Cancer Therapy Advisor January/February 2018 Issue

JANUARY/FEBRUARY 2018 | VOL 4, ISSUE 3

CancerTherapyAdvisor.com

CancerTherapyAdvisor

A20 FEATURE

The Warburg Effect: Can Cancer Be Starved of Sugar?

A recent study may be helping to identify a therapeutic route to starve tumors of sugar without killing normal cells.

FEATURING Cancer Therapy Regimens and Oncology Drug Monographs from

1 Bone Cancer



3 Brain Cancer

 14 Breast Cancer 26 Endocrine Cancer

A9 LATEST NEWS

Headlines in oncology research, including data from the 2017 ASH Annual Meeting

 30 Gastrointestinal Cancer  40 Genitourinary Cancer 51 Gynecologic Cancer

A22 VIEWPOINT

53 Head and Neck Cancer

Beta-blockers May Prevent Stress-induced Lung Cancer Treatment Resistance

55 Hematologic Cancer 76 Lung Cancer

JANUARY/FEBRUARY 2018 | VOL 4, ISSUE 3

83 Sarcoma

A24 EXPERT PERSPECTIVE

Cancer Drug Addiction: Prospects for Integrated Therapeutic Management

A19 IN THE CLINIC Monitoring for Post–organ Transplant Skin Cancer

84 Skin Cancer



Regimen included

B:16.125” T:15.5” S:14.25”

For mCRPC patients with symptomatic bone metastases1

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

1,2a

S I G N I F I C A N T LY E X T E N D OV E R A L L S U R V I VA L ( OS ) MME EDDI AI ANNOOSSWI INT HA NO RE XWP ILTOHROAT U TO RC YO NA CNOA M LYIST A I SN1,2b T U S E O F A B I R AT E R O N E 9 a 100

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

Probability of survival (%)

90

14.9 MONTHS

Planned course of Xofigo treatment is 6 doses

80 70 60 50 40

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

30 %

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

11.3 MONTHS

30

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

20 10 0 0

3

6

9

12

15

18

21

24

27

30

33

36

39

41 14

18 7

7 4

1 2

0 1

0 0

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

578 288

504 228

369 157

277 104

178 67

105 39

60 24

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

a

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

with myelosuppression were observed in 1% of Xofigo-treated patients compared to 0.3% of patients treated with placebo.

The incidence of infection-related deaths (2%), serious infections (10%), and febrile neutropenia (<1%) was similar for patients treated with Xofigo and placebo. Myelosuppression— notably thrombocytopenia, neutropenia, pancytopenia, and leukopenia—has been reported in patients treated with Xofigo.

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

S:10”

mCRPC=Metastatic Castration-Resistant Prostate Cancer.

– P=0.00185; Hazard ratio [HR]=0.695 (95% CI: 0.552-0.875)

peripheral edema (13% vs 10%). Grade 3 and 4 adverse • Concomitant Use With Chemotherapy: Safety and efficacy of events were reported in 57% of Xofigo-treated patients concomitant chemotherapy with Xofigo have not been established. and 63% of placebo-treated patients. The most common Outside of a clinical trial, concomitant use of Xofigo in patients on chemotherapy is not recommended due to the potential for additive hematologic laboratory abnormalities in the Xofigo arm (≥10%) vs the placebo arm, respectively, were myelosuppression. If chemotherapy, other systemic radioisotopes, anemia (93% vs 88%), lymphocytopenia (72% vs 53%), or hemibody external radiotherapy are administered during the leukopenia (35% vs 10%), thrombocytopenia (31% vs 22%), treatment period, Xofigo should be discontinued and neutropenia (18% vs 5%) • Administration and Radiation Protection: Xofigo should be received, used, and administered only by authorized persons References: 1. Xofigo® (radium Ra 223 dichloride) injection [prescribing information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc.; in designated clinical settings. The administration of Xofigo is March 2016. 2. Parker C, Nilsson S, Heinrich D, et al; ALSYMPCA associated with potential risks to other persons from radiation or Investigators. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369(3):213-223. contamination from spills of bodily fluids such as urine, feces, or vomit. Therefore, radiation protection precautions must be taken Please see following pages for brief summary of in accordance with national and local regulations full Prescribing Information.

• Adverse Reactions: The most common adverse reactions (≥10%) in the Xofigo arm vs the placebo arm, respectively, were nausea (36% vs 35%), diarrhea (25% vs 15%), vomiting (19% vs 14%), and

radium Ra 223 dichloride INJECTION

© 2017 Bayer. All rights reserved.

BAYER, the Bayer Cross, and Xofigo are registered trademarks of Bayer.

PP-600-US-2892 05/17 Printed in USA

FS:7”

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

FS:7”

F:7.75”

F:7.75”

PP-600-US-2892_HCP_JA_Std_Re_FR.indd 1

5/4/17 1:43 PM

PREPARED BY AREA 23 Job #: 10766017 Client: BAYER

Releasing as: PDF-X1a Colors: 4C

Product: XOFIGO

Live: 7" x 10”

Client Code: PP-600-US-2892

Trim: 7.75"w x 10.5"h

Date: May 4, 2017 1:42 PM

Bleed: 8.375"w x 11.125"h

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BioPharm Cover Wrap Resize

T:10.5”

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

• Evaluated in a double-blind, randomized, placebo-controlled phase 3 clinical trial of 921 patients with castration-resistant prostate cancer (CRPC) with symptomatic bone metastases1 • Prespecified interim analysis: median OS was 14.0 months for Xofigo (95% Conf idence interval [CI]: 12.1-15.8) vs 11.2 months for placebo (95% CI: 9.0-13.2)1

B:11.125”

b

B:16.125” T:15.5” S:14.25”

For mCRPC patients with symptomatic bone metastases1

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

1,2a

S I G N I F I C A N T LY E X T E N D OV E R A L L S U R V I VA L ( OS ) MME EDDI AI ANNOOSSWI INT HA NO RE XWP ILTOHROAT U TO RC YO NA CNOA M LYIST A I SN1,2b T U S E O F A B I R AT E R O N E 9 a 100

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

Probability of survival (%)

90

14.9 MONTHS

Planned course of Xofigo treatment is 6 doses

80 70 60 50 40

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

30 %

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

11.3 MONTHS

30

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

20 10 0 0

3

6

9

12

15

18

21

24

27

30

33

36

39

41 14

18 7

7 4

1 2

0 1

0 0

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

578 288

504 228

369 157

277 104

178 67

105 39

60 24

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

a

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

with myelosuppression were observed in 1% of Xofigo-treated patients compared to 0.3% of patients treated with placebo.

The incidence of infection-related deaths (2%), serious infections (10%), and febrile neutropenia (<1%) was similar for patients treated with Xofigo and placebo. Myelosuppression— notably thrombocytopenia, neutropenia, pancytopenia, and leukopenia—has been reported in patients treated with Xofigo.

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

S:10”

mCRPC=Metastatic Castration-Resistant Prostate Cancer.

– P=0.00185; Hazard ratio [HR]=0.695 (95% CI: 0.552-0.875)

peripheral edema (13% vs 10%). Grade 3 and 4 adverse • Concomitant Use With Chemotherapy: Safety and efficacy of events were reported in 57% of Xofigo-treated patients concomitant chemotherapy with Xofigo have not been established. and 63% of placebo-treated patients. The most common Outside of a clinical trial, concomitant use of Xofigo in patients on chemotherapy is not recommended due to the potential for additive hematologic laboratory abnormalities in the Xofigo arm (≥10%) vs the placebo arm, respectively, were myelosuppression. If chemotherapy, other systemic radioisotopes, anemia (93% vs 88%), lymphocytopenia (72% vs 53%), or hemibody external radiotherapy are administered during the leukopenia (35% vs 10%), thrombocytopenia (31% vs 22%), treatment period, Xofigo should be discontinued and neutropenia (18% vs 5%) • Administration and Radiation Protection: Xofigo should be received, used, and administered only by authorized persons References: 1. Xofigo® (radium Ra 223 dichloride) injection [prescribing information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc.; in designated clinical settings. The administration of Xofigo is March 2016. 2. Parker C, Nilsson S, Heinrich D, et al; ALSYMPCA associated with potential risks to other persons from radiation or Investigators. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369(3):213-223. contamination from spills of bodily fluids such as urine, feces, or vomit. Therefore, radiation protection precautions must be taken Please see following pages for brief summary of in accordance with national and local regulations full Prescribing Information.

• Adverse Reactions: The most common adverse reactions (≥10%) in the Xofigo arm vs the placebo arm, respectively, were nausea (36% vs 35%), diarrhea (25% vs 15%), vomiting (19% vs 14%), and

radium Ra 223 dichloride INJECTION

© 2017 Bayer. All rights reserved.

BAYER, the Bayer Cross, and Xofigo are registered trademarks of Bayer.

PP-600-US-2892 05/17 Printed in USA

FS:7”

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

FS:7”

F:7.75”

F:7.75”

PP-600-US-2892_HCP_JA_Std_Re_FR.indd 1

5/4/17 1:43 PM

PREPARED BY AREA 23 Job #: 10766017 Client: BAYER

Releasing as: PDF-X1a Colors: 4C

Product: XOFIGO

Live: 7" x 10”

Client Code: PP-600-US-2892

Trim: 7.75"w x 10.5"h

Date: May 4, 2017 1:42 PM

Bleed: 8.375"w x 11.125"h

Production: Laurette Mercer x2664 AD: AE: Producer: Pearle x6840 Digital Artist: CL, LA

Gutter: 0.125”

Proof: FR

Fonts: Meta Pro

M1 Spellcheck: CC FR Spellcheck: GT

Path: Area23:Bayer:Xofigo:10766017:Packaged_Jobs:PP-600-US-2892_HCP_JA_Std_Re_FR:PP-600-US-2892_HCP_JA_Std_Re_FR 4C

BioPharm Cover Wrap Resize

T:10.5”

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

• Evaluated in a double-blind, randomized, placebo-controlled phase 3 clinical trial of 921 patients with castration-resistant prostate cancer (CRPC) with symptomatic bone metastases1 • Prespecified interim analysis: median OS was 14.0 months for Xofigo (95% Conf idence interval [CI]: 12.1-15.8) vs 11.2 months for placebo (95% CI: 9.0-13.2)1

B:11.125”

b

XOFIGO (radium Ra 223 dichloride) Injection, for intravenous use Initial U.S. Approval: 2013 BRIEF SUMMARY oF pREScRIBIng InFoRMAtIon conSULt pAcKAgE InSERt FoR FULL pREScRIBIng InFoRMAtIon 1 INDICATIONS AND USAGE Xofigo® is indicated for the treatment of patients with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastatic disease.

2 DOSAGE AND ADMINISTRATION 2.3 Instructions for Use/Handling General warning Xofigo (an alpha particle-emitting pharmaceutical) should be received, used and administered only by authorized persons in designated clinical settings. The receipt, storage, use, transfer and disposal Xofigo are subject to the regulations and/or appropriate licenses of the competent official organization.

Xofigo should be handled by the user in a manner which satisfies both radiation safety and pharmaceutical quality requirements. Appropriate aseptic precautions should be taken.

Radiation protection The administration of Xofigo is associated with potential risks to other persons (e.g., medical staff, caregivers and patient’s household members) from radiation or contamination from spills of bodily fluids such as urine, feces, or vomit.

Therefore, radiation protection precautions must be taken in accordance with national and local regulations.

For drug handling Follow the normal working procedures for the handling of radiopharmaceuticals and use universal precautions for handling and administration such as gloves and barrier gowns when handling blood and bodily fluids to avoid contamination. In case of contact with skin or eyes, the affected area should be flushed immediately with water. In the event of spillage of Xofigo, the local radiation safety officer should be contacted immediately to initiate the necessary measurements and required procedures to decontaminate the area. A complexing agent such as 0.01 M ethylene-diamine-tetraacetic acid (EDTA) solution is recommended to remove contamination.

For patient care Whenever possible, patients should use a toilet and the toilet should be flushed several times after each use. When handling bodily fluids, simply wearing gloves and hand washing will protect caregivers. Clothing soiled with Xofigo or patient fecal matter or urine should be washed promptly and separately from other clothing.

Radium-223 is primarily an alpha emitter, with a 95.3% fraction of energy emitted as alpha-particles. The fraction emitted as beta-particles is 3.6%, and the fraction emitted as gamma-radiation is 1.1%. The external radiation exposure associated with handling of patient doses is expected to be low, because the typical treatment activity will be below 8,000 kBq (216 microcurie). In keeping with the As Low As Reasonably Achievable (ALARA) principle for minimization of radiation exposure, it is recommended to minimize the time spent in radiation areas, to maximize the distance to radiation sources, and to use adequate shielding. Any unused product or materials used in connection with the preparation or administration are to be treated as radioactive waste and should be disposed of in accordance with local regulations.

The gamma radiation associated with the decay of radium-223 and its daughters allows for the radioactivity measurement of Xofigo and the detection of contamination with standard instruments.

4 CONTRAINDICATIONS Xofigo is contraindicated in pregnancy.

Xofigo can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Xofigo is not indicated for use in women. Xofigo is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus [see Use in Specific Populations (8.1)].

5 WARNINGS AND PRECAUTIONS 5.1 Bone Marrow Suppression In the randomized trial, 2% of patients on the Xofigo arm experienced bone marrow failure or ongoing pancytopenia compared to no patients treated with placebo. There were two deaths due to bone marrow failure and for 7 of 13 patients treated with Xofigo, bone marrow failure was ongoing at the time of death. Among the 13 patients who experienced bone marrow failure, 54% required blood transfusions. Four percent (4%) of patients on the Xofigo arm and 2% on the placebo arm permanently discontinued therapy due to bone marrow suppression.

In the randomized trial, deaths related to vascular hemorrhage in association with myelosuppression were observed in 1% of Xofigo-treated patients compared to 0.3% of patients treated with placebo. The incidence of infectionrelated deaths (2%), serious infections (10%), and febrile neutropenia (<1%) were similar for patients treated with Xofigo and placebo. Myelosuppression; notably thrombocytopenia, neutropenia, pancytopenia, and leukopenia; has been reported in patients treated with Xofigo. In the randomized trial, complete blood counts (CBCs) were obtained every 4 weeks prior to each dose and the nadir CBCs and times of recovery were not well characterized. In a separate singledose phase 1 study of Xofigo, neutrophil and platelet count nadirs occurred 2 to 3 weeks after Xofigo administration at doses that were up to 1 to 5 times the recommended dose, and most patients recovered approximately 6 to 8 weeks after administration [see Adverse Reactions (6)].

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

Hematologic evaluation of patients must be performed at baseline and prior to every dose of Xofigo. Before the first administration of Xofigo, the absolute neutrophil count (ANC) should be ≥ 1.5 x 109/L, the platelet count ≥ 100 x 109/L and hemoglobin ≥ 10 g/dL. Before subsequent administrations of Xofigo, the ANC should be ≥ 1 x 109/L and the platelet count ≥ 50 x 109/L. If there is no recovery to these values within 6 to 8 weeks after the last administration of Xofigo, despite receiving supportive care, further treatment with Xofigo should be discontinued. Patients with evidence of compromised bone marrow reserve should be monitored closely and provided with supportive care measures when clinically indicated. Discontinue Xofigo in patients who experience lifethreatening complications despite supportive care for bone marrow failure.

The safety and efficacy of concomitant chemotherapy with Xofigo have not been established. Outside of a clinical trial, concomitant use with chemotherapy is not recommended due to the potential for additive myelosuppression.

If chemotherapy, other systemic radioisotopes or hemibody external radiotherapy are administered during the treatment period, Xofigo should be discontinued.

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in another section of the label: • Bone Marrow Suppression [see Warnings and Precautions (5.1)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In the randomized clinical trial in patients with metastatic castration-resistant prostate cancer with bone metastases, 600 patients received intravenous injections of 55 kBq/kg (1.49 microcurie/kg) of Xofigo and best standard of care and 301 patients received placebo and best standard of care once every 4 weeks for up to 6 injections. Prior to randomization, 58% and 57% of patients had received docetaxel in the Xofigo and placebo arms, respectively. The median duration of treatment was 20 weeks (6 cycles) for Xofigo and 18 weeks (5 cycles) for placebo.

The most common adverse reactions (≥ 10%) in patients receiving Xofigo were nausea, diarrhea, vomiting, and peripheral edema (Table 3). Grade 3 and 4 adverse events were reported among 57% of Xofigo-treated patients and 63% of placebo-treated patients. The most common hematologic laboratory abnormalities in Xofigo-treated patients (≥ 10%) were anemia, lymphocytopenia, leukopenia, thrombocytopenia, and neutropenia (Table 4).

Treatment discontinuations due to adverse events occurred in 17% of patients who received Xofigo and 21% of patients who received placebo. The most common hematologic laboratory abnormalities leading to discontinuation for Xofigo were anemia (2%) and thrombocytopenia (2%).

Table 3 shows adverse reactions occurring in ≥ 2% of patients and for which the incidence for Xofigo exceeds the incidence for placebo.

Table 3: Adverse Reactions in the Randomized Trial System/Organ Class Xofigo (n=600) Placebo (n=301) Preferred Term Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4 % % % % Blood and lymphatic system disorders Pancytopenia 2 1 0 0 Gastrointestinal disorders Nausea 36 2 35 2 Diarrhea 25 2 15 2 Vomiting 19 2 14 2 General disorders and administration site conditions Peripheral edema 13 2 10 1 Renal and urinary disorders Renal failure and impairment 3 1 1 1 Laboratory Abnormalities Table 4 shows hematologic laboratory abnormalities occurring in > 10% of patients and for which the incidence for Xofigo exceeds the incidence for placebo.

Table 4: Hematologic Laboratory Abnormalities Hematologic Xofigo (n=600) Placebo (n=301) Laboratory Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4 Abnormalities % % % % Anemia 93 6 88 6 Lymphocytopenia 72 20 53 7 Leukopenia 35 3 10 <1 Thrombocytopenia 31 3 22 <1 Neutropenia 18 2 5 <1 Laboratory values were obtained at baseline and prior to each 4-week cycle.

As an adverse reaction, grade 3-4 thrombocytopenia was reported in 6% of patients on Xofigo and in 2% of patients on placebo. Among patients who received Xofigo, the laboratory abnormality grade 3-4 thrombocytopenia occurred in 1% of docetaxel naïve patients and in 4% of patients who had received prior docetaxel.

Grade 3-4 neutropenia occurred in 1% of docetaxel naïve patients and in 3% of patients who have received prior docetaxel.

Fluid Status Dehydration occurred in 3% of patients on Xofigo and 1% of patients on placebo. Xofigo increases adverse reactions such as diarrhea, nausea, and vomiting which may result in dehydration. Monitor patients’ oral intake and fluid status carefully and promptly treat patients who display signs or symptoms of dehydration or hypovolemia.

Injection Site Reactions Erythema, pain, and edema at the injection site were reported in 1% of patients on Xofigo.

Secondary Malignant Neoplasms Xofigo contributes to a patient’s overall long-term cumulative radiation exposure.

Long-term cumulative radiation exposure may be associated with an increased risk of cancer and hereditary defects. Due to its mechanism of action and neoplastic changes, including osteosarcomas, in rats following administration of radium-223 dichloride, Xofigo may increase the risk of osteosarcoma or other secondary malignant neoplasms [see Nonclinical Toxicology (13.1)].

However, the overall incidence of new malignancies in the randomized trial was lower on the Xofigo arm compared to placebo (<1% vs. 2%; respectively), but the expected latency period for the development of secondary malignancies exceeds the duration of follow up for patients on the trial.

Subsequent Treatment with Cytotoxic Chemotherapy In the randomized clinical trial, 16% patients in the Xofigo group and 18% patients in the placebo group received cytotoxic chemotherapy after completion of study treatments. Adequate safety monitoring and laboratory testing was not performed to assess how patients treated with Xofigo will tolerate subsequent cytotoxic chemotherapy.

7 DRUG INTERACTIONS No formal clinical drug interaction studies have been performed.

Subgroup analyses indicated that the concurrent use of bisphosphonates or calcium channel blockers did not affect the safety and efficacy of Xofigo in the randomized clinical trial.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Category X [see Contraindications (4)] Xofigo can cause fetal harm when administered to a pregnant woman based on its mechanism of action. While there are no human or animal data on the use of Xofigo in pregnancy and Xofigo is not indicated for use in women, maternal use of a radioactive therapeutic agent could affect development of a fetus. Xofigo is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with Xofigo.

8.3 Nursing Mothers Xofigo is not indicated for use in women. It is not known whether radium-223 dichloride is excreted in human milk. Because many drugs are excreted in human milk, and because of potential for serious adverse reactions in nursing infants from Xofigo, a decision should be made whether to discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother.

8.4 Pediatric Use The safety and efficacy of Xofigo in pediatric patients have not been established.

In single- and repeat-dose toxicity studies in rats, findings in the bones (depletion of osteocytes, osteoblasts, osteoclasts, fibro-osseous lesions, disruption/ disorganization of the physis/growth line) and teeth (missing, irregular growth, fibro-osseous lesions in bone socket) correlated with a reduction of osteogenesis that occurred at clinically relevant doses beginning in the range of 22 – 88 kBq (0.59 - 2.38 microcurie) per kg body weight.

8.5 Geriatric Use Of the 600 patients treated with Xofigo in the randomized trial, 75% were 65 years of age and over and while 33% were 75 years of age and over. No dosage adjustment is considered necessary in elderly patients. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

8.6 Patients with Hepatic Impairment No dedicated hepatic impairment trial for Xofigo has been conducted. Since radium-223 is neither metabolized by the liver nor eliminated via the bile, hepatic impairment is unlikely to affect the pharmacokinetics of radium-223 dichloride [see Clinical Pharmacology (12.3)]. Based on subgroup analyses in the randomized clinical trial, dose adjustment is not needed in patients with mild hepatic impairment. No dose adjustments can be recommended for patients with moderate or severe hepatic impairment due to lack of clinical data.

8.7 Patients with Renal Impairment No dedicated renal impairment trial for Xofigo has been conducted. Based on subgroup analyses in the randomized clinical trial, dose adjustment is not needed in patients with existing mild (creatinine clearance [CrCl] 60 to 89 mL/min) or moderate (CrCl 30 to 59 mL/min) renal impairment. No dose adjustment can be recommended for patients with severe renal impairment (CrCl less than 30 mL/ min) due to limited data available (n = 2) [see Clinical Pharmacology (12.3)].

8.8 Males of Reproductive Potential Contraception Because of potential effects on spermatogenesis associated with radiation, advise men who are sexually active to use condoms and their female partners of reproductive potential to use a highly effective contraceptive method during and for 6 months after completing treatment with Xofigo.

Infertility There are no data on the effects of Xofigo on human fertility. There is a potential risk that radiation by Xofigo could impair human fertility [see Nonclinical Toxicology (13.1)].

10 OVERDOSAGE There have been no reports of inadvertent overdosing of Xofigo during clinical studies.

There is no specific antidote. In the event of an inadvertent overdose of Xofigo, utilize general supportive measures, including monitoring for potential hematological and gastrointestinal toxicity, and consider using medical countermeasures such as aluminum hydroxide, barium sulfate, calcium carbonate, calcium gluconate, calcium phosphate, or sodium alginate.

Single Xofigo doses up to 274 kBq (7.41 microcurie) per kg body weight were evaluated in a phase 1 clinical trial and no dose-limiting toxicities were observed.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Animal studies have not been conducted to evaluate the carcinogenic potential of radium-223 dichloride. However, in repeat-dose toxicity studies in rats, osteosarcomas, a known effect of bone-seeking radionuclides, were observed at clinically relevant doses 7 to 12 months after the start of treatment. The presence of other neoplastic changes, including lymphoma and mammary gland carcinoma, was also reported in 12- to 15-month repeat-dose toxicity studies in rats.

Genetic toxicology studies have not been conducted with radium-223 dichloride.

However, the mechanism of action of radium-223 dichloride involves induction of double-strand DNA breaks, which is a known effect of radiation.

Animal studies have not been conducted to evaluate the effects of radium-223 dichloride on male or female fertility or reproductive function. Xofigo may impair fertility and reproductive function in humans based on its mechanism of action.

17 PATIENT COUNSELING INFORMATION Advise patients: • To be compliant with blood cell count monitoring appointments while receiving Xofigo. Explain the importance of routine blood cell counts. Instruct patients to report signs of bleeding or infections.

• To stay well hydrated and to monitor oral intake, fluid status, and urine output while being treated with Xofigo. Instruct patients to report signs of dehydration, hypovolemia, urinary retention, or renal failure / insufficiency.

• There are no restrictions regarding contact with other people after receiving Xofigo. Follow good hygiene practices while receiving Xofigo and for at least 1 week after the last injection in order to minimize radiation exposure from bodily fluids to household members and caregivers. Whenever possible, patients should use a toilet and the toilet should be flushed several times after each use. Clothing soiled with patient fecal matter or urine should be washed promptly and separately from other clothing. Caregivers should use universal precautions for patient care such as gloves and barrier gowns when handling bodily fluids to avoid contamination. When handling bodily fluids, wearing gloves and hand washing will protect caregivers.

• Who are sexually active to use condoms and their female partners of reproductive potential to use a highly effective method of birth control during treatment and for 6 months following completion of Xofigo treatment.

Manufactured for:

Bayer HealthCare Pharmaceuticals Inc. Whippany, NJ 07981 Manufactured in Norway Xofigo is a trademark of Bayer Aktiengesellschaft. © 2013, Bayer HealthCare Pharmaceuticals Inc. All rights reserved.

Revised: March 2016 6708401BS

5/20/16 5:44 PM

XOFIGO (radium Ra 223 dichloride) Injection, for intravenous use Initial U.S. Approval: 2013 BRIEF SUMMARY oF pREScRIBIng InFoRMAtIon conSULt pAcKAgE InSERt FoR FULL pREScRIBIng InFoRMAtIon 1 INDICATIONS AND USAGE Xofigo® is indicated for the treatment of patients with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastatic disease.

2 DOSAGE AND ADMINISTRATION 2.3 Instructions for Use/Handling General warning Xofigo (an alpha particle-emitting pharmaceutical) should be received, used and administered only by authorized persons in designated clinical settings. The receipt, storage, use, transfer and disposal Xofigo are subject to the regulations and/or appropriate licenses of the competent official organization.

Xofigo should be handled by the user in a manner which satisfies both radiation safety and pharmaceutical quality requirements. Appropriate aseptic precautions should be taken.

Radiation protection The administration of Xofigo is associated with potential risks to other persons (e.g., medical staff, caregivers and patient’s household members) from radiation or contamination from spills of bodily fluids such as urine, feces, or vomit.

Therefore, radiation protection precautions must be taken in accordance with national and local regulations.

For drug handling Follow the normal working procedures for the handling of radiopharmaceuticals and use universal precautions for handling and administration such as gloves and barrier gowns when handling blood and bodily fluids to avoid contamination. In case of contact with skin or eyes, the affected area should be flushed immediately with water. In the event of spillage of Xofigo, the local radiation safety officer should be contacted immediately to initiate the necessary measurements and required procedures to decontaminate the area. A complexing agent such as 0.01 M ethylene-diamine-tetraacetic acid (EDTA) solution is recommended to remove contamination.

For patient care Whenever possible, patients should use a toilet and the toilet should be flushed several times after each use. When handling bodily fluids, simply wearing gloves and hand washing will protect caregivers. Clothing soiled with Xofigo or patient fecal matter or urine should be washed promptly and separately from other clothing.

Radium-223 is primarily an alpha emitter, with a 95.3% fraction of energy emitted as alpha-particles. The fraction emitted as beta-particles is 3.6%, and the fraction emitted as gamma-radiation is 1.1%. The external radiation exposure associated with handling of patient doses is expected to be low, because the typical treatment activity will be below 8,000 kBq (216 microcurie). In keeping with the As Low As Reasonably Achievable (ALARA) principle for minimization of radiation exposure, it is recommended to minimize the time spent in radiation areas, to maximize the distance to radiation sources, and to use adequate shielding. Any unused product or materials used in connection with the preparation or administration are to be treated as radioactive waste and should be disposed of in accordance with local regulations.

The gamma radiation associated with the decay of radium-223 and its daughters allows for the radioactivity measurement of Xofigo and the detection of contamination with standard instruments.

4 CONTRAINDICATIONS Xofigo is contraindicated in pregnancy.

Xofigo can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Xofigo is not indicated for use in women. Xofigo is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus [see Use in Specific Populations (8.1)].

5 WARNINGS AND PRECAUTIONS 5.1 Bone Marrow Suppression In the randomized trial, 2% of patients on the Xofigo arm experienced bone marrow failure or ongoing pancytopenia compared to no patients treated with placebo. There were two deaths due to bone marrow failure and for 7 of 13 patients treated with Xofigo, bone marrow failure was ongoing at the time of death. Among the 13 patients who experienced bone marrow failure, 54% required blood transfusions. Four percent (4%) of patients on the Xofigo arm and 2% on the placebo arm permanently discontinued therapy due to bone marrow suppression.

In the randomized trial, deaths related to vascular hemorrhage in association with myelosuppression were observed in 1% of Xofigo-treated patients compared to 0.3% of patients treated with placebo. The incidence of infectionrelated deaths (2%), serious infections (10%), and febrile neutropenia (<1%) were similar for patients treated with Xofigo and placebo. Myelosuppression; notably thrombocytopenia, neutropenia, pancytopenia, and leukopenia; has been reported in patients treated with Xofigo. In the randomized trial, complete blood counts (CBCs) were obtained every 4 weeks prior to each dose and the nadir CBCs and times of recovery were not well characterized. In a separate singledose phase 1 study of Xofigo, neutrophil and platelet count nadirs occurred 2 to 3 weeks after Xofigo administration at doses that were up to 1 to 5 times the recommended dose, and most patients recovered approximately 6 to 8 weeks after administration [see Adverse Reactions (6)].

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

Hematologic evaluation of patients must be performed at baseline and prior to every dose of Xofigo. Before the first administration of Xofigo, the absolute neutrophil count (ANC) should be ≥ 1.5 x 109/L, the platelet count ≥ 100 x 109/L and hemoglobin ≥ 10 g/dL. Before subsequent administrations of Xofigo, the ANC should be ≥ 1 x 109/L and the platelet count ≥ 50 x 109/L. If there is no recovery to these values within 6 to 8 weeks after the last administration of Xofigo, despite receiving supportive care, further treatment with Xofigo should be discontinued. Patients with evidence of compromised bone marrow reserve should be monitored closely and provided with supportive care measures when clinically indicated. Discontinue Xofigo in patients who experience lifethreatening complications despite supportive care for bone marrow failure.

The safety and efficacy of concomitant chemotherapy with Xofigo have not been established. Outside of a clinical trial, concomitant use with chemotherapy is not recommended due to the potential for additive myelosuppression.

If chemotherapy, other systemic radioisotopes or hemibody external radiotherapy are administered during the treatment period, Xofigo should be discontinued.

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in another section of the label: • Bone Marrow Suppression [see Warnings and Precautions (5.1)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In the randomized clinical trial in patients with metastatic castration-resistant prostate cancer with bone metastases, 600 patients received intravenous injections of 55 kBq/kg (1.49 microcurie/kg) of Xofigo and best standard of care and 301 patients received placebo and best standard of care once every 4 weeks for up to 6 injections. Prior to randomization, 58% and 57% of patients had received docetaxel in the Xofigo and placebo arms, respectively. The median duration of treatment was 20 weeks (6 cycles) for Xofigo and 18 weeks (5 cycles) for placebo.

The most common adverse reactions (≥ 10%) in patients receiving Xofigo were nausea, diarrhea, vomiting, and peripheral edema (Table 3). Grade 3 and 4 adverse events were reported among 57% of Xofigo-treated patients and 63% of placebo-treated patients. The most common hematologic laboratory abnormalities in Xofigo-treated patients (≥ 10%) were anemia, lymphocytopenia, leukopenia, thrombocytopenia, and neutropenia (Table 4).

Treatment discontinuations due to adverse events occurred in 17% of patients who received Xofigo and 21% of patients who received placebo. The most common hematologic laboratory abnormalities leading to discontinuation for Xofigo were anemia (2%) and thrombocytopenia (2%).

Table 3 shows adverse reactions occurring in ≥ 2% of patients and for which the incidence for Xofigo exceeds the incidence for placebo.

Table 3: Adverse Reactions in the Randomized Trial System/Organ Class Xofigo (n=600) Placebo (n=301) Preferred Term Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4 % % % % Blood and lymphatic system disorders Pancytopenia 2 1 0 0 Gastrointestinal disorders Nausea 36 2 35 2 Diarrhea 25 2 15 2 Vomiting 19 2 14 2 General disorders and administration site conditions Peripheral edema 13 2 10 1 Renal and urinary disorders Renal failure and impairment 3 1 1 1 Laboratory Abnormalities Table 4 shows hematologic laboratory abnormalities occurring in > 10% of patients and for which the incidence for Xofigo exceeds the incidence for placebo.

Table 4: Hematologic Laboratory Abnormalities Hematologic Xofigo (n=600) Placebo (n=301) Laboratory Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4 Abnormalities % % % % Anemia 93 6 88 6 Lymphocytopenia 72 20 53 7 Leukopenia 35 3 10 <1 Thrombocytopenia 31 3 22 <1 Neutropenia 18 2 5 <1 Laboratory values were obtained at baseline and prior to each 4-week cycle.

As an adverse reaction, grade 3-4 thrombocytopenia was reported in 6% of patients on Xofigo and in 2% of patients on placebo. Among patients who received Xofigo, the laboratory abnormality grade 3-4 thrombocytopenia occurred in 1% of docetaxel naïve patients and in 4% of patients who had received prior docetaxel.

Grade 3-4 neutropenia occurred in 1% of docetaxel naïve patients and in 3% of patients who have received prior docetaxel.

Fluid Status Dehydration occurred in 3% of patients on Xofigo and 1% of patients on placebo. Xofigo increases adverse reactions such as diarrhea, nausea, and vomiting which may result in dehydration. Monitor patients’ oral intake and fluid status carefully and promptly treat patients who display signs or symptoms of dehydration or hypovolemia.

Injection Site Reactions Erythema, pain, and edema at the injection site were reported in 1% of patients on Xofigo.

Secondary Malignant Neoplasms Xofigo contributes to a patient’s overall long-term cumulative radiation exposure.

Long-term cumulative radiation exposure may be associated with an increased risk of cancer and hereditary defects. Due to its mechanism of action and neoplastic changes, including osteosarcomas, in rats following administration of radium-223 dichloride, Xofigo may increase the risk of osteosarcoma or other secondary malignant neoplasms [see Nonclinical Toxicology (13.1)].

However, the overall incidence of new malignancies in the randomized trial was lower on the Xofigo arm compared to placebo (<1% vs. 2%; respectively), but the expected latency period for the development of secondary malignancies exceeds the duration of follow up for patients on the trial.

Subsequent Treatment with Cytotoxic Chemotherapy In the randomized clinical trial, 16% patients in the Xofigo group and 18% patients in the placebo group received cytotoxic chemotherapy after completion of study treatments. Adequate safety monitoring and laboratory testing was not performed to assess how patients treated with Xofigo will tolerate subsequent cytotoxic chemotherapy.

7 DRUG INTERACTIONS No formal clinical drug interaction studies have been performed.

Subgroup analyses indicated that the concurrent use of bisphosphonates or calcium channel blockers did not affect the safety and efficacy of Xofigo in the randomized clinical trial.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Category X [see Contraindications (4)] Xofigo can cause fetal harm when administered to a pregnant woman based on its mechanism of action. While there are no human or animal data on the use of Xofigo in pregnancy and Xofigo is not indicated for use in women, maternal use of a radioactive therapeutic agent could affect development of a fetus. Xofigo is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with Xofigo.

8.3 Nursing Mothers Xofigo is not indicated for use in women. It is not known whether radium-223 dichloride is excreted in human milk. Because many drugs are excreted in human milk, and because of potential for serious adverse reactions in nursing infants from Xofigo, a decision should be made whether to discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother.

8.4 Pediatric Use The safety and efficacy of Xofigo in pediatric patients have not been established.

In single- and repeat-dose toxicity studies in rats, findings in the bones (depletion of osteocytes, osteoblasts, osteoclasts, fibro-osseous lesions, disruption/ disorganization of the physis/growth line) and teeth (missing, irregular growth, fibro-osseous lesions in bone socket) correlated with a reduction of osteogenesis that occurred at clinically relevant doses beginning in the range of 22 – 88 kBq (0.59 - 2.38 microcurie) per kg body weight.

8.5 Geriatric Use Of the 600 patients treated with Xofigo in the randomized trial, 75% were 65 years of age and over and while 33% were 75 years of age and over. No dosage adjustment is considered necessary in elderly patients. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

8.6 Patients with Hepatic Impairment No dedicated hepatic impairment trial for Xofigo has been conducted. Since radium-223 is neither metabolized by the liver nor eliminated via the bile, hepatic impairment is unlikely to affect the pharmacokinetics of radium-223 dichloride [see Clinical Pharmacology (12.3)]. Based on subgroup analyses in the randomized clinical trial, dose adjustment is not needed in patients with mild hepatic impairment. No dose adjustments can be recommended for patients with moderate or severe hepatic impairment due to lack of clinical data.

8.7 Patients with Renal Impairment No dedicated renal impairment trial for Xofigo has been conducted. Based on subgroup analyses in the randomized clinical trial, dose adjustment is not needed in patients with existing mild (creatinine clearance [CrCl] 60 to 89 mL/min) or moderate (CrCl 30 to 59 mL/min) renal impairment. No dose adjustment can be recommended for patients with severe renal impairment (CrCl less than 30 mL/ min) due to limited data available (n = 2) [see Clinical Pharmacology (12.3)].

8.8 Males of Reproductive Potential Contraception Because of potential effects on spermatogenesis associated with radiation, advise men who are sexually active to use condoms and their female partners of reproductive potential to use a highly effective contraceptive method during and for 6 months after completing treatment with Xofigo.

Infertility There are no data on the effects of Xofigo on human fertility. There is a potential risk that radiation by Xofigo could impair human fertility [see Nonclinical Toxicology (13.1)].

10 OVERDOSAGE There have been no reports of inadvertent overdosing of Xofigo during clinical studies.

There is no specific antidote. In the event of an inadvertent overdose of Xofigo, utilize general supportive measures, including monitoring for potential hematological and gastrointestinal toxicity, and consider using medical countermeasures such as aluminum hydroxide, barium sulfate, calcium carbonate, calcium gluconate, calcium phosphate, or sodium alginate.

Single Xofigo doses up to 274 kBq (7.41 microcurie) per kg body weight were evaluated in a phase 1 clinical trial and no dose-limiting toxicities were observed.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Animal studies have not been conducted to evaluate the carcinogenic potential of radium-223 dichloride. However, in repeat-dose toxicity studies in rats, osteosarcomas, a known effect of bone-seeking radionuclides, were observed at clinically relevant doses 7 to 12 months after the start of treatment. The presence of other neoplastic changes, including lymphoma and mammary gland carcinoma, was also reported in 12- to 15-month repeat-dose toxicity studies in rats.

Genetic toxicology studies have not been conducted with radium-223 dichloride.

However, the mechanism of action of radium-223 dichloride involves induction of double-strand DNA breaks, which is a known effect of radiation.

Animal studies have not been conducted to evaluate the effects of radium-223 dichloride on male or female fertility or reproductive function. Xofigo may impair fertility and reproductive function in humans based on its mechanism of action.

17 PATIENT COUNSELING INFORMATION Advise patients: • To be compliant with blood cell count monitoring appointments while receiving Xofigo. Explain the importance of routine blood cell counts. Instruct patients to report signs of bleeding or infections.

• To stay well hydrated and to monitor oral intake, fluid status, and urine output while being treated with Xofigo. Instruct patients to report signs of dehydration, hypovolemia, urinary retention, or renal failure / insufficiency.

• There are no restrictions regarding contact with other people after receiving Xofigo. Follow good hygiene practices while receiving Xofigo and for at least 1 week after the last injection in order to minimize radiation exposure from bodily fluids to household members and caregivers. Whenever possible, patients should use a toilet and the toilet should be flushed several times after each use. Clothing soiled with patient fecal matter or urine should be washed promptly and separately from other clothing. Caregivers should use universal precautions for patient care such as gloves and barrier gowns when handling bodily fluids to avoid contamination. When handling bodily fluids, wearing gloves and hand washing will protect caregivers.

• Who are sexually active to use condoms and their female partners of reproductive potential to use a highly effective method of birth control during treatment and for 6 months following completion of Xofigo treatment.

Manufactured for:

Bayer HealthCare Pharmaceuticals Inc. Whippany, NJ 07981 Manufactured in Norway Xofigo is a trademark of Bayer Aktiengesellschaft. © 2013, Bayer HealthCare Pharmaceuticals Inc. All rights reserved.

Revised: March 2016 6708401BS

5/20/16 5:44 PM

A24 EXPERT PERSPECTIVE Cancer Drug Addiction: Prospects for Integrated Therapeutic Management

A6 FEATURED PRODUCTS Drug Descriptions of Calquence and Verzenio

PAUL W. EWALD, PhD AND

A8 IN THE PIPELINE The Latest on Oncology Drugs A9 LATEST NEWS Headlines in Oncology Research and Practice A19 IN THE CLINIC Monitoring for Post–organ Transplant Skin Cancer C. ANDREW KISTLER, MD, PharmD, RPh

A20

FEATURE The Warburg Effect: Can Cancer Be Starved of Sugar?

CARLOS HARRISON

A22

VIEWPOINT Beta-blockers May Prevent Stress-induced Lung Cancer Treatment Resistance

HOLLY A. SWAIN EWALD, PhD

A26 REGIMEN & MONOGRAPH INDEX 1-88 CANCER THERAPY REGIMENS & ONCOLOGY DRUG MONOGRAPHS Highlighted topics () contain both treatment regimens and drug monographs.

1 Bone Cancer

 3 Brain Cancer

 14 Breast Cancer 26 Endocrine Cancer

 30 Gastrointestinal Cancer

 40 Genitourinary Cancer 51 Gynecologic Cancer 53 Head and Neck Cancer 55 Hematologic Cancer 76 Lung Cancer 83 Sarcoma 84 Skin Cancer

89 ALPHABETICAL INDEX

ANDREA S. BLEVINS PRIMEAU, PhD, MBA

9 4 MANUFACTURERS INDEX

Cancer Therapy Advisor (ISSN 2375-558X), January/February 2018, Volume 4, Number 3. Published 6 times annually by Haymarket Media, Inc., 275 7th Avenue, 10th Floor, New York, NY 10001. For Advertising Sales & Editorial, 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.

A4 CANCER THERAPY ADVISOR | JANUARY/FEBRUARY 2018 | CancerTherapyAdvisor.com

EDITORIAL & BUSINESS STAFF

EDITORIAL ADVISORY BOARD

Managing Editor, Haymarket Oncology

Barbara Ann Burtness, MD

Lauren Burke

Yale Cancer Center  New Haven, CT

Oncology Editor

Steven J. Cohen, MD

Jonathan Goodman, MPhil

Thomas Jefferson University Hospital  Philadelphia, PA

Oncology Writer James Nam, PharmD

E. David Crawford, MD

Senior Manager, Drug Information

University of Colorado, Denver  Aurora, CO

Anissa Lee, RPh

Group Art Director, Medical Communications Jennifer Dvoretz

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

Graphic Designer

Don S. Dizon, MD, FACP

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Lifespan Cancer Institute  Providence, RI

Production Editor

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Fox Chase Cancer Center  Philadelphia, PA

Production Manager Brian Wask; (646) 638-6066

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Circulation Manager

Atlantic Urology Clinics  Myrtle Beach, SC

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Account Manager

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Contact the Editor: editor.cancertherapyadvisor@haymarketmedia.com

CancerTherapyAdvisor.com | JANUARY/FEBRUARY 2018 | CANCER THERAPY ADVISOR A5

FEATURED PRODUCT

Calquence

Rx

Company: AstraZeneca Pharmacologic class: Bruton tyrosine kinase (BTK) inhibitor Active ingredients: Acalabrutinib 100mg; capsules.

Indication: Mantle cell lymphoma (MCL) in adult patients who have received at least one prior therapy.

Pharmacology: Acalabrutinib and its active metabolite form a covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK enzymatic activity. In nonclinical studies, acalabrutinib inhibited BTK-mediated activation of downstream signaling proteins CD86 and CD69 as well as inhibiting malignant B cell proliferation and survival.

Clinical trials: The efficacy of Calquence was evaluated in Trial LY-004 involving 124 patients with MCL who had received at least one prior therapy. Patients who received prior treatment with BTK inhibitors were excluded.

Calquence 100 mg was given twice daily until disease progression or unacceptable toxicity. The major efficacy outcome was overall response rate (ORR) and the median follow-up was 15.2 months.

Tumor response was assessed according to the Lugano Classification for NonHodgkin lymphoma (NHL).

The investigator-assessed ORR was 81% (95% CI, 73-87) with 40% (95% CI, 31-49) achieving complete response and 41% (95% CI, 32-50) achieving partial response.

The median duration of response (DoR) was not reached at time of analysis (range, 1+ to 20+ months).

The ORR as assessed by an independent review committee was 80% (95% CI, 72-87), with 40% achieving in both complete response and partial response.

The median time to best response was 1.9 months.

For more clinical trial data, see full labeling.

Adults: Swallow whole with water. 100 mg approximately every 12hrs until progression or unacceptable toxicity. Concomitant moderate CYP3A inhibitors: 100 mg once daily. Concomitant strong CYP3A inducers: avoid; if needed, increase dose to 200 mg twice daily. Dose modifications for adverse reactions: see full labeling.

Children: Not established.

Warnings/Precautions: Risk of hemorrhage; consider the benefit/risk of withholding treatment for 3 to 7 days pre-and post-surgery. Monitor for infections; consider prophylaxis if at risk for opportunistic infections. Monitor for cytopenias; obtain complete blood counts monthly. Risk of second primary malignancies (eg, skin cancer or other carcinomas); advise patients to protect from sun exposure. Monitor for atrial fibrillation/flutter; manage appropriately. Pregnancy. Nursing mothers: not

A6 CANCER THERAPY ADVISOR | JANUARY/FEBRUARY 2018 | CancerTherapyAdvisor.com

recommended (during and for at least 2 weeks after final dose).

Interactions: Avoid concomitant strong CYP3A inhibitors (eg, itraconazole); if short-term use (eg, anti-infectives for â&#x2030;¤7 days), interrupt acalabrutinib therapy.

Concomitant moderate CYP3A inhibitors: reduce acalabrutinib dose (see Adult).

Avoid concomitant strong CYP3A inducers (eg, rifampin); if unavoidable, increase acalabrutinib dose (see Adult). Increased risk of hemorrhage with concomitant antiplatelets or anticoagulants; monitor. Antagonized by gastric acid reducing agents (eg, PPI [avoid], H2-receptor antagonist, or antacid); if needed, consider ranitidine, famotidine, or calcium carbonate. Separate dosing by at least 2 hours with antacids. Take acalabrutinib 2 hours before H2-receptor antagonist use.

Adverse reactions: Anemia, thrombocytopenia, headache, neutropenia, diarrhea, fatigue, myalgia, bruising; hemorrhage, infections, second primary malignancy, atrial fibrillation/flutter.

How supplied: Capsâ&#x20AC;&#x201D;60 For more information call (800) 236-9933 or visit www.Calquence.com.

FEATURED PRODUCT

Verzenio

Rx

Company: Eli Lilly Pharmacologic class: Kinase inhibitor Active ingredients: Abemaciclib 50mg, 100mg, 150mg, 200mg; tablets.

Indication: In combination with fulvestrant for the treatment of women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)negative advanced or metastatic breast cancer with disease progression following endocrine therapy. As monotherapy for the treatment of adults with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting.

Pharmacology: Abemaciclib inhibits cyclin-dependent kinases 4 and 6, which results in the inhibition of retinoblastoma protein phosphorylation and blockage of cell cycle progression from G1 into S phase, leading to senescence and apoptosis.

Clinical trials: The efficacy of Verzenio in combination with fulvestrant was evaluated in MONARCH 2, a randomized, placebo-controlled, multicenter study involving 669 women with HR-positive, HER2-negative metastatic breast cancer with disease progression following endocrine therapy and had not received chemotherapy in the metastatic setting. Patients treated with Verzenio + fulvestrant had a median progression-free survival of 16.4 months vs 9.3 months in those treated with placebo + fulvestrant (P < .0001).

Verzenio as monotherapy was evaluated in MONARCH 1, an open-label study in 132 women with metastatic breast cancer with disease progression following endocrine therapy, had received a taxane in any setting, and 1 or 2 prior chemotherapy regimens in the metastatic setting.

The objective response rate for Verzenio was 19.7% (investigator assessed) vs 17.4% (independent review), with a mean duration of response of 8.6 months vs 7.2 months, respectively.

For more clinical trial data, see full labeling.

Adults: Swallow whole. Take at the same time every day. Combination with fulvestrant (see full labeling): initially 150 mg twice daily; in pre/perimenopausal women: also treat with a gonadotropin-releasing hormone agonist according to current practice standards.

Monotherapy: initially 200 mg twice daily. Both: continue until disease progression or unacceptable toxicity. Dose modifications for adverse reactions, concomitant strong CYP3A4 inhibitors: see full labeling. Severe hepatic impairment: reduce frequency to once daily.

Children: Not established.

Warnings/Precautions: Advise patients to initiate antidiarrheal (eg, loperamide) and increase fluids at first sign of loose stools; discontinue if grade 3/4 diarrhea occurs or hospitalization required, until resolves to grade 1 or better, then resume at next lower dose. Monitor complete blood counts and liver function tests prior to initiation and every 2 weeks for the first 2 months, then monthly for the next 2 months, and as clinically indicated. Dose interruption/reduction/discontinuation or

delay in starting treatment cycles if grade 3/4 neutropenia, recurrent grade 2 or grade 3/4 transaminase elevation occurs.

Monitor for signs/symptoms of venous thromboembolic events; treat appropriately. Severe hepatic impairment (ChildPugh C). Embryo-fetal toxicity. Females of reproductive potential should use effective contraception during therapy and for at least 3 weeks after last dose. Pregnancy; exclude status prior to initiation. Nursing mothers: not recommended (during and for at least 3 weeks after the last dose).

Interactions: Avoid concomitant ketoconazole, grapefruit products.

Concomitant other strong CYP3A inhibitors: reduce abemaciclib dose. Avoid concomitant strong CYP3A inducers (eg, rifampin): consider alternative agents.

Adverse reactions: Diarrhea, neutropenia, nausea, abdominal pain, infections, fatigue, anemia, leukopenia, decreased appetite, vomiting, headache, thrombocytopenia; venous thromboembolic events, hepatotoxicity.

How supplied: Blister packâ&#x20AC;&#x201D;14 For more information call (800) 545-5979 or visit www.Verzenio.com.

CancerTherapyAdvisor.com | JANUARY/FEBRUARY 2018 | CANCER THERAPY ADVISOR A7

IN THE PIPELINE FDA Accepts Supplemental New Drug Application for Osimertinib as First-line Treatment in EGFRmutant NSCLC

FDA Grants Priority Review to Dabrafenib and Trametinib Combination for Resected Melanoma

Apalutamide Granted Priority Review for Castration-resistant Prostate Cancer

The US Food and Drug Administration (FDA) accepted a supplemental New Drug Application for osimertinib as a first-line treatment for patients with EGFR-mutated metastatic non–small cell lung cancer (NSCLC), according to a press release.

The FDA’s acceptance was based on data from the phase 3 FLAURA trial (ClinicalTrials.gov Identifier: NCT02296125), which showed a median progression-free survival (PFS) of 18.9 months among patients with EGFR-mutant disease — an improvement of over 8 months vs the current standard of care.

Osimertinib, a third-generation tyrosine kinase inhibitor (TKI) of EGFR, has shown improved efficacy over erlotinib and gefitinib — both of which are EGFR TKIs with proven efficacy — and activity against central nervous system (CNS) metastases.

Patients who develop resistance to erlotinib and gefitinib may also still respond to osimertinib. Data from FLAURA may position osimertinib as the standard of care for patients with EGFR-mutant NSCLC. EGFR mutations are found in 10% to 15% of patients living in the United States or Europe and in 30% to 40% of patients in Asia.

Osimertinib was granted Priority Review by the FDA. The drug was also previously granted Breakthrough Therapy Designation.

The US Food and Drug Administration (FDA) granted Priority Review to a supplemental New Drug Application (sNDA) for combined dabrafenib and trametinib as an adjuvant therapy for patients with BRAF-mutant stage III melanoma, according to a press release.

The drug combination was studied in patients with BR AF V600E/K mutations in the phase 3 COMBI-AD study (ClinicalTrials.gov Identifier: NCT01682083), the results of which led to the FDA’s Priority Review designation.

For COMBI-AD, 870 patients with completely resected melanoma were randomly assigned to receive adjuvant dabrafenib and trametinib (438 patients) or placebo (432 patients). Patients were stratified by variety of BRAF mutation.

The study met its primary endpoint of relapse-free survival (RFS): after a median follow-up of 2.8 years, the estimated 3-year RFS rates were 58% in the therapy group and 39% in the placebo group (hazard ratio, 0.47; P < .001).

The 3-year overall survival rates were 86% in the therapy group and 77% in the placebo group (hazard ratio, 0.57; P = .0006), though this result did not meet the prespecified statistical boundary of P = .000019, according to The New England Journal of Medicine. The authors also noted that the “safety profile of dabrafenib plus trametinib was consistent with that observed with the combination in patients with metastatic melanoma.”

Combination dabrafenib and trametinib are already approved by the FDA for BRAF V600E-mutant unresectable or metastatic melanoma.

The US Food and Drug Administration (FDA) granted Priority Review to a New Drug Application for apalutamide, an androgen receptor inhibitor, for patients with castration-resistant prostate cancer (CRPC) without metastases, according to a press release.

Data from the phase 3 SPARTAN trial (ClinicalTrials.gov Identifier: NCT01946204), which will be presented at the upcoming American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium in February 2018, led to the FDA’s Priority Review designation for apalutamide.

In SPARTAN, patients with CRPC and a rapidly rising prostate-specific antigen (PSA), which continued to rise despite receipt of androgen-deprivation therapy, were randomly assigned to receive apalutamide or placebo. Patients with CRPC and rising PSA are at a particularly high risk of metastatic disease.

The FDA will take action on the New Drug Application within 6 months.

Priority Review is granted only to drugs likely to drastically improve outcomes among patients with limited therapeutic options.

Apalutamide is a next-generation, orally administered inhibitor of the androgen receptor. Preclinical studies suggest that apalutamide prevents androgen binding to the androgen receptor.

Cancer Therapy Advisor will report on updated data from SPARTA N, which will be presented at the ASCO Genitourinary Cancers Symposium on February 8, 2018.

For more information, visit https://www. astrazeneca.com/.

For more information, visit https://www. novartis.com/.

For more information, visit https://www. astrazeneca.com/.

A8 CANCER THERAPY ADVISOR | JANUARY/FEBRUARY 2018 | CancerTherapyAdvisor.com

LATEST NEWS High BMI and Diabetes May Be Increasing Global Cancer Burden The increasing frequencies of obesity and diabetes may be driving up the global cancer burden, according to a study published in The Lancet Diabetes & Endocrinology.

Diabetes and high body mass index (BMI) are known leading causes of mortality worldwide, but their association with cancer risk was previously undetermined. Worldwide, about 422 million adults have diabetes and 2.01 billion have a high BMI, defined as a BMI of at least 25 kg/m².

For this risk assessment analysis, researchers determined the 2012 incidence rates of 12 cancer types in 175 countries.

Cancer incidence among patients with a high BMI, diabetes, or both was compared with the general population.

The authors did not, however, distinguish between type 1 and type 2 diabetes.

Of 14,067,894 reported cancer cases, 280,100 (2%) were attributed to diabetes alone, 544,300 (3.9%) were attributed to a high BMI alone, and 792,600 (5.6%) were attributed to both.

The combination led to a higher cancer risk among females (496,700 cases) than in males (295,500 cases). Liver cancer was the most common diagnosis among males with diabetes and a high BMI; breast cancer was the most common among females.

Noting that the number of cancers attributable to diabetes and a high BMI is likely to increase dramatically by 2025, the authors concluded that these “projections are particularly alarming in view of the high, and growing, economic cost of cancers and metabolic diseases, and highlight the importance of integrated control measures to tackle common modifiable risk factors.”

© YACOBCHUK / GETTY IMAGES

Neoadjuvant Docetaxel-containing Chemotherapy Effective, Though Toxic, in HER2-positive Breast Cancer Compared with neoadjuvant trastuzumab plus pertuzumab, docetaxel plus carboplatin, trastuzumab, and pertuzumab confer a higher pathological complete response (pCR) rate among patients with HER2-positive breast cancer, according to a study published in The Lancet Oncology. Docetaxel-containing therapy was, however, associated with a significantly worse toxicity profile.

While neoadjuvant docetaxel-containing therapy yields high 10-year overall survival rates among patients with HER2positive breast cancer, systemic chemotherapy with docetaxel

can lead to serious adverse events (AEs). Trastuzumab targets HER2-overexpressing cells, possibly mitigating or avoiding docetaxel-associated AEs. For the phase 3 KRISTINE trial (ClinicalTrials.gov Identifier: NCT02131064), researchers randomly assigned 444 patients with stage II to III operable cancer to receive neoadjuvant trastuzumab plus pertuzumab (223 patients) or docetaxel, carboplatin, trastuzumab, and pertuzumab (221 patients). pCRs were noted in 44.4% of patients in the trastuzumab group vs 55.7% of patients in the docetaxel group (P = .016). Superiority was seen regardless of patient age, ECOG status, and ethnicity.

Grade 3 to 4 AEs were, however, much more common in the docetaxel group (64%) than in the trastuzumab group (13%).

While patients who received docetaxel had faster quality of life deterioration, quality of life was low in both groups by the end of treatment.

The authors concluded that “future efforts should improve the efficacy of chemotherapy without imparting more toxicity. Results from the adjuvant phase of KRISTINE will be reported in the future.”

Adjuvant Gefitinib Improves Disease-free Survival Among Patients With NSCLC Adjuvant EGFR inhibition with gefitinib improves disease-free survival (DFS) compared with chemotherapy among patients with resected stage II-IIIA (N1-N2) non–small cell lung cancer (NSCLC), according to a study published in The Lancet Oncology.

Cisplatin-based chemotherapy is the standard adjuvant therapy for patients with resected stage II-IIIA disease, though 5-year survival rates are still low and adverse events are common. While EGFR inhibition is a standard first-line therapy for patients with EGFR-mutant disease, it is unknown whether this strategy benefits patients over chemotherapy in the adjuvant setting.

For the 1:1 randomized phase 3 ADJUVANT study (ClinicalTrials.gov Identifier: NCT01405079), researchers enrolled 222 patients with completely resected stage II-IIIA (N1-N2) NSCLC to receive adjuvant gefitinib or cisplatin plus vinorelbine. All patients were Chinese (among whom EGFR mutations are more common), the median age was 58 years, and 92% of patients had an adenocarcinoma.

Of the 222 initially assigned patients, 24 did not receive treatment in the chemotherapy group and 5 did not receive treatment in the gefitinib group, leaving 87 patients and 106 patients in the respective modified intention-to-treat populations.

CancerTherapyAdvisor.com | JANUARY/FEBRUARY 2018 | CANCER THERAPY ADVISOR A9

The first and only third-generation EGFR TKI1

TAGRISSO®—ELEGANT DESIGN MEETS SELECTIVE TARGETING exon 19

exon 21 L858R EGFR

TAGRISSO

TAGRISSO binds irreversibly to EGFR with exon 19 deletions, a mutation seen in approximately 46% of EGFRm metastatic NSCLC2,3

T790M

EGFR

EGFR

TAGRISSO

TAGRISSO

TAGRISSO binds irreversibly to EGFR with exon 21 L858R substitution, a mutation seen in approximately 39% of EGFRm metastatic NSCLC2,3

TAGRISSO inhibits mutated EGFR with the T790M mutation, which is responsible for resistance in more than half of EGFRm metastatic NSCLC cases at progression2,4

EGFRm=epidermal growth factor receptor mutation, NSCLC=non-small cell lung cancer, TKI=tyrosine kinase inhibitor.

INDICATION TAGRISSO (osimertinib) is indicated for the treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC), as detected by an FDA-approved test, whose disease has progressed on or after EGFR tyrosine kinase inhibitor therapy.

IMPORTANT SAFETY INFORMATION • There are no contraindications for TAGRISSO • Interstitial Lung Disease (ILD)/Pneumonitis occurred in 3.5% and was fatal in 0.6% of 833 TAGRISSOtreated patients. Withhold TAGRISSO and promptly investigate for ILD in patients who present with worsening of respiratory symptoms indicative of ILD (eg, dyspnea, cough, and fever). Permanently discontinue TAGRISSO if ILD is confirmed • Heart rate-corrected QT (QTc) interval prolongation occurred in TAGRISSO-treated patients. Of the 833 TAGRISSO-treated patients, 0.7% of patients were found to have a QTc > 500 msec, and 2.9% of patients had an increase from baseline QTc > 60 msec. No QTc-related arrhythmias were reported.

Conduct periodic monitoring with ECGs and electrolytes in patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval. Permanently discontinue TAGRISSO in patients who develop QTc interval prolongation with signs/symptoms of life-threatening arrhythmia

TAGRISSO is a registered trademark of the AstraZeneca group of companies. ©2017 AstraZeneca. All rights reserved. US-15010 10/17

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TAGRISSO is designed to target EGFR sensitizing mutations and EGFR T790M mutations.1 TAGRISSO binds irreversibly to these key drivers of disease and resistance while demonstrating a lower affinity for wild-type EGFR2

With a lower affinity for wild-type EGFR, TAGRISSO binds at approximately 9-fold lower concentrations2 wild-type EGFR

TAGRISSO

• Cardiomyopathy occurred in 1.9% and was fatal in 0.1% of 833 TAGRISSO-treated patients.

Left Ventricular Ejection Fraction (LVEF) decline ≥ 10% and a drop to < 50% occurred in 4% of 655 TAGRISSO-treated patients. Conduct cardiac monitoring, including an assessment of LVEF at baseline and during treatment in patients with cardiac risk factors. Assess LVEF in patients who develop relevant cardiac signs or symptoms during treatment. For symptomatic congestive heart failure or persistent, asymptomatic LV dysfunction that does not resolve within 4 weeks, permanently discontinue TAGRISSO • Keratitis was reported in 0.7% of 833 TAGRISSO-treated patients in clinical trials. Promptly refer patients with signs and symptoms suggestive of keratitis (such as eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain, and/or red eye) to an ophthalmologist • Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during TAGRISSO treatment and for 6 weeks after the final dose. Advise males with female partners of reproductive potential to use effective contraception for 4 months after the final dose • The most common adverse reactions (≥ 20%) in patients treated with TAGRISSO were diarrhea (41%), rash (34%), dry skin (23%), nail toxicity (22%), and fatigue (22%)

Please see accompanying complete Brief Summary of Prescribing Information on adjacent pages.

References: 1. Cross DAE, Ashton SE, Ghiorghiu S, et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov. 2014;4: 1046-1061. 2. TAGRISSO [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2017. 3. Shigematsu H, Lin L, Takahashi T, et al. Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst. 2005;97(5): 339-346. 4. Yu HA, Arcila ME, Rekhtman N, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers.

Clin Cancer Res. 2013;19:2240-2247.

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TAGRISSO® (osimertinib) tablets, for oral use Brief Summary of Prescribing Information.

For complete prescribing information consult official package insert.

INDICATIONS AND USAGE TAGRISSO is indicated for the treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC), as detected by an FDA-approved test, whose disease has progressed on or after EGFR tyrosine kinase inhibitor (TKI) therapy.

DOSAGE AND ADMINISTRATION Patient Selection Confirm the presence of a T790M EGFR mutation in tumor or plasma specimens prior to initiation of treatment with TAGRISSO [see Indications and Usage (1) and Clinical Studies (14) in full Prescribing Information]. Testing for the presence of the mutation in plasma specimens is recommended only in patients for whom a tumor biopsy cannot be obtained. If this mutation is not detected in a plasma specimen, re-evaluate the feasibility of biopsy for tumor tissue testing. Information on FDA-approved tests for the detection of T790M mutations is available at http://www.fda.gov/ companiondiagnostics.

Recommended Dosage Regimen The recommended dose of TAGRISSO is 80 mg tablet once a day until disease progression or unacceptable toxicity. TAGRISSO can be taken with or without food.

If a dose of TAGRISSO is missed, do not make up the missed dose and take the next dose as scheduled.

Administration to Patients Who Have Difficulty Swallowing Solids Disperse tablet in 60 mL (2 ounces) of non-carbonated water only. Stir until tablet is dispersed into small pieces (the tablet will not completely dissolve) and swallow immediately. Do not crush, heat, or ultrasonicate during preparation. Rinse the container with 120 mL to 240 mL (4 to 8 ounces of) water and immediately drink.

If administration via nasogastric tube is required, disperse the tablet as above in 15 mL of non-carbonated water, and then use an additional 15 mL of water to transfer any residues to the syringe. The resulting 30 mL liquid should be administered as per the nasogastric tube instructions with appropriate water flushes (approximately 30 mL).

Dosage Modification Adverse Reactions Table 1.

Recommended Dose Modifications for TAGRISSO Target Organ Pulmonary

Cardiac

Other

a b †

Adverse Reactiona Interstitial lung disease (ILD)/Pneumonitis QTc† interval greater than 500 msec on at least 2 separate ECGsb

QTc interval prolongation with signs/symptoms of life-threatening arrhythmia Symptomatic congestive heart failure or asymptomatic left ventricular dysfunction that persists ≥ 4 weeks Adverse reaction of Grade 3 or greater severity If improvement to Grade 0-2 within 3 weeks If no improvement within 3 weeks

Dose Modification Permanently discontinue TAGRISSO. Withhold TAGRISSO until QTc interval is less than 481 msec or recovery to baseline if baseline QTc is greater than or equal to 481 msec, then resume at 40 mg dose.

Permanently discontinue TAGRISSO. Permanently discontinue TAGRISSO. Withhold TAGRISSO for up to 3 weeks.

Resume at 80 mg or 40 mg daily.

Permanently discontinue TAGRISSO.

Adverse reactions graded by the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (NCI CTCAE v4.0).

ECGs = Electrocardiograms QTc = QT interval corrected for heart rate

Drug Interactions Strong CYP3A4 Inducers If concurrent use is unavoidable, increase TAGRISSO dosage to 160 mg daily when coadministering with a strong CYP3A inducer. Resume TAGRISSO at 80 mg 3 weeks after discontinuation of the strong CYP3A4 inducer [see Drug Interactions (7), and Clinical Pharmacology (12.3) in full Prescribing Information].

CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS The following information for ILD/ Pneumonitis, QTc Interval Prolongation, Cardiomyopathy and Keratitis reflects exposure to TAGRISSO in 833 patients with EGFR T790M mutation-positive non-small cell lung cancer (NSCLC) who received TAGRISSO at the recommended dose of 80 mg once daily in AURA3 (n=279), AURA Extension (n=201), AURA2 (n=210), and an expansion cohort in the first-in-human trial of osimertinib (AURA1, n=143).

Interstitial Lung Disease/Pneumonitis Interstitial lung disease (ILD)/pneumonitis occurred in 3.5% (n=29) of TAGRISSO-treated patients (n=833); 0.6% (n=5) of cases were fatal.

Withhold TAGRISSO and promptly investigate for ILD in patients who present with worsening of respiratory symptoms which may be indicative of ILD (e.g., dyspnea, cough and fever).

Permanently discontinue TAGRISSO if ILD is confirmed [see Dosage and Administration (2.4) and Adverse Reactions (6) in full Prescribing Information].

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QTc Interval Prolongation Heart rate-corrected QT (QTc) interval prolongation occurs in patients treated with TAGRISSO. Of the 833 patients treated with TAGRISSO in clinical trials, 0.7% (n=6) were found to have a QTc greater than 500 msec, and 2.9% of patients (n=24) had an increase from baseline QTc greater than 60 msec [see Clinical Pharmacology (12.2) in full Prescribing Information]. No QTc-related arrhythmias were reported.

Clinical trials of TAGRISSO did not enroll patients with baseline QTc of greater than 470 msec.

Conduct periodic monitoring with ECGs and electrolytes in patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval. Permanently discontinue TAGRISSO in patients who develop QTc interval prolongation with signs/symptoms of life-threatening arrhythmia [see Dosage and Administration (2.4) in full Prescribing Information].

Cardiomyopathy Across clinical trials, cardiomyopathy (defined as cardiac failure, congestive heart failure, pulmonary edema or decreased ejection fraction) occurred in 1.9% (n=16) of 833 TAGRISSOtreated patients: 0.1% (n=1) of cases were fatal.

Left Ventricular Ejection Fraction (LVEF) decline greater than or equal to 10% and a drop to less than 50% occurred in 4.0% (26/655) of patients who had baseline and at least one follow-up LVEF assessment.

Conduct cardiac monitoring, including an assessment of LVEF at baseline and during treatment in patients with cardiac risk factors. Assess LVEF in patients who develop relevant cardiac signs or symptoms during treatment. For symptomatic congestive heart failure or persistent, asymptomatic LV dysfunction that does not resolve within 4 weeks, permanently discontinue TAGRISSO [see Dosage and Administration (2.4) in full Prescribing Information].

Keratitis Keratitis was reported in 0.7% (n=6) of 833 patients treated with TAGRISSO in clinical trials.

Promptly refer patients with signs and symptoms suggestive of keratitis (such as eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain and/or red eye) to an ophthalmologist.

Embryo-Fetal Toxicity Based on data from animal studies and its mechanism of action, TAGRISSO can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, osimertinib caused postimplantation fetal loss when administered during early development at a dose exposure 1.5 times the exposure at the recommended human dose. When males were treated prior to mating with untreated females, there was an increase in preimplantation embryonic loss at plasma exposures of approximately 0.5-times those observed in patients at the 80 mg dose level.

Advise pregnant women of the potential risk to a fetus.

Advise females of reproductive potential to use effective contraception during treatment with TAGRISSO and for 6 weeks after the final dose. Advise males with female partners of reproductive potential to use effective contraception for 4 months after the final dose [see Use in Specific Populations (8.1), (8.3) and Clinical Pharmacology (12.3) in full Prescribing Information].

ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.1) in full Prescribing Information] QTc Interval Prolongation [see Warnings and Precautions (5.2) in full Prescribing Information] Cardiomyopathy [see Warnings and Precautions (5.3) in full Prescribing Information] Keratitis [see Warnings and Precautions (5.4) in full Prescribing Information] 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.

The data described below reflect exposure to TAGRISSO (80 mg daily) in patients with EGFR T790M mutation-positive metastatic NSCLC in an open-label, randomized, active-controlled trial (AURA3, n=279) and in two single arm trials, AURA Extension (n=201) and AURA2 (n=210). Patients with a history of interstitial lung disease, drug induced interstitial disease or radiation pneumonitis that required: steroid treatment, serious arrhythmia or baseline QTc interval greater than 470 msec on electrocardiogram were excluded from trial enrollment.

AURA3 Trial The safety of TAGRISSO was evaluated in AURA3, a multicenter international open label randomized (2:1) controlled trial conducted in 419 patients with unresectable or metastatic EGFR T790M mutation-positive NSCLC who had progressive disease following first line EGFR TKI treatment.

A total of 279 patients received TAGRISSO 80 mg orally once daily until intolerance to therapy, disease progression, or investigator determination that the patient was no longer benefiting from treatment. A total of 136 patients received pemetrexed plus either carboplatin or cisplatin every three weeks for up to 6 cycles; patients without disease progression after 4 cycles of chemotherapy could continue maintenance pemetrexed until disease progression, unacceptable toxicity, or investigator determination that the patient was no longer benefiting from treatment. Left Ventricular Ejection Fraction (LVEF) was evaluated at screening and every 12 weeks. The median duration of treatment was 8.1 months for patients treated with TAGRISSO and 4.2 months for chemotherapytreated patients. The trial population characteristics were: median age 62 years, age less than 65 (58%), female (64%), Asian (65%), never smokers (68%), and ECOG PS 0 or 1 (100%).

The most common adverse reactions (≥20%) in patients treated with TAGRISSO were diarrhea (41%), rash (34%), dry skin (23%), nail toxicity (22%), and fatigue (22%). Serious adverse reactions were reported in 18% of patients treated with TAGRISSO and 26% in the chemotherapy group. No single serious adverse reaction was reported in 2% or more patients treated with TAGRISSO. One patient (0.4%) treated with TAGRISSO experienced a fatal adverse reaction (ILD/pneumonitis).

Dose reductions occurred in 2.9% of patients treated with TAGRISSO. The most frequent adverse reactions leading to dose reductions or interruptions were prolongation of the QT interval as assessed by ECG (1.8%), neutropenia (1.1%), and diarrhea (1.1%). Adverse reactions resulting in permanent discontinuation of TAGRISSO occurred in 7% of patients treated with TAGRISSO. The most frequent adverse reaction leading to discontinuation of TAGRISSO was ILD/pneumonitis (3%).

Tables 2 and 3 summarize common adverse reactions and laboratory abnormalities which occurred in TAGRISSO-treated patients in AURA3. AURA3 was not designed to demonstrate a

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TAGRISSO® (osimertinib) tablets, for oral use statistically significant reduction in adverse reaction rates for TAGRISSO, or for the control arm, for any adverse reaction listed in Tables 2 and 3.

Table 2.

Adverse Reactions Occurring in ≥10% of Patients Receiving TAGRISSO in AURA3 Adverse Reaction

TAGRISSO (N=279) All Gradesa (%)

Grade 3/4a (%)

Gastrointestinal disorders Diarrhea 41 1.1 Nausea 16 0.7 Stomatitis 15 0 Constipation 14 0 Vomiting 11 0.4 Skin disorders Rashb 34 0.7 Dry skinc 23 0 Nail toxicityd 22 0 Prurituse 13 0 Metabolism and Nutrition Disorders Decreased appetite 18 1.1 Respiratory, Thoracic and Mediastinal Disorders Cough 17 0 Musculoskeletal and Connective Tissue Disorders Back pain 10 0.4 General Disorders and Administration Site Conditions 22 1.8 Fatiguef

Chemotherapy (Pemetrexed/Cisplatin or Pemetrexed/Carboplatin) (N=136) All Gradesa Grade 3/4a (%) (%) 11 49 15 35 20

1.5 3.7 1.5 0 2.2

5.9 4.4 1.5 5.1

0 0 0 0

36

2.9

14

0

9

0.7

40

5.1

* NCI CTCAE v4.0. a No grade 4 events were reported. b Includes rash, rash generalized, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pustular, erythema, folliculitis, acne, dermatitis and acneform dermatitis. c Includes dry skin, eczema, skin fissures, xerosis. d Includes nail disorders, nail bed disorders, nail bed inflammation, nail bed tenderness, nail discoloration, nail disorder, nail dystrophy, nail infection, nail ridging, nail toxicity, onychoclasis, onycholysis, onychomadesis, paronychia. e Includes pruritus, pruritus generalized, eyelid pruritus. f Includes fatigue, asthenia.

Table 3.

Common Laboratory Abnormalities (>20% for all NCI CTCAE Grades) in AURA3 TAGRISSO (N=279)

Laboratory Abnormality

Leukopenia Lymphopenia Thrombocytopenia Neutropenia a

Chemotherapy (Pemetrexed/Cisplatin or Pemetrexed/Carboplatin) (N=131a) Change from Change from Change from Change from Baseline to Baseline Baseline to Baseline Grade 3 or All Grades Grade 3 or Grade All Grades Grade 4 (%) 4 (%) (%) (%) 61 1.1 75 5.3 63 8.2 61 9.9 46 0.7 48 7.4 27 2.2 49 12

Based on the number of patients with available follow-up laboratory data

AURA Extension and AURA2 Trials The safety of TAGRISSO was evaluated in two single arm trials, AURA Extension (n=201) and AURA2 (n=210). A total of 411 patients with EGFR 790M mutation-positive NSLC who received one or more prior EGFR therapies including an EGFR TKI were treated with TAGRISSO (80 mg daily).

The majority of patients were heavily pretreated. Prior to enrollment, 68% of patients had received at least 2 prior treatment regimens, 46% had received 3 or more prior lines of therapy, and 63% had received prior platinum-based chemotherapy.

Median duration of exposure to TAGRISSO was 7.7 months (range: <0.1 to 11.6 months). The toxicity profile of TAGRISSO observed in the AURA Extension and AURA2 trials was generally consistent with the toxicity profile observed in the AURA3 trial. Four patients (1%) treated with TAGRISSO developed fatal adverse reactions of ILD/pneumonitis. Discontinuation of therapy due to adverse reactions occurred in 5.6% of patients treated with TAGRISSO. The most frequent adverse reactions that led to discontinuation were ILD/pneumonitis.

DRUG INTERACTIONS Effect of Other Drugs on Osimertinib Strong CYP3A Inducers Coadministering TAGRISSO with a strong CYP3A4 inducer decreased the exposure of osimertinib compared to administering TAGRISSO alone [see Clinical Pharmacology (12.3) in full Prescribing Information]. Decreased osimertinib exposure may lead to reduced efficacy.

Avoid coadministering TAGRISSO with strong CYP3A inducers (e.g., phenytoin, rifampin, carbamazepine, St. John’s Wort) [note: effect of St. John’s Wort varies widely and is preparationdependent]. Increase the TAGRISSO dosage when coadministering with a strong CYP3A4 inducer if concurrent use is unavoidable [see Dosage and Administration (2.4) in full Prescribing Information]. No dose adjustments are required when TAGRISSO is used with moderate and/or weak CYP3A inducers.

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2

Effect of Osimertinib on Other Drugs Coadministering TAGRISSO with a BCRP substrate increased the exposure of the BCRP substrate compared to administering the BCRP substrate alone [see Clinical Pharmacology (12.3) in full Prescribing Information]. Increased BCRP substrate exposure may increase the risk of exposurerelated toxicity.

Monitor for adverse reactions of the BCRP substrate (e.g., rosuvastatin, sulfasalazine, topotecan), unless otherwise instructed in its approved labeling, when coadministered with TAGRISSO. USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary Based on data from animal studies and its mechanism of action, TAGRISSO can cause fetal harm when administered to a pregnant woman. There are no available data on TAGRISSO use in pregnant women. Administration of osimertinib to pregnant rats was associated with embryolethality and reduced fetal growth at plasma exposures 1.5 times the exposure at the recommended human dose [see Data]. Advise pregnant women of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically-recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data Animal Data When administered to pregnant rats prior to embryonic implantation through the end of organogenesis (gestation days 2-20) at a dose of 20 mg/kg/day, which produced plasma exposures of approximately 1.5 times the clinical exposure, osimertinib caused post-implantation loss and early embryonic death. When administered to pregnant rats from implantation through the closure of the hard palate (gestation days 6 to 16) at doses of 1 mg/kg/day and above (0.1-times the AUC observed in patients at the recommended dose of 80 mg), an equivocal increase in the rate of fetal malformations and variations was observed in treated litters relative to those of concurrent controls.

When administered to pregnant dams at doses of 30 mg/kg/day during organogenesis through lactation Day 6, osimertinib caused an increase in total litter loss and postnatal death. At a dose of 20 mg/kg/day, osimertinib administration during the same period resulted in increased postnatal death as well as a slight reduction in mean pup weight at birth that increased in magnitude between lactation days 4 and 6.

Lactation Risk Summary There are no data on the presence of osimertinib in human milk, the effects of osimertinib on the breastfed infant or on milk production. Administration to rats during gestation and early lactation was associated with adverse effects, including reduced growth rates and neonatal death [see Use in Specific Populations (8.1) in full Prescribing Information]. Because of the potential for serious adverse reactions in breastfed infants from osimertinib, advise a lactating woman not to breastfeed during treatment with TAGRISSO and for 2 weeks after the final dose.

Females and Males of Reproductive Potential Contraception Females Advise females of reproductive potential to use effective contraception during treatment with TAGRISSO and for 6 weeks after the final dose [see Use in Specific Populations (8.1) in full Prescribing Information].

Males Advise male patients with female partners of reproductive potential to use effective contraception during and for 4 months following the final dose of TAGRISSO [see Nonclinical Toxicology (13.1) in full Prescribing Information].

Infertility Based on animal studies, TAGRISSO may impair fertility in females and males of reproductive potential. The effects on female fertility showed a trend toward reversibility. It is not known whether the effects on male fertility are reversible [see Nonclinical Toxicology (13.1) in full Prescribing Information].

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

Geriatric Use Three hundred and forty-six (42%) of the 833 patients in AURA3 (n=279), AURA Extension (n=201), AURA2 (n=210), and an expansion cohort in the first-in-human trial of osimertinib (AURA1, n=143) were 65 years of age and older. No overall differences in effectiveness were observed based on age. Exploratory analysis suggests a higher incidence of Grade 3 and 4 adverse reactions (9.8% versus 6.8%) and more frequent dose modifications for adverse reactions (10.1% versus 6.0%) in patients 65 years or older as compared to those younger than 65 years.

Renal Impairment No dose adjustment is recommended in patients with mild, [creatinine clearance (CLcr) 60-89 mL/min, as estimated by the Cockcroft Gault method (C-G)] moderate, (CLcr 30-59 mL/min, as estimated by C-G) or severe (CLcr 15-29 mL/min) renal impairment. There is no recommended dose of TAGRISSO for patients with end-stage renal disease [see Clinical Pharmacology (12.3) in full Prescribing Information].

Hepatic Impairment No dose adjustment is recommended in patients with mild hepatic impairment [total bilirubin less than or equal to upper limit of normal (ULN) and AST greater than ULN or total bilirubin between 1.0 to 1.5 times ULN and any AST] or moderate hepatic impairment (total bilirubin between 1.5 to 3 times ULN and any AST). There is no recommended dose for TAGRISSO for patients with severe hepatic impairment [see Clinical Pharmacology (12.3) in full Prescribing Information].

Distributed by: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850 TAGRISSO is a registered trademark of the AstraZeneca group of companies. ©AstraZeneca 2017 Iss. 03/17 3338004 4/17

1/4/18 12:35 PM

LATEST NEWS

Tumor-treating Fields Improve Glioblastoma Outcomes Using tumor-treating fields (TTFields) with maintenance temozolomide improves progression-free survival (PFS) and overall survival (OS) among patients with glioblastoma, according to the final analysis of a phase 3 study published in JAMA. Although resection and maintenance temozolomide have improved outcomes among patients with glioblastoma, survival rates remain poor, with as few as 1 in 20 patients surviving for longer than 5 years. TTFields, which are applied directly to the scalp, induce mitotic arrest in glioblastoma cells, and showed synergistic activity with temozolomide in tumor models.

For this open-label phase 3 study (ClinicalTrials.gov Identifier: NCT00916409), researchers randomly assigned 695 participants 2:1 to receive maintenance temozolomide with TTFields (466 patients) or temozolomide alone (229 patients). The median patient age was 56 years; all patients had undergone tumor resection or biopsy and completed concomitant radiochemotherapy.

The median PFS was 6.7 months in the TTFields group vs 4 months in the temozolomide only group (P < .001); the median OS was 20.9 months in the TTFields group vs 16 months in the temozolomide only group (P < .001). Improvement was seen in all subgroups.

Patients in the TTFields group who underwent biopsy rather than gross total resection, however, had better a hazard ratio for OS (.50 vs .70, respectively).

Adverse event rates were similar in both groups, though patients treated with TTFields were much more likely to have mild to moderate skin toxicity (52% vs no patients in the temozolomide group).

The authors concluded that “the addition of TTFields to maintenance temozolomide chemotherapy vs maintenance temozolomide alone […] resulted in statistically significant improvement in progression-free survival and overall survival.”

Vemurafenib Effective in BRAFmutated Erdheim-Chester Disease and Langerhans Cell Histiocytosis Vemurafenib confers a durable and clinically beneficial effect among patients with BRAF V600 -mutant Erdheim-Chester disease (ECD) or Langerhans cell histiocytosis (LCH), according to a study published in JAMA Oncology.

Although patients with ECD or LCH frequently have BR AF V600 mutations and respond to BR AF V600 inhibitor therapy, there is a lack of data describing long-term efficacy and safety.

For this cohort of the open-label phase 2 VE-BASKET study (ClinicalTrials.gov Identifier: NCT01524978), researchers assigned 26 patients (22 patients with ECD, 4 patients with LCH) to receive vemurafenib 960 mg twice daily. Patient response to therapy was assessed twice, separated by at least 4 weeks; 18F-fluorodeoxygluclose (FDG) positron-emission tomography (PET)/computed tomography (CT) scans were performed at baseline and every 8 weeks.

The overall response rate (ORR) was 61.5% (95% CI, 40.6%-79.8%) for the cohort overall and 54.5% (95% CI, 32.2%-75.6%) among patients with ECD. All evaluable patients achieved at least minimum stable disease.

Median progression-free survival (PFS) and overall survival (OS) were not reached after the median follow-up of 28.8 months, but the 2-year PFS and 2-year OS rates were 86% (95% CI, 72%-100%) and 96% (95% CI, 87%-100%), respectively.

Patients evaluated by FDG-PET/CT all had a metabolic response; 80% had a complete metabolic response.

The most frequently reported adverse events (AEs) included arthralgia, fatigue, maculopapular rash, QT prolongation, alopecia, hyperkeratosis, and skin papilloma.

The authors concluded that “vemurafenib had prolonged efficacy in patients with [BRAF V600-mutant] ECD and LCH and warrants consideration as a new standard of care for these patients.”

A14 CANCER THERAPY ADVISOR | JANUARY/FEBRUARY 2018 | CancerTherapyAdvisor.com

© BSIP / SCIENCE SOURCE

The median follow-up was 36.5 months. Patients in the gefitinib group had a median DFS of 28.7 months vs 18 months with chemotherapy (hazard ratio, 0.6; P = .0054).

Overall survival data are not, however, yet mature.

While the grade 1 to 2 adverse event (AE) rate was higher in the gefitinib group (45%) than in the chemotherapy group (32%), fewer patients in the gefitinib group (12%) had a grade 3 to 4 AE than those in the chemotherapy group (48%). The most common grade 3 or worse AEs in the gefitinib group were elevated alanine aminotransferase and elevated aspartate aminotransferase; the most common grade 3 or worse AEs in the chemotherapy group were neutropenia and leukopenia.

The authors concluded that “gefitinib could be considered a treatment option for this population of patients; however, mature data for overall survival are needed.”

LATEST NEWS The following articles are coverage of practice-changing research presented at the 59th American Society of Hematology (ASH) Annual Meeting, which took place on December 9-12, 2017, in Atlanta, Georgia.

Radotinib May Yield Superior Outcomes to Imatinib in Newly Diagnosed Chronic Myeloid Leukemia Radotinib yields earlier, deeper, and significantly higher major molecular response (MMR) rates in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) compared with imatinib, according to an oral presentation at the 2017 ASH Annual Meeting.

In the open-label phase 3 RERISE study, researchers randomly assigned 241 patients to receive radotinib 300 mg twice daily, radotinib 400 mg twice daily, or imatinib 400 mg once daily. Analyses at 12 and 24 months showed that patients treated with radotinib twice daily achieved significantly higher and faster rates of MMR and MR4.5 compared with imatinib. Patients who had a complete cytogenic response after 12 months were followed for 3 years.

This 36-month analysis showed that patients in the radotinib 300 mg arm had a significantly higher MMR rate of 75% than the 54% MMR rate noted in the imatinib arm (P = .0076). The MR4.5 rate was also higher, at 43% vs 28% in the radotinib arm vs the imatinib arm, respectively (P = .0538).

The estimated 36-month overall survival rates were 98% and 97% in the radotinib arm and the imatinib arm (P = .0554), respectively, and the 36-month progression-free survival rates were 99% vs 95%, respectively (P = .4707).

Fewer deaths and treatment failures occurred in the radotinib arm (6%) compared with the imatinib arm (17%) during the study, though this difference was insignificant.

The safety profiles were consistent with those previously reported: the most frequent adverse events included rash, nausea/vomiting, fatigue, and hyperbilirubinemia.

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Inotuzumab Ozogamicin Plus Bosutinib May Be Safe, Effective for Relapsed/Refractory ALL and CML Inotuzumab ozogamicin with bosutinib is a safe, tolerable, and potentially effective treatment for patients with Philadelphia chromosomeâ&#x20AC;&#x201C;positive relapsed or refractory acute lymphoblastic leukemia (ALL) or chromic myeloid leukemia (CML) in blast phase, according to interim results of a study presented at the 2017 American Society of Hematology (ASH) Annual Meeting in Atlanta, Georgia.

Despite therapeutic advances, patients with relapsed/ refractory ALL or CML in blast phase have poor outcomes.

In this setting, ALL exhibits high CD22 expression, which is inhibited by inotuzumab ozogamicin.

For this phase 1/2 study (ClinicalTrials.gov Identifier: NCT02311998), researchers evaluated the safety and efficacy of inotuzumab ozogamicin in combination with bosutinib, a tyrosine kinase inhibitor approved for blast-phase CML, among patients with relapsed/refractory ALL or CML. Of 14 patients enrolled and treated, 12 had ALL and 2 had blast-phase CML; the median age was 62 years. One dose-limiting toxicity was observed with bosutinib 400 mg daily; none were observed with bosutinib 300 mg daily. Dose-limiting toxicity evaluation is ongoing for bosutinib 500 mg daily.

Eleven patients had a complete response: 10 had complete cytogenic remission, 8 were negative by flow cytometry, 6 had undetectable BCR-ABL. Three patients did not respond.

The median event-free survival was 8.1 months; the median overall survival was 8.2 months. Four patients are still in remission after allogeneic hematopoietic stem cell transplantation.

The authors added that once the maximum tolerated dose is established, phase 2 will begin.

Imatinib Effective as Front-line Therapy for Pediatric Chronic Myeloid Leukemia First-line imatinib is effective and safe among pediatric patients with chronic myeloid leukemia (CML), according to a study presented at the 2017 ASH Meeting in Atlanta, Georgia.

For the prospective CML-PAED-II study, researchers enrolled 156 patients with newly diagnosed CML. Patients received imatinib 300 mg/m2, 400 mg/m2, and 500 mg/m2 for chronic phase (CML-CP), accelerated phase (CML-AP), and blast phase (CML-BP) disease, respectively. Of the enrolled patients, 148 had evaluable data.

The median follow-up was 25 months. Patients with CMLCP had an 18-month event-free survival rate of 97% (95% CI, 94.2%-99.9%).

Complete hematologic response at month 3 was observed in 98% of patients, complete cytogenic response (CCyR) at month 12 was observed in 63% of patients, and molecular

CancerTherapyAdvisor.com | JANUARY/FEBRUARY 2018 | CANCER THERAPY ADVISOR A15

LATEST NEWS

Nilotinib Dose, Frequency Reduction Maintains Efficacy in Chronic Myeloid Leukemia Switching from nilotinib twice daily to once daily at a reduced dose does not compromise clinical activity among patients with chronic myeloid leukemia (CML) who have a major molecular response (MMR), according to data presented at the 2017 American Society of Hematology (ASH) Annual Meeting in Atlanta, Georgia.

Standard nilotinib regimens involve twice-daily oral administration but present a barrier for therapy adherence because of the specificity of scheduling and dietary considerations.

Once-daily dosing is recommended only for toxicity-related dose reductions.

For the observational NILO-RED study, researchers analyzed the outcomes of 67 patients with BCR-ABL1-positive CML in chronic phase who had an MMR on nilotinib twice daily and who then switched to a once-daily reduced-dose regimen.

The primary reasons for switching to reduced dose were non-serious adverse events and patient convenience. The median duration of once-daily nilotinib was 24 months.

At baseline, 13.4%, 25.4%, and 61.2% of patients had an MMR, MR4, and greater than MR4.5, respectively, and 47.8% of patients had undetectable levels of BCR-ABL1 transcripts.

Two patients lost MMR after dose reduction, but spontaneously recovered it without any treatment modifications.

Survival without MMR loss was 97.2% at 12 months, and a molecular response category analysis showed that no patients who were at least MR4 at baseline lost MMR. At the last follow-up, 6.3%, 16.4%, and 77.6% of patients had MMR, MR4, and greater than MR4.5, respectively; 55.2% of patients had undetectable BCR-ABL1 transcripts levels.

The authors concluded that these “results may pave the way for clinical trials aiming at systematic avoidance of overtreatment and improvement of [patients’] convenience in treatment with nilotinib.”

Induction to Deepen Pre-transplant Response Does Not Improve OS in Multiple Myeloma Pre-transplant induction therapy with lenalidomide, bortezomib, or carfilzomib did not improve overall survival (OS) among patients with multiple myeloma (MM), suggesting that many patients should proceed directly to autologous stem cell transplantation (ASCT) after first-line therapy, according to a study presented at the 2017 American Society of Hematology Annual Meeting (ASH) in Atlanta, Georgia.

For this study, researchers evaluated the outcomes of 496 patients with MM who underwent ASCT. All patients received dexamethasone, 86% of patients received a bortezomib-containing treatment regimen, 70% received a lenalidomide-containing regimen, 61% received bortezomib plus lenalidomide, and 2% received a carfilzomib-containing regimen. Five percent of patients did not receive bortezomib, lenalidomide, or carfilzomib. The median follow-up time was 52.2 months.

There was no difference in OS among patients treated with bortezomib, lenalidomide, or carfilzomib as induction monotherapy or combination therapy compared with patients who did not receive these treatments (P = .4599).

Progressive disease (PD) at time of transplantation was significantly associated with a lower OS (P = .002), and no significant impact was observed among patients with a complete response, a very good partial response, a partial response, or stable disease. Of patients that did not have PD and received subsequent treatments to deepen their response, 29 had PD at time of transplantation.

The authors concluded that “our data supports continuing to second-line therapy only for patients in PD after first line.

All other patients should proceed to mobilization and ASCT.”

A16 CANCER THERAPY ADVISOR | JANUARY/FEBRUARY 2018 | CancerTherapyAdvisor.com

© DNDAVIS / GETTY IMAGES

response (MR3.0) at month 18 was observed in 59% of patients.

After 3 years of receiving continuous first-line imatinib or second-generation tyrosine kinase inhibitor (TKI) therapy, 86% and 74% of patients achieved CCyR and MR3.0, respectively.

Approximately 66% of patients reported at least 1 adverse event (AE); the most frequently reported AE of any grade was imatinib-related anemia and the most frequently reported grade 3 to 4 hematologic AE was neutropenia. Gastrointestinal and musculoskeletal AEs were also common.

Eighteen percent of patients had to suspend therapy and 6% of patients discontinued treatment because of intolerable AEs; 27% of patients failed therapy because of unsatisfactory response or intolerance. Nineteen percent of patients underwent stem cell transplantation (SCT), of which 3 patients died of relapse and 2 died of SCT-related complications.

The authors concluded that “long term outcome and effects of potentially life-long TKI treatment have to be registered in cooperation with adult hematologists in extended surveillance follow-up studies.”

LATEST NEWS

LATEST NEWS

© IMAGEBROKER RM / WERNER BACHMEIER / MEDICAL IMAGES

Bortezomib-based Induction Improves PFS, OS in High-risk Newly Diagnosed Multiple Myeloma High-risk patients with newly diagnosed multiple myeloma (NDMM) who receive bortezomib-based induction therapy have improved progression-free survival (PFS) and overall survival (OS) compared with patients who receive lenalidomide-based therapy, according to an oral presentation at the 2017 ASH Annual Meeting.

A relevant prognostic factor for patients with MM is cytogenetic abnormalities determined by fluorescence in situ hybridization (FISH), but the effect these abnormalities have among high-risk transplant-ineligible patients treated with bortezomib or lenalidomide was previously not investigated.

In the phase 3 GIMEMA-MM-03-05-trial (ClinicalTrials. gov Identifier: NCT01063179), patients were randomly assigned to receive bortezomib, melphalan, prednisone, and thalidomide for 9 cycles, followed by maintenance bortezomib plus thalidomide (VMPT-VT), or bortezomib, melphalan, and prednisone (VMP) for 9 cycles without maintenance.

For the phase 3 EMN01-trial (ClinicalTrials.gov Identifier: NCT01093196), patients were randomly assigned to receive cyclophosphamide, prednisone, and lenalidomide (CPR), melphalan, prednisone, and lenalidomide (MPR), or lenalidomide plus low-dose dexamethasone (Rd) for 9 cycles. All study patients received maintenance therapy with lenalidomide with or without prednisone.

All 1165 study patients underwent cytogenetic testing by FISH and were stratified according to their International Myeloma Working Group cytogenetic risk criteria; patients with del(17p), t(4;14), or t(14;16) were considered to be high risk, all other patients were standard risk.

Nine-hundred and two patients had evaluable cytogenetic profiles, of whom 27% and 73% were characterized as high risk and standard risk, respectively. The median follow-up of patients treated with bortezomib was 72.3 months; the median follow-up was 63.6 months among patients treated with lenalidomide.

The median PFS was 30.8 months compared with 14.8 months in bortezomib-treated patients vs lenalidomide-treated patients who were high risk, respectively (hazard ratio [HR], 0.54; 95% CI, 0.41-0.72), and 29.1 months compared with 22.1 months among patients who were standard risk, respectively (HR, 0.87; 95% CI, 0.72-1.05).

Median OS was 62.4 months among high-risk patients in the bortezomib arm vs 43.2 months in the lenalidomide arm

(HR, 0.68; 95% CI, 0.47-0.96); median OS was 78.1 months among standard-risk patients in the bortezomib arm vs not reached in the lenalidomide arm (HR, 1.06; 95% CI, 0.821.36) (interaction-P = .04).

Median PFS was 18.0 vs 12.9 months among patients with del(17p) who received bortezomib vs lenalidomide, respectively (HR, 0.71; 95% CI; 0.49-1.04). Median PFS was 31.5 vs 15.2 months among patients with t(4;14) who received bortezomib vs lenalidomide, respectively (HR, 0.41; 95% CI, 0.27-0.62). Median PFS was 36.2 vs 9.8 months among patients with t(14;16) who received bortezomib vs lenalidomide, respectively (HR, 0.34; 95% CI, 0.16-0.76).

The authors concluded the results of this study “support VMP induction as a standard treatment option for patients with NDMM who are ineligible for transplant with [high-risk] cytogenetics.”

Elotuzumab Meets Primary Endpoint of ORR for Newly Diagnosed Multiple Myeloma Elotuzumab plus lenalidomide and dexamethasone (ELd) is safe and effective among patients with newly diagnosed multiple myeloma (NDMM) and improves the overall response rate (ORR) compared with lenalidomide and dexamethasone (Ld) alone, according to an oral presentation at the ASH Annual Meeting in Atlanta, Georgia.

For this open-label, phase 2 study (ClinicalTrials.gov Identifier: NCT02272803), investigators randomly assigned 82 patients with NDMM ineligible for high-dose chemotherapy plus hematopoietic cell transplantation to receive intravenous ELd or Ld alone. Patients in the ELd arm received prophylactic medication to prevent infusion reactions (IR), and in the absence of IR the infusion rate was increased from 0.5-2.0 mL/min to 5 mL/min.

At time of data analysis minimum follow-up was 6 months; 78% and 60% of patients in the ELd and Ld arms remained in the study, respectively. The investigator-assessed ORR was 88% in the ELd arm compared with 74% in the Ld arm.

A very good partial response was observed in 45% and 29% of ELd- and Ld-treated patients, respectively.

Adverse events (AEs) were reported by 100% of patients in the ELd arm and by 98% of patients in the Ld arm.

The most frequently reported AEs included constipation, pyrexia, rash, diarrhea, nasopharyngitis, dysgeusia, malaise, peripheral edema, neutropenia, leukopenia, and back pain; the most common grade 3 to 4 AEs were neutropenia and leukopenia.

CancerTherapyAdvisor.com | JANUARY/FEBRUARY 2018 | CANCER THERAPY ADVISOR A17

LATEST NEWS Only 1 IR was reported in the ELd arm and treatment was interrupted, but the patient did not have any further IR in subsequent treatments. Ninety-five percent of patients received elotuzumab at the increased rate of 5 mL/min without any incidence of IR. The authors concluded that “ELd had an acceptable safety profile in this pt population, and an increased infusion rate of 5 mL/min, which reduced infusion time and did not induce additional IRs.”

to A + AVD towards the end of the study were recommended G-CSF by the Independent Data Monitoring Committee to reduce the incidence of febrile neutropenia.

The authors concluded that this study “establishes A + AVD as a new frontline option for patients with advanced-stage HL.”

Brentuximab Vedotin Plus Doxorubicin, Vinblastine, and Dacarbazine Prolongs PFS in Hodgkin Lymphoma

Ibrutinib is a safe and highly active treatment among previously untreated patients with Waldenstrom macroglobulinemia (WM), according to a poster presented at t he 2017 A merican Societ y of Hematology Annual Meeting.

Ibrutinib — a Bruton’s tyrosine kinase (BTK) inhibitor — is currently used among patients with WM who have previously received treatment, but its efficacy as a first-line therapy among treatment-naive patients is unknown.

For this prospective, open-label, single group assignment phase 2 study (ClinicalTrials.gov Identifier: NCT02604511), researchers enrolled 30 patients with untreated WM and administered ibrutinib 420 mg daily. Patients’ baseline characteristics included median serum IgM of 4369 and median bone marrow disease involvement of 65%. All patients had MYD88 mutation–positive disease, and 47% of patients had a CXCR4 mutation.

The median time on therapy was 8.1 months; the median time on therapy for patients with a CXCR4 wild-type or CXCR4 mutation was 9.4 months vs 8.0 months, respectively (P = .98).

The overall response rate was 96.7%, the major response rate (greater than partial response) was 80%, and a very good partial response was reached by 17% of patients. No patients had a complete response.

Median serum IgM levels decreased from 4380 to 1786 (P = .0001) at best response; at baseline, 60% of patients had a serum IgM greater than 3000 mg/dL compared with just 7% of patients at best response (P < .0001).

At best response, median bone marrow involvement was reduced to 20% from 65% (P < .0001), and 70% and 80% of patients with adenopathy and splenomegaly, respectively, had a reduction or resolution of these conditions. Patients also had an increase in median hemoglobin levels, from 10.3 to 13.6 g/dL (P < .0001).

Mutated CXCR4 was associated with delayed patient response to ibrutinib.

The authors concluded that ibrutinib is “highly active and well-tolerated as a single agent, with no unexpected toxicities.”

A18 CANCER THERAPY ADVISOR | JANUARY/FEBRUARY 2018 | CancerTherapyAdvisor.com

© DOROTHEA ZUCKER-FRANKLIN / MEDICAL IMAGES

First-line therapy with brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (A + AVD) improves progression-free survival (PFS) among patients with Hodgkin lymphoma (HL) compared with the long-time standard of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), according to an oral presentation at the 2017 American Society of Hematology Annual Meeting.

For the open-label, phase 3 Echelon-1 study (ClinicalTrials. gov Identifier: NCT01712490), researchers randomly assigned 1334 patients with untreated stage III or IV HL to receive A + AVD or ABVD for 6 cycles.

Modified PFS outcomes were determined by both independent review facility (IRF; hazard ratio [HR], 0.770; 95% CI, 0.603-0.982; P = .035) and investigator (INV; HR, 0.725; 95% CI, 0.574-0.916; P = .007) assessment, with 146 events in the ABVD arm noted compared with 116 events in the A + AVD arm. The A + AVD and ABVD arms had 90 and 102 instances of disease progression, respectively, 18 and 22 deaths, and 9 and 22 cases of additional therapy being needed for an incomplete response.

Twenty-eight deaths were reported in the A + AVD arm compared with 39 deaths in the ABVD arm (HR, 0.721; 95% CI, 0.443-1.173; P = .186).

The safety profile of both regimens remained consistent with previous reports. A + AVD and ABVD had respective neutropenia rates of 58% and 45% (febrile neutropenia in 19% and 8%), peripheral neuropathy rates of 67% and 43%, pulmonary toxicity rates of 3% and less than 1%, and grade 3 or worse infection rates of 18% and 10%. Of the patients who had peripheral neuropathy in the A + AVD arm, 67% had resolution or improvement by the last follow-up.

Prophylaxis with a granulocyte colony-stimulating factor (G-CSF) reduced the rate of febrile neutropenia and grade 3 or worse infections and infestations. New patients assigned

Ibrutinib Effective as First-line Therapy for Waldenstrom Macroglobulinemia

C. ANDREW KISTLER, MD, PharmD, RPh

Monitoring for Post–organ Transplant Skin Cancer As medications are used to reduce the immune reaction to a foreign organ, they may also reduce the body’s ability to accurately survey for malignant cells.

T

ransplant surgery can be a challenging process. The patient’s post-operative course can, however, also be demanding. After transplant, patients are frequently placed on anti-rejection medications such as tacrolimus, sirolimus, cyclosporine, mycophenolate mofetil, and occasionally steroids.

Many of these patients also receive significant polypharmacy for other chronic conditions. Although there have been advances in the medications used to help prevent rejection, there are also associated side effects and long-term risks that should be explained to the patient. One such long-term risk of using anti-rejection medications is cancer, the most common variety of which is a skin malignancy.1-4 Up to 40% of all malignancies that develop in this setting are skin cancers, which are typically basal cell carcinomas (BCCs) or squamous cell carcinomas (SCCs). Post-transplant Caucasians have a significantly increased risk of skin cancer: more than 50% of these patients will develop the malignancy. A recent retrospective cohort study found, after evaluating close to 11,000 post–solid organ transplant patients, that approximately 8% developed skin cancer.4 The incidence rate was estimated at 1437 per 100,000 patient-years; the most common skin cancers included SCCs and melanomas. Risk factors for the diseases included being male, Caucasian, at least 50 years old at time of transplant, having

undergone thoracic organ transplant, and incidence of pre-transplant skin cancer.

The pathophysiology underlying this increased risk of skin cancer is not entirely understood, though some evidence suggests that a major contributor is the immunosuppressant medication these patients receive for anti-rejection.

The medications themselves, especially the calcineurin inhibitors, may be toxic to cells by impairing their ability correct damaged cellular DNA. As these medications are used to reduce the body’s immune

| IN THE CLINIC immunosuppressants associated with a lower risk of skin cancer compared with calcineurin inhibitors.6 A thorough dermatological exam prior to transplantation is vital for diagnosis as well as for documenting a detailed baseline for post-surgery reference. The patient should complete a comprehensive family history questionnaire regarding skin cancer incidence.

Patients should also be extensively counselled on performing self-skin exams monthly, with the aim of being able to identify suspicious lesions and of understanding appropriate sun protection.

While there are no definitive guidelines for intervals of formal dermatologic screenings with a physician, most asymptomatic patients with no history of skin cancer are typically screened every 6 to 12 months after transplant. ■ References 1. Vajdic CM, van Leeuwen MT. Cancer incidence and risk factors after solid organ transplantation. Int J Cancer. 2009; 125(8):1747-54.

Post-transplant Caucasians have a significantly increased risk of skin cancer.

2. Mittal A, Colegio OR. Skin cancers in organ transplant recipients. Am J Transplant.

2017;17(10):2509-30.

3. Euvrard S, Kanitakis J, Claudy A. Skin cancers after organ transplantation. N Engl J

Med. 2003;348:1681-91.

4. Garrett GL, Blanc PD, Boscardin J. Incidence

reaction to a foreign organ, they may also reduce the body’s ability to accurately survey for malignant cells — and allow established cancer cells and associated viruses to multiply without any regulation.5 The viruses most associated with post-transplant cancers include human T cell lymphotropic virus 1 (HTLV-1), Epstein-Barr virus (EBV), and Kaposi sarcoma herpes virus (KSHV), many of which have been linked in particular to skin cancer. Interestingly, some studies support the mTOR class of medications (everolimus, sirolimus) as the class of

of and risk factors for skin cancer in organ transplant recipients in the United States.

JAMA Dermatol. 2017;153(3):296-303.

5. Wheless L, Jacks S, Mooneyham Potter KA, Leach BC, Cook J. Skin cancer in organ transplant recipients: more than the immune system. J Am Acad Dermatol.

2014;71(2):359-65.

6. Knoll GA, Kokolo MB, Mallick R. Effect of sirolimus on malignancy and survival after kidney transplantation: systematic review and meta-analysis of individual patient data.

BMJ. 2014;349:g6679. doi: 10.1136/bmj. g6679

CancerTherapyAdvisor.com | JANUARY/FEBRUARY 2018 | CANCER THERAPY ADVISOR A19

FEATURE

The Warburg Effect: Can Cancer Be Starved of Sugar?

BY CARLOS HARRISON

T

he mysterious relationship between the Warburg effect and oncogenesis has been debated for nearly a century.

Recently, however, a team of Belgian molecular biologists found a possible explanation — and a direct link between sugar intake and cancer.1 The result of their 9-year study not only provides a clear warning for patients to reduce sugar consumption, but also a new and novel avenue for therapy, the lead author, Johan Thevelein, PhD, a professor at KU Leuven and Vlaams Instituut for Biotechnology in Belgium, said in a telephone interview with Cancer Therapy Advisor.

“The direct significance of our work is that patients have to be careful with sugar,” he said, “because we have identified a mechanism by which high sugar activates the aggressiveness of cancer.”

Simply put, Dr Thevelein said, he and his colleagues found a clear link between fructose 1,6-bisphosphate and activation of oncogenic Ras proteins.

The study appeared almost simultaneously to an opinion article positing that similarities between the glycogen shunt in yeast and cancer explains lactate produced in the Warburg effect.

The “glycogen shunt,” the paper explains, “describes conditions when glucose is shunted to glycogen and subsequently consumed through glycolysis even though adequate glucose and other energy supplies are present, thereby coupling glycogen synthesis and breakdown pathways to glycolysis.”2 That, the authors suggested, would explain the central paradox of the Warburg effect — aerobic glycolysis, or why cancer cells ferment glucose to produce lactate even when oxygen is present.

“The coordinated action of the glycogen shunt and glycolysis allows the cells to store

glucose as glycogen while maintaining homeostasis of glycolytic intermediates and ATP and supplying glycolytic substrates for the PPP [pentose phosphate pathway] when needed,” they wrote. “The storage of excess glucose intake as glycogen allows energy to be preserved for future use, even though efficiency is slightly reduced by the net production of lactate.”

The Warburg effect takes its name from Otto Warburg’s discovery in the 1920s that tumors take up huge amounts of glucose, which they ferment into lactate rather than respire. He postulated that dysfunctional mitochondria might be to blame, and that aerobic glycolysis is the primary cause of cancer.

Since then, thousands of papers have been published with multiple explanations of the effect proposed. Among them, a 2016 review noted, is “an adaptation mechanism to support the biosynthetic requirements of uncontrolled proliferation,” as “a tradeoff to support

© TTSZ / GETTY IMAGES

A recent study into the relationship between glucose and cancer cell proliferation may be helping to identify a therapeutic route to starve tumors.

Conceptual depiction of the Warburg effect

A20 CANCER THERAPY ADVISOR | JANUARY/FEBRUARY 2018 | CancerTherapyAdvisor.com

FEATURE biosynthesis,” in acidification of the tumor microenvironment, and “in direct signaling functions to tumor cells.”3 That led the review’s authors to conclude that “it is likely we will require a better understanding of the biology of Warburg Effect if therapeutic advances are to be made in treating and preventing cancer using dietary and pharmacological intervention in metabolism, and in using glucose metabolism to manipulate the immune system, which are currently subjects of intense interest.”

The connection between Ras proteins and cancer development is, however, much better understood.

As a 2011 overview stated: “Studies during the last quarter century have characterized the Ras proteins as essential components of signaling networks controlling cellular proliferation, differentiation, or survival. The oncogenic mutations of the H-ras, N-ras, or K-ras genes frequently found in human tumors are known to throw off balance the normal outcome of those signaling pathways, thus leading to tumor development.

“Interestingly, the oncogenic Ras mutations and the mutations in other components of Ras/MAPK signaling pathways appear to be mutually exclusive events in most tumors, indicating that deregulation of Ras-dependent signaling is the essential requirement for tumorigenesis.”4 Sugar has long been linked to cancer indirectly through, for example, well-established associations between obesity and cancer. A 2014 policy paper by the American Society of Clinical Oncology (ASCO) noted that “obesity is a major under-recognized contributor to the nation’s cancer toll and is quickly overtaking tobacco as the leading preventable cause of cancer.”5 The ASCO paper did not mention sugar, but as Clare McKindley, a clinical dietitian, explained, “too much daily sugar can cause weight gain. And,

unhealthy weight gain and a lack of exercise can increase your cancer risks.”6 In fact, a study recently published in The Lancet Diabetes & Endocrinology determined that diabetes and obesity were the cause of nearly 6% of all cancers in 2012, accounting for some 792,600 cases around the world. And, the authors estimated, at current rates of increase in the prevalence of diabetes and obesity, “a substantially larger share of cancers would be attributable to these risk factors.”7 Regardless, a direct connection between sugar and tumor growth remains elusive.

“I think that we have a lead to find the primary cause of the high influx of sugar into the cancer cells,” Dr Thevelein said. “This hyper-rapid influx of sugar into the cancer cells is not present in regular mammalian cells.

“We can go for drugs that inhibit this hyper-rapid sugar influx and these drugs should then make life for the cancer cells very difficult because the cancer cells need this rapid influx for survival.

This is what we are following up now.” ■ References 1. Peeters K, Van Leemputte F, Fischer B, et al. Fructose-1,6-bisphosphate couples

“Obesity is a major under-recognized contributor to the nation’s cancer toll.”

glycolytic flux to activation of Ras. Nat

Commun. 2017;8(1):922. doi: 10.1038/ s41467-017-01019-z 2. Shulman RG, Rothman DL. The glycogen shunt maintains glycolytic homeostasis and the Warburg effect in cancer. Trends

Cancer. 2017;3(11):761-7. doi: 10.1016/j.

Dr Thevelein noted, however, that there is a clear correlation between diabetes and cancer, which may be a result of higher sugar levels in their blood. And, he continued, some recent clinical trials indicate that “sugar-poor diets are beneficial for recovery of patients with cancer.”

An immediate takeaway of his study’s findings, he added, is that hospitals should revisit the practice of giving patients glucose infusions to help strengthen them for continued chemotherapy. “The message now is that strengthening of the normal cells with high sugar may actually lead to activation of the cancer,” he said.

The challenge, Dr Thevelein said, is that all cells need sugar, so eliminating sugar intake completely would not only kill cancer cells, but normal cells as well.

If, however, oncologists can block the hyperactivity of the sugar to lactic acid conversion pathway only, normal cells might be spared.

The study’s results might therefore still offer a new target for cancer treatment.

trecan.2017.09.007 3. Liberti MV, Locasale JW. The Warburg effect: how does it benefit cancer cells?

Trends Biochem Sci. 2016;41(3):211-8. doi: 10.1016/j.tibs.2015.12.001 4. Fernández-Medarde A, Santos E. Ras in cancer and developmental diseases. Genes

Cancer. 2011;2(3):344-58.

5. Ligibel JA, Alfano CM, Courneya KS, et al.

American Society of Clinical Oncology position statement on obesity and cancer. J Clin

Oncol. 2014;32(31):3568-74.

6. Espat A. Does sugar cause cancer? The University of Texas MD Anderson Cancer Center website. http://bit.ly/1T1fHSB. Published May 2015. Accessed November 2017.

7. Pearson-Stuttard J, Zhou B, Kontis V, Bentham J, Gunter MJ, Ezzati M. Worldwide burden of cancer attributable to diabetes and high body-mass index: a comparative risk assessment. Lancet Diabetes

Endocrinol. 2017 Nov 28. doi: 10.1016/ S2213-8587(17)30366-2 [Epub ahead of print]

CancerTherapyAdvisor.com | JANUARY/FEBRUARY 2018 | CANCER THERAPY ADVISOR A21

VIEWPOINT | ANDREA S. BLEVINS PRIMEAU, P D, MBA h

Beta-blockers May Prevent Stress-induced Lung Cancer Treatment Resistance Psychological distress may be associated with an increased risk of mortality in patients with lung cancer.

B

y attenuating treatment resistance, beta (β)-blockers may improve clinical outcomes among patients with non–small cell lung cancer (NSCLC) receiving an EGFR inhibitor, according to a hypothesis-generating study published in Science Translational Medicine.1 Though second- and third-generation EGFR inhibitors have efficacy against resistant disease caused by the T790M mutation, about 50% of patients have disease resistant because of another mechanism. This study evaluated stress hormones as a potential mechanism driving T790M-independent EGFR inhibitor resistance using in vitro techniques and assessed clinical outcomes using data from 3 clinical trials.

Preclinical Findings “We knew from our previous studies that stress hormones cause dramatic increases in IL [interleukin]-6 in ovarian cancer cells. That led us to ask the question whether stress hormones could also increase IL-6 expression in NSCLC cells and in turn promote resistance to EGFR-targeted therapies,” said Monique B. Nilsson, PhD, of the University of Texas MD Anderson Cancer Center in Houston, and lead author of the study.

The study demonstrated that EGFR tyrosine kinase inhibitor (TKI)–resistant NSCLC cell lines had significantly greater mRNA expression of IL-6 compared with nonresistant parental cells (P = .0005).

The stress hormones norepinephrine and epinephrine, as well as β-adrenergic agonists, induced IL-6 mRNA expression in the resistant NSCLC cell lines, but not in normal human bronchial epithelial cells. β-adrenergic antagonists, however, prevented norepinephrine from inducing IL-6 expression.

In a xenograft mouse model, in which the EGFR TKI–resistant NSCLC cells were injected into mice, stress resulted in

“We knew from our previous studies that stress hormones cause dramatic increases in interleukin-6 in ovarian cancer cells.” significantly higher IL-6 levels (P = .002) and over 2-fold greater tumor volumes (P ≤ .04) compared with mice who were not stressed. Xenograft mice treated with a β-adrenergic agonist also demonstrated greater levels of IL-6 mRNA. Treatment of the xenograft mice with erlotinib resulted in tumor regression, though mice treated with erlotinib plus the β-adrenergic agonist became treatment resistant. The addition of a β-blocker or the anti-IL-6 antibody siltuximab to erlotinib and the

A22 CANCER THERAPY ADVISOR | JANUARY/FEBRUARY 2018 | CancerTherapyAdvisor.com

β-adrenergic agonist, however, prevented the development of treatment resistance.

These data suggest that blocking the β-adrenergic receptor or IL-6 may prevent erlotinib resistance, even in the presence of a β-adrenergic agonist.

Clinical Findings According to Dr Nilsson, “each of the trials we utilized had unique information available for our analyses — the ZEST trial allowed us to validate preclinical findings that high IL-6 is associated with worse response to EGFR inhibitors.”

In the phase 3 ZEST trial, 209 pretreatment plasma samples from patients with platinum-refractory NSCLC receiving erlotinib demonstrated that high levels of IL-6 were significantly associated with shorter overall survival (P < .0001) and progression-free survival (PFS; P = .0092) compared with lower levels of IL-6.

“The BATTLE clinical study allowed us to determine whether β-blocker use was associated with lower levels of IL-6,” Dr Nilsson said.

Circulating levels of IL-6 were significantly lower among patients receiving incidental pan β-blockers compared with patients who were not taking β-blockers during BATTLE. “Our preclinical data further indicated that the effect of stress hormones may be most pronounced in EGFRmutant NSCLC, so we evaluated data from the LUX-Lung3 study, which included only patients with NSCLC with EGFR mutations,” Dr Nilsson said.

In the phase 3 LUX-Lung3 trial, patients who were incidentally taking β-blockers experienced a greater benefit with afatinib compared with patients who did not use β-blockers.

A mong patients who did not use β-blockers, afatinib resulted in a median PFS of 11.1 months compared with 6.9 Continued on page A25

Lung Cancer Advisor A section of Cancer Therapy Advisor that features exclusive news and clinical content for oncologists who specialize in the treatment of patients with lung cancer.

Visit CancerTherapyAdvisor.com/lung to gain access to the following and more: • Articles on the latest news in lung cancer written by experts • • Lung cancer Treatment Regimens adapted from NCCN Guidelines® • • An extensive range of current and concise drug information • • Videos of oncology experts speaking about key topics in the field of lung cancer management •

EXPERT PERSPECTIVE | PAUL W. EWALD, P D AND HOLLY A. SWAIN EWALD, P D h

Cancer Drug Addiction: Prospects for Integrated Therapeutic Management The drug addiction strategy must be broadened to account for non-addicted cells, sensitive or resistant, that remain after therapy.

I

t is now recognized that cancer cells evolve resistance to therapeutic drugs in a way that parallels the evolution of microbial resistance to antimicrobials. This similarity is particularly evident for chemotherapeutic agents, which exert a strong selective pressure against sensitive cancer cells.

Yet the long-term development of chemotherapeutic and antimicrobial resistances differ, as cancer cells are not, as a rule, transmitted interpersonally.

The time over which resistance can evolve among cancer cells is, therefore, markedly truncated. This difference suggests that using chemotherapeutics may be sustainable over longer periods of time if the evolution of resistance within each patient can be managed.

One possibility for managing resistance is exploiting the evolved drug “addiction” among cancer cells, which we define as the dependence of cancer cells on the chemotherapeutic agent to which they are resistant.

When addiction develops, removal of the chemotherapeutic agent puts the addicted cancer cells in a compromised state that may result in their death or reduced malignancy.

Application of this strategy to humans has been suggested by case studies of melanoma in which the BRAF signaling pathway was inhibited by vemurafenib:

the inhibitory effect appeared to persist after the cessation of therapy.1,2 In a recent study, Kong et al investigated the mechanism of drug addiction.3 In melanoma cell lines they found that resistance and addiction to dabrafenib, a BRAF inhibitor, involved a change in the BRAF/ERK-2 signaling pathway, which controls cellular proliferation. The

One possibility for managing resistance is exploiting the evolved drug “addiction.” addiction was associated with ERK-2 inhibition of microphthalmia-associated transcription factor (MITF), a protein that fosters cellular survival and proliferation.

Restoration of MITF activity allowed the cell lines to survive, demonstrating the role of MITF inhibition in the addiction process.

Phenotypic variation of cancer cells is generated during oncogenesis through genetic and epigenetic modifications. An evolutionary perspective emphasizes the need to consider how selection acts on all the cancer cell variants within a particular patient. If a therapy eliminates only some of the cells, other cancer cells may still

A24 CANCER THERAPY ADVISOR | JANUARY/FEBRUARY 2018 | CancerTherapyAdvisor.com

h

be present to generate a relapse, though these remaining cells could be sensitive to a chemotherapeutic agent if it was not able to reach all of the cancerous cells — or they could be resistant but not addicted.

The drug addiction strategy must therefore be broadened to account for non-addicted cells, sensitive or resistant, that remain after therapy. Much as selection should favor the development of drug-resistant tumor cell lineages, it should also favor lineages that are resistant to addiction.

Kong et al suggest that drug addiction may allow for alternating therapy, but it is hard to imagine how alternating therapy could deal with cancer cells that are both resistant and not addicted.

However small this population, it will be expected to predominate over time.

The in vivo validation results presented by Kong et al show, in a mouse model, that melanoma transplants continued to decrease in size upon removal of the addictive drug. One problem with this evidence, however, is that the melanoma cells introduced into the mice were selected for resistance — and from the data it’s apparent that they are addicted.

Yet in a particular patient, many combinations of relevant phenotypes exist or can be generated, including resistant non-addicted variants, and therefore can be present during each treatment.

The addicted phenotype they characterize includes, furthermore, a switch from proliferative to invasive properties.

This shift to invasiveness might be trivial if all addicted cells die, but surviving cells may be pro-metastatic. An association of decreased proliferation and increased invasiveness with lower MITF levels and melanoma prognosis has been documented.4 It is also important to recognize that so long as cancer cells persist, the outcomes of chemotherapeutic interventions are not evolutionarily stable. Upon cessation of an addictive chemotherapeutic agent,

EXPERT PERSPECTIVE the outcome is evolutionarily unstable because the death or impairment of resistant cells may lead to a return to drug sensitivity. The patient will benefit from a temporarily suppressed population of cancer cells, but non-addicted cells will then repopulate. Kong et al found, for example, that the lethality in melanoma cell lines associated with removal of the dabrafenib was close to 100%, but the cells that persisted generated many clones of lineages that emerged within 30 days.

The evolutionary instability of the responses to chemotherapy draws attention to the need to use the drug addiction strategy as part of integrated therapeutic management, in which complementary treatment is directed against the residual cells before they can proliferate and evolve back to a more damaging state. In Kong et al’s cell line experiments, when cessation of dabrafenib exposure was timed with administration of dacarbazine, which inhibits MITF, the damaging effect of the addiction to dabrafenib was enhanced. A strategy that incorporates this “double hit” on addicted cells, together with additional

Viewpoint Continued from page A22

months with chemotherapy (hazard ratio [HR], 0.60; P = .001). Among patients who used β-blockers, afatinib resulted in a median PFS of 13.6 months compared with 2.5 months with chemotherapy (HR, 0.25; P = .0001).

Larger Implications The results of this study support previous findings that psychological distress is associated with an increased risk of mortality among patients with lung cancer. β-blockers may prevent EGFR TKI resistance by blocking this stress-induced

targeting of non-addicted cells, should enhance long-term control.

Sequential and joint use of antimicrobials are integrated into strategies for managing antimicrobial resistance. This approach may prove more powerful in cancer treatment: the lack of transmissibility of cancer cells between people truncates the time over which sophisticated, low-cost resistance to chemotherapeutics could evolve. ■

Paul Ewald) have contributed to the development of a general theory of oncogenesis, which integrates biological mechanisms at the molecular, cellular, and immunological levels with evolutionary processes that shape vulnerability to cancer.

References 1. Dooley AJ, Gupta A, Middleton MR. Ongoing response in BRAF V600E-mutant melanoma after cessation of intermittent vemurafenib therapy: a case report. Target

Paul W. Ewald, PhD, is a professor at University of Louisville, holding appointments in the department of biology and the department of microbiology and

Oncol. 2017;12(3):385. doi: 10.1007/ s11523-017-0483-8 2. Seifert H, Fisher R, Martin-Liberal J,

immunology. His books — Evolution of Infectious

et al. Prognostic markers and tumour

Disease, Plague Time, and Controlling Cancer —

growth kinetics in melanoma patients

and his scientific articles integrate evolutionary

progressing on vemurafenib. Melanoma

principles with medical issues. He was identified by

Res. 2016;26(2):138-44. doi: 10.1097/

Utne Reader as one of the “25 Visionaries Who Are

CMR.0000000000000218

Changing Your World” for his cancer research and the first recipient of the Smithsonian Institution’s

3. Kong X, Kuilman T, Shahrabi A, et al. Cancer drug addiction is relayed by an ERK2-

George E. Burch Fellowship in Theoretic Medicine

dependent phenotype switch. Nature. 2017;

and Affiliated Sciences for pioneering advance-

550(7675):270-4. doi: 10.1038/nature24037

ments in health sciences.

4. Howlin J, Cirenajwis H, Lettiero B, et al. Loss

Holly A. Swain Ewald, PhD, is an adjunct faculty

of CITED1, an MITF regulator, drives a pheno-

member in the department of biology at the

type switch in vitro and can predict clinical

University of Louisville. Her scientific articles and

outcome in primary melanoma tumours.

her book Controlling Cancer (co-authored with

PeerJ. 2015;3:e788. doi: 10.7717/peerj.788

signaling, resulting in better outcomes among patients with NSCLC treated with an EGFR TKI. Mindfulness, a form of meditation, has been shown to reduce physiologic markers of stress and improve quality of life among patients with cancer.2 Exercise has also been shown to improve functional and clinical outcomes among patients with cancer.3 Neither technique, however, has been studied in a prospective fashion in terms of improving survival or preventing EGFR TKI resistance.

“Given all the different ways that stress can affect patients, it certainly seems that it is worth studying further,” Dr Nilsson said. ■

References 1. Nilsson MB, Sun H, Diao L, et al. Stress hormones promote EGFR inhibitor resistance in NSCLC: Implications for combinations with b-blockers. Sci Transl Med. 2017;9:eaao4307.

2. Pascoe MC, Thompson DR, Jenkins ZM, Ski CF. Mindfulness mediates the physiological markers of stress: systematic review and meta-analysis. J Psychiatr

Res. 2017;95:156-78. doi: 10.1016/j. jpsychires.2017.08.004 3. Stout NL, Baima J, Swisher AK, WintersStone KM, Welsh J. A systematic review of exercise systematic reviews in the cancer literature (2005-2017). PM R. 2017;9:S34784. doi: 10.1016/j.pmrj.2017.07.074

CancerTherapyAdvisor.com | JANUARY/FEBRUARY 2018 | CANCER THERAPY ADVISOR A25

REGIMEN & MONOGRAPH INDEX CANCER THERAPY REGIMENS & DRUG MONOGRAPHS 1 Bone Cancer 3 Brain Cancer

 Brain Cancer

14 Breast Cancer

 Breast Cancer (Recurrent/Metastatic)

26 Endocrine Cancer 30 Gastrointestinal Cancer

 ➢Rectal Cancer

40 Genitourinary Cancer

 ➢Prostate Cancer

51 Gynecologic Cancer 53 Head and Neck Cancer 55 Hematologic Cancer 76 Lung Cancer 83 Sarcoma 84 Skin Cancer

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

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

A26 CANCER THERAPY ADVISOR | JANUARY/FEBRUARY 2018 | CancerTherapyAdvisor.com

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

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

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

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

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

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

The prescribing decision is ultimately the responsibility of the physician. MPR is offered to assist physicians in this area. © 2018 Haymarket Media, Inc.

DRUG MONOGRAPHS

BONE CANCER HALAVEN Eisai

℞

Non-taxane microtubule dynamics inhibitor.

Eribulin mesylate 0.5mg/mL, soln for IV inj.

Indications: Treatment of unresectable or metastatic liposarcoma in patients who have received prior anthracycline-containing regimen.

Adults: Give by IV inj over 2–5mins. 1.4mg/m² on Days 1 and 8 of a 21-day cycle. Mild hepatic impairment (Child-Pugh A) or moderate-to-severe renal impairment (CrCl 15–49mL/min): 1.1mg/m² on Days 1 and 8 of a 21-day cycle. Moderate hepatic impairment (Child-Pugh B): 0.7mg/m² on Days 1 and 8 of a 21-day cycle. Hold dose for ANC <1000/mm³, platelets <75000/mm³, or grade 3 or 4 non-hematological toxicities. Delay or reduce dose according to toxicities; see full labeling. Do not re-escalate dose after it is reduced.

Children: <18yrs: not established.

Warnings/Precautions: Monitor CBCs prior to each dose; increase frequency of monitoring if grade 3 or 4 cytopenias develop, delay and reduce subsequent doses if febrile neutropenia or grade 4 neutropenia lasting >7 days develops. Monitor for peripheral neuropathy; withhold dose if grade 3 or 4 peripheral neuropathy develops until resolution to grade 2 or less. Congenital long QT syndrome: avoid.

CHF, bradyarrhythmias, electrolyte abnormalities: monitor ECG for prolonged QT interval. Correct electrolyte abnormalities (K+, Mg+) before treatment; monitor. Severe hepatic impairment (Child-Pugh C): insufficient data. Embryofetal toxicity. Pregnancy (avoid). Use effective contraception during treatment and for ≥2 weeks (females) or 3.5 months (male partners) after final dose. Nursing mothers: not recommended (during and for 2 weeks after final dose).

Interactions: Caution with other drugs that prolong QT interval (eg, Class IA and III antiarrhythmics); monitor.

Adverse reactions: Neutropenia, anemia, asthenia/fatigue, alopecia, peripheral neuropathy, nausea, constipation, abdominal pain, pyrexia, hypokalemia, hypocalcemia; febrile neutropenia, possible QT prolongation, elevated liver enzymes.

Note: Do not mix with dextrose-containing solutions. Do not administer in same line as other drugs or fluids.

How supplied: Single-use vial (2mL)—1

LARTRUVO Lilly

℞

PDGFR-alpha inhibitor. Olaratumab 500mg/50mL; soln for IV infusion; preservative-free.

Indications: In combination with doxorubicin, for the treatment of adults with soft tissue sarcoma with a histologic subtype for which an

anthracycline-containing regimen is appropriate and which is not amenable to curative treatment with radiotherapy or surgery.

Adults: Premedicate with IV diphenhydramine and IV dexamethasone prior to infusion on Day 1 of cycle 1. Give with doxorubicin for the first 8 cycles: refer to doxorubicin PI for dosing and modifications. Give by IV infusion over 60mins.

15mg/kg on Days 1 and 8 of each 21-day cycle until disease progression or unacceptable toxicity.

Dose modifications: see full labeling.

Children: Not established.

Warnings/Precautions: Have resuscitative equipment available. Monitor for signs/symptoms of infusion-related reactions during and postinfusion. Permanently discontinue for Grade 3/4 infusion-related reactions; interrupt for Grade 1/2 infusion-related reactions; resume at 50% of initial rate after resolution. If neutropenic fever/infection or Grade 4 neutropenia lasts >1 week, discontinue until ANC ≥1,000μL then permanently reduce dose to 12mg/kg. Embryofetal toxicity. Females of reproductive potential should use effective contraception during and for 3 months after last dose. Pregnancy. Nursing mothers: not recommended (during and for 3 months after last dose).

Adverse reactions: With doxorubicin: nausea, fatigue, musculoskeletal pain, mucositis, alopecia, vomiting, diarrhea, decreased appetite, abdominal pain, neuropathy, headache, anxiety, dry eyes, lymphopenia, neutropenia, thrombocytopenia, hyperglycemia, elevated aPTT, hypokalemia, hypophosphatemia, increased alkaline phosphatase.

How supplied: Single-dose vial—1

Methotrexate injection

℞

Bedford

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

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

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

Children: See literature.

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

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

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

Diabetes. Peptic ulcer. Ulcerative colitis. Infection.

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

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

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

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

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

VOTRIENT GlaxoSmithKline

℞

Tyrosine kinase inhibitor. Pazopanib 200mg; tabs.

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

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

Adults: Take on an empty stomach. Swallow whole.

800mg once daily. Dose adjustments: see full labeling. Hepatic impairment: moderate: 200mg once daily; severe: not recommended. Concomitant

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DRUG MONOGRAPHS

BONE CANCER 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.

Warnings/Precautions: Not indicated for use in combination with other cancer agents. Risk of severe and fatal hepatotoxicity (esp. ≥65yrs old).

Monitor liver tests before starting and at Weeks 3, 5, 7, and 9, thereafter at Months 3 and 4, then periodically. If ALT between 3xULN and 8xULN continue therapy with weekly monitoring until ALT returns to Grade 1 or baseline. If ALT >8xULN interrupt therapy until ALT returns to Grade 1 or baseline; may consider reintroducing at a reduced dose, measure liver tests weekly for 8 weeks; if ALT>3xULN recurs, permanently discontinue.

Permanently discontinue if ALT>3xULN and bilirubin >2xULN. Gilbert’s syndrome (see full labeling). History of QT prolongation. Cardiac dysfunction risk (including previous anthracycline exposure): evaluate LVEF at baseline and periodically; monitor for CHF. Monitor ECG, electrolytes (eg, calcium, magnesium, potassium), thyroid function. History of hemoptysis, cerebral, or clinically significant GI hemorrhage in the past 6 months: not recommended. Risk of arterial thrombotic events (within previous 6 months: not recommended). Monitor for VTE, PE, infection, proteinuria (reduce dose if 24-hour urine protein ≥3g), thrombotic microangiopathy, interstitial lung disease (ILD)/pneumonitis, GI perforation or fistula.

Monitor BP and manage hypertension promptly.

Discontinue if severe and persistent hypertension (despite antihypertensives and dose reduction), if repeat episodes of proteinuria (despite dose reductions), thrombotic microangiopathy, serious infection, ILD or pneumonitis occurs. Stop therapy at least 7 days before surgery; discontinue in patients with wound dehiscence. Embryo-fetal toxicity. Pregnancy: exclude status prior to starting.

Females of reproductive potential must use effective contraception and males (use condoms) during therapy and for ≥2 weeks after final dose.

Nursing mothers: not recommended (during and for 2 weeks after final dose).

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. Avoid concomitant drugs that raise gastric pH (eg, PPIs, H2-blockers). 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; hepatotoxicity, QT prolongation, hemorrhagic events, arterial thrombotic events (eg, MI, angina, ischemic stroke, TIA), venous thrombotic events (eg, VTE, PE), GI perforation or fistula, ILD/pneumonitis, impaired wound healing, hypothyroidism, proteinuria, infection, reversible posterior leukoencephalopathy syndrome (discontinue if occurs).

How supplied: Tabs—120

XGEVA Amgen

℞

Osteoclast inhibitor (RANKL inhibitor).

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

Indications: Treatment of adults and 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, magnesium levels and Vit.D intake in susceptible patients (eg, severe renal impairment, receiving dialysis). Risk of osteonecrosis of the jaw (ONJ) in diabetes, gingival infections. Perform oral exam and preventive dentistry before and regularly during therapy. Maintain good oral hygiene. Avoid invasive dental procedures during treatment; consider temporary discontinuation if procedure is necessary. Evaluate for atypical fractures if thigh/groin pain develops; consider withholding therapy until risk/benefit assessment. Monitor for hypercalcemia after treatment discontinuation in patients with growing skeletons. Embryofetal toxicity. Pregnancy; exclude status prior to initiation. 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. Increased risk of ONJ with concomitant corticosteroids, chemotherapy, angiogenesis inhibitors or duration of denosumab exposure.

Adverse reactions: Fatigue, asthenia, hypophosphatemia, nausea, arthralgia, headache, back pain, pain in extremity, dyspnea, decreased appetite, peripheral edema, vomiting, anemia, constipation, diarrhea; ONJ, hypocalcemia (may be fatal), hypersensitivity reactions (discontinue if occur).

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

YONDELIS Janssen

℞

Alkylating agent. Trabectedin 1mg; per vial; lyophilized pwd for IV infusion after reconstitution and dilution; contains sucrose.

Indications: Treatment of unresectable or metastatic liposarcoma or leiomyosarcoma in patients who have received prior anthracyclinecontaining regimen.

Adults: Give by IV infusion over 24hrs.

1.5mg/m2 every 21 days until disease progression or unacceptable toxicity. Moderate hepatic impairment: 0.9mg/m2 every 21 days. Premedicate 30 mins prior to each dose with IV dexamethasone 20mg. Delay, reduce, or permanently discontinue dose according to severity of adverse reactions: see full labeling. Do not increase dose in subsequent cycles once reduced.

Children: <18yrs: not established.

Warnings/Precautions: Assess neutrophil count prior to each dose and periodically during the cycle; withhold if <1,500 cells/μL on day of dosing; permanently reduce dose if life-threatening or prolonged, severe neutropenia occurs in prior cycle. Assess CPK levels prior to each dose; withhold if serum CPK >2.5XULN; permanently discontinue if rhabdomyolysis occurs. Assess LFTs prior to each dose and as indicated based on pre-existing hepatic impairment; interrupt, reduce, or permanently discontinue dose based on severity/duration. Assess LVEF by echocardiogram or MUGA scan prior to initiation and every 2–3 months thereafter until discontinued; withhold if LVEF below LLN; permanently discontinue if symptomatic cardiomyopathy occurs or persistent LV dysfunction not recover to LLN within 3 weeks.

Monitor for capillary leak syndrome; discontinue and treat promptly if occurs. Severe hepatic impairment: not recommended. Embryo-fetal toxicity. Pregnancy. Females of reproductive potential should use effective contraception during and for 2 months and males (for 5 months) after final dose. Nursing mothers: not recommended.

Interactions: Avoid concomitant strong CYP3A inhibitors (eg, oral ketoconazole, itraconazole, posaconazole, voriconazole, clarithromycin, telithromycin, indinavir, lopinavir, ritonavir, boceprevir, nelfinavir, saquinavir, telaprevir, nefazodone, conivaptan), grapefruit or grapefruit juice; if short-term use (<14 days) necessary, give inhibitor 1 week after infusion and discontinue the day prior to next infusion. Avoid concomitant strong CYP3A inducers (eg, rifampin, phenobarbital, St. John’s wort).

Adverse reactions: Nausea, fatigue, vomiting, constipation, decreased appetite, diarrhea, peripheral edema, dyspnea, headache, neutropenia, increased ALT, thrombocytopenia, anemia, increased AST and CPK; anaphylaxis, neutropenic sepsis, rhabdomyolysis, hepatotoxicity, cardiomyopathy, capillary leak syndrome, extravasation resulting in tissue necrosis, infertility.

How supplied: Single-dose vial—1

2 CANCER THERAPY ADVISOR | JANUARY/FEBRUARY 2018 | CancerTherapyAdvisor.com

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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 provided only 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 orally.

Repeat cycle every 28 days.

Recurrent or Progressive, Low Grade Disease Temozolomide3,6a

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 IV Days 1–3: Teniposide 50mg/m2 IV. 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

CancerTherapyAdvisor.com | JANUARY/FEBRUARY 2018 | CANCER THERAPY ADVISOR 3

CANCER TREATMENT REGIMEN

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

DOSING

Adjuvant Treatment Temozolomide13,14

Days 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.

Recurrence Therapy 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.

Bevacizumab18–20b

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

Bevacizumab + irinotecan21,22c

Day 1: Bevacizumab 10mg/kg IV plus irinotecan 125mg/m2 IV. 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 IV Days 1–3: Teniposide 50mg/m2 IV. 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.

4 CANCER THERAPY ADVISOR | JANUARY/FEBRUARY 2018 | CancerTherapyAdvisor.com

CANCER TREATMENT REGIMEN

BRAIN CANCER Systemic Therapy for Anaplastic Gliomas1 (continued) REGIMEN

DOSING

Recurrence Therapy (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 IV 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 Bevacizumab34–36b

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

Bevacizumab + irinotecan22,34–36c

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 + nitrosurea23c

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)24,25c

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

CancerTherapyAdvisor.com | JANUARY/FEBRUARY 2018 | CANCER THERAPY ADVISOR 5

CANCER TREATMENT REGIMEN

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 IV Days 1–3: Teniposide 50mg/m2 IV. 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.

Bevacizumab34–37b

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 orally.

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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CANCER TREATMENT REGIMEN

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 High dose cyclophosphamide ± etoposide Carboplatin + etoposide + cyclophosphamide Cisplatin + etoposide + cyclophosphamide 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 High dose cyclophosphamide ± etoposide 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 orally 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

CancerTherapyAdvisor.com | JANUARY/FEBRUARY 2018 | CANCER THERAPY ADVISOR 7

CANCER TREATMENT REGIMEN

BRAIN CANCER Brain Cancer Treatment Regimens Primary CNS Lymphoma1 (continued) REGIMEN

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: etoposide75 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.

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

CancerTherapyAdvisor.com | JANUARY/FEBRUARY 2018 | CANCER THERAPY ADVISOR 9

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. a For patients not previously treated b Patients who have good performance status but evidence of radiographic progression may benefit from continuation of bevacizumab to prevent rapid

neurologic deterioration

c Bevacizumab + chemotherapy can be considered for patients who have failed monotherapy with bevacizumab

References 1. NCCN Clinical Practice Guidelines in Oncology™. Central Nervous System Cancers. v 1.2016. Available at http://www.nccn.org/professionals/physician_gls/pdf/cns. pdf. Accessed October 18, 2016.

2. Shaw EG, Wang M, Coons SW, et al. Randomized trial of radiation therapy plus procarbazine, lomustine, and vincristine chemotherapy for supratentorial adult lowgrade glioma: initial results of RTOG 902. J Clin Oncol. 2012;30:3065–3070.

3. Kesari S, Schiff D, Drappatz J, et al. Phase II study of protracted daily temozolomide for low-grade gliomas in adults. Clin Cancer Res. 2009;15:330–337.

4. Nicholson HS, Kretschmar CS, Krailo M, et al. Phase 2 study of temozolomide in children and adolescents with recurrent central nervous system tumors: a report from the Children’s Oncology Group. Cancer. 2007;110:1542–1550.

5. Pouratian N, Gasco J, Sherman JH, Shaffrey ME, Schiff D. Toxicity and efficacy of protracted low dose temozolomide for the treatment of low grade gliomas.

J Neurooncol. 2007;82: 281–288.

6. Perry JR, Rizek P, Cashman R, Morrison M, Morrison T. Temozolomide rechallenge in recurrent malignant glioma by using a continuous temozolomide schedule: the “rescue” approach. Cancer. 2008;113:2152–2157.

7. Triebels VH, Taphoorn MJ, Brandes AA, et al. Salvage PCV chemotherapy for temozolomide-resistant oligodendrogliomas. Neurology. 2004;63:904–906.

8. Brandes AA, Basso U, Vastola F, et al. Carboplatin and teniposide as third-line chemotherapy in patients with recurrent oligodendroglioma or oligoastrocytoma: a phase II study. Ann Oncol. 2003;14:1727–1731.

9. Moghrabi A, Friedman HS, Ashley DM, et al. Phase II study of carboplatin (CBDCA) in progressive low-grade gliomas. Neurosurg Focus. 1998;4:e3.

10. Massimino M, Spreafico F, Riva D, et al. A lower-dose, lowertoxicity cisplatinetoposide regimen for childhood progressive low-grade glioma. J Neurooncol.

2010;100:65–71.

11. Lomustine (CeeNU) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company. 2012.

12. Carmustine (BiCNU) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company. 2011.

13. Wick W, Hartmann C, Engel C, et al. NOA-04 randomized phased III trials of sequential radiochemotherapy of ana plastic glioma with procarbazine, lomustine, and vincristine or temozolamide. J Clin Oncol. 2009;27:5874–5880.

14. Taliansky-Aronov A, Bokstein F, Lavon I, Siegal T. Temozolomide treatment for newly diagnosed anaplastic oligodendrogliomas: a clinical efficacy trial.

J Neurooncol. 2006;79:153–157.

15. Stupp R, Mason WP, van den Bent MJ, et al. European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005; 352:987–996.

16. Perry JR, Bélanger K, Mason WP, et al. Phase II trial of continuous dose-intense temozolomide in recurrent malignant glioma: RESCUE study. J Clin Oncol.

2010;28:2051–2057.

17. Wick W, Puduvalli VK, Chamberlain MC, et al. Phase III study of enzastaurin compared with lomustine in the treatment of recurrent intracranial glioblastoma. J Clin Oncol. 2010;28: 1168–1174.

18. Chamberlain MC, Johnston S. Bevacizumab for recurrent alkylator-refractory anaplastic oligodendroglioma. Cancer. 2009;115:1734–1743.

19. Chamberlain MC, Johnston S. Salvage chemotherapy with bevacizumab for recurrent alkylator-refractory anaplastic astrocytoma. J Neurooncol. 2009;91:359–367.

20. Norden AD, Young GS, Setayesh K, et al. Bevacizumab for recurrent malignant gliomas: efficacy, toxicity, and patterns of recurrence. Neurology. 2008;70:779–787.

21. Taillibert S, Vincent LA, Granger B, et al. Bevacizumab and irinotecan for recurrent oligodendroglial tumors. Neurology. 2009;72:1601–1606.

22. Vredenburgh JJ, Desjardins A, Herndon JE 2nd, et al. Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clin Cancer Res. 2007;13:1253–1259.

23. Soffietti R, Rudà R, Trevisan E, et al. Phase II study of bevacizumab and nitrosourea in patients with recurrent malignant glioma: a multicenter Italian study [abstract 2012] J Clin Oncol. 2009;27(Suppl 15):90s.

24. Mrugala MM, Crew LK, Fink JR, Spence AM. Carboplatin and bevacizumab for recurrent malignant glioma. Oncol Lett. 2012;4:1082–1086.

25. Thompson EM, Dosa E, Kraemer DF, Neuwelt EA. Treatment with bevacizumab plus carboplatin for recurrent malignant glioma. Neurosurgery. 2010;67:87–93.

26. Chamberlain MC, Wei-Tsao DD, Blumenthal DT, Glantz MJ. Salvage chemotherapy with CPT-11 for recurrent temozolomiderefractory anaplastic astrocytoma. Cancer.

2008;112: 2038–2045.

27. Chamberlain MC. Salvage chemotherapy with CPT-11 for recurrent oligodendrogliomas. J Neurooncol. 2002;59: 157–163.

28. Chamberlain MC, Tsao-Wei DD. Salvage chemotherapy with cyclophosphamide for recurrent, temozolomide-refractory glioblastoma multiforme. Cancer.

2004;100:1213–1220.

29. Chamberlain MC, Tsao-Wei DD, Groshen S. Salvage chemotherapy with cyclophosphamide for recurrent temozolomiderefractory anaplastic astrocytoma. Cancer.

2006;106: 172–179.

30. Fulton D, Urtasun R, Forsyth P. Phase II study of prolonged oral therapy with etoposide (VP16) for patients with recurrent malignant glioma. J Neurooncol.

1996;27:149–155.

31. van den Bent MJ, Brandes AA, Taphoorn MJ, et al. Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-term follow-up of EORTC brain tumor group study 26951. J Clin Oncol.

2013;31:344–350.

10 CANCER THERAPY ADVISOR | JANUARY/FEBRUARY 2018 | CancerTherapyAdvisor.com

CANCER TREATMENT REGIMEN

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 noncomparative 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.

Pediatr Neurol. 1997;17:230–234.

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.

J Clin Oncol. 2007; 25:4730–4735.

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. 2012;118:3743–3748.

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.

2006;24:466-8.

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.

78. Grommes C, Oxnard GR, Kris MG et al. ‘Pulsatile’ highdose weekly erlotinib for CNS metastases from EGFR mutant non-small cell lung cancer. Neuro Oncol.

2011;13:1364–1369.

(Revised 12/2016) © 2018 Haymarket Media, Inc.

CancerTherapyAdvisor.com | JANUARY/FEBRUARY 2018 | CANCER THERAPY ADVISOR 11

DRUG MONOGRAPHS

BRAIN CANCER AFINITOR Novartis

then return to dose used prior to initiating strong inducer. 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; discontinue, reduce dose, and/or manage with corticosteroids if non-infectious pneumonitis occurs. Increased risk of infections (may be severe or fatal); monitor and treat promptly if occur. Pre-existing invasive fungal infections: treat before starting. Use dexamethasone mouthwash at initiation to reduce the incidence and severity of stomatitis; use alcohol-, peroxide-, iodine-, or thyme-free products if occurs. 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. Embryo-fetal toxicity. Must use effective contraception during and for 8 weeks (females) or 4 weeks (males) after last dose. Pregnancy, 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,

℞

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

Indications: In adults and children with tuberous sclerosis complex (TSC) for the treatment of subependymal giant cell astrocytoma (SEGA) that requires therapeutic intervention but cannot be curatively resected.

Adults and Children: <1yr: not recommended.

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

Do not combine the 2 dosage forms to achieve the desired total dose. Use therapeutic drug monitoring to guide subsequent dosing. Adjust dose at 2 week intervals as needed to achieve and maintain trough concentrations of 5–15ng/mL (see full labeling). Continue therapy until disease progression or unacceptable toxicity. 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,

fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem); see Adult.

Antagonized by strong CYP3A4/PgP inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital), St. John’s Wort; avoid or increase dose (see Adult). Increased risk of angioedema with concomitant ACE inhibitor.

Adverse reactions: Stomatitis, infections, rash, fatigue, diarrhea, edema, abdominal pain, nausea, fever, asthenia, cough, headache, decreased appetite, RTI; decreased hemoglobin, WBC, platelets, lymphocytes, neutrophils, serum phosphate, potassium, albumin; increased cholesterol, blood glucose, AST, ALT, triglycerides, serum creatinine, proteinuria, renal failure.

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: Recurrent gliobastoma in adults.

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

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

12 CANCER THERAPY ADVISOR | JANUARY/FEBRUARY 2018 | CancerTherapyAdvisor.com

601-73395_CTA_JAN-FEB18_2P.indd 12

1/6/18 10:53 AM

DRUG MONOGRAPHS

BRAIN CANCER 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 (PRES), 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.

Interactions: Increased risk of CHF and decline in LVEF with concomitant anthracycline-based therapy (not indicated use); discontinue if CHF develops.

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, PRES, infusion reactions, ovarian failure, neutropenia, 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 for 5 consecutive days if tolerated; continue until disease progression, discontinue if minimum dose not tolerated.

Children: Not established.

Contraindications: Hypersensitivity to dacarbazine.

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

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

Interactions: Concomitant carbamazepine, phenytoin, sulfamethoxazole/trimethoprim may complicate myelosuppression assessment. May be potentiated by valproic acid.

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

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

UNITUXIN United Therapeutics

℞

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

Indications: In combination with granulocytemacrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2) and 13-cis-retinoic acid (RA), for the treatment of children with highrisk neuroblastoma who achieve at least a

partial response to prior first-line multiagent, multimodality therapy.

Adults: Not applicable.

Children: Confirm adequate hematologic, respiratory, hepatic, and renal function prior to each course. Hydrate and premedicate with antihistamines, analgesics (eg, IV opioids), and antipyretics prior to each dose: see full labeling. Give via IV infusion over 10–20 hours for 4 consecutive days; max 5 cycles. Initial rate: 0.875mg/m2/hr for 30mins; may gradually increase as tolerated up to max 1.75mg/m2/hr. Cycles 1, 3, and 5 (24-day cycle): 17.5mg/m2/day on Days 4–7.

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

Warnings/Precautions: Risk of serious infusion reactions; monitor during and at least 4 hours after completion of each infusion; interrupt or discontinue if severe or prolonged infusion reactions occur. Have resuscitative medications and equipment available. Risk of serious neurotoxicity including severe neuropathic pain and peripheral 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, urinary retention that persists following opioid discontinuation, transverse myelitis, signs/symptoms of RPLS, signs of atypical hemolytic uremic syndrome occurs. Interrupt or discontinue if symptomatic or 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

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1/6/18 10:53 AM

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

Paclitaxel5,6

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

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

Capecitabine7

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

Repeat cycle every 21 days.

Gemcitabine8

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

Vinorelbine9

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

Eribulin10

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

Other Single Agents1 Cyclophosphamide11

Days 1–21: Cyclophosphamide 50mg orally daily.

Repeat cycle every 28 days.

Carboplatin12

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

Docetaxel13-15

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

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

Albumin-bound paclitaxel16,17

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

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

Cisplatin18

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

Epirubicin19

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

Ixabepilone20

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

14 CANCER THERAPY ADVISOR | JANUARY/FEBRUARY 2018 | CancerTherapyAdvisor.com

CANCER TREATMENT REGIMEN

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

DOSING

CAF21

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

FAC22

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

FEC23

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

AC24

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

EC25

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

CMF26

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

Docetaxel + capecitabine27

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

Repeat cycle every 21 days.

GT28

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

Repeat cycle every 21 days.

Gemcitabine + carboplatin29

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

Paclitaxel + bevacizumab30

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

Repeat cycle every 28 days.

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

Pertuzumab + trastuzumab + docetaxel (Category 1)31

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

Pertuzumab + trastuzumab + paclitaxel32,33

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

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

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

CancerTherapyAdvisor.com | JANUARY/FEBRUARY 2018 | CANCER THERAPY ADVISOR 15

CANCER TREATMENT REGIMEN

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

DOSING

Paclitaxel + carboplatin + trastuzumab33,35

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

Weekly paclitaxel + carboplatin + trastuzumab33,36

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

Trastuzumab + paclitaxel33,37,38

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

Trastuzumab + docetaxel33,39,40

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

Trastuzumab + vinorelbine33,41

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

Trastuzumab + capecitabine33,42,43

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

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

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

Repeat cycle every 21 days.

Trastuzumab + capecitabine33,37,43,45

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

Trastuzumab + lapatinib33,46

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

References 1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer V.1.2016. Available at: http://www.nccn. org/professionals/physician_gls/pdf/breast.pdf. Accessed February 25, 2016.

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

1999;17(8):2341–2354.

3. Gasparini G, Dal Fior S, Panizzoni GA, Favretto S, Pozza F. Weekly epirubicin versus doxorubicin as second line therapy in advanced breast cancer. A randomized clinical trial. Am J Clin Oncol. 1991;14(1):38-44.

4. 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(3):440–449.

5. Seidman AD, Tiersten A, Hudis C, et al. Phase II trial of paclitaxel by 3-hour infusion

6.

7.

8.

9.

10.

as initial and salvage chemotherapy for metastatic breast cancer. J Clin Oncol.

1995;13(10):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(22):4216–4223.

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(10):2155–2161.

Seidman AD. Gemcitabine as single-agent therapy in the management of advanced breast cancer. Oncology. (Williston Park) 2001;15(2 suppl 3):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(9):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

continued

16 CANCER THERAPY ADVISOR | JANUARY/FEBRUARY 2018 | CancerTherapyAdvisor.com

CANCER TREATMENT REGIMEN

BREAST CANCER Breast Cancer (Recurrent or Metastatic) Treatment Regimens References (continued) phase 3 open-label randomized study. Lancet. 2011;377(9769):914–923.

11. Licchetta A, Correale P, Migali C, et al. Oral metronomic chemo- hormonal-therapy of metastatic breast cancer with cyclophosphamide and megestrol acetate. J Chemother. 2010;22(3):201–204.

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

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

Semin Oncol. 1999;26(3 suppl 9):1–6.

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

2006;24(31): 4963–4970.

15. Rivera E, Mejia JA, Arun BK, et al. Phase 3 study comparing the use of docetaxel on an every-3-week versus weekly schedule in the treatment of metastatic breast cancer. Cancer. 2008;112(7):1455–1461.

16. Gradishar W, Tjulandin S. Davidson N, et al. Phase Ill trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol. 2005;23(31):7794–7803.

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

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

19. Bastholt L, Dalmark M, Gjedde SB, et al. Dose-response relationship of epirubicin in the treatment of postmenopausal patients with metastatic breast cancer a randomized study of epirubicin at four different dose levels performed by the Danish Breast Cancer Cooperative Group. J Clin Oncol. 1996;14(4):1146–1155.

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

21. Bull JM, Tormey DC, Li SH, et al. A randomized comparative trial of adriamycin versus methotrexate in combination drug therapy. Cancer. 1978;41(5):1649–1657.

22. Hortobagyi GN, Gutterman JU, Blumenschein GR, et al. Combination chemoimmunotherapy of metastatic breast cancer with 5-fluorouracil, adriamycin, cyclophosphamide, and BCG. Cancer. 1979;43(4):1225–33.

23. Ackland SR, Anton A, Breithach GR, et al. Dose-intensive epirubicin-based chemotherapy is superior to an intensive intravenous cyclophosphamide, methotrexate, and fluorouracil regimen in metastatic breast cancer a randomized multinational study. J Clin Oncol. 2001;19(4):943–953.

24. Nabholtz JM, Falkson C, Campos O, et al. Docetaxel and doxorubicin compared with doxorubicin and cyclophosphamide as first-line chemotherapy for metastatic breast cancer results of a randomized, multicenter, phase Ill trial. J Clin Oncol.

2003;21(6):968–975.

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

2005;23(33):8322–8330.

26. Bonadonna G, Brusamolino E, Valagussa P, et al. Combination chemotherapy as an adjuvant treatment in operable breast cancer. N Engl J Med. 1976;294(8):405–410.

27. Mavroudis D, Papakotoulas P, Ardavanis A, et al; Breast Cancer Investigators of the Hellenic Oncology Research Group. Randomized phase III trial comparing docetaxel plus epirubicin versus docetaxel plus capecitabine as first-line treatment in women with advanced breast cancer. Ann Oncol. 2010;21(1):48–54.

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

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

30. Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizurriab versus paclitaxel alone for metastatic breast cancer. N EngI J Med. 2007;357(26):2666–2676.

31. Baselga J, Cones J, Kim SB, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N EngI J Med. 2012;366(2):109–119.

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

33. Leyland-Jones B, Gelmon K, Ayoub JP, et al. Pharmacokinetics, safety, and efficacy of trastuzumab administered every three weeks in combination with paclitaxel. J Clin Oncol. 2003; 21(21): 3965–3971.

34. Verma S, Miles O, Gianni L, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N EngI J Med. 2012; 367(19):1783–1791.

35. Robert N, Leyland-Jones B, Asmar L, et al. Randomized phase III study of trastuzumab, paclitaxel, and carboplatin compared with trastuzumab and paclitaxel in women with HER-2-overexpressing metastatic breast cancer. J Clin Oncol.

2006;24(18):2786–2792.

36. Perez EA, Suman VJ, Rowland KM, et al. Two concurrent phase II trials of paclitaxel/ carboplatin/trastuzumab (weekly or every-3-week schedule) as first-line therapy in women with HER2-overexpressing metastatic breast cancer: NCCTG study 983252. Clin Breast Cancer. 2005;6(5):425–432.

37. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N EngI J Med. 2001;344(11):783–792.

38. Seidman A, Berry DA, Cirrincione C, et al. Randomized phase Ill trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol 9840. J Clin Oncol. 2008;26(10):1642–1649.

39. Marty M, Cognetti F, Maraninchi O, et al. Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 study group. J Clin Oncol. 2005;23(19):4265–4274.

40. Esteva FJ, Valero V, Booser O, et al. Phase II study of weekly docetaxel and trastuzumab for patients with HER-2-overexpressing metastatic breast cancer. J Clin Oncol. 2002; 20(7):1800–1808.

41. Burstein HJ, Keshaviah A, Baron AD, et al. Trastuzumab plus vinorelbine or taxane chemotherapy for HER2-overexpressing metastatic breast cancer the trastuzumab and vinorelbine or taxane study. Cancer. 2007;110(5):965–972.

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

2009;27(12):1999–2006.

43. Cobleigh MA, Vogel CL, Tripathy D, et al. Multinational study of the efficacy and safety of humanized anti-l-IER2 ruonodonal antibody in women who have HER2overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol. 1999; 17(9):2639–2648.

44. Geyer C, Forster J, Undquist O, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 2006:355(26):2733–2743.

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

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

(Revised 4/2016) © 2018 by Haymarket Media, Inc.

Access Cancer Therapy Advisor treatment regimens in a user-friendly format.

CancerTherapyAdvisor.com/TreatmentRegimens.

CancerTherapyAdvisor.com | JANUARY/FEBRUARY 2018 | CANCER THERAPY ADVISOR 17

DRUG MONOGRAPHS

BREAST CANCER ABRAXANE Celgene

℞

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

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

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

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

Children: Not evaluated.

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

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

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

Interactions: May potentiate or be potentiated

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

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

How supplied: Single-use vial—1

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

Indications: Postmenopausal women with advanced hormone receptor-positive, HER2negative breast cancer (advanced HR+ BC) in combination with exemestane after

℞

failure of treatment with letrozole or anastrozole.

Adults: Swallow tabs whole with water. Take at the same time each day either consistently with or without food. 10mg once daily; continue until disease progression or unacceptable toxicity.

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 risks. 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: avoid; if required, 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. 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; discontinue, reduce dose, and/or manage with corticosteroids if non-infectious pneumonitis occurs. Increased risk of infections (may be severe or fatal); monitor and treat promptly if occur. Pre-existing invasive fungal infections: treat before starting. Use dexamethasone mouthwash at initiation to reduce the incidence and severity of stomatitis; use alcohol-, peroxide-, iodine-, or thyme-free products if occurs. 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. Embryo-fetal toxicity.

Must use effective contraception during and for 8 weeks (females) or 4 weeks (males) after last dose. Pregnancy, 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); see Adult. Antagonized by

strong CYP3A4/PgP inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital), St. John’s Wort; avoid or increase dose (see Adult). Increased risk of angioedema with concomitant ACE inhibitor.

Adverse reactions: Stomatitis, infections, rash, fatigue, diarrhea, edema, abdominal pain, nausea, fever, asthenia, cough, headache, decreased appetite, RTI; decreased hemoglobin, WBC, platelets, lymphocytes, neutrophils, serum phosphate, potassium, albumin; increased cholesterol, blood glucose, AST, ALT, triglycerides, serum creatinine, proteinuria, renal failure.

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 inhibitor. 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.

Warnings/Precautions: Not for treatment in premenopausal women. Osteoporosis; assess bone mineral density (BMD) at start of treatment.

Monitor all patients for BMD loss and treat as

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DRUG MONOGRAPHS

BREAST CANCER appropriate. Perform routine assessment of Vit. D levels prior to initiation; supplement if deficient. Hepatic or renal impairment. Embryofetal toxicity. Pregnancy. Females of reproductive potential: should undergo pregnancy testing within 7 days prior to initiation; use effective contraception during and for 1 month after final dose. Nursing mothers: not recommended (during and for 1 month after final dose).

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 BMD. How supplied: Tabs—30

FASLODEX AstraZeneca

℞

Estrogen receptor antagonist. Fulvestrant 50mg/mL; soln for IM inj.

Indications: As monotherapy: for hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer in postmenopausal women not previously treated with endocrine therapy, or HR-positive advanced breast cancer in postmenopausal women with disease progression following endocrine therapy. In combination therapy with palbociclib or abemaciclib: for HR-positive, HER2-negative advanced or metastatic breast cancer in women with disease progression after endocrine therapy.

Adults: Give by IM inj slowly (1–2 mins/injection). 500mg (as two 5mL injections, one in each buttock) on Days 1, 15, 29, then once monthly thereafter. For combination therapy: give with palbociclib 125mg daily with food for 21 days, followed by 7 days off, or with abemaciclib 150mg twice daily; in pre/perimenopausal women: also treat with LHRH agonists. Moderate hepatic impairment: 250mg (as one 5mL injection) on Days 1, 15, 29, then once monthly thereafter. Other dose modification: see full labeling.

Children: Not established.

Warnings/Precautions: Bleeding diatheses, thrombocytopenia, or anticoagulant use.

Moderate-to-severe hepatic impairment. When administering at the dorsogluteal inj site due to proximity of the sciatic nerve. Embryo-fetal toxicity. Pregnancy: do testing within 7 days prior to initiating; use effective contraception during therapy and for 1 year after last dose. Nursing mothers: not recommended (during therapy and for 1 year after last dose).

Interactions: May interfere with estradiol measurement by immunoassay, resulting in falsely elevated estradiol levels.

Adverse reactions: Inj site pain (including sciatica, neuralgia, neuropathic pain, peripheral neuropathy), nausea, vomiting, bone pain, arthralgia, headache, back pain, fatigue, pain in extremity, hot flash, anorexia, asthenia, musculoskeletal pain, cough, dyspnea, constipation; increased hepatic enzymes, hypersensitivity reactions.

How supplied: Prefilled syringe kit (2 × 5mL)—1

FEMARA Novartis

℞

Aromatase inhibitor. Letrozole 2.5mg; tabs.

Indications: In postmenopausal women: Adjuvant treatment of hormone receptor positive early breast cancer; Extended adjuvant treatment of early breast cancer after 5 years of adjuvant tamoxifen therapy; First-line treatment of hormone receptor positive or unknown, locally advanced or metastatic breast cancer; Treatment of advanced breast cancer with disease progression following antiestrogen therapy.

Adults: 2.5mg once daily. Adjuvant or extended adjuvant therapy: discontinue at tumor relapse; see full labeling. Advanced breast cancer: continue until tumor progression is evident.

Severe hepatic impairment or cirrhosis: 2.5mg every other day.

Children: Not established.

Contraindications: Pregnancy.

Warnings/Precautions: Monitor bone mineral density, serum cholesterol. Severe renal or hepatic impairment. Embryo-fetal toxicity; exclude pregnancy prior to initiation. Use effective contraception during and for ≥3wks after last dose. Nursing mothers: not recommended (during and for ≥3wks after last dose).

Adverse reactions: Pain (bone, musculoskeletal, and others), hot flashes, arthralgia, flushing, asthenia, edema, headache, dizziness, hypercholesterolemia, sweating increased, GI upset, fatigue, somnolence, dyspnea, cough, insomnia, hypertension, anorexia, weight changes; thromboembolic or cardio- or cerebrovascular events (rare).

How supplied: Tabs—30

Fluorouracil (various) Antimetabolite. Fluorouracil 50mg/mL; soln for IV inj.

Indications: Palliative management of carcinoma of the breast.

Adults: Give by IV inj. 12mg/kg once daily for 4 successive days; max 800mg/day. If no

℞

toxicity is observed, 6mg/kg are given on the 6th, 8th, 10th, and 12th days unless toxicity occurs.

Maintenance therapy: repeat dosage of 1st course every 30 days after the last day of the previous course 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 inj over 2–5mins. 1.4mg/m² on Days 1 and 8 of a 21-day cycle. Mild hepatic impairment (Child-Pugh A) or moderate-tosevere renal impairment (CrCl 15–49mL/min): 1.1mg/m² on Days 1 and 8 of a 21-day cycle.

Moderate hepatic impairment (Child-Pugh B): 0.7mg/m² on Days 1 and 8 of a 21-day cycle. Hold dose for ANC <1000/mm³, platelets <75000/mm³, or grade 3 or 4 nonhematological toxicities. Delay or reduce dose

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DRUG MONOGRAPHS

BREAST CANCER according to toxicities; see full labeling. Do not re-escalate dose after it is reduced.

Children: <18yrs: not established.

Warnings/Precautions: Monitor CBCs prior to each dose; increase frequency of monitoring if grade 3 or 4 cytopenias develop, delay and reduce subsequent doses if febrile neutropenia or grade 4 neutropenia lasting >7 days develops.

Monitor for peripheral neuropathy; withhold dose if grade 3 or 4 peripheral neuropathy develops until resolution to grade 2 or less.

Congenital long QT syndrome: avoid. CHF, bradyarrhythmias, electrolyte abnormalities: monitor ECG for prolonged QT interval.

Correct electrolyte abnormalities (K+, Mg+) before treatment; monitor. Severe hepatic impairment (Child-Pugh C): insufficient data.

Embryo-fetal toxicity. Pregnancy (avoid). Use effective contraception during treatment and for ≥2 weeks (females) or 3.5 months (male partners) after final dose. Nursing mothers: not recommended (during and for 2 weeks after final dose).

Interactions: Caution with other drugs that prolong QT interval (eg, Class IA and III antiarrhythmics); monitor.

Adverse reactions: Neutropenia, anemia, asthenia/fatigue, alopecia, peripheral neuropathy, nausea, constipation, abdominal pain, pyrexia, hypokalemia, hypocalcemia; febrile neutropenia, possible QT prolongation, elevated liver enzymes.

Note: Do not mix with dextrose-containing solutions. Do not administer in same line as other drugs or fluids.

How supplied: Single-use vial (2mL)—1

HERCEPTIN Genentech

℞

Human epidermal growth factor receptor (HER2) inhibitor. Trastuzumab 440mg/vial; lyophilized pwd for IV infusion after reconstitution and dilution; preservative-free.

Indications: HER2-overexpressing metastatic breast cancer as a single agent in patients who have received one or more chemotherapy regimens; or in combination with paclitaxel in patients who have not received chemotherapy.

Adjuvant treatment in HER2-overexpressing, node-positive or node-negative breast cancer (as a single agent following multi-modality anthracycline based therapy; in combination with doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel; or in combination with docetaxel and carboplatin).

Adults: Do not substitute for or with adotrastuzumab emtansine. Give as IV infusion.

Initially 4mg/kg over 90 mins, followed by 2mg/kg over 30 mins weekly; administer until tumor progression. Adjuvant treatment (administer trastuzumab weekly for 52 weeks; therapy >52 weeks: not recommended); In combination therapy: with doxorubicin and cyclophosphamide, followed by either paclitaxel or docetaxel; or with docetaxel/carboplatin:

initially 4mg/kg over 90 mins, followed by 2mg/kg over 30 mins once weekly for the 1st 12 weeks (concurrently w. paclitaxel or docetaxel) or 1st 18 weeks (concurrently w. docetaxel/carboplatin). One week after the last trastuzumab weekly dose, give trastuzumab 6mg/kg over 30–90 mins every 3 weeks.

Following multi-modality anthracycline based therapy: initially 8mg/kg over 90 mins, then 6mg/kg over 30–90 mins every 3 weeks.

Infusion reactions or cardiomyopathy: see full labeling.

Children: Not established.

Warnings/Precautions: Increased risk of cardiomyopathy. Conduct cardiac assessment (eg, history, physical exam, LVEF) at baseline, every 3 months during and after therapy or every 6 months for ≥2yrs after therapy (if adjuvant); repeat LVEF at 4 week intervals if dose is withheld due to significant left ventricular cardiac dysfunction. Interrupt therapy if dyspnea or significant hypotension occurs; consider discontinuing permanently if severe infusion reactions, CHF, pulmonary toxicity, or significant left ventricular myocardial dysfunction develops. Symptomatic intrinsic lung disease. Extensive tumor involvement of the lungs. Test for HER2 protein overexpression and HER2 gene amplification using FDAapproved tests for specific tumor type (breast or gastric/gastroesophageal adenocarcinoma).

Embryo-fetal toxicity (eg, oligohydramnios): exclude pregnancy status before initiation.

Pregnancy: avoid; use effective contraception during and for 7 months after therapy. Nursing mothers.

Interactions: Increased cardiomyopathy with anthracycline-containing chemotherapy.

Increased toxicity with other myelosuppressives.

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

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

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

IBRANCE Pfizer

℞

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

Indications: Treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or

metastatic breast cancer in combination with an aromatase inhibitor as initial endocrine based therapy in postmenopausal women; or fulvestrant in women with disease progression following endocrine therapy.

Adults: Swallow whole. Take with food. 125mg once daily for 21 consecutive days followed by 7 days off to complete a 28-day cycle, in combination with an aromatase inhibitor or with fulvestrant 500mg on Days 1, 15, 29, and once monthly thereafter (see each drug’s full labeling for dosing/duration). In the combination with fulvestrant therapy: pre/perimenopausal women should be treated with LHRH agonists according to clinical practice standards. Dose modification for adverse reactions: First reduction: 100mg/day; Second dose reduction: 75mg/day; discontinue if <75mg/day required. Dose modification for hematologic or non-hematologic toxicities: see full labeling. Concomitant strong CYP3A inhibitors: avoid and consider alternative drug; if use necessary, reduce palbociclib dose to 75mg/day.

Children: Not established.

Warnings/Precautions: Monitor CBCs prior to initiation and at start of each cycle, as well as on Day 15 of first 2 cycles, and as clinically indicated. Interrupt, reduce dose, or delay starting treatment cycles if Grade 3 or 4 neutropenia develops. If maximum of Grade 1–2 neutropenia develops in first 6 cycles, monitor CBCs for subsequent cycles every 3 months, at start of each cycle, and as clinically indicated. Monitor for fever. Moderate or severe hepatic impairment.

Severe renal impairment. Embryo-fetal toxicity.

Use effective contraception during therapy and for at least 3 weeks (females) or 3 months (males) after last dose. Pregnancy; exclude status prior to initiation. Nursing mothers: not recommended (during and for 3 weeks after last dose).

Interactions: Avoid concomitant strong CYP3A inhibitors (eg, clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole), grapefruit or grapefruit juice; if unavoidable, reduce dose (see Adults).

Avoid concomitant strong CYP3A inducers (eg, phenytoin, rifampin, carbamazepine, enzalutamide, St. John’s wort). May potentiate midazolam or other CYP3A substrates with narrow therapeutic index (eg, alfentanil, cyclosporine, dihydroergotamine, ergotamine, everolimus, fentanyl, pimozide, quinidine, sirolimus, tacrolimus); reduce dose of these drugs.

Adverse reactions: Neutropenia, leukopenia, infections, fatigue, anemia, nausea, stomatitis, alopecia, diarrhea, thrombocytopenia, decreased appetite, vomiting, rash, asthenia, pyrexia; febrile neutropenia.

How supplied: Caps—21

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DRUG MONOGRAPHS

BREAST CANCER IXEMPRA Bristol-Myers Squibb

℞

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

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

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

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

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

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

Children: Not recommended.

Contraindications: Baseline neutrophils <1500cells/mm3 or platelets <100,000cells/mm3.

AST or ALT >2.5XULN or bilirubin >1XULN (in combination with capecitabine).

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

Cardiac disease (discontinue if cardiac ischemia or cardiac dysfunction occurs). Monitor for signs/symptoms of neuropathy, neutropenia.

Pregnancy (Cat.D), nursing mothers: not recommended.

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

Avoid St. John’s wort.

Adverse reactions: Peripheral sensory neuropathy, fatigue, asthenia, myalgia, arthralgia, alopecia, GI upset, stomatitis, mucositis, musculoskeletal pain, 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 >3XULN and with total bilirubin >2XULN. Risk of left ventricular dysfunction. Assess LVEF prior to initiation and every 3 months during treatment; interrupt and discontinue as appropriate.

Embryo-fetal toxicity: verify pregnancy status prior to initiation. 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: avoid. Use effective contraception during therapy and for 7 months (females) or 4 months (males) after last dose. Nursing mothers: not recommended (during and for 7 months after last dose).

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, oligohydramnios (do fetal testing if occurs), infertility.

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

How supplied: Single-use vial—1

KISQALI Novartis

℞

Kinase inhibitor. Ribociclib 200mg; tabs.

Indications: In combination with an aromatase inhibitor, as initial endocrine-based therapy for the treatment of postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer.

Adults: Swallow whole. 600mg once daily for 21 consecutive days followed by 7 days off treatment for a complete 28-day cycle. Take preferably in the AM with letrozole 2.5mg once daily throughout the 28-day cycle (see full labeling of letrozole or for dosing/administration with other aromatase inhibitors). Dose modifications for toxicity: see full labeling.

Moderate and severe hepatic impairment: initially 400mg once daily.

Children: Not established.

Warnings/Precautions: Avoid in patients with long QT syndrome, uncontrolled or significant cardiac disease including recent MI, CHF, unstable angina and bradyarrhythmias, electrolyte abnormalities. Assess ECG prior to initiation; start therapy only if QTcF values <450 msec. Repeat ECG at Day 14 of Cycle 1, beginning of Cycle 2, and as clinically indicated; monitor more frequently if any QTcF prolongation occurs. Monitor serum electrolytes prior to initiation, at the beginning of the first 6 cycles, and as clinically indicated; correct any abnormality before starting.

Permanently discontinue if QTcF >500msec or >60msec change from baseline and associated with any of the following: Torsades de Pointes, polymorphic ventricular tachycardia, unexplained syncope, or serious arrhythmia.

Perform LFTs prior to initiation; monitor every 2 weeks for first 2 cycles, at the beginning of

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DRUG MONOGRAPHS

BREAST CANCER each subsequent 4 cycles, and as clinically indicated; monitor more frequently if Grade ≥2 abnormalities noted. Discontinue if AST/ALT >20XULN, Grade 3 (AST/ALT >5 to 20XULN) recurs, or AST/ALT >3XULN with total bilirubin >2XULN. Perform CBCs prior to initiation; monitor every 2 weeks for first 2 cycles, at the beginning of each subsequent 4 cycles, and as clinically indicated.

Hepatic impairment. Embryo-fetal toxicity.

Pregnancy: avoid; exclude status prior to initiation. Females of reproductive potential should use effective contraception during and for ≥3 weeks after last dose. Nursing mothers: not recommended (during and for ≥3 weeks after last dose).

Interactions: Avoid concomitant with strong CYP3A inhibitors (eg, boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, voriconazole); consider alternatives; if unavoidable, reduce to Kisqali 400mg once daily. Avoid grapefruit, grapefruit juice, pomegranates, pomegranate juice. Avoid concomitant with strong CYP3A inducers (eg, phenytoin, rifampin, carbamazepine, St. John’s wort); consider alternatives. Caution with concomitant CYP3A substrates with a narrow therapeutic index (eg, alfentanil, cyclosporine, ergots, everolimus, fentanyl, midazolam, pimozide, quinidine, sirolimus, tacrolimus); may need to reduce these doses. Avoid concomitant with drugs known to prolong QT interval (eg, amiodarone, bepridil, chloroquine, clarithromycin, disopyramide, halofantrine, haloperidol, methadone, moxifloxacin, IV ondansetron, pimozide, procainamide, quinidine, sotalol).

Adverse reactions: Neutropenia, nausea, fatigue, diarrhea, leukopenia, alopecia, vomiting, constipation, headache, back pain; QT prolongation, hepatobiliary toxicity, possible infertility.

How supplied: Blister pack—14, 21

KISQALI FEMARA CO-PACK ℞

Novartis

Kinase inhibitor + aromatase inhibitor. Ribociclib 200mg; with letrozole 2.5mg; tabs.

Indications: Initial endocrine-based therapy for the treatment of postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer.

Adults: Take together preferably in the AM. Swallow whole. Kisqali: initially 600mg once daily for 21 consecutive days, followed by 7 days off treatment for a complete 28-day cycle. Femara: 2.5mg once daily throughout the 28-day cycle.

Concomitant strong CYP3A4 inhibitors: avoid; if coadmin necessary, reduce Kisqali to 400mg once daily. Hepatic impairment: initially Kisqali

400mg once daily (moderate and severe); Femara 2.5mg every other day (cirrhosis and severe dysfunction). Dose modifications for toxicity: see full labeling.

Children: Not established.

Warnings/Precautions: Avoid in patients with long QT syndrome, uncontrolled or significant cardiac disease including recent MI, CHF, unstable angina and bradyarrhythmias, electrolyte abnormalities. Assess ECG prior to initiation; start therapy only if QTcF values <450 msec. Repeat ECG at Day 14 of Cycle 1, beginning of Cycle 2, and as clinically indicated; monitor more frequently if any QTcF prolongation occurs. Monitor serum electrolytes prior to initiation, at the beginning of the first 6 cycles, and as clinically indicated; correct any abnormality before starting. Permanently discontinue if QTcF >500msec or >60msec change from baseline and associated with any of the following: Torsades de Pointes, polymorphic ventricular tachycardia, unexplained syncope, or serious arrhythmia. Perform LFTs prior to initiation; monitor every 2 weeks for first 2 cycles, at the beginning of each subsequent 4 cycles, and as clinically indicated; monitor more frequently if Grade ≥2 abnormalities noted. Discontinue if AST/ALT >20XULN, Grade 3 (AST/ALT >5 to 20XULN) recurs, or AST/ALT >3XULN with total bilirubin >2XULN. Perform CBCs prior to initiation; monitor every 2 weeks for first 2 cycles, at the beginning of each subsequent 4 cycles, and as clinically indicated. Hepatic impairment. Embryo-fetal toxicity. Pregnancy: avoid; exclude status prior to initiation. Females of reproductive potential should use effective contraception during and for ≥3 weeks after last dose. Nursing mothers: not recommended (during and for ≥3 weeks after last dose).

Interactions: Avoid concomitant with strong CYP3A inhibitors (eg, boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, voriconazole); consider alternatives or see Adult. Avoid grapefruit, grapefruit juice, pomegranates, pomegranate juice. Avoid concomitant with strong CYP3A inducers (eg, phenytoin, rifampin, carbamazepine, St. John’s wort); consider alternatives. Caution with concomitant CYP3A substrates with a narrow therapeutic index (eg, alfentanil, cyclosporine, ergots, everolimus, fentanyl, midazolam, pimozide, quinidine, sirolimus, tacrolimus); may need to reduce these doses. Avoid concomitant with drugs known to prolong QT interval (eg, amiodarone, bepridil, chloroquine, clarithromycin, disopyramide, halofantrine, haloperidol, methadone, moxifloxacin, IV ondansetron, pimozide, procainamide, quinidine, sotalol).

Adverse reactions: Neutropenia, nausea, fatigue, diarrhea, leukopenia, alopecia,

vomiting, constipation, headache, back pain; QT prolongation, hepatobiliary toxicity.

How supplied: Cartons—28 days of therapy (63 tabs × 200mg + 28 tabs); (42 tabs × 200mg + 28 tabs); (21 tabs × 200mg + 28 tabs)

NERLYNX Puma Biotechnology

℞

Kinase inhibitor. Neratinib 40mg; tabs.

Indications: Extended adjuvant treatment of early stage HER2-overexpressed/amplified breast cancer following adjuvant trastuzumab-based therapy.

Adults: Initiate antidiarrheal prophylaxis (loperamide) with the first dose and continue during the first 2 treatment cycles (56 days); see full labeling. Swallow whole. Take with food.

240mg once daily for 1 year. Severe hepatic impairment (Child-Pugh C): reduce initial dose to 80mg. Dose modifications for adverse reactions: First dose reduction: 200mg/day; Second dose reduction: 160mg/day; Third dose reduction: 120mg/day; discontinue if unable to tolerate 120mg/day. Dose modifications for diarrhea, hepatotoxicity, or other general toxicities: see full labeling.

Children: Not established.

Warnings/Precautions: Monitor and treat diarrhea as needed; interrupt and reduce subsequent doses if severe diarrhea with dehydration occurs. Perform stool cultures as clinically indicated to exclude infectious causes of Grade 3/4 or any grade of diarrhea with complications. Measure total bilirubin, AST/ALT, alkaline phosphatase prior to initiation, monthly for the first 3 months, then every 3 months during treatment and as clinically indicated. Severe hepatic impairment: reduce dose. Embryo-fetal toxicity. Use effective contraception during therapy and for at least 1 month (females) or 3 months (males) after last dose. Pregnancy; exclude status prior to initiation. Nursing mothers: not recommended (during and for at least 1 month after last dose).

Interactions: Avoid concomitant PPIs, H2-receptor antagonists, strong or moderate CYP3A4 inhibitors (eg, boceprevir, clarithromycin, cobicistat, conivaptan, danoprevir/ritonavir, diltiazem, elvitegravir/ritonavir, grapefruit juice, idelalisib, indinavir/ritonavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, paritaprevir/ritonavir and [ombitasvir and/or dasabuvir], posaconazole, ritonavir, saquinavir/ritonavir, tipranavir/ritonavir, troleandomycin, voriconazole, aprepitant, cimetidine, ciprofloxacin, clotrimazole, crizotinib, cyclosporine, dronedarone, erythromycin, fluconazole, fluvoxamine, imatinib, tofisopam, verapamil), and strong or moderate CYP3A4 inducers (eg, carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, St. John’s wort, bosentan, efavirenz, etravirine, modafinil).

Separate dosing by 3hrs after antacids.

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DRUG MONOGRAPHS

BREAST CANCER Increased cardiotoxicity risk with digoxin.

May inhibit transport of P-gp substrates (eg, dabigatran, fexofenadine).

Adverse reactions: Diarrhea, nausea, abdominal pain, fatigue, vomiting, rash, stomatitis, decreased appetite, muscle spasms, dyspepsia, AST/ALT increase, nail disorder, dry skin, abdominal distention, weight decreased, urinary tract infection; hepatotoxicity.

How supplied: Tabs—126, 180

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

Assess LVEF at baseline and at regular intervals (eg, every 3 months in metastatic setting,

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

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

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

How supplied: Single-use vial—1

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 nodepositive 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 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,

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DRUG MONOGRAPHS

BREAST CANCER planned pregnancy. Pregnancy (Cat.D). Nursing mothers.

Warnings/Precautions: See literature. Do gynecological exam at least annually. DCIS and risk reduction: consider increased risk of uterine cancer (endometrial adenocarcinoma, uterine sarcoma) and thrombotic events. Women with advanced disease: discontinue if severe hypercalcemia occurs. Monitor blood, lipids, liver function, for thromboembolism symptoms (eg, leg swelling, unexplained shortness of breath), and for uterine changes/cancer (eg, pelvic pain or pressure); promptly investigate any abnormal vaginal bleeding. Breast cancer treatment: history of thromboembolic events.

Premenopausal: use effective non-hormonal contraception during and within 2 months of discontinuing therapy; begin therapy during menses or, if irregular menses, obtain (–) B-hCG pregnancy test first.

Interactions: May potentiate oral anticoagulants (see Contraindications).

Antagonizes anastrozole (avoid concomitant use); letrozole. Plasma levels reduced by CYP3A4 inducers (eg, rifampin). Cytotoxic drugs increase risk of thrombotic events. Potentiated by bromocriptine.

Adverse reactions: Hot flashes, vaginal discharge, altered menses, rash, headache, nausea, cough, edema, fatigue, abdominal cramps, bone and tumor pain (in advanced disease), local disease flare, hypercalcemia, thrombotic events, ovarian cysts, uterine fibroids or cancer (endometrial adenocarcinoma, uterine sarcoma), endometrial or visual changes, jaundice, hypertriglyceridemia, blood dyscrasias, hair loss.

How supplied: Contact supplier. ℞

(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)

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

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

TREXALL Teva

TYKERB GlaxoSmithKline

℞

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: Risk of severe and fatal hepatotoxicity; discontinue if occurs; do not retreat. Monitor liver function tests before, every 4–6 weeks during therapy and as indicated. Confirm normal LVEF before starting.

Discontinue if ≥grade 2 decrease in LVEF occurs, or if LVEF falls below institution’s lower limit of normal; may restart after at least 2 weeks at reduced dose if asymptomatic and LVEF recovers. Conditions that impair left ventricular function, or risk factors for QT prolongation (eg, hypokalemia, hypomagnesemia, congenital long QT syndrome, concomitant antiarrhythmics, cumulative high dose anthracyclines); correct electrolyte disturbances before starting. Monitor for interstitial lung disease or pneumonitis; discontinue if pulmonary symptoms ≥grade 3 (NCI CTCAE). Discontinue if severe skin reaction (eg, Stevens-Johnson syndrome, toxic epidural necrolysis) is suspected.

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

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DRUG MONOGRAPHS

BREAST CANCER unavoidable. May affect drugs that are affected by p-glycoprotein, CYP2C8, CYP3A4.

Adverse reactions: Diarrhea (may be severe), hand/foot syndrome, nausea, rash (may be severe), vomiting, fatigue; hepatotoxicity, decreased LVEF, QT prolongation, interstitial lung disease, pneumonitis.

Testing considerations: HER2 protein overexpression How supplied: Tabs—150

VERZENIO Lilly

℞

Kinase inhibitor. Abemaciclib 50mg, 100mg, 150mg, 200mg; tabs.

Indications: In combination with fulvestrant for the treatment of women with HR-positive, HER2negative advanced or metastatic breast cancer with disease progression following endocrine therapy. As monotherapy for the treatment of adults with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting.

Adults: Swallow whole. Take at the same time every day. Combination with fulvestrant (see full labeling): initially 150mg twice daily; in pre/perimenopausal women: also treat with a gonadotropin-releasing hormone agonist according to current practice standards.

Monotherapy: initially 200mg twice daily.

Both: continue until disease progression or unacceptable toxicity. Dose modifications for adverse reactions, concomitant strong CYP3A4 inhibitors: see full labeling. Severe hepatic impairment: reduce frequency to once daily.

Children: Not established.

Warnings/Precautions: Advise patients to initiate antidiarrheal (eg, loperamide) and increase fluids at first sign of loose stools; discontinue if Grade 3/4 diarrhea occurs or hospitalization required, until resolves to ≤Grade 1, then resume at next lower dose. Monitor CBCs and LFTs prior to initiation and every 2 weeks for the first 2 months, then monthly for the next 2 months, and as clinically indicated. Dose interruption/reduction/discontinuation or delay in starting treatment cycles if Grade 3/4 neutropenia, recurrent Grade 2 or Grade 3/4 transaminase elevation occurs. Monitor for signs/symptoms of venous thromboembolic events; treat appropriately. Severe hepatic impairment (Child-Pugh C). Embryo-fetal toxicity. Females of reproductive potential should use effective contraception during

therapy and for at least 3 weeks after last dose. Pregnancy; exclude status prior to initiation. Nursing mothers: not recommended (during and for at least 3 weeks after the last dose).

Interactions: Avoid concomitant ketoconazole, grapefruit products. Concomitant other strong CYP3A inhibitors: reduce abemaciclib dose. Avoid concomitant strong CYP3A inducers (eg, rifampin): consider alternative agents.

Adverse reactions: Diarrhea, neutropenia, nausea, abdominal pain, infections, fatigue, anemia, leukopenia, decreased appetite, vomiting, headache, thrombocytopenia; venous thromboembolic events, hepatotoxicity.

How supplied: Blister pack—14

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 (eg, 950mg/m2 twice daily).

Children: <18yrs: not established.

Contraindications: Severe renal impairment (CrCl <30mL/min).

Warnings/Precautions: Hepatic or renal impairment. Monitor and correct dehydration at initiation. Coronary artery disease.

Interrupt therapy if Grade 2/3 hand-and-foot syndrome, Grade 2/3 or 4 diarrhea occurs (give antidiarrheals) until resolves or reduces to Grade 1. Permanently discontinue if severe mucocutaneous reactions (eg, SJS, TEN) occur.

Dihydropyrimidine dehydrogenase deficiency.

Elderly. Embryo-fetal toxicity. Pregnancy: avoid; exclude status prior to initiation. Females of reproductive potential should use effective contraception (during therapy and for 6 months) and males with female partners (during and for 3 months) after final dose. Nursing mothers: not recommended (during and for 2 weeks after final dose.

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.

Testing considerations: TS (thymidylate synthase), MSI (microsatellite instability), DPD (dihydropyrimidine dehydrogenase) How supplied: Tabs 150mg—60; 500mg—120

GENERIC NAME The active ingredients and strengths are listed under the name of each dosage form. If the product contains tartrazine, alcohol, flavors, or is alcohol-, sugar-, or dye-free, it is noted. Abbreviations are used to describe the dosage form and its formulation, e.g.: tabs = tablets caps = capsules e-c = enteric coated sust rel = sustained-release ext rel = extended-release

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

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DRUG MONOGRAPHS

ENDOCRINE CANCER ABRAXANE Celgene

℞

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

Indications: First-line treatment of metastatic adenocarcinoma of the pancreas, in combination with gemcitabine.

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

125mg/m2 IV over 30–40 mins on Days 1, 8, and 15 of each 28-day cycle. Moderate to severe hepatic impairment (total bilirubin >1.5): not recommended. Dose reductions for hematologic and neurologic adverse reactions: see full labeling. Avoid extravasation.

Children: Not evaluated.

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

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

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

Interactions: May potentiate or be potentiated

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

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

How supplied: Single-use vial—1

AFINITOR Novartis

℞

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

Indications: In adults with progressive neuroendocrine tumors of pancreatic origin (PNET) or progressive, well-differentiated, nonfunctional neuroendocrine tumors (NET) of gastrointestinal or lung origin with unresectable, locally advanced or metastatic disease. Not for treating functional carcinoid tumors.

Adults: Swallow tabs whole with water. Take at the same time each day either consistently with or without food. 10mg once daily; continue until disease progression or unacceptable toxicity.

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 risks. 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: avoid; if required, 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. 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; discontinue, reduce dose, and/or manage with corticosteroids if non-infectious pneumonitis occurs. Increased risk of infections (may be severe or fatal); monitor and treat promptly if occur. Pre-existing invasive fungal infections: treat before starting. Use dexamethasone mouthwash at initiation to reduce the incidence and severity of stomatitis; use alcohol-, peroxide-, iodine-, or thyme-free products if occurs. 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. Embryo-fetal toxicity.

Must use effective contraception during and for 8 weeks (females) or 4 weeks (males) after last dose. Pregnancy, 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); see Adult. Antagonized by strong CYP3A4/PgP inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital), St. John’s Wort; avoid or increase dose (see Adult). Increased risk of angioedema with concomitant ACE inhibitor.

Adverse reactions: Stomatitis, infections, rash, fatigue, diarrhea, edema, abdominal

pain, nausea, fever, asthenia, cough, headache, decreased appetite, RTI; decreased hemoglobin, WBC, platelets, lymphocytes, neutrophils, serum phosphate, potassium, albumin; increased cholesterol, blood glucose, AST, ALT, triglycerides, serum creatinine, proteinuria, renal failure.

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

CAPRELSA Sanofi Genzyme

℞

Kinase inhibitor. Vandetanib 100mg, 300mg, tabs.

Indications: Symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease.

Adults: Do not crush tabs. May disperse tabs in 2oz noncarbonated water for oral or NGT administration; avoid contact of dispersion with skin, mucous membranes. 300mg once daily.

Renal impairment (CrCl<50mL/min): initially 200mg once daily. Dose adjustments for adverse reactions: see full labeling. Do not take a missed dose within 12hrs of the next dose.

Children: Not established.

Contraindications: Congenital long QT syndrome.

Warnings/Precautions: Hypocalcemia, hypokalemia, hypomagnesemia, QTcF interval >450msec, history of Torsades de pointes, bradyarrhythmias, uncompensated heart failure, recent hemoptysis: not recommended.

Ventricular arrhythmias. Recent MI. Monitor electrolytes (esp. K+, Ca++, Mg++), TSH, and ECG for QT prolongation at baseline, 2–4 weeks and 8–12 weeks after starting, then every 3 months, and after dose reductions or dose interruptions >2 weeks; reduce dose as needed. Correct electrolyte disturbances before starting. Maintain serum K+ at least 4mEq/mL. Hepatic impairment (Child-Pugh B or C): not recommended. Interrupt therapy and follow-up if acute or worsening pulmonary symptoms, QTcF >500msec, or CTCAE Grade ≥3 toxicity occurs. Monitor for heart failure; consider discontinuing if occurs. Discontinue if confirmed interstitial lung disease, severe ischemic cerebrovascular event, hemorrhage, uncontrolled hypertension, or posterior leukoencephalopathy symptoms (RPLS) occur. Avoid sun, UV light. Elderly. Pregnancy (Cat.D) (may cause fetal harm; use appropriate effective contraception during and for 4 months after stopping therapy), nursing mothers: not recommended.

Interactions: Avoid strong CYP3A4 inducers (eg, rifampicin, St. John’s Wort). Avoid other drugs that can prolong QT interval (eg, amiodarone, disopyramide, procainamide, sotalol, dofetilide, chloroquine, clarithromycin, dolasetron, granisetron, haloperidol, pimozide, methadone, moxifloxacin). Potentiates OCT2 transporters (eg, metformin), digoxin; monitor.

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DRUG MONOGRAPHS

ENDOCRINE CANCER 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, toxic epidermal necrolysis, Stevens-Johnson syndrome; permanently discontinue if occurs), photosensitivity.

Note: Prescribers and pharmacies must enroll in the Caprelsa REMS program by calling (800) 236-9933 or visit www. caprelsarems.com.

How supplied: Tabs—30

COMETRIQ Exelixis

℞

Kinase inhibitor. Cabozantinib 20mg, 80mg; caps.

Indications: Treatment of progressive, metastatic medullary thyroid cancer (MTC).

Adults: Not interchangeable with cabozantinib tabs. Swallow whole. 140mg daily. Do not eat at least 2 hours before or 1 hour after dose. Continue until disease progression or unacceptable toxicity. Withhold for Grade 4 hematologic adverse reactions, ≥Grade 3 non-hematologic reactions or intolerable Grade 2 reactions. Upon improvement to Grade 1 or to baseline, reduce dose as follows: previously on 140mg daily, resume at 100mg daily; previously on 100mg daily, resume at 60mg daily; previously on 60mg daily, resume at 60mg if tolerated, otherwise discontinue. Mildto-moderate hepatic impairment: initially 80mg daily. Concomitant strong CYP3A4 inhibitors: reduce daily dose by 40mg; resume dose used prior to starting inhibitor 2–3 days after discontinuation of inhibitor. Concomitant strong CYP3A4 inducers: increase daily dose by 40mg; resume dose used prior to starting inducer 2–3 days after discontinuation of inducer. Max daily dose: 180mg.

Children: Not studied.

Warnings/Precautions: Permanently discontinue if the following occurs: GI or non-GI perforation/fistula formation, severe hemorrhage, serious arterial thromboembolic events (eg, MI, cerebral infarction), nephrotic syndrome, malignant hypertension, hypertensive crisis, persistent uncontrolled hypertension despite optimal medical management, osteonecrosis of the jaw, reversible posterior leukoencephalopathy syndrome. 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. Severe hepatic impairment: not recommended. Severe renal impairment. Monitor for bleeding, hypertension, proteinuria (measure urine protein regularly).

Pregnancy. Females of reproductive potential should use effective contraception during and for 4 months after final dose. 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, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, St. John’s Wort): see Adult dose. May be potentiated by MRP2 inhibitors (eg, abacavir, adefovir, cidofovir, furosemide, lamivudine, nevirapine, ritonavir, probenecid, saquinavir, tenofovir); monitor for increased toxicity.

Adverse reactions: Diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome, decreased weight/appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, constipation, increased AST, ALT, alkaline phosphatase, lymphopenia, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, hyperbilirubinemia.

How supplied: 140mg daily-dose carton—4 blister cards (each: 7x80mg and 21x20mg caps); 100mg daily-dose carton—4 blister cards (each: 7x80mg and 7x20mg caps); 60mg daily-dose carton—4 blister cards (each: 21x20mg caps)

Fluorouracil (various)

℞

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

Indications: Palliative management of carcinoma of the pancreas.

Adults: Give by IV inj. 12mg/kg once daily for 4 successive days; max 800mg/day. If no toxicity is observed, 6mg/kg are given on the 6th, 8th, 10th, and 12th days unless toxicity occurs.

Maintenance therapy: repeat dosage of 1st course every 30 days after the last day of the previous course of treatment; or give a maintenance dose of 10–15mg/kg per week as a single dose; max: 1g/week. Poor risk patients: see literature for dose adjustments.

Children: Not recommended.

Contraindications: Poor nutritional state.

Depressed bone marrow function. Potentially serious infections.

Warnings/Precautions: Narrow margin of safety; monitor for toxicity. Consider hospitalization for 1st course. History of highdose pelvic irradiation. Previous use of alkylating agents. Widespread involvement of bone marrow by metastatic tumors. Renal or hepatic impairment. Discontinue if signs of toxicity appear (eg, stomatitis, esophagopharyngitis, leukopenia, intractable vomiting, diarrhea, GI ulceration or bleeding, thrombocytopenia, hemorrhage). Monitor WBCs with differential before each dose. Avoid extravasation. Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended.

Interactions: Potentiated by leucovorin.

Adverse reactions: Stomatitis, esophagopharyngitis, GI upset, anorexia, leukopenia, alopecia, dermatitis, hand-foot syndrome; others.

Testing considerations: TS (thymidylate synthase), MSI (microsatellite instability), DPD (dihydropyrimidine dehydrogenase).

How supplied: Contact supplier.

LENVIMA Eisai

℞

Kinase inhibitor. Lenvatinib 4mg, 10mg; capsules.

Indications: Treatment of locally recurrent or metastatic, progressive, radioactive iodinerefractory differentiated thyroid cancer.

Adults: Swallow whole or may dissolve capsule contents into liquid. 24mg once daily until disease progression or unacceptable toxicity occurs. Severe renal impairment (CrCl <30mL/min) or severe hepatic impairment (Child-Pugh C): 14mg once daily. Dose modifications for adverse reactions or lab abnormalities: see full labeling.

Children: Not established.

Warnings/Precautions: Control blood pressure prior to treatment; monitor after 1 week, every 2 weeks for the first 2 months, and then at least monthly thereafter during therapy. Discontinue if life-threatening hypertension, Grade 4 cardiac dysfunction or hemorrhage, arterial thrombotic event, hepatic failure, nephrotic syndrome, GI perforation or life-threatening fistula, or severe and persistent neurologic symptoms occur. Withhold if Grade 3 hypertension persists despite therapy, Grade 3 cardiac dysfunction or hemorrhage, ≥Grade 3 liver impairment or QT prolongation >500ms, Grade 3 or 4 renal failure/impairment, ≥2g of proteinuria/24hrs, or reversible posterior

Access Cancer Therapy Advisor treatment regimens in a user-friendly format.

CancerTherapyAdvisor.com/TreatmentRegimens.

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DRUG MONOGRAPHS

ENDOCRINE CANCER 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. Monitor for dehydration and treat if diarrhea develops; interrupt if Grade 3 or 4 and permanently discontinue if Grade 4 diarrhea persists despite therapy. 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 function prior to initiation and at least monthly thereafter; treat hypothyroidism as needed. ESRD. Embryofetal toxicity. Pregnancy: avoid. Use effective contraception during and for at least 2 weeks after treatment completion. Nursing mothers: not recommended.

Adverse reactions: Hypertension, fatigue, diarrhea, arthralgia/myalgia, decreased appetite, weight decreased, nausea, stomatitis, headache, vomiting, proteinuria, palmar-plantar erythrodysesthesia syndrome, abdominal pain, dysphonia.

How supplied: Blister cards—6

NEXAVAR Bayer and Onyx

℞

Multikinase inhibitor. Sorafenib 200mg; tabs.

Indications: Locally recurrent or metastatic, progressive, differentiated thyroid carcinoma refractory to radioactive iodine treatment.

Adults: Take on an empty stomach. 400mg twice daily. If toxicity occurs, may reduce dose to 400mg and 200mg 12hrs apart (either dose can come first); if second reduction is required, may reduce dose to 200mg twice daily; if third reduction is required, may reduce to 200mg once daily (see full labeling). Concomitant strong CYP3A4 inducers: consider increasing dose, monitor for toxicity.

Children: Not established.

Contraindications: Concomitant carboplatin/paclitaxel in patients with squamous cell lung cancer.

Warnings/Precautions: Avoid in congenital long QT syndrome. Monitor patients with CHF, bradyarrhythmias, drugs known to prolong the QT interval, electrolyte abnormalities.

Discontinue if severe dermatologic toxicity, hypertension, GI perforation, hemorrhage, cardiac ischemia, MI occurs. Suspend therapy before major surgery. Monitor BP weekly during the first 6 weeks and thereafter. Monitor hepatic function regularly; discontinue if transaminases significantly elevated. Severe hepatic impairment (Child-Pugh C) or on dialysis.

Monitor TSH levels monthly and adjust thyroid therapy. Use effective contraception during and for 2 weeks after stopping treatment.

Pregnancy (Cat.D), nursing mothers: not recommended.

Interactions: See Contraindications. Avoid strong CYP3A4 inducers (eg, St. John’s Wort, dexamethasone, phenytoin, carbamazepine, rifabutin, rifampin, phenobarbital) and neomycin; may decrease sorafenib levels. May potentiate warfarin (monitor PT & INR), other drugs metabolized by UGT1A1 or UGT1A9 pathway, or substrates of CYP2B6, CYP2C8, CYP2C9, P-gp.

Concomitant Class Ia and III antiarrhythmics; may prolong QT interval.

Adverse reactions: Dermatologic toxicity (eg, rash, hand-foot skin reaction, alopecia, pruritus, dry skin, Stevens-Johnson syndrome, toxic epidermal necrolysis), fatigue, weight loss, diarrhea, anorexia, abdominal pain, hypertension, hemorrhage, electrolyte abnormalities; druginduced hepatitis, QT prolongation.

How supplied: Tabs—120

ONIVYDE Ipsen

℞

Topoisomerase inhibitor. Irinotecan 43mg/10mL; liposomal dispersion for IV infusion after dilution.

Indications: In combination with fluorouracil and leucovorin, for treatment of metastatic adenocarcincoma of the pancreas after disease progression following gemcitabine-based therapy.

Limitations of use: as a single agent, not for the treatment of metastatic adenocarcinoma of the pancreas.

Adults: Do not substitute for other irinotecan HCl-containing drugs. Give by IV infusion over 90 mins prior to fluorouracil and leucovorin.

70mg/m2 every 2 weeks. If homozygous UGT1A1*28 allele: initially 50mg/m2; may increase to 70mg/m2 as tolerated in subsequent cycles. If serum bilirubin >ULN: no dose recommended. Premedicate with corticosteroid and antiemetic 30 mins prior to infusion. Dose modifications: see full labeling.

Children: Not established.

Warnings/Precautions: Severe and lifethreatening neutropenia, neutropenic sepsis, diarrhea can occur. Monitor CBCs on Days 1 and 8 of every cycle and more frequently if indicated; withhold if ANC <1500/mm3 or neutropenic fever occurs; reduce dose in subsequent cycles for Grade 3–4 neutropenia or neutropenic fever after recovery. Bowel obstruction: do not administer. Withhold for Grade 2–4 diarrhea; initiate loperamide if late onset or atropine IV/SC (unless contraindicated) if early onset; resume at reduced dose after recovery to Grade 1.

Withhold if new or progressive dyspnea, cough, and fever occurs, pending evaluation; discontinue if interstitial lung disease confirmed. Permanently discontinue if severe hypersensitivity reaction occurs. Females of reproductive potential should use effective contraception during therapy and for 1 month after final dose; males should use condoms

during and for 4 months after final dose.

Pregnancy. Nursing mothers: not recommended (during therapy and for 1 month after final dose).

Interactions: Avoid concomitant strong CYP3A4 inducers (eg, rifampin, phenytoin, carbamazepine, rifabutin, rifapentine, phenobarbital, St. John’s wort) if possible; substitute non-enzyme inducing therapies at least 2 weeks before initiating irinotecan.

Avoid concomitant strong CYP3A4 (eg, clarithromycin, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telaprevir, voriconazole) or UGT1A1 inhibitors (eg, atazanavir, gemfibrozil, indinavir) if possible; discontinue CYP3A inhibitors at least 1 week before initiating irinotecan.

Adverse reactions: Diarrhea, fatigue/asthenia, vomiting, nausea, decreased appetite, stomatitis, pyrexia; neutropenic fever or sepsis, dehydration, septic shock, pneumonia, acute renal failure, thrombocytopenia.

How supplied: Single-dose vial—1

SOMATULINE DEPOT Ipsen

℞

Somatostatin analogue. Lanreotide 60mg/0.2mL, 90mg/0.3mL, 120mg/0.5mL; 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. Renal or hepatic impairment. Monitor growth hormone (GH), IGF-1 levels, thyroid function, gallbladder, glucose. Pregnancy. 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, vomiting, inj site reactions, musculoskeletal pain, headache, dizziness, muscle spasm; gallbladder sludge, gallstones, hyperglycemia, hypoglycemia, sinus bradycardia, hypertension, anemia; rare: hypothyroidism.

How supplied: Single-dose prefilled syringe—1

SUTENT Pfizer

℞

Multikinase inhibitor. Sunitinib (as malate) 12.5mg, 25mg, 37.5mg, 50mg; hard gel caps.

Indications: Progressive, well-differentiated pancreatic neuroendocrine tumors (pNET) in

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DRUG MONOGRAPHS

ENDOCRINE CANCER 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; max 50mg daily. 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: Risk of hepatotoxicity (may be severe or fatal). Monitor LFTs 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 pre-existing cardiac disease, bradycardia, electrolyte disturbances; perform periodic ECG, monitor electrolytes. Monitor BP; suspend if severe hypertension develops until controlled. Not for use in lung cancer patients. Perform serial CBCs and physical exams. 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. Temporary interrupt if undergoing major surgery.

Discontinue if severe cutaneous reactions (eg, erythema multiforme, SJS, TEN) develop; do not restart if diagnosis suspected. ESRD on dialysis.

Severe hepatic impairment. Embryo-fetal toxicity. Use effective contraception during and for ≥4 weeks (females) or 7 weeks (males) after last dose. Pregnancy; exclude status prior to initiation. Nursing mothers: not recommended (during and for ≥4 weeks after last dose).

Interactions: May be potentiated by strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir,

telithromycin, voriconazole), grapefruit; consider alternatives or reduce dose if needed (see Adult).

May be antagonized by CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital); consider alternatives or increase dose if needed (see Adult). Concomitant St. John’s wort: not recommended. Caution with concomitant antiarrhythmics.

Adverse reactions: Fatigue/asthenia, diarrhea, mucositis/stomatitis, nausea, decreased appetite/anorexia, vomiting, abdominal pain, hand-foot syndrome, hypertension, bleeding events, dysguesia/altered taste, dyspepsia, thrombocytopenia; 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).

How supplied: Caps—28

TARCEVA Astellas and Genentech

℞

Kinase inhibitor. Erlotinib (as HCl) 25mg, 100mg, 150mg; tabs.

Indications: In combination with gemcitabine: first-line treatment of locally advanced, unresectable or metastatic pancreatic cancer.

Adults: Take on empty stomach. 100mg once daily + gemcitabine (see full labeling). Use until disease progression or unacceptable toxicity occurs. Dose modifications for adverse reactions: see full labeling. Concomitant strong CYP3A4 inhibitors (see Interactions): reduce by 50mg decrements; avoid use if possible. Concomitant CYP3A4 inducers (see Interactions): increase by 50mg increments at 2-week intervals (max 450mg); avoid use if possible. Concurrent cigarette smoking: increase by 50mg increments at 2-week intervals (max 300mg); upon cessation, reduce to 150mg or 100mg daily.

Children: Not established.

Warnings/Precautions: Discontinue if interstitial lung disease, severe hepatic toxicity, GI perforation, severe bullous, blistering or exfoliating skin conditions, or corneal perforation or severe ulceration occurs. Withhold or consider discontinuing therapy if severe renal failure due to dehydration, or acute/worsening ocular disorders occur. Monitor LFTs periodically; withhold in patients without history of hepatic impairment for total bilirubin >3XULN or transaminases >5XULN, or in patients with history of hepatic impairment or biliary obstruction for doubling

of bilirubin or tripling of transaminases over baseline. Discontinue if abnormal LFTs do not improve or resolve within 3 weeks. Withhold for acute onset of unexplained pulmonary symptoms pending evaluation, persistent severe diarrhea unresponsive to loperamide, severe rash, grade 3–4 keratitis or grade 2 lasting ≥2 weeks.

Monitor renal function, serum electrolytes, pulmonary function, INR, prothrombin time.

History of peptic ulcers or diverticular disease.

Embryo-fetal toxicity. Pregnancy: avoid. Females of reproductive potential should use effective contraception during therapy and at least 1 month after the last dose. Nursing mothers: not recommended (during and for 2 weeks after the last dose).

Interactions: Potentiated by CYP3A4 inhibitors (eg, atazanavir, boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telithromycin, troleandomycin, voriconazole, grapefruit) or a combined CYP3A4 and CYP1A2 inhibitor (eg, ciprofloxacin); reduce dose if unavoidable. Plasma levels decreased

by CYP3A4 inducers (eg, rifampin, rifabutin, rifapentine, phenytoin, carbamazepine, phenobarbital, St. John’s wort); increase dose if unavoidable. Avoid concomitant moderate CYP1A2 inducers (eg, teriflunomide, rifampin, phenytoin) or smoking tobacco; increase dose if unavoidable. Avoid concomitant proton pump inhibitors if possible. Separate dosing of antacids by several hours or for H2 blockers (take erlotinib 10hrs after and at least 2hrs before next dose). 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 with thrombocytopenia, cerebrovascular accident (in pancreatic cancer), 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

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

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

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

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

General Treatment Notes1 • Consists of regimens that include both concurrent chemotherapy and radiotherapy and adjuvant chemotherapy.

• Six months of perioperative therapy is preferred in the adjuvant therapy setting.

• Following a shortage of leucovorin, the FDA approved levoleucovorin in combination with 5-FU for the palliative treatment of patients with advanced metastatic colorectal cancer. Levoleucovorin 200mg/m2 is the equivalent of leucovorin 400mg/m2.

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

Postoperative Adjuvant Therapy for Patients Not Receiving Preoperative Therapy1 REGIMEN

DOSING

mFOLFOX6 (oxaliplatin + leucovorin + 5-fluorouracil [5-FU])2–4,a

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

Repeat cycle every 2 weeks for a total of 6 months perioperative therapy.

Capecitabine5,d

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

Repeat cycle every 3 weeks for 6 months perioperative therapy.

CapeOX (oxaliplatin + capecitabine)6,7,a,d

Day 1: Oxaliplatin 130mg/m2 IV. Days 1–14: Capecitabine 1,000mg/m2 orally twice daily.

Repeat cycle every 3 weeks for 6 months perioperative therapy.

Simplified biweekly infusional 5-FU/ LV (sLV5FU2)8

Day 1: Leucovorin 400mg/m2 IV, followed by 5-FU 400mg/m2 IV bolus, followed by 5-FU 1,200mg/m2/day IV x 2 days (total 2,400mg/m2) as a 46–48 hour continuous infusion.

Repeat cycle every 2 weeks for 6 months perioperative therapy.

5-FU + leucovorin9

5-FU 500mg/m2 IV bolus weekly x 6 + leucovorin 500mg/m2 IV weekly x 6, each 8-week cycle.

Repeat cycle every 8 weeks for 6 months perioperative therapy.

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

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

XRT + 5-FU + leucovorin11,c

Days 1–4: 5-FU 400mg/m2 IV bolus + leucovorin 20mg/m2 IV bolus.

Repeat cycle during weeks 1 and 5 of XRT.

XRT + capecitabine12,13

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

Systemic Therapy for Advanced or Metastatic Disease1 mFOLFOX62–4,a

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

Repeat cycle every 2 weeks.

mFOLFOX737,a

Day 1: Oxaliplatin 85mg/m2 IV + leucovorin 400mg/m2 IV Days 1-2: 5-FU 1200mg/m2/day IV (total 2400mg/m2) as 46-48 continuous infusion.

Repeat cycle every 2 weeks.

mFOLFOX6 + bevacizumab3,14,a

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

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

Day 1: Oxaliplatin 85mg/m2 IV over 2 hours + leucovorin 400mg/m2 IV over 2 hours, followed by 5-FU 400mg/m2 IV bolus, followed by 5-FU 1,200mg/m2/day IV 2 days (total 2,400mg/m2) as a 46–48-hour continuous infusion Day 1: Panitumumab 6mg/kg IV over 1 hour.

Repeat cycle every 2 weeks.

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CANCER TREATMENT REGIMEN

GASTROINTESTINAL CANCER Systemic Therapy for Advanced or Metastatic Disease1 (continued) REGIMEN

DOSING

FOLFOX + cetuximab (KRAS/NRAS wild-type gene only)

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

OR Day 1: Cetuximab 500mg/m2 IV over 2 hours every 2 weeks.

CapeOX6,7,17,a,d

Day 1: Oxaliplatin 130mg/m2 IV Days 1–14: Capecitabine 1,000mg/m2 orally twice daily.

Repeat cycle every 3 weeks.

CapeOX + bevacizumab6,7,17,a,c,d

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

FOLFIRI18,19

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

Repeat cycle every 2 weeks.

FOLFIRI + bevacizumab18,19,38,c

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

FOLFIRI + cetuximab19, 20,21 (KRAS/NRAS wild-type gene only)

Day 1: Irinotecan 180mg/m2 IV + leucovorin 400mg/m2 IV, to match duration off irinotecan infusion, followed by 5-FU 400mg/m2 IV bolus, followed by 5-FU 1,200mg/m2/day IV 2 days (total 2,400mg/m2) as a 46–48-hour continuous infusion.

Repeat cycle every 2 weeks.

PLUS Day 1: Cetuximab 400mg/m2 IV over 2 hours first infusion, then 250mg/m2 IV over 60 minutes weekly.

OR Day 1: Cetuximab 500mg/m2 IV over 2 hours every 2 weeks.

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

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

Day 1: Panitumumab 6mg/kg IV over 1 hour.

Repeat cycle every 2 weeks.

FOLFIRI + ziv-aflibercept33

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

FOLFIRI + ramucirumab39

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

Day 1: Ramucirumab 8mg/kg over 1 hour.

Repeat cycle every 2 weeks.

Capecitabine17

Days 1–14: Capecitabine 850–1,250mg/m2 orally twice daily.

Repeat cycle every 3 weeks.

Capecitabine + bevacizumab40,c

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

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

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

Repeat cycle every 8 weeks.

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

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

Repeat cycle every 2 weeks.

2,16,a

continued

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GASTROINTESTINAL CANCER Rectal Cancer Treatment Regimens Systemic Therapy for Advanced or Metastatic Disease1 (continued) REGIMEN Weekly 5-FU + leucovorin

DOSING 26

Day 1: Leucovorin 20mg/m2 IV over 2 hours, followed by 5-FU 500mg/m2 IV bolus 1 hour after start of leucovorin.

Repeat cycle weekly.

OR Day 1: Leucovorin 500mg/m2 IV, followed by 5-FU 2,600mg/m2 continuous infusion.

Repeat cycle weekly.

IROX28,a

Day 1: Oxaliplatin 85mg/m2 IV + irinotecan 200mg/m2 IV over 30–90 minutes.

Repeat cycle every 3 weeks.

FOLFOXIRI ± bevacizumab29,30,a

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

Irinotecan31,32

Days 1 and 8: Irinotecan 125mg/m2 IV over 30–90 minutes.

Repeat cycle every 3 weeks.

OR Day 1: Irinotecan 180mg/m2 IV over 30–90 minutes.

Repeat cycle every 2 weeks.

OR Day 1: Irinotecan 300–350mg/m2 IV over 30–90 minutes.

Repeat cycle every 3 weeks.

Cetuximab + irinotecan21,23 (KRAS/NRAS wild-type gene only)

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

OR Day 1: Irinotecan 180mg/m2 IV over 30–90 minutes every 2 weeks.

OR Days 1 and 8: Irinotecan 125mg/m2 IV over 30–90 minutes every 3 weeks.

Cetuximab21,23 (KRAS/NRAS wild-type gene only)

Cetuximab 400mg/m2 first infusion, then 250mg/m2 IV weekly.

OR Cetuximab 500mg/m2 IV over 2 hours every 2 weeks.

Panitumumab34 (KRAS/NRAS wild-type gene only)

Day 1: Panitumumab 6mg/kg IV over 60 minutes.

Repeat cycle every 2 weeks.

Regorafenib35,e,f

Days 1–21: Regorafenib 160mg orally once daily.

Repeat cycle every 28 days.

Trifluridine/tipiracil36

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

Repeat every 28 days.

Pembrolizumab41

Day 1: Pembrolizumab 2mg/kg.

Repeat cycle every 3 weeks.

Nivolumab42

Day 1: Nivolumab 3mg/kg.

Repeat cycle every 2 weeks.

OR Day 1: Nivolumab 240mg IV. Repeat cycle every 2 weeks.

a Oxaliplatin may be given either over 2 hours, or may be infused over a shorter time at a rate of 1mg/m2/min. Leucovorin infusion should match time of oxaliplatin. Cercek A, Park V, Yaeger R, et al. Faster FOLFOX: oxaliplatin can be safely infused at a rate of 1mg/m2/min. J Oncol Pract. 2016;12:e548-553. b Bolus 5-FU/leucovorin/XRT is an option for patients not able to tolerate capecitabine or infusional 5-FU. c Bevacizumab may be safely given at a rate of 0.5mg/kg/minute (5mg/kg over 10 minutes and 7.5mg/kg over 15 minutes). d Most of the safety and efficacy data for this regimen have come from Europe, where a capecitabine starting dose of 1,000mg/m2 twice daily for 14 days, repeated every 21 days, is standard. Evidence suggests North American patients may experience greater toxicity with capecitabine (as well as with other fluoropyrimidines) than European patients, necessitating the use of a lower dose of capecitabine. e It is common practice to start at a lower dose of regorafenib (80 or 120mg) and escalate, as tolerated. f Regorafenib or trifluridine + tipiracil are treatment options for patients who have progressed through all available regimens.

32 CANCER THERAPY ADVISOR | JANUARY/FEBRUARY 2018 | CancerTherapyAdvisor.com

CANCER TREATMENT REGIMEN

GASTROINTESTINAL CANCER References 1. NCCN Clinical Practice Guidelines in Oncology™. Rectal Cancer. v 2.2016. Available at: http://www.nccn.org/professionals/physician_gls/pdf/rectal.pdf. Accessed May 3, 2016.

2. Andre T, Boni C, Mounedji-Boudiaf L, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N EngI J Med. 2004;350:2343–2351.

3. Cheeseman SL, Joel SP, Chester JD, et al. A “modified deGramont” regimen of fluorouracil, alone and with oxaliplatin, for advanced colorectal cancer. Br J Cancer.

2002;87(4):393–399.

4. Maindrault-Goebel F, deGramont A, Louvet C, et al. Evaluation of oxaliplatin dose intensity in bimonthly leucovorin and 48-hour 5-fluorouracil continuous infusion regimens (FOLFOX) in pretreated metastatic colorectal cancer. Oncology Multidisciplinary Research Group (GERCOR). Ann Oncol. 2000;11(11):1477–1483.

5. Twelves C, Wong A, Nowacki MP, et al. Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med. 2005;354(26):2696–2704.

6. Schmoll HJ, Cartwright T, Tabernero J, et al. Phase III trial of capecitabine plus oxaliplatin as adjuvant therapy for stage III colon cancer: a planned safety analysis in 1,864 patients. J Clin Oncol. 2007;25(1):102–109.

7. Haller DG, Tabernero J, Maroun J, et al. Capecitabine plus oxaliplatin compared with fluorouracil and folinic acid as adjuvant therapy for stage III colon cancer. J Clin Oncol. 2011;29(11):1465–1471.

8. André T, Louvet C, Maindrault-Goebel F, et al. CPT-11 (irinotecan) addition to bimonthly, high-dose leucovorin and bolus and continuous-infusion 5-fluorouracil (FOLFIRI) for pretreated metastatic colorectal cancer. GERCOR. Eur J Cancer. 1999;35(9):1343–1347.

9. Petrelli N, Douglass HO Jr, Herrare L, et al. The modulation of fluorouracil with leucovorin in metastatic colorectal carcinoma: a prospective randomized phase III trial. Gastrointestinal Tumor Study Group. J Clin Oncol. 1989;7(10):1419–1426. Erratum in: J Clin Oncol. 1990;8(1):185.

10. O’Connell MJ, Martenson JA, Wieand HS, et al. Improving adjuvant therapy for rectal cancer by combining protracted-infusion fluorouracil with radiation therapy after curative surgery. N Engl J Med. 1994;331(8):502–507.

11. Tepper JE, O’Connell M, Niedzwiecki D, et al. Adjuvant therapy in rectal cancer: analysis of stage, sex, and local control—final report of intergroup 0114. J Clin Oncol. 2002;20(7):1744–1750.

12. O’Connell MJ, Colangelo LH, Beart RW, et al. Capecitabine and oxaliplatin in the preoperative multimodality treatment of rectal cancer: surgical end points from National Surgical Adjuvant Breast and Bowel Project trial R-04. J Clin Oncol.

2014;32(18):1927–1934.

13. Hofheinz R, Wenz FK, Post S et al. Capecitabine (Cape) versus 5-fluorouracil (5-FU)-based (neo)adjuvant chemotherapy (CRT) for locally advanced rectal cancer (LARC): long-term results of a randomized, phase III trial [abstract]. J Clin Oncol. 2011;29(suppl):3504.

14. Emmanouilides C, Sfakiotaki G, Androulakis N, et al. Front-line bevacizumab in combination with oxaliplatin, leucovorin and 5-fluorouracil (FOLFOX) in patients with metastatic colorectal cancer: a multicenter phase II study. BMC Cancer. 2007;7:91.

15. Douillard JY, Siena S, Cassidy J, et al. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol. 2010;28(31):4697–4705.

16. Venook AP, Niedzwiecki D, Lenz H-J, et al. CALGB/SWOG 80405: Phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab or cetuximab for patients with KRAS wild-type untreated metastatic adenocarcinoma of the colon or rectum [abstract]. ASCO Meeting Abstracts 2014;32:LBA3. Available at: http://meeting.ascopubs.org/cgi/content/abstract/32/15_suppl/LBA3 17. Saltz LB, Clarke S, Diaz-Rubio E, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008;26(12):2013–2019.

18. Andre T, Louvet C, Maindrault-Goebel F, et al. CPT-11 (irinotecan) addition to bimonthly, high-dose leucovorin and bolus and continuous-infusion 5-fluorouracil (FOLFIRI) for pretreated metastatic colorectal cancer. Eur J Cancer.

1999;35(9):1343–1347.

19. Fuchs CS, Marshall J, Mitchell E, et al. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol. 2007;25(30): 4779–4786.

20. Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004;351(4): 337–345.

21. Martin-Martorell P, Roselló S, Rodriguez-Braun, et al. Biweekly cetuximab and irinotecan in advanced colorectal cancer patients progressing after at least one previous line of chemotherapy: results of a phase II single institution trial. Br J Cancer. 2008; 99(3):455–458.

22. Peeters M, Price TJ, Cervantes A, et al. Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol. 2010;28(31):4706–4713.

23. Van Cutsem E, Tejpar S, Vanbeckevoort D, et al. Intrapatient ­cetuximab dose escalation in metastatic colorectal cancer ­according to the grade of early skin reactions: the randomized EVEREST study. J Clin Oncol. 2012;30(23):2861–2868.

24. Van Cutsem E, Twelves C, Cassidy J, et al; Xeloda Colorectal Cancer Study Group.

Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. J Clin Oncol. 2001;19(21):4097–4106.

25. Wolmark N, Rockette H, Fisher B, et al. The benefit of leucovorin-modulated fluorouracil as postoperative adjuvant therapy for primary colon cancer: results from National Surgical Adjuvant Breast and Bowel Protocol C-03. J Clin Oncol. 1993;11(10): 1879–1887.

26. Jager E, Heike M, Bernhard H, et al. Weekly high-dose leuco­vorin versus low-dose leucovorin combined with fluorouracil in advanced colorectal cancer: results of a randomized multicenter trial. Study Group for Palliative Treatment of Metastatic Colorectal Cancer Study Protocol 1. J Clin Oncol. 1996;14(8):2274–2279.

27. Douillard JY, Cunningham D, Roth AD, et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multi-centre randomised trial. Lancet. 2000;355(9209):1041–1047.

28. Haller DG, Rothenberg ML, Wong AO, et al. Oxaliplatin plus irinotecan compared with irinotecan alone as second-line treatment after single-agent fluoropyrimidine therapy for metastatic colorectal carcinoma. J Clin Oncol. 2008;26(28):4544–4550.

29. Loupakis F, Cremonlini C, Masi G et al. FOLFOXIRI plus bevacizu­mab versus FOLFIRI plus bevacizumab as first-line treatment of metastatic colorectal cancer: Results of the phase III randomized TRIBE trial. J Clin Oncol. 2013;31(suppl 4): abstract 336.

30. Falcone A, Ricci S, Brunetti I, et al. Gruppo Oncologico Nord Ovest. Phase III trial of infusional fluorouracil, leucovorin, o­ xaliplatin, 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.

31. Cunningham D, Pyrhönen S, James RD, et al. Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet. 1998;352(9138):1413–1418.

32. Fuchs CS, Moore MR, Harker G, Villa L, Rinaldi D, Hecht JR. Phase III comparison of two irinotecan dosing regimens in second-line therapy of metastatic colorectal cancer. J Clin Oncol. 2003;21(5):807–814.

33. Van Cutsem E, Tabernero J, Lakomy R, et al. Addition of ­aflibercept to fluorouracil, leucovorin, and irinotecan improves ­survival in a phase III randomized trial in patients with ­metastatic colorectal cancer previously treated with an o­ xaliplatin-based regimen. J Clin Oncol. 2012;30(28):3499–3506.

34. Van Cutsem E, Peeters M, Siena S, et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol. 2007; 25(13):1658–1664.

35. Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib mono­therapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381(9863):303–312.

36. Mayer RJ, Van Cutsem E, Falcone A, et al. RECOURSE Study Group. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med. 2015;372(20):1909–1919.

37. Hochster HS, Grothey A, Hart L, et al. Improved time to treatment failure with an intermittent oxaliplatin strategy: results of CONcePT. Ann Oncol. 2014;25:1172–1178.

38. Heinemann V, von Weikersthal LF, Decker T, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomized, open-label, phase 3 trial. Lancet Oncol. 2014.

39. Tabernero K, 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.

40. Cunningham D, Lang I, Marcuello E, et al. Bevacizumab plus capecitabine versus capecitabine alone in elderly patients with previously untreated metastatic colorectal cancer (AVEX): an open-label, randomised phase 3 trial. Lancet Oncol. 2013;14:1077–1085.

41. Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;273:2509–2520.

42. Overman MJ, Kopetz S, McDermott RS, et al. Nivolumab (+/-) ipilumumab in treatment of patients with metastatic colorectal cancer (mCRC) with and without high microsatellite instability (MSI-H): CheckMate-142 interim results [abstract]. ASCO Meeting Abstracts. 2016;34:3501. 36. Mayer RJ, Van Cutsem E, Falcone A, et al. RECOURSE Study Group. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med. 2015;372(20):1909–1919.

(Revised 11/2017) © 2018 by Haymarket Media, Inc.

CancerTherapyAdvisor.com | JANUARY/FEBRUARY 2018 | CANCER THERAPY ADVISOR 33

DRUG MONOGRAPHS

GASTROINTESTINAL CANCER AVASTIN Genentech

℞

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

Indications: Metastatic colorectal carcinoma, in combination with 5-FU-based chemotherapy for first- or second-line treatment; or in combination with fluoropyrimidine-irinotecanor fluoropyrimidine-oxaliplatin-based therapy for second-line treatment in patients who have progressed on a first-line Avastin-containing regimen. Limitation of use: not for adjuvant treatment of colon cancer.

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

5mg/kg (when used with bolus-IFL) or 10mg/kg (when used with FOLFOX-4) once every 2 weeks until disease progression detected; 5mg/kg every 2 weeks or 7.5mg/kg every 3 weeks (when used with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based therapy).

Children: Not established.

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

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

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

Interactions: Increased risk of CHF and decline in LVEF with concomitant anthracycline-based therapy (not indicated use); discontinue if CHF develops.

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, PRES, infusion reactions, ovarian failure, neutropenia, infection.

How supplied: Single-use vial—1

CYRAMZA Lilly

℞

Human IgG1 monoclonal antibody. Ramucirumab 10mg/mL; per vial; soln for IV infusion after dilution; preservative-free.

Indications: As a single agent, or in combination with paclitaxel, for treatment of advanced or metastatic, gastric or gastro-esophageal junction adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinumcontaining chemotherapy. In combination with FOLFIRI (irinotecan, folinic acid, and 5-fluorouracil), for the treatment of metastatic colorectal cancer (mCRC) with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine.

Adults: Give by IV infusion over 60 mins.

Premedicate with IV histamine H1-antagonist (eg, diphenhydramine) prior to each infusion; or with dexamethasone and acetaminophen in those who have experienced Grade 1 or 2 infusion reaction. Gastric cancer: 8mg/kg every 2 weeks.

When given in combination: administer prior to paclitaxel. mCRC: 8mg/kg every 2 weeks prior to FOLFIRI. Continue until disease progression or unacceptable toxicity. Dose modifications: see full labeling.

Children: Not established.

Warnings/Precautions: Increased risk of hemorrhage; permanently discontinue if severe bleeding occurs. Control hypertension prior to initiating. Monitor blood pressure every 2 weeks or more frequently as indicated; if severe hypertension develops, temporarily suspend until medically controlled. Monitor for infusionrelated reactions during therapy. Have emergency resuscitative equipment available. Permanently discontinue if severe arterial thromboembolic events, severe uncontrolled hypertension (despite antihypertensives), hypertensive crisis or encephalopathy, Grade 3 or 4 infusion-related reactions, urine protein >3g/24hrs, nephrotic syndrome, or GI perforation occurs. Impaired wound healing: withhold Cyramza prior to surgery; resume based on adequate healing; discontinue if complications develops during therapy until wound is fully healed. 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 full labeling. Premedicate with antiemetics. Give by IV infusion every two weeks for a total of 6 months (12 cycles) for adjuvant use or until disease progression or unacceptable toxicity for advanced disease. Day 1: 85mg/m2 + leucovorin, followed by 5-FU. Day 2: Leucovorin followed by 5-FU. Severe renal impairment: initially 65mg/m2. Neuropathy, other toxicities: see full labeling for dose adjustments.

Children: Not established.

Contraindications: Known allergy to other platinum compounds.

Warnings/Precautions: Monitor for allergic reactions; discontinue if occurs; do not rechallenge. Have epinephrine, corticosteroids, antihistamines available during infusion. Monitor for neuropathy; reduce dose or discontinue if needed. Severe neutropenia: delay therapy until neutrophils ≥1.5 × 109/L; withhold for sepsis or septic shock; reduce dose after recovery.

Monitor WBCs with differential, hemogloblin, platelets, blood chemistries (including ALT, AST, bilirubin, creatinine) before each cycle.

Discontinue if interstitial lung disease or pulmonary fibrosis is suspected. Patients with CHF, bradyarrhythmias, concomitant drugs known to prolong the QT interval, and electrolyte abnormalities: monitor ECG. Correct hypokalemia or hypomagnesemia prior to initiation; monitor periodically during therapy.

Congenital long QT syndrome; avoid. Renal impairment. Avoid extravasation. Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended.

Interactions: Caution with concomitant nephrotoxic agents. Monitor oral anticoagulants.

Adverse reactions: Peripheral sensory neuropathy, neutropenia, thrombocytopenia, anemia, GI upset, increased liver enzymes, fatigue, stomatitis; allergic reactions, pulmonary fibrosis (may be fatal), hepatotoxicity, QT prolongation, ventricular arrhythmias, rhabdomyolysis (may be fatal; discontinue if occurs).

Testing considerations: ERCC1 overexpression How supplied: Single-use vials (50mg, 100mg)—1

34 CANCER THERAPY ADVISOR | JANUARY/FEBRUARY 2018 | CancerTherapyAdvisor.com

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DRUG MONOGRAPHS

GASTROINTESTINAL CANCER ERBITUX Lilly

℞

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: Confirm EGFR expression status (using FDA-approved tests) and absence of Ras mutation prior to initiation. Pretreat with H1 blocker. Give by IV infusion (use filter); max rate: 10mg/min. Initial dose: 400mg/m2 once over 2hrs; then 250mg/m2 once weekly over 1 hour until disease progression or unacceptable toxicity. Complete administration 1hr prior to FOLFIRI. Permanently reduce infusion rate by 50% if Grade 1 or 2 and non-serious Grade 3 infusion reaction occurs; permanently discontinue if Grade 3 or 4 serious reaction occurs. Monitor patient during and for 1hr postinfusion. Skin toxicity: see full labeling.

Children: Not established.

Warnings/Precautions: Monitor for serious infusion reactions; immediately interrupt and permanently discontinue if occur. Risk of cardiopulmonary arrest and/or sudden death; carefully consider use (w. irradiation or platinumbased therapy with 5-FU) in coronary artery disease, CHF, or arrhythmias. Monitor electrolytes (eg, magnesium, potassium, calcium) during and for ≥8wks after cetuximab therapy. Interrupt for acute onset or worsening pulmonary symptoms; permanently discontinue if interstitial lung disease confirmed. Monitor for dermatologic toxicities (eg, acneiform rash) and infection; avoid sun exposure. Additive cutaneous reactions with irradiation. 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 (eg, rash, pruritus, nail changes), headache, diarrhea, infection; infusion reactions (may be severe), cardiopulmonary arrest, interstitial lung disease,

dermatologic toxicities, electrolyte abnormalities (eg, hypomagnesemia), sepsis, renal failure, pulmonary embolus.

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,

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DRUG MONOGRAPHS

GASTROINTESTINAL CANCER bi-weekly for 2nd month, then periodically (eg, every 2–3 months); liver function at baseline then monthly or as needed; renal function at baseline and during therapy; GI symptoms at baseline. Cardiovascular disease or risk factors; monitor. Diabetes. Hypertension. CHF. 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. Embryo-fetal toxicity. Pregnancy (avoid); exclude status prior to initiation. Females of reproductive potential should use highly effective contraception during treatment and for 14 days after cessation. Nursing mothers: not recommended (during and for 1 month after final dose).

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) or CYP2C9 (use heparin instead of warfarin). Caution with concomitant CYP2D6 substrates that have a narrow therapeutic window.

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

HERCEPTIN Genentech

℞

Human epidermal growth factor receptor (HER2) inhibitor. Trastuzumab 440mg/vial; lyophilized pwd for IV infusion after reconstitution and dilution; preservative-free.

Indications: HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma, in combination with cisplatin and capecitabine or 5-fluorouracil, in patients who have not received prior treatment.

Adults: Do not substitute for or with adotrastuzumab emtasine. Give as IV infusion.

Initially 8mg/kg over 90 mins, followed by 6mg/kg over 30–90 mins every 3 weeks until disease progression. Infusion reactions or cardiomyopathy: see full labeling.

Children: Not established.

Warnings/Precautions: Increased risk of cardiomyopathy. Conduct cardiac assessment (eg, history, physical exam, LVEF) at baseline, every 3 months during and after therapy or every 6 months for ≥2yrs after therapy (if adjuvant); repeat LVEF at 4 week intervals if dose is withheld due to significant left ventricular cardiac dysfunction. Interrupt therapy if dyspnea or significant hypotension occurs; consider discontinuing permanently if severe infusion reactions, CHF, pulmonary toxicity, or significant left ventricular myocardial dysfunction develops. Symptomatic intrinsic lung disease.

Extensive tumor involvement of the lungs. Test for HER2 protein overexpression and HER2 gene amplification using FDA-approved tests for specific tumor type (breast or gastric/gastroesophageal adenocarcinoma). Embryo-fetal toxicity (eg, oligohydramnios): exclude pregnancy status before initiation. Pregnancy: avoid; use effective contraception during and for 7 months after therapy. Nursing mothers.

Interactions: Increased cardiomyopathy with anthracycline-containing chemotherapy.

Increased toxicity with other myelosuppressives.

Adverse reactions: Diarrhea, fatigue, anemia, stomatitis, weight loss, upper respiratory tract infections, fever, thrombocytopenia, mucosal inflammation, nasopharyngitis, dysgeusia, infections; severe infusion reactions, febrile neutropenia/exacerbation of 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)

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, microsatellite instability-high (MSI-H) or mismatch repair deficient: colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan; solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options. Recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma whose tumors express PD-L1 as determined by an FDA-approved test, with disease progression

on or after ≥2 prior therapies including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neutargeted therapy. Limitations of use: the safety and efficacy of Keytruda in pediatrics with MSI-H CNS cancers have not been established.

Adults: Give as IV infusion over 30mins.

200mg every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. Dose modifications: see full labeling. Administer corticosteroids for most Grade ≥2 related immune-mediated reactions.

Children: Gastric cancer: not established.

Give as IV infusion over 30mins. MSI-H cancer: 2mg/kg (max 200mg) every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. Dose modifications: see full labeling.

Administer corticosteroids for most Grade ≥2 related immune-mediated reactions.

Warnings/Precautions: Monitor for pneumonitis; withhold dose if Grade 2 pneumonitis; permanently discontinue if Grade 3 or 4, or recurrent Grade 2 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 changes in renal function; withhold dose if Grade 2 nephritis; permanently discontinue if Grade 3 or 4 develops.

Monitor for hypophysitis; withhold dose if Grade 2 hypophysitis; withhold or discontinue if Grade 3 or 4 develops. Monitor for changes in thyroid function (at treatment initiation, during, and as clinically indicated) and signs/symptoms of thyroid disorders; withhold or discontinue if Grade 3 or 4 hyperthyroidism develops. Monitor for hyperglycemia and other diabetes symptoms; withhold if severe hyperglycemia until controlled.

Withhold dose if Grade 4 hematological toxicity in cHL patients develops. Monitor for severe skin reactions; permanently discontinue if SJS or TEN is confirmed. Permanently discontinue if any severe or Grade 3 immune-mediated adverse reaction recurs, for any life-threatening immune-mediated adverse reaction (except endocrinopathies controlled with hormone replacement or hematological toxicity in cHL patients), persistent Grade 2 or 3 reactions that do not recover to Grade 0–1 within 12wks after last dose, or inability to reduce corticosteroid dose to ≤10mg/day of prednisone or equivalent within 12wks. Monitor for infusion-related reactions; permanently discontinue if Grade 3 or 4 develops. Complications of allogeneic HSCT after Keytruda: monitor for hepatic VOD, Grade 3 or 4 acute GVHD, steroid-requiring febrile syndrome, and others. Solid organ transplant recipients. Embryo-fetal toxicity. Females of reproductive potential should use highly effective contraception during therapy and for 4 months after the final dose. Pregnancy: avoid. Nursing

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DRUG MONOGRAPHS

GASTROINTESTINAL CANCER mothers: not recommended (during therapy and for 4 months after the final dose).

Interactions: Increased mortality when pembrolizumab is added to thalidomide analogue plus dexamethasone regimen in multiple myeloma: not recommended.

Adverse reactions: Fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation; immune-mediated disorders, infusion-related reactions.

How supplied: Single-use vial 50mg—1; Singleuse vial 25mg/mL (4mL)—1

Leucovorin Teva

℞

Folic acid derivative. Leucovorin calcium 100mg/vial, 350mg/vial; lyophilized pwd for IV or IM inj after reconstitution; preservative-free.

Indications: Palliative treatment of advanced colorectal cancer in combination with 5-fluorouracil.

Adults: Max IV infusion rate: 160mg/min.

200mg/m2 by slow IV inj over a minimum of 3 minutes, followed by 5-fluorouracil (370mg/m2); or 20mg/m2 IV followed by 5-fluorouracil (425mg/m2); both regimens: daily for 5 days, may be repeated at 4-week intervals for 2 courses and then repeated at 4–5 week intervals (if completely recovered from toxic effects of previous course).

Children: See literature.

Contraindications: Pernicious anemia and other megaloblastic anemias due to Vit. B12 deficiency.

Warnings/Precautions: Do not administer intrathecally. CNS metastases. Monitor CBCs with differential, platelets, electrolytes, liver function tests prior to each treatment, then periodically.

Elderly. Debilitated. Pregnancy (Cat.C). Nursing mothers.

Interactions: Potentiates toxicity of 5-fluorouracil; use lower 5-fluorouracil dose.

May antagonize phenobarbital, phenytoin, and primidone. Caution with trimethoprimsulfamethoxazole.

Adverse reactions: Leukopenia, thrombocytopenia, infection, GI upset, stomatitis, constipation, lethargy, malaise, fatigue, alopecia, dermatitis, anorexia; seizures, syncope.

How supplied: Single-use vials—1

LONSURF Taiho Oncology Antineoplastic thymidine-based nucleoside analog + thymidine phosphorylase inhibitor.

Trifluridine, tipiracil; 15mg/6.14mg, 20mg/8.19mg; tabs.

℞

Indications: Treatment of metastatic colorectal cancer in patients previously treated with fluoropyrimidine-, oxaliplatin- and irinotecanbased chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy.

Adults: Take within 1 hour after completion of AM & PM meals. Initially 35mg/m2 twice daily on Days 1–5 and 8–12 of each 28-day cycle until disease progression or unacceptable toxicity; max 80mg per dose (based on trifluridine component). Dose modifications: see full labeling.

Children: Not established.

Warnings/Precautions: Obtain CBC prior to and on Day 15 of each cycle, and as clinically indicated. Do not initiate cycle until ANC ≥1,500/mm3 or febrile neutropenia is resolved, platelets ≥75,000/mm3 or Grade 3/4 nonhematological adverse reactions resolved to Grade 0/1. Withhold dose if ANC <500/mm3 or febrile neutropenia, platelets <50,000/mm3, or Grade 3/4 non-hematological adverse reactions occur; upon recovery, resume at a reduced dose (see full labeling). Moderate or severe hepatic impairment: do not initiate. Moderate renal impairment: may require dose modification; severe (CrCl <30mL/min) or ESRD: not studied.

Elderly. Pregnancy. Females of reproductive potential must use effective contraception during treatment; males must use condoms during and for ≥3 months after final dose. Nursing mothers: not recommended (during treatment and for 1 day after final dose).

Adverse reactions: Anemia, neutropenia, asthenia/fatigue, nausea, thrombocytopenia, decreased appetite, diarrhea, vomiting, abdominal pain, pyrexia.

How supplied: Tabs—20, 40, 60

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

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: Microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) in patients ≥12yrs who has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. Hepatocellular carcinoma (HCC) in patients previously treated with sorafenib.

Adults: Give as IV infusion over 60mins. 240mg every 2 weeks until disease progression or unacceptable toxicity. Dose modifications: see full labeling.

Children: Not established.

Warnings/Precautions: See full labeling.

Monitor for any immune-mediated adverse reactions; permanently discontinue or withhold, and give corticosteroids (at 1–2mg/kg/day prednisone equivalents) based on severity of event. Permanently discontinue for any lifethreatening (Grade 4) adverse reaction, Grade

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DRUG MONOGRAPHS

GASTROINTESTINAL CANCER 3 or 4 pneumonitis, Grade 3/4 or recurrent colitis (with ipilimumab), Grade 4 or recurrent colitis (as single agent), AST/ALT >5XULN (non-HCC) or AST/ALT >10XULN (HCC) or total bilirubin >3XULN, SCr >6XULN, Grade 4 hypophysitis, Grade 3 or 4 adrenal insufficiency, Grade 4 hyperglycemia, Grade 4 rash (or confirmed SJS or TEN), immune-mediated encephalitis, recurring Grade 3 adverse reactions, requirement for ≥10mg/day prednisone (or equivalent) for >12 weeks, or persistent Grade 2 or 3 adverse reactions lasting ≥12 weeks. Grade 2 pneumonitis, Grade 2 or 3 (as single agent) colitis, AST/ALT >3–5XULN or total bilirubin >1.5–3XULN, SCr >1.5–6XULN, Grade 2 or 3 hypophysitis, Grade 2 adrenal insufficiency, Grade 3 hyperglycemia, Grade 3 rash (or suspected SJS or TEN), new onset moderate-to-severe neurologic symptoms, other Grade 3 adverse reactions (1st occurrence); withhold dose, give corticosteroids, and resume when return to Grade 0 or 1. Interrupt or decrease infusion rate if mild or moderate infusion reactions occur; discontinue if severe or lifethreatening. Monitor for abnormal liver tests, elevated serum creatinine, hyperglycemia, and thyroid function prior to and during treatment; give replacement therapy for hypothyroidism.

Monitor for transplant-related complications (eg, hyperacute or Grade 3/4 acute GVHD, steroid-requiring febrile syndrome, hepatic venoocclusive disease) and treat promptly. Moderate or severe hepatic impairment: not studied.

Embryo-fetal toxicity. Females of reproductive potential should use effective contraception during and for ≥5 months after final dose.

Pregnancy (esp. during 2nd & 3rd trimesters), nursing mothers: not recommended.

Adverse reactions: Asthenia/fatigue, musculoskeletal pain, decreased appetite, nausea, cough, rash, dyspnea, diarrhea, constipation, back pain, arthralgia; immunemediated reactions (may be fatal).

How supplied: Single-use vial (4mL, 10mL)—1

STIVARGA Bayer

℞

Kinase inhibitor. Regorafenib 40mg; tabs.

Indications: Metastatic colorectal cancer in patients who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecanbased chemotherapy, an anti-VEGF therapy, and, if RAS wild type, an anti-EGFR therapy.

Locally advanced, unresectable or metastatic gastrointestinal stromal tumor (GIST) in patients who have been previously treated with imatinib mesylate or sunitinib malate. Hepatocellular carcinoma (HCC) in patients previously treated with sorafenib.

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: reduce by 40mg increments (see full labeling).

Children: <18yrs: not established.

Warnings/Precautions: Risk of severe liver injury (may be fatal). Obtain LFTs before starting and at least every 2 weeks during first 2 months of treatment; interrupt and reduce or discontinue if persistent hepatotoxicity or hepatocellular necrosis occurs. Severe hepatic impairment: not recommended. Increased risk of infections; withhold if Grade 3/4 occurs or infection of any grade worsens; resume when resolved. Permanently discontinue if severe or life-threatening hemorrhage occurs. Interrupt and reduce or permanently discontinue if dermatological toxicity occurs (eg, hand-foot skin reaction [a.k.a. palmarplantar 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.

Increased risk of 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. Asian patients (monitor). Dialysis.

Embryo-fetal toxicity. Females and males of reproductive potential should use effective contraception during treatment and up to 2 months after completion. Pregnancy. Nursing mothers: not recommended (during and for 2 weeks after final dose).

Interactions: Potentiated by strong CYP3A4 inhibitors (eg, clarithromycin, grapefruit juice, itraconazole, ketoconazole, nefazodone, posaconazole, telithromycin, voriconazole); avoid. Antagonized by strong CYP3A4 inducers (eg, rifampin, phenytoin, carbamazepine, phenobarbital, St. John’s Wort); avoid. Potentiates BCRP substrates (eg, methotrexate, fluvastatin, atorvastatin); monitor closely. Monitor INR levels with concomitant warfarin.

Adverse reactions: Asthenia/fatigue, decreased appetite and food intake, handfoot skin reaction, diarrhea, mucositis, weight loss, infection, hypertension, dysphonia, hyperbilirubinemia, 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; hard gel 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: Risk of hepatotoxicity (may be severe or fatal). Monitor LFTs 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 pre-existing cardiac disease, bradycardia, electrolyte disturbances; perform periodic ECG, monitor electrolytes.

Monitor BP; suspend if severe hypertension develops until controlled. Not for use in lung cancer patients. Perform serial CBCs and physical exams. 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. Temporary interrupt if undergoing major surgery. Discontinue if severe cutaneous reactions (eg, erythema multiforme, SJS, TEN) develop; do not restart if diagnosis suspected. ESRD on dialysis. Severe hepatic impairment. Embryo-fetal toxicity. Use effective contraception during and for ≥4 weeks (females) or 7 weeks (males) after last dose. Pregnancy; exclude status prior to initiation. Nursing mothers: not recommended (during and for ≥4 weeks after last dose).

Interactions: May be potentiated by strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole), grapefruit; consider alternatives or reduce dose if needed (see Adult).

May be antagonized by CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital); consider alternatives or increase dose if needed (see Adult). Concomitant St. John’s wort: not recommended. Caution with concomitant antiarrhythmics.

Adverse reactions: Fatigue/asthenia, diarrhea, mucositis/stomatitis, nausea, decreased appetite/anorexia, vomiting, abdominal pain, hand-foot syndrome, hypertension, bleeding events, dysguesia/altered taste, dyspepsia, thrombocytopenia; hepatotoxicity, left ventricular dysfunction, QT prolongation, osteonecrosis of the jaw, tumor lysis syndrome, thyroid dysfunction, impaired wound healing,

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DRUG MONOGRAPHS

GASTROINTESTINAL CANCER hypoglycemia, thrombotic microangiopathy (discontinue if develops), proteinuria, necrotizing fasciitis (discontinue if occurs).

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 RAS (both KRAS and NRAS as determined by an FDA-approved test) metastatic colorectal carcinoma (mCRC) in combination with FOLFOX, or as monotherapy following disease progression after prior fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy. Limitation of use: not for treating RAS-mutant mCRC or for whom RAS mutation status is unknown.

Adults: Confirm absence of a RAS mutation using an FDA-approved test prior to initiation.

6mg/kg by IV infusion over 60mins once every 14 days. If 1st infusion is tolerated, give subsequent infusions over 30–60mins.

Doses >1000mg: infuse over 90mins. Dose modifications: see full labeling.

Children: Not established.

Warnings/Precautions: Monitor for dermatologic or soft tissue toxicities; withhold or discontinue if severe or life-threatening inflammatory or infectious complications occur.

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 8wks after completing therapy. Monitor for ocular toxicities (eg, keratitis); interrupt or discontinue if develop or worsen. Embryo-fetal toxicity; use effective contraception during and for 2mos after last dose. Pregnancy. Nursing mothers: not recommended during and for 2mos after last dose.

Interactions: Concomitant bevacizumab and chemotherapy: increased mortality and toxicity may occur. Risk of acute renal failure with concomitant chemotherapy.

Adverse reactions: Rash, paronychia, fatigue, nausea, diarrhea; dermatologic or soft tissue toxicities (may be fatal), hypomagnesemia, hypocalcemia, hypokalemia, infusion reactions, ILD, pulmonary fibrosis, photosensitivity, keratitis. With FOLFOX: also stomatitis, mucosal inflammation, asthenia, anorexia.

Testing considerations: EGFR amplification analysis, K-RAS mutation analysis.

How supplied: Single-use vial (5mL, 20mL)—1

XELODA Genentech

℞

Fluoropyrimidine. Capecitabine (prodrug of 5-fluorouracil) 150mg, 500mg; tabs.

Indications: First-line treatment of metastatic colorectal carcinoma when fluoropyrimidine therapy alone is preferred. Adjuvant treatment of Dukes’ C colon cancer after complete resection of the primary tumor when fluoropyrimidine therapy alone is preferred.

Adults: See full labeling. Give cyclically (2 weeks on, 1 week off). Swallow whole. Take with water within 30 minutes after AM & PM meals. ≥18yrs: 1250mg/m2 twice daily. Continue for a total of 8 cycles. Interrupt, adjust dose, and/or treat symptoms if toxicity occurs (eg, hyperbilirubinemia, diarrhea, nausea, vomiting, hand-and-foot syndrome, stomatitis) (see full labeling); do not increase dose afterwards.

Renal impairment (CrCl 51–80mL/min): monitor carefully; (CrCl 30–50mL/min): reduce capecitabine dose to 75% of starting dose (eg, 950mg/m2 twice daily).

Children: <18yrs: not established.

Contraindications: Severe renal impairment (CrCl <30mL/min).

Warnings/Precautions: Hepatic or renal impairment. Monitor and correct dehydration at initiation. Coronary artery disease.

Interrupt therapy if Grade 2/3 hand-and-foot syndrome, Grade 2/3 or 4 diarrhea occurs (give antidiarrheals) until resolves or reduces to Grade 1.

Permanently discontinue if severe mucocutaneous reactions (eg, SJS, TEN) occur. Dihydropyrimidine dehydrogenase deficiency. Elderly. Embryo-fetal toxicity. Pregnancy: avoid; exclude status prior to initiation. Females of reproductive potential should use effective contraception (during therapy and for 6 months) and males with female partners (during and for 3 months) after final dose. Nursing mothers: not recommended (during and for 2 weeks after final dose.

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.

Testing considerations: TS (thymidylate synthase), MSI (microsatellite instability), DPD (dihydropyrimidine dehydrogenase) How supplied: Tabs 150mg—60; 500mg—120

ZALTRAP Sanofi US and Regeneron

℞

Fusion protein. Ziv-aflibercept 25mg/mL; soln for IV infusion after dilution; preservative-free.

Indications: In combination with 5-fluorouracil, leucovorin, irinotecan (FOLFIRI) for patients with metastatic colorectal cancer (mCRC) that is resistant to or has progressed following an oxaliplatin-containing regimen.

Adults: Start ziv-aflibercept prior to any component of the FOLFIRI regimen on treatment day. Give 4mg/kg as an IV infusion over 1hr every 2 weeks; continue until disease progression or unacceptable toxicity. For recurrent or severe hypertension, suspend until controlled. Upon resumption, permanently reduce to 2mg/kg. For recurrent proteinuria, suspend until proteinuria <2g per 24hrs, then permanently reduce to 2mg/kg.

Children: Not established.

Warnings/Precautions: Increased risk of hemorrhage; monitor for signs/symptoms.

Do not start in patients with severe hemorrhage; discontinue if develops.

Monitor for GI perforation, fistula formation, compromised wound healing; discontinue if occurs. Suspend therapy at least 4 weeks prior to elective surgery; do not resume for at least 4 weeks following major surgery and until wound is fully healed. Monitor BP every 2 weeks and treat appropriately if hypertension occurs; temporarily suspend until controlled; discontinue if hypertensive crisis/encephalopathy occurs. Discontinue if arterial thromboembolic events (eg, transient ischemic attack, cerebrovascular accident, angina pectoris) occur. Monitor for proteinuria; suspend if proteinuria ≥2g per 24hrs; discontinue if nephrotic syndrome or thrombotic microangiopathy occurs.

Monitor CBC with differential at baseline and prior to start of each cycle; delay until neutrophils ≥1.5x109/L. Risk of severe diarrhea and dehydration esp. in elderly (monitor). Discontinue if reversible posterior leukoencephalopathy syndrome occurs.

Pregnancy (Cat. C). Use effective contraception during and up to 3 months after the last dose.

Nursing mothers: not recommended.

Adverse reactions: Leukopenia, diarrhea, neutropenia, proteinuria, AST/ALT increased, stomatitis, fatigue, thrombocytopenia, hypertension, weight decreased, decreased appetite, epistaxis, abdominal pain, dysphonia, serum creatinine increased, headache.

How supplied: Single-use vials (100mg/4mL)—1, 3; (200mg/8mL)—1

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CANCER TREATMENT REGIMEN

GENITOURINARY CANCER Prostate 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 NCCN 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.

Castration-recurrent Prostate Cancer1 Note: All recommendations are Category 2A unless otherwise indicated.

REGIMEN

DOSING

First-line Therapy1 No Visceral Metastases Enzalutamide (Category 1)2-4

Enzalutamide 160mg (four 40mg capsules) orally daily with or without food; prednisone can be given concurrently but is not required.

Abiraterone acetate + prednisone (Category 1)5-8

Abiraterone 1,000mg orally once daily on an empty stomach, plus prednisone 5mg orally twice daily.

Docetaxel + prednisone (Category 1)9,10

Day 1: Docetaxel 75mg/m2 IV once every 3 weeks + prednisone 5mg orally twice daily.

Repeat for up to 10 cycles if tolerated.

Radium-223 (for symptomatic bone metastases) (Category 1)11,12

Radium-223 50kBq/kg every 4 weeks for 6 injections.

Visceral Metastases Docetaxel + prednisone (Category 1)9,10

Day 1: Docetaxel 75mg/m2 IV once every 3 weeks + prednisone 5mg orally twice daily.

Repeat for up to 10 cycles if tolerated. Addition of estramustine to this regimen is not recommended.

Enzalutamide (Category 1)2-4

Enzalutamide 160mg (four 40mg capsules) orally daily with or without food; prednisone can be given concurrently but is not required.

Abiraterone acetate + prednisone5-8

Abiraterone 1,000mg orally once daily on an empty stomach, plus prednisone 5mg orally twice daily.

Mitoxantrone + prednisone

Day 1: Mitoxantrone 12–14mg/m2 IV every 3 weeks + prednisone 10mg orally daily or 5mg twice daily.

Repeat for up to 10 cycles if tolerated.

9,10

Subsequent Therapy1 No Visceral Metastases Prior Therapy Enzalutamide/Abiraterone Docetaxel + prednisone (Category 1)9,10

Day 1: Docetaxel 75mg/m2 IV once every 3 weeks + prednisone 5mg orally twice daily.

Repeat for up to 10 cycles if tolerated.

Abiraterone acetate + prednisone5-8

Abiraterone 1,000mg orally once daily on an empty stomach, plus prednisone 5mg orally twice daily.

Enzalutamide

Enzalutamide 160mg (four 40mg capsules) orally daily with or without food; prednisone can be given concurrently but is not required.

2-4

Radium-223 (for symptomatic bone metastases) (Category 1)11,12

Radium-223 50kBq/kg every 4 weeks for 6 injections.

Sipuleucel-T (if no or minimal symptoms, no liver metastases, life expectancy >6 months, and an ECOG score of 0–1)13,14*

Sipuleucel-T three complete doses (50 million autologous CD54+ cells), given at 2-week intervals (range 1–15 weeks).

40 CANCER THERAPY ADVISOR | JANUARY/FEBRUARY 2018 | CancerTherapyAdvisor.com

CANCER TREATMENT REGIMEN

GENITOURINARY CANCER Prostate Cancer Treatment Regimens Castration-recurrent Prostate Cancer1 (continued) REGIMEN

DOSING

Subsequent Therapy (continued) 1

No Visceral Metastases (continued) Prior Therapy Docetaxel Enzalutamide (Category 1)2-4

Enzalutamide 160mg (four 40mg capsules) orally daily with or without food; prednisone can be given concurrently but is not required.

Abiraterone acetate + prednisone (Category 1)5-8

Abiraterone 1,000mg orally once daily on an empty stomach, plus prednisone 5mg orally twice daily.

Radium-223 (for symptomatic bone metastases) (Category 1)11,12

Radium-223 50kBq/kg every 4 weeks for 6 injections.

Cabazitaxel + prednisone (Category 1)15-17

Day 1: Cabazitaxel 25mg/m2 IV every 3 weeks + prednisone 10mg orally daily or 5mg twice daily throughout cabazitaxel treatment (starting doses are reduced by 5 mg/m2 and 10 mg/m2 for mild and moderate hepatic impairment, respectively).

Repeat for up to 10 cycles if tolerated.

Sipuleucel-T (if no or minimal symptoms, no liver metastases, life expectancy >6 months, and an ECOG score of 0–1)13, 14*

Sipuleucel-T three complete doses (≥50 million autologous CD54+ cells), given at 2-week intervals (range 1–15 weeks).

Docetaxel rechallenge9,10

Day 1: Docetaxel 75mg/m2 IV once every 3 weeks + prednisone 5mg orally twice daily.

Repeat for up to 10 cycles if tolerated.

Mitoxantrone + prednisone9,10

Day 1: Mitoxantrone 12mg/m2 IV every 3 weeks + prednisone 10mg orally daily or 5mg twice daily.

Repeat for up to 10 cycles if tolerated.

Visceral Metastases Prior Therapy Enzalutamide/Abiraterone Docetaxel + prednisone (Category 1)9,10

Day 1: Docetaxel 75mg/m2 IV once every 3 weeks + prednisone 5mg orally twice daily.

Repeat for up to 10 cycles if tolerated.

Abiraterone acetate + prednisone5-8

Abiraterone 1,000mg orally once daily on an empty stomach, plus prednisone 5mg orally twice daily.

Enzalutamide2-4

Enzalutamide 160mg (four 40mg capsules) orally daily with or without food; prednisone can be given concurrently but is not required.

Prior Therapy Docetaxel Enzalutamide (Category 1)2-4

Enzalutamide 160mg (four 40mg capsules) orally daily with or without food; prednisone can be given concurrently but is not required.

Abiraterone acetate + prednisone (Category 1)5-8

Abiraterone 1,000mg orally once daily on an empty stomach, plus prednisone 5mg orally twice daily.

Cabazitaxel + prednisone (Category 1)15-17

Day 1: Cabazitaxel 25mg/m2 IV every 3 weeks + prednisone 10mg orally daily or 5mg twice daily throughout cabazitaxel treatment (starting doses are reduced by 5 mg/m2 and 10 mg/m2 for mild and moderate hepatic impairment, respectively).

Repeat for up to 10 cycles if tolerated.

Docetaxel rechallenge9,10

Day 1: Docetaxel 75mg/m2 IV once every 3 weeks + prednisone 5mg orally twice daily.

Repeat for up to 10 cycles if tolerated.

Mitoxantrone + prednisone9,10

Day 1: Mitoxantrone 12mg/m2 IV every 3 weeks + prednisone 10mg orally daily or 5mg twice daily.

Repeat for up to 10 cycles if tolerated. continued

CancerTherapyAdvisor.com | JANUARY/FEBRUARY 2018 | CANCER THERAPY ADVISOR 41

CANCER TREATMENT REGIMEN

GENITOURINARY CANCER Castration-Recurrent Prostate Cancer1 (continued) General treatment notes: • Encourage men with advanced prostate cancer to participate in clinical trials and refer early to a medical oncologist.

• Reserve systemic chemotherapy for men with castration-resistant metastatic prostate cancer except when enrolled in a clinical trial.

• Secondary hormone therapy (eg, antiandrogens, antiandrogen withdrawal, ketoconazole, corticosteroids) is also an option for patients with castration-resistant prostate cancer.

• Many variables should be considered when tailoring prostate cancer therapy for the individual patient, including adjusted life expectancy, disease characteristics, predicated outcomes, and patient preferences.

• All prostate cancer patients should receive best supportive care throughout treatment. *The maximum dosing interval has not been established.13

References 1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology™.

Prostate Cancer. v 2.2017. Available at: http://www.nccn.org/professionals/ physician_gls/pdf/prostate.pdf. Accessed May 9, 2017.

2. Xtandi [prescribing information]. Northbrook, IL: Astellas Pharma US, Inc.; 2016.

3. Scher HI, Fizazi K, Saad F, et al; AFFIRM Investigators. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367(13):1187–1197.

4. Beer TM, Armstrong AJ, Rathkopf DE, et al; PREVAIL Investigators.

Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014;371(5):424–433.

5. Zytiga [prescribing information]. Horsham, PA: Janssen Biotech, Inc.; 2017.

6. de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364(21):1995–2005.

7. Fizazi K, Scher HI, Molina A, et al. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COUAA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol.

2012;13(10):983–992.

8. Logothetis CJ, Basch E, Molina A, et al. Effect of abiraterone acetate and prednisone compared with placebo and prednisone on pain control and skeletal-related events in patients with metastatic castration-resistant prostate cancer: exploratory analysis of data from the COU-AA-301 randomised trial. Lancet Oncol.

2012;13(12):1210–1217.

9. Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351(15):1502–1512.

10. Berthold DR, Pond GR, Soban F, de Wit R, Eisenberger M, Tannock IF. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the TAX 327 study. J Clin Oncol. 2008;26:242–245.

11. Xofigo [prescribing information]. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc.; 2016.

12. Parker C, Nilsson S, Heinrich D, et al; ALSYMPCA Investigators. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013(3);369:213–223.

13. Provenge [prescribing information]. Seattle, WA: Dandreon Corp.; 2014.

14. Kantoff PW, Higano CS, Shore ND, et al; IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363(5):411–422.

15. Jevtana [prescribing information] Bridgewater, NJ: sanofi-aventis U.S. LLC; 2016.

16. de Bono JS, Oudard S, Ozguroglu M, et al; TROPIC Investigators. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet.

2010;376(9747):1147–1154.

17. Bahl A, Oudard S, Tombal B, et al; TROPIC Investigators. Impact of cabazitaxel on 2-year survival and palliation of tumour-related pain in men with metastatic castration-resistant prostate cancer treated in the TROPIC trial. Ann Oncol. 2013;24(9):2402–2408.

(Revised 5/2017) © 2018 by Haymarket Media, Inc.

Prostate Cancer Advisor A section of Cancer Therapy Advisor that features exclusive news and clinical content for oncologists who specialize in the treatment of patients with prostate cancer.

Visit CancerTherapyAdvisor.com/Prostate to gain access to the following and more: • Articles on the latest news in prostate cancer written by experts • Prostate Cancer Treatment Regimens adapted from NCCN Guidelines® • An extensive range of current and concise drug information • Videos of oncology experts speaking about key topics in the field of prostate cancer management

42 CANCER THERAPY ADVISOR | JANUARY/FEBRUARY 2018 | CancerTherapyAdvisor.com

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; continue until disease progression or unacceptable toxicity.

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 risks. 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: avoid; if required, 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. 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; discontinue, reduce dose, and/or manage with corticosteroids if non-infectious pneumonitis occurs. Increased risk of infections (may be severe or fatal); monitor and treat promptly if occur. Pre-existing invasive fungal infections: treat before starting. Use dexamethasone mouthwash at initiation to reduce the incidence and severity of stomatitis; use alcohol-, peroxide-, iodine-, or thyme-free products if occurs. 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. Embryo-fetal toxicity.

Must use effective contraception during and for 8 weeks (females) or 4 weeks (males) after last dose. Pregnancy, 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); see Adult. Antagonized by strong CYP3A4/PgP inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital), St. John’s Wort; avoid or increase dose (see Adult). Increased risk of angioedema with concomitant ACE inhibitor.

Adverse reactions: Stomatitis, infections, rash, fatigue, diarrhea, edema, abdominal pain, nausea, fever, asthenia, cough, headache, decreased appetite, RTI; decreased hemoglobin, WBC, platelets, lymphocytes, neutrophils, serum phosphate, potassium, albumin; increased cholesterol, blood glucose, AST, ALT, triglycerides, serum creatinine, proteinuria, renal failure.

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.

Interactions: Increased risk of CHF and decline in LVEF with concomitant anthracycline-based therapy (not indicated use); discontinue if CHF develops.

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

BAVENCIO EMD Serono

℞

Programmed death-ligand 1 (PD-L1) blocking antibody. Avelumab 20mg/mL; soln for IV infusion after dilution; preservative-free; contains mannitol.

Indications: Treatment of locally advanced or metastatic urothelial carcinoma (UC) in patients who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant platinumcontaining chemotherapy.

Adults: Premedicate with an antihistamine and acetaminophen prior to the first 4 infusions; then subsequent doses as clinically indicated.

Give as IV infusion over 60mins. 10mg/kg every 2 weeks until disease progression or unacceptable toxicity. Dose modifications: see full labeling.

Children: <12yrs: not established.

Warnings/Precautions: See full labeling.

Monitor for any immune-mediated adverse reactions; permanently discontinue or withhold, and give corticosteroids (at 1–2mg/kg/day prednisone equivalents) based on severity of event. Permanently discontinue for Grade 3/4 pneumonitis or recurrent Grade 2 pneumonitis, Grade 4 diarrhea or colitis or recurrent Grade 3 diarrhea or colitis, AST/ALT >5XULN or total bilirubin >3XULN, SCr >6XULN, any life-threatening (Grade 4) or recurrent severe (Grade 3) immune-mediated adverse reactions, requirement for ≥10mg/day prednisone (or

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CancerTherapyAdvisor.com | JANUARY/FEBRUARY 2018 | CANCER THERAPY ADVISOR 43

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DRUG MONOGRAPHS

GENITOURINARY CANCER equivalent) for >12 weeks, or persistent Grade 2/3 immune-mediated adverse reactions lasting ≥12 weeks. Grade 2 pneumonitis, Grade 2/3 diarrhea or colitis, Grade 3/4 adrenal insufficiency, Grade 3/4 thyroid disorders, Grade 3/4 hyperglycemia, AST/ALT >3–5XULN or total bilirubin >1.5–3XULN, SCr >1.5–6XULN; withhold dose, give corticosteroids, and resume when return to Grade 0 or 1. Interrupt or decrease infusion rate if Grade 1/2 infusion-related reactions occur; permanently discontinue if Grade 3/4. Monitor for abnormal liver tests, adrenal insufficiency, elevated serum creatinine, hyperglycemia, and thyroid function prior to and during treatment; give replacement therapy for hypothyroidism. Embryo-fetal toxicity. Females of reproductive potential should use effective contraception during and for ≥1 month after final dose. Pregnancy. Nursing mothers: not recommended (during and for ≥1 month after final dose).

Adverse reactions: Fatigue, musculoskeletal pain, diarrhea, nausea, infusion-related reaction, rash, decreased appetite, peripheral edema, UTI; other immune-mediated adverse reactions (may be fatal).

How supplied: Single-dose vial (10mL)—1

CABOMETYX Exelixis

℞

Kinase inhibitor. Cabozantinib 20mg, 40mg, 60mg; tabs.

Indications: Treatment of advanced renal cell carcinoma (RCC) in patients who have received prior anti-angiogenic therapy.

Adults: Do not substitute with cabozantinib caps. Swallow whole. 60mg daily. Do not eat at least 2 hours before or 1 hour after dose. Continue until disease progression or unacceptable toxicity. Stop treatment at least 28 days prior to scheduled surgery (including dental). Withhold for Grade 4 adverse reactions, Grade 3 or intolerable Grade 2 adverse reactions that are unmanageable with dose reduction or supportive care. Upon improvement to Grade 1 or to baseline, reduce dose as follows: previously on 60mg daily, resume at 40mg daily; previously on 40mg daily, resume at 20mg daily; previously on 20mg daily, resume at 20mg if tolerated, otherwise discontinue. Concomitant a strong CYP3A4 inhibitor: reduce daily dose by 20mg; resume dose used prior to starting inhibitor 2–3 days after discontinuation of inhibitor.

Concomitant a strong CYP3A4 inducer: increase daily dose by 20mg; resume dose used prior to starting inducer 2–3 days after discontinuation of inducer. Max daily dose: 80mg. Mild or moderate hepatic impairment: initially 40mg once daily.

Children: Not studied.

Warnings/Precautions: Permanently discontinue if the following occurs: unmanageable GI perforation/fistula, severe hemorrhage, serious arterial thromboembolic

events (eg, MI, cerebral infarction), hypertensive crisis or severe hypertension despite optimal medical management, nephrotic syndrome, reversible posterior leukoencephalopathy syndrome. Recent history or risk of severe hemorrhage: do not administer. Monitor for GI perforations/fistulas. Monitor BP regularly; withhold for hypertension inadequately controlled with medical management; resume at reduced dose when resolved. Withhold therapy if intolerable Grade 2 diarrhea, unmanageable Grade 3/4 diarrhea, or intolerable Grade 2/3 palmar-plantar erythrodysesthesia syndrome (PPES) develops until improvement to Grade 1; resume at reduced dose. Severe hepatic impairment: not recommended. Embryo-fetal toxicity. Females of reproductive potential should use effective contraception during and for 4 months after final dose. Pregnancy. Nursing mothers: not recommended (during and for 4 months after final dose).

Interactions: Avoid concomitant strong CYP3A4 inhibitors (eg, boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telithromycin, voriconazole, grapefruit or grapefruit juice) and strong CYP3A4 inducers (eg, rifampin, phenytoin, carbamazepine, phenobarbital, rifabutin, rifapentine, St. John’s Wort); if unavoidable, see Adult dose.

Adverse reactions: Diarrhea, fatigue, nausea, decreased appetite, PPES, hypertension, vomiting, weight decreased, constipation, lab abnormalities.

How supplied: Tabs—30

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. Pregnancy.

Warnings/Precautions: Moderate to severe hepatic impairment. Monitor prostate specific antigen and hepatic function (discontinue if ALT >2xULN or if jaundice occurs). Males with female partners of reproductive potential should use effective contraception during therapy and for 130 days after final dose.

Nursing mothers.

Interactions: Monitor oral anticoagulants.

Adverse reactions: Hot flashes, gynecomastia, breast pain, diarrhea, pain, asthenia, infection, dyspnea, impotence, loss of libido, others (see full labeling); rare: hepatitis.

How supplied: Tabs—30, 100

ELIGARD Tolmar

℞

GnRH analogue. Leuprolide acetate 7.5mg, 22.5mg, 30mg, 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. Rotate inj sites. 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.

Children: Not established.

Contraindications: 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, local reactions (eg, burning/stinging, pain, erythema, bruising, pruritus); transient worsening of signs/symptoms (eg, bone pain, neuropathy, hematuria, bladder outlet obstruction), spinal cord compression, hyperglycemia, decreased bone density; rare: pituitary apoplexy.

How supplied: Single-use kit—1 (with sterile or sterile safety needle)

IFEX Baxter

℞

Alkylating agent. Ifosfamide 1g, 3g; per vial; pwd for IV infusion after reconstitution.

Indications: Third-line adjunctive treatment of germ cell testicular cancer.

Adults: Give by slow IV infusion over at least 30 mins. 1.2g/m2 per day for 5 consecutive days; repeat every 3 weeks or after hematological recovery (platelets ≥100000/μL, WBC ≥4000/μL).

Children: Not recommended.

Contraindications: Urinary outflow obstruction.

Warnings/Precautions: Risk of myelosuppression, immunosuppression, and infections. Do hematologic profile before each dose; discontinue if WBCs <2000/μL or platelets <50000/μL. Risk of CNS toxicity and other neurotoxic effects. Discontinue if encephalopathy develops. Do urinalysis before each dose, postpone dose if hematuria occurs.

Give mesna and at least 2L fluids daily. Active

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DRUG MONOGRAPHS

GENITOURINARY CANCER urinary tract infections. Impaired hepatic, renal, or hematopoetic function. Preexisting cardiac disease. May interfere with wound healing. Prior radiation therapy or other cytotoxic agents. Ensure adequate hydration.

Pregnancy (Cat.D); avoid. Nursing mothers: not recommended.

Interactions: Increased risk of myelosuppression with other chemotherapy agents. Caution with drugs acting on the CNS (eg, antiemetics, sedatives, narcotics, antihistamines).

Adverse reactions: Alopecia, nausea, vomiting, leukopenia, anemia, CNS toxicity, hematuria, infection, renal or liver dysfunction, phlebitis, fever, urotoxicity (eg, hemorrhagic cystitis), thrombocytopenia, pulmonary toxicity, secondary malignancies.

How supplied: Single-dose vials—1

IMFINZI AstraZeneca

℞

Programmed death-ligand 1 (PD-L1) blocking antibody. Durvalumab 50mg/mL; soln for IV infusion after dilution; preservative-free.

Indications: Locally advanced or metastatic urothelial carcinoma in patients who have disease progression during or after platinumcontaining chemotherapy or within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy.

Adults: Give as IV infusion over 60mins.

10mg/kg every 2 weeks until disease progression or unacceptable toxicity.

Children: Not established.

Warnings/Precautions: Permanently discontinue if Grade 3/4 pneumonitis, AST or ALT >8×ULN or total bilirubin >5×ULN, concurrent AST or ALT >3×ULN and total bilirubin >2×ULN (with no other cause), Grade 3/4 colitis or diarrhea, creatinine ≥3×ULN, Grade 3/4 infusion-related reactions, or Grade 4 rash/dermatitis.

Withhold for Grade 2 pneumonitis, AST or ALT >3–5×ULN or total bilirubin >1.5–3×ULN, AST or ALT ≤8×ULN or total bilirubin ≤5×ULN, Grade 2 colitis or diarrhea, Grade ≥2 hypophysitis/hypopituitarism, Grade ≥2 adrenal insufficiency, Grade ≥2 hyperthyroidism, Grade ≥2 type 1 diabetes, creatinine >1.5–3×ULN, Grade 3/4 infection, Grade 2 (if >1 week) or Grade 3 rash. Monitor for immune-related pneumonitis, hepatitis (obtain LFTs each cycle), colitis/diarrhea, endocrinopathies (thyroid disorders, adrenal insufficiency, diabetes, hypophysitis/hypopituitarism), rash,

thrombocytopenia purpura, nephritis; see full labeling for adverse reaction management details. Monitor for signs/symptoms of infection and treat with anti-infectives for suspected or confirmed infections. Interrupt or slow the infusion rate in patients with mild or moderate infusion reactions. Embryo-fetal toxicity.

Pregnancy. Females of reproductive potential should use effective contraception during therapy and for ≥3 months after final dose.

Nursing mothers: not recommended (during and for ≥3 months after final dose).

Adverse reactions: Fatigue, musculoskeletal pain, constipation, decreased appetite, nausea, peripheral edema, urinary tract infection; other immune-related reactions (eg, aseptic meningitis, hemolytic anemia), infusion-related reactions, lab abnormalities.

How supplied: Single-dose vial (2.4mL, 10mL)—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 for the treatment of metastatic castration-resistant prostate cancer previously treated with a docetaxel-containing regimen.

Adults: Premedicate with IV antihistamine, corticosteroid, and H2 blocker 30 mins before each dose (see full labeling) and with antiemetic (IV or oral as needed). Infuse over 1hr. 20mg/m2 every 3 weeks, with oral prednisone 10mg/day during treatment; 25mg/m2 may be used in select patients.

Prolonged grade ≥3 neutropenia (>1 week), febrile neutropenia, grade ≥3 diarrhea, grade 2 peripheral neuropathy: delay treatment and/or reduce by one dose level (see full labeling). Discontinue if grade ≥3 peripheral neuropathy. Hepatic impairment: (mild): 20mg/m2; (moderate): 15mg/m2. If concomitant strong CYP3A inhibitor necessary, consider a 25% cabazitaxel dose reduction.

Children: Not established.

Contraindications: Neutrophil count ≤1,500cells/mm3. Allergy to polysorbate 80.

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

GENITOURINARY CANCER Severe hepatic impairment (total bilirubin >3XULN). Pregnancy.

Warnings/Precautions: Increased risk of neutropenia complications; consider G-CSF prophylaxis (recommended in high risk patients). Monitor CBC weekly in 1st cycle and before each subsequent cycle. Patients with hemoglobin <10g/dL; monitor closely. Monitor for hypersensitivity reactions esp. during 1st and 2nd infusions; discontinue if 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.

Underlying lung disease. Monitor closely for respiratory disorders; interrupt if new or worsening pulmonary symptoms develop.

Hepatic impairment (monitor). ESRD (CrCl <15mL/min). Elderly (increased susceptibility to adverse reactions); monitor closely.

Female partners of reproductive potential must use effective contraception during and for 3 months after last dose. Nursing mothers.

Interactions: Potentiated by strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole); avoid. May be antagonized by rifampin. 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.

How supplied: Kit (single-use vial + diluent)—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: Locally advanced or metastatic urothelial carcinoma in patients who are ineligible for cisplatin-containing chemotherapy, or in patients who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

Adults: Give as IV infusion over 30mins.

200mg every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months in

patients without disease progression. 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, or recurrent Grade 2 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 changes in renal function; withhold dose if Grade 2 nephritis; permanently discontinue if Grade 3 or 4 develops. Monitor for hypophysitis; withhold dose if Grade 2 hypophysitis; withhold or discontinue if Grade 3 or 4 develops. Monitor for changes in thyroid function (at treatment initiation, during, and as clinically indicated) and signs/symptoms of thyroid disorders; withhold or discontinue if Grade 3 or 4 hyperthyroidism develops. Monitor for hyperglycemia and other diabetes symptoms; withhold if severe hyperglycemia until controlled. Withhold dose if Grade 4 hematological toxicity in cHL patients develops. Monitor for severe skin reactions; permanently discontinue if SJS or TEN is confirmed. Permanently discontinue if any severe or Grade 3 immune-mediated adverse reaction recurs, for any life-threatening immune-mediated adverse reaction (except endocrinopathies controlled with hormone replacement or hematological toxicity in cHL patients), persistent Grade 2 or 3 reactions that do not recover to Grade 0–1 within 12wks after last dose, or inability to reduce corticosteroid dose to ≤10mg/day of prednisone or equivalent within 12wks.

Monitor for infusion-related reactions; permanently discontinue if Grade 3 or 4 develops. Complications of allogeneic HSCT after Keytruda: monitor for hepatic VOD, Grade 3 or 4 acute GVHD, steroidrequiring febrile syndrome, and others. Solid organ transplant recipients. Embryo-fetal toxicity. Females of reproductive potential should use highly effective contraception during therapy and for 4 months after the final dose. Pregnancy: avoid. Nursing mothers: not recommended (during therapy and for 4 months after the final dose).

Interactions: Increased mortality when pembrolizumab is added to thalidomide analogue plus dexamethasone regimen in multiple myeloma: not recommended.

Adverse reactions: Fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation; immune-mediated disorders, infusion-related reactions.

How supplied: Single-use vial 50mg—1; Singleuse vial 25mg/mL (4mL)—1

LENVIMA Eisai

℞

Kinase inhibitor. Lenvatinib 4mg, 10mg; capsules.

Indications: In combination with everolimus, for treatment of advanced renal cell carcinoma, following one prior anti-angiogenic therapy.

Adults: Swallow whole or may dissolve capsule contents into liquid. 18mg (in combination with everolimus 5mg) once daily until disease progression or unacceptable toxicity occurs. Severe renal impairment (CrCl <30mL/min) or severe hepatic impairment (Child-Pugh C): 10mg once daily. Dose modifications for adverse reactions or lab abnormalities: see full labeling.

Children: Not established.

Warnings/Precautions: Control blood pressure prior to treatment; monitor after 1 week, every 2 weeks for the first 2 months, and then at least monthly thereafter during therapy. Discontinue if life-threatening hypertension, Grade 4 cardiac dysfunction or hemorrhage, arterial thrombotic event, hepatic failure, nephrotic syndrome, GI perforation or life-threatening fistula, or severe and persistent neurologic symptoms occur.

Withhold if Grade 3 hypertension persists despite therapy, Grade 3 cardiac dysfunction or hemorrhage, ≥Grade 3 liver impairment or QT prolongation >500ms, 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. Monitor for dehydration and treat if diarrhea develops; interrupt if Grade 3 or 4 and permanently discontinue if Grade 4 diarrhea persists despite therapy.

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 function prior to initiation and at least monthly thereafter; treat hypothyroidism as needed. ESRD. Embryofetal toxicity. Pregnancy: avoid. Use effective contraception during and for at least 2 weeks after treatment completion. Nursing mothers: not recommended.

Adverse reactions: Hypertension, fatigue, diarrhea, arthralgia/myalgia, decreased appetite, weight decreased, nausea, stomatitis, headache, vomiting, proteinuria, palmar-plantar erythrodysesthesia syndrome, abdominal pain, dysphonia.

How supplied: Blister cards—6

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DRUG MONOGRAPHS

GENITOURINARY CANCER MENEST Pfizer

℞

Estrogen. Esterified estrogens 0.3mg, 0.625mg, 1.25mg, 2.5mg; tabs.

Indications: Palliative treatment of androgendependent advanced prostate cancer.

Adults: 1.25–2.5mg 3 times daily.

Children: Not applicable.

Contraindications: Thrombophlebitis.

Thromboembolic disorders. Cerebrovascular or coronary artery disease. Pregnancy (Cat.X).

Warnings/Precautions: Hepatic dysfunction.

Gallbladder disease. Conditions aggravated by fluid retention. Familial hyperlipoproteinemia.

Discontinue if jaundice occurs. Nursing mothers.

Adverse reactions: See literature. Migraine, depression, edema, weight changes, hypertension, GI upset, gynecomastia, impotence.

How supplied: Tabs 2.5mg—50; 0.3mg, 0.625mg, 1.25mg—100

NEXAVAR Bayer and Onyx

℞

Multikinase inhibitor. Sorafenib 200mg; tabs.

Indications: Advanced renal cell carcinoma.

Adults: Take on an empty stomach. 400mg twice daily. If toxicity occurs, may reduce dose to 400mg once daily; if further dose reduction required, may reduce dose to 400mg every other day (see full labeling). Concomitant strong CYP3A4 inducers: consider increasing dose, monitor for toxicity.

Children: Not established.

Contraindications: Concomitant carboplatin/paclitaxel in patients with squamous cell lung cancer.

Warnings/Precautions: Avoid in congenital long QT syndrome. Monitor patients with CHF, bradyarrhythmias, drugs known to prolong the QT interval, electrolyte abnormalities. Discontinue if severe dermatologic toxicity, hypertension, GI perforation, hemorrhage, cardiac ischemia, MI occurs. Suspend therapy before major surgery.

Monitor BP weekly during the first 6 weeks and thereafter. Monitor hepatic function regularly; discontinue if transaminases significantly elevated. Severe hepatic impairment (Child-Pugh C) or on dialysis. Use effective contraception during and for 2 weeks after stopping treatment.

Pregnancy (Cat.D), nursing mothers: not recommended.

Interactions: See Contraindications. Avoid strong CYP3A4 inducers (eg, St. John’s Wort, dexamethasone, phenytoin, carbamazepine, rifabutin, rifampin, phenobarbital) and neomycin;

may decrease sorafenib levels. May potentiate warfarin (monitor PT & INR), other drugs metabolized by UGT1A1 or UGT1A9 pathway, or substrates of CYP2B6, CYP2C8, CYP2C9, P-gp.

Concomitant Class Ia and III antiarrhythmics; may prolong QT interval.

Adverse reactions: Dermatologic toxicity (eg, rash, hand-foot skin reaction, alopecia, pruritus, dry skin, Stevens-Johnson syndrome, toxic epidermal necrolysis), fatigue, weight loss, diarrhea, anorexia, abdominal pain, hypertension, hemorrhage, electrolyte abnormalities; drug-induced hepatitis, QT prolongation.

How supplied: Tabs—120

OPDIVO Bristol-Myers Squibb

℞

Human programmed death receptor-1 (PD-1)blocking antibody. Nivolumab 10mg/mL; per vial; soln for IV infusion after dilution; preservativefree; contains mannitol.

Indications: Advanced renal cell carcinoma (RCC) in patients who have received prior anti-angiogenic therapy. Locally advanced or metastatic urothelial carcinoma in patients who have disease progression during or following platinum-containing chemotherapy or who have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinumcontaining chemotherapy.

Adults: Give as IV infusion over 60mins. 240mg every 2 weeks until disease progression or unacceptable toxicity. Dose modifications: see full labeling.

Children: Not established.

Warnings/Precautions: See full labeling.

Monitor for any immune-mediated adverse reactions; permanently discontinue or withhold, and give corticosteroids (at 1–2mg/kg/day prednisone equivalents) based on severity of event. Permanently discontinue for any life-threatening (Grade 4) adverse reaction, Grade 3 or 4 pneumonitis, Grade 3/4 or recurrent colitis (with ipilimumab), Grade 4 or recurrent colitis (as single agent), AST/ALT >5XULN (non-HCC) or AST/ALT >10XULN (HCC) or total bilirubin >3XULN, SCr >6XULN, Grade 4 hypophysitis, Grade 3 or 4 adrenal insufficiency, Grade 4 hyperglycemia, Grade 4 rash (or confirmed SJS or TEN), immunemediated encephalitis, recurring Grade 3 adverse reactions, requirement for ≥10mg/day prednisone (or equivalent) for >12 weeks, or persistent Grade 2 or 3 adverse reactions lasting ≥12 weeks. Grade 2 pneumonitis, Grade 2 or 3 (as single agent) colitis, AST/ALT >3–5XULN or

total bilirubin >1.5–3XULN, SCr >1.5–6XULN, Grade 2 or 3 hypophysitis, Grade 2 adrenal insufficiency, Grade 3 hyperglycemia, Grade 3 rash (or suspected SJS or TEN), new onset moderate-to-severe neurologic symptoms, other Grade 3 adverse reactions (1st occurrence); withhold dose, give corticosteroids, and resume when return to Grade 0 or 1. Interrupt or decrease infusion rate if mild or moderate infusion reactions occur; discontinue if severe or life-threatening. Monitor for abnormal liver tests, elevated serum creatinine, hyperglycemia, and thyroid function prior to and during treatment; give replacement therapy for hypothyroidism.

Monitor for transplant-related complications (eg, hyperacute or Grade 3/4 acute GVHD, steroidrequiring febrile syndrome, hepatic venoocclusive disease) and treat promptly. Moderate or severe hepatic impairment: not studied.

Embryo-fetal toxicity. Females of reproductive potential should use effective contraception during and for ≥5 months after final dose.

Pregnancy (esp. during 2nd & 3rd trimesters), nursing mothers: not recommended.

Adverse reactions: Asthenia/fatigue, musculoskeletal pain, decreased appetite, nausea, cough, rash, dyspnea, diarrhea, constipation, back pain, arthralgia; immunemediated reactions (may be fatal).

How supplied: Single-use vial (4mL, 10mL)—1

PROVENGE Dendreon

℞

Autologous cellular immunotherapy.

Sipuleucel-T (autologous CD54+ cells activated with PAP-GM-CSF); 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.

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DRUG MONOGRAPHS

GENITOURINARY CANCER 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; hard gel caps.

Indications: Advanced renal cell carcinoma (RCC). Adjuvant treatment of patients at high risk of recurrent RCC following nephrectomy.

Adults: 50mg once daily for 4 weeks, then 2 weeks off (see full labeling). Adjuvant: treat for nine 6-week cycles. 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: Risk of hepatotoxicity (may be severe or fatal). Monitor LFTs 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 pre-existing cardiac disease, bradycardia, electrolyte disturbances; perform periodic ECG, monitor electrolytes. Monitor BP; suspend if severe hypertension develops until controlled. Not for use in lung cancer patients. Perform serial CBCs and physical exams. 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. Temporary interrupt if undergoing major surgery.

Discontinue if severe cutaneous reactions (eg, erythema multiforme, SJS, TEN) develop; do not restart if diagnosis suspected. ESRD on dialysis. Severe hepatic impairment. Embryofetal toxicity. Use effective contraception during and for ≥4 weeks (females) or 7 weeks (males) after last dose. Pregnancy; exclude status prior to initiation. Nursing mothers: not recommended (during and for ≥4 weeks after last dose).

Interactions: May be potentiated by strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole), grapefruit; consider alternatives or reduce dose if needed (see Adult). May be antagonized

by CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital); consider alternatives or increase dose if needed (see Adult). Concomitant St. John’s wort: not recommended. Caution with concomitant antiarrhythmics.

Adverse reactions: Fatigue/asthenia, diarrhea, mucositis/stomatitis, nausea, decreased appetite/anorexia, vomiting, abdominal pain, hand-foot syndrome, hypertension, bleeding events, dysguesia/altered taste, dyspepsia, thrombocytopenia; 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).

How supplied: Caps—28

TECENTRIQ Genentech

℞

Programmed death-ligand 1 (PD-L1) blocking antibody. Atezolizumab 60mg/mL; soln for IV infusion after dilution; preservative-free.

Indications: Locally advanced or metastatic urothelial carcinoma in patients who are ineligible for cisplatin-containing chemotherapy, or who have disease progression during or after any platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant chemotherapy.

Adults: Give as IV infusion over 60mins. 1200mg every 3 weeks until disease progression or unacceptable toxicity. May give subsequent infusions over 30mins if first infusion tolerated.

Children: Not established.

Warnings/Precautions: Permanently discontinue if Grade 3/4 pneumonitis, AST or

ALT >5×ULN or total bilirubin >3×ULN, Grade 4 diarrhea or colitis, Grade 4 hypophysitis, myasthenic syndrome/myasthenia gravis, Guillain-Barre or meningoencephalitis, Grade 3/4 ocular inflammatory toxicity, Grade 4 or recurrent pancreatitis, Grade 3/4 infusionrelated reactions, or Grade 4 rash. Withhold for Grade 2 pneumonitis, AST or ALT >3–5×ULN or total bilirubin >1.5–3×ULN, Grade 2/3 diarrhea or colitis, symptomatic hypophysitis, adrenal insufficiency, hypothyroidism, hyperthyroidism, Grade 3/4 hyperglycemia, Grade 2 ocular inflammatory toxicity, Grade 2/3 pancreatitis or Grade 3/4 increases in amylase or lipase levels (>2×ULN), Grade 3/4 infection, Grade 2 infusion-related reactions, or Grade 3 rash; may be resumed when recover to Grade 0–1.

Monitor for immune-related pneumonitis, hepatitis (obtain AST, ALT, bilirubin prior to and during treatment), diarrhea/colitis, endocrinopathies (hypophysitis, thyroid function, adrenal insufficiency, diabetes), meningitis or encephalitis, motor and sensory neuropathy, and acute pancreatitis; see full labeling for adverse reaction management details. Monitor for signs/symptoms of infection and treat with antibiotics for suspected or confirmed bacterial infections.

Interrupt or slow the infusion rate in patients with mild or moderate infusion reactions.

Moderate or severe hepatic impairment: not studied. Embryo-fetal toxicity. Pregnancy.

Use effective contraception during and for ≥5 months after final dose. Nursing mothers: not recommended (during and for ≥5 months after final dose).

Adverse reactions: Fatigue, decreased appetite, nausea, urinary tract infection, pyrexia, constipation; immune-related reactions, lab abnormalities.

How supplied: Single-dose vial (20mL)—1

TRELSTAR Allergan

℞

GnRH analogue. Triptorelin pamoate 3.75mg, 11.25mg, 22.5mg; lyophilized microgranules 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: Pregnancy (Cat.X).

Warnings/Precautions: Not for use in women.

Must administer under physician supervision.

Discontinue if hypersensitivity occurs. Initial transient increase in serum testosterone may result in worsening of signs/symptoms including bone pain, neuropathy, hematuria, or urethral/bladder obstruction. Spinal cord compression. Renal or hepatic impairment.

Metastatic vertebral lesions. Upper or lower urinary tract obstruction. May prolong

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DRUG MONOGRAPHS

GENITOURINARY CANCER QT/QTc interval in patients with congenital long QT syndrome, CHF, frequent electrolyte abnormalities. Correct any electrolyte abnormalities; monitor ECGs and electrolytes periodically. Increased risk of diabetes, MI, sudden cardiac death, stroke; monitor blood glucose and/or HbA1c, and for signs/symptoms of cardiovascular disease. Measure serum testosterone periodically. Nursing mothers: not recommended.

Interactions: Concomitant hyperprolactinemic drugs: not recommended. Avoid concomitant drugs that are known to prolong the QT interval.

May interfere with pituitary gonadotropic function tests.

Adverse reactions: Inj site reactions, hot flushes, skeletal pain, impotence, headache, leg edema/pain, erectile dysfunction, testicular atrophy; hyperglycemia.

How supplied: Single-dose vial—1; MixJect system—1 (vial + vial adapter + prefilled syringe)

VALSTAR Endo

℞

Anthracycline. Valrubicin 40mg/mL; soln for intravesical instillation after dilution; contains 50% polyoxyl castor oil/50% dehydrated alcohol; preservative-free.

Indications: Intravesical therapy of BCGrefractory carcinoma in situ (CIS) of the urinary bladder in patients for whom immediate cystectomy would be associated with unacceptable morbidity or mortality.

Adults: Drain bladder before instilliation. 800mg given intravesically via urethral catheter once weekly for 6 weeks. Retain drug for 2 hours before voiding, then void.

Children: Not recommended.

Contraindications: Concurrent UTI. Small bladder capacity (eg, unable to tolerate a 75mL instillation).

Warnings/Precautions: Monitor for disease recurrence or progression with cystoscopy, biopsy, and urine cytology every 3 months; if there is not a complete response of CIS to treatment after 3 months or if CIS recurs, cystectomy must be reconsidered. Severe irritable bladder symptoms. Perforated bladder. Bladder mucosa compromised.

Delay administration for at least 2 weeks after transurethral resection and/or fulguration.

Maintain adequate hydration. Pregnancy (Cat. C); avoid, both males and females should use effective birth control. Nursing mothers: not recommended.

Adverse reactions: Bladder symptoms (eg, urinary frequency, dysuria, urinary urgency,

spasm, hematuria, pain, incontinence, cystitis, nocturia, local burning, urethral pain, pelvic pain, UTI).

How supplied: Single-use vials—4, 24

VANTAS Endo

℞

GnRH analogue. Histrelin acetate 50mg; SC implant.

Indications: Palliative treatment of advanced prostate cancer.

Adults: Insert 1 implant SC in the inner aspect of the upper arm. Remove after 12 months; may replace.

Children: Not applicable.

Contraindications: Pregnancy (Cat.X).

Nursing mothers. Not for use in women or children.

Warnings/Precautions: Initial transient increase in serum testosterone may result in worsening signs/symptoms (eg, bone pain, neuropathy, hematuria). Metastatic vertebral lesions, urinary tract obstruction (monitor closely in 1st few weeks). Avoid wetting inserted arm for 24hrs and heavy lifting or strenuous exertion for 1st week. Increased risk of developing diabetes; monitor blood glucose and HbA1c periodically; treat if occurs.

Increased risk of developing MI, sudden cardiac death, stroke; monitor for signs/symptoms of cardiovascular disease. May prolong QT/QTc interval in patients with congenital long QT syndrome, CHF, electrolyte abnormalities; monitor ECGs. If electrolyte abnormalities occur, correct and monitor. Measure serum testosterone, PSA levels periodically. Implant not visible on X-ray.

Interactions: May interfere with pituitary gonadotropic and gonadal function tests. Caution with concomitant drugs known to prolong the QT interval.

Adverse reactions: Hot flashes, fatigue, implant site reactions, testicular atrophy, renal impairment; hyperglycemia, diabetes, cardiovascular disease.

How supplied: Kit—1 (w. implant and supplies)

VOTRIENT GlaxoSmithKline

℞

Tyrosine kinase inhibitor. Pazopanib 200mg; tabs.

Indications: Advanced renal cell carcinoma.

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

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

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

Children: Not established.

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

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

Monitor BP and manage hypertension promptly.

Discontinue if severe and persistent hypertension (despite antihypertensives and dose reduction), if repeat episodes of proteinuria (despite dose reductions), thrombotic microangiopathy, serious infection, ILD or pneumonitis occurs.

Stop therapy at least 7 days before surgery; discontinue in patients with wound dehiscence.

Embryo-fetal toxicity. Pregnancy: exclude status prior to starting. Females of reproductive potential must use effective contraception and males (use condoms) during therapy and for ≥2 weeks after final dose. Nursing mothers: not recommended (during and for 2 weeks after final dose).

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,

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DRUG MONOGRAPHS

GENITOURINARY CANCER 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. Avoid concomitant drugs that raise gastric pH (eg, PPIs, H2-blockers). 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; hepatotoxicity, QT prolongation, hemorrhagic events, arterial thrombotic events (eg, MI, angina, ischemic stroke, TIA), venous thrombotic events (eg, VTE, PE), GI perforation or fistula, ILD/pneumonitis, impaired wound healing, hypothyroidism, proteinuria, infection, reversible posterior leukoencephalopathy syndrome (discontinue if occurs).

How supplied: Tabs—120

XOFIGO Bayer

℞

Alpha particle-emitting radioactive therapeutic agent. Radium Ra 223 dichloride 1000 kBq/mL (27 microcurie/mL) with a total radioactivity of 6000 kBq/vial (162 microcurie/vial) at the reference date; IV injection.

Indications: Treatment of patients with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastatic disease.

Adults: See full labeling. Administer by slow IV over 1 min. 50kBq (1.35 microcurie) per kg given at 4 week intervals for 6 injections.

Children: <18yrs: not established.

Contraindications: Women who are or may become pregnant. Pregnancy (Cat. X).

Warnings/Precautions: Not for use in women. Bone marrow suppression. Perform hematologic evaluation at baseline and prior to every dose. Before 1st dose, the ANC should be ≥1.5 X 109/L, platelets ≥100 X 109/L and hemoglobin ≥10g/dL. Before subsequent doses, the ANC should be ≥1 X 109/L and platelets ≥50 X 109/L; discontinue if no recovery within 6–8 weeks after last dose despite receiving supportive care. Monitor closely if evidence of compromised bone marrow reserve. Discontinue if life-threatening complications occur despite supportive care for bone marrow failure.

Monitor oral intake and fluid status carefully.

Males (use condoms) and female partners of reproductive potential should use highly effective contraceptive method during and 6 months after completion. Nursing mothers: not recommended.

Interactions: Concomitant chemotherapy: not established. Discontinue if concomitant with

chemotherapy, other systemic radioisotopes or hemibody external radiotherapy.

Adverse reactions: Nausea, diarrhea, vomiting, peripheral edema, anemia, lymphocytopenia, leukopenia, thrombocytopenia, neutropenia.

How supplied: Single-use vials (6mL)—1

XTANDI Astellas

ZYTIGA Janssen Biotech

℞

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.

Warnings/Precautions: Risk of seizure; permanently discontinue if develops during treatment. Severe renal or hepatic impairment.

Nursing mothers: not recommended.

Interactions: Avoid concomitant strong CYP2C8 inhibitors (eg, gemfibrozil) if possible; reduce enzalutamide dose if cannot be avoided. Avoid concomitant CYP2C8 inducers (eg, rifampin), CYP3A4 inducers (eg, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, bosentan, efavirenz, etravirine, modafinil, nafcillin), and St. John’s Wort if possible. Potentiated by CYP3A4 inhibitors (itraconazole). Antagonizes midazolam (CYP3A4 substrate), warfarin (CYP2C9 substrate), and omeprazole (CYP2C19 substrate). Avoid concomitant drugs with narrow therapeutic indexes metabolized by CYP3A4 (eg, alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus), CYP2C9 (eg, phenytoin, warfarin), CYP2C19 (eg, S-mephenytoin); enzalutamide may decrease their exposure.

Caution with concomitant drugs that may lower the seizure threshold. Conduct more INR monitoring if concomitant warfarin cannot be avoided.

Adverse reactions: Asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight decreased, headache, hypertension, dizziness/vertigo.

How supplied: Caps—120

℞

CYP17 inhibitor. Abiraterone acetate 250mg, 500mg; tabs.

Indications: In combination with prednisone for the treatment of metastatic castration-resistant prostate cancer.

Adults: Take on empty stomach (no food ≥2hrs before or ≥1hr 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; monitor frequently. 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 recommended.

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

Warnings/Precautions: Risk of mineralocorticoid excess: patients with history of cardiovascular disease, LVEF <50%, Class II-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 hepatotoxicity occurs. Permanently discontinue if concurrent ALT elevation >3xULN and total bilirubin >2xULN develops without biliary obstruction or other causes of elevation. Nursing mothers: not recommended.

Interactions: CYP2D6 substrates with narrow therapeutic index (eg, thioridazine); avoid.

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, hypokalemia, edema, myalgia, hot flush, GI upset, UTI, cough, hypertension, 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 250mg—120; 500mg—60

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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/cisplatin, or paclitaxel/topotecan.

Recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer (platinum-resistant): in combination with paclitaxel, pegylated liposomal doxorubicin or topotecan in patients who received no more than 2 prior chemotherapy regimens; (platinum-sensitive): in combination with carboplatin/paclitaxel or carboplatin/gemcitabine, followed by Avastin as a single agent.

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 (platinum-resistant): 10mg/kg every 2 weeks with either paclitaxel, pegylated liposomal doxorubicin, or topotecan (weekly); or, 15mg/kg every 3 weeks with topotecan (every 3 weeks); (platinum-sensitive): 15mg/kg every 3 weeks with carboplatin/paclitaxel for 6 cycles and up to 8 cycles or carboplatin/gemcitabine for 6 cycles and up to 10 cycles; followed by Avastin 15mg/kg every 3 weeks as a single agent until disease progression.

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 (PRES), 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.

Interactions: Increased risk of CHF and decline in LVEF with concomitant anthracycline-based therapy (not indicated use); discontinue if CHF develops.

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, PRES, infusion reactions, ovarian failure, neutropenia, infection.

How supplied: Single-use vial—1

DOXIL Janssen Biotech

℞

Anthracycline. Doxorubicin HCl (liposomal) 2mg/mL; dispersion for IV infusion after dilution; preservative-free.

Indications: Ovarian cancer refractory to platinum-based chemotherapy.

Adults: Give by IV infusion at initial rate of 1mg/min; may increase rate to complete infusion over 1hr if no infusion reactions occur; may premedicate with antiemetics. 50mg/m2 once every 4 weeks; continue for at least 4 cycles as tolerated. Hepatic dysfunction (serum bilirubin ≥1.2mg/dL), hand-foot syndrome, hematologic toxicity (esp. ANC, platelets), or stomatitis: reduce dose. Consider total anthracycline and anthracenedione doses and irradiation when calculating total cumulative dose. See full labeling.

Children: Not established.

Warnings/Precautions: Not substitutable on a mg/mg basis with other doxorubicin products. Cardiomyopathy (including left ventricular failure), acute infusion-related reactions, myelosuppression may occur. Have medications to treat infusion-related reactions and resuscitative equipment available. Hepatic impairment. Monitor blood (esp. CBC + platelets), hepatic (esp. SGOT/SGPT, alkaline phosphatase), and cardiac function (eg, MUGA, ECG). Monitor periodically for secondary oral cancers with long-term use. Avoid extravasation. Embryo-fetal toxicity. Use effective contraception during and for 6 months after last dose. 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

LYNPARZA AstraZeneca

℞

Poly (ADP-ribose) polymerase (PARP) inhibitor.

Olaparib 50mg; caps.

Indications: Treatment of 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.

Concomitant strong or moderate CYP3A inhibitors: avoid; if co-admin unavoidable, reduce olaparib dose to 150mg twice daily (with strong inhibitors) or 200mg twice daily (with moderate inhibitors).

Moderate renal impairment (CrCl 31–50mL/min): reduce to 300mg twice daily; max 600mg daily.

Children: Not established. ℞ Also: LYNPARZA TABLETS Olaparib 100mg, 150mg.

Indications: Maintenance treatment of recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer, in adults who are in complete or partial response to platinum-based chemotherapy. Treatment of deleterious or suspected deleterious germline BRCA-mutated (as detected by an FDA-approved test) advanced ovarian cancer in adults who have been treated with ≥3 prior lines of chemotherapy.

Adults: Swallow whole. 300mg twice daily; max 600mg daily. Continue until disease progression or unacceptable toxicity. Dose adjustments for adverse reactions: reduce to 250mg twice daily; may further reduce to 200mg twice daily. Concomitant strong or moderate CYP3A inhibitors: avoid; if co-admin unavoidable, reduce olaparib dose to 100mg twice daily (with strong inhibitors) or 150mg twice daily (with moderate inhibitors). Moderate renal impairment (CrCl 31–50mL/min): reduce to 200mg twice daily.

Children: Not established.

Warnings/Precautions: Caps and tabs are not interchangeable on a mg-to-mg basis. Monitor CBC for cytopenia at baseline and monthly thereafter; do

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DRUG MONOGRAPHS

GYNECOLOGIC CANCER 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 and treat if pneumonitis is confirmed. Mild renal impairment: monitor closely. Moderate or severe hepatic impairment, severe renal impairment or ESRD (CrCl ≤30mL/min): not studied. Embryo-fetal toxicity. Pregnancy; avoid. Obtain pregnancy testing prior to initiating therapy. Females of reproductive potential should use effective contraception during therapy and for 6 months after last dose.

Nursing mothers: not recommended (during and for 1 month after last dose).

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, grapefruit juice, Seville oranges, and Seville orange juice. 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/URI, arthralgia/musculoskeletal pain, myalgia, cough, constipation, back pain, dizziness, UTI, dyspnea, rash, stomatitis, lab abnormalities (see full labeling); MDS/AML, pneumonitis.

How supplied: Caps—112; Tabs—60, 120

RUBRACA Clovis Oncology

℞

Poly (ADP-ribose) polymerase (PARP) inhibitor.

Rucaparib 200mg, 300mg; tabs.

Indications: Monotherapy in patients with deleterious BRCA-mutation (germline and/or somatic) associated advanced ovarian cancer who have been treated with ≥2 prior lines of chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic test.

Adults: Swallow whole. 600mg twice daily until disease progression or unacceptable toxicity.

Dose modifications or adjustments for adverse reactions: 1st reduction: 500mg twice daily; 2nd reduction: 400mg twice daily; 3rd reduction: 300mg 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 (Grade ≤1). Discontinue if myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) is confirmed. Embryo-fetal toxicity. Pregnancy; avoid. Females of reproductive potential must obtain pregnancy test prior to initiating therapy. Use effective contraception during therapy and for at least 6 months after last dose. Nursing mothers: not recommended (during and for 2 weeks after last dose).

Adverse reactions: Nausea, fatigue, asthenia, vomiting, anemia, abdominal pain, dysgeusia, constipation, decreased appetite, diarrhea, thrombocytopenia, dyspnea, lab abnormalities (increased: creatinine, ALT/AST, cholesterol; decreased: hemoglobin, lymphocytes, platelets, ANC).

How supplied: Tabs—60

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, 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)

ZEJULA Tesaro

℞

Poly (ADP-ribose) polymerase (PARP) inhibitor.

Niraparib 100mg; caps.

Indications: Maintenance treatment in adults with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy.

Adults: Start treatment within 8 weeks after most recent platinum-containing regimen. Swallow whole. 300mg once daily until disease progression or unacceptable toxicity. Dose adjustments for adverse reactions: see full labeling.

Children: Not established.

Warnings/Precautions: Discontinue if myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) is confirmed. Monitor CBC weekly for the first month, monthly for the next 11 months then periodically thereafter; do not start therapy until recovery from hematological toxicity due to previous chemotherapy (CTCAE Grade ≤1); discontinue if toxicities unresolved within 28 days after interruption (see full labeling). Monitor BP and heart rate monthly for the first year then periodically thereafter. Cardiovascular disorders (eg, coronary insufficiency, arrhythmias, hypertension); monitor closely. Embryo-fetal toxicity. Pregnancy; exclude status prior to initiating therapy. Females of reproductive potential should use effective contraception during therapy and for ≥6 months after last dose. Nursing mothers: not recommended (during and for 1 month after last dose).

Interactions: Concomitant antihypertensives; dose adjustments of Zejula may be needed.

Adverse reactions: Thrombocytopenia, anemia, neutropenia, leukopenia, palpitations, nausea, constipation, vomiting, abdominal pain/distention, mucositis/stomatitis, diarrhea, dyspepsia, dry mouth, fatigue/asthenia, decreased appetite, urinary tract infection, AST/ALT elevation, myalgia, back pain, arthralgia, headache, dizziness, dysgeusia, insomnia, anxiety, nasopharyngitis, dyspnea, cough, rash, hypertension.

How supplied: Caps—90

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DRUG MONOGRAPHS

HEAD AND NECK CANCER ERBITUX Lilly

℞

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 platinumbased 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: Monitor for serious infusion reactions; immediately interrupt and permanently discontinue if occur. Risk of cardiopulmonary arrest and/or sudden death; carefully consider use (w. irradiation or platinumbased therapy with 5-FU) in coronary artery disease, CHF, or arrhythmias. Monitor electrolytes (eg, magnesium, potassium, calcium) during and for ≥8wks after cetuximab therapy. Interrupt for acute onset or worsening pulmonary symptoms; permanently discontinue if interstitial lung disease confirmed. Monitor for dermatologic toxicities (eg, acneiform rash) and infection; avoid sun exposure. Additive cutaneous reactions with irradiation. 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 (eg, rash, pruritus, nail changes), headache, diarrhea, infection; infusion reactions (may be severe), cardiopulmonary arrest, interstitial lung disease, dermatologic toxicities, electrolyte abnormalities (eg, hypomagnesemia), sepsis, renal failure, pulmonary embolus.

How supplied: Single-use vials—1

HYDREA Bristol-Myers Squibb

℞

Antimetabolite. Hydroxyurea 500mg; caps.

Indications: Adjunct with irradiation therapy in locally advanced squamous cell carcinomas of the head and neck, excluding the lip.

Adults: Base dose on ideal or actual weight, whichever is less. Individualize. Initially 15mg/kg/day. Renal impairment (CrCl <60mL/min or ESRD): initially 7.5mg/kg/day; give dose following dialysis (monitor). Dose modifications: see full labeling.

Children: Not established.

Warnings/Precautions: Risk of severe myelosuppression; reduce dose or discontinue if necessary. Monitor blood counts at baseline and at least once a week during therapy. Correct severe anemia before starting. Markedly depressed bone marrow function: do not initiate. Monitor for malignancies. Avoid sun exposure. Previous irradiation therapy (monitor for skin erythema) or chemotherapy. Macrocytosis may mask folic acid deficiency; prophylactic folic acid is recommended.

Myeloproliferative disorders; discontinue if cutaneous vasculitic ulcerations occur. Renal or hepatic impairment. Elderly. Embryo-fetal toxicity.

Pregnancy; avoid. Exclude pregnancy prior to initiating; use effective contraception during and for ≥6 months (females) or ≥1 year (males) after therapy. Nursing mothers: not recommended.

Interactions: Avoid concomitant didanosine, with or without stavudine, or other antiretrovirals (may cause pancreatitis [monitor], fatal hepatotoxicity, peripheral neuropathy). Avoid live vaccines. Increased risk of vasculitic toxicities with interferon therapy. May cause falsely elevated results in urea, uric acid, and lactic acid assays.

Adverse reactions: Leukopenia, thrombocytopenia, anemia, GI upset, anorexia; secondary malignancies, macrocytosis.

Note: Wear disposable gloves when handling caps or bottle.

How supplied: Caps—100

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: Recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinumcontaining chemotherapy.

Adults: Give as IV infusion over 30mins.

200mg every 3 weeks until disease progression,

℞

unacceptable toxicity, or up to 24 months in patients without disease progression. 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, or recurrent Grade 2 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 changes in renal function; withhold dose if Grade 2 nephritis; permanently discontinue if Grade 3 or 4 develops.

Monitor for hypophysitis; withhold dose if Grade 2 hypophysitis; withhold or discontinue if Grade 3 or 4 develops. Monitor for changes in thyroid function (at treatment initiation, during, and as clinically indicated) and signs/symptoms of thyroid disorders; withhold or discontinue if Grade 3 or 4 hyperthyroidism develops. Monitor for hyperglycemia and other diabetes symptoms; withhold if severe hyperglycemia until controlled.

Withhold dose if Grade 4 hematological toxicity in cHL patients develops. Monitor for severe skin reactions; permanently discontinue if SJS or TEN is confirmed. Permanently discontinue if any severe or Grade 3 immune-mediated adverse reaction recurs, for any life-threatening immune-mediated adverse reaction (except endocrinopathies controlled with hormone replacement or hematological toxicity in cHL patients), persistent Grade 2 or 3 reactions that do not recover to Grade 0–1 within 12wks after last dose, or inability to reduce corticosteroid dose to ≤10mg/day of prednisone or equivalent within 12wks. Monitor for infusion-related reactions; permanently discontinue if Grade 3 or 4 develops. Complications of allogeneic HSCT after Keytruda: monitor for hepatic VOD, Grade 3 or 4 acute GVHD, steroid-requiring febrile syndrome, and others. Solid organ transplant recipients. Embryo-fetal toxicity. Females of reproductive potential should use highly effective contraception during therapy and for 4 months after the final dose. Pregnancy: avoid. Nursing mothers: not recommended (during therapy and for 4 months after the final dose).

Interactions: Increased mortality when pembrolizumab is added to thalidomide analogue plus dexamethasone regimen in multiple myeloma: not recommended.

Adverse reactions: Fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea,

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DRUG MONOGRAPHS

HEAD AND NECK CANCER reactions (1st occurrence); withhold dose, give corticosteroids, and resume when return to Grade 0 or 1. Interrupt or decrease infusion rate if mild or moderate infusion reactions occur; discontinue if severe or life-threatening. Monitor for abnormal liver tests, elevated serum creatinine, hyperglycemia, and thyroid function prior to and during treatment; give replacement therapy for hypothyroidism. Monitor for transplant-related complications (eg, hyperacute or Grade 3/4 acute GVHD, steroid-requiring febrile syndrome, hepatic veno-occlusive disease) and treat promptly. Moderate or severe hepatic impairment: not studied. Embryo-fetal toxicity. Females of reproductive potential should use effective contraception during and for ≥5 months after final dose. Pregnancy (esp. during 2nd & 3rd trimesters), nursing mothers: not recommended.

Adverse reactions: Fatigue, rash, musculoskeletal pain, pruritus, diarrhea, nausea, asthenia, cough, dyspnea; immune-mediated reactions (may be fatal).

How supplied: Single-use vial (4mL, 10mL)—1

constipation; immune-mediated disorders, infusion-related reactions.

How supplied: Single-use vial 50mg—1; Singleuse vial 25mg/mL (4mL)—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: Recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease progression on or after platinumbased therapy.

Adults: Give as IV infusion over 60mins. 3mg/kg every 2 weeks until disease progression or unacceptable toxicity. Dose modifications: see full labeling.

Children: Not established.

Warnings/Precautions: See full labeling. Monitor for any immune-mediated adverse reactions; permanently discontinue or withhold, and give corticosteroids (at 1–2mg/kg/day prednisone equivalents) based on severity of event. Permanently discontinue for any life-threatening (Grade 4) adverse reaction, Grade 3 or 4 pneumonitis, Grade 3/4 or recurrent colitis (with ipilimumab), Grade 4 or recurrent colitis (as single agent), AST/ALT >5XULN (non-HCC) or AST/ALT >10XULN (HCC) or total bilirubin >3XULN, SCr >6XULN, Grade 4 hypophysitis, Grade 3 or 4 adrenal insufficiency, Grade 4 hyperglycemia, Grade 4 rash (or confirmed SJS or TEN), immune-mediated encephalitis, recurring Grade 3 adverse reactions, requirement for ≥10mg/day prednisone (or equivalent) for >12 weeks, or persistent Grade 2 or 3 adverse reactions lasting ≥12 weeks. Grade 2 pneumonitis, Grade 2 or 3 (as single agent) colitis, AST/ALT >3–5XULN or total bilirubin >1.5–3XULN, SCr >1.5–6XULN, Grade 2 or 3 hypophysitis, Grade 2 adrenal insufficiency, Grade 3 hyperglycemia, Grade 3 rash (or suspected SJS or TEN), new onset moderate-to-severe neurologic symptoms, other Grade 3 adverse

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)

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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DRUG MONOGRAPHS

HEMATOLOGIC CANCER ADCETRIS Seattle Genetics

℞

CD30-directed antibody-drug conjugate.

Brentuximab vedotin 50mg/vial; lyophilized pwd for IV infusion after reconstitution; preservativefree.

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. Treatment of patients with primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides (MF) who have received prior systemic therapy.

Adults: Give by IV infusion over 30mins.

1.8mg/kg up to max 180mg/dose every 3 weeks; continue until disease progression or unacceptable toxicity. Post-auto-HSCT consolidation: initiate within 4–6 weeks postauto-HSCT or upon recovery from auto-HSCT; max 16 cycles. MF or pcALCL: max 16 cycles.

Mild hepatic impairment: initially 1.2mg/kg up to 120mg. Peripheral neuropathy: if Grade 2/3: withhold until resolve to ≤Grade 1, then restart with 1.2mg/kg; if Grade 4: discontinue therapy.

Neutropenia: Grade 3/4: withhold until resolve to ≤Grade 2; may consider G-CSF prophylaxis for subsequent cycles; recurrent Grade 4: consider discontinue or dose reduction to 1.2mg/kg.

Patients with prior infusion-related reaction: premedicate with APAP, antihistamine, and corticosteroid for subsequent doses.

Children: Not established.

Contraindications: Concomitant bleomycin.

Warnings/Precautions: Risk of JC virus infection. Monitor for progressive multifocal leukoencephalopathy (PML); withhold dose if suspected and discontinue if confirmed.

Monitor for neuropathy; delay, change dose, or discontinue if new or worsening symptoms occur. Monitor for infusion-related reactions; permanently discontinue and treat if anaphylaxis occurs. Monitor CBCs prior to each dose and frequently for fever or Grade 3 or 4 neutropenia; delay, reduce, discontinue dose or consider G-CSF prophylaxis if develops. Increased risk of tumor lysis syndrome in rapidly proliferating tumor/high tumor burden patients; monitor closely. Monitor for emergence of bacterial, fungal, or viral infections. Monitor for pulmonary toxicity; if

symptoms occur, withhold dose during evaluation and until improvement. Monitor liver enzymes and bilirubin; delay, change dose, or discontinue if hepatotoxicity occurs. Severe renal impairment or moderate or severe hepatic impairment: avoid.

Discontinue if serious skin reactions (eg, SJS, TEN) occur. GI complications: evaluate and treat if new or worsening GI symptoms develop. Embryofetal toxicity. Females and males of reproductive potential should use effective contraception during and for ≥6 months after final dose.

Pregnancy: verify status before initiation. Nursing mothers: not recommended.

Interactions: See Contraindications.

Potentiated by strong CYP3A4 inhibitors (eg, ketoconazole) or P-gp inhibitors; monitor closely.

May be antagonized by potent CYP3A4 inducers (eg, rifampin).

Adverse reactions: Neutropenia, peripheral sensory neuropathy, fatigue, nausea, anemia, upper respiratory tract infection, diarrhea, pyrexia, rash, thrombocytopenia, cough, vomiting.

How supplied: Single-use vial—1

ALIQOPA Bayer

℞

Kinase inhibitor. Copanlisib 60mg; per vial; lyophilized pwd for IV infusion after reconstitution and dilution.

Indications: Treatment of adults with relapsed follicular lymphoma (FL) who have received at least two prior systemic therapies.

Adults: Give 60mg as IV infusion over 1hr on Days 1, 8, and 15 of a 28-day cycle on an intermittent schedule (3 weeks on, 1 week off) until disease progression or unacceptable toxicity.

Concomitant strong CYP3A inhibitors: reduce to 45mg. Dose modifications for toxicities: see full labeling.

Children: Not established.

Warnings/Precautions: Monitor for signs/symptoms of infection (eg, pneumonia); withhold if Grade ≥3 infection develops. Risk of serious pneumocystis jiroveci pneumonia (PJP); consider PJP prophylaxis for those at risks prior to initiation. Diabetes. Obtain optimal blood glucose and blood pressure (BP) control prior to each infusion; monitor closely. Discontinue if blood glucose ≥500mg/dL is persistent at Copanlisib 30mg dose. Discontinue if post-dose BP remains uncontrolled (>150/90mmHg) despite antihypertensives or elevated with lifethreatening consequences. Withhold and treat if non-infectious pneumonitis occurs; discontinue if Grade 2 recurs or if Grade ≥3 develops. Monitor ANC at least weekly; withhold if ANC <0.5 × 103 cells/mm3; reduce to 45mg if ANC ≤0.5 × 103

cells/mm3 recurs. Monitor for severe cutaneous reactions; withhold for Grade 3 reaction; discontinue if life-threatening. Monitor for thrombocytopenia, other severe and non-lifethreatening toxicities; see full labeling. Embryofetal toxicity. Females of reproductive potential and males (w. female partners) should use highly effective contraception during treatment and for ≥1 month after last dose. Pregnancy; exclude status prior to initiation. Nursing mothers: not recommended (during and for ≥1 month after last dose).

Interactions: May be antagonized by strong CYP3A inducers (eg, carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, St. John’s wort); avoid. Potentiated by strong CYP3A inhibitors (eg, boceprevir, clarithromycin, cobicistat, conivaptan, danoprevir/ritonavir, diltiazem, elvitegravir/ritonavir, grapefruit juice, idelalisib, indinavir/ritonavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, paritaprevir/ritonavir and (ombitasvir and/or dasabuvir), posaconazole, ritonavir, saquinavir/ritonavir, tipranavir/ritonavir, troleandomycin, voriconazole); if concomitant use unavoidable, reduce Copanlisib dose (see Adult).

Adverse reactions: Hyperglycemica, diarrhea, decreased general strength/energy, hypertension, leukopenia, neutropenia, nausea, lower respiratory tract infections, thrombocytopenia.

How supplied: Single-dose vial—1

ARZERRA Novartis

℞

CD20-directed cytolytic monoclonal antibody.

Ofatumumab 20mg/mL; soln for IV infusion after dilution; preservative-free.

Indications: In combination with chlorambucil in previously untreated patients with chronic lymphocytic leukemia (CLL), for whom fludarabine-based therapy is considered inappropriate. Extended treatment of patients who are in complete or partial response after at least two lines of therapy for recurrent or progressive CLL. Treatment of CLL refractory to fludarabine and alemtuzumab.

Adults: Premedicate with acetaminophen (oral), antihistamine (oral or IV), corticosteroid (IV) 30mins to 2hrs prior to each infusion. Give

by IV infusion (rate varies with dose and during infusion); see full labeling. Previously untreated: initially 300mg on Day 1, then 1 week later by 1000mg on Day 8 (Cycle 1), followed by 1000mg on Day 1 of subsequent 28-day cycles for at least 3 cycles until best response or max 12 cycles.

Extended treatment: initially 300mg on Day 1,

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER then by 1000mg 1 week later on Day 8, followed by 1000mg 7 weeks later and every 8 weeks thereafter for up to max 2 years. Refractory: initially 300mg on Day 1, then 1 week later by 2000mg weekly for 7 doses, followed 4 weeks later by 2000mg every 4 weeks for 4 doses.

Dose modification for infusion reactions: see full labeling.

Children: Not established.

Warnings/Precautions: Increased risk of HBV reactivation. Test/treat HBV infection prior to initiating therapy. Monitor for signs of hepatitis or HBV reactivation during and for several months after therapy; discontinue if HBV reactivation occurs. Monitor CBCs at regular intervals during and after therapy, increase frequency if Grade 3/4 cytopenias develop. Monitor for new onset of or changes in pre-existing neurological signs/symptoms; discontinue and evaluate if progressive multifocal leukoencephalopathy (PML) is suspected. 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), PML, infections (eg, sepsis), hepatotoxicity, TLS. How supplied: Single-use vial (5mL)—3; (50mL)—1

BELEODAQ Spectrum

℞

Histone deacetylase inhibitor. Belinostat 500mg; per vial; lyophilized pwd for IV inj after reconstitution and dilution.

Indications: Relapsed or refractory peripheral T-cell lymphoma.

Adults: Give 1000mg/m2 once daily by IV infusion over 30 mins on Days 1–5 of a 21-day cycle; can repeat cycles every 21 days until disease progression or unacceptable toxicity.

Dose modifications: Hematologic toxicities: if ANC nadir <0.5x109/L or platelet count <25x109/L: decrease dose by 25% (750mg/m2); discontinue if recurrent ANC <0.5x109/L or platelet count <25x109/L nadirs after 2 dose reductions; Non-hematologic toxicities: if any CTCAE Grade 3/4 reaction: decrease dose by 25% (750mg/m2); discontinue if recurrent CTCAE Grade 3/4 reaction after 2 dose reductions.

Patients with homozygous UGT1A1*28 allele: initially 750mg/m2.

Children: Not established.

Warnings/Precautions: Risk of hematologic toxicity; monitor blood counts with differential at baseline and weekly during therapy; adjust dose as necessary. Active infection: do not administer.

History of extensive or intensive chemotherapy: may be at higher risk of life-threatening infections. Renal or hepatic impairment. Monitor serum chemistry, renal and hepatic function before treatment and the start of each cycle; interrupt, adjust, or discontinue dose based on severity of hepatotoxicity. Tumor lysis syndrome; monitor patients with advanced stage disease and/or high tumor syndrome. GI toxicity; may require use of antiemetics and antidiarrheals.

Embryo-fetal toxicity. Pregnancy (Cat. D), nursing mothers: not recommended.

Interactions: Avoid concomitant use of strong UGT1A1 inhibitors.

Adverse reactions: Nausea, fatigue, pyrexia, anemia, vomiting; hematologic toxicity, infection, hepatotoxicity, tumor lysis syndrome, GI toxicity.

How supplied: Single-use vial (30mL)—1

BENDEKA Teva

℞

Alkylating agent. Bendamustine HCl 25mg/mL; soln for IV infusion after dilution; preservativefree.

Indications: Chronic lymphocytic leukemia (CLL). Indolent B-cell non-Hodgkin’s lymphoma (NHL) that has progressed during or within 6 months of treatment with rituximab or a rituximab–containing regimen.

Adults: CLL: Give by IV infusion over 10mins.

100mg/m2 on Days 1 and 2 of a 28-day cycle, up to 6 cycles. Hematologic toxicity (≥Grade 3): reduce dose to 50mg/m2 on Days 1 and 2 of each cycle; if toxicity recurs, reduce dose to 25mg/m2 on Days 1 and 2. Non-hematologic toxicity (clinically significant ≥Grade 3): reduce dose to 50mg/m2 on Days 1 and 2 of each cycle. Subsequent cycles: may consider dose re-escalation. NHL: Give by IV infusion over 10mins. 120mg/m2 on Days 1 and 2 of a 21-day cycle, up to 8 cycles. Hematologic toxicity (Grade 4) or non-hematologic toxicity (≥Grade 3): reduce dose to 90mg/m2 on Days 1 and 2 of each cycle; if toxicity recurs, reduce dose to 60mg/m2 on Days 1 and 2. Delay treatment for Grade 4 hematologic toxicity or clinically significant ≥Grade 2 non-hematologic toxicity.

Children: Not established.

Warnings/Precautions: Myelosuppression; monitor CBCs including leukocytes, platelets, hemoglobin, neutrophils frequently; restart treatment based on ANC and platelet count recovery. Monitor for signs of infection or reactivation of infections (eg, hepatitis B, CMV, tuberculosis, herpes zoster); prophylaxis and treat prior to therapy if occur. Monitor for infusion or skin reactions (may be fatal), tumor lysis syndrome. Monitor LFTs prior to and during therapy. Renal impairment (mild or moderate): caution; (CrCl <40mL/min): not recommended.

Hepatic impairment (mild): caution; (moderate or severe): not recommended. Avoid extravasation.

Embryo-fetal toxicity. Pregnancy (Cat.D); avoid during and for 3 months after therapy cessation.

Nursing mothers: not recommended.

Interactions: May be potentiated by CYP1A2 inhibitors (eg, fluvoxamine, ciprofloxacin) or antagonized by CYP1A2 inducers (eg, omeprazole, smoking); if needed, consider alternatives.

Adverse reactions: Lymphopenia, anemia, leukopenia, thrombocytopenia, neutropenia, pyrexia, nausea, vomiting, fatigue, diarrhea, constipation, anorexia, cough, headache, weight loss, dyspnea, stomatitis; infection, infusion reactions (discontinue if severe), tumor lysis syndrome, skin reactions (if severe or progressive, withhold dose or discontinue), hepatotoxicity, other malignancies (eg, myelodysplastic syndrome, acute myeloid leukemia, bronchial carcinoma).

How supplied: Multi-dose vial (4mL)—1

BLINCYTO Amgen

℞

Bispecific CD19-directed CD3 T-cell engager.

Blinatumomab 35mcg; per vial; lyophilized pwd for IV infusion after reconstitution; preservativefree.

Indications: Relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).

Adults and Children: Strictly follow preparation and administration instructions. Pre-medicate with dexamethasone 20mg (adults) or 5mg/m2 to max 20mg (pediatrics) 1 hour prior to 1st dose of each cycle, prior to a step dose, or when restarting infusion after interruption (≥4 hours). Treat up to 9 cycles (2 cycles for induction, followed by 3 cycles for consolidation, and up to 4 additional cycles of continued therapy). One single cycle = 28 days of continuous IV infusion followed by a 14-day treatment-free interval (during Cycles 1–5) or 56-day treatment-free interval (during Cycles 6–9). Hospitalization recommended for first 9 days of Cycle 1 and first 2 days of Cycle 2. Give by continuous IV infusion at a rate of 10mL/hr over 24hrs, 5mL/hr over 48hrs, or 0.6mL/hr over 7 days (not recommended for patients <22kg). <45kg (Cycle 1): 5mcg/m2/day (max 9mcg/day) on Days 1–7 and 15mcg/m2/day (max 28mcg/day) on Days 8–28; (Cycles 2–9): 15mcg/m2/day (max 28mcg/day) on Days 1–28. ≥45kg (Cycle 1): 9mcg/day on Days 1–7 and 28mcg/day on Days 8–28; (Cycles 2–9): 28mcg/day on Days 1–28. Dose adjustments or using 7-day infusion of Blincyto (with preservative): see full labeling.

Warnings/Precautions: Monitor for signs/symptoms of cytokine release syndrome or neurological toxicities; interrupt or discontinue as recommended (see full labeling). Monitor for infections; give antibiotic prophylaxis as appropriate. Monitor for tumor lysis syndrome; interrupt or discontinue as needed. Obtain lab tests (including WBC,

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER ANC) during infusion; interrupt if prolonged neutropenia occurs. Monitor ALT, AST, GGT, and total bilirubin prior to and during treatment; interrupt if transaminases rise >5XULN or if bilirubin rises >3XULN. Evaluate if signs/symptoms of pancreatitis develop; interrupt or discontinue as appropriate. Risk of leukoencephalopathy, esp. in those with prior treatment with cranial irradiation and antileukemic chemotherapy (including highdose methotrexate or intrathecal cytarabine).

Elderly. Neonates/infants: risk of gasping syndrome (due to benzyl alcohol preservative).

Pregnancy; verify status prior to initiation.

Females of reproductive potential should use effective contraception during and for at least 48hrs after last dose. Nursing mothers: not recommended (during and for at least 48hrs after last dose).

Interactions: Concomitant live vaccines: not recommended (for at least 2 weeks prior to initiation, during treatment, and until immune recovery after last cycle). Caution with concomitant CYP450 substrates esp. drugs with narrow therapeutic index (eg, warfarin, cyclosporine); monitor and adjust dose as needed.

Adverse reactions: Infections, pyrexia, headache, infusion-related reactions, anemia, febrile neutropenia, thrombocytopenia, neutropenia.

How supplied: Pack—1 (single-use vial + IV solution stabilizer)

BOSULIF Pfizer

℞

Tyrosine kinase inhibitor. Bosutinib 100mg, 500mg; tabs.

Indications: Treatment of chronic, accelerated, or blast phase Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) with resistance or intolerance to prior therapy.

Adults: Take with food. Initially 500mg once daily 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. Hepatic impairment: initially 200mg daily. Renal impairment (CrCl 30–50mL/min): initially 400mg daily; (CrCl <30mL/min): initially 300mg daily. Dose modifications for toxicity: see full labeling.

Children: <18yrs: not established.

Warnings/Precautions: Monitor and manage GI toxicity, fluid retention; withhold, reduce

dose, or discontinue as necessary. Perform CBC weekly for first month, then monthly; hepatic enzyme tests monthly for first three months (more frequently if transaminase elevations occur); withhold, reduce dose, or discontinue as necessary. Monitor renal function at baseline and during therapy; consider adjusting dose if renal impairment occurs. Dialysis: not studied. Pregnancy (Cat.D); avoid. Use effective contraception during and for ≥30 days after last dose. Nursing mothers: not recommended.

Interactions: Potentiated by concomitant strong or moderate CYP3A inhibitors (eg, boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole, or amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fosamprenavir, imatinib, verapamil, grapefruit products); avoid. Antagonized by concomitant strong or moderate CYP3A inducers (eg, carbamazepine, phenytoin, rifampin, St. John’s Wort, or bosentan, efavirenz, etravirine, modafinil, nafcillin); avoid. Antagonized by proton pump inhibitors (eg, lansoprazole); consider short-acting antacids or H2 blockers instead; separate dosing by ≥2hrs.

Adverse reactions: Diarrhea, nausea, thrombocytopenia, rash, vomiting, abdominal pain, RTI, anemia, pyrexia, abnormal LFTs, fatigue, cough, headache; fluid retention, hepatic or renal toxicity.

How supplied: Tabs 100mg—120; 500mg—30

CALQUENCE AstraZeneca Bruton tyrosine kinase (BTK) inhibitor.

Acalabrutinib 100mg; caps.

Indications: Mantle cell lymphoma (MCL) in adult patients who have received at least one prior therapy.

Adults: Swallow whole with water. 100mg approx. every 12hrs until disease progression or unacceptable toxicity. Concomitant moderate CYP3A inhibitors: 100mg once daily.

Concomitant strong CYP3A inducers: avoid; if needed, increase dose to 200mg twice daily.

Dose modifications for adverse reactions: 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 infections; consider prophylaxis if

℞

at risk for opportunistic infections. Monitor for cytopenias; obtain CBCs monthly. Risk of second primary malignancies (eg, skin cancer or other carcinomas); advise patients to protect from sun exposure. Monitor for atrial fibrillation/flutter; manage appropriately. Pregnancy. Nursing mothers: not recommended (during and for at least 2 weeks after final dose).

Interactions: Avoid concomitant strong CYP3A inhibitors (eg, itraconazole); if short-term use (eg, anti-infectives for ≤7days), interrupt acalabrutinib therapy. Concomitant moderate CYP3A inhibitors: reduce acalabrutinib dose (see Adult). Avoid concomitant strong CYP3A inducers (eg, rifampin); if unavoidable, increase acalabrutinib dose (see Adult). Increased risk of hemorrhage with concomitant antiplatelets or anticoagulants; monitor. Antagonized by gastric acid reducing agents (eg, PPI [avoid], H2-receptor antagonist, or antacid); if needed, consider ranitidine, famotidine, or calcium carbonate.

Separate dosing by at least 2hrs with antacids.

Take acalabrutinib 2hrs before H2-receptor antagonist use.

Adverse reactions: Anemia, thrombocytopenia, headache, neutropenia, diarrhea, fatigue, myalgia, bruising; hemorrhage, infections, second primary malignancy, atrial fibrillation/flutter.

How supplied: Caps—60

CAMPATH Sanofi 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

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER 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 full labeling. Infusion reactions, cytopenias (eg, neutropenia, lymphopenia, thrombocytopenia, anemia), infections (eg, CMV), nausea, emesis, diarrhea, 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 Sanofi Genzyme

SIRS/capillary leak syndrome, hemorrhage (may be fatal), enterocolitis (monitor), serious skin reactions (discontinue for exfoliative or bullous rash or if Stevens-Johnson syndrome or toxic epidermal necrolysis suspected), hepatotoxicity (may be fatal), acute renal failure, embryo-fetal toxicity.

How supplied: Single-use vial (20mL)—1

DACOGEN Otsuka ℞

Purine nucleoside antimetabolite. Clofarabine 1mg/mL; soln for IV infusion after dilution; preservative-free.

Indications: Acute lymphoblastic leukemia (ALL) in patients 1–21 years of age after relapses from, and/or refractoriness to, at least two prior regimens.

Adults: Not established.

Children: Monitor blood pressure, cardiac, renal, and hepatic function before and during therapy. Give by IV infusion over 2 hours.

1–21yrs: 52mg/m2 daily for 5 consecutive days; repeat approximately every 2–6 weeks following recovery or return to baseline organ function. Provide supportive care (eg, IV fluids, antihyperuricemics, alkalinize urine, steroids, antiemetics, diuretics, albumin) throughout treatment. Renal impairment (CrCl 30–60mL/min): reduce dose by 50%. Dose modifications: see full labeling.

Warnings/Precautions: Obtain CBCs, platelets, and coagulation parameters during the 5 days of therapy. Discontinue if hypotension develops during administration. Monitor for signs/symptoms of infection, tumor lysis syndrome, cytokine release (eg, tachypnea, hypotension); if cytokine release progresses to systemic inflammatory response syndrome (SIRS)/capillary leak syndrome and/or if organ dysfunction occurs, discontinue and treat; may restart at lower dose if organ function recovers and patient is stable. Monitor for venous occlusive disease of the liver in patients who previously received hematopoietic stem cell transplant; discontinue if suspected. Monitor hepatic function; discontinue immediately if Grade ≥3 liver enzyme and/or bilirubin elevation occurs. Monitor for renal toxicity; interrupt or discontinue if Grade ≥3 creatinine elevation occurs. Pregnancy (Cat.D; avoid); 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: Vomiting, nausea, diarrhea, febrile neutropenia, pruritus, headache, bacteremia, pyrexia, rash, tachycardia, abdominal pain, chills, fatigue, anorexia, extremity pain, hypotension, epistaxis, petechiae; bone marrow suppression, infections, hyperuricemia,

℞

Nucleoside analogue. Decitabine 50mg/vial; lyophilized pwd for IV infusion after reconstitution and dilution.

Indications: Myelodysplastic syndromes (MDS) including previously treated and untreated, de novo and secondary MDS of all FrenchAmerican-British subtypes and Intermediate-1, Intermediate-2, and High-risk International Prognostic Scoring System groups.

Adults: May premedicate with antiemetics.

Treat for a minimum of 4 cycles; may take longer for a complete or partial response.

Regimen 1: Give by continuous IV infusion over 3 hours. 15mg/m2 every 8 hours for 3 days; repeat every 6 weeks. Regimen 2: Give by continuous IV infusion over 1 hour. 20mg/m2 once daily for 5 days; repeat every 4 weeks.

Both: dose adjustment based on hematology values: see literature. Non-hematologic toxicities (eg, serum creatinine ≥2mg/dL; SGPT, total bilirubin ≥ 2 X ULN; active or uncontrolled infection): do not restart until toxicity resolved.

Children: Not recommended.

Warnings/Precautions: Renal or hepatic impairment. Obtain CBC and platelet counts before each dosing cycle and as needed.

Monitor hepatic function (do baseline liver chemistries and serum creatinine). Pregnancy (Cat.D); use appropriate contraception (both men and women). Nursing mothers: not recommended.

Adverse reactions: Neutropenia, thrombocytopenia, anemia, leukopenia, fatigue, pyrexia, nausea, cough, petechiae, constipation, diarrhea, hyperglycemia.

How supplied: Single-use vial—1

DARZALEX Janssen Biotech

℞

CD38-directed monoclonal antibody.

Daratumumab 100mg/5mL, 400mg/20mL; per vial; soln for IV infusion after dilution; contains mannitol; preservative-free.

Indications: Treatment of multiple myeloma: as combination therapy with lenalidomide and dexamethasone, or bortezomib and dexamethasone, in patients who have received ≥1 prior therapy; as combination therapy with pomalidomide and dexamethasone in patients who have received ≥2 prior therapies including lenalidomide and a proteasome inhibitor (PI); or as monotherapy in patients who have received ≥3 prior lines of therapy including a PI and an

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HEMATOLOGIC CANCER immunomodulatory agent or who are doublerefractory to a PI and an immunomodulatory agent.

Adults: Pre-medicate with corticosteroids (long- or intermediate-acting), oral antipyretics, oral or IV antihistamines 1–3 hours prior to every infusion and administer oral corticosteroids post-infusion. Give only as IV infusion. Initially infuse at 50mL/hr for first two infusions, then 100mL/hr for subsequent infusions; may increase by 50mL/hr every hour; max 200mL/hr. Monotherapy and combination therapy with lenalidomide or pomalidomide and dexamethasone: 16mg/kg weekly at Weeks 1–8, every 2 weeks at Weeks 9–24, then every 4 weeks at Week 25 onwards until disease progression. Combination therapy with bortezomib and dexamethasone: 16mg/kg weekly at Weeks 1–9, every three weeks at Weeks 10–24, then every four weeks at Week 25 onwards until disease progression.

Management of infusion reactions, pre- and post-infusion medications, others: see full labeling. Prophylaxis for herpes zoster reactivation: initiate antiviral prophylaxis within 1 week after starting therapy and continue for 3 months after treatment.

Children: Not established.

Warnings/Precautions: Should be administered by a healthcare professional with immediate access to emergency equipment and appropriate medical support. Monitor frequently for infusion reactions; interrupt treatment for infusion reactions of any severity. Permanently discontinue if life-threatening (Grade 4) or upon 3rd recurrence of Grade 3 infusion reactions occur; for Grade 1, 2, or 3 reactions, reduce the infusion rate when restarting. History of COPD: may require additional post-infusion drugs; consider prescribing short- or long-acting bronchodilators and inhaled corticosteroids.

Interference with cross-matching and RBC antibody screening; type/screen patients prior to initiating treatment. Increased neutropenia (monitor for infections) and thrombocytopenia: obtain CBCs during therapy; dose delay may be required to allow recovery of neutrophils and platelets. Neonates/infants: defer live vaccines if exposed to drug in utero until hematology evaluation. Pregnancy. Females of reproductive potential should use effective contraception during treatment and for 3 months after cessation. Nursing mothers.

Interactions: Interferes with Indirect Antiglobulin (Coombs) Test, serum protein electrophoresis and immunofixation assays leading to false (+) results.

Adverse reactions: Infusion reactions, neutropenia, thrombocytopenia, fatigue, nausea, diarrhea, constipation, vomiting, muscle spasms, arthralgia, back pain, pyrexia, chills, dizziness, insomnia, cough, dyspnea, peripheral edema, peripheral sensory neuropathy, upper respiratory tract infection.

How supplied: Single-dose vial—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. Cardiomyopathy (including left ventricular failure), acute infusion-related reactions, myelosuppression may occur. Have medications to treat infusion-related reactions and resuscitative equipment available. Hepatic impairment. Monitor blood (esp. CBC + platelets), hepatic (esp. SGOT/SGPT, alkaline phosphatase), and cardiac function (eg, MUGA, ECG). Monitor periodically for secondary oral cancers with long-term use. Avoid extravasation.

Embryo-fetal toxicity. Use effective contraception during and for 6 months after last dose. Pregnancy (Cat.D); avoid. Nursing mothers: not recommended.

Interactions: Caution with cyclosporine, phenobarbital, phenytoin, streptozocin, digoxin, myelosuppressants, others. Previous mediastinal irradiation, cyclophosphamide, other cardiotoxic drugs: monitor for cardiotoxicity and hepatotoxicity.

Adverse reactions: Asthenia, fatigue, fever, anorexia, nausea, vomiting,

stomatitis, diarrhea, constipation, hand and foot syndrome, rash, neutropenia, thrombocytopenia, anemia; infusion reactions, cardiovascular events (eg, cardiomyopathy, CHF, acute LV failure), recall of skin reaction from prior radiation therapy, toxoplasmosis, urine discoloration (red/orange).

How supplied: Single-use vials (10mL, 25mL)—1

EMPLICITI Bristol-Myers Squibb

℞

SLAMF7-directed immunostimulatory antibody.

Elotuzumab 300mg, 400mg; per vial; lyophilized pwd for IV infusion after reconstitution; preservative-free.

Indications: In combination with lenalidomide and dexamethasone, for the treatment of patients with multiple myeloma who have received 1–3 prior therapies.

Adults: Give by IV infusion at initial rate of 0.5mL/min; may increase stepwise if no reactions develop; max rate 2mL/min (see full labeling). After 4 cycles, infusion rate may be increased up to max 5mL/min. Administer with lenalidomide and dexamethasone (see full labeling for dosing schedule). 10mg/kg every week for the first 2 cycles then every 2 weeks thereafter; continue until disease progression or unacceptable toxicity. Premedicate with dexamethasone, H1 blocker, H2 blocker, and acetaminophen before each infusion. Dose modifications: see full labeling.

Children: Not established.

Contraindications: Consult lenalidomide and dexamethasone prescribing information for contraindications before starting therapy.

Warnings/Precautions: Interrupt infusion if Grade ≥2 infusion reactions occur and manage appropriately. Monitor for development of infections and treat promptly. Monitor for second primary malignancies. Monitor liver function periodically; discontinue if Grade ≥3 elevation of liver enzymes occur; consider resuming after return to baseline values.

Pregnancy: not studied. Nursing mothers: not recommended.

Interactions: May interfere with correct response classification in SPEP and serum immunofixation assays.

Adverse reactions: Fatigue, diarrhea, pyrexia, constipation, cough, peripheral neuropathy, nasopharyngitis, upper respiratory tract infection, decreased appetite, pneumonia.

Note: For lenalidomide and dexamethasone specific dosing and safety information, refer to the respective full prescribing labels.

How supplied: Single-dose vial—1

Access Cancer Therapy Advisor treatment regimens in a user-friendly format.

CancerTherapyAdvisor.com/TreatmentRegimens.

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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 ≥2XULN occurs. Withhold therapy if mild pancreatitis; may resume after resolution.

Monitor glucose levels at baseline and during therapy. Discontinue if thrombotic or hemorrhagic event occurs; may resume after resolution. Pregnancy (Cat.C). Nursing mothers: not recommended.

Adverse reactions: Systemic hypersensitivity, hyperglycemia, abnormal transaminases, fever, pancreatitis, local reactions, vomiting, nausea, thrombosis, hyperbilirubinemia, abdominal pain/discomfort, diarrhea.

How supplied: Vials (3mL)—5

EVOMELA Spectrum

℞

Alkylating agent. Melphalan HCl 50mg/vial; lyophilized pwd; for IV infusion after reconstitution.

Indications: High-dose conditioning treatment prior to hematopoietic progenitor (stem) cell transplantation in patients with multiple myeloma. Palliative treatment of multiple myeloma when oral therapy is not appropriate.

Adults: Give prophylactic antiemetics.

Conditioning treatment: Give by IV infusion over 30 minutes. 100mg/m2 daily for 2 consecutive days (Days -3 and -2) prior to transplantation (Day 0). If patient weighs >130% of their ideal body weight, use adjusted ideal body weight. Palliative treatment: Give by IV infusion over 15–20 minutes. 16mg/m2 as a single infusion at 2-week intervals for 4 doses,

then at 4-week intervals after recovery from toxicity. Renal impairment (BUN ≥30mg/dL): consider up to 50% dose reduction for palliative treatment.

Children: Not established.

Warnings/Precautions: Prior irradiation or chemotherapy. Severe bone marrow suppression. Monitor CBCs during treatment; provide supportive care for infections, anemia, thrombocytopenia until adequate recovery.

GI toxicity; provide supportive care. Monitor LFTs. Renal impairment. Embryo-fetal toxicity; use effective contraception during and after treatment. Pregnancy, nursing mothers: not recommended.

Interactions: Caution with cyclosporine, BCNU, nalidixic acid.

Adverse reactions: Decreased neutrophil, WBC, lymphocyte, and platelet counts, diarrhea, nausea, fatigue, hypokalemia, anemia, vomiting; hypersensitivity reactions, hepatic disorders, secondary malignancies, infertility.

How supplied: Single-dose vial (20mL)—1

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). Embryo-fetal toxicity. Pregnancy: avoid. Obtain pregnancy test prior to and during treatment. Use effective contraception during and for ≥3 months after last dose; males: use condoms during and for ≥6 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 Sanofi 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).

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER 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

℞

CD20-directed cytolytic monoclonal antibody.

Obinutuzumab 25mg/mL; soln for IV infusion after dilution; preservative-free.

Indications: In combination with chlorambucil, for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL).

In combination with bendamustine followed

by Gazyva monotherapy, for the treatment of patients with follicular lymphoma (FL) who relapsed after, or are refractory to, a rituximab-containing regimen. In combination with chemotherapy followed by Gazyva monotherapy, for the treatment of previously untreated stage II bulky, III or IV follicular lymphoma in patients achieving at least a partial remission.

Adults: See full labeling. Premedicate (eg, glucocorticoid, APAP, antihistamine) before each infusion. Provide prophylactic hydration and antihyperuricemics to those at high risk of TLS. Give by IV infusion for 6 treatment cycles (28 days duration). CLL: Cycle 1: 100mg on Day 1 at 25mg/hr over 4 hours; 900mg on Day 2 at 50mg/hr, can increase at 50mg/hr every 30mins to max 400mg/hr; 1000mg on Days 8 and 15 at 100mg/hr if no infusion reaction occurred previously, and increased by 100mg/hr increments every 30mins to max 400mg/hr; Cycles 2–6: 1000mg on Day 1 at 100mg/hr if no infusion reaction occurred previously, and increased by 100mg/hr increments every 30mins to max 400mg/hr. FL: Relapsed/refractory: give with bendamustine for six 28-day cycles; Previously untreated: give with either bendamustine for six 28-day cycles, with CVP for eight 21-day cycles, or with CHOP for six 21-day cycles followed by two additional 21-day cycles of Gayva monotherapy. Cycle 1: 1000mg on Day 1 at 50mg/hr, can increase at 50mg/hr every 30mins to max 400mg/hr; 1000mg on Days 8 and 15 at 100mg/hr if no infusion reaction occurred previously, and

increased by 100mg/hr increments every 30mins to max 400mg/hr; Cycles 2–6 or 2–8: 1000mg on Day 1 at 100mg/hr if no infusion reaction occurred previously, and increased by 100mg/hr increments every 30mins to max 400mg/hr; followed by Gazyva monotherapy: 1000mg every 2 months for 2 years at 100mg/hr if no infusion reaction occurred previously, and increased by 100mg/hr increments every 30mins to max 400mg/hr. Management of infusion reactions, premedication: see full labeling.

Children: Not established.

Warnings/Precautions: Risk of hepatitis B virus (HBV) reactivation; immediately discontinue and any concomitant chemotherapy if occurs. Screen for HBV infection prior to initiation; if positive evidence, monitor and consider antiviral therapy. Discontinue treatment and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressives if progressive multifocal leukoencephalopathy (PML) develops. Monitor closely for infusion reactions; if Grade 4: discontinue permanently; if Grade 3: interrupt until resolved; if Grade 1 or 2: interrupt or reduce the infusion rate and manage symptoms.

Preexisting cardiac or pulmonary conditions: monitor more frequently during and postinfusion period for severe reactions. Risk of TLS in high tumor burden, high circulating lymphocyte count (>25 × 109/L), or renal impairment. Active infection: do not administer.

Risk of neutropenia; monitor for signs of infection. Severe or prolonged neutropenia, give antimicrobial prophylaxis until resolved to Grade 1 or 2; consider antiviral and antifungal prophylaxis. Monitor for thrombocytopenia and hemorrhagic events esp. during the 1st cycle; if Grade 3 or 4 thrombocytopenia, obtain platelet counts more frequently until resolved; transfusion of blood products may be necessary.

Consider interrupting therapy if infection, Grade 3 or 4 cytopenia, or ≥Grade 2 non-hematologic toxicity develops. Permanently discontinue if hypersensitivity reaction including serum sickness is suspected; do not retreat. Hepatic or renal impairment (CrCl <30mL/min).

Pregnancy; risk of fetal B-cell depletion. Nursing mothers.

Interactions: Concomitant live viral vaccines: not recommended during treatment and until B-cell recovery (esp. neonates/infants if exposed to Gazyva in utero). Consider withholding antihypertensives for 12hrs prior to, during, and for 1hr after infusion until BP is stable. Consider withholding drugs that may increase bleeding

risk (eg, platelet inhibitors, anticoagulants) esp. during 1st cycle.

Adverse reactions: Infusion reactions, neutropenia, thrombocytopenia, diarrhea, cough, constipation, pyrexia, upper RTI, arthralgia, sinusitis, asthenia, UTI, headache, insomnia, pneumonia, decreased appetite, alopecia, pruritus; HBV reactivation, PML, TLS, infections (may be fatal), hypersensitivity reactions.

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 re-arrangements as determined with an FDAapproved test. 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 (determine PDGFRb gene status prior to initiation): 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%.

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

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HEMATOLOGIC CANCER 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 non-hematologic 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; renal function at baseline and during therapy; GI symptoms at baseline. Cardiovascular disease or risk factors; monitor. Diabetes. Hypertension.

CHF. Immunosuppression and potential toxicities (liver, kidney, cardiac) from longterm 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.

Embryo-fetal toxicity. Pregnancy (avoid); exclude status prior to initiation. Females of reproductive potential should use highly effective contraception during treatment and for 14 days after cessation. Nursing mothers: not recommended (during and for 1 month after final dose).

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) or CYP2C9 (use heparin instead of warfarin). Caution with concomitant CYP2D6 substrates that have a narrow therapeutic window.

Adverse reactions: Edema (may be severe), nausea, vomiting, musculoskeletal pain, diarrhea, muscle cramps, rash (may be severe; eg, erythema multiforme, Stevens-Johnson

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

Testing considerations: BCR-Abl t(9;22) in Ph+CML patients How supplied: 100mg—90; 400mg—30

HYDREA Bristol-Myers Squibb

℞

Antimetabolite. Hydroxyurea 500mg; caps.

Indications: Resistant chronic myeloid leukemia.

Adults: Base dose on ideal or actual weight, whichever is less. Individualize. Initially 15mg/kg/day. Renal impairment (CrCl <60mL/min or ESRD): initially 7.5mg/kg/day; give dose following dialysis (monitor). Dose modifications: see full labeling.

Children: Not established.

Warnings/Precautions: Risk of severe myelosuppression; reduce dose or discontinue if necessary. Monitor blood counts at baseline and at least once a week during therapy.

Correct severe anemia before starting.

Markedly depressed bone marrow function: do not initiate. Monitor for malignancies. Avoid sun exposure. Previous irradiation therapy (monitor for skin erythema) or chemotherapy.

Macrocytosis may mask folic acid deficiency; prophylactic folic acid is recommended.

Myeloproliferative disorders; discontinue if cutaneous vasculitic ulcerations occur. Renal or hepatic impairment. Elderly. Embryo-fetal toxicity. Pregnancy; avoid. Exclude pregnancy prior to initiating; use effective contraception during and for ≥6 months (females) or ≥1 year (males) after therapy. Nursing mothers: not recommended.

Interactions: Avoid concomitant didanosine, with or without stavudine, or other antiretrovirals (may cause pancreatitis [monitor], fatal hepatotoxicity, peripheral neuropathy). Avoid live vaccines. Increased risk of vasculitic toxicities with interferon therapy. May cause falsely elevated results in urea, uric acid, and lactic acid assays.

Adverse reactions: Leukopenia, thrombocytopenia, anemia, GI upset, anorexia; secondary malignancies, macrocytosis.

Note: Wear disposable gloves when handling caps or bottle.

How supplied: Caps—100

ICLUSIG Takeda

℞

Kinase inhibitor. Ponatinib 15mg, 30mg, 45mg; tabs; contains lactose.

Indications: Treatment of adults with chronic, accelerated, or blast phase chronic myeloid leukemia (CML) or Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) for whom no other tyrosine kinase inhibitor (TKI)

therapy is indicated. Treatment of adults with T315I-positive CML (chronic, accelerated, or blast phase) or T315I-positive Ph+ ALL. Limitations of use: not for treating patients with newly diagnosed chronic phase CML. Adults: Swallow whole. ≥18yrs: initially 45mg once daily; consider reducing dose in chronic and accelerated phase CML if major cytogenic response achieved. Consider discontinuing if no response occurred by 3 months. Concomitant strong CYP3A inhibitors or hepatic impairment: reduce to 30mg once daily. Dose modification for hematologic and non-hematologic toxicity: see full labeling.

Children: <18yrs: not established.

Warnings/Precautions: Risk of venous thromboembolism and arterial occlusion (including 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. Monitor and manage BP elevations; interrupt, reduce dose or discontinue if not controlled; evaluate for renal artery stenosis if significant worsening, labile or treatment-resistant hypertension occurs. Risk of pancreatitis; check serum lipase every 2 weeks for the first 2 months and then monthly thereafter or as clinically indicated; do not restart until complete resolution and lipase levels <1.5XULN. Increased toxicity in newly diagnosed chronic phase CML: not recommended. 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. Interrupt therapy if reversible posterior leukoencephalopathy syndrome occurs; resume only when resolved and if the benefit outweighs the risk. Elderly.

Embryo-fetal toxicity. Pregnancy (avoid). Females of reproductive potential should use effective contraception during and for 3 weeks after last dose. Nursing mothers: not recommended.

Interactions: Potentiated by strong CYP3A inhibitors (eg, boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole,

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER ritonavir, saquinavir, telaprevir, telithromycin, voriconazole); see Adult dose. Avoid concomitant strong CYP3A inducers (eg, carbamazepine, rifampin, phenytoin, St. John’s Wort). Caution with concomitant drugs that elevate gastric pH (eg, PPIs), P-gp and ABCG2 substrates.

Adverse reactions: Hypertension, rash, abdominal pain, fatigue, headache, dry skin, constipation, arthralgia, nausea, pyrexia, diarrhea, increased lipase, vomiting, myalgia, extremity pain; myelosuppression.

How supplied: Tabs 15mg—30, 60, 180; 30mg—30; 45mg—30, 90

IDAMYCIN Pfizer

℞

Anthracycline. Idarubicin HCl 20mg/vial; lyophilized pwd for IV infusion after reconstitution. ℞ Also: IDAMYCIN PFS Idarubicin 1mg/mL; soln for IV infusion; preservative-free.

Indications: Acute myeloid leukemia.

Adults: Give by slow IV infusion (over 10–15 mins). 12mg/m2 daily for 3 days (in combination with cytarabine). May give 2nd course if needed; if toxicity develops after 1st course, delay until resolved; reduce dose by 25%. Hepatic and renal impairment: consider reduce dose.

Children: Not established.

Warnings/Precautions: Pre-existing bone marrow suppression. Cardiovascular disease.

Thoracic irradiation. Previous anthracycline therapy at high cumulative doses. Renal or hepatic impairment. Monitor CBCs, cardiac, renal and hepatic function prior to and during treatment. Avoid extravasation. Elderly.

Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended.

Interactions: Concomitant drugs that suppress cardiac contractility or cardiotoxic drugs (eg, trastuzumab, cyclophosphamide, paclitaxel): not recommended; avoid use for 5 half-lives after discontinuing cardiotoxic drug.

Adverse reactions: Myelosuppression, GI upset, mucositis, abdominal pain, alopecia, rash, inj site reactions, hepatotoxicity, renal toxicity, cardiotoxicity (eg, CHF, arrhythmias, chest pain, MI, asymptomatic declines in LVEF), hyperuricemia.

How supplied: Single-dose vials—1; PFS: Singledose vials (5mL, 10mL, 20mL)—1

IDHIFA Celgene Isocitrate dehydrogenase-2 (IDH2) inhibitor.

Enasidenib 50mg, 100mg; tabs.

Indications: Treatment of adults with relapsed or refractory acute myeloid leukemia

℞

(AML) with an isocitrate dehydrogenase-2 (IDH2) mutation as detected by an FDAapproved test.

Adults: Swallow whole. Take at same time each day. Initially 100mg once daily until disease progression or unacceptable toxicity; treat for a minimum of 6 months to allow time for response.

Monitoring and dose modifications for toxicities: see full labeling.

Children: Not established.

Warnings/Precautions: Risk of differentiation syndrome (may be fatal if not treated). If differentiation syndrome is suspected, initiate oral or IV corticosteroids and hemodynamic monitoring until resolution; interrupt dose if severe pulmonary symptoms requiring intubation or ventilator support, and/or renal dysfunction persist >48hrs after corticosteroid initiation. Assess blood counts/chemistries for leukocytosis and tumor lysis syndrome prior to initiation; monitor at minimum of every 2 weeks for at least the first 3 months during therapy.

Embryo-fetal toxicity. Females of reproductive potential and males (w. female partners) should use effective contraception during and for at least 1 month after final dose. Pregnancy: not recommended (exclude status prior to initiation). Nursing mothers: not recommended (during and for at least 1 month after final dose).

Interactions: May increase or decrease concentrations of combined hormonal contraceptives.

Adverse reactions: Nausea, vomiting, diarrhea, elevated bilirubin, decreased appetite; differentiation syndrome, leukocytosis, tumor lysis syndrome.

How supplied: Tabs—30

IMBRUVICA

℞

Pharmacyclics and Janssen Biotech

Bruton 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)/small lymphocytic lymphoma (SLL).

CLL/SLL in patients with 17p deletion.

Waldenstrom’s macroglobulinemia (WM).

Marginal zone lymphoma (MZL) in patients who require systemic treatment and have received at least one prior anti-CD20-based therapy.

Adults: Swallow whole with water. MCL and MZL: 560mg once daily. CLL/SLL (with or without bendamustine/rituximab) and WM: 420mg once daily. Treat until disease progression or

unacceptable toxicity. Concomitant moderate CYP3A inhibitors, posaconazole (≤200mg twice daily), voriconazole: 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 postsurgery. Monitor for fever and infections; evaluate promptly if occurs. Monitor for myelosuppression; obtain CBCs monthly.

Periodically monitor for atrial fibrillation (esp. in those with cardiac risk factors, acute infections, history of atrial fibrillation); do ECG if arrhythmic symptoms or new onset dyspnea develop. Monitor for new onset or uncontrolled hypertension; adjust and/or initiate antihypertensives as appropriate. Risk of second primary malignancies (eg, skin cancer or other carcinomas). Monitor for tumor lysis syndrome in patients at risk (eg, high tumor burden).

Moderate or severe hepatic impairment: not recommended. Maintain adequate hydration.

Embryo-fetal toxicity. Pregnancy; avoid during and for 1 month after treatment cessation.

Nursing mothers.

Interactions: See Adult. Avoid concomitant strong CYP3A inhibitors (eg, boceprevir, clarithromycin, cobicistat, conivaptan, diltiazem, elvitegravir/ritonavir, idelalisib, indinavir/ritonavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, paritaprevir/ritonavir/ombitasvir ± dasabuvir, ritonavir, saquinavir/ritonavir, tipranavir/ritonavir, troleandomycin, posaconazole (at higher doses); if short-term use (eg, anti-infectives for ≤7days), consider interrupting ibrutinib therapy. Concomitant moderate CYP3A inhibitors (eg, aprepitant, cimetidine, ciprofloxacin, clotrimazole, crizotinib, cyclosporine, dronedarone, erythromycin, fluconazole, fluvoxamine, imatinib, verapamil): reduce ibrutinib dose (see Adult). Avoid grapefruit and Seville oranges during treatment. Avoid concomitant strong CYP3A inducers (eg, carbamazepine, enzalutamide, mitotane, rifampin, phenytoin, St. John’s Wort).

Increased risk of hemorrhage with concomitant antiplatelets or anticoagulants; monitor.

Adverse reactions: Neutropenia, thrombocytopenia, diarrhea, anemia, musculoskeletal pain, rash, nausea, bruising, fatigue, hemorrhage, pyrexia, muscle spasms, stomatitis, pneumonia.

How supplied: Caps—90, 120

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER 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 highrisk myelofibrosis (MF), including primary MF, post-polycythemia vera MF and post-essential thrombocythemia MF. Treatment of polycythemia vera (PV) in patients with an inadequate response to, or intolerant of, hydroxyurea.

Adults: Doses may be given by NG tube if unable to swallow tabs. MF: Platelets >200X109/L:

initially 20mg twice daily. Platelets 100–200X109/L: initially 15mg twice daily. Platelets 50–<100X109/L: initially 5mg twice daily. May increase doses by 5mg twice daily to a max of 25mg twice daily; do not increase during the first 4 weeks of therapy and not more frequently than every 2 weeks. Discontinue treatment after 6 months if no reduction in spleen size or symptom improvement. Interrupt treatment if platelets <50X109/L or ANC <0.5X109/L. May restart after recovery of platelets or ANC (see full labeling for max allowable restarting doses).

Consider dose reductions if platelets decrease but remain ≥50X109/L (see full labeling). Dose modifications for patients starting treatment with platelets 50–<100X109/L: see full labeling.

PV: initially 10mg twice daily. May increase doses by 5mg twice daily to a max of 25mg twice daily; do not increase during the first 4 weeks of therapy and not more frequently than every 2 weeks. Consider dose reductions for Hgb and/or platelet decreases (see full labeling).

Interrupt treatment if Hgb <8g/dL, platelets <50X109/L, or ANC <1.0X109/L. May restart after recovery of hematologic parameters (see full labeling for max allowable restarting doses). Concomitant strong CYP3A4 inhibitors (see Interactions) or fluconazole ≤200mg (MF): initially 10mg twice daily if platelets ≥100X109/L; if platelets 50–<100X109/L: initially 5mg once daily; (PV): initially 5mg twice daily. Other reductions, hepatic or renal impairment, ESRD: see full labeling.

Children: Not established.

Warnings/Precautions: Monitor for thrombocytopenia, anemia, neutropenia; manage by reducing dose, interrupt, or transfusion if occur. Obtain CBC and platelets before initiating therapy, every 2–4 weeks until doses are stabilized, and then as clinically indicated. Risk of serious bacterial, mycobacterial, fungal, and viral infections; evaluate and treat if occur; delay starting until active infections resolved. May exacerbate MF following treatment interruption or discontinuation. Risk of non-melanoma skin cancer; perform periodic skin exams. Increases in lipid parameters including total-C, LDL, triglycerides; assess 8–12 weeks after starting and treat if hyperlipidemia develops. Avoid abrupt cessation. Renal or hepatic impairment: reduce doses (see full labeling). Pregnancy.

Nursing mothers: not recommended (during and for 2 weeks after final dose).

Interactions: Avoid concomitant fluconazole doses >200mg daily. Potentiated by strong CYP3A4 inhibitors (eg, ketoconazole) and moderate CYP3A4 inhibitors (eg, erythromycin); consider Jakafi dose reduction.

Antagonized by strong CYP3A4 inducers (eg, rifampin); monitor and adjust dose based on efficacy.

Adverse reactions: Thrombocytopenia, anemia, bruising, dizziness, headache; herpes

zoster, tuberculosis (monitor promptly and test for latent infection), progressive multifocal leukoencephalopathy (discontinue if occurs), Hepatitis B. How supplied: Tabs—60

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: Refractory classical Hodgkin lymphoma (cHL) or in patients who have relapsed after ≥3 prior lines of therapy.

Adults: Give as IV infusion over 30mins.

200mg every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. Dose modifications: see full labeling. Administer corticosteroids for most Grade ≥2 related immune-mediated reactions.

Children: Give as IV infusion over 30mins.

2mg/kg (max 200mg) every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. Dose modifications: see full labeling.

Administer corticosteroids for most Grade ≥2 related immune-mediated reactions.

Warnings/Precautions: Monitor for pneumonitis; withhold dose if Grade 2 pneumonitis; permanently discontinue if Grade 3 or 4, or recurrent Grade 2 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 changes in renal function; withhold dose if Grade 2 nephritis; permanently discontinue if Grade 3 or 4 develops. Monitor for hypophysitis; withhold dose if Grade 2 hypophysitis; withhold or discontinue if Grade 3 or 4 develops. Monitor for changes in thyroid function (at treatment initiation, during, and as clinically indicated) and signs/symptoms of thyroid disorders; withhold or discontinue if Grade 3 or 4 hyperthyroidism develops. Monitor for hyperglycemia and other diabetes symptoms; withhold if severe hyperglycemia until controlled. Withhold dose if Grade 4 hematological toxicity in cHL patients develops. Monitor for severe skin reactions; permanently discontinue if SJS or TEN is confirmed. Permanently discontinue if any severe or Grade 3 immune-mediated adverse reaction recurs, for any life-threatening immune-mediated adverse reaction (except endocrinopathies controlled with hormone replacement or hematological toxicity in cHL patients), persistent Grade 2 or 3 reactions that do not recover to Grade 0–1 within 12wks after last dose, or inability to reduce corticosteroid dose to ≤10mg/day of prednisone or equivalent within 12wks. Monitor for infusion-related

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER reactions; permanently discontinue if Grade 3 or 4 develops. Complications of allogeneic HSCT after Keytruda: monitor for hepatic VOD, Grade 3 or 4 acute GVHD, steroid-requiring febrile syndrome, and others. Solid organ transplant recipients. Embryo-fetal toxicity. Females of reproductive potential should use highly effective contraception during therapy and for 4 months after the final dose. Pregnancy: avoid.

Nursing mothers: not recommended (during therapy and for 4 months after the final dose).

Interactions: Increased mortality when pembrolizumab is added to thalidomide analogue plus dexamethasone regimen in multiple myeloma: not recommended.

Adverse reactions: Fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation; immune-mediated disorders, infusion-related reactions.

How supplied: Single-use vial 50mg—1; Singleuse vial 25mg/mL (4mL)—1

KYPROLIS Amgen

℞

Proteasome inhibitor. Carfilzomib 30mg/vial, 60mg/vial; lyophilized pwd for IV inj after reconstitution; preservative-free.

Indications: In combination with dexamethasone or lenalidomide plus dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma who have received 1–3 lines of therapy. As a single agent for the treatment of patients with relapsed or refractory multiple myeloma who have received ≥1 lines of therapy.

Adults: See full labeling. Hydrate prior to and following administration as needed. Premedicate with dexamethasone prior to all Cycle 1 doses, during subsequent cycles, and if infusion reactions occur. Give by IV on two consecutive days each week for 3 weeks (Days 1, 2, 8, 9, 15, and 16), followed by a 12-day rest period (Days 17–28). Lenalidomide/dexamethasone combination: Infuse over 10 mins. In Cycle 1: initially 20mg/m2 per dose on Days 1 and 2; if tolerated increase to 27mg/m2 on Day 8 and subsequent cycles. From Cycle 13, omit the Day 8 and 9 doses. Discontinue carfilzomib after Cycle 18. See full labeling for lenalidomide and dexamethasone dosing. Dexamethasone combination: Infuse over 30 mins. In Cycle 1: initially 20mg/m2 per dose on Days 1 and 2; if tolerated increase to 56mg/m2 on Day 8 and subsequent cycles. Monotherapy: initially 20mg/m2 per dose in Cycle 1 on Days 1 and 2; if tolerated increase to 27mg/m2 on Day 8 (by

10-min infusion regimen) or 56mg/m2 on Day 8 (by 30-min infusion regimen) and continue same dose for subsequent cycles. From Cycle 13, omit the Day 8 and 9 doses. All: continue until disease progression or unacceptable toxicity occurs. Toxicity dose modification: see full labeling. Mild or moderate hepatic impairment: reduce dose by 25%. ESRD on dialysis: give dose after session.

Children: Not established.

Warnings/Precautions: Monitor for signs/symptoms of cardiac failure or ischemia; evaluate promptly if toxicity is suspected.

Increased risk of cardiac complications in patients with NYHA Class III and IV heart failure, recent MI, conduction abnormalities, angina, uncontrolled arrhythmias; do full medical assessment prior to starting. Pulmonary hypertension; if suspected, withhold therapy until resolved; may consider restarting after reevaluation.

Discontinue if pulmonary toxicity occurs.

Monitor for dyspnea or tumor lysis syndrome (TLS), and manage promptly if occurs; interrupt therapy until resolved. Maintain adequate hydration. Monitor for volume overload. Monitor platelets frequently during therapy. Evaluate signs/symptoms of blood loss; reduce or withhold dose as appropriate. 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, liver enzymes, electrolytes (eg, potassium) regularly; reduce or withhold dose as needed. Renal or hepatic impairment. Give thromboprophylaxis for combination therapy. Consider antiviral prophylaxis to prevent herpes zoster reactivation.

Elderly (≥75yrs). Embry-fetal toxicity. Use effective contraception during and for ≥30 days (females) or ≥90 days (males) after therapy completion. Pregnancy: avoid. Nursing mothers.

Interactions: Increased risk of thrombosis with oral or hormonal contraceptives; consider alternatives during combination therapy.

Increased fatal/serious toxicities in combination with melphalan + prednisone in newly diagnosed transplant-ineligible patients.

Adverse reactions: Anemia, neutropenia, diarrhea, dyspnea, fatigue, thrombocytopenia, pyrexia, insomnia, muscle spasm, cough, upper RTI, hypokalemia, nausea, headache, peripheral edema; cardiac events, pulmonary HTN, acute kidney injury, infusion reactions, hemorrhage, TLS, hepatic toxicity/failure, TTP/HUS, PRES. How supplied: Single-use vial—1

LEUKERAN GlaxoSmithKline

℞

Alkylating agent. Chlorambucil 2mg; tabs.

Indications: Palliative treatment of chronic lymphatic (lymphocytic) leukemia and malignant lymphomas (including lymphosarcoma, giant follicular lymphoma, and Hodgkin’s disease).

Adults: See literature. 0.1–0.2mg/kg per day for 3–6 weeks. Reduce dose if leukocyte or platelet counts fall below normal values and discontinue if more severe depression occurs. Do not give full dose within 4 weeks of radio- or chemotherapy.

Children: Not recommended.

Warnings/Precautions: Compromised bone marrow function. History of seizure disorder or head trauma. Monitor blood weekly (during first 3–6 weeks, do WBC count 3–4 days after each weekly CBC). Discontinue if skin reactions occur.

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

Interactions: Avoid live vaccines.

Myelosuppressives, radiotherapy potentiate antineoplastic effect. Caution with drugs that lower seizure threshold.

Adverse reactions: Bone marrow suppression, seizures, fever, rash, hypersensitivity, urticaria, azoospermia, amenorrhea, sterility, hepato- and pulmonary toxicity, secondary malignancies, GI upset.

How supplied: Tabs—50

MARQIBO Spectrum

℞

Vinca alkaloid. Vincristine sulfate liposome injection; after preparation, each vial contains 0.16mg/mL; for IV infusion.

Indications: Philadelphia chromosome-negative (Ph–) acute lymphoblastic leukemia (ALL) in second or greater relapse or has progressed following ≥2 anti-leukemia therapies.

Adults: 2.25mg/m2 IV over 1hr once every 7 days.

Dose modifications for peripheral neuropathy: see full labeling.

Children: Not established.

Contraindications: Demyelinating conditions, including Charcot-Marie-Tooth syndrome.

Intrathecal administration (death has occurred).

Warnings/Precautions: For IV use only; fatal if given by other routes. Discontinue and treat if extravasation is suspected. Preexisting neuromuscular disorders. Monitor for symptoms of neuropathy before and during therapy; if occurs or worsens, delay, reduce or discontinue dose. Monitor CBCs prior to each dose; if Grade 3 or 4 myelosuppression develops, consider dose modification or reduction. Monitor for tumor lysis syndrome; manage if occurs. Institute a

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER 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)

NINLARO Takeda

℞

Proteasome inhibitor. Ixazomib 2.3mg, 3mg, 4mg; gel caps.

Indications: In combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least 1 prior therapy.

Adults: Swallow whole. Take ≥1hr before or ≥2hrs after food. Initially 4mg once weekly on Days 1, 8, and 15 of a 28-day cycle; continue until disease progression or unacceptable toxicity. Give with lenalidomide 25mg daily on Days 1–21 and dexamethasone 40mg on Days 1, 8, 15, and 22. Moderate or severe hepatic impairment, severe renal impairment, or ESRD on dialysis: initially 3mg. Prior to new cycle, ensure ANC ≥1,000/mm3, platelets ≥75,000/mm3, recovery of non-hematologic toxicities to baseline or Grade ≤1. Consider antiviral prophylaxis to decrease risk of herpes zoster reactivation. Dose modifications: see full labeling.

Children: Not established.

Warnings/Precautions: Thrombocytopenia: monitor platelets at least monthly during treatment; consider more frequently for first 3 cycles. Adjust dose for Grade 3/4 GI symptoms or Grade ≥2 rash. Monitor for peripheral neuropathy; adjust dose if worsens.

Adjust dosing of dexamethasone or ixazomib if Grade 3/4 peripheral edema symptoms occur. Hepatic impairment; monitor enzymes regularly and adjust for Grade 3/4 symptoms.

Severe renal impairment or ESRD. Embryo-fetal toxicity. Pregnancy: avoid. Males and females of reproductive potential must use effective contraception during therapy and for 90 days after final dose. Females using hormonal contraceptives should also use barrier method.

Nursing mothers: not recommended (during and for 90 days after final dose).

Interactions: Avoid concomitant strong CYP3A inducers (eg, rifampin, phenytoin, carbamazepine, St. John’s Wort). Risk of reduced hormonal contraceptives efficacy with concomitant dexamethasone.

Adverse reactions: Diarrhea, constipation, thrombocytopenia, peripheral neuropathy, nausea, peripheral edema, vomiting, back pain; rash, hepatotoxicity, herpes zoster, eye disorders.

How supplied: Caps—1, 3

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: Classical Hodgkin lymphoma (cHL) that relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and brentuximab vedotin, or after 3 or more lines of systemic therapy that includes autologous HSCT. Adults: Give as IV infusion over 60mins.

3mg/kg every 2 weeks until disease progression or unacceptable toxicity. Dose modifications: see full labeling.

Children: Not established.

Warnings/Precautions: See full labeling.

Monitor for any immune-mediated adverse reactions; permanently discontinue or withhold, and give corticosteroids (at 1–2mg/kg/day prednisone equivalents) based on severity of event. Permanently discontinue for any lifethreatening (Grade 4) adverse reaction, Grade 3 or 4 pneumonitis, Grade 3/4 or recurrent colitis (with ipilimumab), Grade 4 or recurrent colitis (as single agent), AST/ALT >5XULN (non-HCC) or AST/ALT >10XULN (HCC) or total bilirubin >3XULN, SCr >6XULN, Grade 4 hypophysitis, Grade 3 or 4 adrenal insufficiency, Grade 4 hyperglycemia, Grade 4 rash (or confirmed SJS or TEN), immune-mediated encephalitis, recurring Grade 3 adverse reactions, requirement for ≥10mg/day prednisone (or equivalent) for >12 weeks, or persistent Grade 2 or 3 adverse reactions lasting ≥12 weeks. Grade 2 pneumonitis, Grade 2 or 3 (as single agent) colitis, AST/ALT >3–5XULN or total bilirubin >1.5–3XULN, SCr >1.5–6XULN, Grade 2 or 3 hypophysitis, Grade 2 adrenal insufficiency, Grade 3 hyperglycemia, Grade 3 rash (or suspected SJS or TEN), new onset moderate-to-severe neurologic symptoms, other Grade 3 adverse reactions (1st occurrence); withhold dose, give corticosteroids, and resume when return to Grade 0 or 1. Interrupt or decrease infusion rate if mild or moderate infusion reactions occur; discontinue if severe or lifethreatening. Monitor for abnormal liver tests, elevated serum creatinine, hyperglycemia, and thyroid function prior to and during treatment; give replacement therapy for hypothyroidism.

Monitor for transplant-related complications

(eg, hyperacute or Grade 3/4 acute GVHD, steroid-requiring febrile syndrome, hepatic venoocclusive disease) and treat promptly. Moderate or severe hepatic impairment: not studied.

Embryo-fetal toxicity. Females of reproductive potential should use effective contraception during and for ≥5 months after final dose.

Pregnancy (esp. during 2nd & 3rd trimesters), nursing mothers: not recommended.

Adverse reactions: Fatigue, upper RTI, pyrexia, diarrhea, cough; immune-mediated reactions (may be fatal).

How supplied: Single-use vial (4mL, 10mL)—1

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 (with or without food). 4mg once daily on Days 1–21 of repeated 28-day cycles until disease progression; give with dexamethasone.

Concomitant strong CYP1A2 inhibitors: consider alternatives, if necessary, reduce Pomalyst dose by 50%. Severe renal impairment requiring dialysis: initially 3mg daily; give dose after dialysis session on hemodialysis days. Hepatic impairment (mild or moderate): initially 3mg daily; (severe): 2mg daily. Dose modification for hematologic and other Grade 3/4 toxicities: see full labeling.

Children: <18yrs: not established.

Contraindications: Pregnancy: 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 4 weeks 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. Hepatic or severe renal impairment on hemodialysis:

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER adjust doses (see Adults). 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: Increased mortality when PD-1 or PD-L1 blocking antibody (eg, pembrolizumab) is added to thalidomide analogue plus dexamethasone regimen in multiple myeloma: not recommended. Potentiated by strong CYP1A2 inhibitors (eg, ciprofloxacin, fluvoxamine); avoid (see Adults). May be affected by strong CYP3A4 and P-gp inhibitors (eg, ketoconazole) and strong CYP1A2 or CYP3A4 (eg, carbamazepine) inducers. Smoking may reduce efficacy.

Adverse reactions: Fatigue, asthenia, neutropenia, anemia, constipation, nausea, diarrhea, dyspnea, upper respiratory tract infections, back pain, pyrexia; thromboembolism, thrombocytopenia, hepatotoxicity, dizziness, confusion, neuropathy, pneumonia, tumor lysis syndrome.

Note: Available only through Pomalyst REMS program.

How supplied: Caps—21, 100

PURINETHOL Teva

℞

Antimetabolite. Mercaptopurine (6-MP) 50mg; scored tabs.

Indications: Maintenance therapy of acute lymphatic leukemia as part of a combination regimen.

Adults and Children: 1.5–2.5mg/kg per day as a single dose. Concomitant allopurinol: reduce dose of mercaptopurine to 1/3–1/4 of the usual dose. TPMT-deficient, renal or hepatic impairment: reduce dose, see literature.

Contraindications: Prior resistance to mercaptopurine.

Warnings/Precautions: Not effective in CNS leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, the lymphomas (including Hodgkin’s disease), or solid tumors. Renal impairment. Monitor liver function tests weekly at start of therapy, then monthly thereafter; discontinue if hepatotoxicity occurs. Preexisting liver disease (monitor more frequently).

Obtain CBCs with differential, hemoglobin, hematocrit, platelets; discontinue if severe bone marrow suppression occurs. ThiopurineS-methyltransferase (TPMT) deficient: increased risk of myelosuppression, consider

genotypic/phenotypic testing. Pregnancy (Cat. D); esp. 1st trimester, nursing mothers: not recommended.

Interactions: Increased risk of bone marrow suppression with allopurinol, aminosalicylate derivatives (eg, olsalazine, mesalazine, sulphasalazine), trimethoprim-sulfamethoxazole.

Antagonizes warfarin. Caution with concomitant hepatotoxic agents.

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

How supplied: Tabs—60

PURIXAN Rare Disease

℞

Antimetabolite. Mercaptopurine (6-MP) 20mg/mL; oral susp; contains fruit extract, aspartame.

Indications: Maintenance therapy of acute lymphoblastic leukemia as part of a combination regimen.

Adults and Children: Shake bottle vigorously for at least 30 secs. Initially 1.5–2.5mg/kg (50–75mg/m2) per day as a single dose. Monitor subsequent doses to maintain desirable ANC level and adjust for excessive hematological toxicity. Thiopurine-S-methyltransferase (TPMT)-deficient: if homozygous, may require up to a 90% dose reduction; if heterozygous, some may require dose reduction based on toxicities. Renal or hepatic impairment: use lower starting doses; monitor for toxicity. See full labeling.

Warnings/Precautions: Myelosuppression; monitor CBCs and adjust dose for severe neutropenia and thrombocytopenia. Consider testing for TPMT gene polymorphism in patients who experience repeated severe bone marrow toxicities. Monitor serum transaminase, alkaline phosphatase, and bilirubin levels at weekly intervals when starting therapy, then monthly thereafter; interrupt treatment if evidence of hepatotoxicity occurs.

Concomitant other hepatotoxic drugs or with pre-existing liver disease; monitor LFTs more frequently. Immunosuppression. Increased risk of lymphoproliferative disorders and other malignancies (eg, skin cancers, sarcomas, uterine cervical cancer). Concomitant multiple immunosuppressants increase risk of Epstein-Barr virus (EBV)-associated lymphoproliferative disorders. Monitor and treat for EBV or cytomegalovirus; discontinue if macrophage activation syndrome occurs,

or is suspected. Renal or hepatic impairment.

Elderly. Embryo-fetal toxicity. 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, rash, urticaria, hyperuricemia, oral lesions, elevated transaminases, hyperbilirubinemia, hyperpigmentation, pancreatitis; hepatotoxicity.

How supplied: Susp—100mL (w. oral syringes)

REVLIMID Celgene

℞

Immunomodulator. Lenalidomide 2.5mg, 5mg, 10mg, 15mg, 20mg, 25mg; caps; contains lactose.

Indications: Multiple myeloma (MM): for combination treatment with dexamethasone; or for maintenance therapy following autologous hematopoietic stem cell transplantation (autoHSCT). Mantle cell lymphoma (MCL) in patients whose disease has relapsed or progressed after 2 prior therapies, one of which included bortezomib.

Adults: Swallow whole with water. MM (combo therapy), MCL: 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. MM (post auto-HSCT): Ensure ANC ≥1000/mcL and/or platelets ≥75,000/mcL. Initially 10mg once daily on Days 1–28 of each 28-day cycle until disease progression or unacceptable toxicity; may increase to 15mg once daily after 3 cycles, if tolerated. Renal impairment: MM (combo therapy), MCL: (CrCl 30–60mL/min): initially 10mg/day; for MM, consider increasing to 15mg after 2 cycles, if tolerant; (CrCl <30mL/min without dialysis): initially 15mg every other day; (CrCl <30mL/min with dialysis): initially 5mg/day; administer after dialysis on dialysis days. MM (auto-HSCT): (CrCl 30–60mL/min): initially 5mg/day; (CrCl <30mL/min without dialysis): initially 2.5mg/day; (CrCl <30mL/min with dialysis): initially 2.5mg/day; administer after dialysis on dialysis days. Adjust dose based on patient tolerance. Auto-HSCT eligible: refer for hematopoietic cell mobilization within 4 cycles;

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER if non-eligible, continue therapy until disease progression or unacceptable toxicity. Dose adjustments for hematologic toxicities: see full labeling.

Children: Not established.

Contraindications: Pregnancy.

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. Patients must not donate blood during and for 1 month after therapy; males must not donate sperm. Monitor for signs/symptoms of thromboembolic events; base thromboprophylaxis on patient’s risks.

Monitor for signs of infection, bleeding, or bruising. 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), thyroid function before and during therapy.

Monitor for second primary malignancies.

Lactose intolerance. Max 28-day supply 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: Diarrhea, fatigue, anemia, constipation, neutropenia, leukopenia, peripheral edema, insomnia, muscle cramp/spasms, abdominal pain, back pain, nausea, asthenia, pyrexia, upper RTI, bronchitis, nasopharyngitis, gastroenteritis, cough, rash, dyspnea, dizziness, decreased appetite, thrombocytopenia, tremor, pruritus; birth defects, thromboembolism, allergic reactions (discontinue if severe; do not resume), hepatotoxicity, tumor flare reaction (monitor; esp. in MCL), impaired stem cell mobilization, thyroid disorders.

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 and Biogen

℞

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 rituximab in combination with chemotherapy, as singleagent maintenance therapy. Non-progressing (including stable disease), low-grade, CD20(+), B-cell NHL as a single agent after first-line CVP chemotherapy. Previously untreated diffuse large B-cell, CD20(+) NHL (DLBCL) in combination with CHOP or other anthracycline-based chemotherapy regimens. CD20(+) chronic lymphocytic leukemia (CLL) in combination with fludarabine and cyclophosphamide. Limitation of use: not recommended for use in patients with severe, active infections.

Adults: Give by IV infusion. Premedicate with an antihistamine and acetaminophen prior to each infusion. First infusion: initially at a rate of 50mg/hr; may increase infusion rate in 50mg/hr increments every 30 mins. Subsequent infusions: initially at a rate of 100mg/hr; may increase infusion rate in 100mg/hr increments every 30 mins. Both: max 400mg/hr if infusion reactions do not occur. Previously untreated follicular NHL and DLBCL patients: if no Grade 3 or 4 infusion related adverse events during Cycle 1, a 90-minute infusion may be given in Cycle 2 with a glucocorticoid-containing chemotherapy regimen (see full labeling).

NHL: 375mg/m2 once weekly for 4 or 8 doses.

Retreatment therapy: 375mg/m2 once weekly for 4 doses. Previously untreated, follicular, CD20(+), B-cell NHL: 375mg/m2 on day 1 of each cycle of CVP chemotherapy for up to 8 doses. In patients with complete or partial response, initiate Rituxan maintenance 8 weeks following completion of Rituxan in combination with chemotherapy.

Administer Rituxan as a single-agent every 8 weeks for 12 doses. Low-grade, CD20(+), B-cell NHL after CVP chemotherapy: 375mg/m2 once weekly for 4 doses every 6 months for up to 16 doses. Diffuse large B-cell NHL: 375mg/m2 on day 1 of each cycle for up to 8 infusions. CLL: 375mg/m2 the day prior to FC chemotherapy, then 500mg/m2 on day 1 of cycles 2–6 (every 28 days). Give PCP and antiherpetic viral prophylaxis during and up to 12 months after CLL therapy. As a component of Zevalin regimen: see full labeling.

Children: Not established.

Warnings/Precautions: Discontinue if severe infusion or mucocutaneous reactions occur (eg, urticaria, hypotension, angioedema, hypoxia, pulmonary infiltrates, acute respiratory distress syndrome, MI, ventricular fibrillation, cardiogenic shock, paraneoplastic pemphigus, Stevens-

Johnson syndrome, lichenoid or vesiculobullous dermatitis, toxic epidermal necrolysis). Increased risk of HBV reactivation. Test/treat HBV infection prior to initiating therapy. Monitor for signs of hepatitis or HBV reactivation during and for several months after therapy; discontinue if HBV reactivation occurs. Tumor lysis syndrome (esp. with high tumor burden); monitor for renal toxicity, fluid balance, electrolyte abnormalities (correct if occurs); discontinue if SCr rises or oliguria occurs. Monitor for new-onset neurologic manifestations; discontinue if progressive multifocal leukoencephalopathy (PML) develops.

Discontinue and treat if serious infections (eg, bacterial, fungal, viral) occur. Pre-existing cardiovascular disease; monitor during and after treatment. Monitor CBCs, platelet counts during treatment, then periodically. Elderly. Pregnancy (Cat.C). Nursing mothers: not recommended.

Interactions: Live virus vaccines: not recommended. Renal toxicity with concomitant 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

RITUXAN HYCELA

℞

Genentech and Biogen

CD20-directed cytolytic monoclonal antibody + endoglycosidase. Rituximab, hyaluronidase human 1400mg/23400 Units, 1600mg/26800 Units; soln for SC inj; preservative-free.

Indications: Relapsed or refractory, follicular lymphoma (FL) as a single agent. Previously untreated FL in combination with first line chemotherapy and, in patients achieving a complete or partial response to rituximab in combination with chemotherapy, as singleagent maintenance therapy. Non-progressing (including stable disease) FL as a single agent after first-line CVP chemotherapy. Previously untreated diffuse large B-cell lymphoma (DLBCL) in combination with CHOP or other anthracycline-based chemotherapy regimens. Chronic lymphocytic leukemia (CLL) in combination with fludarabine and cyclophosphamide.

Adults: Give by SC inj into abdomen.

Premedicate with an antihistamine and acetaminophen prior to each dose; may consider

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER glucocorticoids. Monitor for at least 15mins after each dose. Relapsed or refractory FL: 1400mg/23400 Units over 5mins once weekly for 3 or 7 weeks following a full dose of IV rituximab at Week 1. May give retreatment once weekly for 3 weeks following a full dose of IV rituximab at Week 1. Previously untreated FL: 1400mg/23400 Units over 5mins on Day 1 of Cycles 2–8 of chemotherapy (every 21 days) for up to 7 cycles following a full dose of IV rituximab on Day 1 of Cycle 1; if complete or partial response, initiate Rituxan Hycela maintenance 8 weeks following completion of Rituxan Hycela in combination with chemotherapy. Administer Rituxan Hycela as a single-agent every 8 weeks for 12 doses. Nonprogressing FL after first-line CVP chemotherapy: 1400mg/23400 Units over 5mins once weekly for 3 weeks at 6-month intervals following completion of 6–8 cycles of CVP and a full dose of IV rituximab at Week 1; max 16 doses. DLBCL: 1400mg/23400 Units over 5mins on Day 1 of Cycles 2–8 of CHOP chemotherapy for up to 7 cycles following a full dose of IV rituximab on Day 1 of Cycle 1. CLL: 1600mg/26800 Units over 7mins on Day 1 of Cycles 2–6 (every 28 days) for 5 cycles following a full dose of IV rituximab on Day 1 of Cycle 1. Give PCP and antiherpetic viral prophylaxis during and up to 12 months after CLL therapy.

Children: Not established.

Warnings/Precautions: Discontinue if severe injection or mucocutaneous reactions occur (eg, urticaria, hypotension, angioedema, hypoxia, pulmonary infiltrates, acute respiratory failure, 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 renal function, 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 cardiac or pulmonary conditions, prior cardiopulmonary adverse events, high malignant cell count; monitor during and after treatment. Elderly.

Embryo-fetal toxicity. Females of reproductive potential should use effective contraception during and for at least 12 months after last dose. Pregnancy (monitor newborns/infants for

infection). Nursing mothers: not recommended (during and for at least 6 months after last dose).

Interactions: Live virus vaccines: not recommended. Renal toxicity with concomitant cisplatin.

Adverse reactions: Infections, neutropenia, nausea, constipation, cough, fatigue, alopecia, anemia, thrombocytopenia, pyrexia, vomiting, injection site erythema, mucocutaneous reactions (may be fatal), hypersensitivity, PML, tumor lysis syndrome, renal toxicity, bowel obstruction/perforation (when concomitant chemotherapy), HBV reactivation, arrhythmias (discontinue if serious).

How supplied: Single-dose vial—1

RYDAPT Novartis

℞

Kinase inhibitor. Midostaurin 25mg; caps.

Indications: Treatment of adults with newly diagnosed FLT3 mutation-positive acute myeloid leukemia (AML) as detected by an FDA-approved test, in combination with standard cytarabine and daunorubicin induction + cytarabine consolidation. Treatment of adults with aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated hematological neoplasm (SM-AHN), or mast cell leukemia (MCL). Limitations of use: not for use as singleagent induction therapy for AML. Adults: Swallow whole. Take with food approx.

12hrs apart. Give prophylactic antiemetics prior to initiation. AML: 50mg twice daily on Days 8–21 of each induction cycle with cytarabine and daunorubicin, and on Days 8–21 of each consolidation cycle with high-dose cytarabine.

ASM, SM-AHN, MCL: 100mg twice daily until disease progression or unacceptable toxicity.

Dose modifications: see full labeling.

Children: Not established.

Warnings/Precautions: For ASM, SM-AHN, MCL: Monitor for toxicity at least weekly for first 4 weeks, every other week for next 8 weeks, and monthly thereafter. Discontinue if low ANC, platelet count, or hemoglobin persists >21 days.

Interrupt dose if Grade 3/4 nausea and/or vomiting despite antiemetics or other Grade 3/4 non-hematological toxicities; resume at reduced dose and increase if tolerated (see full labeling). Both: monitor for signs/symptoms of interstitial lung disease or pneumonitis; discontinue if pulmonary toxicity develops.

Embryo-fetal toxicity. Pregnancy; exclude status within 7 days prior to initiation. Females of reproductive potential and males should use effective contraception during and for at least 4 months after last dose. Nursing mothers: not

recommended (during and for at least 4 months after last dose).

Interactions: Concomitant drugs that prolong QT interval; monitor EKG periodically.

Potentiated by strong CYP3A inhibitors (eg, boceprevir, clarithromycin, cobicistat, conivaptan, danoprevir/ritonavir, diltiazem, elvitegravir/ritonavir, grapefruit juice, idelalisib, indinavir/ritonavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, paritaprevir/ritonavir and [ombitasvir and/or dasabuvir], posaconazole, ritonavir, saquinavir/ritonavir, tipranavir/ritonavir, troleandomycin, voriconazole); consider alternatives; if co-administration needed, monitor for increased adverse reactions.

Avoid concomitant strong CYP3A inducers (eg, carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, St. John’s wort).

Adverse reactions: AML: Febrile neutropenia, nausea, mucositis, vomiting, headache, petechiae, musculoskeletal pain, epistaxis, device-related infection, hyperglycemia, upper respiratory tract infection. ASM, SM-AHN, MCL: also diarrhea, edema, abdominal pain, fatigue, constipation, pyrexia, dyspnea; pulmonary toxicity.

How supplied: Caps—56, 112

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 in adults. Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy in adults.

Adults: Swallow whole. 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. Continue until disease progression or unacceptable toxicity. Avoid concomitant strong CYP3A4 inhibitors; if unavoidable, consider reducing Sprycel dose (see full labeling).

Avoid concomitant strong CYP3A4 inducers; if unavoidable, consider increasing Sprycel dose (monitor). Dose adjustments for toxicity: see full labeling.

Children: Swallow whole. Chronic phase CML: <10kg: not recommended. 10–<20kg:

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER initially 40mg once daily; may increase to max 50mg/day. 20–<30kg: initially 60mg once daily; may increase to max 70mg/day. 30–<45kg: initially 70mg once daily; may increase to max 90mg/day. ≥45kg: initially 100mg once daily; may increase to max 120mg/day. Recalculate dose every 3 months based on changes in body weight. Continue until disease progression or unacceptable toxicity. Avoid concomitant strong CYP3A4 inhibitors; if unavoidable, consider reducing Sprycel dose (see full labeling).

Avoid concomitant strong CYP3A4 inducers; if unavoidable, consider increasing Sprycel dose (monitor). Dose adjustments for toxicity: see full labeling.

Warnings/Precautions: Monitor for signs/symptoms of cardiac dysfunction; treat appropriately if occur. Congenital long QT syndrome. Proarrhythmic conditions. Cumulative high-dose anthracycline therapy. Hypokalemia, hypomagnesemia; correct electrolyte imbalances before starting and during therapy. Monitor for pleural effusions. Increased risk of pulmonary arterial hypertension (PAH); evaluate for signs/symptoms of underlying cardiopulmonary disease before and during treatment; permanently discontinue if occurs. Obtain CBCs every 2 weeks for 12 weeks, then every 3 months thereafter (chronic phase CML) or weekly for the first 2 months, then monthly thereafter (advanced phase CML or Ph+ ALL). Permanently discontinue if severe skin reactions (eg, StevensJohnson syndrome) occur. Increased risk of tumor lysis syndrome in advanced stage disease and/or high tumor burden. Maintain adequate hydration. Correct uric acid levels before therapy and monitor electrolytes. Hepatic impairment.

Elderly. Embryo-fetal toxicity. Pregnancy; avoid. Females of reproductive potential should use effective contraception during and for 30 days after final dose. Nursing mothers: not recommended (during and for 2 weeks after final dose).

Interactions: May be potentiated by strong CYP3A4 inhibitors (eg, ketoconazole), grapefruit juice; see Adult. May be antagonized by strong CYP3A4 inducers (eg, rifampin), St. John’s wort; see Adult. Separate dosing of antacids by at least 2hrs; H2 blockers, proton pump inhibitors: not recommended. Caution with concomitant anticoagulants or drugs that inhibit platelet function. Caution with antiarrhythmics or other drugs that may lead to QT prolongation.

Adverse reactions: Myelosuppression (eg, severe thrombocytopenia, neutropenia, anemia), fluid retention, diarrhea, headache, dyspnea, musculoskeletal pain, rash, fatigue, nausea, severe hemorrhage (eg, CNS, GI); QT prolongation, cardiac events, PAH, severe skin reactions. Also in children: effects on bone growth and development (monitor).

How supplied: Tabs 20mg, 50mg, 70mg—60; 80mg, 100mg, 140mg—30

SYNRIBO Teva

℞

Protein synthesis inhibitor. Omacetaxine mepesuccinate 3.5mg/vial; lyophilized pwd for SC inj after reconstitution; contains mannitol; preservative-free.

Indications: Treatment of 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 inj twice daily (approx. 12hrs apart) 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 inj 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) or hemorrhage (cerebral, GI). Monitor CBCs with platelets weekly during induction and initial maintenance cycles, then every 2wks during later cycles. Diabetes: monitor glucose levels frequently; if poorly controlled, avoid until glycemic control is established. Elderly.

Embryo-fetal toxicity. Pregnancy (Cat. D); avoid.

Nursing mothers: not recommended.

Interactions: Avoid concomitant anticoagulants, aspirin, NSAIDs if platelets <50,000/microliters.

Adverse reactions: Thrombocytopenia, anemia, neutropenia, diarrhea, nausea, fatigue, asthenia, injection site reaction, pyrexia, infection, lymphopenia; bleeding, hyperglycemia.

How supplied: Single-use vial—1

TARGRETIN Valeant

℞

Retinoid. Bexarotene 75mg; caps.

Indications: Cutaneous manifestations of cutaneous T-cell lymphoma in patients who are refractory to at least one prior systemic therapy.

Adults: Take with food. Initially 300mg/m2 once daily; may increase after 8 weeks to 400mg/m2 once daily if no tumor response and if well tolerated; monitor carefully. If toxicity occurs, reduce to 200mg/m2 then 100mg/m2 once daily, or suspend therapy.

Children: Not recommended.

Contraindications: Pregnancy (Cat.X).

Warnings/Precautions: Be fully familiar with this drug’s toxicity before use. Pancreatitis or risk of pancreatitis (eg, history of pancreatitis, uncontrolled hyperlipidemia, excess alcohol consumption, uncontrolled diabetes, biliary tract disease, drugs that can cause pancreatitis).

Counsel patients monthly about need for contraception. Women of childbearing potential: obtain reliable negative pregnancy test within 1 week of start; repeat monthly. Start therapy on 2nd or 3rd day of normal menstrual period. Use two effective forms of contraception 1 month

prior to, during, and for 1 month after therapy.

Max 1 month/℞. Men with partners who are or may become pregnant: use condoms during and for at least 1 month after therapy. Monitor lipids before treatment, weekly until stable, then every 8 weeks; try to keep triglycerides <400mg/dL; treat hyperlipidemia, or reduce or suspend bexarotene if needed. Hepatic or renal insufficiency. Monitor liver function at baseline, 1, 2, and 4 weeks after start, then (if stable) at least every 8 weeks during therapy; consider suspending or discontinuing treatment if SGOT/AST, SGPT/ALT, or bilirubin >3xULN occurs. Monitor WBC with differential and thyroid function at baseline and during treatment; treat hypothyroidism if needed. Avoid sun and UV light.

Nursing mothers: not recommended.

Interactions: Concomitant gemfibrozil: not recommended. Levels may be increased

by CYP3A4 inhibitors (eg, ketoconazole, itraconazole, erythromycin, grapefruit juice).

Levels may be reduced by CYP3A4 inducers (eg, rifampin, phenobarbital, phenytoin). May potentiate antihyperglycemics (eg, insulin, sulfonylureas, thiazolidinediones); monitor. May potentiate or be potentiated by protein-bound drugs. May antagonize tamoxifen, hormonal contraceptives, other CYP3A4 substrates. Limit Vit. A supplements to avoid toxicity. May increase CA125 assay values.

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

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HEMATOLOGIC CANCER after therapy. Hepatic or renal insufficiency.

Discontinue temporarily if severe irritation occurs.

Avoid sun, UV light, and mucosal membranes.

Nursing mothers: not recommended.

Interactions: Avoid concomitant products that contain DEET. May be potentiated by CYP3A4 inhibitors (eg, ketoconazole, itraconazole, erythromycin, grapefruit juice). Caution with gemfibrozil. Limit Vit. A supplements to avoid toxicity.

Adverse reactions: Application site reactions (eg, rash, pruritus, skin disorders, pain, contact dermatitis).

How supplied: Gel—60g

TASIGNA Novartis

℞

Kinase inhibitor. Nilotinib (as HCl monohydrate) 150mg, 200mg; caps; contains lactose.

Indications: Newly diagnosed adults with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase.

Chronic and accelerated phase Ph+ CML in adults resistant or intolerant to imatinib.

Adults: Take on an empty stomach. Swallow whole with water; if unable, may disperse capsule contents in 1 tsp of applesauce, then take immediately (within 15 mins). Newly diagnosed Ph+ CML: 300mg every 12hrs. Hepatic impairment (mild, moderate, severe): initially 200mg twice daily, followed by dose increase to 300mg twice daily if tolerated. Resistant or intolerant Ph+ CML: 400mg every 12hrs. Hepatic impairment (mild or moderate): initially 300mg twice daily, followed by dose increase to 400mg twice daily if tolerated; severe: initially 200mg twice daily, followed by sequential dose increase to 300mg twice daily, and then 400mg twice daily if tolerated. May give concomitant hematopoietic growth factors, hydroxyurea, or anagrelide if clinically indicated. See full labeling for dose adjustments in QT prolongation, hematological and non-hematological toxicities, concomitant strong CYP3A4 inhibitors and inducers.

Children: Not established.

Contraindications: Hypokalemia.

Hypomagnesemia. Long QT syndrome.

Warnings/Precautions: Prolongs QT interval, sudden deaths have been reported; correct electrolyte abnormalities before starting; monitor. Monitor ECG at baseline, after 7 days, then periodically and after dose changes.

Cardiovascular status should be evaluated; monitor cardiovascular risk factors and actively manage during therapy. Hereditary galactose intolerance, severe lactase deficiency, glucosegalactose malabsorption: not recommended.

Hepatic impairment. History of pancreatitis.

Monitor for myelosuppression; withhold or reduce dose if occurs; perform CBCs every 2 weeks for 1st 2 months then once monthly. Monitor serum lipase, liver function monthly. Monitor lipids and glucose periodically during first year, then yearly.

Total gastrectomy (monitor frequently); consider dose increase or alternative therapy. Tumor lysis syndrome possible; maintain adequate hydration, correct uric acid levels prior to initiating therapy.

Pregnancy (Cat.D) (use adequate contraception), nursing mothers: not recommended.

Interactions: Avoid concomitant food (for at least 2hrs before and 1hr after dose), antiarrhythmics (eg, amiodarone, disopyramide, procainamide, quinidine, sotalol), or other drugs that may prolong QT interval (eg, chloroquine, haloperidol, methadone, moxifloxacin, pimozide). Avoid strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole), grapefruit; if necessary, interrupt therapy or consider dose reduction of nilotinib; if unavoidable, monitor closely for QT prolongation. Avoid strong CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital), St. John’s wort. May affect, or be affected by, other drugs metabolized by CYP3A4, 2B6, 2C8, 2C9, 2D6, UGT1A1, P-glycoprotein. Concomitant proton pump inhibitors: not recommended. Administer H2blockers 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

TREANDA Teva Alkylating agent. Bendamustine HCl 25mg, 100mg; per vial; lyophilized pwd for IV infusion after reconstitution; preservative-free.

Indications: Chronic lymphocytic leukemia (CLL). Indolent B-cell non-Hodgkin’s lymphoma

℞

(NHL) that has progressed during or within 6 months of treatment with rituximab or a rituximab–containing regimen.

Adults: CLL: Give by IV infusion over 30mins.

100mg/m2 on Days 1 and 2 of a 28-day cycle, up to 6 cycles. Hematologic toxicity (≥Grade 3): reduce dose to 50mg/m2 on Days 1 and 2 of each cycle; if toxicity recurs, reduce dose to 25mg/m2 on Days 1 and 2. Nonhematologic toxicity (clinically significant ≥Grade 3): reduce dose to 50mg/m2 on Days 1 and 2 of each cycle. Subsequent cycles: may consider dose re-escalation. NHL: Give by IV infusion over 60mins. 120mg/m2 on Days 1 and 2 of a 21-day cycle, up to 8 cycles. Hematologic toxicity (Grade 4) or non-hematologic toxicity (≥Grade 3): reduce dose to 90mg/m2 on Days 1 and 2 of each cycle; if toxicity recurs, reduce dose to 60mg/m2 on Days 1 and 2. Delay treatment for Grade 4 hematologic toxicity or clinically significant ≥Grade 2 non-hematologic toxicity.

Children: Not established.

Warnings/Precautions: Myelosuppression; monitor CBCs including leukocytes, platelets, hemoglobin, neutrophils frequently; restart treatment based on ANC and platelet count recovery. Monitor for signs of infection or reactivation of infections (eg, hepatitis B, CMV, tuberculosis, herpes zoster); prophylaxis and treat prior to therapy if occur. Monitor for infusion or skin reactions, tumor lysis syndrome.

Monitor LFTs prior to and during therapy. Renal impairment (mild or moderate): caution; (CrCl <40mL/min): not recommended. Hepatic impairment (mild): caution; (moderate or severe): not recommended. Avoid extravasation. Embryofetal toxicity. Pregnancy (Cat.D); avoid during and for 3 months after therapy cessation. Nursing mothers: not recommended.

Interactions: May be potentiated CYP1A2 inhibitors (eg, fluvoxamine, ciprofloxacin) or antagonized by CYP1A2 inducers (eg, omeprazole, smoking); if needed, consider alternatives.

Adverse reactions: Lymphopenia, anemia, leukopenia, thrombocytopenia, neutropenia, pyrexia, nausea, vomiting, fatigue, diarrhea, constipation, anorexia, cough, headache, weight loss, dyspnea, stomatitis, increased bilirubin, increased AST/ALT; infection, infusion reactions (discontinue if severe), tumor lysis syndrome, skin reactions (if severe or progressive, withhold dose or discontinue), other malignancies (eg, myelodysplastic syndrome, acute myeloid leukemia, bronchial carcinoma).

How supplied: Single-use vial—1

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

HEMATOLOGIC CANCER 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)

VALCHLOR Actelion

℞

Alkylating agent. Mechlorethamine 0.016%; topical gel; contains propylene glycol, isopropyl alcohol.

Indications: Treatment of Stage IA and IB mycosis fungoides-type cutaneous T-cell lymphoma in patients who have received prior skin-directed therapy.

Adults: Apply a thin film once daily to affected areas of the skin. Apply to completely dry skin ≥4 hours before or 30 minutes after showering or washing. Allow treated areas to completely dry for 5–10 minutes after applying. Wash hands thoroughly after application. Discontinue if any grade of skin ulceration, blistering, or moderatelyto-severe, or severe dermatitis occur; restart at reduced frequency of once every 3 days upon improvement; if reintroduction is tolerated for at least 1 week, can increase to every other day for 1 week and then once daily if tolerated.

Children: Not established.

Warnings/Precautions: Mucosal (oral, nasal) or eye exposure; blindness and severe irreversible anterior eye injury may occur; immediately irrigate for ≥15 minutes with copious amounts of water. Secondary exposure; avoid direct skin contact with patient. Risk of dermatitis (eg, face, genitalia, anus, and intertriginous skin); monitor for redness, swelling, inflammation, itchiness, blisters, ulceration, and secondary skin infections.

Monitor for nonmelanoma skin cancer during and after treatment. Flammable (avoid fire and flame until gel has dried). Pregnancy (Cat.D); may cause fetal harm. Nursing mothers: not recommended.

Adverse reactions: Dermatitis, pruritus, bacterial skin infection, skin ulceration or blistering, hyperpigmentation.

How supplied: Gel—60g

VELCADE Millennium

℞

Proteasome inhibitor. Bortezomib 3.5mg/vial; lyophilized pwd for IV or SC inj after reconstitution; contains mannitol.

Indications: Multiple myeloma. Mantle cell lymphoma.

Adults: Give as a 3–5 second IV bolus inj or as SC inj into thigh or abdomen (rotate sites). Previously

untreated multiple myeloma: Treat for nine 6-week cycles in combination with oral melphalan and oral prednisone. Cycles 1–4: 1.3mg/m2 twice weekly (Days 1, 4, 8, 11, 22, 25, 29, 32); Cycles 5–9: 1.3mg/m2 once weekly (Days 1, 8, 22, 29).

Previously untreated mantle cell lymphoma: Treat for six 3-week cycles in combination with IV rituximab, cyclophosphamide, doxorubicin, and oral prednisone. 1.3mg/m2 twice weekly for 2 weeks (Days 1, 4, 8, 11) then 10 day rest period (Days 12–21); if response first documented at Cycle 6, two more cycles are recommended.

Relapsed multiple myeloma or mantle cell lymphoma: Standard schedule: 1.3mg/m2 twice weekly for 2 weeks (Days 1, 4, 8, 11) then 10 day rest period (Days 12–21); Extended therapy (if using >8 cycles): may use standard schedule, or maintenance schedule: 1.3mg/m2 once weekly for 4 weeks (Days 1, 8, 15, 22) then 13-day rest period (Days 23–35). Multiple myeloma patients who have previously responded to bortezomib (alone or in combination) and have relapsed at least 6 months after completing prior bortezomib therapy: may retreat starting at last tolerated dose, given twice weekly every 3 weeks (Days 1, 4, 8, 11); max 8 cycles. Allow at least 72hrs between consecutive doses. May be given as a single agent or in combination with dexamethasone.

Dose modifications: see full labeling. SC inj may be considered for patients with pre-existing or at high-risk of peripheral neuropathy. Moderate-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: May be antagonized by concomitant strong CYP3A4 inducers (eg, rifampin, St. John’s Wort): not recommended.

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

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HEMATOLOGIC CANCER if severe), thrombocytopenia, neutropenia, peripheral neuropathy, fatigue, neuralgia, anemia, leukopenia, lymphopenia, rash, pyrexia, anorexia; hypotension, CHF, decreased LVEF, ARDS, diffuse infiltrative lung disease, hepatotoxicity; rare: posterior reversible encephalopathy syndrome (discontinue if occurs).

How supplied: Single-dose vial—1

VENCLEXTA AbbVie and Genentech ℞ BCL-2 inhibitor. Venetoclax 10mg, 50mg, 100mg; tabs.

Indications: Treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion, as detected by an FDA-approved test, who have received at least one prior therapy.

Adults: Assess for level of tumor lysis syndrome risk; provide prophylactic hydration and antihyperuricemics prior to 1st dose. Swallow whole.

Take with food and water. Initially 20mg once daily for Week 1, then 50mg once daily for Week 2, then 100mg once daily for Week 3, then 200mg once daily for Week 4, then 400mg once daily for Week 5 and beyond until disease progression or unacceptable toxicity. Dose modifications for toxicities: see full labeling.

Children: Not established.

Contraindications: Concomitant strong CYP3A inhibitors at initiation or during dose ramp-up phase.

Warnings/Precautions: Risk of tumor lysis syndrome (esp. with high tumor burden, comorbidities, CrCl <80mL/min); perform tumor burden assessment, radiographic evaluation, blood chemistry; correct preexisting abnormalities prior to initiation. Risk of neutropenia; monitor CBCs during therapy; interrupt or reduce dose if severe. Severe renal impairment or on dialysis. Moderate or severe hepatic impairment: monitor closely.

Embryo-fetal toxicity. Females of reproductive potential: should undergo pregnancy testing prior to initiation. Pregnancy; avoid. Use effective contraception during and for ≥1 month after final dose. Nursing mothers: not recommended.

Interactions: See Contraindications.

Concomitant strong CYP3A inhibitors after ramp-up phase (eg, ketoconazole, conivaptan, clarithromycin, indinavir, itraconazole, lopinavir, ritonavir, telaprevir, posaconazole, voriconazole); avoid use or reduce venetoclax steady daily dose by ≥75%. Avoid concomitant moderate CYP3A inhibitors (eg, erythromycin, ciprofloxacin, diltiazem, dronedarone, fluconazole, verapamil) or P-gp inhibitors (eg, amiodarone, azithromycin, captopril, carvedilol, cyclosporine, felodipine,

quercetin, quinidine, ranolazine, rifampin, ticagrelor); consider alternatives; if inhibitor necessary, reduce venetoclax dose by ≥50% and monitor closely. Resume at prior venetoclax dose 2–3 days after discontinuing the inhibitor.

Avoid concomitant strong CYP3A inducers (eg, carbamazepine, phenytoin, rifampin, St. John’s Wort) or moderate CYP3A inducers (eg, bosentan, efavirenz, etravirine, modafinil, nafcillin); consider alternatives. Avoid live attenuated vaccines until B-cell recovery. Avoid grapefruit, Seville oranges, and starfruit during treatment. Monitor INR closely with concomitant warfarin. Avoid P-gp substrates with narrow therapeutic index (eg, digoxin, everolimus, sirolimus); if necessary, take ≥6hrs before venetoclax.

Adverse reactions: Neutropenia, diarrhea, nausea, anemia, upper respiratory tract infection, thrombocytopenia, fatigue.

How supplied: Starting Packs—1; Wallets 10mg—14; 50mg—7; Tabs 100mg—120

VIDAZA Celgene

℞

Cytidine analogue. Azacitidine 100mg/vial; lyophilized pwd for SC inj after reconstitution or IV inj after reconstitution and dilution; contains mannitol; preservative-free.

Indications: Myelodysplastic syndromes (refractory anemias, chronic myelomonocytic leukemia).

Adults: Premedicate for nausea & vomiting.

Rotate SC inj sites. Initially 75mg/m2 SC (doses >4mL divide equally into 2 syringes and inject into 2 separate sites, must administer within 1hr of reconstitution) or IV (infuse over 10–40mins, must complete within 1hr of reconstitution) daily for 7 days; repeat cycle every 4 weeks.

May increase to 100mg/m2 after 2 cycles if no response and no toxicity. Treat for at least 4–6 cycles. Adjust subsequent doses based on nadir counts, hematologic response, and toxicities (eg, neutropenia, thrombocytopenia, decreased serum bicarbonate, BUN or SCr elevation); see full labeling.

Children: Not established.

Contraindications: Advanced malignant hepatic tumors.

Warnings/Precautions: Myelosuppression.

Monitor CBCs frequently for response and/or toxicity, at a minimum, prior to each dosing cycle.

Renal or hepatic impairment. High tumor burden.

Monitor serum bicarbonate, liver chemistries, and serum creatinine prior to initiation and with each cycle. Monitor for tumor lysis syndrome and treat as appropriate. Elderly. Embryo-fetal toxicity.

Females and males of reproductive potential

should use effective contraception. Pregnancy: avoid; verify status prior to initiation. Nursing mothers: not recommended.

Adverse reactions: Nausea, anemia, thrombocytopenia, vomiting, pyrexia, leukopenia, diarrhea, inj site erythema, constipation, neutropenia, ecchymosis, petechiae, rigors, weakness, hypokalemia; renal failure/tubular acidosis, hepatic coma.

How supplied: Single-use vial—1

VYXEOS Jazz

℞

Anthracycline + antimetabolite. Daunorubicin, cytarabine 44mg/100mg (encapsulated in liposomes); per vial; lyophilized cake for IV infusion after reconstitution; contains copper; preservative-free.

Indications: Treatment of newly-diagnosed therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC).

Adults: Calculate the prior cumulative anthracycline exposure before initiating each cycle. Give prophylactic antiemetics.

Administer by IV infusion over 90mins. First induction: daunorubicin 44mg/m2 and cytarabine 100mg/m2 on Days 1, 3, and 5.

Second induction (may give after 2–5 weeks if remission not achieved and no unacceptable toxicity): daunorubicin 44mg/m2 and cytarabine 100mg/m2 on Days 1 and 3. Consolidation (give 5–8 weeks after last induction): daunorubicin 29mg/m2 and cytarabine 65mg/m2 on Days 1 and 3. May give second consolidation 5–8 weeks after if no disease progression or unacceptable toxicity.

Do not initiate consolidation until ANC recovers to >0.5Gi/L and platelet count >50Gi/L in the absence of unacceptable toxicity.

Children: Not established.

Warnings/Precautions: Do not interchange with other daunorubicin and/or cytarabinecontaining products. Prior anthracycline therapy, pre-existing cardiac disease, or radiotherapy to mediastinum: increased risk of cardiotoxicity.

Assess CBCs, cardiac, liver, and renal function prior to initiation. Discontinue if impaired cardiac function unless benefit outweighs risk.

If LVEF below normal or max lifetime cumulative anthracycline exposure limit reached: not recommended. Monitor for hypersensitivity reactions; interrupt and reduce infusion rate if mild or moderate symptoms; permanently discontinue if severe/life-threatening reactions occur. Wilson’s disease: use only if benefit outweighs risk. Monitor copper levels and serial neuropsychological exam; discontinue

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HEMATOLOGIC CANCER if signs/symptoms of acute copper toxicity develops. Avoid extravasation. Hepatic or severe renal impairment or ESRD: not studied. Embryofetal toxicity. Females of reproductive potential and males (with female partners) should use effective contraception during and for ≥6 months after last dose. Pregnancy; exclude status prior to initiation. Nursing mothers: not recommended (during and for ≥2 weeks after last dose).

Interactions: Increased toxicity with concomitant cardiotoxic or hepatotoxic agents; monitor more frequently.

Adverse reactions: Hemorrhagic events, febrile neutropenia, rash, edema, nausea, mucositis, diarrhea, constipation, musculoskeletal pain, fatigue, abdominal pain, dyspnea, headache, cough, decreased appetite, arrhythmia, pneumonia, bacteremia, chills, sleep disorders, vomiting; cardiotoxicity, copper overload, tissue necrosis.

How supplied: Single-dose vials—2, 5

XATMEP Silvergate

℞

Folate analogue inhibitor. Methotrexate 2.5mg/mL; oral soln.

Indications: Treatment of pediatrics with acute lymphoblastic leukemia (ALL) as part of a multiphase, combination chemotherapy maintenance regimen.

Adults: Not applicable.

Children: For oral use only; use other methotrexate formulation if dosing via other routes required. Use accurate measuring device.

Initially 20mg/m2 once weekly; adjust subsequent dosing based on ANC and platelet count.

Contraindications: Pregnancy in patients with non-malignant diseases.

Warnings/Precautions: Be fully familiar with this drug’s toxicity before use. Discontinue if secondary malignant lymphomas occur. Obtain baseline and monitor CBCs for bone marrow suppression, and hepatic, renal and pulmonary function; adjust dose, interrupt, or discontinue if needed. During therapy, monitor hematology at least monthly, renal and hepatic function every 1–2 months, more often during dose changes or when predisposed to toxicity (eg, dehydration).

Increased risk of serious infections (eg, bacterial, fungal, viral) including opportunistic infections; monitor and treat promptly. Peptic ulcer disease.

Ulcerative colitis. Avoid in chronic liver disease.

Increased risk of hepatotoxicity with alcoholism, obesity, diabetes, hyperlipidemia, previous significant exposure to liver toxins, history of liver disease, family history of liver disease, persistent abnormal liver tests, treatment duration, advanced age. Discontinue if anaphylaxis, other serious hypersensitivity or severe dermatologic reactions occur. Evacuate significant thirdspace accumulations prior to administration.

Embryo-fetal toxicity. Exclude pregnancy in females of reproductive potential; use effective contraception during therapy and for 6 months after final dose and for at least 3 months

after final dose for men. Nursing mothers: not recommended.

Interactions: Avoid live virus vaccines. Severe and fatal GI toxicity with concomitant NSAIDs. May be potentiated by penicillins (monitor) or probenecid (consider alternative). May potentiate theophylline. Increased bone marrow suppression with trimethoprim/sulfamethoxazole; monitor.

Increased risk of soft tissue necrosis and osteonecrosis with radiation therapy. Caution with other hepatotoxic drugs (eg, azathioprine, retinoids, sulfasalazine).

Adverse reactions: Ulcerative stomatitis, leukopenia, nausea, abdominal distress, elevated liver function tests, malaise, fatigue, chills, fever, dizziness, decreased resistance to infection; bone marrow suppression, infections, renal toxicity, GI toxicity, hepatotoxicity, pulmonary toxicity, hypersensitivity, dermatologic reactions, secondary malignancies, infertility.

How supplied: Oral soln—120mL ℞

itraconazole, voriconazole, clarithromycin, saquinavir, ritonavir, indinavir, nelfinavir); consider alternatives. Avoid concomitant strong CYP3A4 inducers (eg, phenytoin, carbamazepine, rifampin); consider alternatives, or increase dose (see Adult). Avoid concomitant CYP1A2 (eg, tizanidine) and P-gp (eg, digoxin) substrates with narrow therapeutic indices; if unavoidable, consider dose reduction of substrates and monitor. Increased transaminase and bilirubin with concomitant ipilimumab.

Concomitant or sequential administration with radiation treatment; monitor closely.

Adverse reactions: Arthralgia, rash, alopecia, fatigue, photosensitivity, nausea, pruritus, skin papilloma; severe hypersensitivity or dermatologic reactions (permanently discontinue if occur), QT prolongation, hepatotoxicity, uveitis, blurry vision, photophobia, other malignancies, radiation sensitization and recall, renal failure, Dupuytren’s contracture (may be severe), plantar fascial fibromatosis.

How supplied: Tabs—112, 120

Kinase inhibitor. Vemurafenib 240mg; tabs.

Indications: Erdheim-Chester Disease (ECD) with BRAF V600 mutation.

Adults: Swallow whole. ≥18yrs: 960mg every 12hrs; continue until disease progression or unacceptable toxicity. Concomitant strong CYP3A4 inducer: avoid; if unavoidable, increase dose by 240mg as tolerated (see full labeling).

Dose modifications for adverse reactions: see full labeling.

Children: <18yrs: not established.

Warnings/Precautions: 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. Measure SCr before initiating and periodically during treatment.

Monitor for ophthalmologic reactions routinely.

Avoid sun exposure. Embryo-fetal toxicity.

Females of reproductive potential should use effective contraception during therapy and for at least 2 weeks after final dose. Pregnancy.

Nursing mothers: not recommended (during and for 2 weeks after final dose).

Interactions: Avoid concomitant strong CYP3A4 inhibitors (eg, ketoconazole,

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

ZELBORAF Genentech

ZEVALIN Spectrum

℞

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER weekly until levels recover. Avoid extravasation.

Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended.

Interactions: Caution with anticoagulants, platelet aggregation inhibitors, or live viral vaccines. Separate growth factor treatment by 2 weeks before and after Zevalin therapy.

Adverse reactions: Neutropenia, leukopenia, thrombocytopenia, anemia, infections, asthenia, musculoskeletal symptoms, GI upset, abdominal pain, fatigue, nasopharyngitis, cough, dizziness, hemorrhage, altered biodistribution; infusion reactions, severe cutaneous/mucocutaneous reactions: both may be fatal, discontinue if occurs; leukemia and myelodysplastic syndrome.

Note: Indium-11 chloride sterile solution must be ordered separately at the time the In-11 Zevalin kit is ordered. Yttrium-90 chloride sterile solution will be shipped directly upon placement of order for Y-90 Zevalin kit.

How supplied: In-111 Zevalin kit (ibritumomab tiuxetan 3.2mg/2mL vial + sodium acetate vial + formulation buffer vial + empty reaction vial)—1 Y-90 Zevalin kit (ibritumomab tiuxetan 3.2mg/2mL vial + sodium acetate vial + formulation buffer vial + empty reaction vial)—1

ZOLINZA Merck

℞

Histone deacetylase inhibitor. Vorinostat 100mg; caps.

Indications: Refractory cutaneous T-cell lymphoma.

Adults: Take with food. Swallow whole. 400mg once daily. If not tolerated, may reduce to 300mg once daily, then to 300mg once daily 5 days/week if needed. Continue until disease progression or not tolerated.

Children: <18yrs: not recommended.

Warnings/Precautions: Renal or hepatic impairment. Monitor for DVT, pulmonary embolism. Correct electrolyte disturbances before starting therapy. Maintain adequate hydration. Diabetes. Monitor CBC, platelets, blood glucose, serum creatinine, electrolytes (esp. potassium, calcium, magnesium) every 2 weeks for 1st 2 months, then monthly. Pregnancy (Cat.D).

Nursing mothers: not recommended.

Interactions: Increased risk of thrombocytopenia and GI bleed with other HDAC inhibitors (eg, valproic acid). Concomitant warfarin: monitor PT, INR. Adverse reactions: GI upset, fatigue, chills; thrombocytopenia, anemia (may need to modify dose or discontinue); anorexia, dysgeusia, pulmonary embolism, DVT, hyperglycemia.

How supplied: Caps—120

ZOMETA Novartis

℞

Bisphosphonate. Zoledronic acid 4mg/5mL concentrated soln for IV infusion after dilution; 4mg/100mL ready-to-use soln for IV infusion.

Indications: Adjunct in multiple myeloma and bone metastases of solid tumors.

Adults: Give by IV infusion over at least 15mins.

CrCl >60mL/min: 4mg; CrCl 50–60mL/min: 3.5mg; CrCl 40–49mL/min: 3.3mg; CrCl 30–39mL/min: 3mg; CrCl <30mL/min: see full labeling; all: every 3–4 weeks (give oral multivitamin supplement with calcium 500mg + Vit. D 400 IU daily).

Children: Not indicated.

Warnings/Precautions: Not recommended for use in patients with bone metastases with severe renal impairment. Renal or hepatic insufficiency. Check serum creatinine before each dose: withhold until serum creatinine is within 10% of baseline if serum creatinine increases by 0.5mg/dL from a normal pre-treatment level, or by 1mg/dL from an abnormal pre-treatment level, within 2 weeks of next dose. Assure adequate hydration when treating hypercalcemia of malignancy. Correct hypocalcemia before initiating treatment; supplement with calcium and vitamin D. Closely monitor electrolytes (esp. calcium, magnesium, phosphate), CBC/differential, hematocrit, hemoglobin.

Evaluate if thigh or groin pain develops and consider discontinuing if atypical femur fracture is suspected. Aspirin-sensitive asthma. Avoid invasive dental surgery (do preventative dental work before therapy). Pregnancy (Cat.D). Nursing mothers: not recommended.

Interactions: Avoid concomitant other bisphosphonates. Additive hypocalcemic effect with aminoglycosides, calcitonin, loop diuretics.

Caution with other nephrotoxic drugs.

Adverse reactions: Nausea, fatigue, anemia, musculoskeletal pain (discontinue if severe), constipation, fever, vomiting, dyspnea, flu-like syndrome, electrolyte disturbances, hypotension, CNS effects, rigors, headache, paresthesia, renal toxicity; osteonecrosis of the jaw, atypical subtrochanteric, diaphyseal femoral fractures, severe hypocalcemia.

How supplied: Single-use vial, ready-to-use bottle—1

ZYDELIG Gilead

℞

Phosphatidylinositol 3-kinase inhibitor. Idelalisib 100mg, 150mg; tabs.

Indications: Relapsed chronic lymphocytic leukemia (CLL), in combination with rituximab,

in patients for whom rituximab alone would be considered appropriate due to other co-morbidities. Relapsed follicular B-cell 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. Limitations of use: not recommended for first-line treatment of CLL, FL, or SLL. Adults: Swallow whole. ≥18yrs: initially 150mg twice daily; continue until disease progression or unacceptable toxicity. Dose modifications: see full labeling.

Children: <18yrs: not established.

Contraindications: History of serious allergic reactions including anaphylaxis and toxic epidermal necrolysis.

Warnings/Precautions: Risk of fatal/serious hepatotoxicity: monitor ALT/AST every 2 weeks for the first 3 months, every 4 weeks for the next 3 months, then every 1–3 months thereafter; if ALT/AST >3XULN, monitor weekly until resolved; if ALT/AST >5XULN, withhold and continue monitoring weekly until resolved; if ALT/AST >20XULN, discontinue permanently. Monitor for diarrhea or colitis; withhold if severe or hospitalization; discontinue if life-threatening.

Risk of fatal/serious pneumonitis; monitor for pulmonary symptoms or a decline by >5% in oxygen saturation; if suspected, interrupt or discontinue as indicated. Risk of fatal/serious infections; monitor for signs/symptoms and interrupt if Grade ≥3. 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 6 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, ALT/AST elevations.

How supplied: Tabs—60

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DRUG MONOGRAPHS

LUNG CANCER ABRAXANE Celgene

℞

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

Indications: First-line treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC), in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy.

Adults: Do not treat if neutrophil count <1,500 cells/mm3 or platelets <100,000 cells/mm3. In combination with carboplatin: 100mg/m2 IV over 30 mins on Days 1, 8, and 15 of each 21-day cycle.

Dose reductions for hematologic and neurologic adverse reactions, hepatic impairment: see full labeling. Avoid extravasation.

Children: Not evaluated.

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

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

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

Interactions: May potentiate or be potentiated

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

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

How supplied: Single-use vial—1

ALECENSA Genentech

℞

Kinase inhibitor. Alectinib 150mg; caps.

Indications: Treatment of patients with anaplastic lymphoma kinase (ALK)-positive, metastatic non-small cell lung cancer (NSCLC) as detected by an FDA-approved test.

Adults: Swallow whole. Take with food.

600mg twice daily until disease progression or unacceptable toxicity. Dose modifications or dose reduction schedule: see full labeling.

Children: Not established.

Warnings/Precautions: Monitor liver function tests (eg, ALT, AST, total bilirubin) every 2 weeks for the first 3 months, then monthly and as clinically

indicated; test more frequently if transaminase and bilirubin elevated; withhold, resume at reduced dose, or permanently discontinue based on severity. Evaluate if presence of worsening respiratory symptoms; withhold if ILD/pneumonitis diagnosed; permanently discontinue if no other cause identified. Withhold for Grade 3 renal toxicity until recovery to ≤1.5×ULN, then resume at reduced dose; permanently discontinue if Grade 4 occurs. Monitor HR, BP regularly. If nonlife-threatening symptomatic bradycardia occurs, withhold until asymptomatic or HR ≥60bpm; permanently discontinue in case(s) of recurrence or life-threatening bradycardia if no contributing concomitant medication identified. Assess CPK every 2 weeks for the first month and as clinically indicated; withhold, resume, or reduce dose based on severity. Embryo-fetal toxicity. Pregnancy: avoid.

Use effective contraception during and for 1 week (females) or 3 months (males) after final dose.

Nursing mothers: not recommended (during and for 1 week after final dose).

Interactions: Increased bradycardia with concomitant antihypertensives or other drugs known to cause bradycardia.

Adverse reactions: Fatigue, constipation, edema, myalgia, anemia; hepatotoxicity, ILD/pneumonitis, renal impairment, bradycardia, CPK elevation.

How supplied: Caps—240

ALIMTA Lilly

℞

Antifolate. Pemetrexed 100mg/vial, 500mg/vial; pwd for IV inj after reconstitution and dilution; preservative-free.

Indications: Locally advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC): in combination with cisplatin as initial treatment, or as maintenance in patients whose disease has not progressed after 4 cycles of platinumbased 1st-line chemotherapy, as a single agent.

Treatment of patients with recurrent, metastatic nonsquamous, NSCLC after prior chemotherapy, as a single agent. Limitations of use: not for the treatment of squamous cell NSCLC. Malignant pleural mesothelioma (MPM): in combination with cisplatin, for the initial treatment of patients whose disease is either unresectable or who are otherwise not candidates for curative surgery.

Adults: See full labeling. 500mg/m2 by IV infusion over 10 mins on Day 1 of each 21-day cycle.

Combination therapy: Give cisplatin beginning 30 mins after pemetrexed infusion. Supplement with oral folic acid and intramuscular vitamin B12 one week prior to 1st pemetrexed dose, continue during treatment, and for 21 days after the last dose.

Pretreat with dexamethasone for 3 consecutive days, beginning the day before each pemetrexed dose. Dose modifications: see full labeling.

Children: Not established.

Warnings/Precautions: See full labeling.

Increased risk of myelosuppression without vitamin supplementation. Permanently discontinue if Grade 3 or 4 neurologic toxicity,

recurrent Grade 3 or 4 non-hematologic toxicity after two dose reductions, severe/life-threatening skin toxicity, interstitial pneumonitis, or signs of radiation recall occur. Do not start a treatment cycle unless ANC is ≥1500cells/mm3, platelets ≥100,000cells/mm3 and CrCl ≥45mL/min.

Monitor CBCs, platelets, renal and hepatic function.

Renal impairment (CrCl <45mL/min). Severe third space fluid. Embryo-fetal toxicity. Pregnancy; avoid.

Use effective contraception during treatment and for 6 months (females) or 3 months (males) after final dose. Nursing mothers: not recommended (during and for 1 week after final dose).

Interactions: Increased risk of toxicity with concomitant ibuprofen in renal impairment (CrCl 45–79mL/min): avoid for 2 days before, the day of, and 2 days following pemetrexed dose; if unavoidable, monitor more frequently for effects.

Adverse reactions: Fatigue, nausea, anorexia, vomiting, fatigue, stomatitis/pharyngitis, constipation, rash/desquamation, neutropenia, anemia, thrombocytopenia, elevated creatinine, sensory neuropathy; rare: renal failure.

Testing considerations: TS (thymidylate synthase) expression for response and toxicity.

How supplied: Single-use vial—1

ALUNBRIG Takeda

℞

Kinase inhibitor. Brigatinib 30mg; tabs.

Indications: Treatment of patients with anaplastic lymphoma kinase (ALK)-positive, metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib.

Adults: Swallow whole. Initially 90mg once daily for first 7 days; if tolerated, increase to 180mg once daily until disease progression or unacceptable toxicity. Dose modifications or dose reduction levels: see full labeling.

Children: Not established.

Warnings/Precautions: Monitor for new or worsening respiratory symptoms esp. during 1st week of initiation; if occurs, withhold and evaluate for ILD/pneumonitis; resume at same dose for Grade 1 or reduced dose for Grade 2 severity; permanently discontinue for Grade 3/4 or recurrent Grade 1/2 ILD/pneumonitis. Monitor BP after 2 weeks and at least monthly thereafter; withhold for Grade 3 hypertension despite optimal antihypertensive therapy; resume at reduced dose upon improvement to Grade 1 severity; consider permanent discontinuation for Grade 4 or recurrent Grade 3 hypertension. Monitor HR and BP regularly; if symptomatic bradycardia occurs, withhold and evaluate any concomitant drugs that are known to cause bradycardia; resume at same or reduced dose after resolution; discontinue for life-threatening bradycardia if no contributing concomitant medication identified. Withhold and evaluate for new or worsening visual symptoms of Grade ≥2 severity; resume at reduced doses upon recovery to Grade 1 or baseline; permanently discontinue for Grade 4 visual disturbances.

Monitor CPK, lipase, and amylase levels during treatment; withhold for Grade 3/4 elevation;

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DRUG MONOGRAPHS

LUNG CANCER resume at same or reduced dose upon recovery to Grade 1 or baseline. Assess fasting serum glucose prior to initiation and periodically thereafter; if not adequately controlled with optimal antihyperglycemics, withhold then consider dose reduction, or permanently discontinue based on severity. Embryo-fetal toxicity. Pregnancy: avoid.

Females of reproductive potential should use effective non-hormonal contraception during treatment and for at least 4 months after final dose; males should use effective contraception during treatment and for at least 3 months after final dose. Nursing mothers: not recommended (during and for 1 week after final dose).

Interactions: Avoid concomitant strong CYP3A inhibitors (eg, boceprevir, cobicistat, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, clarithromycin, itraconazole, ketoconazole, posaconazole, voriconazole, conivaptan); if unavoidable, reduce Alunbrig dose by ~50%.

Avoid grapefruit or grapefruit juice. Avoid concomitant strong CYP3A inducers (eg, rifampin, carbamazepine, phenytoin, St. John’s wort). May reduce efficacy of CYP3A substrates (eg, hormonal contraceptives). Caution with antihypertensives that cause bradycardia.

Adverse reactions: Nausea, diarrhea, fatigue, cough, headache; ILD/pneumonitis, hypertension, bradycardia, visual disturbances, CPK elevation, pancreatic enzyme elevation, hyperglycemia, possible infertility in males.

How supplied: Tabs 30mg—21, 180

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 (PRES), 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.

Interactions: Increased risk of CHF and decline in LVEF with concomitant anthracycline-based therapy (not indicated use); discontinue if CHF develops.

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, PRES, infusion reactions, ovarian failure, neutropenia, 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 healing: withhold Cyramza prior to surgery; resume based on adequate healing; discontinue if complications develops during therapy until wound is fully healed. 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 have not been established in patients whose tumors have other EGFR mutations. Treatment of patients with metastatic squamous NSCLC progressing after platinum-based chemotherapy.

Adults: Take on an empty stomach at least 1 hr before or 2 hrs after a meal. 40mg once daily until disease progression or not tolerated. Severe renal impairment (CrCl 15–29mL/min): 30mg once

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LUNG CANCER daily. Concomitant P-gp inhibitors: reduce afatinib daily dose by 10mg if not tolerated; resume previous dose after discontinuing the inhibitor.

Concomitant P-gp inducers: increase afatinib daily dose by 10mg as tolerated; resume previous dose 2–3 days after discontinuing the inducer.

Dose modification: see full labeling.

Children: Not established.

Warnings/Precautions: Permanently discontinue for life-threatening bullous, blistering, or exfoliative skin lesions, confirmed interstitial lung disease (ILD), severe drug-induced hepatic impairment, persistent ulcerative keratitis, symptomatic left ventricular dysfunction, or severe/intolerable adverse reactions (at dose 20mg/day). Withhold for prolonged diarrhea Grade ≥2 lasting for ≥2 consecutive days while taking antidiarrheal, prolonged cutaneous reaction Grade ≥2 (lasting >7 days) or intolerable, during evaluation of suspected ILD, renal dysfunction Grade ≥2, or worsening liver function. History of keratitis, ulcerative keratitis, or severe dry eye. Obtain LFTs periodically during treatment.

Severe renal or hepatic impairment; monitor and adjust dose (see Adults). Embryo-fetal toxicity.

Pregnancy (avoid). Females of reproductive potential should use effective contraception during therapy and for at least 2 weeks after final dose. Nursing mothers: not recommended (during and for 2 weeks after final dose).

Interactions: See Adults. Potentiated by P-gp inhibitors (eg, ritonavir, cyclosporine A, ketoconazole, itraconazole, erythromycin, verapamil, quinidine, tacrolimus, nelfinavir, saquinavir, amiodarone). Antagonized by P-gp inducers (eg, rifampicin, carbamazepine, phenytoin, phenobarbital, St. John’s wort).

Adverse reactions: Diarrhea, rash/acneiform dermatitis, stomatitis, paronychia, dry skin, decreased appetite, nausea, vomiting, pruritus; bullous/exfoliative skin disorders, ILD, hepatotoxicity, keratitis.

How supplied: Tabs—30

IRESSA AstraZeneca

℞

Tyrosine kinase inhibitor. Gefitinib 250mg; tabs.

Indications: First-line treatment of metastatic non-small cell lung cancer (NSCLC) with EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test.

Limitations of use: not established in metastatic NSCLC with EGFR mutations other than exon 19 deletions or exon 21 substitution mutations.

Adults: May disperse tabs in water; drink immediately or give via NG tube. Give 250mg once daily until disease progression or unacceptable toxicity occurs. Dose modifications for adverse reactions: see full labeling.

Concomitant strong CYP3A4 inducers: increase to 500mg daily; resume at 250mg seven days after discontinuation of the CYP3A4 inducer.

Children: Not established.

Warnings/Precautions: Permanently discontinue if confirmed interstitial lung disease (ILD), severe

hepatic impairment, GI perforation, or persistent ulcerative keratitis occurs. Withhold for up to 14 days if acute onset or worsening pulmonary symptoms, NCI CTCAE Grade ≥2 ALT and/or AST elevations, Grade ≥3 diarrhea or skin reactions, or severe or worsening ocular disorders (including keratitis) occurs. Interrupt or discontinue therapy if severe bullous and exfoliative skin disorders develop. Obtain periodic LFTs. Moderate and severe hepatic impairment; monitor. Use effective contraception during treatment and for at least 2 weeks after completion. Pregnancy, nursing mothers: not recommended.

Interactions: Potentiated by strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole); monitor. Antagonized by strong CYP3A4 inducers (eg, rifampicin, phenytoin, tricyclics); see Adults. May be antagonized by drugs that increase gastric pH (eg, H2-blockers, antacids); take gefitinib 6 hours after or 6 hours before an H2-blocker or antacid. Avoid concomitant PPIs; if necessary, take gefitinib 12 hours after last dose or 12 hours before next PPI dose. May potentiate warfarin; monitor INR. Adverse reactions: Skin reactions, diarrhea, vomiting, decreased appetite, stomatitis; ILD, hepatotoxicity, GI perforation, ocular disorders.

Testing considerations: EGFR mutation analysis.

How supplied: Tabs—30

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: First-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have high PD-L1 expression [Tumor Proportion Score (TPS) ≥50%)] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations. Treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy.

Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving Keytruda. First-line treatment of patients with metastatic nonsquamous NSCLC, in combination with pemetrexed and carboplatin.

Adults: Give as IV infusion over 30mins.

200mg every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. In combination with pemetrexed/carboplatin: give prior to chemotherapy when given on the same day (see full labeling). 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, or recurrent Grade 2 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 changes in renal function; withhold dose if Grade 2 nephritis; permanently discontinue if Grade 3 or 4 develops.

Monitor for hypophysitis; withhold dose if Grade 2 hypophysitis; withhold or discontinue if Grade 3 or 4 develops. Monitor for changes in thyroid function (at treatment initiation, during, and as clinically indicated) and signs/symptoms of thyroid disorders; withhold or discontinue if Grade 3 or 4 hyperthyroidism develops. Monitor for hyperglycemia and other diabetes symptoms; withhold if severe hyperglycemia until controlled.

Withhold dose if Grade 4 hematological toxicity in cHL patients develops. Monitor for severe skin reactions; permanently discontinue if SJS or TEN is confirmed. Permanently discontinue if any severe or Grade 3 immune-mediated adverse reaction recurs, for any life-threatening immune-mediated adverse reaction (except endocrinopathies controlled with hormone replacement or hematological toxicity in cHL patients), persistent Grade 2 or 3 reactions that do not recover to Grade 0–1 within 12wks after last dose, or inability to reduce corticosteroid dose to ≤10mg/day of prednisone or equivalent within 12wks. Monitor for infusion-related reactions; permanently discontinue if Grade 3 or 4 develops.

Complications of allogeneic HSCT after Keytruda: monitor for hepatic VOD, Grade 3 or 4 acute GVHD, steroid-requiring febrile syndrome, and others.

Solid organ transplant recipients. Embryo-fetal toxicity. Females of reproductive potential should use highly effective contraception during therapy and for 4 months after the final dose. Pregnancy: avoid. Nursing mothers: not recommended (during therapy and for 4 months after the final dose).

Interactions: Increased mortality when pembrolizumab is added to thalidomide analogue plus dexamethasone regimen in multiple myeloma: not recommended.

Adverse reactions: Fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation; immune-mediated disorders, infusion-related reactions.

How supplied: Single-use vial 50mg—1; Singleuse vial 25mg/mL (4mL)—1

MEKINIST Novartis

℞

Kinase inhibitor. Trametinib 0.5mg, 2mg; tabs.

Indications: In combination with dabrafenib for the treatment of metastatic non-small cell lung cancer (NSCLC) with BRAF V600E mutation, as detected by an FDA-approved test.

Adults: Confirm presence of BRAF V600E mutation prior to initiation. Take at same time each day, at least 1hr before or 2hrs after a meal.

Monotherapy or in combination with dabrafenib:

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DRUG MONOGRAPHS

LUNG CANCER 2mg once daily; continue until disease progression or unacceptable toxicity. Dose modifications: see full labeling.

Children: Not established.

Warnings/Precautions: See full labeling for dabrafenib 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. Monitor for non-cutaneous malignancies, pulmonary embolism (permanently discontinue if life-threatening), colitis, GI perforations, skin toxicities and secondary infections. Permanently discontinue for all Grade 4 hemorrhagic events or any Grade 3 events that do not improve. 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 baseline and is less than the lower limit of normal; permanently discontinue if symptomatic cardiomyopathy or persistent asymptomatic LV dysfunction is unresolved within 4wks. Perform eye exam periodically and at any time for visual disturbances; permanently discontinue if retinal vein occlusion develops or retinal pigment epithelial detachment persists. Permanently discontinue if interstitial lung disease or pneumonitis occurs.

Withhold if fever >104°F or any serious febrile reaction occurs and evaluate for infection; prophylaxis with antipyretics may be needed when resuming. Pre-existing diabetes or hyperglycemia; monitor serum glucose levels. Severe renal or moderate-to-severe hepatic impairment. Embryofetal toxicity. Females of reproductive potential should use effective contraception during and for 4 months after treatment. Pregnancy. Nursing mothers: not recommended (during and for 4 months after last dose).

Adverse reactions: Rash, diarrhea, lymphedema. In combination with dabrafenib: also pyrexia, chills, fatigue, nausea, vomiting, hypertension, peripheral edema, dry skin, decreased appetite, hemorrhage, cough, dyspnea.

How supplied: Tabs—30

OPDIVO Bristol-Myers Squibb

℞

Human programmed death receptor-1 (PD-1)blocking antibody. Nivolumab 10mg/mL; per vial; soln for IV infusion after dilution; preservativefree; contains mannitol.

Indications: Metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy.

Adults: Give as IV infusion over 60mins. 240mg every 2 weeks until disease progression or

unacceptable toxicity. Dose modifications: see full labeling.

Children: Not established.

Warnings/Precautions: See full labeling.

Monitor for any immune-mediated adverse reactions; permanently discontinue or withhold, and give corticosteroids (at 1–2mg/kg/day prednisone equivalents) based on severity of event.

Permanently discontinue for any life-threatening (Grade 4) adverse reaction, Grade 3 or 4 pneumonitis, Grade 3/4 or recurrent colitis (with ipilimumab), Grade 4 or recurrent colitis (as single agent), AST/ALT >5XULN (non-HCC) or AST/ALT >10XULN (HCC) or total bilirubin >3XULN, SCr >6XULN, Grade 4 hypophysitis, Grade 3 or 4 adrenal insufficiency, Grade 4 hyperglycemia, Grade 4 rash (or confirmed SJS or TEN), immunemediated encephalitis, recurring Grade 3 adverse reactions, requirement for ≥10mg/day prednisone (or equivalent) for >12 weeks, or persistent Grade 2 or 3 adverse reactions lasting ≥12 weeks. Grade 2 pneumonitis, Grade 2 or 3 (as single agent) colitis, AST/ALT >3–5XULN or total bilirubin >1.5–3XULN, SCr >1.5–6XULN, Grade 2 or 3 hypophysitis, Grade 2 adrenal insufficiency, Grade 3 hyperglycemia, Grade 3 rash (or suspected SJS or TEN), new onset moderate-to-severe neurologic symptoms, other Grade 3 adverse reactions (1st occurrence); withhold dose, give corticosteroids, and resume when return to Grade 0 or 1. Interrupt or decrease infusion rate if mild or moderate infusion reactions occur; discontinue if severe or life-threatening.

Monitor for abnormal liver tests, elevated serum creatinine, hyperglycemia, and thyroid function prior to and during treatment; give replacement therapy for hypothyroidism. Monitor for transplantrelated complications (eg, hyperacute or Grade 3/4 acute GVHD, steroid-requiring febrile syndrome, hepatic veno-occlusive disease) and treat promptly. Moderate or severe hepatic impairment: not studied. Embryo-fetal toxicity. Females of reproductive potential should use effective contraception during and for ≥5 months after final dose. Pregnancy (esp. during 2nd & 3rd trimesters), nursing mothers: not recommended.

Adverse reactions: Fatigue, musculoskeletal pain, decreased appetite, cough, constipation; immune-mediated reactions (may be fatal).

How supplied: Single-use vial (4mL, 10mL)—1

PORTRAZZA Lilly

℞

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

Indications: In combination with gemcitabine and cisplatin, for first-line treatment of metastatic

squamous non-small cell lung cancer. Limitations of use: not for treatment of non-squamous nonsmall cell lung cancer.

Adults: Give by IV infusion over 60 mins prior to gemcitabine and cisplatin infusion. 800mg on Days 1 and 8 of each 3-week cycle; continue until disease progression or unacceptable toxicity.

May premedicate with diphenhydramine HCl (or equivalent) if previously experienced a Grade 1/2 infusion-related reaction. Dose modifications: see full labeling.

Children: Not established.

Warnings/Precautions: Risk of cardiopulmonary arrest and/or sudden death, hypomagnesemia. History of coronary artery disease, CHF, or arrhythmias. Monitor serum electrolytes (eg, magnesium, potassium, calcium) prior to each infusion during therapy and for 8 weeks after last dose; withhold for Grade 3/4 electrolyte abnormalities and may resume once improved to Grade ≤2. Discontinue if serious or life-threatening venous/arterial thromboembolic events or infusion-related reactions occur.

Discontinue if Grade 4 skin reactions or Grade 3 skin induration/fibrosis occurs. Limit sun exposure. Embryo-fetal toxicity. Pregnancy; avoid.

Use effective contraception during treatment and for 3 months after last dose. Nursing mothers: not recommended (during therapy and for 3 months after last dose).

Adverse reactions: Rash, dermatitis acneiform, vomiting, diarrhea, thromboembolic events, hypomagnesemia, hypocalcemia, hypokalemia; cardiopulmonary arrest, dermatologic toxicities, infusion reactions.

How supplied: Single-use vial—1

TAFINLAR Novartis

℞

Kinase inhibitor. Dabrafenib 50mg, 75mg; caps.

Indications: In combination with trametinib for the treatment of metastatic non-small cell lung cancer (NSCLC) with BRAF V600E mutation, as detected by an FDA-approved test. Limitation of use: not indicated for the treatment of wild-type BRAF NSCLC. Adults: Confirm presence of BRAF V600E 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 (approx. 12hrs apart); continue until disease progression or unacceptable toxicity. Dose modifications: see full labeling.

Children: Not established.

Warnings/Precautions: See full labeling for trametinib prior to starting combination therapy.

Increased incidence of new primary cutaneous

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DRUG MONOGRAPHS

LUNG CANCER malignancies; perform skin evaluation prior to initiation, every 2 months during therapy, and up to 6 months after discontinuation. Monitor for non-cutaneous malignancies; permanently discontinue if RAS mutation-positive malignancy occurs. Permanently discontinue for all Grade 4 hemorrhagic events or any persistent Grade 3 events. Risk of cardiomyopathy with trametinib; assess LVEF prior to initiation, after one month, and then at every 2–3 month intervals during treatment; withhold for symptomatic cardiomyopathy or asymptomatic LV dysfunction of >20% from baseline that is below institutional lower limit of normal. Withhold if fever ≥101.3°F or any serious febrile 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; permanently discontinue for persistent Grade ≥2 lasting >6wks.

G6PD deficiency: monitor for hemolytic anemia.

Severe renal or moderate-to-severe hepatic impairment. Embryo-fetal toxicity. Females of reproductive potential should use highly effective non-hormonal contraception during and for 2wks after last dose. Pregnancy. Nursing mothers: not recommended (during and for 2wks after last dose).

Interactions: Avoid concomitant strong CYP3A4 or CYP2C8 inhibitors (eg, ketoconazole, nefazodone, clarithromycin, gemfibrozil); if unavoidable, monitor closely. May antagonize effects of CYP3A4, CYP2C8, CYP2C9, CYP2C19, CYP2B6 substrates (eg, midazolam, warfarin, dexamethasone, hormonal contraceptives); consider alternatives or monitor.

Adverse reactions: Hyperkeratosis, headache, pyrexia, arthralgia, papilloma, alopecia, palmarplantar erythrodysesthesia syndrome; skin toxicity (may be serious). In combination with trametinib: also chills, fatigue, rash, nausea, vomiting, diarrhea, dry skin, decreased appetite, edema, hemorrhage, cough, dyspnea.

How supplied: Caps—120

TAGRISSO AstraZeneca

inducers (if use is unavoidable): increase dose to 160mg daily; resume at 80mg 3 weeks after discontinuing CYP3A4 inducer. Dose modification: see full labeling.

Children: Not established.

Warnings/Precautions: Confirm presence of T790M mutation prior to treatment initiation.

Permanently discontinue if interstitial lung disease (ILD)/pneumonitis is confirmed; QTc interval prolongation with signs/symptoms of life-threatening arrhythmia; symptomatic CHF or persistent, asymptomatic LV dysfunction that does not resolve within 4 weeks; or if no improvement within 3 weeks. Withhold dose if worsening respiratory symptoms indicative of ILD occur; if QTc interval >500msec on ≥2 separate ECGs; or adverse reactions of Grade ≥3 severity. Monitor ECGs and electrolytes periodically in patients with congenital long QTc syndrome, CHF, electrolyte abnormalities, or those who are taking drugs known to prolong the QTc interval. Conduct cardiac monitoring (including LVEF at baseline and during treatment in patients with cardiac risk factors). Evaluate if signs/symptoms of keratitis occur. ESRD. Severe hepatic impairment. Embryo-fetal toxicity. Females of reproductive potential should use effective contraception during and for 6 weeks after final dose; males (with female partners of reproductive potential) should use effective contraception during and for 4 months after final dose. Pregnancy.

Nursing mothers: not recommended (during and for 2 weeks after final dose).

Interactions: Antagonized by strong CYP3A inducers (eg, phenytoin, rifampin, carbamazepine, St. John’s Wort); avoid; if use is unavoidable, increase Tagrisso dose (see Adults). Potentiates BCRP substrates (eg, rosuvastatin, sulfasalazine, topotecan); monitor closely for related toxicity.

Adverse reactions: Diarrhea, rash, dry skin, nail toxicity, fatigue, lab abnormalities; possibly infertility.

How supplied: Tabs—30

TARCEVA Astellas and Genentech ℞

Kinase inhibitor. Osimertinib 40mg, 80mg; tabs.

Indications: Treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC), as detected by an FDAapproved test, who have progressed on or after EGFR tyrosine kinase inhibitor therapy.

Adults: 80mg once daily until disease progression or unacceptable toxicity. If swallowing difficulty, may disperse tab in 2oz (60mL) of non-carbonated water only; stir and swallow immediately, then rinse container with 4–8oz water and drink immediately; or if administration via NG tube is required, disperse tab in 15mL of non-carbonated water and use an additional 15mL of water to transfer any residues to the syringe; give resulting 30mL via NG tube as instructed with appropriate water flushes (~30mL). Concomitant strong CYP3A4

℞

Kinase inhibitor. Erlotinib (as HCl) 25mg, 100mg, 150mg; tabs.

Indications: Treatment of 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 receiving first-line, maintenance, or second or greater line treatment after progression following at least one prior chemotherapy regimen. Limitations of use: not established in patients with NSCLC whose tumors have other EGFR mutations.

Not recommended for use in combination with platinum-based chemotherapy.

Adults: Take on empty stomach. 150mg once daily. Use until disease progression or unacceptable toxicity occurs. Dose modifications for adverse reactions: see full labeling.

Concomitant strong CYP3A4 inhibitors (see Interactions): reduce by 50mg decrements; avoid

use if possible. Concomitant CYP3A4 inducers (see Interactions): increase by 50mg increments at 2-week intervals (max 450mg); avoid use if possible. Concurrent cigarette smoking: increase by 50mg increments at 2-week intervals (max 300mg); upon cessation, reduce to 150mg or 100mg daily.

Children: Not established.

Warnings/Precautions: Discontinue if interstitial lung disease, severe hepatic toxicity, GI perforation, severe bullous, blistering or exfoliating skin conditions, or corneal perforation or severe ulceration occurs. Withhold or consider discontinuing therapy if severe renal failure due to dehydration, or acute/worsening ocular disorders occur. Monitor LFTs periodically; withhold in patients without history of hepatic impairment for total bilirubin >3XULN or transaminases >5XULN, or in patients with history of hepatic impairment or biliary obstruction for doubling of bilirubin or tripling of transaminases over baseline. Discontinue if abnormal LFTs do not improve or resolve within 3 weeks. Withhold for acute onset of unexplained pulmonary symptoms pending evaluation, persistent severe diarrhea unresponsive to loperamide, severe rash, grade 3–4 keratitis or grade 2 lasting ≥2 weeks. Monitor renal function, serum electrolytes, pulmonary function, INR, prothrombin time. History of peptic ulcers or diverticular disease. Embryo-fetal toxicity. Pregnancy: avoid. Females of reproductive potential should use effective contraception during therapy and at least 1 month after the last dose. Nursing mothers: not recommended (during and for 2 weeks after the last dose).

Interactions: Potentiated by CYP3A4 inhibitors (eg, atazanavir, boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telithromycin, troleandomycin, voriconazole, grapefruit) or a combined CYP3A4 and CYP1A2 inhibitor (eg, ciprofloxacin); reduce dose if unavoidable.

Plasma levels decreased by CYP3A4 inducers (eg, rifampin, rifabutin, rifapentine, phenytoin, carbamazepine, phenobarbital, St. John’s wort); increase dose if unavoidable. Avoid concomitant moderate CYP1A2 inducers (eg, teriflunomide, rifampin, phenytoin) or smoking tobacco; increase dose if unavoidable. Avoid concomitant proton pump inhibitors if possible. Separate dosing of antacids by several hours or for H2 blockers (take erlotinib 10hrs after and at least 2hrs before next dose). 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,

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DRUG MONOGRAPHS

LUNG CANCER keratitis, corneal ulceration/perforation), MI/ischemia, hemolytic anemia with thrombocytopenia, cerebrovascular accident (in pancreatic cancer), 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

TECENTRIQ Genentech

℞

Programmed death-ligand 1 (PD-L1) blocking antibody. Atezolizumab 60mg/mL; soln for IV infusion after dilution; preservative-free.

Indications: Metastatic non-small cell lung cancer (NSCLC) in patients with disease progression during or after platinum-containing chemotherapy.

Adults: Give as IV infusion over 60mins. 1200mg every 3 weeks until disease progression or unacceptable toxicity. May give subsequent infusions over 30mins if first infusion tolerated.

Children: Not established.

Warnings/Precautions: Permanently discontinue if Grade 3/4 pneumonitis, AST or ALT >5×ULN or total bilirubin >3×ULN, Grade 4 diarrhea or colitis, Grade 4 hypophysitis, myasthenic syndrome/myasthenia gravis, Guillain-Barre or meningoencephalitis, Grade 3/4 ocular inflammatory toxicity, Grade 4 or recurrent pancreatitis, Grade 3/4 infusion-related reactions, or Grade 4 rash. Withhold for Grade 2 pneumonitis, AST or ALT >3–5×ULN or total bilirubin >1.5–3×ULN, Grade 2/3 diarrhea or colitis, symptomatic hypophysitis, adrenal insufficiency, hypothyroidism, hyperthyroidism, Grade 3/4 hyperglycemia, Grade 2 ocular inflammatory toxicity, Grade 2/3 pancreatitis or Grade 3/4 increases in amylase or lipase levels (>2×ULN), Grade 3/4 infection, Grade 2 infusion-related reactions, or Grade 3 rash; may be resumed when recover to Grade 0–1. Monitor for immune-related pneumonitis, hepatitis (obtain AST, ALT, bilirubin prior to and during treatment), diarrhea/colitis, endocrinopathies (hypophysitis, thyroid function, adrenal insufficiency, diabetes), meningitis or encephalitis, motor and sensory neuropathy, and acute pancreatitis; see full labeling for adverse reaction management details.

Monitor for signs/symptoms of infection and treat with antibiotics for suspected or confirmed bacterial infections. Interrupt or slow the infusion rate in patients with mild or moderate infusion reactions. Moderate or severe hepatic impairment: not studied. Embryo-fetal toxicity. Pregnancy.

Use effective contraception during and for ≥5 months after final dose. Nursing mothers: not recommended (during and for ≥5 months after final dose).

Adverse reactions: Fatigue, decreased appetite, nausea, urinary tract infection, pyrexia, constipation; immune-related reactions, lab abnormalities.

How supplied: Single-dose vial (20mL)—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: Lung cancer (squamous cell and small cell types).

Adults: See literature.

Children: Not established.

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

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

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

Diabetes. Peptic ulcer. Ulcerative colitis. Infection.

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

Interactions: Avoid live virus vaccines. Toxicity increased by NSAIDs, salicylates, phenytoin, sulfonylureas, sulfonamides, probenecid, folic acid antagonists. May be potentiated by penicillins (monitor), tetracyclines, chloramphenicol, non-absorbable broad spectrum antibiotics. May be antagonized

by folic acid. May potentiate theophylline, mercaptopurine. Increased risk of soft tissue necrosis and osteonecrosis with radiotherapy.

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

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

How supplied: Tabs—30; soln (2mL, 4mL, 8mL, 10mL)—10 (single-use vials); pwd (1 gram)—1 (single-use vial)

XALKORI Pfizer

℞

Tyrosine kinase inhibitor. Crizotinib 200mg, 250mg; hard gel caps.

Indications: Treatment of metastatic non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test. Treatment of metastatic NSCLC that is ROS1-positive.

Adults: Confirm ALK-positive NSCLC with an FDA-approved test before treating. 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 nonhematologic toxicities: see full labeling.

Children: Not established.

Warnings/Precautions: Monitor ALT, AST and total bilirubin every 2 weeks during first 2 months, then monthly, and more frequently for elevated transaminases; temporarily suspend, reduce dose, or permanently discontinue as clinically indicated. Monitor CBCs with differential monthly and more frequently if Grade 3 or 4 abnormalities, fever or infection occurs. Risk of severe pneumonitis: monitor for pulmonary symptoms; permanently discontinue if occurs.

Congenital long QT syndrome; avoid. History of or predisposition for QTc prolongation (eg, CHF, bradyarrhythmias, electrolyte abnormalities, or those who are taking drugs known to prolong the QT interval): consider monitoring ECG, electrolytes periodically. Torsade de pointes, ventricular tachycardia, serious arrhythmia: permanently discontinue if QTc >500ms or

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DRUG MONOGRAPHS

LUNG CANCER ≥60ms change from baseline. Monitor HR and BP regularly; discontinue if life-threatening bradycardia occurs. Discontinue if onset of severe visual loss; perform eye evaluation.

Hepatic impairment. Severe renal impairment.

Embryo-fetal toxicity. Pregnancy; avoid. Use effective contraception during therapy and for at least 45 days (females) or 90 days (males) after final dose. Nursing mothers: not recommended (during therapy and for 45 days after final dose).

Interactions: Avoid concomitant strong CYP3A inhibitors (eg, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, voriconazole), grapefruit juice, or strong CYP3A inducers (eg, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, St. John’s Wort). Avoid concomitant CYP3A substrates with narrow therapeutic indices (eg, alfentanil, cyclosporine, ergots, fentanyl, pimozide, quinidine, sirolimus, tacrolimus); if needed, reduce doses. Avoid concomitant agents known to cause bradycardia (eg, beta-blockers, non-dihydropyridine calcium channel blockers, clonidine, digoxin); adjust dose or discontinue.

Caution with moderate CYP3A inhibitors. Dose reduction may be needed with coadministered drugs metabolized by CYP3A. Adverse reactions: Vision disorders, nausea, diarrhea, vomiting, edema, constipation, elevated transaminases, fatigue, decreased appetite, upper RTI, dizziness, neuropathy, neutropenia; hepatotoxicity (may be fatal), pneumonitis (may be fatal), QT prolongation, bradycardia.

How supplied: Caps—60

ZYKADIA Novartis

℞

Tyrosine kinase inhibitor. Ceritinib 150mg; hard gel caps.

Indications: Treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test.

Adults: Take on an empty stomach (at least 1hr before or 2hrs after a meal). 750mg once daily until disease progression or unacceptable toxicity.

Discontinue if 300mg once daily not tolerated.

Severe hepatic impairment or if concomitant use of strong CYP3A4 inhibitors unavoidable: reduce ceritinib dose by ⅓. Dose modifications: see full labeling.

Children: Not established.

Warnings/Precautions: Monitor for severe or persistent GI toxicity; if occurs, withhold until improved; resume at reduced dose. Monitor ALT/AST and total bilirubin once monthly, and more frequently if elevated transaminases develop; withhold then reduce dose, or permanently discontinue if ALT/AST elevation >3xULN with total bilirubin >2xULN in the absence of cholestasis or hemolysis. Congenital long QT syndrome; avoid. Patients with CHF, bradyarrhythmias, electrolyte abnormalities, or those who are taking drugs known to prolong the QTc interval; monitor ECG, electrolytes periodically. Permanently discontinue if QTc prolongation in combination with Torsade de pointes or polymorphic ventricular tachycardia

or serious arrhythmia develop. Monitor HR and BP regularly; fasting serum glucose, lipase, amylase prior to initiation and periodically thereafter. Monitor for pulmonary symptoms as clinically indicated. Permanently discontinue if treatment-related interstitial lung disease (ILD)/pneumonitis, uncontrolled hyperglycemia, or life-threatening bradycardia occur. Severe hepatic impairment. Embryo-fetal toxicity.

Pregnancy. Use effective contraception during treatment and for 6 months (females) or 3 months (males) after completion. Nursing mothers: not recommended (during and for 2 weeks after completion).

Interactions: See Adults. Potentiated by strong CYP3A4 inhibitors (eg, ritonavir, macrolides, ketoconazole, nefazodone), grapefruit juice; avoid.

Avoid concomitant strong CYP3A4 inducers (eg, carbamazepine, phenytoin, rifampin, St. John’s Wort). Avoid concomitant CYP3A substrates (eg, alfentanil, cyclosporine, ergots, fentanyl, pimozide, quinidine, sirolimus, tacrolimus) or CYP2C9 substrates with narrow therapeutic indices (eg, phenytoin, warfarin); if unavoidable, reduce doses of these drugs. Avoid concomitant agents known to cause bradycardia (eg, betablockers, non-dihydropyridine CCBs, clonidine, digoxin).

Adverse reactions: Diarrhea, nausea, fatigue, vomiting, abdominal pain, decreased appetite, weight loss; hepatotoxicity, ILD/pneumonitis, QT prolongation, hyperglycemia, bradycardia, pancreatitis.

How supplied: Caps—70

ERROR-PRONE SYMBOLS The symbols found in this table have been reported to the Institute for Safe Medical Practices (ISMP) through the ISMP Medication Error Reporting Program as being frequently misinterpreted and involved in harmful medication errors. These symbols should never be used when communicating medical information.

Symbol

Intended Meaning

Misinterpretation

Correction

ʒ c x3d > and <

Dram Minim For three days Greater than and less than

Use the metric system Use the metric system Use “for three days” Use “greater than” or “less than”

/ (slash mark)

Separates two doses or indicates “per”

@ & + °

At And Plus or and Hour

Mistaken as “3” Mistaken as “mL” Mistaken as “3 doses” Mistaken as opposite of intended; incorrect symbol used mistakenly; “<10” mistaken as “40” (forty) Mistaken as the number 1 (eg, “25 units/10units” misread as “25 units and 110 units”) Mistaken as “2” Mistaken as “2” Mistaken as “4” Mistaken as a zero (eg, q2° seen as q 20)

Φ or ∅

Zero, null sign

Mistaken as numerals 4, 6, 8, and 9

Use 0 or zero, or describe intent using whole words

Use “per” rather than a slash mark to separate doses Use “at” Use “and” Use “and” Use “hr”, “h”, or “hour”

References Source: Institute for Safe Medication Practices. Error-Prone Abbreviations, Symbols, and Dose Designations. 2015.

Available at: http://www.ismp.org/Tools/errorproneabbreviations.pdf.

(Rev. 7/2016)

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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. Cardiomyopathy (including left ventricular failure), acute infusion-related reactions, myelosuppression may occur. Have medications to treat infusion-related reactions and resuscitative equipment available. Hepatic impairment. Monitor blood (esp. CBC + platelets), hepatic (esp. SGOT/SGPT, alkaline phosphatase), and cardiac function (eg, MUGA, ECG). Monitor periodically for secondary oral cancers with long-term use. Avoid extravasation.

Embryo-fetal toxicity. Use effective contraception during and for 6 months after last dose. 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.

Not for patients with rapidly progressive visceral disease.

Adults: Use appropriate preparation and route: see full labeling. Use pwd form only.

30 million IU/m2 IM or SC three times weekly; continue until 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: <18yrs: not established.

Contraindications: Decompensated liver disease. Autoimmune hepatitis.

Warnings/Precautions: Risk of fatal or lifethreatening neuropsychiatric, autoimmune, ischemic, or infectious disorders: monitor closely, discontinue if they worsen.

Cardiovascular disease (eg, MI, arrhythmias); monitor closely. Pulmonary disease (eg, COPD). Discontinue if severe psychiatric disorders (eg, suicidal behavior) or new/worsening ophthalmologic reactions develop. Severe myelosuppression; discontinue if neutrophil count <0.5 X109/L or platelets 25X109/L. Permanently discontinue if severe (Grade 3) hepatic injury or decompensation (Child-Pugh score >6 [Class B and C]) develop. Thyroid abnormalities; discontinue if uncontrolled by medication. Diabetes.

Coagulation disorders. Maintain adequate hydration. Monitor CBCs, platelets, thyroid, visual and liver function before and during therapy; EKG in cardiovascular disease and cancer patients. Pwd: contains human albumin; monitor for possible viral disease and Creutzfeldt-Jakob disease transmission.

Pre-existing psoriasis or sarcoidosis. Renal impairment. Transplant recipients. Elderly.

Pregnancy (Cat.C). Nursing mothers: not recommended.

Interactions: Caution with myelosuppressive agents (eg, zidovudine), and drugs that can exacerbate depression. May potentiate theophylline. Increased risk of peripheral neuropathy with concomitant telbivudine.

Dental/periodontal disorders, dry mouth with concomitant ribavirin.

Adverse reactions: Flu-like symptoms (fever, headache, chills, myalgia, fatigue); abnormal LFTs, blood, cardiovascular, pulmonary, thyroid, and GU disorders, GI upset, abnormal vision, skin reactions, CNS/psychiatric reactions,

colitis, hypertriglyceridemia, pancreatitis; rare: autoimmune disorders, hypersensitivity. 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

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

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.

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

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DRUG MONOGRAPHS

SKIN CANCER BAVENCIO EMD Serono

℞

Programmed death-ligand 1 (PD-L1) blocking antibody. Avelumab 20mg/mL; soln for IV infusion after dilution; preservative-free; contains mannitol.

Indications: Treatment of metastatic Merkel cell carcinoma (MCC).

Adults: Premedicate with an antihistamine and acetaminophen prior to the first 4 infusions; then subsequent doses as clinically indicated. Give as IV infusion over 60mins. 10mg/kg every 2 weeks until disease progression or unacceptable toxicity.

Dose modifications: see full labeling.

Children: <12yrs: not established.

Warnings/Precautions: See full labeling.

Monitor for any immune-mediated adverse reactions; permanently discontinue or withhold, and give corticosteroids (at 1–2mg/kg/day prednisone equivalents) based on severity of event. Permanently discontinue for Grade 3/4 pneumonitis or recurrent Grade 2 pneumonitis, Grade 4 diarrhea or colitis or recurrent Grade 3 diarrhea or colitis, AST/ALT >5XULN or total bilirubin >3XULN, SCr >6XULN, any life-threatening (Grade 4) or recurrent severe (Grade 3) immune-mediated adverse reactions, requirement for ≥10mg/day prednisone (or equivalent) for >12 weeks, or persistent Grade 2/3 immune-mediated adverse reactions lasting ≥12 weeks. Grade 2 pneumonitis, Grade 2/3 diarrhea or colitis, Grade 3/4 adrenal insufficiency, Grade 3/4 thyroid disorders, Grade 3/4 hyperglycemia, AST/ALT >3–5XULN or total bilirubin >1.5–3XULN, SCr >1.5–6XULN; withhold dose, give corticosteroids, and resume when return to Grade 0 or 1. Interrupt or decrease infusion rate if Grade 1/2 infusion-related reactions occur; permanently discontinue if Grade 3/4. Monitor for abnormal liver tests, adrenal insufficiency, elevated serum creatinine, hyperglycemia, and thyroid function prior to and during treatment; give replacement therapy for hypothyroidism. Embryofetal toxicity. Females of reproductive potential should use effective contraception during and for ≥1 month after final dose. Pregnancy. Nursing mothers: not recommended (during and for ≥1 month after final dose).

Adverse reactions: Fatigue, musculoskeletal pain, diarrhea, nausea, infusion-related reaction, rash, decreased appetite, peripheral edema, UTI; other immune-mediated adverse reactions (may be fatal).

How supplied: Single-dose vial (10mL)—1

COTELLIC Genentech Kinase inhibitor. Cobimetinib 20mg; tabs.

Indications: In combination with vemurafenib for the treatment of unresectable or metastatic melanoma with BRAF V600E or V600K mutations.

Adults: Confirm presence of BRAF V600E or V600K mutation prior to initiation. In

℞

combination with vemurafenib: 60mg once daily for first 21 days of each 28-day cycle until disease progression or unacceptable toxicity.

Concomitant CYP3A inhibitors: see Interactions.

Other dose modifications: see full labeling.

Children: Not established.

Warnings/Precautions: Review full labeling for vemurafenib prior to initiation. Monitor for new malignancies (cutaneous and non-cutaneous); perform skin evaluations prior to initiation, every 2 months during therapy, and for 6 months after discontinuation. Monitor for signs/symptoms of bleeding; withhold if Grade 3 hemorrhagic events occur; resume at lower dose if improved to Grade 0/1 within 4 weeks; discontinue if no improvement. Risk of cardiomyopathy; assess LVEF prior to initiation, after 1 month, and then every 3 months thereafter until discontinuation.

Patients with baseline LVEF below institutional lower limit of normal or <50%: not established.

Interrupt, reduce dose, or discontinue if severe skin reactions occur. Perform eye exams at regular intervals and for any visual disturbances. Manage serous retinopathy with treatment interruption, dose reduction, or discontinuation. Permanently discontinue if retinal vein occlusion occurs.

Monitor liver tests prior to initiation, monthly during treatment, or more frequently as indicated; dose interruption, reduction, or discontinuation if Grade 3/4 abnormalities occur. Obtain baseline CPK and creatinine levels prior to initiation, periodically during treatment, and as clinically indicated for signs/symptoms of rhabdomyolysis.

Avoid sun exposure. Severe renal impairment.

Embryo-fetal toxicity. Females of reproductive potential should use effective contraception during therapy and for 2 weeks after final dose.

Pregnancy. Nursing mothers: not recommended (during therapy and for 2 weeks after final dose).

Interactions: Avoid concomitant strong or moderate CYP3A inhibitors (eg, itraconazole, erythromycin, ciprofloxacin). If short-term (≤14 days) use of moderate CYP3A inhibitors is unavoidable for patients taking cobimetinib 60mg, reduce to 20mg and resume at previous dose upon discontinuing the CYP3A inhibitor; for patients taking cobimetinib 20mg or 40mg, use alternative. Avoid concomitant strong or moderate CYP3A inducers (eg, carbamazepine, efavirenz, phenytoin, rifampin, St. John’s wort).

Adverse reactions: Diarrhea, photosensitivity, nausea, pyrexia, vomiting, increased GGT, CPK, ALT/AST and alkaline phosphatase, hypophosphatemia, lymphopenia, hyponatremia.

How supplied: Tabs—63

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. Females of reproductive potential should use effective contraception during therapy and for 24 months after final dose; male patients should use condoms (even after a vasectomy) during and for 3 months after final dose. Advise patients not to donate blood or blood products during therapy and for 24 months after final dose. Advise male patients not to donate semen during and for 3 months after final dose. Premature fusion of the epiphyses may occur in pediatrics if exposed. Pregnancy: avoid. Nursing mothers: not recommended (during and for 24 months after final dose).

Adverse reactions: Muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea, diarrhea, vomiting, 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 as determined with an FDA-approved

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DRUG MONOGRAPHS

SKIN CANCER test 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 (determine D816V c-Kit mutation status prior to initiation): 400mg once daily. ASM associated with eosinophilia: initially 100mg once daily; may increase to 400mg once daily if insufficient response. DFSP: 400mg twice daily.

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; renal function at baseline and during therapy; GI symptoms at baseline. Cardiovascular disease or risk factors; monitor. Diabetes. Hypertension. CHF. 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. Embryo-fetal toxicity. Pregnancy (avoid); exclude status prior to initiation. Females of reproductive potential should use highly effective contraception during treatment and for 14 days after cessation. Nursing mothers: not recommended (during and for 1 month after final dose).

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) or CYP2C9 (use heparin instead of warfarin). Caution with concomitant CYP2D6 substrates that have a narrow therapeutic window.

Adverse reactions: Edema (may be severe), nausea, vomiting, musculoskeletal pain, diarrhea, muscle cramps, rash (may be severe; eg, erythema multiforme, Stevens-Johnson syndrome), fatigue, abdominal pain, dizziness, blurred vision, somnolence, fever, headache, cough, arthralgia/myalgia, dyspnea, hypokalemia, night sweats, anorexia, pruritus, hemorrhage, anemia, neutropenia, thrombocytopenia, weight gain, renal or hepatotoxicity, immunosuppression, hypothyroidism; rare: severe CHF, LV dysfunction.

How supplied: 100mg—90; 400mg—30

IMLYGIC Amgen

℞

Genetically modified oncolytic viral therapy.

Talimogene laherparepvec 106 (1 million) PFU/mL, 108 (100 million) PFU/mL; susp for intralesional inj; preservative-free.

Indications: Treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrent after initial surgery. Limitations of use: not shown to improve overall survival or have an effect on visceral metastases.

Adults: See full labeling. Inject intralesionally into cutaneous, subcutaneous, and/or nodal lesions that are visible, palpable, or detectable by ultrasound guidance. Total inj volume per treatment visit: max 4mL for all injected lesions combined. Initial dose: up to 4mL of 106 (1 million) PFU/mL. 2nd dose: up to 4mL of 108 (100 million) PFU/mL given 3 weeks later. All subsequent doses (including reinitiation): up to 4mL of 108 (100 million) PFU/mL given 2 weeks apart.

Continue for ≥6 months unless other treatment required or until no injectable lesions to treat; reinitiate if new lesions appear after a complete response.

Children: Not established.

Contraindications: Immunocompromised or pregnant patients.

Warnings/Precautions: For intralesional inj only. Avoid accidental exposure (esp. skin, eyes, mucous membranes) and direct contact with patient’s injected lesions, dressings, or body fluids. Advise patients to avoid inadvertent transfer of drug to other areas of the body (eg, touching/scratching inj sites or occlusive dressings). Evaluate lesions if suspected

herpetic infection occurs. Inj site complications (eg, necrosis or ulceration of tumor tissue, cellulitis, systemic bacterial infection).

Persistent infection or delayed healing of inj site. Underlying autoimmune disease. Multiple myeloma or plasmacytoma. Pregnancy. Women of childbearing potential should use effective method of contraception. Nursing mothers: not recommended.

Interactions: Acyclovir or other antiherpetic viral agents may interfere with efficacy.

Adverse reactions: Fatigue, chills, pyrexia, nausea, influenza-like illness, inj site pain; immune-mediated events.

Note: Report suspected herpetic lesions to Amgen at (855) 465-9442.

How supplied: Single-use vial (1mL)—1

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.

Adults: Give as IV infusion over 30mins. 200mg 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, or recurrent Grade 2 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 changes in renal function; withhold dose if Grade 2 nephritis; permanently discontinue if Grade 3 or 4 develops.

Monitor for hypophysitis; withhold dose if Grade 2 hypophysitis; withhold or discontinue if Grade 3 or 4 develops. Monitor for changes in thyroid function (at treatment initiation, during, and as clinically indicated) and signs/symptoms of thyroid disorders; withhold or discontinue if Grade 3 or 4 hyperthyroidism develops. Monitor for hyperglycemia and other diabetes symptoms; withhold if severe hyperglycemia until controlled.

Withhold dose if Grade 4 hematological toxicity in cHL patients develops. Monitor for severe skin reactions; permanently discontinue if SJS or TEN is confirmed. Permanently discontinue

Access Cancer Therapy Advisor treatment regimens in a user-friendly format.

CancerTherapyAdvisor.com/TreatmentRegimens.

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DRUG MONOGRAPHS

SKIN CANCER if any severe or Grade 3 immune-mediated adverse reaction recurs, for any life-threatening immune-mediated adverse reaction (except endocrinopathies controlled with hormone replacement or hematological toxicity in cHL patients), persistent Grade 2 or 3 reactions that do not recover to Grade 0–1 within 12wks after last dose, or inability to reduce corticosteroid dose to ≤10mg/day of prednisone or equivalent within 12wks. Monitor for infusion-related reactions; permanently discontinue if Grade 3 or 4 develops. Complications of allogeneic HSCT after Keytruda: monitor for hepatic VOD, Grade 3 or 4 acute GVHD, steroid-requiring febrile syndrome, and others. Solid organ transplant recipients. Embryo-fetal toxicity. Females of reproductive potential should use highly effective contraception during therapy and for 4 months after the final dose. Pregnancy: avoid. Nursing mothers: not recommended (during therapy and for 4 months after the final dose).

Interactions: Increased mortality when pembrolizumab is added to thalidomide analogue plus dexamethasone regimen in multiple myeloma: not recommended.

Adverse reactions: Fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation; immune-mediated disorders, infusion-related reactions.

How supplied: Single-use vial 50mg—1; Singleuse vial 25mg/mL (4mL)—1

MEKINIST Novartis

℞

Kinase inhibitor. Trametinib 0.5mg, 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: not indicated for treatment of patients who have progressed on prior BRAF-inhibitor therapy.

Adults: Confirm presence of BRAF V600E or V600K mutation prior to initiation. Take at same time each day, 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.

Dose modifications: see full labeling.

Children: Not established.

Warnings/Precautions: See full labeling for dabrafenib 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.

Monitor for non-cutaneous malignancies, pulmonary embolism (permanently discontinue if life-threatening), colitis, GI perforations, skin toxicities and secondary infections. Permanently discontinue for all Grade 4 hemorrhagic events or any Grade 3 events that do not improve.

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 baseline and is less than the lower limit of normal; permanently discontinue if symptomatic cardiomyopathy or persistent asymptomatic LV dysfunction is unresolved within 4wks. Perform eye exam periodically and at any time for visual disturbances; permanently discontinue if retinal vein occlusion develops or retinal pigment epithelial detachment persists. Permanently discontinue if interstitial lung disease or pneumonitis occurs. Withhold if fever >104°F or any serious febrile reaction occurs and evaluate for infection; prophylaxis with antipyretics may be needed when resuming. Pre-existing diabetes or hyperglycemia; monitor serum glucose levels.

Severe renal or moderate-to-severe hepatic impairment. Embryo-fetal toxicity. Females of reproductive potential should use effective contraception during and for 4 months after treatment. Pregnancy. Nursing mothers: not recommended (during and for 4 months after last dose).

Adverse reactions: Rash, diarrhea, lymphedema. In combination with dabrafenib: also pyrexia, chills, fatigue, nausea, vomiting, hypertension, peripheral edema, dry skin, decreased appetite, hemorrhage, cough, dyspnea.

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 >2.5XULN until symptoms resolve. Pregnancy.

Nursing mothers: not recommended during therapy and for 20 months after last dose.

Interactions: Avoid concomitant strong CYP3A inhibitors (eg, saquinavir, telithromycin, ketoconazole, itraconazole, voriconazole, posaconazole, nefazodone) or moderate CYP3A inhibitors (eg, atazanavir, diltiazem, fluconazole); if moderate CYP3A inhibitor use necessary, administer for <14 days and monitor closely.

Avoid concomitant strong or moderate CYP3A inducers (eg, carbamazepine, efavirenz, modafinil, phenobarbital, phenytoin, rifabutin, rifampin, St. John’s Wort).

Adverse reactions: Muscle spasms, alopecia, dysgeusia, fatigue, nausea, musculoskeletal pain, diarrhea, decreased weight, decreased appetite, myalgia, abdominal pain, headache, pain, vomiting, pruritus; anemia, hyperglycemia, increased SCr, CK, and LFTs. Note: To report exposure to Odomzo during pregnancy, call Novartis at (888) 669-6682.

How supplied: Caps—30

OPDIVO Bristol-Myers Squibb

℞

Human programmed death receptor-1 (PD-1)blocking antibody. Nivolumab 10mg/mL; per vial; soln for IV infusion after dilution; preservativefree; contains mannitol.

Indications: As a single agent for patients with BRAF V600 wild-type or BRAF V600 mutation (+) unresectable or metastatic melanoma. In combination with ipilimumab for unresectable or metastatic melanoma.

Adults: Give as IV infusion over 60mins.

240mg every 2 weeks until disease progression or unacceptable toxicity. In combination with ipilimumab: 1mg/kg (followed by ipilimumab on the same day) every 3 weeks for 4 doses, then followed by 240mg every 2 weeks (as single agent) until disease progression or unacceptable toxicity. Dose modifications: see full labeling.

Children: Not established.

Warnings/Precautions: See full labeling.

Monitor for any immune-mediated adverse reactions; permanently discontinue or withhold, and give corticosteroids (at 1–2mg/kg/day prednisone equivalents) based on severity of event. Permanently discontinue for any lifethreatening (Grade 4) adverse reaction, Grade 3 or 4 pneumonitis, Grade 3/4 or recurrent colitis (with ipilimumab), Grade 4 or recurrent colitis (as single agent), AST/ALT >5XULN (non-HCC) or AST/ALT >10XULN (HCC) or total bilirubin >3XULN, SCr >6XULN, Grade 4 hypophysitis, Grade 3 or 4 adrenal insufficiency, Grade 4 hyperglycemia, Grade 4 rash (or confirmed SJS or TEN), immune-mediated encephalitis, recurring Grade 3 adverse reactions, requirement for ≥10mg/day prednisone (or equivalent) for >12 weeks, or persistent Grade 2 or 3 adverse reactions lasting ≥12 weeks. Grade 2 pneumonitis, Grade 2 or 3 (as single agent) colitis, AST/ALT >3–5XULN or total bilirubin >1.5–3XULN, SCr >1.5–6XULN, Grade 2 or 3 hypophysitis, Grade

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DRUG MONOGRAPHS

SKIN CANCER 2 adrenal insufficiency, Grade 3 hyperglycemia, Grade 3 rash (or suspected SJS or TEN), new onset moderate-to-severe neurologic symptoms, other Grade 3 adverse reactions (1st occurrence); withhold dose, give corticosteroids, and resume when return to Grade 0 or 1. Interrupt or decrease infusion rate if mild or moderate infusion reactions occur; discontinue if severe or lifethreatening. Monitor for abnormal liver tests, elevated serum creatinine, hyperglycemia, and thyroid function prior to and during treatment; give replacement therapy for hypothyroidism.

Monitor for transplant-related complications (eg, hyperacute or Grade 3/4 acute GVHD, steroid-requiring febrile syndrome, hepatic venoocclusive disease) and treat promptly. Moderate or severe hepatic impairment: not studied.

Embryo-fetal toxicity. Females of reproductive potential should use effective contraception during and for ≥5 months after final dose.

Pregnancy (esp. during 2nd & 3rd trimesters), nursing mothers: not recommended.

Adverse reactions: Fatigue, rash, musculoskeletal pain, pruritus, diarrhea, nausea, asthenia, cough, dyspnea, constipation, decreased appetite, back pain, arthralgia, upper RTI; also with Ipilimumab: pyrexia, vomiting; immune-mediated reactions (may be fatal).

How supplied: Single-use vial (4mL, 10mL)—1

PROLEUKIN Prometheus

℞

Interleukin-2, recombinant. Aldesleukin 22 million IU/vial; pwd for IV infusion after reconstitution and dilution; contains mannitol; preservative-free.

Indications: Metastatic melanoma.

Adults: ≥18yrs: 600,000 IU/kg (0.037mg/kg) every 8 hours by IV infusion over 15 minutes for a max of 14 doses, followed by 9 days rest, then repeat for another 14 doses (max 28 doses/course), as tolerated. Retreatment and dose adjustments: see literature.

Children: <18yrs: not established.

Contraindications: Abnormal thallium stress test or pulmonary function tests. Organ allografts.

Previous drug related toxicity (eg, sustained ventricular tachycardia [≥5 beats], uncontrolled or unresponsive arrhythmias, chest pain with ECG changes consistent with angina, or MI, cardiac tamponade, intubation >72hrs, renal failure requiring dialysis >72hrs, coma or toxic psychosis >48hrs, repetitive or difficult seizures, bowel ischemia or perforation, GI bleeding requiring surgery).

Warnings/Precautions: See literature.

History of cardiac or pulmonary disease. Renal, hepatic, or CNS impairment. Seizure disorder.

Bacterial infections (treat prior to starting therapy; esp. patients with indwelling central lines). Withhold dose if organ perfusion is not maintained, urine output is reduced, systolic BP <90mmHg, CHF, cardiac ischemia or arrhythmias occur; or if moderate-to-severe lethargy or somnolence (continuing may result in coma) develops. Evaluate and treat CNS metastases; obtain negative scan before starting treatment.

Do thallium stress test; monitor vital signs, weight, fluid intake and output daily. Correct hypovolemia or fluid accumulations if occur.

Obtain CBCs, differential and platelets, blood chemistries (electrolytes, renal and hepatic function tests), chest X-rays, serum creatinine (should be ≤1.5mg/dL before starting therapy), pulmonary function tests, arterial blood gases.

Monitor for capillary leak syndrome, mental status changes, thyroid changes, diabetes onset.

Elderly. Pregnancy (Cat.C). Nursing mothers: not recommended.

Interactions: Psychotropics may increase CNS toxicity. Increased toxicity with other nephrotoxic, hepatotoxic, myelotoxic, or cardiotoxic drugs. Hypersensitivity reactions with other antineoplastics. Myocardial injury and rhabdomyolysis risk increased with interferonalfa. Antagonized by glucocorticoids (avoid). β-blockers and other antihypertensives may potentiate hypotension. Delayed reactions to iodinated contrast media. May increase risk of allograft rejection.

Adverse reactions: Hypotension, GI upset, oliguria, flu-like syndrome, respiratory disorders (eg, dyspnea), CNS effects (eg, confusion, somnolence), rash, metabolic and nutritional disorders (eg, bilirubinemia, increased creatinine), hyperglycemia, thyroid disorder, thrombocytopenia, anemia, impaired neutrophil function, capillary leak syndrome, cardiotoxicity, exacerbation of autoimmune and inflammatory disease, eosinophilia, possible antibody formation; others.

How supplied: Single-use vials—1

TAFINLAR Novartis

℞

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 (approx. 12hrs apart); continue until disease progression or unacceptable toxicity.

Dose modifications: 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. Monitor for non-cutaneous malignancies; permanently discontinue if RAS mutation-positive malignancy occurs. Permanently discontinue for all Grade 4 hemorrhagic events or any persistent Grade 3 events. Risk of cardiomyopathy with trametinib; assess LVEF prior to initiation, after one month, and then at every 2–3 month intervals during treatment; withhold for symptomatic cardiomyopathy or asymptomatic LV dysfunction of >20% from baseline that is below institutional lower limit of normal. Withhold if fever ≥101.3°F or any serious febrile 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; permanently discontinue for persistent Grade ≥2 lasting >6wks. G6PD deficiency: monitor for hemolytic anemia. Severe renal or moderate-tosevere hepatic impairment. Embryo-fetal toxicity.

Females of reproductive potential should use highly effective non-hormonal contraception during and for 2wks after last dose. Pregnancy.

Nursing mothers: not recommended (during and for 2wks after last dose).

Interactions: Avoid concomitant strong CYP3A4 or CYP2C8 inhibitors (eg, ketoconazole, nefazodone, clarithromycin, gemfibrozil); if unavoidable, monitor closely. May antagonize effects of CYP3A4, CYP2C8, CYP2C9, CYP2C19, CYP2B6 substrates (eg, midazolam, warfarin, dexamethasone, hormonal contraceptives); consider alternatives or monitor.

Adverse reactions: Hyperkeratosis, headache, pyrexia, arthralgia, papilloma, alopecia, palmarplantar erythrodysesthesia syndrome; skin toxicity (may be serious). In combination with trametinib: also chills, fatigue, rash, nausea, vomiting, diarrhea, dry skin, decreased appetite, edema, hemorrhage, cough, dyspnea.

How supplied: Caps—120

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

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DRUG MONOGRAPHS

SKIN CANCER 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 in patients ≥12yrs. Adjuvant treatment of cutaneous melanoma in patients with pathologic involvement of regional lymph nodes >1mm who have undergone complete resection, including total lymphadenectomy.

Adults: Give by IV infusion over 90 mins.

Unresectable, metastatic: 3mg/kg every 3 weeks for a maximum of 4 doses; may delay doses if toxicity occurs, but all treatment must be given within 16 weeks of the first dose. Adjuvant: 10mg/kg every 3 weeks for 4 doses, followed by 10mg/kg every 12 weeks for up to 3 years; may omit doses if toxicity occurs. Dose modifications: see full labeling.

Children: Not established.

Warnings/Precautions: Severe and fatal immune-mediated adverse reactions can develop.

Permanently discontinue therapy and initiate systemic high-dose corticosteroids for severe, persistent, or recurring immune-mediated reactions. Withhold dose for moderate immunemediated adverse reactions until return to baseline, improvement to mild severity, or complete resolution, and patient is receiving <7.5mg prednisone or equivalent per day. Monitor for enterocolitis, hepatitis, dermatitis, neuropathy, endocrinopathy, and others including ocular manifestations; perform clinical chemistries including LFTs, ACTH levels, and thyroid tests at baseline and before each dose.

Moderate or severe hepatic impairment. Embryofetal toxicity. Females of reproductive potential should use effective contraception during and

for 3 months after final dose. Pregnancy. Nursing mothers: not recommended (during and for 3 months after final dose).

Adverse reactions: Fatigue, diarrhea, pruritus, rash, colitis, headache, weight loss, nausea, pyrexia, decreased appetite, vomiting, insomnia; immune-mediated reactions.

Note: To enroll pregnant patients in the Pregnancy Safety Surveillance Study, call (844) 593-7869.

How supplied: Single-use vial (50mg, 200mg)—1

ZELBORAF Genentech

℞

Kinase inhibitor. Vemurafenib 240mg; tabs.

Indications: Treatment of unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test. Limitation of use: not for treatment of wild-type BRAF melanoma.

Adults: Confirm BRAF V600E mutation-positive melanoma with FDA-approved test before initiating.

Swallow whole. ≥18yrs: 960mg every 12hrs; continue until disease progression or unacceptable toxicity. Concomitant strong CYP3A4 inducer: avoid; if unavoidable, increase dose by 240mg as tolerated (see full labeling). Dose modifications for adverse reactions: see full labeling.

Children: <18yrs: not established.

Warnings/Precautions: 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.

Measure SCr before initiating and periodically during treatment. Monitor for ophthalmologic reactions routinely. Avoid sun exposure. Embryo-fetal toxicity.

Females of reproductive potential should use effective contraception during therapy and for at least 2 weeks after final dose. Pregnancy. Nursing mothers: not recommended (during and for 2 weeks after final dose).

Interactions: Avoid concomitant strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, voriconazole, clarithromycin, saquinavir, ritonavir, indinavir, nelfinavir); consider alternatives.

Avoid concomitant strong CYP3A4 inducers (eg, phenytoin, carbamazepine, rifampin); consider alternatives, or increase dose (see Adult). Avoid concomitant CYP1A2 (eg, tizanidine) and P-gp (eg, digoxin) substrates with narrow therapeutic indices; if unavoidable, consider dose reduction of substrates and monitor. Increased transaminase and bilirubin with concomitant ipilimumab.

Concomitant or sequential administration with radiation treatment; monitor closely.

Adverse reactions: Arthralgia, rash, alopecia, fatigue, photosensitivity, nausea, pruritus, skin papilloma; severe hypersensitivity or dermatologic reactions (permanently discontinue if occur), QT prolongation, hepatotoxicity, uveitis, blurry vision, photophobia, other malignancies, radiation sensitization and recall, renal failure, Dupuytren’s contracture (may be severe), plantar fascial fibromatosis.

How supplied: Tabs—112, 120

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

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

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

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

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

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

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ALPHABETICAL INDEX

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

A Abemaciclib Verzenio

25

18

Aromasin

18

Bortezomib Velcade (inj)

72

55

Bosulif

57

Arzerra (inj) Asparaginase Erwinia chrysanthemi

Abiraterone Zytiga

Arimidex

50

Abraxane (inj) cancer, breast

18

cancer, pancreatic

26

non-small cell lung cancer

76

Acalabrutinib

Erwinaze (inj)

60

Breast cancer

Atezolizumab Tecentriq (inj)

48, 81

Avastin (inj) cancer, cervical

12, 34, 43, 51, 77

cancer, colorectal

12, 34, 43,51, 77

cancer, ovarian

12, 34, 51, 77

57

cancer, renal

12, 34, 43, 51, 77

Actinic keratoses

84

glioblastoma

12, 34, 43, 51, 77

Adcetris (inj)

55

non-small cell lung

12, 34, 43, 51, 77

Calquence

Ado-trastuzumab Kadcyla Afatinib Gilotrif

77 18

cancer, renal

43

progressive neuroendocrine

26

tumors of pancreatic origin 26

neuroendocrine tumors (NET) of gastrointestinal or lung origin 12

astrocytoma (SEGA) 87 76

Alectinib Alecensa

76 57

Alimta (inj)

76

Aliqopa (inj)

55

Alitretinoin Panretin (ext)

83

Alunbrig

76

Anaplastic astrocytoma

13

73

B

18

55

Brigatinib Alunbrig

76

C Cabazitaxel Jevtana (inj)

45

Cabometyx

44

Cabozantinib Cabometyx Cometriq

44 27

Calquence

57

Campath (inj) Cancer, bladder Cancer, blood

84, 86

Cancer, breast

cancer, bladder

43

Cancer, cervical

cancer, renal

43

Cancer, colorectal

melanoma

84

Beleodaq (inj) Beleodaq (inj)

57 22, 25

Brentuximab vedotin Adcetris (inj)

Bavencio (inj)

56 Cancer, GI

57 43, 45–46, 48–49, 81 74 1, 18–25, 27, 35–36, 39, 52, 54, 72, 81 12, 34, 43, 51, 77 12, 19, 25, 27, 34–35, 37–39, 43, 51, 53, 77 20, 34, 36

56

Cancer, head and neck

Bendeka (inj)

56

Cancer, liver

37, 47

Treanda (inj)

71

Cancer, lung

1, 24, 52, 54, 72, 76–81

Bendamustine

Bendeka (inj) Avastin (inj)

56

Targretin

70

Targretin (ext)

70

Casodex

Bone metastases

Cancer, pancreatic

19, 26–29, 35, 38, 48, 80

Cancer, prostate

44

44–45, 47–50 12, 34, 37, 43–49, 51, 77, 81, 87

Cancer, sarcoma

1–2

56

Cancer, stomach

19, 27, 35

56

Cancer, testicular

Blinatumomab Blincyto (inj)

12, 34, 51–52, 59, 77, 83

Cancer, renal

Bicalutamide

1, 13, 24, 35, 52–54, 72, 81

Cancer, ovarian 12, 34, 43, 51, 77

Bexarotene

Blincyto (inj)

Anastrozole Arimidex

Vidaza (inj)

Bevacizumab

Alemtuzumab Campath (inj)

45

Belinostat

Aldesleukin Alecensa

Inlyta

Basal cell carcinoma

(pNET)

Proleukin (inj)

43, 84

Azacitidine

cancer, breast

subependymal giant cell

Bavencio (inj) Axitinib

Afinitor

progressive non-functional

cancer Avelumab

21

Bosutinib Bosulif

2, 75

Cancer, thyroid

44 26–28, 37, 47

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ALPHABETICAL INDEX Capecitabine Xeloda

Decitabine 25, 39

Caprelsa

26

Carfilzomib Kyprolis (inj)

65 44

Ceritinib Zykadia

82

Cerubidine (inj)

58

Cetuximab Erbitux (inj)

35, 53

Chlorambucil Leukeran

65

Chorioadenoma destruens

1, 24, 52, 54, 72, 81

Choriocarcinoma, gestational

1, 24, 52, 54, 72, 81

Clofarabine Clolar (inj)

58

Clolar (inj)

58

Cobimetinib Cotellic Colorectal cancer Cometriq

Cotellic

Dacogen (inj)

84 35–36 27

Dermatofibrosarcoma

Unituxin (inj)

13

Doxil (inj) cancer, ovarian

51, 59, 83

Kaposi’s sarcoma

51, 59, 83

multiple myeloma

51, 59, 83

Doxorubicin, liposomal Doxil (inj)

51, 59, 83

Durvalumab Imfinzi (inj)

45

E Efudex (ext)

84

Eligard (inj)

44

Elotuzumab Empliciti (inj)

59

Eloxatin (inj)

34

55

Empliciti (inj)

59

84

Enasidenib Idhifa Enzalutamide

Cyramza (inj) cancer, GI cancer, lung

34 77

Erbitux (inj)

Xtandi

73

79, 87

Dacogen (inj)

58

Daratumumab Darzalex (inj)

58

Darzalex (inj)

58

Dasatinib Sprycel

69

35, 53 35, 53

Eribulin 1, 19 84

Erlotinib Tarceva Erwinaze (inj)

29, 80 60

Estrogens, esterified Menest Afinitor

60

Faslodex (inj)

19

Femara

19

Fludara (inj)

60

Fludarabine Fludara (inj)

60

Fluorouracil Efudex (ext) Fluorouracil

84 19, 27, 35

Fluorouracil cancer, breast cancer, colorectal cancer, pancreatic cancer, stomach

19, 27, 35 19, 27, 35 19, 27, 35 19, 27, 35

Fulvestrant Faslodex (inj)

19

Fusilev (inj)

35

G Gazyva (inj) Gefitinib Iressa GI stromal tumors

Gleevec dermatofibrosarcoma protuberans GI stromal tumors hypereosinophilic syndrome leukemia, acute myeloid leukemia, chronic eosinophilic leukemia, chronic myelogenous mastocytosis myelodysplastic syndromes Glioblastoma

12, 18, 26, 43 60

Exemestane Aromasin

Farydak

47

Everolimus Evomela (inj)

58 73

50

cancer, head and neck

Erivedge

F

Gilotrif 63

cancer, colorectal

Halaven (inj)

D

Daunorubicin Cerubidine (inj) Vyxeos (inj)*

35, 61, 84

Dinutuximab

81

Dabrafenib Tafinlar

2

protuberans

Crizotinib Xalkori

Cytarabine Vyxeos (inj)*

58

Denosumab Xgeva (inj)

Casodex

Copanlisib Aliqopa (inj)

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

18

61 78 28, 35, 38, 48, 61, 84 77 35, 61, 84 35, 61, 84 35, 61, 84 35, 61, 84 35, 61, 84 35, 61, 84 35, 61, 84 35, 61, 84 12–13, 34, 43, 51, 77

H Halaven (inj) cancer, breast cancer, sarcoma

19 1

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

Herceptin (inj) cancer, breast cancer, GI Histrelin Vantas Hodgkin lymphoma Hyaluronidase human Rituxan Hycela (inj)* Hydatidiform mole Hydrea cancer, head and neck leukemia, chronic myeloid Hydroxyurea Hydrea Hypercalcemia Hypereosinophilic syndrome

Iressa 20, 36 20, 36 49 55, 64, 66 68 1, 24, 52, 54, 72, 81 53 62

75 35, 61, 84

Leukemia, acute lymphoblastic

56, 58, 60, 62, 65, 67, 69, 74

Ixabepilone Ixempra (inj)

58, 67

21

Leukemia, acute lymphocytic

Ixazomib Ninlaro

66

Ixempra (inj)

21

Leukemia, acute myeloid

Jakafi

64

Jevtana (inj)

45

K Kadcyla

62 63

Kisqali

74 63

63

21 51, 59, 83

Leukemia, acute nonlymphocytic

58 57, 60

Leukemia, chronic eosinophilic

35, 61, 84

Leukemia, chronic lymphocytic

55–56, 61, 63, 68, 71, 73, 75

Leukemia, chronic myelogenous

35, 57, 61, 69–71, 84

Leukemia, chronic myeloid

62

Leukeran

65

Leuprolide Eligard (inj)

44

Levoleucovorin Fusilev (inj)

35

46 53 46 36 64 85 78

Lymphoma, cutaneous T-cell

64, 70, 75

21

Lymphoma, follicular

55, 68, 75

Kisqali Femara Co-Pack

22

Lymphoma, lymphocytic

Kyprolis (inj)

65

Lonsurf

Lymphoma, malignant Lymphoma, mantle cell

Idelalisib Zydelig

75

Idhifa

63

Ifex (inj)

44

Ifosfamide Ifex (inj)

Lanreotide Somatuline Depot (inj)

28

44

Imatinib Gleevec

Lapatinib Tykerb

24

35, 61, 84

Lartruvo (inj)

Imbruvica

63

Imfinzi (inj)

45

Lenalidomide Revlimid

Imlygic (inj)

85

Inlyta

45

Interferon alfa-2b Intron A (inj)

83

Intron A (inj)

83

Ipilimumab Yervoy (inj)

35, 61, 63, 69, 73, 84

Leukemia, B-cell chronic lymphocytic

J

Idamycin (inj)

Ibritumomab Zevalin (inj)

65

64

Iclusig

20

37

Leukemia

Istodax

Kaposi’s sarcoma

Ibrance

Leucovorin

28

Keytruda (inj) cancer, bladder cancer, head and neck cancer, renal colorectal cancer Hodgkin lymphoma melanoma non-small cell lung cancer

Idarubicin Idamycin (inj)

78

Irinotecan Onivyde (inj)

53, 62

I

Ibrutinib Imbruvica

ALPHABETICAL INDEX

88

L

Lenvatinib Lenvima

Lymphoma, marginal zone

1 67 27, 46

37

68 65 57, 63, 72 63

Lymphoma, peripheral T-cell

56, 64

Lymphoma, small lymphocytic

63, 75

Lynparza

51

M Malignant pleural mesothelioma

76

Mantle cell lymphoma

67

Marqibo (inj)

65

Mastocytosis

35, 61, 69, 84

Lenvima cancer, renal cancer, thyroid

46 27

Mechlorethamine Valchlor (ext)

72

Letrozole Femara Kisqali Femara Co-Pack*

19 22

Mekinist melanoma non-small cell lung cancer

86 78

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ALPHABETICAL INDEX Melanoma

84–88

Melanoma, metastatic

87

Menest

61

60

Odomzo

86

47

Ofatumumab Arzerra (inj)

55

Olaparib Lynparza

51

Mercaptopurine Purinethol

67

Purixan

67

Methotrexate Trexall

1, 24, 52, 54, 72, 81

Xatmep

74

Midostaurin Rydapt

69

Multiple myeloma

51, 58–60, 65–67, 72, 75, 83

Mycosis fungoides

1, 24, 52, 54, 72, 81

Mycosis fungoides-type

72

cutaneous T-cell lymphoma Myelodysplastic

35, 58, 61, 73, 84

syndromes

N Necitumumab Portrazza (inj)

1

Omacetaxine mepesuccinate Synribo (inj)

70

Onivyde (inj)

28

Opdivo (inj) cancer, colorectal cancer, head and neck cancer, lung cancer, renal Hodgkin lymphoma melanoma

37 54 79 47 66 86

Osimertinib Tagrisso

80

Oxaliplatin Eloxatin (inj)

34

48

P

22

Paclitaxel, protein-bound Abraxane (inj)

Neratinib Nerlynx Nerlynx

22

Neuroblastoma

13

Neuroendocrine tumors

28, 38, 48

Nexavar cancer, liver

37, 47

cancer, renal

37, 47

cancer, thyroid

28, 37, 47

Nilotinib Tasigna

71

Ninlaro

66

Niraparib Zejula

Palbociclib Ibrance

18, 26, 76 20

Panitumumab Vectibix (inj)

39

Panobinostat Farydak

60

Panretin (ext)

83

Pazopanib Votrient Pembrolizumab Keytruda (inj)

52

1, 49 36, 46, 53, 64, 78, 85

Pomalidomide Pomalyst

66

Pomalyst

66

Ponatinib Iclusig

62

Portrazza (inj)

79

Progressive neuroendocrine tumors of pancreatic origin (pNET)

26

Progressive non-functional neuroendocrine tumors (NET) of gastrointestinal or lung origin

26

Proleukin (inj)

87

Provenge (inj)

47

Purinethol

67

Purixan

67

R Radium Ra 223 dichloride Xofigo (inj) Ramucirumab Cyramza (inj)

Revlimid

67

Ribociclib Kisqali Kisqali Femara Co-Pack*

21 22

Rituxan (inj)

68

Rituxan Hycela (inj)

68

Rituximab Rituxan (inj) Rituxan Hycela (inj)*

68 68

Romidepsin Istodax

64

Rubraca

52

Rucaparib Rubraca

52

Ruxolitinib Jakafi

64

Rydapt

69

S

1, 24, 52, 54, 56,

Perjeta (inj)

23

Sarcoma, soft tissue

68, 71–72, 74, 81

Pertuzumab Perjeta (inj)

23

Sipuleucel-T Provenge (inj)

Polycythemia vera

64

Skeletal-related events

Non-small cell lung cancer

12, 29, 34, 43, 51, 76–82

34, 77 38

76

37, 47, 54, 66, 79, 86

50

Regorafenib Stivarga

Pemetrexed Alimta (inj)

Nivolumab Non-Hodgkin’s lymphoma

Olaratumab Lartruvo (inj)

79

Neoplasms

Opdivo (inj)

O Obinutuzumab Gazyva (inj)

Melphalan Evomela (inj)

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

1 47 2

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

Soltamox

23

Trametinib

Somatuline Depot (inj)

28

Mekinist

Sonidegib Odomzo

86

Sorafenib Nexavar

28, 37, 47 69

Stivarga

38

Subependymal giant cell astrocytoma (SEGA)

12

Superficial basal cell carcinoma Sutent cancer, pancreatic GI stromal tumors neuroendocrine tumors

78, 86

Trastuzumab

Sprycel

Sunitinib Sutent

ALPHABETICAL INDEX

28, 38, 48 84

Herceptin (inj)

71

Vismodegib

48

Erivedge

cancer, breast

1, 24, 52, 54, 72, 81

cancer, head and

1, 24, 52, 54, 72, 81

cancer, lung

cancer, sarcoma

1, 24, 52, 54, 72, 81

chorioadenoma

1, 24, 52,

destruens

54, 72, 81 1, 24, 52

Tarceva cancer, pancreatic non-small cell lung cancer

Xalkori

81

Xatmep

74

1, 24, 52, 54, 72, 81

72, 81

Trifluridine Lonsurf* Trelstar (inj) Tykerb

Unituxin (inj)

24

Valchlor (ext)

Targretin (ext)

70

Valstar

Tasigna

71

Vandetanib Caprelsa

cancer, breast

25, 39

cancer, colorectal

25, 39

Xgeva (inj)

2

Xofigo (inj)

50

Xtandi

50

Y Yondelis (inj)

88 2

13

Z 72

Valrubicin Valstar

Xeloda

Yervoy (inj)

V

70

48, 81 48, 81

48

U

Targretin

Tecentriq (inj) cancer, bladder cancer, renal

37

Triptorelin

29, 80 29, 80

73

1, 24, 52, 54,

54, 72, 81

23 23

1

hydatidiform mole

lymphoma

Tamoxifen Soltamox Tamoxifen

Vyxeos (inj)

49

X

1, 24, 52,

85

75

54, 72, 81

gestational

non-Hodgkin’s

Talimogene laherparepvec Imlygic (inj)

Zolinza cancer, renal

55

80

84

Votrient

neck

Systemic anaplastic large cell lymphoma (sALCL)

Tagrisso

65

Vorinostat

Trexall

mycosis fungoides

87 79

Marqibo (inj)

Trelstar (inj)

70

Tafinlar melanoma non-small cell lung cancer

73

Vincristine sulfate liposome 20, 36

Synribo (inj)

T

25

Vidaza (inj)

Treanda (inj)

choriocarcinoma, 28, 38, 48 28, 38, 48 28, 38, 48

Verzenio

49 49

Zaltrap (inj)

39

Zejula

52

Zelboraf cancer, blood

74

melanoma

88

Zevalin (inj) 26

Ziv-aflibercept

Vantas

49

Zaltrap (inj)

Vectibix (inj)

39

Zoledronic acid

Velcade (inj)

72

74 39

Temodar

13

Temozolomide Temodar

13

Vemurafenib

Zolinza

75

Tipiracil Lonsurf*

Zelboraf

74, 88

Zometa

75

37

Venclexta

73

Zydelig

75

Trabectedin Yondelis (inj)

Venetoclax 2

Venclexta

73

Zometa

75

Zykadia

82

Zytiga

50

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MANUFACTURERS INDEX AbbVie and Genentech

Eisai Pharmaceuticals

Otsuka America Pharmaceutical, Inc.

(800) 633-9110;

(888) 422-4743;

(800) 441-6763;

(800) 821-8590

(201) 692-1100

(301) 990-0030

Actelion Pharmaceuticals

EMD Serono, Inc.

Pfizer Inc.

(866) 228-3546

(888) 275-7376

(800) 438-1985;

Allergan

Endo Pharmaceuticals

(212) 573-2323

(800) 433-8871;

(800) 462-3636;

Pharmacyclics and Janssen Biotech

(714) 246-4500

(610) 558-9800

(877) 877-3536

Amgen, Inc.

Exelixis, Inc.

Prometheus Labs, Inc.

(800) 772-6436;

(650) 837-7000

(888) 423-5227

Genentech and Biogen

Puma Biotechnology

(805) 447-1000 Astellas Pharma US, Inc. (800) 727-7003; (800) 888-7704 Astellas Pharma US, Inc. and Genentech, Inc. (888) 827-2382 AstraZeneca Pharmaceuticals (800) 237-8898; (800) 236-9933 Baxter (800) 422-9837 Bayer and Onyx (866) 639-2827 Bayer Healthcare Pharmaceuticals Inc. (800) 288-8371; (800) 468-0894 Bedford Laboratories

(800) 821-8590; (866) 633-4636 Genentech, Inc. (800) 821-8590; (650) 225-1000 Gilead Sciences, Inc. (800) 445-3235; (650) 574-3000 GlaxoSmithKline (888) 825-5249 Incyte Corporation (855) 463-3463 Ipsen Biopharmaceuticals, Inc. (866) 837-2422 Janssen Biotech, Inc. (800) 526-7736

(424) 248-6500 Rare Disease Therapeutics, Inc. (615) 399-0700 Sanofi Aventis (800) 446-6267; (800) 633-1610 Sanofi Genzyme Company (800) 745-4447; (617) 252-7500 Sanofi US and Regeneron (800) 633-1610 Seattle Genetics, Inc. (855) 473-2436 Silvergate Pharmaceuticals (855) 379-0382 Spectrum Pharmaceuticals, Inc. (877) 387-4538

(800) 521-5169;

Janssen Pharmaceuticals, Inc.

(800) 562-4797

(800) 526-7736

Boehringer Ingelheim Pharmaceuticals

Jazz Pharmaceuticals plc

Takeda Pharmaceuticals USA, Inc.

(800) 542-6257;

(650) 496-3777

(877) 825-3327;

(800) 236-4248

Lilly, Eli and Company

(847) 383-3000

Bristol-Myers Squibb

(800) 545-5979;

Tesaro, Inc.

(800) 321-1335

(317) 276-2000

(844) 483-7276

Celgene Corp

Merck & Co., Inc.

Teva Pharmaceuticals

(908) 673-9000

(800) 672-6372;

(215) 591-3000

Clovis Oncology

(800) 609-4618

Tolmar Inc.

(844) 258-7662

Millennium Pharmaceuticals, Inc.

(877) 986-5627

DARA BioSciences, Inc.

(866) 835-2233

United Therapeutics Corp.

(919) 872-5578

Novartis Pharmaceuticals Corp

(877) 864-8437

Dendreon

(800) 693-9993;

Valeant Pharmaceuticals, Inc

(877) 256-4545

(973) 503-8300

(877) 361-2719

Taiho Oncology (609) 750-5300

94 CANCER THERAPY ADVISOR | JANUARY/FEBRUARY 2018 | CancerTherapyAdvisor.com

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