasms, alopecia, dysgeusia, weight loss, fatigue, GI upset,

decreased appetite, constipation, arthralgias, ageusia; amenorrhea.

Note: Report immediately exposure to Erivedge during pregnancy by contacting the Genentech Adverse Event Line at (888) 835-2555.

How supplied: Caps—28

GLEEVEC Novartis

℞

Kinase inhibitor. Imatinib (as mesylate) 100mg, 400mg; scored tabs.

Indications: Adults with aggressive systemic mastocytosis (ASM) without the D816V c-Kit mutation or with c-Kit mutational status unknown. Adults with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans (DFSP).

Adults: Take with food and water. May disperse tab in water or apple juice and take promptly. ≥18yrs: ASM without D816V c-Kit mutation or status unknown: 400mg once daily. ASM associated with eosinophilia: initially 100mg once daily; may increase to 400mg once daily if insufficient response. If severe non-hematologic reactions develop: interrupt dose; resume at a lower dose in hepatic dysfunction. Severe hepatic impairment: reduce dose by 25%. Renal or hematologic reactions: see full labeling. Avoid concomitant strong CYP3A4 inducers (eg, rifampin): if needed, increase imatinib dose by at least 50%.

Children: Not recommended.

Warnings/Precautions: Hepatic or renal impairment. Monitor weight and for fluid retention regularly; CBCs weekly for 1st month, bi-weekly for 2nd month, then periodically (eg, every 2–3 months); liver function at baseline then monthly or as needed; GI symptoms at baseline.

Cardiovascular disease or risk factors; monitor.

Immunosuppression and potential toxicities (liver, kidney, cardiac) from long-term use. Monitor for tumor lysis syndrome; correct clinically significant dehydration and treat high uric acid levels before initiating therapy. Monitor growth in children.

Possible cardiogenic shock/LV dysfunction in conditions with high eosinophil levels (eg, HES/ CEL, MDS/MPD, ASM); consider concomitant systemic steroid prophylaxis (1–2mg/kg) for 1 or 2 wks if abnormal ECG or serum troponin. Monitor TSH levels in thyroidectomy patients undergoing levothyroxine replacement. Pregnancy (Cat.D); avoid. Use highly effective contraception during treatment. Nursing mothers: not recommended.

Interactions: Avoid grapefruit juice. Potentiated

by CYP3A4 inhibitors (eg, azole antifungals, protease inhibitors, nefazodone, clarithromycin, telithromycin). Antagonized by strong CYP3A4 inducers (eg, dexamethasone, fosphenytoin, phenytoin, phenobarbital, carbamazepine,

oxcarbamazepine, primidone, St. John’s wort, rifampin, rifabutin, rifampicin); consider alternatives. May potentiate drugs metabolized

by CYP3A4 (eg, benzodiazepines, dihydropyridine calcium channel blockers, cyclosporine, ergots, alfentanil, fentanyl, pimozide, quinidine, certain statins, sirolimus, tacrolimus), CYP2D6, or CYP2C9 (use heparin instead of warfarin).

Adverse reactions: Edema (may be severe), nausea, vomiting, musculoskeletal pain, diarrhea, muscle cramps, rash (may be severe; eg, erythema multiforme, Stevens-Johnson syndrome), fatigue, abdominal pain, dizziness, blurred vision, somnolence, fever, headache, cough, arthralgia/myalgia, dyspnea, hypokalemia, night sweats, anorexia, pruritus, hemorrhage, anemia, neutropenia, thrombocytopenia, weight gain, renal or hepatotoxicity, immunosuppression, hypothyroidism; rare: severe CHF, LV dysfunction.

How supplied: 100mg—90; 400mg—30

HYDREA Bristol-Myers Squibb

℞

Substituted urea. Hydroxyurea 500mg; caps.

Indications: Melanoma.

Adults: See literature. Intermittant therapy for solid tumors: 80mg/kg as single dose every 3rd day. Continuous therapy for solid tumors: 20–30mg/kg/day as single dose. Renal impairment: reduce dose.

Children: Not recommended.

Contraindications: Marked bone marrow depression.

Warnings/Precautions: Previous irradiation therapy or chemotherapy. Correct anemia before starting. Monitor hematologic, renal, hepatic function before and during treatment. Marked renal dysfunction. Myeloproliferative disorders; discontinue if cutaneous vasculitic ulcerations develop and use alternative agents. Elderly.

Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended.

Interactions: Avoid concomitant didanosine, with or without stavudine, or other antiretrovirals (may cause pancreatitis [monitor], fatal 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

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DRUG MONOGRAPHS

SKIN CANCER INTRON A Merck

℞

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

Also: INTRON A SOLN ℞ Interferon alfa-2b, recombinant; 10 million IU, 18 million IU, 25 million IU; per vial; for inj; contains m-cresol.

Indications: Malignant melanoma.

Adults: Induction: 20million IU/m2 IV over 20 mins, 5 consecutive days per week, for 4 weeks.

Maintenance: 10 million IU/m2 SC 3 times per week for 48 weeks. See full labeling for appropriate preparation and route and for dose adjustments.

Children: Not recommended.

Contraindications: Decompensated liver disease. Autoimmune hepatitis.

Warnings/Precautions: May cause or exacerbate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, or infectious disorders: monitor closely, discontinue if they worsen. Severe psychiatric disorders (esp. depression). Cardiovascular or pulmonary disease. Severe myelosuppression; discontinue if neutrophil count <0.5 X109/L or platelets 25×109/L. Permanently discontinue if severe (Grade 3) hepatic injury or decompensation (Child-Pugh score >6 [Class B and C]) develop.

Thyroid abnormalities; discontinue if uncontrolled by medication. Diabetes. Coagulation disorders.

Maintain adequate hydration. Monitor blood, thyroid, visual and liver function before and during therapy; EKG in cardiovascular disease and cancer patients. Psoriasis. Renal dysfunction. Transplant recipients. Elderly. Debilitated. Pregnancy (Cat.C).

Nursing mothers: not recommended.

Interactions: Caution with myelosuppressives, and drugs that can exacerbate depression. May potentiate theophylline (may double its levels).

Adverse reactions: Flu-like symptoms (fever, headache, myalgia, fatigue); hepatic, hematologic, respiratory, skin, genitourinary system, CNS, cardiovascular, endocrine (esp. thyroid), GI, or visual disorders; colitis, hypertriglyceridemia, pancreatitis, infections, injection site reactions, dental and periodontal disorders; others (see full labeling).

How supplied: Pwd (w. diluent): 10million, 18million, 50million IU/vial—1; Soln (multidose vials): 18million, 25million IU/vial—1

KEYTRUDA Merck

℞

Human programmed death receptor-1 (PD-1)-blocking antibody. Pembrolizumab 50mg/vial; lyophilized pwd for IV infusion after reconstitution; 25mg/mL; per vial; soln for IV infusion after dilution; both: preservative-free.

Indications: Unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor.

Adults: Give as IV infusion over 30mins.

2mg/kg every 3 weeks until disease progression

or unacceptable toxicity. Dose modifications: see full labeling. Administer corticosteroids for most Grade ≥2 related immune-mediated reactions.

Children: Not established.

Warnings/Precautions: Monitor for pneumonitis; withhold dose if Grade 2 pneumonitis; permanently discontinue if Grade 3 or 4 develops. Monitor for colitis; withhold dose if Grade 2 or 3 colitis; permanently discontinue if Grade 4 develops. Monitor for changes in liver function; withhold dose or discontinue based on severity of elevated liver enzymes.

Monitor for hypophysitis; withhold dose if Grade 2 hypophysitis; withhold or discontinue if Grade 3; permanently discontinue if Grade 4 develops. Monitor for changes in renal function; withhold dose if Grade 2 nephritis; permanently discontinue if Grade 3 or 4 develops. Monitor thyroid function at treatment initiation, during, and as clinically indicated; withhold if Grade 3 hyperthyroidism; permanently discontinue if Grade 4 develops. Monitor for hyperglycemia and other diabetes symptoms; withhold if severe hyperglycemia until controlled. Permanently discontinue if any severe or Grade 3 immunemediated adverse reaction recurs and for any life-threatening immune-mediated adverse reaction. Monitor for infusion-related reactions; permanently discontinue if Grade 3 or 4 develops.

Use highly effective contraception during treatment and for at least 4 months after the last dose. Pregnancy (Cat.D), nursing mothers: not recommended.

Adverse reactions: Fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, arthralgia, diarrhea; renal failure, dyspnea, pneumonia, cellulitis; immune-mediated disorders, infusion-related reactions.

How supplied: Single-use vial 50mg—1; Singleuse vial 25mg/mL—1

MEKINIST GlaxoSmithKline

℞

Kinase inhibitor. Trametinib 0.5mg, 1mg, 2mg; tabs.

Indications: As monotherapy or in combination with dabrafenib for the treatment of unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an 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

ODOMZO Novartis

℞

Hedgehog pathway inhibitor. Sonidegib 200mg; caps.

Indications: Treatment of adults with locally advanced basal cell carcinoma (BCC) that has recurred following surgery or radiation, or those who are not candidates for surgery or radiation therapy.

Adults: Take on empty stomach. 200mg once daily until disease progression or unacceptable toxicity. Dose modifications: see full labeling.

Children: Not established.

Warnings/Precautions: Risk of embryofetal death or severe birth defects in pregnant women. Verify pregnancy status of females of reproductive potential prior to initiation. Advise females to use effective contraception during therapy and for at least 20 months after the last dose; male patients must use condoms and not to donate semen during therapy and for at least 8 months after last dose. Advise patients not to donate blood or blood products during therapy and for at least 20 months after last dose. Risk of musculoskeletal adverse reactions accompanied by serum creatine kinase (CK) elevations; temporarily interrupt or discontinue based on severity of reactions. Obtain baseline serum CK and creatinine (SCr) levels prior to initiation; periodically during treatment and as clinically indicated. Obtain serum CK and SCr levels at least weekly in those with musculoskeletal adverse reactions with concurrent serum CK elevation >2.5×ULN until symptoms resolve. Pregnancy.

Nursing mothers: not recommended during therapy and for 20 months after last dose.

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DRUG MONOGRAPHS

SKIN CANCER Interactions: Avoid concomitant strong CYP3A inhibitors (eg, saquinavir, telithromycin, ketoconazole, itraconazole, voriconazole, posaconazole, nefazodone) or moderate CYP3A inhibitors (eg, atazanavir, diltiazem, fluconazole); if moderate CYP3A inhibitor use necessary, administer for <14 days and monitor closely.

Avoid concomitant strong or moderate CYP3A inducers (eg, carbamazepine, efavirenz, modafinil, phenobarbital, phenytoin, rifabutin, rifampin, St. John’s Wort).

Adverse reactions: Muscle spasms, alopecia, dysgeusia, fatigue, nausea, musculoskeletal pain, diarrhea, decreased weight, decreased appetite, myalgia, abdominal pain, headache, pain, vomiting, pruritus; anemia, hyperglycemia, increased SCr, CK, and LFTs. Note: Report exposure to Odomzo during pregnancy by calling (888) 669-6682.

How supplied: Caps—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. Nursing mothers: not recommended.

Adverse reactions: Rash, pruritus; any immunemediated reactions.

How supplied: Single-use vial (4mL, 10mL)—1

PROLEUKIN Prometheus

℞

Interleukin-2, recombinant. Aldesleukin 22 million IU/vial; pwd for IV infusion after reconstitution and dilution; contains mannitol; preservative-free.

Indications: Metastatic melanoma.

Adults: ≥18yrs: 600,000 IU/kg (0.037mg/kg) every 8 hours by IV infusion over 15 minutes for a max of 14 doses, followed by 9 days rest, then repeat for another 14 doses (max 28 doses/ course), as tolerated. Retreatment and dose adjustments: see literature.

Children: <18yrs: not established.

Contraindications: Abnormal thallium stress test or pulmonary function tests. Organ allografts.

Previous drug related toxicity (eg, sustained ventricular tachycardia [≥5 beats], uncontrolled or unresponsive arrhythmias, chest pain with ECG changes consistent with angina, or MI, cardiac tamponade, intubation >72hrs, renal failure requiring dialysis >72hrs, coma or toxic psychosis >48hrs, repetitive or difficult seizures, bowel ischemia or perforation, GI bleeding requiring surgery).

Warnings/Precautions: See literature. History of cardiac or pulmonary disease. Renal, hepatic, or CNS impairment. Seizure disorder. Bacterial infections (treat prior to starting therapy; esp. patients with indwelling central lines). Withhold dose if organ perfusion is not maintained, urine output is reduced, systolic BP <90mmHg, CHF, cardiac ischemia or arrhythmias occur; or if moderate-to-severe lethargy or somnolence (continuing may result in coma) develops. Evaluate and treat CNS metastases; obtain negative scan before starting treatment. Do thallium stress test; monitor vital signs, weight, fluid intake and output daily. Correct hypovolemia or fluid accumulations if occur. Obtain CBCs, differential and platelets, blood chemistries (electrolytes, renal and hepatic function tests), chest X-rays, serum creatinine (should be ≤1.5mg/dL before starting therapy), pulmonary function tests, arterial blood gases.

Monitor for capillary leak syndrome, mental status changes, thyroid changes, diabetes onset.

Elderly. Pregnancy (Cat.C). Nursing mothers: not recommended.

Interactions: Psychotropics may increase CNS toxicity. Increased toxicity with other nephrotoxic, hepatotoxic, myelotoxic, or cardiotoxic drugs. Hypersensitivity reactions with other antineoplastics. Myocardial injury and rhabdomyolysis risk increased with interferon-

alfa. Antagonized by glucocorticoids (avoid). β-blockers and other antihypertensives may potentiate hypotension. Delayed reactions to iodinated contrast media. May increase risk of allograft rejection.

Adverse reactions: Hypotension, GI upset, oliguria, flu-like syndrome, respiratory disorders (eg, dyspnea), CNS effects (eg, confusion, somnolence), rash, metabolic and nutritional disorders (eg, bilirubinemia, increased creatinine), hyperglycemia, thyroid disorder, thrombocytopenia, anemia, impaired neutrophil function, capillary leak syndrome, cardiotoxicity, exacerbation of autoimmune and inflammatory disease, eosinophilia, possible antibody formation; others.

How supplied: Single-use vials—1

SYLATRON Merck

℞

Alpha interferon. Peginterferon alfa-2b 296mcg, 444mcg, 888mcg; per vial; lyophilized pwd for SC inj after reconstitution.

Indications: Adjuvant treatment of melanoma with microscopic or gross nodal involvement within 84 days of definitive surgical resection including complete lymphadenectomy.

Adults: Give by SC inj. Rotate inj sites.

Premedicate with acetaminophen. ≥18yrs: 6mcg/kg/week for 8 doses, followed by 3mcg/kg/week for up to 5yrs. Renal impairment (moderate): initially 4.5mcg/kg/week for 8 doses, followed by 2.25mcg/kg/week for up to 5yrs; (severe or ESRD on dialysis): initially 3mcg/kg/ week for 8 doses, followed by 1.5mcg/kg/week for up to 5yrs. Withhold dose if ANC <0.5×109/L, platelets <50×109/L, ECOG PS ≥2, or for nonhematologic toxicity ≥ Grade 3. Resume at reduced dose (see full labeling) when: ANC ≥0.5×109/L, platelets ≥50×109/L, ECOG PS 0–1, and non-hematologic toxicity has completely resolved or improved to Grade 1.

Children: <18yrs: not established.

Contraindications: Anaphylaxis to peginterferon alfa-2b or interferon alfa-2b.

Autoimmune hepatitis. Hepatic decompensation (Child-Pugh score >6 [Class B and C]).

Warnings/Precautions: Increased risk of serious depression, suicidal ideation, and other neuropsychiatric disorders. Permanently discontinue for: persistent severe or worsening neuropsychiatric disorders (eg, depression, psychosis, encephalopathy); new onset ventricular arrhythmia or cardiovascular decompensation; new or worsening retinopathy; Grade 4 non-hematologic toxicity; severe (Grade 3) hepatic injury or hepatic decompensation; hypothyroidism, hyperthyroidism, or diabetes

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DRUG MONOGRAPHS

SKIN CANCER mellitus that cannot be effectively managed; or if unable to tolerate a dose of 1mcg/kg/week.

Monitor for signs/symptoms of depression/ psychosis every 3 weeks during first 8 weeks, then every 6 months, continue for at least 6 months after last dose. Perform eye exam in patients with retinopathy and those with vision changes during therapy. Monitor hepatic function with serum bilirubin, ALT/AST, alkaline phosphate, and LDH at 2 and 8 weeks, and 2 and 3 months following initiation, then every 6 months. Obtain TSH levels within 4 weeks prior to initiation, at 3 and 6 months following initiation, then every 6 months. Moderate-to-severe renal impairment (monitor). Pregnancy (Cat.C). Nursing mothers: not recommended.

Interactions: Potentiates CYP1A2 (eg, caffeine) or CYP2D6 (eg, desipramine) substrates.

Concomitant drugs with narrow therapeutic range metabolized by CYP1A2 or CYP2D6; monitor for increased toxicities.

Adverse reactions: Fatigue, increased ALT/AST, pyrexia, headache, anorexia, myalgia, nausea, chills, inj site reactions; neuropsychiatric disorders.

How supplied: Single-use vial—1 (w. diluent)

TAFINLAR GlaxoSmithKline

℞

Kinase inhibitor. Dabrafenib 50mg, 75mg; caps.

Indications: As monotherapy for the treatment of unresectable or metastatic melanoma with BRAF V600E mutation, as detected by an FDAapproved test. In combination with trametinib for the treatment of unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test.

Limitation of use: not indicated for the treatment of wild-type BRAF melanoma.

Adults: Confirm presence of BRAF V600E or V600K mutation prior to initiation. Swallow whole.

Take at least 1hr before or 2hrs after a meal.

Monotherapy or in combination with trametinib: 150mg twice daily (about 12hrs apart); continue until disease progression or unacceptable toxicity occurs. Dose modifications or reductions: see full labeling.

Children: Not established.

Warnings/Precautions: See full labeling for trametinib prior to starting combination therapy.

Increased incidence of new primary cutaneous malignancies; perform skin evaluation prior to initiation, every 2 months during therapy, and up to 6 months after discontinuation. Withhold if fever ≥101.3°F or any serious febrile drug reaction occurs and evaluate for infection; prophylaxis with antipyretics may be needed when resuming.

Pre-existing diabetes or hyperglycemia; monitor serum glucose levels. Monitor for visual signs/ symptoms of uveitis. Closely monitor patients with G6PD deficiency for signs of hemolytic anemia. Males (risk of infertility). Embryo-fetal toxicity. Females of reproductive potential should use highly effective non-hormonal contraception during and for 4 weeks after

treatment. Pregnancy (Cat.D). Nursing mothers: not recommended.

Interactions: Concomitant strong inhibitors (eg, ketoconazole, nefazodone, clarithromycin, gemfibrozil) or inducers (eg, rifampin, phenytoin, carbamazepine, phenobarbital, St John’s wort) of CYP3A4 or CYP2C8: not recommended; if unavoidable, monitor closely. Drugs that affect gastric pH (eg, PPIs, H2-blockers, antacids) may decrease dabrafenib exposure. May antagonize effects of CYP3A4, CYP2B6, CYP2C8, CYP2C9, CYP2C19, UGT, transporters, or other substrates (eg, midazolam, warfarin, dexamethasone, hormonal contraceptives).

Adverse reactions: Hyperkeratosis, headache, pyrexia, arthralgia, papilloma, alopecia, palmar-plantar erythrodysesthesia syndrome; combination with trametinib: chills, fatigue, rash, nausea, vomiting, diarrhea, constipation, abdominal pain, peripheral edema, cough, night sweats, decreased appetite, myalgia; hemorrhage, thromboembolic events.

How supplied: Caps—120

YERVOY Bristol-Myers Squibb

℞

Cytotoxic T-lymphocyte antigen 4 (CTLA-4)blocking antibody. Ipilimumab 5mg/mL; soln for IV infusion; preservative-free.

Indications: Treatment of unresectable or metastatic melanoma.

Adults: Give by IV infusion over 90 mins. 3mg/kg every 3 weeks for a total of 4 doses. Withhold dose for moderate immune-mediated reactions or symptomatic endocrinopathy. Complete/partial resolution of adverse reaction and receiving <7.5mg prednisone or equivalent per day: may resume treatment. Permanently discontinue and initiate systemic high-dose corticosteroids for severe adverse reactions.

Children: Not established.

Warnings/Precautions: Permanently discontinue if: persistent moderate adverse reactions or inability to reduce corticosteroid dose to 7.5mg prednisone or equivalent per day; failure to complete full treatment course within 16 weeks from first dose; severe or lifethreatening reactions, including: 1) colitis with abdominal pain, fever, ileus, or peritoneal signs; increase in stool frequency and incontinence, need for IV hydration for >24hrs, GI hemorrhage/ perforation; 2) AST or ALT >5X ULN or total bilirubin >3X ULN; 3) Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; 4) severe motor or sensory neuropathy, GuillainBarre syndrome, or myasthenia gravis; 5) severe immune-mediated reactions involving any organ system; 6) immune-mediated ocular disease that is unresponsive to topical immunosuppressive therapy. Monitor for enterocolitis, dermatitis, neuropathy, endocrinopathy; perform LFTs and thyroid tests at baseline and before each dose. Moderate or severe hepatic impairment.

Pregnancy (Cat.C). Nursing mothers: not recommended.

Adverse reactions: Fatigue, diarrhea, pruritus, rash, colitis; immune-mediated adverse reactions (may be severe and fatal).

How supplied: Single-use vial (50mg, 200mg)—1

ZELBORAF Genentech

℞

Kinase inhibitor. Vemurafenib 240mg; tabs.

Indications: Treatment of unresectable or metastatic melanoma with BRAFV600E mutation as detected by an FDA-approved test. Limitation of use: not for treatment of wild-type BRAF melanoma.

Adults: Swallow whole. ≥18yrs: 960mg every 12hrs; until disease progression or unacceptable toxicity occurs. Dose modifications for adverse reactions or QTc prolongation: see full labeling.

Dose reductions <480mg twice daily: not recommended.

Children: <18yrs: not established.

Warnings/Precautions: Confirm BRAFV600E mutation-positive melanoma with FDA-approved test before initiating. Risk of cutaneous squamous cell carcinoma (cuSCC): ≥65yrs, prior skin cancer, chronic sun exposure; if occurs, do excision and evaluate. Perform dermatologic evaluation before therapy, every 2 months during, and consider monitoring 6 months after discontinuation. Monitor for signs/symptoms of new non-cutaneous SCC and other malignancies.

Long QT syndrome or QTc >500ms, uncorrectable electrolyte abnormalities, or concomitant drugs that prolong the QT interval: not recommended.

Prior to and following initiation or after dose adjustment for QTc prolongation, evaluate ECG and electrolytes after 15 days, monthly during the 1st 3 months, then every 3 months thereafter, or more as clinically indicated. Severe hepatic or renal impairment. Monitor liver enzymes, bilirubin before initiating and monthly during treatment, or as needed. Monitor for ophthalmologic reactions routinely. Avoid sun exposure. Pregnancy (Cat.D); avoid. Use adequate contraception during therapy and for at least 2 months after discontinuation.

Nursing mothers: not recommended.

Interactions: Avoid concomitant strong CYP3A4 inhibitors (eg, azole antifungals, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir) or strong CYP3A4 inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital); consider alternatives. Concomitant CYP1A2 substrates with narrow therapeutic indices: not recommended; if unavoidable, consider dose reduction of substrates and monitor. Increased transaminase and bilirubin with concomitant ipilimumab.

Adverse reactions: Arthralgia, rash, alopecia, fatigue, photosensitivity, nausea, pruritus, skin papilloma; severe hypersensitivity or dermatologic reactions (permanently discontinue if occurs), hepatotoxicity, uveitis, blurry vision, photophobia, other malignancies.

How supplied: Tabs—120

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DRUG MONOGRAPHS

ASSOCIATED HEMATOLOGICAL DISORDERS Anemias

ANADROL-50 Meda

CIII

Androgen. Oxymetholone 50mg; scored tabs.

Indications: Anemia caused by deficient red cell production. Acquired aplastic anemia, congenital anemia, myelofibrosis, and hypoplastic anemias due to myelotoxic drugs.

Adults and Children: Individualized. 1–5mg/kg per day for at least 3–6 months; may attempt to lower dose or discontinue after remission.

Congenital aplastic anemia: may need continued maintenance dose.

Contraindications: Male breast or prostate carcinoma. Breast cancer in females with hypercalcemia. Nephrosis or the nephrotic phase of nephritis. Severe hepatic dysfunction.

Pregnancy (Cat.X).

Warnings/Precautions: Not a replacement for other supportive treatments (eg, transfusion; iron, folic acid, Vit. B12, Vit. B6 replacement). Discontinue if jaundice, abnormal liver function, hypercalcemia, or edema occurs. Cardiac, hepatic, or renal dysfunction.

Monitor hepatic function, blood, and bone age.

Elderly. Young children. Nursing mothers: not recommended.

Interactions: May potentiate oral anticoagulants. May alter insulin needs.

Adverse reactions: Peliosis hepatis, premature epiphyseal closure in adolescents, edema, hepatic carcinoma, prostatic hypertrophy or carcinoma, gynecomastia, priapism, oligospermia, nausea, jaundice, hirsutism, virilization, male pattern baldness, acne, polycythemia, headache, CNS excitation, insomnia, altered libido, fluid and electrolyte disturbances, suppression of clotting factors, increased serum cholesterol.

How supplied: Tabs—100

ARANESP Amgen

℞

Erythropoiesis stimulating protein. Darbepoetin alfa 25mcg/mL, 40mcg/mL, 60mcg/mL, 100mcg/mL, 150mcg/0.75mL, 200mcg/mL, 300mcg/mL, 500mcg/mL; for IV or SC inj; preservative-free; contains albumin (human) or polysorbate 80. ℞ Also: ARANESP SINGLEJECT Darbepoetin alfa 25mcg/0.42mL, 40mcg/0.4mL, 60mcg/0.3mL, 100mcg/0.5mL, 150mcg/0.3mL, 200mcg/0.4mL, 300mcg/0.6mL, 500mcg/mL; per prefilled syringe; for IV or SC inj; preservative-free; contains albumin (human) or polysorbate 80.

Indications: Anemia of chronic renal failure (CRF), including patients on and not on dialysis.

Chemotherapy-induced anemia in patients with non-myeloid malignancies.

Adults: CRF (not currently on epoetin alfa): initially 0.45mcg/kg SC or IV once weekly; alternatively for CRF (not on dialysis): 0.75mcg/kg SC once every 2 weeks. Cancer: initially 2.25mcg/kg SC once weekly or 500mcg SC once every 3 weeks. Discontinue after completion of chemotherapy course. Adjust dose to maintain hemoglobin level (target 10–12g/dL; max 12g/dL) sufficient to avoid red blood cell transfusion; see literature. Converting from epoetin alfa, and for dose adjustment: see literature.

Children: Not recommended.

Contraindications: Uncontrolled hypertension.

Do not use in patients with pure red cell aplasia due to erythropoietin antibodies.

Warnings/Precautions: See literature.

Evaluate serum iron, ferritin, transferrin saturation before and during therapy; most patients will need iron supplementation.

Monitor hemoglobin weekly for 4 weeks after start and dose changes, until stabilized, then periodically; reduce dose if hemoglobin increases >1g/dL in any 2-week period; withhold dose if hemoglobin exceeds 12g/dL. Monitor BP (reduce or withhold dose if hypertension occurs), folate, Vit. B12, renal function, electrolytes, fluid balance, and for premonitory neurological symptoms. Seizure, cardiovascular, or hematologic disorders. Infection, inflammation, malignancy, occult blood loss, severe albumin toxicity, bone marrow fibrosis may reduce effectiveness; consider other etiologies in treatment failures. Adjust dialysis ℞ as needed.

Latex allergy. Pregnancy (Cat.C). Nursing mothers.

Adverse reactions: Infection, hyper- or hypotension, myalgia, headache, GI upset, dyspnea, edema, arthralgia, limb or back pain, arrhythmia/cardiac arrest, cough, fatigue, chest pain, dizziness, pruritus, clotted vascular access, CHF, flu-like symptoms, local reactions, asthenia, seizure, iron deficiency. Increased risk of death, cardiovascular or thrombotic events if hemoglobin >12g/dL. May stimulate tumor growth, shorten time to tumor progression or overall survival if hemoglobin ≥12g/dL. Cancer patients also: pneumonia, dehydration.

How supplied: Single-dose vials (25, 40, 60, 100, 150mcg)—4; Single-dose vial (200, 300mcg)—1; Single-dose prefilled syringes (25, 40, 60, 100, 150mcg)—4; Single-dose prefilled syringes (200, 300, 500mcg)—1

ATGAM Pfizer

℞

Immune globulin. Lymphocyte immune globulin, anti-thymocyte globulin [equine] 50mg/mL; soln for IV infusion after dilution.

Indications: Treatment of moderate to severe aplastic anemia in patients who are unsuitable for bone marrow transplantation.

Adults: Perform intradermal test dose before initiating therapy (see literature). Do not dilute in dextrose injection or highly acidic infusion solutions. Give by IV infusion over >4hrs.

10–20mg/kg daily for 8–14 days. Additional alternate-day therapy up to a total of 21 doses can be administered. May need prophylactic platelet transfusions to maintain platelets.

Children: Limited experience (see literature).

Warnings/Precautions: To be administered by physicians with experience in immunosuppressive therapy and in facilities equipped with adequate lab and supportive medical resources. Discontinue if symptoms of anaphylaxis develop. Contains human plasma; monitor for possible infection transmission.

Monitor for leukopenia, thrombocytopenia, or infection esp. with concomitant corticosteroids and antimetabolites. Pregnancy (Cat.C): not recommended. Nursing mothers.

Interactions: Previously masked reactions may occur when corticosteroids and other immunosuppressant doses are reduced.

Adverse reactions: Fever, skin reactions, chills, arthralgia, headache, myalgia, GI upset, chest pain, phlebitis, diaphoresis, joint stiffness, edema, muscle ache, vomiting, agitation/ lethargy, listlessness, light-headedness, seizures, bradycardia, myocarditis, cardiac irregularity, hepatosplenomegaly, possible encephalitis or post viral encephalopathy, hypotension, CHF, hypertension, burning soles/palms, foot sole pain, lymphadenopathy, post-cervical lymphadenopathy, tender lymph nodes, bilateral pleural effusion, respiratory distress, anaphylactic reaction, proteinuria, abnormal LFTs and renal function, serum sickness.

How supplied: Ampules (5mL)—5

BIFERA Meda

OTC

Iron (as polysaccharide iron complex [PIC] 22mg + heme iron polypeptide [HIP] as Proferrin bovine source 6mg) 28mg; gluten-free tabs.

Indications: Iron supplement. Iron deficiency.

Adults: 1 tab once daily.

Children: Not recommended.

Contraindications: Hemochromatosis.

Hemosiderosis.

Warnings/Precautions: May mask pernicious anemia. Monitor hemoglobin, hematocrit,

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DRUG MONOGRAPHS

ASSOCIATED HEMATOLOGICAL DISORDERS ferritin levels periodically. Pregnancy. Nursing mothers.

Adverse reactions: Allergic sensitization.

How supplied: Tabs—30

BIFERARx Meda

℞

Iron (as polysaccharide iron complex [PIC] 22mg + heme iron polypeptide [HIP] as Proferrin bovine source 6mg) 28mg, folic acid 1mg, Vit. B12 25mcg; tabs.

Indications: Iron supplement. Iron deficiency.

Adults: 1 tab once daily.

Children: Not recommended.

Contraindications: Hemochromatosis.

Hemosiderosis.

Warnings/Precautions: May mask pernicious anemia. Monitor hemoglobin, hematocrit, ferritin levels periodically. Pregnancy. Nursing mothers.

Adverse reactions: Allergic sensitization.

How supplied: Tabs—90

DEXFERRUM American Regent

℞

Hematinic. Iron (as dextran complex) 50mg/mL; soln for IV inj.

Indications: Iron deficiency where oral therapy is unsatisfactory or impossible.

Adults and Children: <4months: not recommended. Give by IV inj. Administer 0.5mL test dose first; if no signs/symptoms of anaphylactictype 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 and toxic range. If blood counts toxic, discontinue until hematologic recovery, see full labeling for dosage adjustments. Renal impairment (CrCl <60mL/min or ESRD): initially 7.5mg/kg/day; give dose following dialysis (monitor).

Children: Not established.

Warnings/Precautions: Risk of severe myelosuppression. Monitor blood counts at baseline and during therapy; interrupt or reduce dose if necessary. Markedly depressed bone marrow function: do not initiate. Monitor for malignancies. Avoid sun exposure. Macrocytosis may mask folic acid deficiency; prophylactic folic acid is recommended. Myeloproliferative disorders; discontinue if cutaneous vasculitic ulcerations occur. Renal or hepatic impairment.

Elderly. Pregnancy (Cat.D); avoid. Use effective contraception during and for ≥30 days (females) or ≥1 year (males) after therapy. Nursing mothers: not recommended.

Interactions: Avoid concomitant didanosine, with or without stavudine, or other antiretrovirals (may cause pancreatitis [monitor], fatal hepatotoxicity, peripheral neuropathy). Increased risk of vasculitic toxicities with interferon therapy.

May cause falsely elevated urease, uricase, lactate dehydrogenase.

Adverse reactions: Neutropenia, thrombocytopenia, anemia, leukopenia, GI upset, anorexia, hair loss, macrocytosis, bleeding, melanonychia; secondary malignancies.

Note: Wear disposable gloves when handling caps or bottle.

How supplied: Caps—60

EPOGEN Amgen

℞

Erythropoietin (human, recombinant). Epoetin alfa 2000 Units, 3000 Units, 4000 Units, 10000 Units, 40000 Units; per mL; soln for IV or SC inj; contains albumin (human); preservative-free. ℞ Also: EPOGEN MULTIDOSE Epoetin alfa 10000 Units, 20000 Units; per mL; soln for IV or SC inj; contains albumin (human) and benzyl alcohol.

Indications: Anemia in chronic renal failure (CRF). Anemia related to zidovudine in HIVinfected patients. Chemotherapy-induced anemia in patients with non-myeloid malignancies (serum erythropoietin ≤200 mUnits/mL). To reduce need for allogeneic blood transfusions in anemic (hemoglobin >10 to ≤13g/dL) patients scheduled for elective, noncardiac, nonvascular surgery.

Adults: Individualize (see literature for titration).

CRF: initially 50–100 Units/kg 3 times per week IV (dialysis or non dialysis) or SC (non dialysis); usual max (non dialysis) 150 Units/kg 3 times

per week; (dialysis) 200 Units/kg 3 times per week; target hemoglobin 10–12g/dL. Zidovudinetreated HIV patients: if serum erythropoietin ≤500 mUnits/mL and zidovudine dose ≤4.2 g/wk: initially 100 Units/kg IV or SC 3 times per week for 8 weeks; usual max 300 Units/kg 3 times per week.

Chemotherapy-induced: initially 150 Units/kg SC 3 times per week; may increase to 300 Units/kg 3 times per week after 8 weeks. Or, initially 40000 Units SC once weekly; may increase to 60000 Units once weekly after 4 weeks. Discontinue after completion of chemotherapy course. Surgery: If ≥21 days until surgery: 600 Units/kg once weekly SC at 21, 14 and 7 days before surgery, and a 4th dose on day of surgery. If <21 days until surgery: 300 Units/kg per day SC for 10 days before, on day of, and for 4 days after surgery. All: adjust dose to maintain the lowest hemoglobin level (target max 12g/dL) sufficient to avoid red blood cell transfusion; see literature.

Children: Individualize (see literature for monitoring). CRF (dialysis): <1 month: not recommended. ≥1 month of age: initially 50 Units/kg three times per week IV or SC. Target hemoglobin: 10–12g/dL. Chemotherapy-induced: ≥5yrs: 600 Units/kg IV weekly (max 40,000 Units); may increase to 900 Units/kg IV weekly (max 60,000 Units) after 4 weeks. Discontinue after completion of chemotherapy course. Other uses: see literature.

Contraindications: Uncontrolled hypertension.

Warnings/Precautions: See literature. Evaluate serum iron, ferritin, transferrin saturation before therapy; all patients will need iron supplementation. Monitor hemoglobin (measure twice weekly for 2–6 weeks after any dosage adjustment; reduce dose if hemoglobin increases >1g/dL in any 2-week period; withhold dose if hemoglobin exceeds 12g/dL), blood pressure, renal function, iron levels, clotting times, serum chemistry, CBC, and for premonitory neurological symptoms. Seizure disorders. Cardiovascular or hematologic disorders. Hypertension (esp. in renal failure). Porphyria. Concurrent infection, inflammation, increased zidovudine dose, or other factors may reduce effectiveness.

Perisurgery: consider DVT prophylaxis. Consider other etiologies in treatment failures. Adjust anticoagulant dose in dialysis patients. Menses may resume. Pregnancy (Cat.C). Nursing mothers.

Adverse reactions: Iron deficiency, hypertension, headache, arthralgia, GI disturbances, edema, local reaction, rash, paresthesia, dizziness, clotted vascular access (A-V shunt), pyrexia, respiratory congestion, seizures. Increased risk of death, cardiovascular or thrombotic events if hemoglobin >12g/dL. May stimulate tumor growth, shorten time to tumor progression or overall survival if hemoglobin ≥12g/dL. Children: also abdominal pain, upper 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

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DRUG MONOGRAPHS

ASSOCIATED HEMATOLOGICAL DISORDERS FERAHEME AMAG

℞

Hematinic. Elemental iron 30mg/mL (as ferumoxytol 510mg/17mL); colloidal iron for IV infusion after dilution; contains mannitol 44mg/mL; preservative-free.

Indications: Iron deficiency anemia in adult patients with chronic kidney disease.

Adults: Give by IV infusion over at least 15 mins.

Initially 510mg, followed by a second 510mg dose 3–8 days later. May repeat in persistent or recurrent iron deficiency anemia. Hemodialysis: give at least 1 hour after starting hemodialysis and after BP is stable.

Children: <18yrs: not established.

Contraindications: History of any IV iron product allergy.

Warnings/Precautions: Iron overload: do not administer. Monitor for severe hypotension, and for hypersensitivity for at least 30 minutes after each infusion. Evaluate hemoglobin, ferritin, iron, transferrin saturation at least 1 month after 2nd infusion. Have equipment/personnel available to treat hypersensitivity reactions. Elderly. Pregnancy (Cat.C). Nursing mothers: not recommended.

Interactions: May reduce absorption of concomitantly administered oral iron preparations. May transiently (up to 3 months) affect diagnostic ability of MRI (see full labeling).

Concomitant chemotherapy or monoclonal antibodies: separate dosing by at least 30 mins.

Adverse reactions: Diarrhea, nausea, hypotension (may be significant), dizziness, constipation, peripheral edema; infusion reactions, anaphylactic reactions (may be fatal), other hypersensitivity reactions (eg, rash, pruritus, urticaria, wheeze).

How supplied: Single-use vials (17mL)—1, 10

FERRALET 90 Mission

℞

Iron (as carbonyl) 90mg, folic acid 1mg, Vit.B12 12mcg, Vit.C 120mg, docusate sodium 50mg; tabs; contains tartrazine.

Indications: Iron deficiency anemia.

Adults: Swallow whole. Take 2hrs after meals.

1 tab once daily.

Children: Not recommended.

Contraindications: Hemolytic anemia.

Hemochromatosis. Hemosiderosis.

Warnings/Precautions: May mask pernicious anemia. Monitor hemoglobin, hematocrit, reticulocyte count periodically. Elderly.

Interactions: Inhibits tetracycline, fluoroquinolone absorption. Aluminum- or magnesium-containing antacids inhibit iron absorption.

Adverse reactions: GI upset or irritation, constipation, dark stools, allergic sensitization.

How supplied: Tabs—90

FERRLECIT Sanofi Aventis

℞

Hematinic. Iron (as sodium ferric gluconate complex in sucrose) 12.5mg/mL; soln for IV inj or infusion; contains benzyl alcohol.

Indications: Iron deficiency anemia in patients on chronic hemodialysis receiving epoetin therapy.

Adults: Give by IV infusion (diluted) or slow IV inj (undiluted). 125mg infused over 1 hour or by slow IV inj (at a rate of up to 12.5mg/min). Minimum cumulative dose: 1g given over 8 sequential dialysis sessions; usual max: 125mg/dose.

Children: <6 yrs: not recommended. Give by IV infusion (diluted) over 1 hour. ≥6yrs: 1.5mg/kg per dose at 8 sequential dialysis sessions; max: 125mg/dose.

Contraindications: Anemias not caused by iron deficiency. Iron overload. Neonates.

Warnings/Precautions: Hemoglobinopathies.

Refractory anemias. Pregnancy (Cat.B). Nursing mothers.

Interactions: May reduce absorption of concomitant oral iron preparations.

Adverse reactions: Hypotension, hypertension, GI upset, chest pain, back pain, abdominal pain, pruritus, inj site reaction, headache, dizziness, syncope, fatigue, fever, cramps, dyspnea, tachycardia; rare: hypersensitivity reactions.

How supplied: Ampules (5mL)—10

Folic acid (various)

℞

Hematinic. Folic acid 1mg; tabs. ℞ Also: Folic acid injection Folic acid 5mg/mL; soln for IV, IM or SC inj; contains benzyl alcohol and aluminum.

Indications: Megaloblastic anemias of folic acid deficiency. Anemias of nutritional origin, pregnancy, infancy or childhood.

Adults and Children: Usual dose: up to 1mg daily; may need higher dose if resistant disease.

Maintenance: infants: 0.1mg/day; <4yrs: 0.3mg/day; ≥4yrs: 0.4mg/day. Pregnant or lactating: 0.8mg/day. Alcoholism, hemolytic anemia, anticonvulsant therapy or chronic infection: may require higher dose.

Warnings/Precautions: Use injectable form if disease is severe or GI absorption impaired.

Rule out or treat vitamin B12 deficiency prior to treatment. May obscure diagnosis of pernicious anemia. Pregnancy (Cat.A).

Interactions: May antagonize phenytoin. False low serum and red cell folate levels may occur with antibiotics (eg, tetracycline).

Adverse reactions: Allergic sensitization.

How supplied: Contact supplier.

INFED Actavis

℞

Hematinic. Iron (as dextran complex) 50mg/mL; soln for IV or IM inj.

Indications: Iron deficiency where oral therapy is unsatisfactory or impossible.

Adults and Children: Give by IV or by deep IM (into upper outer quadrant of buttock only) inj.

Administer 0.5mL test dose first; if no signs/ symptoms of anaphylactic-type reactions, may give full therapeutic dose. Iron deficiency anemia: determine total dose based on hemoglobin and body weight (see literature). Iron replacement for blood loss: Replacement iron (in mg) = blood loss (in mL) × 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.

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DRUG MONOGRAPHS

ASSOCIATED HEMATOLOGICAL DISORDERS Warnings/Precautions: Have epinephrine inj (1:1000) available. Monitor for serious hypersensitivity reactions during and after administration for ≥30 mins and until clinically stable. Monitor for signs/symptoms of hypertension after each administration. Avoid extravasation. Pregnancy (Cat.C). Nursing mothers.

Interactions: Lab assays may result in overestimating serum iron and transferrin bound iron within 24hrs after administration.

Adverse reactions: Nausea, hypertension, flushing, hypophosphatemia, dizziness; rare: hypersensitivity reactions.

How supplied: Single-use vial (15mL)—1, 2

Leucovorin Teva

NASCOBAL Strativa ℞

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

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)

℞

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.

℞

Cyanocobalamin 500mcg/spray; soln for nasal spray; contains benzalkonium chloride.

Indications: Maintenance of normal hematologic status in pernicious anemia patients who are in remission after intramuscular Vit. B12 therapy and who have no nervous system involvement. Supplementation for other Vit. B12 deficiencies.

Adults: Hematological parameters must be within normal range before beginning therapy.

Allow at least 1hr before or after hot foods or liquids. Initial dose: One spray (500mcg) in one nostril once weekly. Monitor response, may increase dose if serum B12 levels decline.

Children: Not recommended.

Warnings/Precautions: Confirm diagnosis.

May need supplemental folate. Risk of hypokalemia or sudden death in severe megablastic anemia. Leber’s disease. Defer dose if nasal congestion, rhinitis, or upper respiratory infections occur. Reevaluate if low levels of Vit. B12 persist despite treatment. Do not use for Schilling Test. Infection, uremia, and iron or folic acid deficiency may reduce response. Increased risk of stomach carcinoma in those with pernicious anemia; perform tests when indicated. May unmask polycythemia vera. Monitor B12 blood levels 1 month after starting therapy, 1 month after any dose increase, and regularly at 3–6 month intervals. Monitor serum potassium, platelet counts. Pregnancy (Cat.C).

Interactions: Antibiotics, methotrexate, pyrimethamine may interfere with lab tests.

Colchicine, chronic heavy alcohol use may impair Vit. B12 absorption. Reduced response with bone marrow suppressants (eg, chloramphenicol).

Adverse reactions: Headache, nausea, rhinitis.

How supplied: Single-use nasal spray (0.125mL)—4

NULECIT Actavis

℞

Hematinic. Iron (as sodium ferric gluconate complex in sucrose) 12.5mg/mL; soln for IV inj or infusion; contains benzyl alcohol.

Indications: Iron deficiency anemia in patients on chronic hemodialysis receiving epoetin therapy.

Adults: Give by IV infusion (diluted) or slow IV inj (undiluted). 125mg infused over 1 hour or by slow

IV inj (at a rate of up to 12.5mg/min). Minimum cumulative dose: 1g given over 8 sequential dialysis sessions; usual max: 125mg/dose.

Children: <6yrs: not recommended. Give by IV infusion (diluted) over 1 hour. ≥6yrs: 1.5mg/kg per dose at 8 sequential dialysis sessions; max: 125mg/dose.

Contraindications: Anemias not caused by iron deficiency. Iron overload.

Warnings/Precautions: Hemoglobinopathies.

Refractory anemias. Avoid in neonates. Pregnancy (Cat.B). Nursing mothers.

Interactions: May reduce absorption of concomitant oral iron preparations.

Adverse reactions: Hypotension, hypertension, GI upset, chest pain, back pain, abdominal pain, pruritus, inj site reaction, cramps, headache, dizziness, syncope, fatigue, fever, dyspnea, tachycardia; rare: hypersensitivity reactions.

How supplied: Vials (5mL)—10

PROCRIT Janssen Biotech

℞

Erythropoietin (human, recombinant). Epoetin alfa 2000 Units, 3000 Units, 4000 Units, 10000 Units, 40000 Units; per mL; soln for IV or SC inj; contains albumin (human); preservativefree. ℞ Also: PROCRIT MULTIDOSE Epoetin alfa 10000 Units, 20000 Units; per mL; soln for IV or SC inj; contains albumin (human) and benzyl alcohol.

Indications: Anemia in chronic renal failure (CRF). Anemia related to zidovudine in HIVinfected patients. Chemotherapy-induced anemia in patients with non-myeloid malignancies (serum erythropoietin ≤200 mUnits/mL). To reduce need for allogeneic blood transfusions in anemic (hemoglobin >10 to ≤13g/dL) patients scheduled for elective, noncardiac, nonvascular surgery.

Adults: Individualize (see literature for titration).

CRF: initially 50–100 Units/kg 3 times per week IV (dialysis or non dialysis) or SC (non dialysis); usual max (non dialysis) 150 Units/kg 3 times per week; (dialysis) 200 Units/kg 3 times per week; target hemoglobin: 10–12g/dL. Zidovudinetreated HIV patients: if serum erythropoietin ≤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.

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ASSOCIATED HEMATOLOGICAL DISORDERS 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. Chemotherapyinduced: ≥5yrs: 600 Units/kg IV weekly (max 40,000 Units); may increase to 900 Units/kg IV weekly (max 60,000 Units) after 4 weeks.

Discontinue after completion of chemotherapy course. Other uses: see literature.

Contraindications: Uncontrolled hypertension.

Warnings/Precautions: See literature.

Evaluate serum iron, ferritin, transferrin saturation before therapy; all patients will need iron supplementation. Monitor hemoglobin (measure twice weekly for 2–6 weeks after any dosage adjustment; reduce dose if hemoglobin increases >1g/dL in any 2-week period; withhold dose if hemoglobin exceeds 12g/dL), blood pressure, renal function, iron levels, clotting times, serum chemistry, CBC, and for premonitory neurological symptoms.

Seizure disorders. Cardiovascular or hematologic disorders. Hypertension (esp. in renal failure). Porphyria. Concurrent infection, inflammation, increased zidovudine dose, or other factors may reduce effectiveness.

Perisurgery: consider DVT prophylaxis. Consider other etiologies in treatment failures. Adjust anticoagulant dose in dialysis patients. Menses may resume. Pregnancy (Cat.C). Nursing mothers.

Adverse reactions: Iron deficiency, hypertension, headache, arthralgia, GI disturbances, edema, local reaction, rash, paresthesia, dizziness, clotted vascular access (A-V shunt), pyrexia, respiratory congestion, seizures. Increased risk of death, cardiovascular or thrombotic events if hemoglobin >12g/dL. May stimulate tumor growth, shorten time to tumor progression or overall survival if hemoglobin ≥12g/dL. Children: also abdominal pain, upper respiratory infection, cough, pharyngitis, constipation.

How supplied: Single-use 1mL vials (2000 Units/mL, 3000 Units/mL, 4000 Units/mL, 10000 Units/mL)—6, 25; Single-use 1mL vials (40000 Units/mL)—4; Multidose 2mL vials (10000 Units/mL)—4, 6; Multidose 1mL vials (20000 Units/mL)—4, 6

PROMACTA GlaxoSmithKline 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

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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

AMICAR TABLETS Clover

℞

Hemostatic (plasmin and plasminogen activator inhibitor). Aminocaproic acid 500mg, 1000mg; scored tabs. ℞ Also: AMICAR ORAL SOLUTION Aminocaproic acid 250mg/mL; raspberry-flavor.

Indications: Bleeding associated with fibrinolysis.

Adults: Initially 5g during 1st hour, then 1g/hour for 8 hours or until bleeding is controlled.

Children: Not recommended.

Also: Aminocaproic Acid Injection (various) ℞ Aminocaproic acid 250mg/mL; soln for IV infusion after dilution; contains benzyl alcohol.

Adults: 4–5g (in 250mL of diluent) by IV infusion during the 1st hour, then 1g/hour (in 50mL of diluent) for 8 hours or until bleeding is controlled.

Children: Not recommended.

Contraindications: Active intravascular clotting process. Disseminated intravascular coagulation without concomitant heparin.

Warnings/Precautions: Upper urinary tract bleeding: not recommended. Cardiac, hepatic or renal disease. Risk of myopathy with longterm use; monitor creatine phosphokinase (CPK); discontinue if CPK rises. Avoid rapid IV administration. Neonates. Pregnancy (Cat.C).

Nursing mothers.

Interactions: Avoid concomitant Factor IX complex or Anti-inhibitor Coagulant concentrates; may increase thrombosis risk.

Adverse reactions: Inj site reactions, bradycardia, hypotension, GI upset, edema, headache, malaise, CNS effects, thrombosis, others; rare: myopathy.

How supplied: Tabs—100; Oral soln—473mL; Inj—contact supplier

CARIMUNE NF CSL Behring

℞

Immune globulin. Immune globulin (human) 3g, 6g, 12g; per vial; pwd for IV infusion after reconstitution; contains sucrose and NaCl; preservative-free.

Indications: Immune thrombocytopenic purpura (ITP).

Adults and Children: Induction: give by IV infusion at a rate of 0.5mg/kg/min for first 30mins, if tolerated may increase to 1mg/kg/min up to max 3mg/kg/min in a stepwise manner.

0.4g/kg on 2–5 consecutive days. Use of 6% immunoglobulin solution is recommended. Acute childhood ITP: discontinue therapy after second day of 5 day course if platelet count response to first two doses is 30–50000/μL. Maintenance: If platelet count falls to <30000/μL and/or clinically significant bleed: give 0.4g/kg as a single infusion, may increase to 0.8–1g/kg as single infusion if inadequate response. Risk of renal dysfunction/failure or thrombosis: max infusion rate <2mg/kg/min.

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DRUG MONOGRAPHS

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. Pre-existing renal insufficiency, diabetes, >65yrs, hypovolemia, sepsis, paraproteinemia: increased risk of renal dysfunction or acute renal failure. Correct volume depletion; assess renal function, BUN, serum creatinine, urine output before and during therapy; discontinue if renal function deteriorates.

Monitor for aseptic meningitis, hemolysis and delayed hemolytic anemia. Monitor for pulmonary dysfunction; perform test for anti-neutrophil antibodies if transfusion-related acute lung injury (TRALI) suspected. Contains human plasma; monitor for possible infection transmission. Have epinephrine inj available. Elderly. Pregnancy (Cat.C).

Interactions: Concomitant nephrotoxic drugs: increased risk of renal toxicity. May affect response to live virus vaccines.

Adverse reactions: Headache, arthralgia, myalgia, transient skin reactions, infusion reactions (eg, flushing, chills, fever), renal toxicities; aseptic meningitis syndrome (esp. high dose 2g/kg), TRALI, thrombosis.

How supplied: Single-use vial—1

CORIFACT CSL Behring

℞

Clotting factor. Factor XIII concentrate (human); 1000–1600 units; per vial; powder for IV injection after reconstitution; preservative-free.

Indications: Routine prophylactic treatment and peri-operative management of surgical bleeding in patients with congenital Factor XIII (FXIII) deficiency.

Adults and Children: Give by slow IV injection at a rate of ≤4mL/min. Initially 40units/kg. Adjust ±5units/kg to maintain 5–20% trough FXIII activity levels using Berichrom Activity Assay: One trough level of <5%: increase by 5units/kg; trough level of 5–20%: no change; two trough levels of >20%: decrease by 5units/kg; one trough level of >25%: decrease by 5units/kg. Routine prophylaxis: give every 28 days. 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 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

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DRUG MONOGRAPHS

ASSOCIATED HEMATOLOGICAL DISORDERS patients receiving doses >100units/kg for DIC development, acute coronary ischemia, and signs/symptoms of other thromboembolic events; discontinue if occurs and treat.

Discontinue if hypersensitivity reactions occur.

Contains human plasma; monitor for possible infection transmission. Elderly. Neonates.

Pregnancy (Cat.C). Nursing mothers.

Interactions: Separate systemic antifibrinolytics by 12hrs.

Adverse reactions: Anemia, diarrhea, hemarthrosis, hep B surface antibody positive, nausea, vomiting; hypersensitivity, thromboembolic events (eg, stroke, DVT, PE).

Note: Report all infections suspected to be transmitted by Feiba to (800) 423-2862.

How supplied: Single-dose vials—1 (w. diluent, transfer device)

GAMUNEX-C Grifols Biologicals

℞

Immune globulin. Immune Globulin (human) 1g/10mL, 2.5g/25mL, 5g/50mL, 10g/100mL, 20g/200mL; soln for IV or SC infusion; preservative- and sucrose-free.

Indications: Idiopathic thrombocytopenic purpura (ITP).

Adults and Children: Give by IV infusion at a rate of 1mg/kg/min for first 30mins, if tolerated may increase to max 8mg/kg/min. 1g/kg once daily given on 2 consecutive days or 0.4g/kg once daily given on 5 consecutive days. If adequate response after first 1g/kg dose, may withhold second dose. Risk of renal dysfunction or thrombosis: give at minimum practicable infusion rate (<8mg/kg/min). Expanded fluid volumes: high dose regimen not recommended.

Contraindications: IgA deficiency with antibodies against IgA. Previous severe reaction to human immune globulin.

Warnings/Precautions: Advanced age, prolonged immobilization, hypercoagulable conditions, history of venous or arterial thrombosis, use of estrogens, indwelling central vascular catheters, hyperviscosity, cardiovascular risk factors: increased risk of thrombosis. Monitor for signs/symptoms of thrombosis and assess blood viscosity in patients at risk for hyperviscosity. Pre-existing renal insufficiency, diabetes, >65yrs, hypovolemia, sepsis, paraproteinemia: increased risk of renal dysfunction or acute renal failure. Correct volume depletion; assess renal function, BUN, serum creatinine, urine output before and during therapy; discontinue if renal function deteriorates.

Monitor for aseptic meningitis, hemolysis, hemolytic anemia. Monitor for pulmonary dysfunction; perform test for anti-neutrophil antibodies if transfusion-related acute lung injury (TRALI) suspected. Contains human plasma; monitor for possible infection transmission. Have epinephrine inj available. Pregnancy (Cat.C).

Nursing mothers: not evaluated.

Interactions: May affect response to live virus vaccines. Concomitant nephrotoxic drugs:

increased risk of acute renal failure. May cause false positive direct or indirect Coombs’ test.

Adverse reactions: Headache, vomiting, fever, nausea, back pain, rash; renal dysfunction (may be fatal), hypersensitivity reactions; rare: hemolytic anemia, aseptic meningitis syndrome (esp. high dose of 2g/kg and/or rapid infusion), TRALI, thrombosis, hyperproteinemia.

Note: Report all infections suspected to be transmitted by Gamunex-C to (800) 520-2807.

How supplied: Vials—1

HELIXATE FS CSL Behring

℞

Clotting factor. Antihemophilic Factor VIII (recombinant) 250 IU, 500 IU, 1000 IU; per bottle; dried concentrate for IV infusion after reconstitution; contains sucrose; preservative-free.

Indications: Prevention and control of hemorrhagic episodes or in order to perform emergency or elective surgery in Hemophilia A patients.

Adults and Children: Dosage Required (IU) = Body Weight (kg) × Desired % Factor VIII Increase × 0.5. Individualize. Infuse over 5–10minutes if tolerated. Minor hemorrhage: 10–20 IU/kg; may repeat dose if needed. Moderate/major hemorrhage or minor surgery: 15–30 IU/kg; may repeat 1 dose at 12–24hrs if needed. Major/ life-threatening hemorrhage, fractures or head trauma: initially 40–50 IU/kg, then 20–25 IU/kg every 8–12hrs. Major surgery: pre-op dose: 50 IU/kg (verify ∼100% activity prior to surgery); may repeat after 6–12hrs initially, and for 10–14 days until completely healed.

Contraindications: Mouse or hamster protein sensitivity.

Warnings/Precautions: Not for treating von Willebrand’s disease. Confirm Factor VIII deficiency prior to treatment. Monitor for development of Factor VIII inhibitors. Pregnancy (Cat.C). Nursing mothers.

Adverse reactions: Inj site reactions, dizziness, rash, dysgeusia, increased BP, pruritus, depersonalization, GI upset, rhinitis; antibody formation, hypersensitivity reactions.

How supplied: Single-use bottle—1 (w. diluent)

HUMATE-P CSL Behring

℞

Clotting factors. Antihemophilic Factor VIII/Von Willebrand Factor Complex (human) 250 IU FVIII + 600 IU VWF, 500 IU FVIII + 1200 IU VWF, 1000 IU FVIII + 2400 IU VWF; per vial; lyophilized pwd for IV infusion after reconstitution; contains albumin.

Indications: Treatment and prevention of bleeding in adults with Hemophilia A. Treatment of spontaneous and trauma-induced bleeding, and prevention of excessive bleeding during and after surgery in adults and children with von Willebrand disease (VWD).

Adults: Max injection rate: 4mL/min. Hemophilia A: Minor bleed: 15 IU FVIII/kg (obtain 30% FVIII increase) once; if needed, may give ½ dose once

or twice daily for 1–2 days. Moderate bleed: initially 25 IU FVIII/kg (obtain 50% FVIII increase), then 15 IU FVIII/kg (maintain 30% FVIII increase) every 8–12hrs for 1–2 days, then repeat dose for 1–2 times daily for a total of 7 days or until healed. Severe bleed: initially 40–50 IU FVIII/kg, then 20–25 IU FVIII/kg every 8hrs (maintain 80–100% FVIII increase) for 7 days, then repeat dose for 1–2 times daily for additional 7 days (maintain 30–50% FVIII increase). VWD: Type 1 (Mild): major bleed: initially 40–60 IU/kg, then 40–50 IU/kg every 8–12hrs for 3 days, then once daily for a total of 7 days. Type 1 (Moderate or severe): minor bleed: 40–50 IU/kg for 1–2 doses; major bleed: initially 50–75 IU/kg, then 40–60 IU/kg every 8–12hrs for 3 days, then once daily for a total of 7 days. Types 2 and 3: minor bleed: 40–50 IU/kg for 1–2 doses; major bleed: initially 60–80 IU/kg, then 40–60 IU/kg every 8–12hrs for 3 days, then once daily for a total of 7 days. For dosing in surgery: see literature.

Children: Max injection rate: 4mL/min. VWD: Type 1 (Mild): major bleed: initially 40–60 IU/kg, then 40–50 IU/kg every 8–12hrs for 3 days, then once daily for a total of 7 days. Type 1 (Moderate or severe): minor bleed: 40–50 IU/kg for 1–2 doses; major bleed: initially 50–75 IU/kg, then 40–60 IU/kg every 8–12hrs for 3 days, then once daily for a total of 7 days. Types 2 and 3: minor bleed: 40–50 IU/kg for 1–2 doses; major bleed: initially 60–80 IU/kg, then 40–60 IU/kg every 8–12hrs for 3 days, then once daily for a total of 7 days. For dosing in surgery: see literature.

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

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DRUG MONOGRAPHS

ASSOCIATED HEMATOLOGICAL DISORDERS major bleeding or need for an urgent surgery/ invasive procedure.

Adults: See full labeling. Administer concomitant Vitamin K. Individualize dosing based on patient’s baseline INR and weight. Potency (units) is defined by Factor IX content. Give by IV Infusion at a rate of 0.12mL/kg/min (∼3 units/kg/min); max rate of 8.4mL/min (∼210 units/min). ≤100kg: Pre-treatment INR: (2–<4): 25 units of Factor IX/kg; max 2500 units; (4–6): 35 units of Factor IX/kg; max 3500 units; (>6): 50 units of Factor IX/kg; max 5000 units. >100kg: do not exceed max dose. Repeat dosing: not recommended.

Children: Not established.

Contraindications: Severe hypersensitivity to heparin, Factors II, VII, IX, X, Proteins C and S, antithrombin III, human albumin. Disseminated intravascular coagulation (DIC). Known heparininduced thrombocytopenia (HIT).

Warnings/Precautions: Risk of arterial and venous thromboembolic complications (may be fatal). History of thromboembolic events within the previous 3 months. Monitor for signs/symptoms of thromboembolic events during and after infusion.

Discontinue immediately if hypersensitivity reactions occur. Measure INR before, during, and after each treatment. Contains human plasma; monitor for possible infection transmission.

Pregnancy (Cat.C). Nursing mothers.

Adverse reactions: Headache, nausea, vomiting, hypotension, anemia; hypersensitivity, thromboembolic events (eg, stroke, PE, DVT).

Note: Report all infections suspected to be transmitted by Kcentra to (866) 915-6958.

How supplied: Kit (500 units, 1000 units)—1 (single-use vial + diluent, supplies)

NEUMEGA Pfizer

℞

Thrombopoietic growth factor (Interleukin-11).

Oprelvekin 5mg/vial; lyophilized pwd for SC inj after reconstitution; preservative-free.

Indications: Prevention of severe thrombocytopenia. To reduce platelet transfusions following myelosuppressive chemotherapy in adults with non-myeloid malignancies who are at high risk of severe thrombocytopenia.

Adults: Initiate 6–24hrs after chemotherapy completion. Give by SC inj into abdomen, thigh, or hip; also upper arm if not self-injecting.

50micrograms/kg once daily until post-nadir platelet count is ≥50,000/microliter; max 21 days.

Discontinue ≥2days prior to next chemotherapy cycle. Severe renal impairment: CrCl <30mL/min: 25micrograms/kg. May give for ≤6 cycles following chemotherapy.

Children: Not recommended.

Warnings/Precautions: Not for use after myeloablative chemotherapy. Monitor fluid balance and electrolytes; increased risk of serious fluid retention with CHF, renal impairment, chronic diuretic or aggressive hydration therapy. Consider draining pre-existing fluid collections (eg, pericardial effusion, ascites).

Obtain CBCs before and during therapy; monitor platelet counts. Pre-existing papilledema or tumors involving the CNS. History of stroke, transient ischemic attack, or atrial arrhythmias.

Effectiveness unknown with chemotherapy regimens >5 days duration or with regimens associated with delayed myelosuppression (eg, nitrosoureas, mitomycin-C). Pregnancy (Cat.C).

Nursing mothers: not recommended.

Adverse reactions: Edema, dyspnea, tachycardia, conjunctival injection, palpitations, atrial arrhythmias, pleural effusions, neutropenic fever, syncope, atrial fibrillation, fever, pneumonia, CHF, pulmonary edema, dilutional anemia, blurred vision, paresthesia, dehydration, skin discoloration, exfoliative dermatitis, eye hemorrhage, stroke, papilledema, hypersensitivity reactions (permanently discontinue if occur).

How supplied: Single-use vials—7 (w. diluent)

NITROPRESS Hospira

℞

Vasodilator. Sodium nitroprusside 25mg/mL; soln for IV infusion after dilution.

Indications: To produce controlled hypotension to reduce surgical bleeding.

Adults and Children: Use infusion pump only.

Monitor BP closely. Initially 0.3microgram/kg/ min; may increase infusion rate every few minutes until desired effect; max 10microgram/kg/min and no more than 10 minutes. Titrate infusion rate (see literature).

Contraindications: Compensatory hypertension due to aortic coarctation or arteriovenous shunting. Inadequate cerebral circulation or moribund patients requiring emergency surgery. Congenital (Lebers) optic atrophy. Tobacco amblyopia. Acute CHF associated with reduced peripheral vascular resistance.

Warnings/Precautions: Use only when available equipment and personnel allow BP to be continuously monitored. Cyanide toxicity possible (esp. at infusion rates >2micrograms/kg/min); monitor acid-base disturbances and venous oxygen concentration. Elevated intracranial pressure. Correct pre-existing anemia and hypovolemia, esp. during anesthesia. Poor surigical risk. Hepatic impairment. Elderly.

Pregnancy (Cat.C). Nursing mothers: not recommended.

Interactions: Hypotensive effect potentiated by ganglionic blocking agents, negative inotropic agents, and inhaled anesthetics.

Adverse reactions: Excessive hypotension, cyanide toxicity, methemoglobinemia, abdominal pain, apprehension, diaphoresis, dizziness, headache, muscle twitch, nausea, palpitations, restlessness, rash, hypothyroidism, ileus, flushing, infusion site reactions.

How supplied: Single-dose vials (2mL)—100

NOVOSEVEN RT Novo Nordisk

℞

Clotting factors. Recombinant Coagulation Factor VIIa (rFVIIa) Room Temperature Stable 1mg, 2mg, 5mg, 8mg; per vial; lyophilized pwd for IV inj after reconstitution; preservative-free.

Indications: Treatment of bleeding and peri-operative management in adults and children with Hemophilia A and B with inhibitors, congenital Factor VII deficiency, and Glanzmann’s thrombasthenia refractory to platelet transfusions, with or without antibodies to platelets. Treatment of bleeding and perioperative management in adults with acquired hemophilia.

Adults and Children: See full labeling. Give

by IV bolus only. Individualize; base treatment schedule modification on hemostasis evaluation.

Hemophilia A or B with inhibitors: Bleeding: 90mcg/kg every 2hrs, adjust until hemostasis is achieved; 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

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DRUG MONOGRAPHS

ASSOCIATED HEMATOLOGICAL DISORDERS 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

(esp. high dose of 2g/kg), hemolysis, TRALI, thrombosis.

How supplied: Single-use vial (50mL, 100mL, 200mL, 400mL)—1

PROMACTA GlaxoSmithKline

℞

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

℞

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.

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ASSOCIATED HEMATOLOGICAL DISORDERS Adverse reactions: Nausea, diarrhea, vomiting, infections, increased ALT/AST, myalgia, pain, pharyngitis, paresthesia, rash, anemia, pyrexia, fatigue, headache, decreased appetite, asthenia, insomnia, cough, pruritus, chills, alopecia, peripheral edema; hepatotoxicity, hemorrhage, thrombotic complications from excessive increases in platelet counts, cataracts.

How supplied: Tabs—30

RECOTHROM ZymoGenetics

℞

Topical hemostatic. Thrombin [recombinant] 5000 IU, 20000 IU; per vial; pwd for topical use after reconstitution; preservative-free.

Indications: Aid to hemostasis for minor bleeding/oozing from capillaries and venules when standard surgical techniques are inadequate or ineffective. May use with absorbable gelatin sponge.

Adults: Apply directly to bleeding area, or soak into absorbable gelatin sponge and apply in a single layer.

Children: Not recommended.

Contraindications: Not for direct injection into circulatory system. Not for treatment of massive or brisk arterial bleeding. Hypersensitivity to hamster proteins.

Warnings/Precautions: Avoid systemic absorption (thrombosis may occur).

Hypersensitivity to snake proteins. Pregnancy (Cat.C).

Adverse reactions: Incision site complication, infection, pain, bleeding, nausea/vomiting, cardiac events, thromboembolic events.

How supplied: Single-use vial (5000 IU, 20000 IU)—1 (w. diluent, supplies) 20000 IU Recothrom kit (co-packaged with ZymoGenetics Spray Applicator Kit)—1

REFACTO Pfizer

℞

Clotting factor. Antihemophilic Factor VIII (recombinant) 250 IU, 500 IU, 1000 IU, 2000 IU; per vial; lyophilized pwd for IV infusion after reconstitution; preservative-free.

Indications: Prevention and control of hemorrhagic episodes and for surgical prophylaxis in Hemophilia A. Short-term routine prophylaxis to reduce frequency of spontaneous bleeding episodes.

Adults and Children: Dosage Required (IU) = Body Weight (kg) × Desired % Factor VIII Increase × 0.5. Individualize. Infuse at rate comfortable to patient. Minor hemorrhage: obtain 20–40% FVIII increase; give every 12–24hrs for at least 1 day until resolved. Moderate hemorrhage and tooth extraction: obtain 30–60% FVIII increase; give every 12–24hrs for 3–4 days until adequate

hemostasis; for tooth extraction: a single infusion plus oral antifibrinolytic therapy within 1hr may be sufficient. Major hemorrhage: obtain 60–100% FVIII increase; give every 8–24hrs until resolved; or, for surgery, until local hemostasis achieved.

Prophylaxis: give ≥2 times weekly; children may need shorter dosage intervals or higher doses.

Contraindications: Mouse or hamster protein sensitivity.

Warnings/Precautions: Not for von Willebrand’s disease. Confirm Factor VIII deficiency prior to treatment. Monitor for development of Factor VIII inhibitors. Pregnancy (Cat.C). Nursing mothers.

Adverse reactions: Allergic reactions, headache, fever, chills, flushing, nausea, vomiting, lethargy, pruritus, antibody formation.

How supplied: Single-use vial—1 (w. diluent, supplies)

RHOPHYLAC CSL Behring

℞

Rho (D) immune globulin human 1500 IU (300mcg)/2mL; syringe; for IV or IM inj; preservative- and latex-free; contains albumin (human); solvent/detergent treated.

Indications: Raising platelet counts in Rho (D) positive non-splenectomized patients with chronic immune thrombocytopenic purpura (ITP).

Adults: See full labeling. 250 IU (50mcg) per kg

by IV only at rate of 2mL per 15–60 secs.

Children: Not recommended.

Contraindications: Rho (D) positive patients.

IgA deficiency.

Warnings/Precautions: Monitor patients 20 mins after administration. Pregnancy (Cat.C).

Interactions: Do not give live vaccines within 3 months.

Adverse reactions: Local or infusion reactions, fever, chills, headache; see full labeling.

How supplied: Single-dose prefilled syringes—1, 10

RIASTAP CSL Behring

℞

Hemostatic. Fibrinogen concentrate (human) 900–1300mg; per vial; lyophilized pwd for IV inj after reconstitution; contains albumin; preservative-free.

Indications: Acute bleeding episodes in patients with congenital fibrinogen deficiency, including afibrinogenemia and hypofibrinogenemia.

Adults and Children: See literature. Give by slow IV inj at rate not exceeding 5mL/min.

Individualize. Calculate dose when baseline fibrinogen level is known: Dose (mg/kg body wt) = [Target level (mg/dL)–measured level (mg/dL)]/1.7 (mg/dL per mg/kg body wt).

When baseline fibrinogen level is not known: 70mg/kg. Monitor fibrinogen level during therapy.

Maintain target fibrinogen level of 100mg/dL until hemostatis is obtained.

Warnings/Precautions: Not for use in dysfibrinogenemia. Monitor for allergic or hypersensitivity reactions; discontinue if occur. Risk of thrombosis (monitor). Contains human plasma; monitor for possible infection transmission. Labor & delivery. Pregnancy (Cat.C). Nursing mothers.

Adverse reactions: Fever, headache, chills, nausea, vomiting; thrombotic episodes (eg, pulmonary embolism, MI, DVT), anaphylactic reactions.

How supplied: Single-use vial—1

THROMBIN-JMI Pfizer

℞

Topical hemostatic. Thrombin [bovine origin] 5000 IU, 20000 IU; per vial; pwd for topical use after reconstitution; preservative-free.

Indications: Aid to hemostasis for oozing blood and minor bleeding from accessible capillaries and small venules. Adjunct for surgical hemostasis with absorbable gelatin sponge.

Adults: For topical use only. See literature. Profuse bleeding (eg, abraided surfaces of liver or spleen): 1000 IU/mL. General use (eg, plastic surgery, dental extractions, skin grafting): 100 IU/mL. May dilute to prepare intermediate strengths, if needed. Oozing surfaces: may use dry form.

Children: Not recommended.

Warnings/Precautions: Not for injection or use in large blood vessels. Antibody formation: do not re-expose, abnormalities in hemostasis (eg, severe bleeding or thrombosis) more likely with repeated use. Pregnancy (Cat.C). Nursing mothers.

Adverse reactions: Hypersensitivity reactions, antibody formation.

How supplied: Vials—1 (w. diluent) Pump Spray Kit (20000 IU)—1 (w. diluent) Syringe Spray Kit (20000 IU)—1 (w. diluent) Epistaxis Kit (5000 IU)—1 (w. diluent)

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.

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ASSOCIATED HEMATOLOGICAL DISORDERS 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)

White blood cell disorders

GRANIX Teva

℞

Granulocyte colony stimulating factor. Tbofilgrastim 300mcg/0.5mL, 480mcg/0.8mL; soln for SC inj; preservative-free.

Indications: To reduce the duration of severe neutropenia in patients with non-myeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia.

Adults: Administer the 1st dose no earlier than 24hrs following myelosuppressive chemotherapy.

Do not administer within 24hrs prior to chemotherapy. Inject 5mcg/kg SC once daily until expected neutrophil nadir is passed and neutrophil count has recovered to normal range. Monitor CBC prior to chemotherapy and twice per week until recovery. Recommended inj sites: the abdomen (except for the 2-inch area around navel), the front of the middle thighs, the upper outer area of the buttocks, or the upper back portion of the upper arms; rotate inj site daily. Avoid injecting into an area that is tender, red, bruised or hard, or that has scars or stretch marks.

Children: <18yrs: not established.

Warnings/Precautions: Risk of splenic rupture; discontinue and evaluate if symptoms of enlarged spleen or rupture occur. Evaluate for acute respiratory distress syndrome if fever and lung infiltrates or respiratory distress develop after treatment; discontinue if acute respiratory distress syndrome is diagnosed. Permanently discontinue if serious allergic reactions occur. Sickle cell disease: consider potential risks and benefits prior to treatment and discontinue if sickle cell crisis develops. Hepatic or moderate-to-severe renal impairment. Pregnancy (Cat.C). Nursing mothers.

Interactions: Caution with drugs that may potentiate release of neutrophils (eg, lithium).

May cause transient positive changes in boneimaging test results.

Adverse reactions: Bone pain; splenic rupture (may be fatal), acute respiratory distress syndrome, serious allergic reactions, sickle cell crisis, potential for tumor growth stimulatory effects on malignant cells.

How supplied: Single-use prefilled syringe (0.5mL, 0.8mL)—1, 10 (w. safety needle guard)

LEUKINE Genzyme

℞

Granulocyte-macrophage colony stimulating factor (recombinant). Sargramostim (recombinant human granulocyte-macrophage colony stimulating factor, or rhu GM-CSF) 250mcg; per vial; pwd for SC inj or IV infusion after reconstitution; preservative-free.

Indications: To speed neutrophil recovery and reduce infections after induction chemotherapy in treatment of acute myelogenous leukemia (AML) in patients >55 years of age. To mobilize hematopoietic progenitor cells into peripheral blood for collection by leukapheresis. To speed myeloid recovery in 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

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ASSOCIATED HEMATOLOGICAL DISORDERS 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; for SC inj or IV infusion; preservative-free.

℞ Also: NEUPOGEN VIALS Filgrastim 300mcg/mL; for SC or IV infusion; preservative-free.

Indications: See full labeling. To decrease incidence of infection in patients with nonmyeloid malignancies receiving certain myelosuppressive anti-cancer drugs. To reduce time to neutrophil recovery and fever duration after induction or consolidation chemotherapy treatment of adults with AML. To reduce duration of neutropenia and related sequelae in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by bonemarrow transplantation (BMT). To mobilize hematopoietic progenitor cells (PBPC) into peripheral blood for collection by leukapheresis.

To reduce the incidence and duration of neutropenia sequelae in severe chronic neutropenia (SCN).

Adults: See full labeling. Do not give for at least 24hrs before or after cytotoxic chemotherapy dose. BMT: Give 1st dose at least 24hrs after bone marrow infusion. SCN: Give on a daily basis.

Children: See full labeling.

Contraindications: Hypersensitivity to E. coliderived products.

Warnings/Precautions: Monitor blood, including CBC and differential and platelets, before and during therapy (myelosuppressive chemotherapy: monitor twice weekly; BMT: at least 3 times weekly; SCN: twice per week during initial 4 weeks of therapy and during 2 weeks after dose adjustment). Discontinue if post nadir absolute neutrophil count (ANC) reaches 10,000/mm3 for patients receiving myelosuppressive chemotherapy; other indications: see full labeling. Monitor for splenomegaly/splenic rupture and for acute respiratory distress syndrome (ARDS); suspend until ARDS resolves if fever or lung infiltrates occur. Confirm diagnosis and do appropriate pretreatment hematological workup in SCN. Preexisting cardiac or hyperplastic skin conditions. Sickle cell disease (may cause sickle cell crisis). Avoid simultaneous chemo- and radiation therapy. Pregnancy (Cat.C). Nursing mothers.

Interactions: Caution with mitomycin C, and with concomitant (same day) drugs that decrease platelets, or increase release of neutrophils (eg, lithium), or cause delayed myelosuppression, or with myelosuppressive doses of antimetabolites (eg, nitrosoureas, 5-FU).

Adverse reactions: Bone pain, cutaneous vasculitis, splenomegaly, others (see literature).

How supplied: Prefilled syringes (0.5mL, 0.8mL)—10; Vials (1mL, 1.6mL)—10

ZARXIO Sandoz

℞

Granulocyte colony stimulating factor. Filgrastimsndz 300mcg/0.5mL, 480mcg/0.8mL; for SC inj or IV infusion; preservative-free.

Indications: See full labeling. To decrease incidence of infection in patients with nonmyeloid malignancies receiving certain myelosuppressive anti-cancer drugs. To reduce time to neutrophil recovery and fever duration after induction or consolidation chemotherapy treatment of adults with AML. To reduce duration of neutropenia and related sequelae in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by bone-marrow transplantation (BMT). To mobilize hematopoietic progenitor cells (PBPC) into peripheral blood for collection by leukapheresis. To reduce the incidence and duration of neutropenia sequelae in severe chronic neutropenia (SCN).

Adults: See full labeling. Do not give for at least 24hrs before or after cytotoxic chemotherapy dose. BMT: Give 1st dose at least 24hrs after bone marrow infusion. SCN: Give on a daily basis.

Children: See full labeling.

Warnings/Precautions: Monitor blood, including CBC and differential and platelets, before and during therapy (myelosuppressive chemotherapy: monitor twice weekly; BMT: monitor frequently; SCN: monitor during initial 4 weeks of therapy and during 2 weeks after dose adjustment) then monthly for the 1st year.

Discontinue if post nadir absolute neutrophil count (ANC) reaches 10,000/mm3 for patients receiving myelosuppressive chemotherapy; other indications: see full labeling. Monitor for splenomegaly/splenic rupture and for acute respiratory distress syndrome (ARDS); discontinue if ARDS occurs. Confirm diagnosis and do appropriate pretreatment hematological workup in SCN. Permanently discontinue if serious allergic reactions occur. Sickle cell disease (may cause sickle cell crisis). Abnormal cytogenetics or myelodysplastic syndrome.

Chronic myeloid leukemia. Hold dose if cutaneous vasculitis occurs; resume at reduced dose after symptoms resolve and the ANC decreased. Avoid simultaneous chemo- and radiation therapy. Latex allergy. Pregnancy (Cat.C). Nursing mothers.

Interactions: May cause transient (+) boneimaging results.

Adverse reactions: Pyrexia, pain, rash, cough, dyspnea, epistaxis, bone pain, headache, anemia, diarrhea, hypoesthesia, alopecia; capillary leak syndrome (monitor), thrombocytopenia.

How supplied: Single-use prefilled syringes (0.5mL, 0.8mL)—1, 10 (w. needle guard)

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DRUG MONOGRAPHS

ASSOCIATED HEMATOLOGICAL DISORDERS Miscellaneous hematological agents

CINRYZE ViroPharma

℞

C1 inhibitor. C1 inhibitor (human) 500 Units/vial; lyophilized pwd for IV infusion after reconstitution; preservative-free.

Indications: Routine prophylaxis against angioedema attacks in adolescent and adult patients with hereditary angioedema.

Adults: Give by IV infusion at a rate of 1mL/min (10mins). 1000 Units every 3–4 days.

Children: Not recommended.

Warnings/Precautions: Contains human plasma; monitor for possible infection transmission. Have epinephrine available to treat hypersensitivity reactions. Monitor patients with known risk factors for thrombotic events. Labor & delivery. Pregnancy (Cat.C). Nursing mothers.

Adverse reactions: Upper respiratory tract infection, sinusitis, rash, headache; thrombotic events, hypersensitivity reactions (may be severe); discontinue if occurs.

Note: To report infections that may have been transmitted by Cinryze, call CinryzeSolutions at (877) 945-1000.

How supplied: Single-use vial—1

EXJADE Novartis

℞

Iron chelating agent. Deferasirox 125mg, 250mg, 500mg; tabs for oral susp.

Indications: Chronic iron overload due to blood transfusions in patients ≥2yrs of age. Chronic iron overload in patients ≥10yrs of age with non-transfusion dependent thalassemia (NTDT) syndromes and with a liver iron concentration (LIC) of at least 5mg Fe per gram of dry weight and a serum ferritin >300 mcg/L. Adults and Children: Calculate dose to nearest whole tab. Take on empty stomach at least 30 mins before food. Do not chew or swallow tabs; disperse completely in water, orange juice or apple juice; drink immediately; resuspend remainder and drink.

Transfusional iron overload: <2yrs: not established. ≥2yrs: initially 20mg/kg once daily; may adjust dose by 5 or 10mg/kg every 3–6 months based on serum ferritin levels or response. If inadequate control at 30mg/kg, may consider increasing up to max 40mg/kg. Adjust dose if severe skin rashes occur; consider suspending therapy if serum ferritin <500mcg/L. NTDT syndromes: <10yrs: not established. ≥10yrs: initially 10mg/kg once daily; if baseline LIC>15mg Fe/g dw, consider increasing dose to 20mg/kg after 4 weeks. Suspend therapy if serum ferritin <300mcg/L and obtain LIC to determine whether it has fallen to <3mg Fe/g dw. After 6 months, if LIC remains >7mg Fe/g

dw, increase dose to max 20mg/kg/day. If after 6 months, LIC is 3–7mg Fe/g dw, continue with max 10mg/kg/day. When LIC is <3mg Fe/g dw, interrupt treatment and continue to monitor LIC. Restart when LIC rises again to >5mg Fe/g dw.

Adjustments based on serum creatinine: see full labeling. Hepatic impairment: moderate: reduce dose by 50%; severe: avoid.

Contraindications: CrCl <40mL/min or serum creatinine >2x age-appropriate ULN. Poor performance status. High risk myelodysplastic syndromes.

Advanced malignancies. Platelets <50×109/L. Warnings/Precautions: May cause renal or hepatic failure, GI hemorrhage; may be fatal (monitor). Hepatic or renal impairment. Advanced disease or co-morbid conditions. Obtain baseline serum ferritin level, monitor monthly and adjust dose accordingly. Measure serum creatinine and CrCl in duplicate before starting therapy; monitor weekly during 1st month then at least monthly thereafter; more frequently if creatinine levels increase. Monitor for proteinuria monthly. Measure serum transaminases, bilirubin before initiating therapy then every 2 weeks during 1st month, then monthly. Monitor blood counts; interrupt therapy if cytopenias develop. For NTDT syndromes: obtain LIC by liver biopsy prior to starting therapy, monitor LIC every 6 months. Do baseline auditory and ocular exams, then every 12 months; if disturbances occur, adjust dose or suspend therapy. Elderly. Pregnancy (Cat.C). Nursing mothers: not recommended.

Interactions: Avoid aluminum-containing antacids, bile acid sequestrants (eg, cholestyramine, colesevelam, colestipol), or UGT inducers (eg, rifampicin, phenytoin, phenobarbital, ritonavir); if co-administration necessary consider increasing initial Exjade dose by 50% and monitor serum ferritin levels and clinical responses. Caution with drugs that have ulcerogenic or hemorrhagic potential (eg, NSAIDs, corticosteroids, oral bisphosphonates, anticoagulants) or drugs metabolized by CYP3A4 (eg, cyclosporine, simvastatin, hormonal contraceptives). Potentiates repaglinide (consider reducing repaglinide dose); monitor blood glucose levels. Caution with other CYP2C8 substrates (eg, paclitaxel). Avoid concomitant theophylline or other CYP1A2 substrates with narrow therapeutic index. Concomitant other iron chelation therapy: not recommended.

Adverse reactions: Diarrhea, vomiting, nausea, abdominal pain, elevated serum creatinine, rash; renal or hepatic impairment/failure (may be fatal), GI hemorrhage, cytopenias (eg, agranulocytosis, neutropenia, thrombocytopenia, anemia), hypersensitivity reactions, severe skin reactions (eg, Stevens-Johnson syndrome, erythema multiforme); discontinue if occurs.

How supplied: Tabs—30

FERRIPROX ApoPharma

℞

Iron chelating agent. Deferiprone 500mg; scored tabs.

Indications: Treatment of transfusional iron overload due to thalassemia syndromes when current chelation therapy is inadequate. Limitations of use: not for use in treating other chronic anemias.

Adults: Individualize. Initially 25mg/kg three times daily (total dose 75mg/kg/day). Max: 33mg/kg three times daily (total dose 99mg/kg/day). Round dose to the nearest 250mg (half-tablet). Adjust dose to individual response and therapeutic goals.

Consider temporary dose interruption if serum ferritin falls consistently <500mcg/L. Children: Not established.

Warnings/Precautions: Risk of neutropenia or fatal agranulocytosis. Measure ANC before starting therapy and monitor weekly during.

Interrupt therapy if infection or neutropenia develops (ANC <1.5×109/L). If neutropenia occurs, obtain CBCs, WBCs, ANC, and platelets daily until recovery (ANC ≥1.5×109/L). Monitor serum ALT monthly; consider interruption if persistent increase in transaminase levels.

Monitor serum ferritin every 2–3 months. Monitor plasma zinc, supplement if deficient. Severe hepatic impairment. Elderly. Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended.

Interactions: Avoid concomitant use with other drugs associated with neutropenia or agranulocytosis. Allow at least 4-hour interval with antacids or mineral supplements containing polyvalent cations (eg, iron, aluminum, zinc).

Concomitant UGT 1A6 inhibitors: closely monitor and may need dose adjustments or interruptions.

Adverse reactions: Chromaturia, GI upset, abdominal pain, increased ALT, arthralgia, neutropenia; agranulocytosis.

Note: This product is available from Centric Health Resources (CHR). CHR is a specialty pharmacy specializing in orphan drugs and is the sole distributor of Ferriprox in the U.S. For more information, contact Ferriprox Total Care at (866) 758-7071.

How supplied: Tabs—100

FIRAZYR Shire

℞

Bradykinin B2 receptor antagonist. Icatibant 10mg/mL; soln for SC inj; preservative-free.

Indications: Treatment of acute attacks of hereditary angioedema.

Adults: ≥18yrs: 30mg SC in abdominal area; may give additional doses at intervals of at least 6 hours if response inadequate or symptoms recur. Max 3 doses/24hrs.

Children: <18yrs: not recommended.

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DRUG MONOGRAPHS

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

2.0–9.5min

Erythrocyte count • Male • Female

4.50–5.90 × 106/mm3 4.00–5.20 × 106/mm3

4.50–5.90 × 1012/L 4.00–5.20 × 1012/L

Erythrocyte sedimentation rate • Male • Female

0–17mm/hr 1–25mm/hr

0–17mm/hr 1–25mm/hr

Ferritin • Male • Female

30–300ng/mL 10–200ng/mL

30–300μg/L 10–200μg/L

Fibrinogen

150–400mg/dL

1.50–4.00g/L

Folate (folic acid) • Normal • Borderline deficient • Deficient • Excess

3.1–17.5ng/mL 2.2–3.0ng/mL <2.2ng/mL >17.5ng/mL

7.0–39.7nmol/L 5.0–6.8nmol/L <5.0nmol/L >39.7nmol/L

Folic acid

150–450ng/mL/cells

340–1020nmol/L/cells

Hematocrit • Male • Female

41.0–53.0% 36.0–46.0%

0.41–0.53 0.36–0.46

Hemoglobin • Plasma • Whole blood, male • Whole blood, female

1–5mg/dL 13.5–17.5g/dL 12.0–16.0g/dL

0.01–0.05g/L 8.4–10.9mmol/L 7.4–9.9mmol/L

Hemoglobin electrophoresis • Hemoglobin A • Hemoglobin A1c • Hemoglobin A2 • Hemoglobin F • Hemoglobins other than A, A2, or F

95–98% 3.8–6.4% 1.5–3.5% 0–2.0% Absent

0.95–0.98 0.038–0.064Hg fraction 0.015–0.035 0–0.02 Absent

Iron (hematology and coagulation values)

30–160μg/dL

5.4–28.7μmol/L

Iron-binding capacity (hematology and coagulation values)

228–428μg/dL

40.8–76.7μmol/L

Iron (clinical chemistry values)

50–150μg/dL

9–27μmol/L

Iron-binding capacity (clinical chemistry values)

250–370μg/dL

45–66μmol/L

Leukocyte count (WBC)

4.5–11.0 × 103/mm3

4.5–11 × 109/L

Mean corpuscular hemoglobin (MCH)

26.0–34.0pg/cell

26.0–34.0pg/cell

Mean corpuscular hemoglobin concentration (MCHC)

31.0–37.0g/dL

310–370g/L

Mean corpuscular volume (MCV)

80–100μm3

80–100fl

Partial-thromboplastin time (activated)

22.1–35.1sec

22.1–35.1sec

Platelet count

150–350 × 103/mm3

150–350 × 109/L

Prothrombin time

11.1–13.1sec

11.1–13.1sec

Reticulocyte count

0.5–2.5% red cells

0.005–0.025 red cells

Transferrin

230–390mg/dL

2.3–3.9g/L

Vitamin B12 • Normal • Borderline • Deficient

>250pg/mL 125–250pg/mL <125pg/mL

>185pmol/L 92–185pmol/L <92pmol/L

References National Institutes of Health. Third report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). September 2002. Available at: www.nhlbi.

(Rev. 8/2012) nih.gov/guidelines/cholesterol/index.htm. Accessed August 2012.

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