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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 who have progressed on or are intolerant to crizotinib
    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 non-small cell lung cancer (NSCLC).
    For the treatment of locally advanced or metastatic, ALK-positive, non-small cell lung cancer (NSCLC) in patients who have not previously received an ALK inhibitor†.
    Oral dosage
    Adults

    90 mg PO once daily for 7 days; if 90 mg is tolerated during the first 7 days, 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. Treatment with brigatinib was superior to crizotinib in terms of PFS in patients with locally advanced or metastatic NSCLC who had not previously been treated with an ALK inhibitor in an interim analysis of an open-label phase 3 clinical trial (ALTA-1L study).[63657]

    For the treatment of metastatic, ALK-positive non-small cell lung cancer (NSCLC) in patients who have progressed on or are intolerant to crizotinib.
    Oral dosage
    Adults

    90 mg PO once daily for 7 days; if 90 mg is tolerated during the first 7 days, 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

    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.

    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.

    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 nonhormonal 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

    bradycardia / Rapid / 5.7-7.6
    pneumonitis / Delayed / 1.8-7.3
    hypertension / Early / 5.5-6.4
    infection / Delayed / 0-5.5
    lymphopenia / Delayed / 2.8-4.5
    hyperamylasemia / Delayed / 2.7-3.7
    hyperglycemia / Delayed / 3.6-3.7
    rash / Early / 1.8-3.6
    hypophosphatemia / Delayed / 1.8-3.6
    dyspnea / Early / 1.8-2.8
    hypoxia / Early / 0-2.7
    elevated hepatic enzymes / Delayed / 0-2.7
    back pain / Delayed / 0-1.8
    vomiting / Early / 0-1.8
    fatigue / Early / 1.8-1.8
    asthenia / Delayed / 0-1.8
    peripheral neuropathy / Delayed / 0.9-1.8
    pulmonary embolism / Delayed / 0-1.0
    macular edema / Delayed / 0-1.0
    visual impairment / Early / 0-0.9
    myalgia / Early / 0-0.9
    arthralgia / Delayed / 0-0.9
    constipation / Delayed / 0-0.9
    nausea / Early / 0.9-0.9
    anorexia / Delayed / 0.9-0.9
    headache / Early / 0-0.9
    fever / Early / 0-0.9
    anemia / Delayed / 0.9-0.9

    Moderate

    meningitis / Delayed / 0-1.0
    cataracts / Delayed / 0-1.0
    photophobia / Early / Incidence not known
    blurred vision / Early / Incidence not known

    Mild

    diarrhea / Early / 19.0-38.0
    cough / Delayed / 18.0-34.0
    abdominal pain / Early / 10.0-17.0
    insomnia / Early / 7.3-11.0
    diplopia / Early / Incidence not known
    musculoskeletal pain / Early / Incidence not known
    paresthesias / Delayed / Incidence not known
    acneiform rash / Delayed / 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.
    Abemaciclib: (Moderate) Monitor for a decrease in the efficacy of abemaciclib if coadministration with brigatinib is necessary. Abemaciclib is 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.
    Acalabrutinib: (Moderate) Monitor for a decrease in the efficacy of acalabrutinib if coadministration with brigatinib is necessary. Acalabrutinib is 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.
    Acetaminophen; Butalbital: (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%.
    Acetaminophen; 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%.
    Acetaminophen; 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) Concomitant use of codeine with brigatinib can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. 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. At clinically relevant concentrations, brigatinib induced CYP3A via activation of the pregnane X receptor (PXR); this may decrease concentrations of sensitive CYP3A substrates.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal if coadministration with brigatinib is necessary; consider increasing the dose of dihydrocodeine as needed. If brigatinib is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Dihydrocodeine is partially metabolized by CYP3A4. At clinically relevant concentrations, brigatinib induced CYP3A via activation of the pregnane X receptor (PXR); this may decrease concentrations of sensitive CYP3A substrates. Concomitant use of dihydrocodeine with brigatinib can decrease dihydrocodeine levels, resulting in less metabolism by CYP2D6 and decreased dihydromorphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with brigatinib can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. 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. At clinically relevant concentrations, brigatinib induced CYP3A via activation of the pregnane X receptor (PXR); this may decrease concentrations of sensitive CYP3A substrates.
    Acetaminophen; Hydrocodone: (Moderate) Concomitant use of hydrocodone with brigatinib can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If brigatinib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a 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.
    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. At clinically relevant concentrations, brigatinib induced CYP3A via activation of the pregnane X receptor (PXR); this may decrease concentrations of sensitive CYP3A substrates. 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.
    Acetaminophen; 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. At clinically relevant concentrations, brigatinib induced CYP3A via activation of the pregnane X receptor (PXR); this may decrease concentrations of sensitive CYP3A substrates. 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.
    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. At clinically relevant concentrations, brigatinib induced CYP3A via activation of the pregnane X receptor (PXR); this may decrease concentrations of sensitive CYP3A substrates. 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; Lansoprazole: (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.
    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; a decrease in aprepitant exposure 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 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%. Aprepitant 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.
    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) Concomitant use of codeine with brigatinib can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. 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. At clinically relevant concentrations, brigatinib induced CYP3A via activation of the pregnane X receptor (PXR); this may decrease concentrations of sensitive CYP3A substrates.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal if coadministration with brigatinib is necessary; consider increasing the dose of dihydrocodeine as needed. If brigatinib is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Dihydrocodeine is partially metabolized by CYP3A4. At clinically relevant concentrations, brigatinib induced CYP3A via activation of the pregnane X receptor (PXR); this may decrease concentrations of sensitive CYP3A substrates. Concomitant use of dihydrocodeine with brigatinib can decrease dihydrocodeine levels, resulting in less metabolism by CYP2D6 and decreased dihydromorphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with brigatinib can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. 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. At clinically relevant concentrations, brigatinib induced CYP3A via activation of the pregnane X receptor (PXR); this may decrease concentrations of sensitive CYP3A substrates.
    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. At clinically relevant concentrations, brigatinib induced CYP3A via activation of the pregnane X receptor (PXR); this may decrease concentrations of sensitive CYP3A substrates. 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.
    Atropine; Hyoscyamine; Phenobarbital; 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.
    Avanafil: (Moderate) Monitor for a decrease in the efficacy of avanafil if coadministration with brigatinib is necessary. Avanafil is 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.
    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) Concurrent use of benzhydrocodone with brigatinib may decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. If concomitant use is necessary, consider increasing the benzhydrocodone dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Discontinuation of brigatinib may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. If brigatinib is discontinued, consider a benzhydrocodone dosage reduction and monitor patients for respiratory depression and sedation at frequent intervals. Benzhydrocodone is a prodrug of hydrocodone, which is a 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.
    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%.
    Bosutinib: (Moderate) Monitor for a decrease in the efficacy of bosutinib if coadministration with brigatinib is necessary. Bosutinib is 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.
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Concomitant use of hydrocodone with brigatinib can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If brigatinib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a 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.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with brigatinib can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If brigatinib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a 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.
    Budesonide: (Moderate) Monitor for a decrease in the efficacy of budesonide if coadministration with brigatinib is necessary. Budesonide is 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.
    Budesonide; Formoterol: (Moderate) Monitor for a decrease in the efficacy of budesonide if coadministration with brigatinib is necessary. Budesonide is 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.
    Buspirone: (Moderate) Monitor for a decrease in the efficacy of buspirone if coadministration with brigatinib is necessary. Buspirone is 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.
    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%.
    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) Concomitant use of hydrocodone with brigatinib can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If brigatinib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a 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.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with brigatinib can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If brigatinib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a 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.
    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) Concomitant use of codeine with brigatinib can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. 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. At clinically relevant concentrations, brigatinib induced CYP3A via activation of the pregnane X receptor (PXR); this may decrease concentrations of sensitive CYP3A substrates.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal if coadministration with brigatinib is necessary; consider increasing the dose of dihydrocodeine as needed. If brigatinib is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Dihydrocodeine is partially metabolized by CYP3A4. At clinically relevant concentrations, brigatinib induced CYP3A via activation of the pregnane X receptor (PXR); this may decrease concentrations of sensitive CYP3A substrates. Concomitant use of dihydrocodeine with brigatinib can decrease dihydrocodeine levels, resulting in less metabolism by CYP2D6 and decreased dihydromorphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal if coadministration with brigatinib is necessary; consider increasing the dose of dihydrocodeine as needed. If brigatinib is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Dihydrocodeine is partially metabolized by CYP3A4. At clinically relevant concentrations, brigatinib induced CYP3A via activation of the pregnane X receptor (PXR); this may decrease concentrations of sensitive CYP3A substrates. Concomitant use of dihydrocodeine with brigatinib can decrease dihydrocodeine levels, resulting in less metabolism by CYP2D6 and decreased dihydromorphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with brigatinib can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If brigatinib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a 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.
    Chlorpheniramine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with brigatinib can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If brigatinib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a 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.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with brigatinib can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If brigatinib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a 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.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with brigatinib can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If brigatinib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a 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.
    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 a decrease in the efficacy of cobimetinib or an increase in cobimetinib-related adverse reactions if coadministration with brigatinib is necessary. Cobimetinib is 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. Brigatinib is also a P-glycoprotein (P-gp) inhibitor in vitro; drugs that inhibit P-gp may increase cobimetinib concentrations.
    Codeine: (Moderate) Concomitant use of codeine with brigatinib can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. 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. At clinically relevant concentrations, brigatinib induced CYP3A via activation of the pregnane X receptor (PXR); this may decrease concentrations of sensitive CYP3A substrates.
    Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with brigatinib can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. 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. At clinically relevant concentrations, brigatinib induced CYP3A via activation of the pregnane X receptor (PXR); this may decrease concentrations of sensitive CYP3A substrates.
    Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of codeine with brigatinib can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. 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. At clinically relevant concentrations, brigatinib induced CYP3A via activation of the pregnane X receptor (PXR); this may decrease concentrations of sensitive CYP3A substrates.
    Codeine; Promethazine: (Moderate) Concomitant use of codeine with brigatinib can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. 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. At clinically relevant concentrations, brigatinib induced CYP3A via activation of the pregnane X receptor (PXR); this may decrease concentrations of sensitive CYP3A substrates.
    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.
    Colchicine; Probenecid: (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. According to the manufacturer of conivaptan, subsequent treatment with a CYP3A4 substrate like brigatinib may be initiated no sooner than 1 week after the infusion of conivaptan is completed. 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 conivaptan, resume the brigatinib dose that was tolerated prior to initiation of conivaptan. Brigatinib is a CYP3A4 substrate; conivaptan is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively.
    Conjugated Estrogens; Medroxyprogesterone: (Major) Females of reproductive potential should use effective non-hormonal contraception during concomitant treatment with medroxyprogesterone and brigatinib, and for at least 4 months after the final dose of brigatinib. Medroxyprogesterone is a 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. Coadministration with brigatinib may reduce the efficacy of hormonal contraceptives; brigatinib can cause fetal harm if administered to a pregnant woman.
    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 increase. 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; brigatinib inhibits P-gp in vitro and may have the potential to increase concentrations of P-gp substrates.
    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.
    Dapagliflozin; Saxagliptin: (Moderate) Monitor blood sugars and watch for an increase in saxagliptin-related adverse reactions if coadministration with brigatinib is necessary. Saxagliptin 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.
    Darifenacin: (Moderate) Monitor for a decrease in the efficacy of darifenacin if coadministration with brigatinib is necessary. Darifenacin is 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.
    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.
    Dasatinib: (Moderate) Monitor for a decrease in the efficacy of dasatinib if coadministration with brigatinib is necessary. Dasatinib is 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.
    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.
    Dienogest; Estradiol valerate: (Major) Females of reproductive potential should use effective non-hormonal contraception during concomitant treatment with dienogest and brigatinib, and for at least 4 months after the final dose of brigatinib. Dienogest is a 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. Coadministration with brigatinib may reduce the efficacy of hormonal contraceptives; brigatinib can cause fetal harm if administered to a pregnant woman. (Major) Females of reproductive potential should use effective non-hormonal contraception during concomitant treatment with estradiol valerate and brigatinib, and for at least 4 months after the final dose of brigatinib. Estradiol valerate is a 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. Coadministration with brigatinib may reduce the efficacy of hormonal contraceptives; brigatinib can cause fetal harm if administered to a pregnant woman.
    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.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) Monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal if coadministration with brigatinib is necessary; consider increasing the dose of dihydrocodeine as needed. If brigatinib is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Dihydrocodeine is partially metabolized by CYP3A4. At clinically relevant concentrations, brigatinib induced CYP3A via activation of the pregnane X receptor (PXR); this may decrease concentrations of sensitive CYP3A substrates. Concomitant use of dihydrocodeine with brigatinib can decrease dihydrocodeine levels, resulting in less metabolism by CYP2D6 and decreased dihydromorphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    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) Concomitant use of hydrocodone with brigatinib can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If brigatinib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a 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.
    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; 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.
    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.
    Drospirenone; Ethinyl Estradiol: (Major) Females of reproductive potential should use effective non-hormonal contraception during concomitant treatment with ethinyl estradiol and brigatinib, and for at least 4 months after the final dose of brigatinib. Ethinyl estradiol is a 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. Coadministration with brigatinib may reduce the efficacy of hormonal contraceptives; brigatinib can cause fetal harm if administered to a pregnant woman.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Major) Females of reproductive potential should use effective non-hormonal contraception during concomitant treatment with ethinyl estradiol and brigatinib, and for at least 4 months after the final dose of brigatinib. Ethinyl estradiol is a 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. Coadministration with brigatinib may reduce the efficacy of hormonal contraceptives; brigatinib can cause fetal harm if administered to a pregnant woman.
    Duvelisib: (Major) Avoid coadministration of brigatinib with duvelisib 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 duvelisib, resume the brigatinib dose that was tolerated prior to initiation of duvelisib. Brigatinib is a CYP3A4 substrate; duvelisib is a moderate CYP3A4 inhibitor. 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.
    Elexacaftor; tezacaftor; ivacaftor: (Moderate) Monitor for a decrease in the efficacy of ivacaftor if coadministration with brigatinib is necessary. Ivacaftor is 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.
    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; 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.
    Enalapril; Felodipine: (Moderate) Monitor for a decrease in the efficacy of felodipine if coadministration with brigatinib is necessary. Felodipine is 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.
    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%.
    Estradiol Cypionate; Medroxyprogesterone: (Major) Females of reproductive potential should use effective non-hormonal contraception during concomitant treatment with medroxyprogesterone and brigatinib, and for at least 4 months after the final dose of brigatinib. Medroxyprogesterone is a 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. Coadministration with brigatinib may reduce the efficacy of hormonal contraceptives; brigatinib can cause fetal harm if administered to a pregnant woman.
    Estradiol: (Major) Females of reproductive potential should use effective non-hormonal contraception during concomitant treatment with estradiol valerate and brigatinib, and for at least 4 months after the final dose of brigatinib. Estradiol valerate is a 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. Coadministration with brigatinib may reduce the efficacy of hormonal contraceptives; brigatinib can cause fetal harm if administered to a pregnant woman.
    Estradiol; Levonorgestrel: (Major) Females of reproductive potential should use effective non-hormonal contraception during concomitant treatment with levonorgestrel and brigatinib, and for at least 4 months after the final dose of brigatinib. Levonorgestrel is a 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. Coadministration with brigatinib may reduce the efficacy of hormonal contraceptives; brigatinib can cause fetal harm if administered to a pregnant woman.
    Estradiol; Progesterone: (Major) Females of reproductive potential should use effective non-hormonal contraception during concomitant treatment with progesterone and brigatinib, and for at least 4 months after the final dose of brigatinib. Progesterone is a 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. Coadministration of brigatinib may reduce the efficacy of hormonal contraceptives; brigatinib can cause fetal harm if administered to a pregnant woman.
    Ethinyl Estradiol: (Major) Females of reproductive potential should use effective non-hormonal contraception during concomitant treatment with ethinyl estradiol and brigatinib, and for at least 4 months after the final dose of brigatinib. Ethinyl estradiol is a 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. Coadministration with brigatinib may reduce the efficacy of hormonal contraceptives; brigatinib can cause fetal harm if administered to a pregnant woman.
    Ethinyl Estradiol; Desogestrel: (Major) Females of reproductive potential should use effective non-hormonal contraception during concomitant treatment with ethinyl estradiol and brigatinib, and for at least 4 months after the final dose of brigatinib. Ethinyl estradiol is a 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. Coadministration with brigatinib may reduce the efficacy of hormonal contraceptives; brigatinib can cause fetal harm if administered to a pregnant woman.
    Ethinyl Estradiol; Ethynodiol Diacetate: (Major) Females of reproductive potential should use effective non-hormonal contraception during concomitant treatment with ethinyl estradiol and brigatinib, and for at least 4 months after the final dose of brigatinib. Ethinyl estradiol is a 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. Coadministration with brigatinib may reduce the efficacy of hormonal contraceptives; brigatinib can cause fetal harm if administered to a pregnant woman.
    Ethinyl Estradiol; Etonogestrel: (Major) Females of reproductive potential should use effective non-hormonal contraception during concomitant treatment with ethinyl estradiol and brigatinib, and for at least 4 months after the final dose of brigatinib. Ethinyl estradiol is a 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. Coadministration with brigatinib may reduce the efficacy of hormonal contraceptives; brigatinib can cause fetal harm if administered to a pregnant woman. (Major) Females of reproductive potential should use effective non-hormonal contraception during concomitant treatment with etonogestrel and brigatinib, and for at least 4 months after the final dose of brigatinib. Etonogestrel is a 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. Coadministration with brigatinib may reduce the efficacy of hormonal contraceptives; brigatinib can cause fetal harm if administered to a pregnant woman.
    Ethinyl Estradiol; Levonorgestrel: (Major) Females of reproductive potential should use effective non-hormonal contraception during concomitant treatment with ethinyl estradiol and brigatinib, and for at least 4 months after the final dose of brigatinib. Ethinyl estradiol is a 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. Coadministration with brigatinib may reduce the efficacy of hormonal contraceptives; brigatinib can cause fetal harm if administered to a pregnant woman. (Major) Females of reproductive potential should use effective non-hormonal contraception during concomitant treatment with levonorgestrel and brigatinib, and for at least 4 months after the final dose of brigatinib. Levonorgestrel is a 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. Coadministration with brigatinib may reduce the efficacy of hormonal contraceptives; brigatinib can cause fetal harm if administered to a pregnant woman.
    Ethinyl Estradiol; Levonorgestrel; Ferrous bisglycinate: (Major) Females of reproductive potential should use effective non-hormonal contraception during concomitant treatment with ethinyl estradiol and brigatinib, and for at least 4 months after the final dose of brigatinib. Ethinyl estradiol is a 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. Coadministration with brigatinib may reduce the efficacy of hormonal contraceptives; brigatinib can cause fetal harm if administered to a pregnant woman. (Major) Females of reproductive potential should use effective non-hormonal contraception during concomitant treatment with levonorgestrel and brigatinib, and for at least 4 months after the final dose of brigatinib. Levonorgestrel is a 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. Coadministration with brigatinib may reduce the efficacy of hormonal contraceptives; brigatinib can cause fetal harm if administered to a pregnant woman.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Major) Females of reproductive potential should use effective non-hormonal contraception during concomitant treatment with ethinyl estradiol and brigatinib, and for at least 4 months after the final dose of brigatinib. Ethinyl estradiol is a 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. Coadministration with brigatinib may reduce the efficacy of hormonal contraceptives; brigatinib can cause fetal harm if administered to a pregnant woman. (Major) Females of reproductive potential should use effective non-hormonal contraception during concomitant treatment with levonorgestrel and brigatinib, and for at least 4 months after the final dose of brigatinib. Levonorgestrel is a 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. Coadministration with brigatinib may reduce the efficacy of hormonal contraceptives; brigatinib can cause fetal harm if administered to a pregnant woman.
    Ethinyl Estradiol; Norelgestromin: (Major) Females of reproductive potential should use effective non-hormonal contraception during concomitant treatment with ethinyl estradiol and brigatinib, and for at least 4 months after the final dose of brigatinib. Ethinyl estradiol is a 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. Coadministration with brigatinib may reduce the efficacy of hormonal contraceptives; brigatinib can cause fetal harm if administered to a pregnant woman.
    Ethinyl Estradiol; Norethindrone Acetate: (Major) Females of reproductive potential should use effective non-hormonal contraception during concomitant treatment with ethinyl estradiol and brigatinib, and for at least 4 months after the final dose of brigatinib. Ethinyl estradiol is a 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. Coadministration with brigatinib may reduce the efficacy of hormonal contraceptives; brigatinib can cause fetal harm if administered to a pregnant woman.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Major) Females of reproductive potential should use effective non-hormonal contraception during concomitant treatment with ethinyl estradiol and brigatinib, and for at least 4 months after the final dose of brigatinib. Ethinyl estradiol is a 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. Coadministration with brigatinib may reduce the efficacy of hormonal contraceptives; brigatinib can cause fetal harm if administered to a pregnant woman.
    Ethinyl Estradiol; Norethindrone: (Major) Females of reproductive potential should use effective non-hormonal contraception during concomitant treatment with ethinyl estradiol and brigatinib, and for at least 4 months after the final dose of brigatinib. Ethinyl estradiol is a 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. Coadministration with brigatinib may reduce the efficacy of hormonal contraceptives; brigatinib can cause fetal harm if administered to a pregnant woman.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Major) Females of reproductive potential should use effective non-hormonal contraception during concomitant treatment with ethinyl estradiol and brigatinib, and for at least 4 months after the final dose of brigatinib. Ethinyl estradiol is a 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. Coadministration with brigatinib may reduce the efficacy of hormonal contraceptives; brigatinib can cause fetal harm if administered to a pregnant woman.
    Ethinyl Estradiol; Norgestimate: (Major) Females of reproductive potential should use effective non-hormonal contraception during concomitant treatment with ethinyl estradiol and brigatinib, and for at least 4 months after the final dose of brigatinib. Ethinyl estradiol is a 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. Coadministration with brigatinib may reduce the efficacy of hormonal contraceptives; brigatinib can cause fetal harm if administered to a pregnant woman.
    Ethinyl Estradiol; Norgestrel: (Major) Females of reproductive potential should use effective non-hormonal contraception during concomitant treatment with ethinyl estradiol and brigatinib, and for at least 4 months after the final dose of brigatinib. Ethinyl estradiol is a 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. Coadministration with brigatinib may reduce the efficacy of hormonal contraceptives; brigatinib can cause fetal harm if administered to a pregnant woman.
    Etonogestrel: (Major) Females of reproductive potential should use effective non-hormonal contraception during concomitant treatment with etonogestrel and brigatinib, and for at least 4 months after the final dose of brigatinib. Etonogestrel is a 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. Coadministration with brigatinib may reduce the efficacy of hormonal contraceptives; brigatinib can cause fetal harm if administered to a pregnant woman.
    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 for clinical response in patients taking everolimus concurrently with brigatinib. For indications where therapeutic drug monitoring is appropriate, monitor everolimus trough concentrations and adjust the dose of everolimus accordingly. Everolimus is a substrate of P-glycoprotein (P-gp). Brigatinib is a P-gp inhibitor and may have the potential to increase concentrations of coadministered substrates of these transporters, such as everolimus. The manufacturer of Afinitor/Afinitor Disperz recommends avoiding coadministration with strong P-gp inhibitors for all indications; for patients receiving moderate P-gp inhibitors with breast cancer, neuroendocrine tumors, renal cell carcinoma, and renal angiolipoma with tubular sclerosis complex (TSC), the manufacturer recommends reducing the dose to 2.5 mg once daily, with a dose increase to 5 mg based on patient tolerance. For patients with subependymal giant cell astrocytoma (SEGA) with TSC receiving moderate P-gp inhibitors, the recommended starting dose of Afinitor/Afinitor Disperz is 2.5 mg/m2 once daily, rounded to the nearest tablet strength; subsequent dosing should be guided by therapeutic drug monitoring (TDM). Zortress dosing for prophylaxis of organ rejection should be guided by TDM.
    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%.
    Felodipine: (Moderate) Monitor for a decrease in the efficacy of felodipine if coadministration with brigatinib is necessary. Felodipine is 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.
    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. Fentanyl is a 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. Coadministration 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.
    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) Concomitant use of hydrocodone with brigatinib can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If brigatinib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a 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.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with brigatinib can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If brigatinib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a 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.
    Homatropine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with brigatinib can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If brigatinib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a 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.
    Hydrocodone: (Moderate) Concomitant use of hydrocodone with brigatinib can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If brigatinib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a 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.
    Hydrocodone; Ibuprofen: (Moderate) Concomitant use of hydrocodone with brigatinib can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If brigatinib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a 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.
    Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with brigatinib can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If brigatinib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a 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.
    Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Concomitant use of hydrocodone with brigatinib can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If brigatinib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a 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.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with brigatinib can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If brigatinib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a 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.
    Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with brigatinib can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If brigatinib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a 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.
    Ibrutinib: (Moderate) Monitor for a decrease in the efficacy of ibrutinib if coadministration with brigatinib is necessary. Ibrutinib is 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.
    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. At clinically relevant concentrations, brigatinib induced CYP3A via activation of the pregnane X receptor (PXR); this may decrease concentrations of sensitive CYP3A substrates. 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; altered concentrations of indinavir 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 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. Indinavir is also a sensitive substrate of CYP3A4 as well as a substrate of P-glycoprotein (P-gp). 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 concentrations of P-gp substrates.
    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; concentrations of isavuconazonium may also decrease. 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%. Isavuconazonium 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.
    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.
    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.
    Ivacaftor: (Moderate) Monitor for a decrease in the efficacy of ivacaftor if coadministration with brigatinib is necessary. Ivacaftor is 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.
    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.
    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%.
    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%.
    Levonorgestrel: (Major) Females of reproductive potential should use effective non-hormonal contraception during concomitant treatment with levonorgestrel and brigatinib, and for at least 4 months after the final dose of brigatinib. Levonorgestrel is a 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. Coadministration with brigatinib may reduce the efficacy of hormonal contraceptives; brigatinib can cause fetal harm if administered to a pregnant woman.
    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.
    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 lopinavir 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 lopinavir, resume the brigatinib dose that was tolerated prior to initiation of lopinavir. Brigatinib is a CYP3A4 substrate; lopinavir 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 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 coadministration of brigatinib with lorlatinib 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 lorlatinib, increase the dose of brigatinib as tolerated in 30 mg increments to a maximum of twice the original brigatinib dose. After discontinuation of lorlatinib, resume the brigatinib dose that was tolerated prior to initiation of lorlatinib. Brigatinib is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Coadministration 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. (Moderate) Monitor for a decrease in the efficacy of ivacaftor if coadministration with brigatinib is necessary. Ivacaftor is 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.
    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.
    Lurasidone: (Moderate) Monitor for a decrease in the efficacy of lurasidone if coadministration with brigatinib is necessary. Lurasidone is 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.
    Maraviroc: (Moderate) Monitor for a decrease in the efficacy of maraviroc or a change in the side effect profile of maraviroc if coadministration with brigatinib is necessary. Maraviroc is a sensitive CYP3A4 substrate as well as 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 like maraviroc. Brigatinib is also a P-gp inhibitor in vitro and may have the potential to increase concentrations of P-gp substrates like maraviroc.
    Medroxyprogesterone: (Major) Females of reproductive potential should use effective non-hormonal contraception during concomitant treatment with medroxyprogesterone and brigatinib, and for at least 4 months after the final dose of brigatinib. Medroxyprogesterone is a 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. Coadministration with brigatinib may reduce the efficacy of hormonal contraceptives; brigatinib can cause fetal harm if administered to a pregnant woman.
    Mefloquine: (Moderate) Monitor for an increase in mefloquine-related adverse reactions if coadministration with brigatinib is necessary. Mefloquine 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.
    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.
    Mestranol; Norethindrone: (Major) Females of reproductive potential should use effective non-hormonal contraception during concomitant treatment with medroxyprogesterone and brigatinib, and for at least 4 months after the final dose of brigatinib. Medroxyprogesterone is a 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. Coadministration with brigatinib may reduce the efficacy of hormonal contraceptives; brigatinib can cause fetal harm if administered to a pregnant woman.
    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; Pioglitazone: (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. (Moderate) Monitor blood sugars and watch for an increase in saxagliptin-related adverse reactions if coadministration with brigatinib is necessary. Saxagliptin 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.
    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 partially metabolized by CYP3A4. At clinically relevant concentrations, brigatinib induced CYP3A via activation of the pregnane X receptor (PXR); this may decrease concentrations of sensitive CYP3A substrates. Concomitant use with CYP3A4 inducers can decrease methadone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Midazolam: (Moderate) Monitor for a decrease in the efficacy of midazolam if coadministration with brigatinib is necessary. Midazolam is 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.
    Midostaurin: (Moderate) Monitor for a decrease in the efficacy of midostaurin if coadministration with brigatinib is necessary. Midostaurin is 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.
    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.
    Naloxegol: (Moderate) Monitor for a decrease in the efficacy of naloxegol if coadministration with brigatinib is necessary. Naloxegol is 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.
    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%.
    Nisoldipine: (Moderate) Monitor for a decrease in the efficacy of nisoldipine if coadministration with brigatinib is necessary. Nisoldipine is 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.
    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.
    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. At clinically relevant concentrations, brigatinib induced CYP3A via activation of the pregnane X receptor (PXR); this may decrease concentrations of sensitive CYP3A substrates. 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.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    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.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    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%.
    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.
    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.
    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.
    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.
    Progesterone: (Major) Females of reproductive potential should use effective non-hormonal contraception during concomitant treatment with progesterone and brigatinib, and for at least 4 months after the final dose of brigatinib. Progesterone is a 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. Coadministration of brigatinib may reduce the efficacy of hormonal contraceptives; brigatinib can cause fetal harm if administered to a pregnant woman.
    Quetiapine: (Moderate) Monitor for a decrease in the efficacy of quetiapine if coadministration with brigatinib is necessary. Quetiapine is 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.
    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.
    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. If concomitant use is unavoidable, after 7 days of concomitant treatment with rifapentine, increase the dose of brigatinib as tolerated in 30 mg increments to a maximum of twice the original brigatinib dose. After discontinuation of rifapentine, resume the brigatinib dose that was tolerated prior to initiation of rifapentine. Brigatinib is a CYP3A4 substrate and rifapentine is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of brigatinib by approximately 50%.
    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%.
    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; altered saquinavir 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 saquinavir, resume the brigatinib dose that was tolerated prior to initiation of saquinavir. Brigatinib is a CYP3A4 substrate; saquinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively. Additionally, saquinavir is a sensitive CYP3A4 substrate as well as a substrate of P-glycoprotein (P-gp). At clinically relevant concentrations, brigatinib induced CYP3A via activation of the pregnane X receptor (PXR); this may decrease concentrations of sensitive CYP3A substrates. Brigatinib is also a P-gp inhibitor in vitro and may have the potential to increase concentrations of P-gp substrates. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance.
    Saxagliptin: (Moderate) Monitor blood sugars and watch for an increase in saxagliptin-related adverse reactions if coadministration with brigatinib is necessary. Saxagliptin 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.
    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%.
    Segesterone Acetate; Ethinyl Estradiol: (Major) Females of reproductive potential should use effective non-hormonal contraception during concomitant treatment with ethinyl estradiol and brigatinib, and for at least 4 months after the final dose of brigatinib. Ethinyl estradiol is a 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. Coadministration with brigatinib may reduce the efficacy of hormonal contraceptives; brigatinib can cause fetal harm if administered to a pregnant woman. (Major) Females of reproductive potential should use effective non-hormonal contraception during concomitant treatment with segesterone and brigatinib, and for at least 4 months after the final dose of brigatinib. Segesterone is a 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. Coadministration with brigatinib may reduce the efficacy of hormonal contraceptives; brigatinib can cause fetal harm if administered to a pregnant woman.
    Sildenafil: (Moderate) Monitor for a decrease in the efficacy of sildenafil if coadministration with brigatinib is necessary. Sildenafil is 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.
    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 for a decrease sirolimus trough concentrations, or alternatively an increase in sirolimus exposure, if coadministration with brigatinib is necessary. Sirolimus is a sensitive CYP3A4 substrate as well as a substrate of P-glycoprotein. At clinically relevant concentrations, brigatinib induced CYP3A via activation of the pregnane X receptor (PXR); this may decrease concentrations of sensitive CYP3A substrates. Brigatinib also inhibits P-gp in vitro and may have the potential to increase concentrations of P-gp substrates.
    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. At clinically relevant concentrations, brigatinib induced CYP3A via activation of the pregnane X receptor (PXR); this may decrease concentrations of sensitive CYP3A substrates. 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 and watch for decreased efficacy of tacrolimus if coadministration with brigatinib is necessary; adjust the dose of tacrolimus as clinically indicated. Tacrolimus is a sensitive CYP3A substrate. At clinically relevant concentrations, brigatinib induced CYP3A via activation of the pregnane X receptor (PXR); this may decrease concentrations of sensitive CYP3A substrates.
    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.
    Tezacaftor; Ivacaftor: (Moderate) Monitor for a decrease in the efficacy of ivacaftor if coadministration with brigatinib is necessary. Ivacaftor is 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.
    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 a decrease in the efficacy of ticagrelor or an increase in ticagrelor-related adverse reactions if coadministration with brigatinib is necessary. Ticagrelor is a sensitive CYP3A4 substrate as well as a substrate of P-glycoprotein (P-gp). At clinically relevant concentrations, brigatinib induced CYP3A via activation of the pregnane X receptor (PXR); this may decrease concentrations of sensitive CYP3A substrates. Brigatinib is also a P-gp inhibitor in vitro and may have the potential to increase concentrations of coadministered substrates of these transporters.
    Tipranavir: (Major) Avoid coadministration of brigatinib with tipranavir if possible due to increased plasma exposure of brigatinib; altered tipranavir exposure may also occur. If concomitant use is unavoidable, closely monitor for changes in the clinical efficacy 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); after discontinuation of tipranavir, resume the brigatinib dose that was tolerated prior to initiation of tipranavir. Brigatinib is a CYP3A4 substrate and tipranavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively. Tipranavir is also a CYP3A substrate and brigatinib induces CYP3A in vitro; plasma concentrations of tipranavir may decrease. Additionally, tipranavir is a sensitive CYP3A4 substrate as well as a substrate of P-glycoprotein (P-gp). 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 concentrations of P-gp substrates.
    Tolvaptan: (Moderate) Monitor for a decrease in the efficacy of tolvaptan or an increase in tolvaptan-related adverse reactions if coadministration with brigatinib is necessary. Tolvaptan is a sensitive CYP3A4 substrate as well as a substrate of P-glycoprotein (P-gp). At clinically relevant concentrations, brigatinib induced CYP3A via activation of the pregnane X receptor (PXR); this may decrease concentrations of sensitive CYP3A substrates. Brigatinib is also a P-gp inhibitor in vitro and may have the potential to increase concentrations of P-gp substrates.
    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. At clinically relevant concentrations, brigatinib induced CYP3A via activation of the pregnane X receptor (PXR); this may decrease concentrations of sensitive CYP3A substrates. 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.
    Triazolam: (Moderate) Monitor for a decrease in the efficacy of triazolam if coadministration with brigatinib is necessary. Triazolam is 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.
    Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
    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: (Moderate) Monitor for a decrease in the efficacy of venetoclax or an increase in venetoclax-related adverse reactions if coadministration with brigatinib is necessary. Venetoclax is a sensitive CYP3A4 substrate as well as a substrate of P-glycoprotein (P-gp). At clinically relevant concentrations, brigatinib induced CYP3A via activation of the pregnane X receptor (PXR); this may decrease concentrations of sensitive CYP3A substrates. Brigatinib is also a P-gp inhibitor in vitro and may have the potential to increase concentrations of P-gp substrates.
    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.
    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.

    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.

    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 nonhormonal 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]

    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 12.7 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, MATE2K
     
    Brigatinib is primarily metabolized by CYP2C8 and CYP3A4 in vitro. Strong CYP3A4 inhibitors and inducers significantly affect brigatinib exposure; the manufacturer of brigatinib recommends avoiding coadministration with these medications. If avoidance of administration with a strong CYP3A4 inhibitor is not possible, a brigatinib dosage reduction is recommended. Coadministration with itraconazole (200 mg twice daily), a strong CYP3A4 inhibitor, increased the Cmax of brigatinib by 21% and the AUC by 101% after a single 90-mg dose. Coadministration with rifampin (600mg daily), a strong CYP3A inducer, decreased the Cmax of brigatinib by 60% and the AUC by 80% after a single 180-mg dose. Although CYP2C8 is strongly involved with brigatinib metabolism, coadministration with gemfibrozil (600 mg twice daily), a strong CYP2C8 inhibitor, decreased the brigatinib Cmax by 41% and the AUC by 12% after a single 90-mg dose; this effect is not clinically meaningful and the mechanism for decreased brigatinib exposure is unknown.
     
    In vitro studies also suggests that brigatinib is a P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) substrate. However, given that brigatinib exhibits high solubility and high permeability in vitro, P-gp and BCRP inhibitors are unlikely to increase brigatinib plasma concentrations. Brigatinib inhibits P-gp, BCRP, OCT1, MATE1, and MATE2K in vitro; it may have the potential to increase concentrations of these transporters. At clinically relevant concentrations, brigatinib induced CYP3A by activating the pregnane X receptor (PXR); it may also induce CYP2C enzymes via the same mechanism.

    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%), 65%) and at a dose of 180 mg was 1,452 ng/mL (CV%, 60%); the corresponding AUC was 8,165 ng*hour/mL (CV%, 57%) at the 90 mg dose and 20,276 ng*hour/mL (CV%, 56%) 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.
     
    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.