Brigatinib

Brigatinib is used for anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) in patients who have progressed on or are intolerant to crizotinib.

Brigatinib is available under the following different brand names: Alunbrig.

Dosages of Brigatinib:

Dosage Forms and Strengths

Tablet

• 30mg
• 90mg
• 180mg

Dosage Considerations – Should be Given as Follows:

Non-Small Cell Lung Cancer

• Indicated for anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) in patients who have progressed on or are intolerant to crizotinib
• 90 mg orally once daily for the first 7 days; if 90 mg/day is tolerated, increase the dose to 180 mg orally once daily
• Continue until disease progression or unacceptable toxicity

Dosage Modifications

If treatment is interrupted for 14 days or more for reasons other than adverse reactions, resume at 90 mg once daily for 7 days before increasing to a previously tolerated dose

Dose reduction levels

• 90 mg/day

First reduction: 60 mg once daily

Second reduction: Permanently discontinue

• 180 mg/day
  • First reduction: 120 mg once daily
  • Second reduction: 90 mg once daily
  • Third reduction: 60 mg once daily
  • Permanently discontinue if unable to tolerate 60 mg/day

Interstitial lung disease/pneumonitis

• Grade 1
  • If new pulmonary symptoms occur during the first 7 days of treatment, withhold drug until recovery to baseline, then resume at the same dose and do not escalate to 180 mg if interstitial lung disease (ILD)/pneumonitis is suspected
  • If new pulmonary symptoms occur after the first 7 days of treatment, withhold drug until recovery to baseline, then resume at the same dose
  • If ILD/pneumonitis recurs, permanently discontinue

• Grade 2
  • If new pulmonary symptoms occur during the first 7 days of treatment, withhold drug until recovery to baseline; resume at next lower dose and do not escalate dose if ILD/pneumonitis is suspected
  • If new pulmonary symptoms occur after the first 7 days of treatment, withhold drug until recovery to baseline; if ILD/pneumonitis is suspected, resume at next lower dose; otherwise, resume at the same dose
  • If ILD/pneumonitis recurs, permanently discontinue

• Grade 3 or 4
  • Permanently discontinue drug for ILD/pneumonitis

Hypertension

• Grade 3 (SBP 160 mmHg or greater or DBP 100 mmHg or greater)
  • Withhold drug until hypertension
  • Recurrence: Withhold drug until recovery

• Grade 4 (life-threatening, urgent intervention indicated)
  • Withhold drug until recovery
  • Recurrence: Permanently discontinue

Bradycardia

• Symptomatic
  • Withhold drug until recovery to asymptomatic bradycardia or a resting heart rate of 60 beats per minute (bpm) or greater
  • Discontinue or adjust the dose of concomitant medication known to cause bradycardia, then resume brigatinib at the same dose or to resting heart rate of 60 bpm or greater
  • If no concomitant medication known to cause bradycardia is identified, or if contributing concomitant medications are not discontinued or dose-adjusted, resume brigatinib at the next lower dose

Coadministration with strong or moderate CYP3A inhibitors

• Avoid use
• If coadministration of a strong CYP3A inhibitor cannot be avoided, reduce brigatinib dose by approximately 50% (e.g., from 180 mg to 90 mg, or from 90 mg to 60 mg)
• If coadministration of a moderate CYP3A inhibitor cannot be avoided, reduce once-daily dose by approximately 40% (e.g., from 180 mg to 120 mg, 120 mg to 90 mg, or from 90 mg to 60 mg)
• After discontinuation of a strong or moderate CYP3A inhibitor, resume brigatinib dose that was previously
• tolerated before coadministration

Coadministration with moderate CYP3A inducers

• Avoid use
• If coadministration of a moderate CYP3A inducer cannot be avoided, increase once-daily dose in 30 mg increments after 7 days of treatment with the current dose as tolerated, up to a maximum of twice the dose that was tolerated before initiating a moderate CYP3A inducer
• After discontinuation of a moderate CYP3A inducer, resume dose that was tolerated before initiating the moderate CYP3A inducer

Hepatic impairment

• Mild or moderate (Child-Pugh A or B): No dose adjustment required
• Severe (Child-Pugh C): Reduce once-daily dose by approximately 40% (e.g., from 180 mg to 120 mg, 120 mg to 90 mg, or from 90 mg to 60 mg)

Renal impairment

• Mild or moderate (CrCl 30-89 mL/minute): No dose adjustment is required
• Severe (CrCl 15-29 mL/minute): Reduce brigatinib dose by approximately 50% (e.g., from 180 mg to 90 mg, or from 90 mg to 60 mg)

Safety and efficacy not established in pediatric patients

Common side effects of brigatinib include:

• Increased AST
• High blood sugar (hyperglycemia)
• Increased ALT
• Nausea
• Fatigue
• Headache
• Increased CPK
• Increased amylase
• Shortness of breath
• Vomiting
• Anemia
• Decreased appetite
• Prolonged aPTT
• Increased lipase
• Diarrhea
• Constipation
• Low lymphocytes (lymphopenia)
• Cough
• Abdominal pain
• Increased alkaline phosphatase
• Decreased phosphorous
• Rash
• Fever
• Joint pain
• Numbness and tingling of extremities
• Muscle spasms
• High blood pressure (hypertension)
• Pain in extremity
• Insomnia
• Back pain
• Muscle pain
• Visual disturbances
• Pneumonia
• Interstitial lung disease/pneumonitis
• Low blood oxygen

This document does not contain all possible side effects and others may occur. Check with your physician for additional information about side effects.

If your doctor has directed you to use this medication, your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor, health care provider or pharmacist first.

• Severe interactions of brigatinib include:
  • doravirine
• Brigatinib has serious interactions with at least 93 different drugs.
• Moderate interactions of brigatinib include:
  • alpelisib
  • cenobamate
  • diazepam intranasal
  • duvelisib
  • elagolix
  • encorafenib
  • erdafitinib
  • fedratinib
  • ifosfamide
  • istradefylline
  • levamlodipine
  • levonorgestrel oral/ethinylestradiol/ferrous bisglycinate
  • siponimod
  • stiripentol
  • sufentanil SL
  • tazemetostat
  • tecovirimat
  • tinidazole
  • ubrogepant
• Brigatinib has no listed mild interactions with other drugs.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist. Check with your physician if you have health questions or concerns.

Warnings

• This medication contains brigatinib. Do not take Alunbrig if you are allergic to brigatinib or any ingredients contained in this drug.
• Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center immediately.

Contraindications

• None

Effects of Drug Abuse

• No information is available

Short-Term Effects

• See "What Are Side Effects Associated with Using Brigatinib?”

Long-Term Effects

• See "What Are Side Effects Associated with Using Brigatinib?”

Cautions

• Severe, life-threatening, and fatal pulmonary adverse reactions consistent with interstitial lung disease (ILD)/pneumonitis have occurred with brigatinib; monitor for new or worsening respiratory symptoms (e.g., dyspnea, cough), particularly during the first week of initiating
• Dose-related hypertension reported; control blood pressure (BP) before treatment; monitor BP after 2 weeks and at least monthly thereafter
• Bradycardia (heart rate [HR] less than 50 bpm) reported; monitor HR and BP; monitor more frequently if concomitant use of drugs known to cause bradycardia cannot be avoided
• May cause visual disturbances; advise patients to report any visual symptoms
• Increased CPK reported; advise patients to report any unexplained muscle pain, tenderness, or weakness; monitor CPK during treatment
• Serum pancreatic enzyme elevation reported; monitor lipase and amylase during treatment
• May cause new or worsening hyperglycemia; assess fasting serum glucose before initiating drug and periodically thereafter; initiate or optimize antihyperglycemic medications as needed
• May cause fetal harm

Drug interaction overview

• Brigatinib is a substrate and inducer of CYP3A
• Strong or moderate CYP3A inhibitors increase brigatinib plasma concentrations and may increase adverse effects; avoid coadministration (see Dosage Modifications)
• Strong or moderate CYP3A inducers may decrease brigatinib plasma concentrations and result in decreased efficacy; avoid coadministration
• CYP3A substrates
  • Brigatinib induces CYP3A in vitro and may decrease concentrations of CYP3A substrates
  • Coadministration with CYP3A substrates, including hormonal contraceptives, can result in decreased concentrations and loss of efficacy

Pregnancy and Lactation

• Based on its mechanism of action and findings in animals, brigatinib can cause fetal harm when administered to pregnant women. Based on findings in male reproductive organs in animals, brigatinib may cause reduced fertility in males.
• Females of reproductive potential are advised to use effective nonhormonal contraception during treatment with brigatinib and for at least 4 months after the final dose. Brigatinib can render some hormonal contraceptives ineffective. Because of the potential for genotoxicity, males with female partners of reproductive potential are advised to use effective contraception during treatment with brigatinib and for at least 3 months after the final dose.
• It is unknown if brigatinib is distributed in human breast milk. Because of the potential for adverse reactions in breastfed infants, lactating women are advised not to breastfeed during treatment with brigatinib and for 1 week following the final dose.