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  • CLASSES

    Small Molecule Antineoplastic Anaplastic Lymphoma Kinase (ALK) Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    Tyrosine kinase inhibitor that targets multiple kinases
    Used for the treatment of patients with ALK-positive metastatic NSCLC
    Warnings include interstitial lung disease/pneumonitis, bradycardia, hypertension, visual disturbances, CPK elevations, elevated pancreatic enzymes, and hypergylcemia; non-hormonal contraception needed for females of reproductive potential

    COMMON BRAND NAMES

    Alunbrig

    HOW SUPPLIED

    Alunbrig/Brigatinib Oral Tab: 30mg, 90mg, 180mg, 90-180mg

    DOSAGE & INDICATIONS

    For the treatment of anaplastic lymphoma kinase (ALK)-positive, non-small cell lung cancer (NSCLC).
    NOTE: The FDA has designated brigatinib as an orphan drug for the treatment of ALK-positive NSCLC.
    NOTE: Patients should be selected based on the presence of ALK positivity in tumor specimens. Information on FDA-approved tests for the detection of ALK rearrangements in NSCLC is available at www.fda.gov/CompanionDiagnostics.
    For the treatment of metastatic, ALK-positive, NSCLC in patients who have not previously received an ALK inhibitor.
    Oral dosage
    Adults

    90 mg PO once daily for 7 days; then increase the dose to 180 mg PO once daily. Continue until disease progression or unacceptable toxicity. If treatment is interrupted for 14 days or longer for reasons other than adverse reactions, resume treatment at 90 mg once daily for 7 days before increasing to the previously tolerated dose. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. After a median follow-up of 24.9 months, treatment with brigatinib was superior to crizotinib in terms of blinded independent review committee (BIRC)-assessed progression-free survival (PFS) (24 months vs. 11 months) and investigator-assessed PFS (29.4 months vs. 9.2 months) in patients with locally advanced or metastatic NSCLC who had not previously been treated with an ALK inhibitor in the second interim analysis of an open-label phase 3 clinical trial (ALTA-1L study). Brigatinib also delayed the median time to worsening of global health status / quality of life scores compared with crizotinib.

    For the treatment of metastatic, ALK-positive, NSCLC in patients who have progressed on or are intolerant to crizotinib.
    Oral dosage
    Adults

    90 mg PO once daily for 7 days; then increase the dose to 180 mg PO once daily. Continue until disease progression or unacceptable toxicity. If treatment is interrupted for 14 days or longer for reasons other than adverse reactions, resume treatment at 90 mg once daily for 7 days before increasing to the previously tolerated dose. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In a multicenter open-label clinical trial (ALTA), patients with locally advanced or metastatic ALK-positive NSCLC who received brigatinib after progression on crizotinib had an overall response rate as assessed by an independent review committee (IRC) of 48% (complete response (CR), 3.6%) after treatment with 90 mg once daily (n = 112), and 53% (CR, 4.5%) after treatment with 180 mg once daily (after 90 mg once daily for 7 days) (n = 110), with a median duration of response of 13.8 months in both groups. In the subgroup of patients with measurable brain metastases, the intracranial overall response rate was 42% (CR, 7.7%; partial response (PR), 35%) in patients treated with brigatinib 90 mg daily (n = 26) and 67% (CR, 0%; PR, 67%) in patients treated with 180 mg daily (n = 18). The duration of intracranial response was not estimable in the 90-mg arm (range, 1.9 to 9.2+ months) and 5.6 months in the 180-mg arm (range, 1.9 to 9.2+ months).[61909]

    MAXIMUM DOSAGE

    Adults

    180 mg PO once daily.

    Geriatric

    180 mg PO once daily.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Baseline Hepatic Impairment
    Mild to moderate hepatic impairment (Child-Pugh A or B): No dosage adjustment necessary.
    Severe hepatic impairment (Child-Pugh C): Reduce the dose of brigatinib by approximately 40% without breaking tablets (i.e., from 180 mg to 120 mg; from 120 mg to 90 mg; from 90 mg to 60 mg).[61909]

    Renal Impairment

    Baseline Renal Impairment
    Mild to moderate renal impairment (CrCL 30 to 89 mL/min): No dosage adjustment necessary.
    Severe renal impairment (CrCL 15 to 29 mL/min): Reduce the dose of brigatinib by approximately 50% without breaking tablets (i.e., from 180 mg to 90 mg; from 90 mg to 60 mg).

    ADMINISTRATION

    Emetic Risk
    Minimal/Low
    Administer prn antiemetics as necessary.

    Oral Administration
    Oral Solid Formulations

    May be taken orally with or without food.
    Swallow tablet whole; do not crush or chew.
    If a dose is missed, or if vomiting occurs after taking a dose, take the dose at the next scheduled time. Do not repeat doses or make up missed doses.

    STORAGE

    Alunbrig:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Pneumonitis, pulmonary disease

    Use brigatinib with caution in patients with pre-existing pulmonary disease. Monitor patients for new or worsening respiratory symptoms (e.g., dyspnea, cough, etc.), especially during the first week of therapy. Hold brigatinib therapy and promptly evaluate any patient with signs or symptoms of interstitial lung disease (ILD) or pneumonitis. After diagnosis of grade 1 or 2 ILD/pneumonitis, brigatinib therapy may either be resumed after recovery to baseline or permanently discontinued. Permanently discontinue brigatinib if grade 3 or 4 ILD/pneumonitis is diagnosed or for recurrent grade 1 or 2 ILD/pneumonitis.

    Bradycardia, hypertension

    Hypertension and bradycardia have occurred in patients treated with brigatinib in clinical trials. Control blood pressure before starting treatment. Monitor blood pressure after 2 weeks of brigatinib therapy, and at least monthly thereafter during treatment. Monitore heart rate during therapy, and more frequently if concomitant use with drugs known to cause bradycardia cannot be avoided. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for either hypertension or bradycardia. Use caution when administering brigatinib in combination with antihypertensive or other medications that cause bradycardia.

    Cataracts, visual disturbance, visual impairment

    Visual impairment and visual disturbance, including cataracts, have been reported in patients treated brigatinib therapy in a multicenter, open-label clinical trial of patients with locally advanced or metastatic NSCLC. Advise patients to report any visual symptoms; hold treatment and obtain an ophthalmic evaluation for any new or worsening visual symptoms of grade 2 or higher severity; an interruption of therapy, dose reduction, or discontinuation of therapy may be necessary.

    Myopathy

    Elevated creatine phosphokinase (CPK) has occurred during treatment with brigatinib in clinical trials. Advise patients to report any unexplained myopathy, muscle tenderness, or muscle weakness. Monitor CPK levels during treatment; an interruption of therapy, dose reduction, or discontinuation of therapy may be necessary in patients who develop an elevated CPK level with grade 2 or higher muscle pain or weakness.

    Pancreatitis

    Use brigatinib with caution in patients who have a history of pancreatitis. Treatment with brigatinib was associated with increases in pancreatic enzymes (i.e., lipase, amylase) in a multicenter, open-label clinical trial. Monitor lipase and amylase during treatment; an interruption of therapy or dose reduction may be necessary. Advise patients to report any new or worsening signs of pancreatitis including abdominal pain, pain with eating, weight loss, or nausea.

    Diabetes mellitus, hyperglycemia

    New or worsening hyperglycemia has been reported with brigatinib therapy in a multicenter, open-label clinical trial. Two patients with diabetes or glucose intolerance at baseline (n = 20) required initiation of insulin while receiving brigatinib. Assess fasting blood glucose prior to initiation of brigatinib therapy and monitor periodically thereafter. Antihyperglycemic medications should be started and medical management of blood glucose optimized as appropriate. If adequate glycemic control cannot be achieved, an interruption of therapy, dose reduction, or discontinuation of therapy may be necessary. Brigatinib should be used with caution in patients with diabetes mellitus.

    Sunlight (UV) exposure

    Brigatinib can cause photosensitivity. Advise patients to limit sunlight (UV) exposure during treatment and for at least 5 days after discontinuation of therapy, including wearing a hat and protective clothing when outside and using broad-spectrum UVA/UVB sunscreen and lip balm (SPF 30 or higher). An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary based on the severity of the reaction.

    Pregnancy

    Pregnancy should be avoided by females of reproductive potential during brigatinib treatment and for at least 4 months after the last dose. Although there are no adequately controlled studies in pregnant women, brigatinib can cause fetal harm when administered during pregnancy based on its mechanism of action and animal studies. Women who are pregnant or who become pregnant while receiving brigatinib should be apprised of the potential hazard to the fetus. When administered to pregnant rats during organogenesis, dose-related skeletal incomplete ossification, small incisors) and visceral anomalies occurred at exposures of approximately 0.7 times the human exposure at the recommended dose of 180 mg once daily, as well as increased post-implantation loss, malformations (anasarca, anophthalmia, forelimb hyperflexion, small, short, and/or bent limbs, fused ribs, bent scapulae, omphalocele, and gastroschisis), visceral findings of moderate bilateral dilatation of the lateral ventricles, and decreased fetal body weight at exposures of approximately 1.26 times the human exposure at the recommended dose or higher.

    Contraception requirements, infertility, pregnancy testing, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during brigatinib treatment. Brigatinib can be teratogenic if taken by the mother during pregnancy. Females of reproductive potential should avoid pregnancy and use effective contraception during treatment with brigatinib and for at least 4 months after the last dose. Male with female partners of reproductive potential should use effective contraception during treatment and for at least 3 months after the last dose. Females of reproductive potential should undergo pregnancy testing prior to initiation of brigatinib. Women who become pregnant while receiving brigatinib should be apprised of the potential hazard to the fetus. Although there are no data regarding the effect of brigatinib on human fertility, male infertility has been observed in animal studies. Testicular toxicity occurred in repeat-dose animal studies at exposures as low as 0.2 times the exposure in humans at the recommended dose of 180 mg once daily. In rats, these findings included lower weight of the testicles, seminal vesicles, and prostate gland, as well as testicular tubular degeneration; these effects were not reversible during the 2-month recovery period. In monkeys, findings included reduced testicular size and microscopic evidence of hypospermatogenesis; these effects were reversible during the recovery period.[61909]

    Breast-feeding

    Due to the potential for serious adverse reactions in nursing infants from brigatinib, advise women to discontinue breast-feeding during treatment and for 1 week after the final dose.

    ADVERSE REACTIONS

    Severe

    hyperkalemia / Delayed / 0-24.0
    hypertension / Early / 6.4-13.0
    lymphopenia / Delayed / 4.5-9.3
    hyperglycemia / Delayed / 3.6-7.5
    hyperamylasemia / Delayed / 2.7-6.8
    infection / Delayed / 0-5.5
    elevated hepatic enzymes / Delayed / 2.7-5.2
    hypophosphatemia / Delayed / 3.6-3.7
    rash / Early / 2.9-3.6
    dyspnea / Early / 1.8-2.9
    hypoxia / Early / 0-2.7
    interstitial lung disease / Delayed / 2.2-2.7
    pneumonitis / Delayed / 2.2-2.7
    anemia / Delayed / 0.9-2.3
    pulmonary embolism / Delayed / 0-2.2
    nausea / Early / 0.9-2.2
    diarrhea / Early / 0-2.2
    headache / Early / 0.9-2.2
    back pain / Delayed / 0.7-1.8
    peripheral neuropathy / Delayed / 0.7-1.8
    fatigue / Early / 0-1.5
    asthenia / Delayed / 0-1.5
    macular edema / Delayed / 0-1.0
    visual impairment / Early / 0-0.9
    myalgia / Early / 0-0.9
    musculoskeletal pain / Early / 0-0.9
    anorexia / Delayed / 0-0.9
    fever / Early / 0.7-0.9
    prolonged bleeding time / Delayed / 0-0.9
    hypoalbuminemia / Delayed / 0-0.8
    stroke / Early / 0-0.7
    bradycardia / Rapid / 0-0.7
    abdominal pain / Early / 0-0.7
    vomiting / Early / 0-0.7
    stomatitis / Delayed / 0-0.7
    dizziness / Early / 0-0.7
    photosensitivity / Delayed / 0-0.7
    pruritus / Rapid / 0-0.7
    edema / Delayed / 0-0.7
    night blindness / Delayed / Incidence not known
    exfoliative dermatitis / Delayed / Incidence not known
    nephrotoxicity / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known

    Moderate

    leukopenia / Delayed / 28.0-28.0
    hypercalcemia / Delayed / 0-22.0
    hypomagnesemia / Delayed / 0-21.0
    hyponatremia / Delayed / 20.0-20.0
    hypokalemia / Delayed / 19.0-19.0
    hypocalcemia / Delayed / 0-15.0
    hypercholesterolemia / Delayed / 0-13.0
    neutropenia / Delayed / 0-12.0
    thrombocytopenia / Delayed / 10.0-10.0
    meningitis / Delayed / 0-1.0
    blurred vision / Early / Incidence not known
    photopsia / Delayed / Incidence not known
    cataracts / Delayed / Incidence not known
    photophobia / Early / Incidence not known
    oral ulceration / Delayed / Incidence not known
    hyperesthesia / Delayed / Incidence not known
    migraine / Early / Incidence not known
    palmar-plantar erythrodysesthesia (hand and foot syndrome) / Delayed / Incidence not known
    erythema / Early / Incidence not known
    bullous rash / Early / Incidence not known
    contact dermatitis / Delayed / Incidence not known
    peripheral edema / Delayed / Incidence not known

    Mild

    cough / Delayed / 34.0-35.0
    muscle cramps / Delayed / 0-17.0
    pharyngitis / Delayed / 0-8.0
    dyspepsia / Early / 0-8.0
    insomnia / Early / 0-7.3
    xerosis / Delayed / 4.7-4.7
    dysgeusia / Early / 0-2.9
    gastroesophageal reflux / Delayed / 0-0.7
    diplopia / Early / Incidence not known
    dysesthesia / Delayed / Incidence not known
    hypoesthesia / Delayed / Incidence not known
    paresthesias / Delayed / Incidence not known
    acneiform rash / Delayed / Incidence not known
    maculopapular rash / Early / Incidence not known
    urticaria / Rapid / Incidence not known

    DRUG INTERACTIONS

    Abacavir; Dolutegravir; Lamivudine: (Moderate) Monitor for an increase in dolutegravir-related adverse reactions if coadministration with brigatinib is necessary. Dolutegravir is a substrate of P-glycoprotein (P-gp) and BCRP. Brigatinib inhibits both P-gp and BCRP in vitro and may have the potential to increase concentrations of substrates of these transporters.
    Acetaminophen; Codeine: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with brigatinib is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If brigatinib is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. brigatinib is a weak CYP3A4 inducer. Concomitant use with brigatinib can increase norcodeine levels via increased CYP3A4 metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Acetaminophen; Hydrocodone: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with brigatinib is necessary; consider increasing the dose of hydrocodone as needed. If brigatinib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and brigatinib is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Acetaminophen; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with brigatinib is necessary; consider increasing the dose of oxycodone as needed. If brigatinib is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and brigatinib is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Afatinib: (Moderate) If the concomitant use of brigatinib and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of brigatinib. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate. Brigatinib is a P-gp inhibitor in vitro and may have the potential to increase concentrations of P-gp substrates. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    Alfentanil: (Moderate) Consider an increased dose of alfentanil and monitor for evidence of opioid withdrawal if coadministration with brigatinib is necessary. If brigatinib is discontinued, consider reducing the alfentanil dosage and monitor for evidence of respiratory depression. Brigatinib is a weak CYP3A inducer. Coadministration of a CYP3A4 inducer like brigatinib with alfentanil, a CYP3A4 substrate, may decrease exposure to alfentanil resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to alfentanil. Alfentanil plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
    Alogliptin; Metformin: (Moderate) Consider the benefits and risks of concomitant therapy of brigatinib with metformin. Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., MATE inhibitors) could increase systemic exposure to metformin and increase the risk for lactic acidosis. Brigatinib inhibits MATE1 and MATE2K in vitro and may have the potential to increase concentrations of coadministered substrates of these transporters.
    Alpelisib: (Major) Avoid coadministration of alpelisib with brigatinib due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and brigatinib is a BCRP inhibitor.
    Amiodarone: (Major) Avoid coadministration of brigatinib with amiodarone if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 40% without breaking tablets (i.e., from 180 mg to 120 mg; from 120 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of amiodarone, resume the brigatinib dose that was tolerated prior to initiation of amiodarone. Brigatinib is a CYP3A4 substrate; amiodarone is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase the AUC of brigatinib by approximately 40%.
    Amlodipine; Atorvastatin: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions including myopathy and rhabdomyolysis if coadministration with brigatinib is necessary. Atorvastatin is a P-glycoprotein (P-gp) substrate. Brigatinib is a P-gp inhibitor in vitro and may have the potential to increase concentrations of P-gp substrates.
    Amobarbital: (Major) Avoid coadministration of brigatinib with amobarbital due to decreased plasma exposure to brigatinib which may result in decreased efficacy. If concomitant use is unavoidable, after 7 days of concomitant treatment with amobarbital, increase the dose of brigatinib as tolerated in 30 mg increments to a maximum of twice the original brigatinib dose. After discontinuation of amobarbital, resume the brigatinib dose that was tolerated prior to initiation of amobarbital. Brigatinib is a CYP3A4 substrate and amobarbital is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of brigatinib by approximately 50%.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid coadministration of brigatinib with clarithromycin if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 50% without breaking tablets (i.e., from 180 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of clarithromycin, resume the brigatinib dose that was tolerated prior to initiation of clarithromycin. Brigatinib is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively.
    Apalutamide: (Major) Avoid coadministration of brigatinib with apalutamide due to decreased plasma exposure to brigatinib which may result in decreased efficacy. Brigatinib is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased the AUC and Cmax of brigatinib by 80% and 60%, respectively.
    Aprepitant, Fosaprepitant: (Major) Avoid coadministration of brigatinib with multiple daily doses of oral aprepitant if possible due to increased plasma exposure of brigatinib. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 40% without breaking tablets (i.e., from 180 mg to 120 mg; from 120 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of aprepitant, resume the brigatinib dose that was tolerated prior to initiation of aprepitant. Brigatinib is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor. When administered as a single oral or single intravenous dose, the inhibitory effect of aprepitant on CYP3A4 is weak and did not result in a clinically significant increase in the AUC of a sensitive substrate. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase the AUC of brigatinib by approximately 40%.
    Aspirin, ASA; Butalbital; Caffeine: (Major) Avoid coadministration of brigatinib with butalbital due to decreased plasma exposure to brigatinib which may result in decreased efficacy. If concomitant use is unavoidable, after 7 days of concomitant treatment with butalbital, increase the dose of brigatinib as tolerated in 30 mg increments to a maximum of twice the original brigatinib dose. After discontinuation of butalbital, resume the brigatinib dose that was tolerated prior to initiation of butalbital. Brigatinib is a CYP3A4 substrate and butalbital is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of brigatinib by approximately 50%.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Avoid coadministration of brigatinib with butalbital due to decreased plasma exposure to brigatinib which may result in decreased efficacy. If concomitant use is unavoidable, after 7 days of concomitant treatment with butalbital, increase the dose of brigatinib as tolerated in 30 mg increments to a maximum of twice the original brigatinib dose. After discontinuation of butalbital, resume the brigatinib dose that was tolerated prior to initiation of butalbital. Brigatinib is a CYP3A4 substrate and butalbital is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of brigatinib by approximately 50%. (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with brigatinib is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If brigatinib is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. brigatinib is a weak CYP3A4 inducer. Concomitant use with brigatinib can increase norcodeine levels via increased CYP3A4 metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with brigatinib is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If brigatinib is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. brigatinib is a weak CYP3A4 inducer. Concomitant use with brigatinib can increase norcodeine levels via increased CYP3A4 metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Aspirin, ASA; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with brigatinib is necessary; consider increasing the dose of oxycodone as needed. If brigatinib is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and brigatinib is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Atazanavir: (Major) Avoid coadministration of brigatinib with atazanavir if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 50% without breaking tablets (i.e., from 180 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of atazanavir, resume the brigatinib dose that was tolerated prior to initiation of atazanavir. Brigatinib is a CYP3A4 substrate; atazanavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively.
    Atazanavir; Cobicistat: (Major) Avoid coadministration of brigatinib with atazanavir if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 50% without breaking tablets (i.e., from 180 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of atazanavir, resume the brigatinib dose that was tolerated prior to initiation of atazanavir. Brigatinib is a CYP3A4 substrate; atazanavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively. (Major) Avoid coadministration of brigatinib with cobicistat if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 50% without breaking tablets (i.e., from 180 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of cobicistat, resume the brigatinib dose that was tolerated prior to initiation of cobicistat. Brigatinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively.
    Atorvastatin: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions including myopathy and rhabdomyolysis if coadministration with brigatinib is necessary. Atorvastatin is a P-glycoprotein (P-gp) substrate. Brigatinib is a P-gp inhibitor in vitro and may have the potential to increase concentrations of P-gp substrates.
    Atorvastatin; Ezetimibe: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions including myopathy and rhabdomyolysis if coadministration with brigatinib is necessary. Atorvastatin is a P-glycoprotein (P-gp) substrate. Brigatinib is a P-gp inhibitor in vitro and may have the potential to increase concentrations of P-gp substrates.
    Avanafil: (Major) Coadministration of avanafil with brigatinib is not recommended by the manufacturer of avanafil due to the potential for decreased avanafil efficacy. Avanafil is a CYP3A4 substrate and brigatinib is a weak CYP3A4 inducer. Although the potential effect of CYP inducers on the pharmacokinetics of avanafil was not evaluated, plasma concentrations may decrease.
    Avapritinib: (Major) Avoid coadministration of avapritinib with brigatinib due to the risk of decreased avapritinib efficacy. Avapritinib is a CYP3A4 substrate and brigatinib is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer is predicted to decrease the AUC and Cmax of avapritinib by 62% and 55%, respectively.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Avoid coadministration of brigatinib with phenobarbital due to decreased plasma exposure to brigatinib which may result in decreased efficacy. Brigatinib is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased the AUC and Cmax of brigatinib by 80% and 60%, respectively.
    Benzhydrocodone; Acetaminophen: (Moderate) Monitor for reduced efficacy of benzhydrocodone and signs of opioid withdrawal if coadministration with brigatinib is necessary; consider increasing the dose of benzhydrocodone as needed. If brigatinib is discontinued, consider a dose reduction of benzhydrocodone and frequently monitor for signs of respiratory depression and sedation. Benzhydrocodone is a prodrug for hydrocodone. Hydrocodone is a CYP3A4 substrate and brigatinib is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Berotralstat: (Major) Avoid coadministration of brigatinib with berotralstat if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 40% without breaking tablets (i.e., from 180 mg to 120 mg; from 120 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of berotralstat, resume the brigatinib dose that was tolerated prior to initiation of berotralstat. Additionally, reduce the berotralstat dose to 110 mg PO once daily as concurrent use may increase berotralstat exposure and the risk of adverse effects. Brigatinib is a CYP3A4 substrate and P-gp and BCRP inhibitor; berotralstat is a P-gp and BCRP substrate and moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase the AUC of brigatinib by approximately 40%, while coadministration with another P-gp and BCRP inhibitor increased berotralstat exposure by 69%.
    Betrixaban: (Moderate) Monitor for an increase in betrixaban-related adverse reactions, including bleeding, if coadministration with brigatinib is necessary; the risk is increased in patients with severe renal impairment. A dose reduction of betrixaban may be necessary. Betrixaban is a P-glycoprotein (P-gp) substrate. Brigatinib is a P-gp inhibitor in vitro and may have the potential to increase concentrations of coadministered P-gp substrates.
    Bexarotene: (Major) Avoid coadministration of brigatinib with bexarotene due to decreased plasma exposure to brigatinib which may result in decreased efficacy. If concomitant use is unavoidable, after 7 days of concomitant treatment with bexarotene, increase the dose of brigatinib as tolerated in 30 mg increments to a maximum of twice the original brigatinib dose. After discontinuation of bexarotene, resume the brigatinib dose that was tolerated prior to initiation of bexarotene. Brigatinib is a CYP3A4 substrate and bexarotene is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of brigatinib by approximately 50%.
    Bictegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Monitor for an increase in tenofovir-related adverse reactions if coadministration with brigatinib is necessary. Tenofovir alafenamide is a substrate of P-glycoprotein (P-gp) and BCRP. Brigatinib inhibits both P-gp and BCRP in vitro and may have the potential to increase concentrations of substrates of these transporters.
    Bosentan: (Major) Avoid coadministration of brigatinib with bosentan due to decreased plasma exposure to brigatinib which may result in decreased efficacy. If concomitant use is unavoidable, after 7 days of concomitant treatment with bosentan, increase the dose of brigatinib as tolerated in 30 mg increments to a maximum of twice the original brigatinib dose. After discontinuation of bosentan, resume the brigatinib dose that was tolerated prior to initiation of bosentan. Brigatinib is a CYP3A4 substrate and bosentan is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of brigatinib by approximately 50%.
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with brigatinib is necessary; consider increasing the dose of hydrocodone as needed. If brigatinib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and brigatinib is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with brigatinib is necessary; consider increasing the dose of hydrocodone as needed. If brigatinib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and brigatinib is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Butabarbital: (Major) Avoid coadministration of brigatinib with butabarbital due to decreased plasma exposure to brigatinib which may result in decreased efficacy. If concomitant use is unavoidable, after 7 days of concomitant treatment with butabarbital, increase the dose of brigatinib as tolerated in 30 mg increments to a maximum of twice the original brigatinib dose. After discontinuation of butabarbital, resume the brigatinib dose that was tolerated prior to initiation of butabarbital. Brigatinib is a CYP3A4 substrate and butabarbital is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of brigatinib by approximately 50%.
    Butalbital; Acetaminophen: (Major) Avoid coadministration of brigatinib with butalbital due to decreased plasma exposure to brigatinib which may result in decreased efficacy. If concomitant use is unavoidable, after 7 days of concomitant treatment with butalbital, increase the dose of brigatinib as tolerated in 30 mg increments to a maximum of twice the original brigatinib dose. After discontinuation of butalbital, resume the brigatinib dose that was tolerated prior to initiation of butalbital. Brigatinib is a CYP3A4 substrate and butalbital is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of brigatinib by approximately 50%.
    Butalbital; Acetaminophen; Caffeine: (Major) Avoid coadministration of brigatinib with butalbital due to decreased plasma exposure to brigatinib which may result in decreased efficacy. If concomitant use is unavoidable, after 7 days of concomitant treatment with butalbital, increase the dose of brigatinib as tolerated in 30 mg increments to a maximum of twice the original brigatinib dose. After discontinuation of butalbital, resume the brigatinib dose that was tolerated prior to initiation of butalbital. Brigatinib is a CYP3A4 substrate and butalbital is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of brigatinib by approximately 50%.
    Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Avoid coadministration of brigatinib with butalbital due to decreased plasma exposure to brigatinib which may result in decreased efficacy. If concomitant use is unavoidable, after 7 days of concomitant treatment with butalbital, increase the dose of brigatinib as tolerated in 30 mg increments to a maximum of twice the original brigatinib dose. After discontinuation of butalbital, resume the brigatinib dose that was tolerated prior to initiation of butalbital. Brigatinib is a CYP3A4 substrate and butalbital is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of brigatinib by approximately 50%. (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with brigatinib is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If brigatinib is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. brigatinib is a weak CYP3A4 inducer. Concomitant use with brigatinib can increase norcodeine levels via increased CYP3A4 metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Canagliflozin; Metformin: (Moderate) Consider the benefits and risks of concomitant therapy of brigatinib with metformin. Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., MATE inhibitors) could increase systemic exposure to metformin and increase the risk for lactic acidosis. Brigatinib inhibits MATE1 and MATE2K in vitro and may have the potential to increase concentrations of coadministered substrates of these transporters.
    Carbamazepine: (Major) Avoid coadministration of brigatinib with carbamazepine due to decreased plasma exposure to brigatinib which may result in decreased efficacy. Brigatinib is a CYP3A4 substrate and carbamazepine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased the AUC and Cmax of brigatinib by 80% and 60%, respectively.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with brigatinib is necessary; consider increasing the dose of hydrocodone as needed. If brigatinib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and brigatinib is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with brigatinib is necessary; consider increasing the dose of hydrocodone as needed. If brigatinib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and brigatinib is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Celecoxib; Tramadol: (Moderate) Monitor for reduced efficacy of tramadol and signs of opioid withdrawal if coadministration with brigatinib is necessary; consider increasing the dose of tramadol as needed. If brigatinib is discontinued, consider a dose reduction of tramadol and frequently monitor for seizures, serotonin syndrome, and signs of respiratory depression and sedation. Tramadol is a CYP3A4 substrate and brigatinib is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease tramadol levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Cenobamate: (Major) Avoid coadministration of brigatinib with cenobamate due to decreased plasma exposure to brigatinib which may result in decreased efficacy. If concomitant use is unavoidable, after 7 days of concomitant treatment with cenobamate, increase the dose of brigatinib as tolerated in 30 mg increments to a maximum of twice the original brigatinib dose. After discontinuation of cenobamate, resume the brigatinib dose that was tolerated prior to initiation of cenobamate. Brigatinib is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of brigatinib by approximately 50%.
    Ceritinib: (Major) Avoid coadministration of brigatinib with ceritinib if possible due to increased plasma exposure of brigatinib. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 50% without breaking tablets (i.e., from 180 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of ceritinib, resume the brigatinib dose that was tolerated prior to initiation of ceritinib. Brigatinib is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively.
    Chloramphenicol: (Major) Avoid coadministration of brigatinib with chloramphenicol if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 50% without breaking tablets (i.e., from 180 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of chloramphenicol, resume the brigatinib dose that was tolerated prior to initiation of chloramphenicol. Brigatinib is a CYP3A4 substrate and chloramphenicol is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively.
    Chlorpheniramine; Codeine: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with brigatinib is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If brigatinib is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. brigatinib is a weak CYP3A4 inducer. Concomitant use with brigatinib can increase norcodeine levels via increased CYP3A4 metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with brigatinib is necessary; consider increasing the dose of hydrocodone as needed. If brigatinib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and brigatinib is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Chlorpheniramine; Hydrocodone: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with brigatinib is necessary; consider increasing the dose of hydrocodone as needed. If brigatinib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and brigatinib is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with brigatinib is necessary; consider increasing the dose of hydrocodone as needed. If brigatinib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and brigatinib is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with brigatinib is necessary; consider increasing the dose of hydrocodone as needed. If brigatinib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and brigatinib is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
    Ciprofloxacin: (Major) Avoid coadministration of brigatinib with ciprofloxacin if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 40% without breaking tablets (i.e., from 180 mg to 120 mg; from 120 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of ciprofloxacin, resume the brigatinib dose that was tolerated prior to initiation of ciprofloxacin. Brigatinib is a CYP3A4 substrate; ciprofloxacin is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase the AUC of brigatinib by approximately 40%.
    Clarithromycin: (Major) Avoid coadministration of brigatinib with clarithromycin if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 50% without breaking tablets (i.e., from 180 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of clarithromycin, resume the brigatinib dose that was tolerated prior to initiation of clarithromycin. Brigatinib is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively.
    Cobicistat: (Major) Avoid coadministration of brigatinib with cobicistat if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 50% without breaking tablets (i.e., from 180 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of cobicistat, resume the brigatinib dose that was tolerated prior to initiation of cobicistat. Brigatinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively.
    Cobimetinib: (Moderate) Monitor for an increase in cobimetinib-related adverse reactions if coadministration with brigatinib is necessary. In vitro, cobimetinib is a P-glycoprotein (P-gp) substrate; drugs that inhibit P-gp may increase cobimetinib concentrations. Brigatinib is a P-gp inhibitor.
    Codeine: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with brigatinib is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If brigatinib is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. brigatinib is a weak CYP3A4 inducer. Concomitant use with brigatinib can increase norcodeine levels via increased CYP3A4 metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Codeine; Guaifenesin: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with brigatinib is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If brigatinib is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. brigatinib is a weak CYP3A4 inducer. Concomitant use with brigatinib can increase norcodeine levels via increased CYP3A4 metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with brigatinib is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If brigatinib is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. brigatinib is a weak CYP3A4 inducer. Concomitant use with brigatinib can increase norcodeine levels via increased CYP3A4 metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Codeine; Phenylephrine; Promethazine: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with brigatinib is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If brigatinib is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. brigatinib is a weak CYP3A4 inducer. Concomitant use with brigatinib can increase norcodeine levels via increased CYP3A4 metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Codeine; Promethazine: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with brigatinib is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If brigatinib is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. brigatinib is a weak CYP3A4 inducer. Concomitant use with brigatinib can increase norcodeine levels via increased CYP3A4 metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Colchicine: (Moderate) Monitor for an increase in colchicine-related adverse reactions if coadministration with brigatinib is necessary; the risk is higher in patients with renal or hepatic impairment. A dose reduction of colchicine may be necessary. Colchicine is a P-glycoprotein (P-gp) substrate with a narrow therapeutic index. Brigatinib is a P-gp inhibitor in vitro and may have the potential to increase concentrations of P-gp substrates.
    Conivaptan: (Major) Avoid coadministration of brigatinib with conivaptan if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 40% without breaking tablets (i.e., from 180 mg to 120 mg; from 120 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of conivaptan, resume the brigatinib dose that was tolerated prior to initiation of conivaptan. Brigatinib is a CYP3A substrate; conivaptan is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase the overall exposure of brigatinib by approximately 40%.
    Crizotinib: (Major) Avoid coadministration of brigatinib with crizotinib if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 40% without breaking tablets (i.e., from 180 mg to 120 mg; from 120 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of crizotinib, resume the brigatinib dose that was tolerated prior to initiation of crizotinib. Brigatinib is a CYP3A4 substrate; crizotinib is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase the AUC of brigatinib by approximately 40%.
    Cyclosporine: (Major) Avoid coadministration of brigatinib with cyclosporine if possible due to increased plasma exposure of brigatinib; cyclosporine concentrations may also be affected. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 40% without breaking tablets (i.e., from 180 mg to 120 mg; from 120 mg to 90 mg; from 90 mg to 60 mg). Monitor cyclosporine levels and adjust the dose as clinically appropriate. After discontinuation of cyclosporine, resume the brigatinib dose that was tolerated prior to initiation of cyclosporine. Brigatinib is a CYP3A4 substrate; cyclosporine is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase the AUC of brigatinib by approximately 40%. Additionally, cyclosporine is a P-glycoprotein (P-gp) substrate and a weak CYP3A substrate. Brigatinib inhibits P-gp in vitro and is also a weak CYP3A inducer.
    Dabigatran: (Moderate) Monitor for an increase in dabigatran-related adverse reactions, including bleeding, if coadministration with brigatinib is necessary; the risk may be higher in patients with renal impairment. Dabigatran is a P-glycoprotein (P-gp) substrate. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran. Brigatinib is a P-gp inhibitor in vitro and may have the potential to increase concentrations of P-gp substrates. Coadministration of dabigatran and a single oral dose of another P-gp inhibitor increased the dabigatran AUC and Cmax by 58% and 50%, respectively; there was additionally a 65% increase in renal clearance of dabigatran.
    Dabrafenib: (Major) Avoid coadministration of brigatinib with dabrafenib due to decreased plasma exposure to brigatinib which may result in decreased efficacy. If concomitant use is unavoidable, after 7 days of concomitant treatment with dabrafenib, increase the dose of brigatinib as tolerated in 30 mg increments to a maximum of twice the original brigatinib dose. After discontinuation of dabrafenib, resume the brigatinib dose that was tolerated prior to initiation of dabrafenib. Brigatinib is a CYP3A4 substrate and dabrafenib is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of brigatinib by approximately 50%.
    Danazol: (Major) Avoid coadministration of brigatinib with danazol if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 40% without breaking tablets (i.e., from 180 mg to 120 mg; from 120 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of danazol, resume the brigatinib dose that was tolerated prior to initiation of danazol. Brigatinib is a CYP3A4 substrate; danazol is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase the AUC of brigatinib by approximately 40%.
    Dapagliflozin; Metformin: (Moderate) Consider the benefits and risks of concomitant therapy of brigatinib with metformin. Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., MATE inhibitors) could increase systemic exposure to metformin and increase the risk for lactic acidosis. Brigatinib inhibits MATE1 and MATE2K in vitro and may have the potential to increase concentrations of coadministered substrates of these transporters.
    Darunavir: (Major) Avoid coadministration of brigatinib with darunavir if possible due to increased plasma exposure of brigatinib and altered exposure to darunavir. If concomitant use is unavoidable, closely monitor for changes in the clinical efficacy or side effect profile of the antiretroviral regimen and reduce the dose of brigatinib by approximately 50% without breaking tablets (i.e., from 180 mg to 90 mg; from 90 mg to 60 mg); if darunavir is discontinued, resume the brigatinib dose that was tolerated prior to initiation of darunavir. Brigatinib is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively. Darunavir is also a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. At clinically relevant concentrations, brigatinib induced CYP3A via activation of the pregnane X receptor (PXR); this may decrease concentrations of sensitive CYP3A substrates. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Brigatinib is also a P-gp inhibitor in vitro and may have the potential to increase exposure to P-gp substrates.
    Darunavir; Cobicistat: (Major) Avoid coadministration of brigatinib with cobicistat if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 50% without breaking tablets (i.e., from 180 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of cobicistat, resume the brigatinib dose that was tolerated prior to initiation of cobicistat. Brigatinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively. (Major) Avoid coadministration of brigatinib with darunavir if possible due to increased plasma exposure of brigatinib and altered exposure to darunavir. If concomitant use is unavoidable, closely monitor for changes in the clinical efficacy or side effect profile of the antiretroviral regimen and reduce the dose of brigatinib by approximately 50% without breaking tablets (i.e., from 180 mg to 90 mg; from 90 mg to 60 mg); if darunavir is discontinued, resume the brigatinib dose that was tolerated prior to initiation of darunavir. Brigatinib is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively. Darunavir is also a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. At clinically relevant concentrations, brigatinib induced CYP3A via activation of the pregnane X receptor (PXR); this may decrease concentrations of sensitive CYP3A substrates. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Brigatinib is also a P-gp inhibitor in vitro and may have the potential to increase exposure to P-gp substrates.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid coadministration of brigatinib with cobicistat if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 50% without breaking tablets (i.e., from 180 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of cobicistat, resume the brigatinib dose that was tolerated prior to initiation of cobicistat. Brigatinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively. (Major) Avoid coadministration of brigatinib with darunavir if possible due to increased plasma exposure of brigatinib and altered exposure to darunavir. If concomitant use is unavoidable, closely monitor for changes in the clinical efficacy or side effect profile of the antiretroviral regimen and reduce the dose of brigatinib by approximately 50% without breaking tablets (i.e., from 180 mg to 90 mg; from 90 mg to 60 mg); if darunavir is discontinued, resume the brigatinib dose that was tolerated prior to initiation of darunavir. Brigatinib is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively. Darunavir is also a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. At clinically relevant concentrations, brigatinib induced CYP3A via activation of the pregnane X receptor (PXR); this may decrease concentrations of sensitive CYP3A substrates. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Brigatinib is also a P-gp inhibitor in vitro and may have the potential to increase exposure to P-gp substrates. (Moderate) Monitor for an increase in tenofovir-related adverse reactions if coadministration with brigatinib is necessary. Tenofovir alafenamide is a substrate of P-glycoprotein (P-gp) and BCRP. Brigatinib inhibits both P-gp and BCRP in vitro and may have the potential to increase concentrations of substrates of these transporters.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid coadministration of brigatinib with ritonavir if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 50% without breaking tablets (i.e., from 180 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of ritonavir, resume the brigatinib dose that was tolerated prior to initiation of ritonavir. Brigatinib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively. (Moderate) Monitor for an increase in dasabuvir-related adverse reactions if coadministration with brigatinib is necessary. Dasabuvir is a substrate of P-glycoprotein (P-gp) and BCRP. Brigatinib inhibits both P-gp and BCRP in vitro and may have the potential to increase concentrations of substrates of these transporters. (Moderate) Monitor for an increase in ombitasvir-related adverse reactions if coadministration with brigatinib is necessary. Ombitasvir is a substrate of P-glycoprotein (P-gp) and BCRP. Brigatinib inhibits both P-gp and BCRP in vitro and may have the potential to increase concentrations of substrates of these transporters. (Moderate) Monitor for an increase in paritaprevir-related adverse reactions if coadministration with brigatinib is necessary. Paritaprevir is a substrate of P-glycoprotein (P-gp) and BCRP. Brigatinib inhibits both P-gp and BCRP in vitro and may have the potential to increase concentrations of substrates of these transporters.
    Delavirdine: (Major) Avoid coadministration of brigatinib with delavirdine if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 50% without breaking tablets (i.e., from 180 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of delavirdine, resume the brigatinib dose that was tolerated prior to initiation of delavirdine. Brigatinib is a CYP3A4 substrate; delavirdine is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively.
    Dexamethasone: (Moderate) Avoid coadministration of brigatinib with dexamethasone due to decreased plasma exposure to brigatinib which may result in decreased efficacy. If concomitant use is unavoidable, after 7 days of concomitant treatment with dexamethasone, increase the dose of brigatinib as tolerated in 30 mg increments to a maximum of twice the original brigatinib dose. After discontinuation of dexamethasone, resume the brigatinib dose that was tolerated prior to initiation of dexamethasone. Brigatinib is a CYP3A4 substrate and dexamethasone is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of brigatinib by approximately 50%.
    Dextromethorphan; Quinidine: (Moderate) Monitor for an increase in quinine-related adverse reactions if coadministration with brigatinib is necessary. Quinidine is a substrate of P-glycoprotein (P-gp). Brigatinib inhibits P-gp in vitro and may have the potential to increase concentrations of P-gp substrates.
    Diazepam: (Moderate) Monitor patients for decreased efficacy of diazepam if coadministration with brigatinib is necessary. Concurrent use may decrease diazepam exposure. Diazepam is a CYP3A4 substrate and brigatinib is a CYP3A4 inducer.
    Digoxin: (Moderate) Monitor digoxin levels and watch for an increase in digoxin-related adverse reactions if coadministration with brigatinib is necessary. Digoxin is a substrate of P-glycoprotein (P-gp). Brigatinib inhibits P-gp in vitro and may have the potential to increase concentrations of P-gp substrates.
    Diltiazem: (Major) Avoid coadministration of brigatinib with diltiazem if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 40% without breaking tablets (i.e., from 180 mg to 120 mg; from 120 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of diltiazem, resume the brigatinib dose that was tolerated prior to initiation of diltiazem. Brigatinib is a CYP3A4 substrate; diltiazem is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase the AUC of brigatinib by approximately 40%.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with brigatinib is necessary; consider increasing the dose of hydrocodone as needed. If brigatinib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and brigatinib is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Docetaxel: (Moderate) Monitor for decreased efficacy of docetaxel if coadministration with brigatinib is necessary. Docetaxel is a CYP3A substrate and brigatinib induces CYP3A in vitro; plasma concentrations of docetaxel may decrease.
    Dolutegravir: (Moderate) Monitor for an increase in dolutegravir-related adverse reactions if coadministration with brigatinib is necessary. Dolutegravir is a substrate of P-glycoprotein (P-gp) and BCRP. Brigatinib inhibits both P-gp and BCRP in vitro and may have the potential to increase concentrations of substrates of these transporters.
    Dolutegravir; Lamivudine: (Moderate) Monitor for an increase in dolutegravir-related adverse reactions if coadministration with brigatinib is necessary. Dolutegravir is a substrate of P-glycoprotein (P-gp) and BCRP. Brigatinib inhibits both P-gp and BCRP in vitro and may have the potential to increase concentrations of substrates of these transporters.
    Dolutegravir; Rilpivirine: (Moderate) Monitor for an increase in dolutegravir-related adverse reactions if coadministration with brigatinib is necessary. Dolutegravir is a substrate of P-glycoprotein (P-gp) and BCRP. Brigatinib inhibits both P-gp and BCRP in vitro and may have the potential to increase concentrations of substrates of these transporters.
    Doravirine: (Minor) Concurrent administration of doravirine and brigatinib may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate; brigatinib is a weak CYP3A4 inducer.
    Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Monitor for an increase in tenofovir-related adverse reactions if coadministration with brigatinib is necessary. Tenofovir disoproxil fumarate is a substrate of P-glycoprotein (P-gp) and BCRP. Brigatinib inhibits both P-gp and BCRP in vitro and may have the potential to increase concentrations of substrates of these transporters. (Minor) Concurrent administration of doravirine and brigatinib may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate; brigatinib is a weak CYP3A4 inducer.
    Doxorubicin Liposomal: (Moderate) Monitor for an increase in doxorubicin-related adverse reactions if coadministration with brigatinib is necessary. Doxorubicin is a substrate of P-glycoprotein (P-gp). Brigatinib inhibits P-gp in vitro and may have the potential to increase concentrations of P-gp substrates. Concurrent use of P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
    Doxorubicin: (Moderate) Monitor for an increase in doxorubicin-related adverse reactions if coadministration with brigatinib is necessary. Doxorubicin is a substrate of P-glycoprotein (P-gp). Brigatinib inhibits P-gp in vitro and may have the potential to increase concentrations of P-gp substrates. Concurrent use of P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
    Dronedarone: (Major) Avoid coadministration of brigatinib with dronedarone if possible due to increased plasma exposure of brigatinib; a decrease in dronedarone concentrations may also occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 40% without breaking tablets (i.e., from 180 mg to 120 mg; from 120 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of dronedarone, resume the brigatinib dose that was tolerated prior to initiation of dronedarone. Brigatinib is a CYP3A4 substrate; dronedarone is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase the AUC of brigatinib by approximately 40%. Dronedarone is also a sensitive CYP3A4 substrate. At clinically relevant concentrations, brigatinib induced CYP3A via activation of the pregnane X receptor (PXR); this may decrease concentrations of sensitive CYP3A substrates.
    Duvelisib: (Major) Avoid coadministration of brigatinib with duvelisib. Coadministration may decrease the exposure of duvelisib, which may reduce the efficacy of duvelisib; plasma exposure of brigatinib may also increase resulting in an increase in brigatinib-related adverse reactions. If concomitant use is necessary, increase the dose of duvelisib on day 12 of coadministration from 25 mg PO twice daily to 40 mg PO twice daily; or from 15 mg PO twice daily to 25 mg PO twice daily; also reduce the dose of brigatinib by approximately 40% without breaking tablets (i.e., from 180 mg to 120 mg; from 120 mg to 90 mg; from 90 mg to 60 mg). When brigatinib has been discontinued for at least 14 days, resume duvelisib at the dose taken prior to initiating treatment with brigatinib. If duvelisib is discontinued, resume the brigatinib dose that was tolerated prior to initiation of duvelisib. Duvelisib is a CYP3A substrate and a moderate CYP3A4 inhibitor. Brigatinib is a CYP3A4 substrate and a moderate CYP3A inducer. Coadministration of duvelisib with another moderate CYP3A inducer for 12 days decreased duvelisib exposure by 35%. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase the AUC of brigatinib by approximately 40%.
    Edoxaban: (Moderate) Monitor for an increase in edoxaban-related adverse reactions if coadministration with brigatinib is necessary. Edoxaban is a substrate of P-glycoprotein (P-gp). Brigatinib inhibits P-gp in vitro and may have the potential to increase concentrations of P-gp substrates.
    Efavirenz: (Major) Avoid coadministration of brigatinib with efavirenz due to decreased plasma exposure to brigatinib which may result in decreased efficacy. If concomitant use is unavoidable, after 7 days of concomitant treatment with efavirenz, increase the dose of brigatinib as tolerated in 30 mg increments to a maximum of twice the original brigatinib dose. After discontinuation of efavirenz, resume the brigatinib dose that was tolerated prior to initiation of efavirenz. Brigatinib is a CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of brigatinib by approximately 50%.
    Efavirenz; Emtricitabine; Tenofovir: (Major) Avoid coadministration of brigatinib with efavirenz due to decreased plasma exposure to brigatinib which may result in decreased efficacy. If concomitant use is unavoidable, after 7 days of concomitant treatment with efavirenz, increase the dose of brigatinib as tolerated in 30 mg increments to a maximum of twice the original brigatinib dose. After discontinuation of efavirenz, resume the brigatinib dose that was tolerated prior to initiation of efavirenz. Brigatinib is a CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of brigatinib by approximately 50%. (Moderate) Monitor for an increase in tenofovir-related adverse reactions if coadministration with brigatinib is necessary. Tenofovir disoproxil fumarate is a substrate of P-glycoprotein (P-gp) and BCRP. Brigatinib inhibits both P-gp and BCRP in vitro and may have the potential to increase concentrations of substrates of these transporters.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of brigatinib with efavirenz due to decreased plasma exposure to brigatinib which may result in decreased efficacy. If concomitant use is unavoidable, after 7 days of concomitant treatment with efavirenz, increase the dose of brigatinib as tolerated in 30 mg increments to a maximum of twice the original brigatinib dose. After discontinuation of efavirenz, resume the brigatinib dose that was tolerated prior to initiation of efavirenz. Brigatinib is a CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of brigatinib by approximately 50%. (Moderate) Monitor for an increase in tenofovir-related adverse reactions if coadministration with brigatinib is necessary. Tenofovir disoproxil fumarate is a substrate of P-glycoprotein (P-gp) and BCRP. Brigatinib inhibits both P-gp and BCRP in vitro and may have the potential to increase concentrations of substrates of these transporters.
    Elagolix: (Major) Avoid coadministration of brigatinib with elagolix due to decreased plasma exposure to brigatinib which may result in decreased efficacy; concentrations of elagolix may also increase. If concomitant use is unavoidable, after 7 days of concomitant treatment with elagolix, increase the dose of brigatinib as tolerated in 30 mg increments to a maximum of twice the original brigatinib dose; monitor for an increase in elagolix-related adverse reactions. After discontinuation of elagolix, resume the brigatinib dose that was tolerated prior to initiation of elagolix. Brigatinib is a CYP3A4 substrate and elagolix is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of brigatinib by approximately 50%. Elagolix is also a P-glycoprotein (P-gp) substrate. Brigatinib is a P-gp inhibitor in vitro and may have the potential to increase concentrations of P-gp substrates.
    Elagolix; Estradiol; Norethindrone acetate: (Major) Avoid coadministration of brigatinib with elagolix due to decreased plasma exposure to brigatinib which may result in decreased efficacy; concentrations of elagolix may also increase. If concomitant use is unavoidable, after 7 days of concomitant treatment with elagolix, increase the dose of brigatinib as tolerated in 30 mg increments to a maximum of twice the original brigatinib dose; monitor for an increase in elagolix-related adverse reactions. After discontinuation of elagolix, resume the brigatinib dose that was tolerated prior to initiation of elagolix. Brigatinib is a CYP3A4 substrate and elagolix is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of brigatinib by approximately 50%. Elagolix is also a P-glycoprotein (P-gp) substrate. Brigatinib is a P-gp inhibitor in vitro and may have the potential to increase concentrations of P-gp substrates.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid coadministration of brigatinib with cobicistat if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 50% without breaking tablets (i.e., from 180 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of cobicistat, resume the brigatinib dose that was tolerated prior to initiation of cobicistat. Brigatinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively. (Moderate) Monitor for an increase in tenofovir-related adverse reactions if coadministration with brigatinib is necessary. Tenofovir alafenamide is a substrate of P-glycoprotein (P-gp) and BCRP. Brigatinib inhibits both P-gp and BCRP in vitro and may have the potential to increase concentrations of substrates of these transporters.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of brigatinib with cobicistat if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 50% without breaking tablets (i.e., from 180 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of cobicistat, resume the brigatinib dose that was tolerated prior to initiation of cobicistat. Brigatinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively. (Moderate) Monitor for an increase in tenofovir-related adverse reactions if coadministration with brigatinib is necessary. Tenofovir disoproxil fumarate is a substrate of P-glycoprotein (P-gp) and BCRP. Brigatinib inhibits both P-gp and BCRP in vitro and may have the potential to increase concentrations of substrates of these transporters.
    Empagliflozin; Linagliptin; Metformin: (Moderate) Consider the benefits and risks of concomitant therapy of brigatinib with metformin. Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., MATE inhibitors) could increase systemic exposure to metformin and increase the risk for lactic acidosis. Brigatinib inhibits MATE1 and MATE2K in vitro and may have the potential to increase concentrations of coadministered substrates of these transporters.
    Empagliflozin; Metformin: (Moderate) Consider the benefits and risks of concomitant therapy of brigatinib with metformin. Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., MATE inhibitors) could increase systemic exposure to metformin and increase the risk for lactic acidosis. Brigatinib inhibits MATE1 and MATE2K in vitro and may have the potential to increase concentrations of coadministered substrates of these transporters.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Monitor for an increase in tenofovir-related adverse reactions if coadministration with brigatinib is necessary. Tenofovir alafenamide is a substrate of P-glycoprotein (P-gp) and BCRP. Brigatinib inhibits both P-gp and BCRP in vitro and may have the potential to increase concentrations of substrates of these transporters.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Moderate) Monitor for an increase in tenofovir-related adverse reactions if coadministration with brigatinib is necessary. Tenofovir disoproxil fumarate is a substrate of P-glycoprotein (P-gp) and BCRP. Brigatinib inhibits both P-gp and BCRP in vitro and may have the potential to increase concentrations of substrates of these transporters.
    Emtricitabine; Tenofovir alafenamide: (Moderate) Monitor for an increase in tenofovir-related adverse reactions if coadministration with brigatinib is necessary. Tenofovir alafenamide is a substrate of P-glycoprotein (P-gp) and BCRP. Brigatinib inhibits both P-gp and BCRP in vitro and may have the potential to increase concentrations of substrates of these transporters.
    Emtricitabine; Tenofovir disoproxil fumarate: (Moderate) Monitor for an increase in tenofovir-related adverse reactions if coadministration with brigatinib is necessary. Tenofovir disoproxil fumarate is a substrate of P-glycoprotein (P-gp) and BCRP. Brigatinib inhibits both P-gp and BCRP in vitro and may have the potential to increase concentrations of substrates of these transporters.
    Entrectinib: (Moderate) Monitor for decreased entrectinib efficacy during coadministration of brigatinib as concurrent use may decrease entrectinib exposure; an entrectinib dose increase may be needed. Entrectinib is a CYP3A4 substrate; brigatinib is a moderate CYP3A4 inducer. Coadministration of a moderate CYP3A4 inducer is predicted to reduce the entrectinib AUC by 56%.
    Enzalutamide: (Major) Avoid coadministration of brigatinib with enzalutamide due to decreased plasma exposure to brigatinib which may result in decreased efficacy. Brigatinib is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased the AUC and Cmax of brigatinib by 80% and 60%, respectively.
    Ertugliflozin; Metformin: (Moderate) Consider the benefits and risks of concomitant therapy of brigatinib with metformin. Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., MATE inhibitors) could increase systemic exposure to metformin and increase the risk for lactic acidosis. Brigatinib inhibits MATE1 and MATE2K in vitro and may have the potential to increase concentrations of coadministered substrates of these transporters.
    Erythromycin: (Major) Avoid coadministration of brigatinib with erythromycin if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 40% without breaking tablets (i.e., from 180 mg to 120 mg; from 120 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of erythromycin, resume the brigatinib dose that was tolerated prior to initiation of erythromycin. Brigatinib is a CYP3A4 substrate; erythromycin is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase the AUC of brigatinib by approximately 40%.
    Erythromycin; Sulfisoxazole: (Major) Avoid coadministration of brigatinib with erythromycin if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 40% without breaking tablets (i.e., from 180 mg to 120 mg; from 120 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of erythromycin, resume the brigatinib dose that was tolerated prior to initiation of erythromycin. Brigatinib is a CYP3A4 substrate; erythromycin is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase the AUC of brigatinib by approximately 40%.
    Eslicarbazepine: (Major) Avoid coadministration of brigatinib with eslicarbazepine due to decreased plasma exposure to brigatinib which may result in decreased efficacy. If concomitant use is unavoidable, after 7 days of concomitant treatment with eslicarbazepine, increase the dose of brigatinib as tolerated in 30 mg increments to a maximum of twice the original brigatinib dose. After discontinuation of eslicarbazepine, resume the brigatinib dose that was tolerated prior to initiation of eslicarbazepine. Brigatinib is a CYP3A4 substrate and eslicarbazepine is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of brigatinib by approximately 50%.
    Etravirine: (Major) Avoid coadministration of brigatinib with etravirine due to decreased plasma exposure to brigatinib which may result in decreased efficacy. If concomitant use is unavoidable, after 7 days of concomitant treatment with etravirine, increase the dose of brigatinib as tolerated in 30 mg increments to a maximum of twice the original brigatinib dose. After discontinuation of etravirine, resume the brigatinib dose that was tolerated prior to initiation of etravirine. Brigatinib is a CYP3A4 substrate and etravirine is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of brigatinib by approximately 50%.
    Everolimus: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions or changes in efficacy if coadministration with brigatinib is necessary. The dose of everolimus may need to be adjusted. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Brigatinib is a moderate CYP3A4 inducer and a P-gp inhibitor. Coadministration with CYP3A4 inducers may increase the metabolism of everolimus and decrease everolimus blood concentrations. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations.
    Fedratinib: (Major) Avoid coadministration of brigatinib with fedratinib if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 40% without breaking tablets (i.e., from 180 mg to 120 mg; from 120 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of fedratinib, resume the brigatinib dose that was tolerated prior to initiation of fedratinib. Brigatinib is a CYP3A4 substrate; fedratinib is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase the AUC of brigatinib by approximately 40%.
    Fentanyl: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if coadministration with brigatinib is necessary. If brigatinib is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a weak CYP3A4 inducer like brigatinib with fentanyl, a CYP3A4 substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
    Fluconazole: (Major) Avoid coadministration of brigatinib with fluconazole if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 40% without breaking tablets (i.e., from 180 mg to 120 mg; from 120 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of fluconazole, resume the brigatinib dose that was tolerated prior to initiation of fluconazole. Brigatinib is a CYP3A4 substrate; fluconazole is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase the AUC of brigatinib by approximately 40%.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) Monitor for an increase in umeclidinium-related adverse reactions if coadministration with brigatinib is necessary. Umeclidinium is a P-glycoprotein (P-gp) substrate. Brigatinib inhibits P-gp in vitro and may have the potential to increase concentrations of P-gp substrates. Coadministration with a P-gp inhibitor increased umeclidinium exposure by 1.4-fold.
    Fluvoxamine: (Major) Avoid coadministration of brigatinib with fluvoxamine if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 40% without breaking tablets (i.e., from 180 mg to 120 mg; from 120 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of fluvoxamine, resume the brigatinib dose that was tolerated prior to initiation of fluvoxamine. Brigatinib is a CYP3A4 substrate; fluvoxamine is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase the AUC of brigatinib by approximately 40%.
    Fosamprenavir: (Major) Avoid coadministration of brigatinib with fosamprenavir if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 50% without breaking tablets (i.e., from 180 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of fosamprenavir, resume the brigatinib dose that was tolerated prior to initiation of fosamprenavir. Brigatinib is a CYP3A4 substrate; fosamprenavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively.
    Fosphenytoin: (Major) Avoid coadministration of brigatinib with fosphenytoin due to decreased plasma exposure to brigatinib, which may result in decreased efficacy. Brigatinib is a CYP3A4 substrate; phenytoin (the active metabolite of fosphenytoin) is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased the AUC and Cmax of brigatinib by 80% and 60%, respectively.
    Glasdegib: (Major) Avoid coadministratrion of glasdegib and brigatinib due to the potential for decreased glasdegib exposure and risk of decreased efficacy. If concurrent use cannot be avoided, increase the glasdegib dosage (i.e., from 100 mg PO daily to 200 mg PO daily; or from 50 mg PO daily to 100 mg PO daily). Resume the previous dose of glasdegib after brigatinib has been discontinued for 7 days. Glasdegib is a CYP3A4 substrate; brigatinib is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer was predicted to decrease the glasdegib AUC value by 55%.
    Glecaprevir; Pibrentasvir: (Moderate) Monitor for an increase in glecaprevir-related adverse reactions if coadministration with brigatinib is necessary. Glecaprevir is a substrate of P-glycoprotein (P-gp) and BCRP. Brigatinib inhibits both P-gp and BCRP in vitro and may have the potential to increase concentrations of substrates of these transporters. (Moderate) Monitor for an increase in pibrentasvir-related adverse reactions if coadministration with brigatinib is necessary. Pibrentasvir is a substrate of P-glycoprotein (P-gp) and BCRP. Brigatinib inhibits both P-gp and BCRP in vitro and may have the potential to increase concentrations of substrates of these transporters.
    Glipizide; Metformin: (Moderate) Consider the benefits and risks of concomitant therapy of brigatinib with metformin. Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., MATE inhibitors) could increase systemic exposure to metformin and increase the risk for lactic acidosis. Brigatinib inhibits MATE1 and MATE2K in vitro and may have the potential to increase concentrations of coadministered substrates of these transporters.
    Glyburide: (Moderate) Monitor blood sugars and watch for an increase in glyburide-related adverse reactions if coadministration with brigatinib is necessary. Glyburide is a substrate of P-glycoprotein (P-gp) and BCRP. Brigatinib inhibits both P-gp and BCRP in vitro and may have the potential to increase concentrations of substrates of these transporters.
    Glyburide; Metformin: (Moderate) Consider the benefits and risks of concomitant therapy of brigatinib with metformin. Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., MATE inhibitors) could increase systemic exposure to metformin and increase the risk for lactic acidosis. Brigatinib inhibits MATE1 and MATE2K in vitro and may have the potential to increase concentrations of coadministered substrates of these transporters. (Moderate) Monitor blood sugars and watch for an increase in glyburide-related adverse reactions if coadministration with brigatinib is necessary. Glyburide is a substrate of P-glycoprotein (P-gp) and BCRP. Brigatinib inhibits both P-gp and BCRP in vitro and may have the potential to increase concentrations of substrates of these transporters.
    Grapefruit juice: (Major) Instruct patients to avoid grapefruit or grapefruit juice while receiving brigatinib due to the potential for increased exposure to brigatinib. Brigatinib is a CYP3A4 substrate; grapefruit is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively.
    Guaifenesin; Hydrocodone: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with brigatinib is necessary; consider increasing the dose of hydrocodone as needed. If brigatinib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and brigatinib is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with brigatinib is necessary; consider increasing the dose of hydrocodone as needed. If brigatinib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and brigatinib is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Homatropine; Hydrocodone: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with brigatinib is necessary; consider increasing the dose of hydrocodone as needed. If brigatinib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and brigatinib is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Hydrocodone: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with brigatinib is necessary; consider increasing the dose of hydrocodone as needed. If brigatinib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and brigatinib is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Hydrocodone; Ibuprofen: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with brigatinib is necessary; consider increasing the dose of hydrocodone as needed. If brigatinib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and brigatinib is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Hydrocodone; Phenylephrine: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with brigatinib is necessary; consider increasing the dose of hydrocodone as needed. If brigatinib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and brigatinib is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with brigatinib is necessary; consider increasing the dose of hydrocodone as needed. If brigatinib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and brigatinib is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with brigatinib is necessary; consider increasing the dose of hydrocodone as needed. If brigatinib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and brigatinib is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Hydrocodone; Pseudoephedrine: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with brigatinib is necessary; consider increasing the dose of hydrocodone as needed. If brigatinib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and brigatinib is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Ibuprofen; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with brigatinib is necessary; consider increasing the dose of oxycodone as needed. If brigatinib is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and brigatinib is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Idelalisib: (Major) Avoid coadministration of brigatinib with idelalisib if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 50% without breaking tablets (i.e., from 180 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of idelalisib, resume the brigatinib dose that was tolerated prior to initiation of idelalisib. Brigatinib is a CYP3A4 substrate; idelalisib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively.
    Imatinib: (Major) Avoid coadministration of brigatinib with imatinib if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 40% without breaking tablets (i.e., from 180 mg to 120 mg; from 120 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of imatinib, resume the brigatinib dose that was tolerated prior to initiation of imatinib. Brigatinib is a CYP3A4 substrate; imatinib is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase the AUC of brigatinib by approximately 40%.
    Indinavir: (Major) Avoid coadministration of brigatinib with indinavir if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 50% without breaking tablets (i.e., from 180 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of indinavir, resume the brigatinib dose that was tolerated prior to initiation of indinavir. Brigatinib is a CYP3A4 substrate; indinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively.
    Infigratinib: (Major) Avoid concurrent use of infigratinib and brigatinib. Coadministration may decrease infigratinib exposure resulting in decreased efficacy. Infigratinib is a CYP3A4 substrate and brigatinib is a moderate CYP3A4 inducer.
    Irinotecan Liposomal: (Moderate) Monitor for an increase in irinotecan-related adverse reactions if coadministration with brigatinib is necessary. Irinotecan is a substrate of BCRP. Brigatinib inhibits BCRP in vitro and may have the potential to increase concentrations of BCRP substrates.
    Irinotecan: (Moderate) Monitor for an increase in irinotecan-related adverse reactions if coadministration with brigatinib is necessary. Irinotecan is a substrate of BCRP. Brigatinib inhibits BCRP in vitro and may have the potential to increase concentrations of BCRP substrates.
    Isavuconazonium: (Major) Avoid coadministration of brigatinib with isavuconazonium if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 40% without breaking tablets (i.e., from 180 mg to 120 mg; from 120 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of isavuconazonium, resume the brigatinib dose that was tolerated prior to initiation of isavuconazonium. Brigatinib is a CYP3A4 substrate; isavuconazonium is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase the AUC of brigatinib by approximately 40%.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid coadministration of brigatinib with rifampin due to decreased plasma exposure to brigatinib, which may result in decreased efficacy. Brigatinib is a CYP3A4 substrate; rifampin is a strong CYP3A4 inducer. Coadministration of rifampin decreased the AUC and Cmax of brigatinib by 80% and 60%, respectively.
    Isoniazid, INH; Rifampin: (Major) Avoid coadministration of brigatinib with rifampin due to decreased plasma exposure to brigatinib, which may result in decreased efficacy. Brigatinib is a CYP3A4 substrate; rifampin is a strong CYP3A4 inducer. Coadministration of rifampin decreased the AUC and Cmax of brigatinib by 80% and 60%, respectively.
    Isradipine: (Moderate) Monitor for decreased efficacy of isradipine if coadministration with brigatinib is necessary. Concomitant use may decrease isradipine exposure. Isradipine is a CYP3A4 substrate and brigatinib is a weak CYP3A4 inducer.
    Itraconazole: (Major) Avoid coadministration of brigatinib with itraconazole if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 50% without breaking tablets (i.e., from 180 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of itraconazole, resume the brigatinib dose that was tolerated prior to initiation of itraconazole. Brigatinib is a CYP3A4 substrate; itraconazole is a strong CYP3A4 inhibitor. Coadministration with itraconazole increased the AUC and Cmax of brigatinib by 101% and 21%, respectively.
    Ketoconazole: (Major) Avoid coadministration of brigatinib with ketoconazole if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 50% without breaking tablets (i.e., from 180 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of ketoconazole, resume the brigatinib dose that was tolerated prior to initiation of ketoconazole. Brigatinib is a CYP3A4 substrate; ketoconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively.
    Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor for an increase in tenofovir-related adverse reactions if coadministration with brigatinib is necessary. Tenofovir disoproxil fumarate is a substrate of P-glycoprotein (P-gp) and BCRP. Brigatinib inhibits both P-gp and BCRP in vitro and may have the potential to increase concentrations of substrates of these transporters.
    Lansoprazole; Amoxicillin; Clarithromycin: (Major) Avoid coadministration of brigatinib with clarithromycin if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 50% without breaking tablets (i.e., from 180 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of clarithromycin, resume the brigatinib dose that was tolerated prior to initiation of clarithromycin. Brigatinib is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively.
    Lefamulin: (Major) Avoid coadministration of brigatinib with oral lefamulin if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 40% without breaking tablets (i.e., from 180 mg to 120 mg; from 120 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of oral lefamulin, resume the brigatinib dose that was tolerated prior to initiation of oral lefamulin. Brigatinib is a CYP3A4 substrate; oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase the AUC of brigatinib by approximately 40%.
    Lemborexant: (Major) Avoid coadministration of lemborexant and brigatinib as concurrent use may decrease lemborexant exposure which may reduce efficacy. Lemborexant is a CYP3A4 substrate; brigatinib is a moderate CYP3A4 inducer.
    Letermovir: (Major) Avoid coadministration of brigatinib with letermovir if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable and the patient is also taking cyclosporine, reduce the dose of brigatinib by approximately 50% without breaking tablets (i.e., from 180 mg to 90 mg; from 90 mg to 60 mg). If the patient is not receiving concomitant cyclosporine, reduce the dose of brigatinib by approximately 40% without breaking tablets (i.e., from 180 mg to 120 mg; from 120 mg to 90 mg; from 90 mg to 60 mg). After discontinuation of letermovir, resume the brigatinib dose that was tolerated prior to initiation of letermovir. Brigatinib is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Coadministration with a strong CYP3A4 inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase the AUC of brigatinib by approximately 40%.
    Levoketoconazole: (Major) Avoid coadministration of brigatinib with ketoconazole if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 50% without breaking tablets (i.e., from 180 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of ketoconazole, resume the brigatinib dose that was tolerated prior to initiation of ketoconazole. Brigatinib is a CYP3A4 substrate; ketoconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively.
    Linagliptin; Metformin: (Moderate) Consider the benefits and risks of concomitant therapy of brigatinib with metformin. Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., MATE inhibitors) could increase systemic exposure to metformin and increase the risk for lactic acidosis. Brigatinib inhibits MATE1 and MATE2K in vitro and may have the potential to increase concentrations of coadministered substrates of these transporters.
    Lonafarnib: (Major) Avoid coadministration of brigatinib with lonafarnib if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 50% without breaking tablets (i.e., from 180 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of lonafarnib, resume the brigatinib dose that was tolerated prior to initiation of lonafarnib. Brigatinib is a CYP3A4 substrate; lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively.
    Loperamide: (Moderate) Monitor for an increase in loperamide-related adverse reactions, including CNS effects (e.g., syncope) ad cardiac effects (e.g., ventricular tachycardia, QT prolongation, torsade de pointes) if coadministration with brigatinib is necessary. Loperamide is a P-glycoprotein (P-gp) substrate. Brigatinib inhibits P-gp in vitro and may have the potential to increase concentrations of P-gp substrates. Coadministration with P-gp inhibitors increased loperamide plasma concentrations by 2-fold to 3-fold.
    Loperamide; Simethicone: (Moderate) Monitor for an increase in loperamide-related adverse reactions, including CNS effects (e.g., syncope) ad cardiac effects (e.g., ventricular tachycardia, QT prolongation, torsade de pointes) if coadministration with brigatinib is necessary. Loperamide is a P-glycoprotein (P-gp) substrate. Brigatinib inhibits P-gp in vitro and may have the potential to increase concentrations of P-gp substrates. Coadministration with P-gp inhibitors increased loperamide plasma concentrations by 2-fold to 3-fold.
    Lopinavir; Ritonavir: (Major) Avoid coadministration of brigatinib with ritonavir if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 50% without breaking tablets (i.e., from 180 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of ritonavir, resume the brigatinib dose that was tolerated prior to initiation of ritonavir. Brigatinib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively.
    Lorlatinib: (Major) Avoid concomitant use of brigatinib and lorlatinib due to decreased plasma concentrations of both drugs, which may reduce their efficacy. If concomitant use is necessary, increase the dose of lorlatinib to 125 mg PO once daily. After 7 days of concomitant treatment, increase the dose of brigatinib as tolerated in 30 mg increments to a maximum of twice the original dose. After discontinuation of lorlatinib, resume the brigatinib dose that was tolerated prior to initiation of lorlatinib. Both drugs are CYP3A4 substrates and moderate inducers. Administration with another moderate CYP3A inducer decreased lorlatinib exposure by 23%. Administration with a moderate CYP3A inducer is predicted to decrease the AUC of brigatinib by approximately 50%.
    Lumacaftor; Ivacaftor: (Major) Avoid coadministration of brigatinib with lumacaftor; ivacaftor due to decreased plasma exposure to brigatinib which may result in decreased efficacy. Brigatinib is a CYP3A4 substrate and lumacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased the AUC and Cmax of brigatinib by 80% and 60%, respectively.
    Lumacaftor; Ivacaftor: (Major) Avoid coadministration of brigatinib with lumacaftor; ivacaftor due to decreased plasma exposure to brigatinib which may result in decreased efficacy. Brigatinib is a CYP3A4 substrate and lumacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased the AUC and Cmax of brigatinib by 80% and 60%, respectively.
    Lumateperone: (Major) Avoid coadministration of lumateperone and brigatinib as concurrent use may decrease lumateperone exposure which may reduce efficacy. Lumateperone is a CYP3A4 substrate; brigatinib is a weak CYP3A4 inducer. Although data are unavailable for weak CYP3A4 inducers, coadministration with a strong CYP3A4 inducer significantly decreased lumateperone exposure.
    Lurbinectedin: (Major) Avoid coadministration of lurbinectedin and brigatinib due to the risk of decreased lurbinectedin exposure which may reduce its efficacy. Lurbinectedin is a CYP3A substrate and brigatinib is a moderate CYP3A inducer.
    Maraviroc: (Moderate) Monitor for an increase in maraviroc-related adverse reactions if coadministration with brigatinib is necessary. Concurrent use may increase the plasma concentrations of maraviroc. Maraviroc is a P-glycoprotein (P-gp) substrate; brigatinib is a P-gp inhibitor.
    Mefloquine: (Moderate) Use mefloquine with caution if coadministration with brigatinib is necessary as concurrent use may affect mefloquine exposure which may reduce efficacy or increase mefloquine-related adverse reactions. Mefloquine is a CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Brigatinib is a weak CYP3A4 inducer and a P-gp inhibitor.
    Meperidine: (Moderate) Monitor for reduced efficacy of meperidine and signs of opioid withdrawal if coadministration with brigatinib is necessary. Consider increasing the dose of meperidine as needed. If brigatinib is discontinued, consider a dose reduction of meperidine and frequently monitor for signs of respiratory depression and sedation. Meperidine is a substrate of CYP3A; brigatinib is a weak CYP3A inducer. Concomitant use can decrease meperidine exposure resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Meperidine; Promethazine: (Moderate) Monitor for reduced efficacy of meperidine and signs of opioid withdrawal if coadministration with brigatinib is necessary. Consider increasing the dose of meperidine as needed. If brigatinib is discontinued, consider a dose reduction of meperidine and frequently monitor for signs of respiratory depression and sedation. Meperidine is a substrate of CYP3A; brigatinib is a weak CYP3A inducer. Concomitant use can decrease meperidine exposure resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Mephobarbital: (Major) Avoid coadministration of brigatinib with mephobarbital due to decreased plasma exposure to brigatinib which may result in decreased efficacy. Brigatinib is a CYP3A4 substrate; mephobarbital is metabolized to phenobarbital, a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased the AUC and Cmax of brigatinib by 80% and 60%, respectively.
    Metformin: (Moderate) Consider the benefits and risks of concomitant therapy of brigatinib with metformin. Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., MATE inhibitors) could increase systemic exposure to metformin and increase the risk for lactic acidosis. Brigatinib inhibits MATE1 and MATE2K in vitro and may have the potential to increase concentrations of coadministered substrates of these transporters.
    Metformin; Repaglinide: (Moderate) Consider the benefits and risks of concomitant therapy of brigatinib with metformin. Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., MATE inhibitors) could increase systemic exposure to metformin and increase the risk for lactic acidosis. Brigatinib inhibits MATE1 and MATE2K in vitro and may have the potential to increase concentrations of coadministered substrates of these transporters.
    Metformin; Rosiglitazone: (Moderate) Consider the benefits and risks of concomitant therapy of brigatinib with metformin. Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., MATE inhibitors) could increase systemic exposure to metformin and increase the risk for lactic acidosis. Brigatinib inhibits MATE1 and MATE2K in vitro and may have the potential to increase concentrations of coadministered substrates of these transporters.
    Metformin; Saxagliptin: (Moderate) Consider the benefits and risks of concomitant therapy of brigatinib with metformin. Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., MATE inhibitors) could increase systemic exposure to metformin and increase the risk for lactic acidosis. Brigatinib inhibits MATE1 and MATE2K in vitro and may have the potential to increase concentrations of coadministered substrates of these transporters.
    Metformin; Sitagliptin: (Moderate) Consider the benefits and risks of concomitant therapy of brigatinib with metformin. Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., MATE inhibitors) could increase systemic exposure to metformin and increase the risk for lactic acidosis. Brigatinib inhibits MATE1 and MATE2K in vitro and may have the potential to increase concentrations of coadministered substrates of these transporters.
    Methadone: (Moderate) Monitor for reduced efficacy of methadone and signs of opioid withdrawal if coadministration with brigatinib is necessary. Consider increasing the dose of methadone as needed. If brigatinib is discontinued, consider a dose reduction of methadone and frequently monitor for signs of respiratory depression and sedation. Methadone is a substrate of CYP3A4, CYP2B6, CYP2C19, CYP2C9, and CYP2D6; brigatinib is a weak CYP3A inducer. Concomitant use can decrease methadone exposure resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Mifepristone: (Major) Avoid coadministration of brigatinib with mifepristone if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 50% without breaking tablets (i.e., from 180 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of mifepristone, resume the brigatinib dose that was tolerated prior to initiation of mifepristone. Brigatinib is a CYP3A4 substrate; mifepristone is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively.
    Mitotane: (Major) Avoid coadministration of brigatinib with mitotane due to decreased plasma exposure to brigatinib which may result in decreased efficacy. Brigatinib is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased the AUC and Cmax of brigatinib by 80% and 60%, respectively.
    Modafinil: (Major) Avoid coadministration of brigatinib with modafinil due to decreased plasma exposure to brigatinib which may result in decreased efficacy. If concomitant use is unavoidable, after 7 days of concomitant treatment with modafinil, increase the dose of brigatinib as tolerated in 30 mg increments to a maximum of twice the original brigatinib dose. After discontinuation of modafinil, resume the brigatinib dose that was tolerated prior to initiation of modafinil. Brigatinib is a CYP3A4 substrate and modafinil is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of brigatinib by approximately 50%.
    Morphine: (Moderate) Monitor for an increase in morphine-related adverse reactions, including sedation and respiratory depression, if coadministration with brigatinib is necessary; consider a reduced dose of morphine with frequent monitoring for respiratory depression and sedation. Morphine is a P-glycoprotein (P-gp) substrate. Brigatinib inhibits P-gp in vitro and may have the potential to increase concentrations of P-gp substrates.
    Morphine; Naltrexone: (Moderate) Monitor for an increase in morphine-related adverse reactions, including sedation and respiratory depression, if coadministration with brigatinib is necessary; consider a reduced dose of morphine with frequent monitoring for respiratory depression and sedation. Morphine is a P-glycoprotein (P-gp) substrate. Brigatinib inhibits P-gp in vitro and may have the potential to increase concentrations of P-gp substrates.
    Nafcillin: (Major) Avoid coadministration of brigatinib with nafcillin due to decreased plasma exposure to brigatinib which may result in decreased efficacy. If concomitant use is unavoidable, after 7 days of concomitant treatment with nafcillin, increase the dose of brigatinib as tolerated in 30 mg increments to a maximum of twice the original brigatinib dose. After discontinuation of nafcillin, resume the brigatinib dose that was tolerated prior to initiation of nafcillin. Brigatinib is a CYP3A4 substrate and nafcillin is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of brigatinib by approximately 50%.
    Naldemedine: (Moderate) Monitor for an increase in naldemedine-related adverse reactions if coadministration with brigatinib is necessary. Naldemedine is a substrate of P-glycoprotein (P-gp). Brigatinib inhibits P-gp in vitro and may have the potential to increase concentrations of P-gp substrates.
    Nanoparticle Albumin-Bound Paclitaxel: (Moderate) Monitor for decreased efficacy of nab-paclitaxel if coadministration with brigatinib is necessary due to the risk of decreased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP3A4 substrate and brigatinib is a weak CYP3A4 inducer.
    Nanoparticle Albumin-Bound Sirolimus: (Moderate) Monitor sirolimus whole blood trough concentrations as appropriate and watch for sirolimus-related adverse reactions or changes in efficacy if coadministration with brigatinib is necessary. The dose of sirolimus may need to be changed. Sirolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate with a narrow therapeutic range. Brigatinib is a P-gp inhibitor and a weak CYP3A4 inducer.
    Nefazodone: (Major) Avoid coadministration of brigatinib with nefazodone if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 50% without breaking tablets (i.e., from 180 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of nefazodone, resume the brigatinib dose that was tolerated prior to initiation of nefazodone. Brigatinib is a CYP3A4 substrate; nefazodone is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively.
    Nelfinavir: (Major) Avoid coadministration of brigatinib with nelfinavir if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 50% without breaking tablets (i.e., from 180 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of nelfinavir, resume the brigatinib dose that was tolerated prior to initiation of nelfinavir. Brigatinib is a CYP3A4 substrate; nelfinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively.
    Netupitant, Fosnetupitant; Palonosetron: (Major) Avoid coadministration of brigatinib with netupitant if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 40% without breaking tablets (i.e., from 180 mg to 120 mg; from 120 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of netupitant, resume the brigatinib dose that was tolerated prior to initiation of netupitant. Brigatinib is a CYP3A4 substrate; netupitant is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase the AUC of brigatinib by approximately 40%.
    Nevirapine: (Major) Avoid coadministration of brigatinib with nevirapine due to decreased plasma exposure to brigatinib which may result in decreased efficacy. If concomitant use is unavoidable, after 7 days of concomitant treatment with nevirapine, increase the dose of brigatinib as tolerated in 30 mg increments to a maximum of twice the original brigatinib dose. After discontinuation of nevirapine, resume the brigatinib dose that was tolerated prior to initiation of nevirapine. Brigatinib is a CYP3A4 substrate and nevirapine is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of brigatinib by approximately 50%.
    Nilotinib: (Major) Avoid coadministration of brigatinib with nilotinib if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 40% without breaking tablets (i.e., from 180 mg to 120 mg; from 120 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of nilotinib, resume the brigatinib dose that was tolerated prior to initiation of nilotinib. Brigatinib is a CYP3A4 substrate; nilotinib is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase the AUC of brigatinib by approximately 40%.
    Nimodipine: (Moderate) Monitor for decreased efficacy of nimodipine if coadministration with brigatinib is necessary as concomitant use may decrease plasma concentrations of nimodipine. Nimodipine is a CYP3A4 substrate and brigatinib is a weak CYP3A4 inducer.
    Nirmatrelvir; Ritonavir: (Major) Avoid coadministration of brigatinib with ritonavir if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 50% without breaking tablets (i.e., from 180 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of ritonavir, resume the brigatinib dose that was tolerated prior to initiation of ritonavir. Brigatinib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively. (Moderate) Monitor for a diminished response to nirmatrelvir if concomitant use of brigatinib is necessary. Concomitant use of nirmatrelvir and brigatinib may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and brigatinib is a weak CYP3A inducer.
    Nisoldipine: (Moderate) Avoid coadministration of nisoldipine with brigatinib as concurrent use may decrease nisoldipine exposure and efficacy. Alternative antihypertensive therapy should be considered. Nisoldipine is a CYP3A4 substrate and brigatinib is a CYP3A4 inducer. Coadministration with a strong CYP3A4 inducer lowered nisoldipine plasma concentrations to undetectable levels.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid coadministration of brigatinib with ritonavir if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 50% without breaking tablets (i.e., from 180 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of ritonavir, resume the brigatinib dose that was tolerated prior to initiation of ritonavir. Brigatinib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively. (Moderate) Monitor for an increase in ombitasvir-related adverse reactions if coadministration with brigatinib is necessary. Ombitasvir is a substrate of P-glycoprotein (P-gp) and BCRP. Brigatinib inhibits both P-gp and BCRP in vitro and may have the potential to increase concentrations of substrates of these transporters. (Moderate) Monitor for an increase in paritaprevir-related adverse reactions if coadministration with brigatinib is necessary. Paritaprevir is a substrate of P-glycoprotein (P-gp) and BCRP. Brigatinib inhibits both P-gp and BCRP in vitro and may have the potential to increase concentrations of substrates of these transporters.
    Omeprazole; Amoxicillin; Rifabutin: (Major) Avoid coadministration of brigatinib with rifabutin due to decreased plasma exposure to brigatinib which may result in decreased efficacy. If concomitant use is unavoidable, after 7 days of concomitant treatment with rifabutin, increase the dose of brigatinib as tolerated in 30 mg increments to a maximum of twice the original brigatinib dose. After discontinuation of rifabutin, resume the brigatinib dose that was tolerated prior to initiation of rifabutin. Brigatinib is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of brigatinib by approximately 50%.
    Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with brigatinib is necessary; consider increasing the dose of oxycodone as needed. If brigatinib is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and brigatinib is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Paclitaxel: (Moderate) Monitor for decreased efficacy of paclitaxel if coadministration with brigatinib is necessary due to the risk of decreased plasma concentrations of paclitaxel. Paclitaxel is a CYP3A4 substrate and brigatinib is a weak CYP3A4 inducer.
    Pazopanib: (Moderate) Monitor for an increase in pazopanib-related adverse reactions if coadministration with brigatinib is necessary. Pazopanib is a substrate of P-glycoprotein (P-gp) and BCRP. Brigatinib inhibits both P-gp and BCRP in vitro and may have the potential to increase concentrations of substrates of these transporters.
    Pemigatinib: (Major) Avoid coadministration of pemigatinib and brigatinib due to the risk of decreased pemigatinib exposure which may reduce its efficacy. Pemigatinib is a CYP3A4 substrate and brigatinib is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A4 inducer is predicted to decrease pemigatinib exposure by more than 50%.
    Pentobarbital: (Major) Avoid coadministration of brigatinib with pentobarbital due to decreased plasma exposure to brigatinib which may result in decreased efficacy. If concomitant use is unavoidable, after 7 days of concomitant treatment with pentobarbital, increase the dose of brigatinib as tolerated in 30 mg increments to a maximum of twice the original brigatinib dose. After discontinuation of pentobarbital, resume the brigatinib dose that was tolerated prior to initiation of pentobarbital. Brigatinib is a CYP3A4 substrate and pentobarbital is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of brigatinib by approximately 50%.
    Pexidartinib: (Major) Avoid coadministration of brigatinib with pexidartinib due to decreased plasma exposure to brigatinib, which may result in decreased efficacy. If concomitant use is unavoidable, after 7 days of concomitant treatment with pexidartinib, increase the dose of brigatinib as tolerated in 30 mg increments to a maximum of twice the original brigatinib dose. After discontinuation of pexidartinib, resume the brigatinib dose that was tolerated prior to initiation of pexidartinib. Brigatinib is a CYP3A4 substrate and pexidartinib is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of brigatinib by approximately 50%.
    Phenobarbital: (Major) Avoid coadministration of brigatinib with phenobarbital due to decreased plasma exposure to brigatinib which may result in decreased efficacy. Brigatinib is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased the AUC and Cmax of brigatinib by 80% and 60%, respectively.
    Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid coadministration of brigatinib with phenobarbital due to decreased plasma exposure to brigatinib which may result in decreased efficacy. Brigatinib is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased the AUC and Cmax of brigatinib by 80% and 60%, respectively.
    Phenytoin: (Major) Avoid coadministration of brigatinib with phenytoin due to decreased plasma exposure to brigatinib, which may result in decreased efficacy. Brigatinib is a CYP3A4 substrate; phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased the AUC and Cmax of brigatinib by 80% and 60%, respectively.
    Pimavanserin: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends avoiding concomitant use of pimavanserin with moderate CYP3A4 inducers, such as brigatinib. Moderate inducers of CYP3A4 can reduce pimavanserin exposure, potentially decreasing the effectiveness of pimavanserin.
    Pioglitazone; Metformin: (Moderate) Consider the benefits and risks of concomitant therapy of brigatinib with metformin. Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., MATE inhibitors) could increase systemic exposure to metformin and increase the risk for lactic acidosis. Brigatinib inhibits MATE1 and MATE2K in vitro and may have the potential to increase concentrations of coadministered substrates of these transporters.
    Posaconazole: (Major) Avoid coadministration of brigatinib with posaconazole if possible due to increased plasma exposure of brigatinib; an increase in posaconazole exposure may also occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 50% without breaking tablets (i.e., from 180 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of posaconazole, resume the brigatinib dose that was tolerated prior to initiation of posaconazole. Brigatinib is a CYP3A4 substrate; posaconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively. Brigatinib is also a P-glycoprotein (P-gp) inhibitor in vitro and may have the potential to increase concentrations of P-gp substrates like posaconazole.
    Praziquantel: (Moderate) Monitor for reduced response to praziquantel if coadministered with brigatinib. Concomitant use may produce therapeutically ineffective concentrations of praziquantel. In vitro and drug interactions studies suggest that the CYP3A4 isoenzyme is the major enzyme involved in praziquantel metabolism. brigatinib is a weak CYP3A4 inducer.
    Primidone: (Major) Avoid coadministration of brigatinib with primidone due to decreased plasma exposure to brigatinib which may result in decreased efficacy. Brigatinib is a CYP3A4 substrate; primidone is metabolized to phenobarbital, a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased the AUC and Cmax of brigatinib by 80% and 60%, respectively.
    Probenecid; Colchicine: (Moderate) Monitor for an increase in colchicine-related adverse reactions if coadministration with brigatinib is necessary; the risk is higher in patients with renal or hepatic impairment. A dose reduction of colchicine may be necessary. Colchicine is a P-glycoprotein (P-gp) substrate with a narrow therapeutic index. Brigatinib is a P-gp inhibitor in vitro and may have the potential to increase concentrations of P-gp substrates.
    Quinidine: (Moderate) Monitor for an increase in quinine-related adverse reactions if coadministration with brigatinib is necessary. Quinidine is a substrate of P-glycoprotein (P-gp). Brigatinib inhibits P-gp in vitro and may have the potential to increase concentrations of P-gp substrates.
    Quinine: (Moderate) Monitor for an increase in quinine-related adverse reactions if coadministration with brigatinib is necessary. Quinine is a substrate of P-glycoprotein (P-gp). Brigatinib inhibits P-gp in vitro and may have the potential to increase concentrations of P-gp substrates.
    Ranolazine: (Moderate) Monitor for an increase in ranolazine-related adverse reactions if coadministration with brigatinib is necessary. Ranolazine is a substrate of P-glycoprotein (P-gp). Brigatinib inhibits P-gp in vitro and may have the potential to increase concentrations of P-gp substrates.
    Relugolix: (Major) Avoid concomitant use of relugolix and oral brigatinib. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. If concomitant use is unavoidable, administer brigatinib at least 6 hours after relugolix and monitor for adverse reactions. Relugolix is a P-glycoprotein (P-gp) substrate. Brigatinib is a P-gp inhibitor.
    Relugolix; Estradiol; Norethindrone acetate: (Major) Avoid concomitant use of relugolix and oral brigatinib. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. If concomitant use is unavoidable, administer brigatinib at least 6 hours after relugolix and monitor for adverse reactions. Relugolix is a P-glycoprotein (P-gp) substrate. Brigatinib is a P-gp inhibitor.
    Ribociclib: (Major) Avoid coadministration of brigatinib with ribociclib if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 50% without breaking tablets (i.e., from 180 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of ribociclib, resume the brigatinib dose that was tolerated prior to initiation of ribociclib. Brigatinib is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively.
    Ribociclib; Letrozole: (Major) Avoid coadministration of brigatinib with ribociclib if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 50% without breaking tablets (i.e., from 180 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of ribociclib, resume the brigatinib dose that was tolerated prior to initiation of ribociclib. Brigatinib is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively.
    Rifabutin: (Major) Avoid coadministration of brigatinib with rifabutin due to decreased plasma exposure to brigatinib which may result in decreased efficacy. If concomitant use is unavoidable, after 7 days of concomitant treatment with rifabutin, increase the dose of brigatinib as tolerated in 30 mg increments to a maximum of twice the original brigatinib dose. After discontinuation of rifabutin, resume the brigatinib dose that was tolerated prior to initiation of rifabutin. Brigatinib is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of brigatinib by approximately 50%.
    Rifampin: (Major) Avoid coadministration of brigatinib with rifampin due to decreased plasma exposure to brigatinib, which may result in decreased efficacy. Brigatinib is a CYP3A4 substrate; rifampin is a strong CYP3A4 inducer. Coadministration of rifampin decreased the AUC and Cmax of brigatinib by 80% and 60%, respectively.
    Rifapentine: (Major) Avoid coadministration of brigatinib with rifapentine due to decreased plasma exposure to brigatinib which may result in decreased efficacy. Brigatinib is a CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of brigatinib by 80% and 60%, respectively.
    Rifaximin: (Moderate) In patients with hepatic impairment, avoid coadministration of brigatinib with rifaximin due to decreased plasma exposure to brigatinib which may result in decreased efficacy; brigatinib may be administered with rifaximin in patients with normal hepatic function. If concomitant use is unavoidable in patients with hepatic impairment, after 7 days of concomitant treatment with rifaximin, increase the dose of brigatinib as tolerated in 30 mg increments to a maximum of twice the original brigatinib dose. After discontinuation of rifaximin, resume the brigatinib dose that was tolerated prior to initiation of rifaximin. Brigatinib is a CYP3A4 substrate. In patients with normal liver function, rifaximin at the recommended dosing regimen is not expected to induce CYP3A4. It is unknown whether rifaximin can have a significant effect on the pharmacokinetics of concomitant CYP3A4 substrates in patients with reduced liver function who have elevated rifaximin concentrations. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of brigatinib by approximately 50%.
    Rimegepant: (Major) Avoid a second dose of rimegepant within 48 hours if coadministered with brigatinib; concurrent use may increase rimegepant exposure. Rimegepant is a P-gp substrate and brigatinib is a P-gp inhibitor.
    Ripretinib: (Major) Avoid coadministration of ripretinib with brigatinib. If concomitant use is unavoidable, increase the frequency of ripretinib dosing from 150 mg once daily to 150 mg twice daily; monitor for clinical response and tolerability. Resume once daily dosing of ripretinib 14 days after discontinuation of brigatinib. Coadministration is predicted to decrease the exposure of ripretinib and its active metabolite (DP-5439), which may decrease ripretinib anti-tumor activity. Ripretinib and DP-5439 are metabolized by CYP3A and brigatinib is a moderate CYP3A inducer. Drug interaction modeling studies suggest coadministration with a moderate CYP3A inducer may decrease ripretinib exposure by 56%.
    Ritonavir: (Major) Avoid coadministration of brigatinib with ritonavir if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 50% without breaking tablets (i.e., from 180 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of ritonavir, resume the brigatinib dose that was tolerated prior to initiation of ritonavir. Brigatinib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively.
    Romidepsin: (Moderate) Monitor for an increase in romidepsin-related adverse reactions if coadministration with brigatinib is necessary. Romidepsin is a substrate of P-glycoprotein (P-gp). Brigatinib inhibits P-gp in vitro and may have the potential to increase concentrations of P-gp substrates.
    Saquinavir: (Major) Avoid coadministration of brigatinib with saquinavir if possible due to increased plasma exposure of brigatinib which may result in an increase in brigatinib-related adverse reactions; saquinavir exposure may also increase. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 50% without breaking tablets (i.e., from 180 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of saquinavir, resume the brigatinib dose that was tolerated prior to initiation of saquinavir. Brigatinib is a CYP3A4 substrate and a P-glycoprotein (P-gp) inhibitor. Saquinavir is a strong CYP3A4 inhibitor and a P-gp substrate. Coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively.
    SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
    Secobarbital: (Major) Avoid coadministration of brigatinib with secobarbital due to decreased plasma exposure to brigatinib which may result in decreased efficacy. If concomitant use is unavoidable, after 7 days of concomitant treatment with secobarbital, increase the dose of brigatinib as tolerated in 30 mg increments to a maximum of twice the original brigatinib dose. After discontinuation of secobarbital, resume the brigatinib dose that was tolerated prior to initiation of secobarbital. Brigatinib is a CYP3A4 substrate and secobarbital is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of brigatinib by approximately 50%.
    Sildenafil: (Moderate) Monitor for decreased efficacy of sildenafil if coadministration with brigatinib is necessary as concurrent use may decrease sildenafil exposure. Sildenafil is a sensitive CYP3A4 substrate and brigatinib is a weak CYP3A4 inducer. Population pharmacokinetic analysis indicates an approximately 3-fold increase in sildenafil clearance with concomitant use of weak CYP3A4 inducers.
    Silodosin: (Moderate) Monitor for an increase in silodosin-related adverse reactions if coadministration with brigatinib is necessary. Silodosin is a substrate of P-glycoprotein (P-gp). Brigatinib inhibits P-gp in vitro and may have the potential to increase concentrations of P-gp substrates.
    Simeprevir: (Moderate) Monitor for an increase in simeprevir-related adverse reactions if coadministration with brigatinib is necessary. Simeprevir is a P-glycoprotein (P-gp) substrate. Brigatinib is a P-gp inhibitor in vitro and may have the potential to increase concentrations of P-gp substrates.
    Sirolimus: (Moderate) Monitor sirolimus whole blood trough concentrations as appropriate and watch for sirolimus-related adverse reactions or changes in efficacy if coadministration with brigatinib is necessary. The dose of sirolimus may need to be changed. Sirolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate with a narrow therapeutic range. Brigatinib is a P-gp inhibitor and a weak CYP3A4 inducer.
    Sotorasib: (Major) Avoid coadministration of brigatinib with sotorasib due to decreased plasma exposure to brigatinib which may result in decreased efficacy. If concomitant use is unavoidable, after 7 days of concomitant treatment with sotorasib, increase the dose of brigatinib as tolerated in 30 mg increments to a maximum of twice the original brigatinib dose. After discontinuation of sotorasib, resume the brigatinib dose that was tolerated prior to initiation of sotorasib. Brigatinib is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of brigatinib by approximately 50%.
    St. John's Wort, Hypericum perforatum: (Major) Avoid coadministration of brigatinib with St. John's Wort due to decreased plasma exposure to brigatinib which may result in decreased efficacy. Brigatinib is a CYP3A4 substrate; St. John's Wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased the AUC and Cmax of brigatinib by 80% and 60%, respectively.
    Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if brigatinib must be administered. Monitor for reduced efficacy of sufentanil injection and signs of opioid withdrawal if coadministration with brigatinib is necessary; consider increasing the dose of sufentanil injection as needed. If brigatinib is discontinued, consider a dose reduction of sufentanil injection and frequently monitor for signs or respiratory depression and sedation. Sufentanil is a CYP3A4 substrate and brigatinib is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease sufentanil concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Tacrolimus: (Moderate) Monitor tacrolimus serum concentrations as appropriate if coadministration with brigatinib is necessary; a tacrolimus dose adjustment may be needed. Concurrent administration may decrease tacrolimus concentrations. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range; brigatinib is a weak CYP3A4 inducer.
    Talazoparib: (Moderate) Monitor for an increase in talazoparib-related adverse reactions if coadministration with brigatinib is necessary. Talazoparib is a BCRP and P-glycoprotein (P-gp) substrate. Brigatinib inhibits both P-gp and BCRP in vitro and may have the potential to increase concentrations of substrates of these transporters. Coadministration with other P-gp inhibitors increased talazoparib exposure by 8% to 45%. The effect of concomitant administration of BCRP inhibitors on the pharmacokinetics of talazoparib has not been studied; however, BCRP inhibitors may increase talazoparib exposure.
    Telithromycin: (Major) Avoid coadministration of brigatinib with telithromycin if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 50% without breaking tablets (i.e., from 180 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of telithromycin, resume the brigatinib dose that was tolerated prior to initiation of telithromycin. Brigatinib is a CYP3A4 substrate; telithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively.
    Temsirolimus: (Moderate) Monitor for an increase in temsirolimus-related adverse reactions if coadministration with brigatinib is necessary. Temsirolimus is a substrate of P-glycoprotein (P-gp). Brigatinib inhibits P-gp in vitro and may have the potential to increase concentrations of P-gp substrates.
    Tenofovir Alafenamide: (Moderate) Monitor for an increase in tenofovir-related adverse reactions if coadministration with brigatinib is necessary. Tenofovir alafenamide is a substrate of P-glycoprotein (P-gp) and BCRP. Brigatinib inhibits both P-gp and BCRP in vitro and may have the potential to increase concentrations of substrates of these transporters.
    Tenofovir Alafenamide: (Moderate) Monitor for an increase in tenofovir-related adverse reactions if coadministration with brigatinib is necessary. Tenofovir alafenamide is a substrate of P-glycoprotein (P-gp) and BCRP. Brigatinib inhibits both P-gp and BCRP in vitro and may have the potential to increase concentrations of substrates of these transporters.
    Tenofovir, PMPA: (Moderate) Monitor for an increase in tenofovir-related adverse reactions if coadministration with brigatinib is necessary. Tenofovir disoproxil fumarate is a substrate of P-glycoprotein (P-gp) and BCRP. Brigatinib inhibits both P-gp and BCRP in vitro and may have the potential to increase concentrations of substrates of these transporters.
    Thiopental: (Major) Avoid coadministration of brigatinib with thiopental due to decreased plasma exposure to brigatinib which may result in decreased efficacy. If concomitant use is unavoidable, after 7 days of concomitant treatment with thiopental, increase the dose of brigatinib as tolerated in 30 mg increments to a maximum of twice the original brigatinib dose. After discontinuation of thiopental, resume the brigatinib dose that was tolerated prior to initiation of thiopental. Brigatinib is a CYP3A4 substrate and thiopental is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of brigatinib by approximately 50%.
    Ticagrelor: (Moderate) Monitor for increased bleeding if ticagrelor is coadministered with brigatinib as concurrent use may increase the exposure of ticagrelor. Ticagrelor is a P-gp substrate and brigatinib is a P-gp inhibitor.
    Tipranavir: (Major) Avoid coadministration of brigatinib with tipranavir if possible due to increased plasma exposure of brigatinib which may result in an increase in brigatinib-related adverse reactions; tipranavir exposure may also increase. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 50% without breaking tablets (i.e., from 180 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of tipranavir, resume the brigatinib dose that was tolerated prior to initiation of tipranavir. Brigatinib is a CYP3A4 substrate and a P-glycoprotein (P-gp) inhibitor. Tipranavir is a strong CYP3A4 inhibitor and a P-gp substrate. Coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively.
    Topotecan: (Moderate) Monitor for an increase in topotecan-related adverse reactions if coadministration of oral topotecan with brigatinib is necessary. Oral topotecan is a substrate of P-glycoprotein (P-gp) and BCRP. Brigatinib inhibits both P-gp and BCRP in vitro and may have the potential to increase concentrations of substrates of these transporters. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Tramadol: (Moderate) Monitor for reduced efficacy of tramadol and signs of opioid withdrawal if coadministration with brigatinib is necessary; consider increasing the dose of tramadol as needed. If brigatinib is discontinued, consider a dose reduction of tramadol and frequently monitor for seizures, serotonin syndrome, and signs of respiratory depression and sedation. Tramadol is a CYP3A4 substrate and brigatinib is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease tramadol levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Tramadol; Acetaminophen: (Moderate) Monitor for reduced efficacy of tramadol and signs of opioid withdrawal if coadministration with brigatinib is necessary; consider increasing the dose of tramadol as needed. If brigatinib is discontinued, consider a dose reduction of tramadol and frequently monitor for seizures, serotonin syndrome, and signs of respiratory depression and sedation. Tramadol is a CYP3A4 substrate and brigatinib is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease tramadol levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Trandolapril; Verapamil: (Major) Avoid coadministration of brigatinib with verapamil if possible due to increased plasma exposure of brigatinib; increased verapamil concentrations may also occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 40% without breaking tablets (i.e., from 180 mg to 120 mg; from 120 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of verapamil, resume the brigatinib dose that was tolerated prior to initiation of verapamil. Monitor blood pressure and heart rate. Brigatinib is a CYP3A4 substrate; verapamil is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase the AUC of brigatinib by approximately 40%. Additionally, verapamil is a P-glycoprotein (P-gp) substrate. Brigatinib is a P-gp inhibitor in vitro and may have the potential to increase concentrations of P-gp substrates.
    Tucatinib: (Major) Avoid coadministration of brigatinib with tucatinib if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 50% without breaking tablets (i.e., from 180 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of tucatinib, resume the brigatinib dose that was tolerated prior to initiation of tucatinib. Brigatinib is a CYP3A4 substrate; tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively.
    Ubrogepant: (Major) Ubrogepant dose adjustment is necessary if coadministered with brigatinib as concurrent use may decrease ubrogepant exposure and efficacy or increase ubrogepant exposure and side effects. Ubrogepant is a P-glycoprotein (P-gp), BCRP, and CYP3A substrate; brigatinib is a P-gp and BRCP inhibitor and a weak CYP3A inducer.
    Umeclidinium: (Moderate) Monitor for an increase in umeclidinium-related adverse reactions if coadministration with brigatinib is necessary. Umeclidinium is a P-glycoprotein (P-gp) substrate. Brigatinib inhibits P-gp in vitro and may have the potential to increase concentrations of P-gp substrates. Coadministration with a P-gp inhibitor increased umeclidinium exposure by 1.4-fold.
    Umeclidinium; Vilanterol: (Moderate) Monitor for an increase in umeclidinium-related adverse reactions if coadministration with brigatinib is necessary. Umeclidinium is a P-glycoprotein (P-gp) substrate. Brigatinib inhibits P-gp in vitro and may have the potential to increase concentrations of P-gp substrates. Coadministration with a P-gp inhibitor increased umeclidinium exposure by 1.4-fold.
    Venetoclax: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with brigatinib due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of brigatinib. Brigatinib is a P-gp inhibitor; venetoclax is a P-gp substrate. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Verapamil: (Major) Avoid coadministration of brigatinib with verapamil if possible due to increased plasma exposure of brigatinib; increased verapamil concentrations may also occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 40% without breaking tablets (i.e., from 180 mg to 120 mg; from 120 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of verapamil, resume the brigatinib dose that was tolerated prior to initiation of verapamil. Monitor blood pressure and heart rate. Brigatinib is a CYP3A4 substrate; verapamil is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase the AUC of brigatinib by approximately 40%. Additionally, verapamil is a P-glycoprotein (P-gp) substrate. Brigatinib is a P-gp inhibitor in vitro and may have the potential to increase concentrations of P-gp substrates.
    Vincristine Liposomal: (Moderate) Monitor for an increased incidence or earlier onset of vincristine-related adverse reactions if coadministration with brigatinib is necessary. Vincristine is a substrate of P-glycoprotein (P-gp). Brigatinib inhibits P-gp in vitro and may have the potential to increase concentrations of P-gp substrates.
    Vincristine: (Moderate) Monitor for an increased incidence or earlier onset of vincristine-related adverse reactions if coadministration with brigatinib is necessary. Vincristine is a substrate of P-glycoprotein (P-gp). Brigatinib inhibits P-gp in vitro and may have the potential to increase concentrations of P-gp substrates.
    Voclosporin: (Major) Avoid coadministration of voclosporin with brigatinib. Coadministration may decrease voclosporin exposure resulting in decreased efficacy. Voclosporin is a sensitive CYP3A4 substrate and brigatinib is a moderate CYP3A4 inducer. Coadministration with moderate CYP3A4 inducers is predicted to decrease voclosporin exposure by 70%.
    Voriconazole: (Major) Avoid coadministration of brigatinib with voriconazole if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 50% without breaking tablets (i.e., from 180 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of voriconazole, resume the brigatinib dose that was tolerated prior to initiation of voriconazole. Brigatinib is a CYP3A4 substrate; voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively.
    Voxelotor: (Major) Avoid coadministration of brigatinib with voxelotor if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 40% without breaking tablets (i.e., from 180 mg to 120 mg; from 120 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of voxelotor, resume the brigatinib dose that was tolerated prior to initiation of voxelotor. Brigatinib is a CYP3A substrate; voxelotor is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase the AUC of brigatinib by approximately 40%.
    Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with brigatinib is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. Brigatinib is a weak CYP3A4 inducer and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.

    PREGNANCY AND LACTATION

    Pregnancy

    Pregnancy should be avoided by females of reproductive potential during brigatinib treatment and for at least 4 months after the last dose. Although there are no adequately controlled studies in pregnant women, brigatinib can cause fetal harm when administered during pregnancy based on its mechanism of action and animal studies. Women who are pregnant or who become pregnant while receiving brigatinib should be apprised of the potential hazard to the fetus. When administered to pregnant rats during organogenesis, dose-related skeletal incomplete ossification, small incisors) and visceral anomalies occurred at exposures of approximately 0.7 times the human exposure at the recommended dose of 180 mg once daily, as well as increased post-implantation loss, malformations (anasarca, anophthalmia, forelimb hyperflexion, small, short, and/or bent limbs, fused ribs, bent scapulae, omphalocele, and gastroschisis), visceral findings of moderate bilateral dilatation of the lateral ventricles, and decreased fetal body weight at exposures of approximately 1.26 times the human exposure at the recommended dose or higher.

    Due to the potential for serious adverse reactions in nursing infants from brigatinib, advise women to discontinue breast-feeding during treatment and for 1 week after the final dose.

    MECHANISM OF ACTION

    Brigatinib is a tyrosine kinase inhibitor that targets multiple kinases, including anaplastic lymphoma kinase (ALK), ROS1, insulin-like growth factor-1 receptor (IGF-1R), and FLT-3, as well as EGFR deletion and point mutations. It inhibits ALK autophosphorylation as well as ALK-mediated activation 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. 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 at clinically achievable concentrations. It also 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.

    PHARMACOKINETICS

    Brigatinib is administered orally. It is 66% bound to plasma proteins, in a nonconcentration-dependent manner in vitro. The blood to plasma concentration ratio is 0.69. At the recommended dose of 180 mg once daily, the mean apparent volume of distribution (Vd) of brigatinib at steady-state was 153 L. The mean apparent clearance was 8.9 L/hour and the mean plasma elimination half-life is 25 hours. The two major metabolic pathways are N-demethylation and cysteine conjugation, with unchanged brigatinib as 92% of the circulating components after administration of a radiolabeled dose. The primary metabolite, AP26123, makes up less than 10% of the AUC of brigatinib in humans and exhibits approximately 3-fold lower potency than brigatinib in vitro. After oral administration of a single dose of brigatinib, 65% was recovered in the feces and 25% in the urine; unchanged brigatinib represented 41% and 86% of the total radioactivity, in the feces and urine, respectively.
    Affected cytochrome P450 (CYP) isoenzymes and drug transporters: CYP3A4, CYP2C8, P-gp, BCRP, OCT1, MATE1, MATE2K
    Brigatinib is primarily metabolized by CYP2C8 and CYP3A4 in vitro. In drug interaction studies, brigatinib has been shown to be a CYP3A4 substrate when administered with strong CYP3A inhibitors and inducers. Coadministration with a strong CYP2C8 inhibitor (gemfibrozil) decreased the brigatinib exposure by 12%; this effect is not clinically meaningful and the mechanism for decreased brigatinib exposure is unknown. In vitro, brigatinib is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) and an inhibitor of P-gp, BCRP, organic cation transporter (OCT)-1, multidrug and toxin extrusion (MATE)-1, and MATE-2K. Brigatinib also induced CYP3A and CYP2C enzymes via activation of the pregnane X receptor at clinically relevant plasma concentrations in vitro.

    Oral Route

    After oral administration, the geometric mean steady-state Cmax of brigatinib at a dose of 90 mg was 552 ng/mL (coefficient of variation (CV%), 49%) and at a dose of 180 mg was 1,452 ng/mL (CV%, 60%); the corresponding AUC was 8,165 ng x hour/mL (CV%, 45%) at the 90 mg dose and 20,276 ng x hour/mL (CV%, 62%) at the 180 mg dose. After single oral doses of 30 mg to 240 mg, the median Tmax of brigatinib ranged from 1 to 4 hours. Systemic exposure of brigatinib was dose proportional over a dose range of 60 mg to 240 mg once daily; the mean accumulation ratio after repeat dosing was 1.9 to 2.4.
    Effects of food: Administration of a high fat meal (approximately 920 calories, 58 grams carbohydrate, 59 grams fat, and 40 grams protein) reduced the Cmax by 13% without affecting the AUC in healthy subjects.