brigatinib (Rx)

Brand and Other Names:Alunbrig
  • Print

Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

tablet

  • 30mg
  • 90mg
  • 180mg

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 PO qDay for the first 7 days; if 90 mg/day is tolerated, increase the dose to 180 mg PO qDay

Continue until disease progression or unacceptable toxicity

Also see Administration

Dosage Modifications

Dose reduction levels

  • 90 mg/day
    • First reduction: 60 mg qDay
    • Second reduction: Permanently discontinue
  • 180 mg/day
    • First reduction: 120 mg qDay
    • Second reduction: 90 mg qDay
    • Third reduction: 60 mg qDay
    • 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 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 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 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 DBP ≥ 100 mmHg)
    • Withhold drug until hypertension <grade 1 (SBP <140 mmHg and DBP <90 mmHg), then resume at next lower dose
    • Recurrence: Withhold drug until recovery to <grade1, then resume at next lower dose or permanently discontinue
  • Grade 4 (life-threatening, urgent intervention indicated)
    • Withhold drug until recovery to <grade 1 and resume at next lower dose or permanently discontinue
    • Recurrence: Permanently discontinue

Bradycardia

  • Symptomatic
    • Withhold drug until recovery to asymptomatic bradycardia or to a resting heart rate ≥60 bpm
    • Discontinue or adjust dose of concomitant medication known to cause bradycardia, then resume brigatinib at same dose or to resting heart rate of ≥60 bpm
    • If no concomitant medication known to cause bradycardia is identified, or if contributing concomitant medications are not discontinued or dose-adjusted, resume brigatinib at next lower dose
  • Life-threating, urgent intervention indicated
    • Permanently discontinue brigatinib if no contributing concomitant medication is identified
    • If contributing concomitant medication is identified and discontinued or dose-adjusted, resume brigatinib at next lower dose upon recovery to asymptomatic bradycardia or to a resting heart rate of ≥60, with frequent monitoring as clinically indicated
    • Recurrence: Permanently discontinue

Visual disturbance

  • Grade 2 or 3: Withhold drug until recovery to grade 1 or baseline, then resume at next lower dose
  • Grade 4: Permanently discontinue

Creatine phosphokinase (CPK) elevation

  • Grade 3 (CPK >5 x ULN): Withhold drug until recovery to ≤grade 1 (<2.5 x ULN) or baseline, then resume at same dose
  • Grade 4 (CPK >10 x ULN) or grade 3 recurrence: Withhold until recovery to ≤grade 1 or to baseline, then resume at next lower dose

Lipase/amylase elevation

  • Grade 3 (lipase or amylase >2 x ULN): Withhold drug until recovery to ≤grade 1 (≤1.5 × ULN) or to baseline, then resume at same dose
  • Grade 4 (lipase or amylase >5 x ULN) or grade 3 recurrence: Withhold drug until recovery to ≤grade 1 or to baseline, then resume at next lower dose

Hyperglycemia

  • ≥Grade 3 (>250 mg/dL): Withhold drug until recovery to ≤grade 1 or baseline, then resume at next lower dose

Other toxicity

  • Grade 3
    • Withhold drug until recovery to baseline, then resume at same dose
    • Recurrence: Withhold drug until recovery to baseline, then resume at next lower dose or discontinue
  • Grade 4
    • First occurrence: Either withhold drug until recovery to baseline and resume at next lower dose or permanently discontinue
    • Recurrence: Permanently discontinue

Coadministration with strong CYP3A inhibitors

  • Avoid concomitant us
  • If a strong CYP3A inhibitor cannot be avoided, reduce brigatinib dose by ~50% (eg, from 180 mg to 90 mg, or from 90 mg to 60 mg)
  • After discontinuation of a strong CYP3A inhibitor, resume brigatinib dose that was previously tolerated before coadministration

Hepatic impairment

  • Mild: No dose adjustment required
  • Moderate-to severe: Not studied

Renal impairment

  • Mild-to-moderate (CrCl 30-89 mL/min): No dose adjustment required
  • Severe (CrCl 15-29 mL/min): Not studied

Dosing Considerations

NSCLC: Approved under accelerated approval based on tumor response rate and duration of response; continued approval may be contingent upon verification and description of clinical benefit in a confirmatory trial

Safety and efficacy not established

Next:

Interactions

Interaction Checker

and brigatinib

No Results

     activity indicator 
    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

          Minor

            All Interactions Sort By:
             activity indicator 
            Previous
            Next:

            Adverse Effects

            >10%

            Increased AST (38%)

            Hyperglycemia (38%)

            Increased ALT (34%)

            Nausea (33%)

            Fatigue (29%)

            Headache (28%)

            Increased CPK (27%)

            Increased amylase (27%)

            Dyspnea (27%)

            Vomiting (24%)

            Anemia (23%)

            Decreased appetite (22%)

            Prolonged aPTT (22%)

            Increased lipase (21%)

            Diarrhea (19%)

            Constipation (19%)

            Lymphopenia (19%)

            Cough (18%)

            Abdominal pain (17%)

            Increased alkaline phosphatase (15%)

            Decreased phosphorous (15%)

            Rash (15%)

            Pyrexia (14%)

            Arthralgia (14%)

            Peripheral neuropathy (13%)

            Muscle spasms (12%)

            Hypertension (11%)

            Pain in extremity (11%)

            Insomnia (11%)

            1-10%

            Back pain (10%)

            Myalgia (9.2%)

            Visual disturbances (7.3%)

            Pneumonia (4.6%)

            Interstitial lung disease/pneumonitis (3.7%)

            <1%

            Hypoxia (0.9%)

            Previous
            Next:

            Warnings

            Contraindications

            None

            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 (eg, dyspnea, cough), particularly during the first week of initiating (see Dosage Modifications)

            Dose-related hypertension reported; control BP prior to treatment; monitor BP after 2 weeks and at least monthly thereafter (see Dosage Modifications)

            Bradycardia (HR <50 bpm) reported; monitor HR and BP; monitor more frequently if concomitant use of drugs known to cause bradycardia cannot be avoided (see Dosage Modifications)

            May cause visual disturbances; advise patients to report any visual symptoms (see Dosage Modifications)

            Increased CPK reported; advise patients to report any unexplained muscle pain, tenderness, or weakness; monitor CPK during treatment (see Dosage Modifications)

            Serum pancreatic enzyme elevation reported; monitor lipase and amylase during treatment (see Dosage Modifications)

            May cause new or worsening hyperglycemia; assess fasting serum glucose before initiating drug and periodically thereafter; initiate or optimize antihyperglycemic medications as needed (see Dosage Modifications)

            May cause fetal harm (see Pregnancy)

            Drug interaction overview

            • Brigatinib is a substrate and inducer of CYP3A
            • Strong CYP3A inhibitors increase brigatinib plasma concentrations and may increase adverse effects; avoid coadministration (see Dosage Modifications)
            • Strong 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
            Previous
            Next:

            Pregnancy

            Pregnancy

            Based on its mechanism of action and findings in animals, can cause fetal harm when administered to pregnant women

            Administration to pregnant rats during the period of organogenesis resulted in dose-related skeletal anomalies at doses as low as 12.5 mg/kg/day (~0.7 times the human exposure by AUC at 180 mg once daily), as well as increased postimplantation loss, malformations, and decreased fetal body weight at doses of 25 mg/kg/day (~1.26 times the human exposure at 180 mg once daily) or greater

            Infertility: Based on findings in male reproductive organs in animals, may cause reduced fertility in males

            Contraception

            • Females: Advise females of reproductive potential to use effective nonhormonal contraception during treatment and for at least 4 months after the final dose
            • Counsel patients to use a nonhormonal method of contraception since brigatinib can render some hormonal contraceptives ineffective
            • Males: Because of the potential for genotoxicity, advise males with female partners of reproductive potential to use effective contraception during treatment and for at least 3 months after the final dose

            Lactation

            Unknown if distributed in human breast milk

            Because of the potential for adverse reactions in breastfed infants, advise lactating women not to breastfeed during treatment and for 1 week following the final dose

            Pregnancy Categories

            A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA:Information not available.

            more...
            Previous
            Next:

            Pharmacology

            Mechanism of Action

            Tyrosine kinase inhibitor with in vitro activity at clinically achievable concentrations against multiple kinases, including ALK, ROS1, insulinlike 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

            Exhibited in vivo antitumor activity against 4 mutant forms of EML4-ALK, including G1202R and L1196M mutants identified in NSCLC tumors in patients who have progressed on crizotinib

            Also reduced tumor burden and prolonged survival in mice implanted intracranially with an ALK-driven tumor cell line

            Absorption

            Peak plasma time: 1-4 hr

            Peak plasma concentration: 552 ng/mL (90 mg); 1452 ng/mL (180 mg)

            AUC: 8165 ng·h/mL (90 mg); 20,276 ng·h/mL (180 mg)

            Distribution

            Protein bound: 66%

            Vd: 153 L (steady-state)

            Metabolism

            Primarily metabolized by CYP2C8 and CYP3A4

            Active metabolite: AP26123 is ~3-fold less potent than brigatinib

            Elimination

            Half-life: 25 hr

            Oral clearance: 12.7 L/h

            Excretion: 65% feces; 25% urine (unchanged brigatinib represented 41% and 86% of the total radioactivity in feces and urine, respectively)

            Previous
            Next:

            Administration

            Oral Administration

            Take with or without food

            Swallow tablets whole; do not crush or chew tablets

            Dosing interrupted for ≥14 days

            • If dosing interrupted for ≥14 days for reasons other than adverse reactions, resume treatment at 90 mg once daily for 7 days before increasing to the previously tolerated dose

            Missed or vomited dose

            • Do not administer an additional dose
            • Take the next dose at the next scheduled time

            Storage

            Store at room temperature 20-25°C (68-77°F); excursion permitted between 15-30°C (59-86°F)

            Previous
            Next:

            Images

            Previous
            Next:

            Formulary

            FormularyPatient Discounts

            Adding plans allows you to compare formulary status to other drugs in the same class.

            To view formulary information first create a list of plans. Your list will be saved and can be edited at any time.

            Adding plans allows you to:

            • View the formulary and any restrictions for each plan.
            • Manage and view all your plans together – even plans in different states.
            • Compare formulary status to other drugs in the same class.
            • Access your plan list on any device – mobile or desktop.

            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
            QL Quantity Limits
            Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
            ST Step Therapy
            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
            OR Other Restrictions
            Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
            Additional Offers
            Email to Patient

            From:

            To:

            The recipient will receive more details and instructions to access this offer.

            By clicking send, you acknowledge that you have permission to email the recipient with this information.

            Email Forms to Patient

            From:

            To:

            The recipient will receive more details and instructions to access this offer.

            By clicking send, you acknowledge that you have permission to email the recipient with this information.

            Previous