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Alunbrig

Generic Name: Brigatinib
Class: Antineoplastic Agents
Chemical Name: 5-chloro-4-N-(2-dimethylphosphorylphenyl)-2-N-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]pyrimidine-2,4-diamine
Molecular Formula: C29H39ClN7O2P
CAS Number: 1197953-54-0

Introduction

Brigatinib is an antineoplastic agent.

Uses for Alunbrig

Brigatinib has the following uses:

Brigatinib is a kinase inhibitor indicated for the 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.1

This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.1

Alunbrig Dosage and Administration

General

Brigatinib is available in the following dosage form(s) and strength(s):

Tablets: 30 mg and 90 mg.1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

90 mg orally once daily for the first 7 days; if tolerated, increase to 180 mg orally once daily. May be taken with or without food.1

Cautions for Alunbrig

Contraindications

None.1

Warnings/Precautions

Interstitial Lung Disease (ILD)/Pneumonitis

Severe, life-threatening, and fatal pulmonary adverse reactions consistent with interstitial lung disease (ILD)/pneumonitis have occurred with brigatinib.1

In Trial ALTA (ALTA), ILD/pneumonitis occurred in 3.7% of patients in the 90 mg group (90 mg once daily) and 9.1% of patients in the 90→180 mg group (180 mg once daily with 7-day lead-in at 90 mg once daily).1

Adverse reactions consistent with possible ILD/pneumonitis occurred early (within 9 days of initiation of brigatinib; median onset was 2 days) in 6.4% of patients, with Grade 3 to 4 reactions occurring in 2.7%.1

Monitor for new or worsening respiratory symptoms (e.g., dyspnea, cough, etc.), particularly during the first week of initiating brigatinib. Withhold brigatinib in any patient with new or worsening respiratory symptoms, and promptly evaluate for ILD/pneumonitis or other causes of respiratory symptoms (e.g., pulmonary embolism, tumor progression, and infectious pneumonia). For Grade 1 or 2 ILD/pneumonitis, either resume brigatinib with dose reduction after recovery to baseline or permanently discontinue brigatinib. Permanently discontinue brigatinib for Grade 3 or 4 ILD/pneumonitis or recurrence of Grade 1 or 2 ILD/pneumonitis.1

Hypertension

In ALTA, hypertension was reported in 11% of patients in the 90 mg group who received brigatinib and 21% of patients in the 90→180 mg group. Grade 3 hypertension occurred in 5.9% of patients overall.1

Control blood pressure prior to treatment with brigatinib. Monitor blood pressure after 2 weeks and at least monthly thereafter during treatment with brigatinib. Withhold brigatinib for Grade 3 hypertension despite optimal antihypertensive therapy. Upon resolution or improvement to Grade 1 severity, resume brigatinib at a reduced dose. Consider permanent discontinuation of treatment with brigatinib for Grade 4 hypertension or recurrence of Grade 3 hypertension.1

Use caution when administering brigatinib in combination with antihypertensive agents that cause bradycardia.1

Bradycardia

Bradycardia can occur with brigatinib. In ALTA, heart rates less than 50 beats per minute (bpm) occurred in 5.7% of patients in the 90 mg group and 7.6% of patients in the 90→180 mg group. Grade 2 bradycardia occurred in 1 (0.9%) patient in the 90 mg group.1

Monitor heart rate and blood pressure during treatment with brigatinib. Monitor patients more frequently if concomitant use of drug known to cause bradycardia cannot be avoided.1

For symptomatic bradycardia, withhold brigatinib and review concomitant medications for those known to cause bradycardia. If a concomitant medication known to cause bradycardia is identified and discontinued or dose adjusted, resume brigatinib at the same dose following resolution of symptomatic bradycardia; otherwise, reduce the dose of brigatinib following resolution of symptomatic bradycardia. Discontinue brigatinib for life-threatening bradycardia if no contributing concomitant medication is identified.1

Visual Disturbance

In ALTA, adverse reactions leading to visual disturbance including blurred vision, diplopia, and reduced visual acuity, were reported in 7.3% of patients receiving brigatinib in the 90 mg group and 10% of patients in the 90→180 mg group. Grade 3 macular edema and cataract occurred in one patient each in the 90→180 mg group.1

Advise patients to report any visual symptoms. Withhold brigatinib and obtain an ophthalmologic evaluation in patients with new or worsening visual symptoms of Grade 2 or greater severity. Upon recovery of Grade 2 or Grade 3 visual disturbances to Grade 1 severity or baseline, resume brigatinib at a reduced dose. Permanently discontinue treatment with brigatinib for Grade 4 visual disturbances.1

Creatine Phosphokinase (CPK) Elevation

In ALTA, creatine phosphokinase (CPK) elevation occurred in 27% of patients receiving brigatinib in the 90 mg group and 48% of patients in the 90 mg→180 mg group. The incidence of Grade 3-4 CPK elevation was 2.8% in the 90 mg group and 12% in the 90→180 mg group.1

Dose reduction for CPK elevation occurred in 1.8% of patients in the 90 mg group and 4.5% in the 90→180 mg group.1

Advise patients to report any unexplained muscle pain, tenderness, or weakness. Monitor CPK levels during brigatinib treatment. Withhold brigatinib for Grade 3 or 4 CPK elevation. Upon resolution or recovery to Grade 1 or baseline, resume brigatinib at the same dose or at a reduced dose.1

Pancreatic Enzyme Elevation

In ALTA, amylase elevation occurred in 27% of patients in the 90 mg group and 39% of patients in the 90→180 mg group. Lipase elevations occurred in 21% of patients in the 90 mg group and 45% of patients in the 90→180 mg group. Grade 3 or 4 amylase elevation occurred in 3.7% of patients in the 90 mg group and 2.7% of patients in the 90→180 mg group. Grade 3 or 4 lipase elevation occurred in 4.6% of patients in the 90 mg group and 5.5% of patients in the 90→180 mg group.1

Monitor lipase and amylase during treatment with brigatinib. Withhold brigatinib for Grade 3 or 4 pancreatic enzyme elevation. Upon resolution or recovery to Grade 1 or baseline, resume brigatinib at the same dose or at a reduced dose. 1

Hyperglycemia

In ALTA, 43% of patients who received brigatinib experienced new or worsening hyperglycemia. Grade 3 hyperglycemia, based on laboratory assessment of serum fasting glucose levels, occurred in 3.7% of patients. Two of 20 (10%) patients with diabetes or glucose intolerance at baseline required initiation of insulin while receiving brigatinib.1

Assess fasting serum glucose prior to initiation of brigatinib and monitor periodically thereafter. Initiate or optimize anti-hyperglycemic medications as needed. If adequate hyperglycemic control cannot be achieved with optimal medical management, withhold brigatinib until adequate hyperglycemic control is achieved and consider reducing the dose of brigatinib or permanently discontinuing brigatinib.1

Embryo-fetal Toxicity

Based on its mechanism of action and findings in animals, brigatinib can cause fetal harm when administered to pregnant women. There are no clinical data on the use of brigatinib in pregnant women. Administration of brigatinib to pregnant rats during the period of organogenesis resulted in dose-related skeletal anomalies at doses as low as 12.5 mg/kg/day (approximately 0.7 times the human exposure by AUC at 180 mg once daily) as well as increased post implantation loss, malformations, and decreased fetal body weight at doses of 25 mg/kg/day (approximately 1.26 times the human exposure at 180 mg once daily) or higher.1

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with brigatinib and for at least 4 months following the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment and for at least 3 months after the last dose of brigatinib.1

Specific Populations

Pregnancy

Based on its mechanism of action and findings in animals, brigatinib can cause fetal harm when administered to a pregnant woman. There are no clinical data on the use of brigatinib in pregnant women. Administration of brigatinib to pregnant rats during the period of organogenesis resulted in dose-related skeletal anomalies at doses as low as 12.5 mg/kg/day (approximately 0.7 times the human exposure by AUC at 180 mg once daily) as well as increased post-implantation loss, malformations, and decreased fetal body weight at doses of 25 mg/kg/day (approximately 1.26 times the human exposure at 180 mg once daily) or greater. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient 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.1

In an embryo-fetal development study in which pregnant rats were administered daily doses of brigatinib during organogenesis, dose-related skeletal (incomplete ossification, small incisors) and visceral anomalies were observed at doses as low as 12.5 mg/kg/day (approximately 0.7 times the human exposure by AUC at 180 mg once daily). Malformations observed at 25 mg/kg/day (approximately 1.26 times the human AUC at 180 mg once daily) included anasarca (generalized subcutaneous edema), anophthalmia (absent eyes), forelimb hyperflexion, small, short and/or bent limbs, multiple fused ribs, bent scapulae, omphalocele (intestine protruding into umbilicus), and gastroschisis (intestines protruding through a defect in the abdominal wall) along with visceral findings of moderate bilateral dilatation of the lateral ventricles.1

Lactation

There are no data regarding the secretion of brigatinib in human milk or its effects on the breastfed infant or milk production. Because of the potential for adverse reactions in breastfed infants, advise lactating women not to breastfeed during treatment with brigatinib and for 1 week following the final dose.1

Females and Males of Reproductive Potential

Brigatinib can cause fetal harm.1

Advise females of reproductive potential to use effective non-hormonal contraception during treatment with brigatinib and for at least 4 months after the final dose. Counsel patients to use a non-hormonal method of contraception since brigatinib can render some hormonal contraceptives ineffective.1

Because of the potential for genotoxicity, advise males with female partners of reproductive potential to use effective contraception during treatment with brigatinib and for at least 3 months after the final dose.1

Based on findings in male reproductive organs in animals, brigatinib may cause reduced fertility in males.1

Pediatric Use

The safety and efficacy of brigatinib in pediatric patients have not been established.1

Geriatric Use

Clinical studies of brigatinib did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients. Of the 222 patients in ALTA, 19.4% were 65-74 years and 4.1% were 75 years or older. No clinically relevant differences in safety or efficacy were observed between patients ≥65 years and younger patients.1

Hepatic Impairment

No dose adjustment is recommended for patients with mild hepatic impairment (total bilirubin within upper limit of normal [ULN] and AST greater than ULN or total bilirubin greater than 1 and up to 1.5 times ULN and any AST). The pharmacokinetics and safety of brigatinib in patients with moderate or severe hepatic impairment have not been studied.1

Renal Impairment

No dose adjustment is recommended for patients with mild and moderate renal impairment [creatinine clearance (CLcr 30 to 89 mL/min estimated by Cockcroft-Gault)]. The pharmacokinetics and safety of brigatinib in patients with severe renal impairment (CLcr 15 to 29 mL/min estimated by Cockcroft-Gault) have not been studied.1

Common Adverse Effects

The most common adverse reactions (≥25%) with brigatinib were nausea, diarrhea, fatigue, cough, and headache.1

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

  • CYP3A Inhibitors: Avoid concomitant use of brigatinib with strong CYP3A inhibitors. If concomitant use of a strong CYP3A inhibitor is unavoidable, reduce the dose of brigatinib.1

  • CYP3A Inducers: Avoid concomitant use of brigatinib with strong CYP3A inducers.1

  • CYP3A Substrates: Hormonal contraceptives may be ineffective due to decreased exposure.1

Actions

Mechanism of Action

Brigatinib is a tyrosine kinase inhibitor with in vitro activity at clinically achievable concentrations against multiple kinases including ALK, ROS1, insulin-like growth factor-1 receptor (IGF-1R), and FLT-3 as well as EGFR deletion and point mutations. Brigatinib inhibited autophosphorylation of ALK and ALK-mediated phosphorylation of the downstream signaling proteins STAT3, AKT, ERK1/2, and S6 in in vitro and in vivo assays. Brigatinib also inhibited the in vitro proliferation of cell lines expressing EML4-ALK and NPM-ALK fusion proteins and demonstrated dose-dependent inhibition of EML4-ALK-positive NSCLC xenograft growth in mice.1

At clinically achievable concentrations (≤ 500 nM), brigatinib inhibited the in vitro viability of cells expressing EML4-ALK and 17 mutant forms associated with resistance to ALK inhibitors including crizotinib, as well as EGFR-Del (E746-A750), ROS1-L2026M, FLT3-F691L, and FLT3-D835Y. Brigatinib exhibited in vivo anti-tumor activity against 4 mutant forms of EML4-ALK, including G1202R and L1196M mutants identified in NSCLC tumors in patients who have progressed on crizotinib. Brigatinib also reduced tumor burden and prolonged survival in mice implanted intracranially with an ALK-driven tumor cell line.1

Advice to Patients

Advise the patient to read the FDA-approved patient labeling (Patient Information).1

Interstitial Lung Disease (ILD)/Pneumonitis

Inform patients of the symptoms and risks of serious pulmonary adverse reactions such as ILD/pneumonitis. Advise patients to immediately report any new or worsening respiratory symptoms.1

Hypertension

Advise patients of risks of hypertension and to promptly report signs or symptoms of hypertension.1

Bradycardia

Advise patients to report any symptoms of bradycardia and to inform their healthcare provider about the use of heart and blood pressure medications.1

Visual Disturbance

Advise patients to inform their healthcare provider of any new or worsening vision symptoms.1

Creatine Phosphokinase (CPK) Elevation

Inform patients of the signs and symptoms of creatine phosphokinase (CPK) elevation and the need for monitoring during treatment. Advise patients to inform their healthcare provider of any new or worsening symptoms of unexplained muscle pain, tenderness, or weakness.1

Pancreatic Enzyme Elevation

Inform patients of the signs and symptoms of pancreatitis and the need to monitor for amylase and lipase elevations during treatment.1

Hyperglycemia

Inform patients of the risks of new or worsening hyperglycemia and the need to periodically monitor glucose levels. Advise patients with diabetes mellitus or glucose intolerance that anti-hyperglycemic medications may need to be adjusted during treatment with brigatinib.1

Females and Males of Reproductive Potential

Advise females and males of reproductive potential that brigatinib can cause fetal harm.1

Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy and to use effective non-hormonal contraception during treatment with brigatinib and for at least 4 months after the final dose.1

Advise males with female partners of reproductive potential to use effective contraception during treatment with brigatinib and for at least 3 months after the final dose.1

Advise females not to breastfeed during treatment with brigatinib and for at least 1 week following the final dose.1

Advise males of reproductive potential of the potential for reduced fertility from brigatinib.1

Drug Interactions

Advise patients to inform their health care provider of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products. Inform patients to avoid grapefruit or grapefruit juice while taking brigatinib.1

Dosing and Administration

Instruct patients to start with 90 mg of brigatinib once daily for the first 7 days and if tolerated, increase the dose to 180 mg once daily. Advise patients to take brigatinib with or without food.1

Missed Dose

Advise patients that if a dose of brigatinib is missed or if the patient vomits after taking a dose of brigatinib, not to take an extra dose, but to take the next dose at the regular time.1

Additional Information

AHFS First Release. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Brigatinib

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablet, Coated

30 mg

Alunbrig

ARIAD Pharmaceuticals Inc.

90 mg

Alunbrig

ARIAD Pharmaceuticals Inc.

AHFS Drug Information. © Copyright 2017, Selected Revisions May 15, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. ARIAD Pharmaceuticals Inc. Alunbrig (Brigatinib) ORAL prescribing information. 2017 May.

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