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  • CLASSES

    Small Molecule Antineoplastic BRAF kinase Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    BRAF inhibitor
    Used for unresectable or metastatic melanoma with a BRAF V600E or V600K mutation in combination with binimetinib, and for BRAF V600E mutated metastatic colorectal cancer in combination with cetuximab
    New primary cutaneous malignancies and QT prolongation have been reported

    COMMON BRAND NAMES

    BRAFTOVI

    HOW SUPPLIED

    BRAFTOVI/Encorafenib Oral Cap: 50mg, 75mg

    DOSAGE & INDICATIONS

    For the treatment of malignant melanoma.
    NOTE: Confirm the BRAF V600E or V600K mutation prior to starting therapy. Information on FDA-approved tests for the detection of BRAF V600 mutations is available at http://www.fda.gov/CompanionDiagnostics.
    NOTE: Encorafenib is not indicated in patients with wild-type BRAF melanoma.
    For the treatment of unresectable or metastatic melanoma in patients with a BRAF V600E or V600K mutations, in combination with binimetinib.
    NOTE: The FDA has designated encorafenib in combination with binimetinib as an orphan drug for the treatment of stage IIB to IV melanoma.
    Oral dosage
    Adults

    450 mg orally once daily in combination with binimetinib 45 mg orally twice daily until disease progression. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Interruption of therapy and/or a dosage reduction may be necessary in patients who develop toxicity or intolerable side effects.[63317] At a median follow-up time of 32.1 months, combination therapy with encorafenib plus binimetinib resulted in a significantly longer median progression-free survival (PFS) time (primary endpoint) compared with single-agent vemurafenib (14.9 months vs. 7.3 months; hazard ratio (HR) = 0.51; 95%CI, 0.39 to 0.67; p less than 0.0001) in patients with locally advanced stage IIIB, IIIC, or IV melanoma, unresectable or metastatic cutaneous melanoma, or unknown primary melanoma and BRAF V600E and/or V600K mutations in a multinational, randomized, 3-arm, phase 3 study (n = 577; the COLOMBUS study). Additionally, the median overall survival (OS) time was significantly improved in the combination therapy arm compared with vemurafenib (33.6 months vs. 16.9 months; HR = 0.61; 95% CI, 0.47 to 0.79) at a median follow-up time of 36.8 months. At the time of analysis, the median PFS (14.9 months vs. 9.6 months; HR = 0.77; 95%CI, 0.59 to 1; p = 0.5) and OS (33.6 months vs. 23.5 months; HR = 0.81; 95%CI, 0.61 to 1.06) times were not significantly longer in the combination therapy arm compared with single-agent encorafenib. Most patients in this study had extensive disease (stage IV M1c disease, 64%; 3 or more organs involved, 45%); 30% of patients had progressed on or after immunotherapy. In the combination therapy arm, the median duration of treatment was 51.2 weeks.[63319] [63693]

    For the treatment of colorectal cancer.
    NOTE: Confirm the BRAF V600E mutation prior to starting therapy. Information on FDA-approved tests for the detection of BRAF V600E mutations is available at http://www.fda.gov/CompanionDiagnostics.
    NOTE: Encorafenib is not indicated in patients with wild-type BRAF colorectal cancer.
    For the treatment of previously treated metastatic colorectal cancer (mCRC) in patients with a BRAF V600E mutation, in combination with cetuximab.
    Oral dosage
    Adults

    300 mg PO once daily in combination with cetuximab (400 mg/m2 IV over 120 minutes on day 1 followed by weekly infusions of cetuximab 250 mg/m2 IV over 60 minutes) until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. If cetuximab is discontinued, also discontinue encorafenib. Treatment with encorafenib plus cetuximab significantly improved overall survival (8.4 months vs. 5.4 months), overall response rate (20% vs. 2%; complete response, 5% vs. 0%), and progression-free survival (4.2 months vs. 1.5 months) compared with either irinotecan plus cetuximab or FOLFIRI plus cetuximab in patients with previously treated BRAF V600E mutation-positive metastatic colorectal cancer in a randomized, open-label clinical trial; the median duration of response was 6.1 months in the encorafenib arm.

    MAXIMUM DOSAGE

    Adults

    450 mg/day PO.

    Geriatric

    450 mg/day PO.

    Adolescents

    Safety and efficacy not established.

    Children

    Safety and efficacy not established.

    Infants

    Safety and efficacy not established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    No encorafenib dosage adjustment is necessary for patients with baseline mild hepatic impairment (Child-Pugh class A) based on a population pharmacokinetic analysis. Encorafenib has not been studied in patients with moderate (Child-Pugh class B) to severe (Child-Pugh class C) hepatic impairment.
     
    Treatment-Related Toxicity:
    Grade 2 elevated hepatic enzymes (AST or ALT levels): Continue current encorafenib dose. If the toxicity does not improve within 4 weeks, hold therapy until toxicity improves to grade 1 or less or to baseline levels. Therapy may be resumed at the same dose.
    Recurrent grade 2 toxicity or first occurrence of grade 3 toxicity: Hold encorafenib for up to 4 weeks. If toxicity improves to grade 1 or less or to baseline level, resume encorafenib at a reduced dose. If the toxicity does not improve within 4 weeks, permanently discontinue encorafenib.
    Recurrent grade 3 toxicity: Consider permanently discontinuing encorafenib.
    Grade 4 toxicity: Consider permanently discontinuing encorafenib or hold encorafenib for up to 4 weeks. If holding encorafenib and the toxicity improves to grade 1 or less or to baseline level within 4 weeks, resume encorafenib at a reduced dose. Permanently discontinue encorafenib if the toxicity does not improve within 4 weeks or for recurrent grade 4 toxicity.

    Renal Impairment

    No encorafenib dosage adjustment is necessary in patients with mild to moderate renal impairment (creatinine clearance (CrCl) of 30 to less than 90 mL/min) based on a population pharmacokinetic analysis. Encorafenib has not been studied in patients with severe renal impairment (CrCl less than 30 mL/min). Encorafenib is highly bound to plasma proteins and is unlikely to be removed by hemodialysis.

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    Encorafenib may be taken with or without food.
    Avoid grapefruit during therapy.
    If a dose is missed, take within 12 hours of missing the dose. If more than 12 hours have passed, skip the dose of the day and take the dose the next day at the scheduled time.
    If vomiting occurs after a dose, do not take an additional dose; take the next dose at the regularly scheduled time.

    STORAGE

    BRAFTOVI:
    - Protect from moisture
    - Store and dispense in original container
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    In in vitro studies, MAP-kinase signaling activation led to increased BRAF wild-type cell proliferation; therefore, encorafenib is not indicated for the treatment of BRAF wild-type melanoma. Prior to starting encorafenib, confirm the presence of a BRAF V600E or V600K mutation using an FDA-approved test.

    New primary malignancy

    New primary malignancy may occur with encorafenib therapy. Monitor patients for signs and symptoms of cutaneous and noncutaneous malignancies. Perform a dermatologic evaluation prior to, every 2 months, and for up to 6 months after the end of treatment; surgically excise and perform a pathologic evaluation on suspicious skin lesions. No dose modification of encorafenib is recommended in patients who develop a new primary cutaneous lesion. Discontinue encorafenib in patients who develop a RAS mutation-positive noncutaneous malignancy.

    Skin disease

    Encorafenib is not indicated for use as monotherapy for the treatment of advanced melanoma. If binimetinib is withheld, reduce the encorafenib dose to 300 mg PO once daily until therapy with binimetinib is resumed. Patients who received single-agent encorafenib had a higher rate of treatment-associated skin disease compared with patients who received combination therapy with encorafenib and binimetinib.

    Iritis, uveitis, visual disturbance, visual impairment

    Uveitis, iritis, and iridocyclitis have been reported in patients who received combination therapy with encorafenib and binimetinib. Monitor patients for signs and symptoms of visual impairment at each clinic visit. Perform an ophthalmologic evaluation regularly and in patients who experience a new, worsening, or persistent visual disturbance. Therapy interruption, a dose reduction, or permanent discontinuation of encorafenib may be necessary in patients who develop persistent or severe ocular toxicity.

    Apheresis, AV block, bradycardia, cardiomyopathy, celiac disease, electrolyte imbalance, females, fever, geriatric, heart failure, human immunodeficiency virus (HIV) infection, hyperparathyroidism, hypocalcemia, hypokalemia, hypomagnesemia, hypothermia, hypothyroidism, long QT syndrome, myocardial infarction, pheochromocytoma, QT prolongation, rheumatoid arthritis, sickle cell disease, sleep deprivation, stroke, systemic lupus erythematosus (SLE)

    Dose-dependent QT prolongation has been reported in patients who received combination therapy with encorafenib and binimetinib. Treatment interruption, a dose reduction, or permanent discontinuation of encorafenib therapy may be necessary in patients who develop QT prolongation. Correct any electrolyte imbalance (e.g., hypokalemia, hypomagnesemia, hypocalcemia) prior to and during encorafenib therapy. Monitor the QT interval in patients who are at increased risk of QT prolongation such as patients with a history of QT prolongation or congenital long QT syndrome, cardiac disease such as clinically significant cardiac arrhythmias (e.g., bradycardia), or severe or uncontrolled heart failure and in patients who are taking medications known to prolong the QT interval. Use encorafenib with caution in patients with conditions that may increase the risk of QT prolongation including AV block, heart failure, stress-related cardiomyopathy, myocardial infarction, stroke, or in patients receiving medications known to cause electrolyte imbalances. Females, geriatric patients, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, hypothermia, systemic inflammation (e.g., human immunodeficiency virus (HIV) infection, fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) may also be at increased risk for QT prolongation.

    Pregnancy

    Encorafenib may cause fetal harm when administered to a pregnant woman, based on its mechanism of action. Advise females of reproductive potential to avoid pregnancy while taking encorafenib. Discuss the potential hazard to the fetus if encorafenib is used during pregnancy or if a patient becomes pregnant while taking this drug. Embryo-fetal toxicities including decreased fetal weights and increased rate of skeletal variations were observed in pregnant rats and rabbits who received encorafenib doses that resulted in drug exposures that were about 26-times and 178-times the recommended human exposure, respectively. However, no clear embryo-fetal toxicity was reported at lower doses.

    Contraception requirements, infertility, pregnancy testing, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during encorafenib therapy. Pregnancy testing prior to starting encorafenib therapy is recommended for females of reproductive potential. These patients should use highly effective non-hormonal contraceptive methods during and for 2 weeks after the last encorafenib dose; encorafenib may decrease the concentration of hormonal contraceptive agents resulting in a loss of contraceptive efficacy. Advise women to contact their healthcare provider if pregnancy is suspected or confirmed. Women who become pregnant while receiving encorafenib should be apprised of the potential hazard to the fetus. Advise male patients of the potential risk for impaired fertility/infertility with encorafenib therapy. Testicular degeneration and oligospermia were reported in male rats who received encorafenib doses that resulted in drug exposures of about 13-times the recommended human exposure.

    Breast-feeding

    It is not known if encorafenib or its metabolites are secreted in human milk or if it has effects on the breast-fed infant or on milk production. Due to the risk of serious adverse reactions in nursing infants, women should discontinue breast-feeding during encorafenib therapy and for 2 weeks after the last dose.

    ADVERSE REACTIONS

    Severe

    elevated hepatic enzymes / Delayed / 0-11.0
    pancreatitis / Delayed / 0-10.0
    new primary malignancy / Delayed / 0-8.0
    lymphopenia / Delayed / 2.1-7.0
    fatigue / Early / 3.0-7.0
    hyperglycemia / Delayed / 5.0-5.0
    GI bleeding / Delayed / 1.0-4.2
    uveitis / Delayed / 4.0-4.0
    anemia / Delayed / 3.6-4.0
    fever / Early / 1.0-4.0
    abdominal pain / Early / 4.0-4.0
    nephrotoxicity / Delayed / 0-3.6
    hyponatremia / Delayed / 2.0-3.6
    bleeding / Early / 1.9-3.2
    neutropenia / Delayed / 0-3.1
    dizziness / Early / 0-3.0
    hypokalemia / Delayed / 0-3.0
    vomiting / Early / 1.0-2.0
    nausea / Early / 1.0-2.0
    headache / Early / 0-2.0
    diarrhea / Early / 0-2.0
    intracranial bleeding / Delayed / 0-1.6
    prolonged bleeding time / Delayed / 0-1.0
    hyperkeratosis / Delayed / 0-1.0
    pruritus / Rapid / 0-1.0
    rash / Early / 0-1.0
    acneiform rash / Delayed / 0-1.0
    arthralgia / Delayed / 1.0-1.0
    hypermagnesemia / Delayed / 0-1.0
    anorexia / Delayed / 0-1.0
    myopathy / Delayed / 0-1.0
    peripheral neuropathy / Delayed / 1.0-1.0

    Moderate

    palmar-plantar erythrodysesthesia (hand and foot syndrome) / Delayed / 0-51.0
    constipation / Delayed / 15.0-22.0
    hypomagnesemia / Delayed / 0-19.0
    erythema / Early / 0-16.0
    leukopenia / Delayed / 0-13.0
    paresis / Delayed / 0-10.0
    iritis / Delayed / 0-4.0
    QT prolongation / Rapid / 0.5-0.5

    Mild

    alopecia / Delayed / 0-56.0
    xerosis / Delayed / 13.0-38.0
    back pain / Delayed / 0-15.0
    dysgeusia / Early / 0-13.0
    insomnia / Early / 0-13.0
    panniculitis / Delayed / 0-10.0
    epistaxis / Delayed / 0-6.9

    DRUG INTERACTIONS

    Acalabrutinib: (Moderate) Coadministration of encorafenib with acalabrutinib may result in increased toxicity or decreased efficacy of acalabrutinib. Acalabrutinib is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
    Acetaminophen; Butalbital: (Major) Avoid coadministration of encorafenib and butalbital due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; butalbital is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
    Acetaminophen; Butalbital; Caffeine: (Major) Avoid coadministration of encorafenib and butalbital due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; butalbital is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Major) Avoid coadministration of encorafenib and butalbital due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; butalbital is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with encorafenib may alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of dihydrocodeine until stable drug effects are achieved. Discontinuation of encorafenib could alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If encorafenib is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Encorafenib is a weak inhibitor and inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine. CYP3A4 inhibitors may increase dihydrocodeine-related adverse effects while CYP3A4 inducers may reduce efficacy.
    Aclidinium; Formoterol: (Moderate) If encorafenib is coadministered with a long-acting beta-agonist, consider monitoring ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib has been associated with dose-dependent QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Albuterol: (Minor) If encorafenib is coadministered with a short-acting beta-agonist, consider monitoring ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Albuterol; Ipratropium: (Minor) If encorafenib is coadministered with a short-acting beta-agonist, consider monitoring ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Alfentanil: (Moderate) Consider a dose adjustment of alfentanil with frequent monitoring for efficacy, respiratory depression and sedation if concurrent use of encorafenib is necessary. If encorafenib is discontinued, consider adjusting the alfentanil dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal or increased or prolonged therapeutic and adverse effects. Encorafenib may increase or decrease alfentanil exposure. Alfentanil is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
    Alfuzosin: (Major) Avoid coadministration of encorafenib and alfuzosin due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Based on electrophysiology studies performed by the manufacturer, alfuzosin may prolong the QT interval in a dose-dependent manner.
    Amiodarone: (Major) Avoid coadministration of encorafenib and amiodarone due to increased encorafenib exposure and QT prolongation. If concurrent use cannot be avoided, reduce the encorafenib dose to one-half of the dose used prior to the addition of amiodarone; monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. If amiodarone is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of amiodarone. Encorafenib is a CYP3A4 substrate that has been associated with dose-dependent QT prolongation; amiodarone is a moderate CYP3A4 inhibitor that is associated with a well established risk of QT prolongation and torsade de pointes (TdP). Coadministration of a moderate CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 2-fold and 45%, respectively. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
    Amitriptyline: (Major) Avoid coadministration of encorafenib and tricyclic antidepressants due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Tricyclic antidepressants share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Amitriptyline; Chlordiazepoxide: (Major) Avoid coadministration of encorafenib and tricyclic antidepressants due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Tricyclic antidepressants share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Avoid coadministration of encorafenib and clarithromycin due to increased encorafenib exposure and QT prolongation. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of clarithromycin. Monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. If clarithromycin is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of clarithromycin. Encorafenib is a CYP3A4 substrate that has been associated with dose-dependent QT prolongation; clarithromycin is a strong CYP3A4 inhibitor that is associated with an established risk for QT prolongation and torsade de pointes (TdP). Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid coadministration of encorafenib and clarithromycin due to increased encorafenib exposure and QT prolongation. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of clarithromycin. Monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. If clarithromycin is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of clarithromycin. Encorafenib is a CYP3A4 substrate that has been associated with dose-dependent QT prolongation; clarithromycin is a strong CYP3A4 inhibitor that is associated with an established risk for QT prolongation and torsade de pointes (TdP). Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
    Anagrelide: (Major) Avoid coadministration of encorafenib and anagrelide due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects.
    Apalutamide: (Major) Avoid coadministration of encorafenib and apalutamide due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; apalutamide is a strong CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
    Apomorphine: (Major) Avoid coadministration of encorafenib and apomorphine due to a possible increased risk of QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Dose-related QTc prolongation is associated with therapeutic apomorphine exposure.
    Aprepitant, Fosaprepitant: (Major) Avoid coadministration of encorafenib and a 3-day oral regimen (125 mg/80 mg/80 mg) of aprepitant due to increased encorafenib exposure. Increased or decreased aprepitant exposure is also possible. If concurrent use of multi-day oral aprepitant cannot be avoided, reduce the encorafenib dose to one-half of the dose used prior to the addition of aprepitant. If aprepitant is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of aprepitant. Encorafenib is a CYP3A4 substrate; In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established. Aprepitant is a sensitive CYP3A4 substrate and when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor. Coadministration of a moderate CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 2-fold and 45%, respectively.
    Arformoterol: (Moderate) If encorafenib is coadministered with a long-acting beta-agonist, consider monitoring ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib has been associated with dose-dependent QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Aripiprazole: (Major) Avoid coadministration of encorafenib and aripiprazole due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose.
    Arsenic Trioxide: (Major) Avoid coadministration of encorafenib and arsenic trioxide due to QT prolongation. Discontinue or select an alternative drug that does not prolong the QT interval prior to starting arsenic trioxide therapy. If concomitant drug use is unavoidable, frequently monitor electrocardiograms. Monitor electrolytes and correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP), QT interval prolongation, and complete atrioventricular block have been reported with arsenic trioxide use.
    Artemether; Lumefantrine: (Major) Avoid coadministration of encorafenib and artemether; lumefantrine due to QT prolongation. Consider ECG monitoring if encorafenib must be used after artemether; lumefantrine treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Artemether; lumefantrine is associated with prolongation of the QT interval. (Major) Avoid coadministration of encorafenib and artemether; lumefantrine due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Artemether; lumefantrine is associated with prolongation of the QT interval.
    Asenapine: (Major) Avoid coadministration of encorafenib and asenapine due to QT prolongation. Encorafenib is associated with dose-dependent prolongation of the QT interval. Asenapine has also been associated with QT prolongation.
    Aspirin, ASA; Butalbital; Caffeine: (Major) Avoid coadministration of encorafenib and butalbital due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; butalbital is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Avoid coadministration of encorafenib and butalbital due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; butalbital is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with encorafenib may alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of dihydrocodeine until stable drug effects are achieved. Discontinuation of encorafenib could alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If encorafenib is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Encorafenib is a weak inhibitor and inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine. CYP3A4 inhibitors may increase dihydrocodeine-related adverse effects while CYP3A4 inducers may reduce efficacy.
    Atazanavir: (Major) Avoid coadministration of encorafenib and atazanavir due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of atazanavir. If atazanavir is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of atazanavir. Encorafenib is a CYP3A4 substrate; atazanavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
    Atazanavir; Cobicistat: (Major) Avoid coadministration of encorafenib and atazanavir due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of atazanavir. If atazanavir is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of atazanavir. Encorafenib is a CYP3A4 substrate; atazanavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively. (Major) Avoid coadministration of encorafenib and cobicistat due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of cobicistat. If cobicistat is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of cobicistat. Encorafenib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
    Atomoxetine: (Major) Avoid coadministration of encorafenib and atomoxetine due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. QT prolongation has occurred during therapeutic use of atomoxetine and following overdose.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Avoid coadministration of encorafenib and phenobarbital due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; phenobarbital is a strong CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
    Avanafil: (Moderate) Coadministration of encorafenib with avanafil may result in increased avanafil toxicity or reduced efficacy. Avanafil is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
    Azithromycin: (Major) Avoid coadministration of azithromycin with encorafenib due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Encorafenib is associated with dose-dependent prolongation of the QT interval. QT prolongation and torsade de pointes (TdP) have been spontaneously reported during azithromycin postmarketing surveillance.
    Bedaquiline: (Major) Avoid coadministration of encorafenib and bedaquiline due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Bedaquiline has been reported to prolong the QT interval. Coadministration may result in additive or synergistic prolongation of the QT interval.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Avoid coadministration of encorafenib and phenobarbital due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; phenobarbital is a strong CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
    Bexarotene: (Major) Avoid coadministration of encorafenib and bexarotene due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; bexarotene is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Avoid coadministration of encorafenib and metronidazole due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Potential QT prolongation has been reported in limited case reports with metronidazole.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Avoid coadministration of encorafenib and metronidazole due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Potential QT prolongation has been reported in limited case reports with metronidazole.
    Bosentan: (Major) Avoid coadministration of encorafenib and bosentan due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; bosentan is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
    Bosutinib: (Moderate) Coadministration of encorafenib with bosutinib may result in increased toxicity or decreased efficacy of bosutinib. Bosutinib is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
    Brodalumab: (Major) Avoid coadministration of encorafenib and brodalumab due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-half of the dose used prior to the addition of brodalumab. If brodalumab is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of brodalumab. Encorafenib is a CYP3A4 substrate; brodalumab is a moderate CYP3A4 inhibitor. Coadministration of a moderate CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 2-fold and 45%, respectively.
    Budesonide: (Moderate) Coadministration of encorafenib with budesonide may result in increased toxicity or decreased efficacy of budesonide. Budesonide is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
    Budesonide; Formoterol: (Moderate) Coadministration of encorafenib with budesonide may result in increased toxicity or decreased efficacy of budesonide. Budesonide is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established. (Moderate) If encorafenib is coadministered with a long-acting beta-agonist, consider monitoring ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib has been associated with dose-dependent QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Budesonide; Glycopyrrolate; Formoterol: (Moderate) Coadministration of encorafenib with budesonide may result in increased toxicity or decreased efficacy of budesonide. Budesonide is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established. (Moderate) If encorafenib is coadministered with a long-acting beta-agonist, consider monitoring ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib has been associated with dose-dependent QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Buprenorphine: (Major) Avoid coadministration of encorafenib and buprenorphine due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP).
    Buprenorphine; Naloxone: (Major) Avoid coadministration of encorafenib and buprenorphine due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP).
    Buspirone: (Moderate) Coadministration of encorafenib with buspirone may result in increased toxicity or decreased efficacy of buspirone. Buspirone is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
    Carbamazepine: (Major) Avoid coadministration of encorafenib and carbamazepine due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; carbamazepine is a strong CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
    Cenobamate: (Major) Avoid coadministration of encorafenib and cenobamate due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; cenobamate is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
    Ceritinib: (Major) Avoid coadministration of encorafenib and ceritinib due to increased encorafenib exposure and QT prolongation. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of ceritinib; monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. If ceritinib is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of ceritinib. Encorafenib is a CYP3A4 substrate that has been associated with dose-dependent QT prolongation; ceritinib is a strong CYP3A4 inhibitor that can also cause concentration-dependent QT prolongation. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
    Chloramphenicol: (Major) Avoid coadministration of encorafenib and chloramphenicol due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of chloramphenicol. If chloramphenicol is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of chloramphenicol. Encorafenib is a CYP3A4 substrate; chloramphenicol is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
    Chloroquine: (Major) Avoid coadministration of chloroquine with encorafenib due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); the risk of QT prolongation is increased with higher chloroquine doses. Encorafenib has been associated with dose-dependent QT prolongation.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Concomitant use of dihydrocodeine with encorafenib may alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of dihydrocodeine until stable drug effects are achieved. Discontinuation of encorafenib could alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If encorafenib is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Encorafenib is a weak inhibitor and inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine. CYP3A4 inhibitors may increase dihydrocodeine-related adverse effects while CYP3A4 inducers may reduce efficacy.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Concomitant use of dihydrocodeine with encorafenib may alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of dihydrocodeine until stable drug effects are achieved. Discontinuation of encorafenib could alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If encorafenib is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Encorafenib is a weak inhibitor and inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine. CYP3A4 inhibitors may increase dihydrocodeine-related adverse effects while CYP3A4 inducers may reduce efficacy.
    Chlorpromazine: (Major) Avoid coadministration of encorafenib and chlorpromazine due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Chlorpromazine, a phenothiazine, is associated with an established risk of QT prolongation and torsade de pointes (TdP).
    Ciprofloxacin: (Major) Avoid coadministration of encorafenib and ciprofloxacin due to increased encorafenib exposure and QT prolongation. If concurrent use cannot be avoided, reduce the encorafenib dose to one-half of the dose used prior to the addition of ciprofloxacin. Monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. If ciprofloxacin is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of ciprofloxacin. Encorafenib is a CYP3A4 substrate that has been associated with dose-dependent QT prolongation; ciprofloxacin is a moderate CYP3A4 inhibitor that has been associated with rare cases of QT prolongation and torsade de pointes (TdP) during postmarketing surveillance. Coadministration of a moderate CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 2-fold and 45%, respectively.
    Cisapride: (Severe) Coadministration of cisapride and encorafenib is contraindicated due to QT prolongation. Encorafenib is associated with a dose-dependent risk of QT prolongation. QT prolongation and ventricular arrhythmias, including torsade de pointes (TdP) and death, have been reported with cisapride.
    Citalopram: (Major) Concurrent use of citalopram with encorafenib is not recommended due to QT prolongation. If concurrent therapy is considered essential, ECG monitoring is recommended. Monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Citalopram causes dose-dependent QT interval prolongation.
    Clarithromycin: (Major) Avoid coadministration of encorafenib and clarithromycin due to increased encorafenib exposure and QT prolongation. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of clarithromycin. Monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. If clarithromycin is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of clarithromycin. Encorafenib is a CYP3A4 substrate that has been associated with dose-dependent QT prolongation; clarithromycin is a strong CYP3A4 inhibitor that is associated with an established risk for QT prolongation and torsade de pointes (TdP). Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
    Clofazimine: (Major) Avoid coadministration of encorafenib and clofazimine due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib has been associated with dose-dependent QT prolongation. QT prolongation and torsade de pointes (TdP) have been reported in patients receiving clofazimine in combination with QT prolonging medications.
    Clomipramine: (Major) Avoid coadministration of encorafenib and tricyclic antidepressants due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Tricyclic antidepressants share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Clozapine: (Major) Avoid coadministration of encorafenib and clozapine due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death.
    Cobicistat: (Major) Avoid coadministration of encorafenib and cobicistat due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of cobicistat. If cobicistat is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of cobicistat. Encorafenib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
    Cobimetinib: (Moderate) Coadministration of encorafenib with cobimetinib may result in increased toxicity or decreased efficacy of cobimetinib. Cobimetinib is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.Coadministration may result in increased toxicity or decreased efficacy of cobimetinib.
    Codeine; Phenylephrine; Promethazine: (Major) Avoid coadministration of encorafenib and promethazine due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Codeine; Promethazine: (Major) Avoid coadministration of encorafenib and promethazine due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Conivaptan: (Major) Avoid coadministration of encorafenib and conivaptan due to increased encorafenib exposure. Altered conivaptan concentrations are also possible. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of conivaptan. If conivaptan is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of conivaptan. Encorafenib is a CYP3A4 substrate; in vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. Conivaptan is a strong CYP3A4 inhibitor and a sensitive CYP3A4 substrate. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
    Crizotinib: (Major) Avoid coadministration of encorafenib and crizotinib due to increased encorafenib exposure and QT prolongation. If concurrent use cannot be avoided, reduce the encorafenib dose to one-half of the dose used prior to the addition of crizotinib. Monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. If crizotinib is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of crizotinib. Encorafenib is a CYP3A4 substrate that has been associated with dose-dependent QT prolongation; crizotinib is a moderate CYP3A4 inhibitor that has also been associated with concentration-dependent QT prolongation. Coadministration of a moderate CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 2-fold and 45%, respectively.
    Cyclosporine: (Major) Avoid coadministration of encorafenib and cyclosporine due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-half of the dose used prior to the addition of cyclosporine. If cyclosporine is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of cyclosporine. Encorafenib is a CYP3A4 substrate; cyclosporine is a moderate CYP3A4 inhibitor. Coadministration of a moderate CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 2-fold and 45%, respectively.
    Dabrafenib: (Major) Avoid coadministration of encorafenib and dabrafenib due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; dabrafenib is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
    Danazol: (Major) Avoid coadministration of encorafenib and danazol due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-half of the dose used prior to the addition of danazol. If danazol is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of danazol. Encorafenib is a CYP3A4 substrate; danazol is a moderate CYP3A4 inhibitor. Coadministration of a moderate CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 2-fold and 45%, respectively.
    Darifenacin: (Moderate) Coadministration of encorafenib with darifenacin may result in increased toxicity or decreased efficacy of darifenacin. Darifenacin is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
    Darunavir: (Major) Avoid coadministration of encorafenib and darunavir due to increased encorafenib exposure. Increased or decreased darunavir exposure is also possible. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of darunavir. If darunavir is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of darunavir. Encorafenib is a CYP3A4 substrate; in vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. Darunavir is a strong CYP3A4 inhibitor and sensitive CYP3A4 substrate. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
    Darunavir; Cobicistat: (Major) Avoid coadministration of encorafenib and cobicistat due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of cobicistat. If cobicistat is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of cobicistat. Encorafenib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively. (Major) Avoid coadministration of encorafenib and darunavir due to increased encorafenib exposure. Increased or decreased darunavir exposure is also possible. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of darunavir. If darunavir is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of darunavir. Encorafenib is a CYP3A4 substrate; in vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. Darunavir is a strong CYP3A4 inhibitor and sensitive CYP3A4 substrate. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid coadministration of encorafenib and cobicistat due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of cobicistat. If cobicistat is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of cobicistat. Encorafenib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively. (Major) Avoid coadministration of encorafenib and darunavir due to increased encorafenib exposure. Increased or decreased darunavir exposure is also possible. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of darunavir. If darunavir is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of darunavir. Encorafenib is a CYP3A4 substrate; in vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. Darunavir is a strong CYP3A4 inhibitor and sensitive CYP3A4 substrate. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid coadministration of encorafenib and ritonavir due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of ritonavir. If ritonavir is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of ritonavir. Encorafenib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
    Dasatinib: (Major) Avoid coadministration of encorafenib and dasatinib due to QT prolongation. Concurrent use may also result in increased toxicity or decreased efficacy of dasatinib. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established. Dasatinib is a sensitive CYP3A4 substrate. In vitro studies have shown that dasatinib has the potential to prolong the QT interval.
    Degarelix: (Major) Avoid coadministration of encorafenib and degarelix due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Androgen deprivation therapy (i.e., degarelix) may also prolong the QT/QTc interval.
    Delavirdine: (Major) Avoid coadministration of encorafenib and delavirdine due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of delavirdine. If delavirdine is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of delavirdine. Encorafenib is a CYP3A4 substrate; delavirdine is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
    Desflurane: (Major) Avoid coadministration of encorafenib and halogenated anesthetics due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Halogenated anesthetics can also prolong the QT interval.
    Desipramine: (Major) Avoid coadministration of encorafenib and tricyclic antidepressants due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Tricyclic antidepressants share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Deutetrabenazine: (Major) Avoid coadministration of encorafenib and deutetrabenazine due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. For patients taking a deutetrabenazine dosage more than 24 mg/day, assess the QTc interval before and after increasing the deutetrabenazine or encorafenib dosage. Encorafenib is associated with dose-dependent prolongation of the QT interval. Clinically relevant QTc prolongation may occur with deutetrabenazine.
    Dexamethasone: (Major) Avoid coadministration of encorafenib and dexamethasone due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; dexamethasone is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
    Dextromethorphan; Promethazine: (Major) Avoid coadministration of encorafenib and promethazine due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Dextromethorphan; Quinidine: (Major) Avoid coadministration of encorafenib and quinidine due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Quinidine administration is associated with QT prolongation and torsade de pointes (TdP).
    Dienogest; Estradiol valerate: (Major) Avoid coadministration of encorafenib and hormonal contraceptives due to the potential for loss of contraceptive efficacy. Advise females of reproductive potential to use an effective, non-hormonal method of contraception during treatment and for 2 weeks after the final dose of encorafenib. Encorafenib can cause fetal harm when administered during pregnancy.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of dihydrocodeine with encorafenib may alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of dihydrocodeine until stable drug effects are achieved. Discontinuation of encorafenib could alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If encorafenib is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Encorafenib is a weak inhibitor and inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine. CYP3A4 inhibitors may increase dihydrocodeine-related adverse effects while CYP3A4 inducers may reduce efficacy.
    Diltiazem: (Major) Avoid coadministration of encorafenib and diltiazem due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-half of the dose used prior to the addition of diltiazem. If diltiazem is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of diltiazem. Encorafenib is a CYP3A4 substrate; diltiazem is a moderate CYP3A4 inhibitor. Coadministration of diltiazem with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 2-fold and 45%, respectively.
    Disopyramide: (Major) Avoid coadministration of encorafenib and disopyramide due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Disopyramide administration is associated with QT prolongation and torsade de pointes (TdP).
    Dofetilide: (Major) Avoid coadministration of encorafenib and dofetilide due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib has been associated with dose-dependent QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP).
    Dolasetron: (Major) Avoid coadministration of encorafenib and dolasetron due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram.
    Dolutegravir; Rilpivirine: (Major) Avoid coadministration of encorafenib and rilpivirine due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Donepezil: (Major) Avoid coadministration of encorafenib and donepezil due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
    Donepezil; Memantine: (Major) Avoid coadministration of encorafenib and donepezil due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
    Doxepin: (Major) Avoid coadministration of encorafenib and tricyclic antidepressants due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Tricyclic antidepressants share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Dronedarone: (Severe) Coadministration of encorafenib with dronedarone is contraindicated due to QT prolongation. Encorafenib is associated with dose-dependent QT interval prolongation. Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
    Droperidol: (Major) Avoid coadministration of encorafenib and droperidol due to QT prolongation. If coadministration cannot be avoided, use extreme caution; initiate droperidol at a low dose and increase the dose as needed to achieve the desired effect. Monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Droperidol administration is associated with an established risk for QT prolongation and torsade de pointes (TdP). Some cases have occurred in patients with no known risk factors for QT prolongation and some cases have been fatal. Encorafenib is associated with dose-dependent prolongation of the QT interval.
    Drospirenone: (Major) Avoid coadministration of encorafenib and hormonal contraceptives due to the potential for loss of contraceptive efficacy. Advise females of reproductive potential to use an effective, non-hormonal method of contraception during treatment and for 2 weeks after the final dose of encorafenib. Encorafenib can cause fetal harm when administered during pregnancy.
    Drospirenone; Estradiol: (Major) Avoid coadministration of encorafenib and hormonal contraceptives due to the potential for loss of contraceptive efficacy. Advise females of reproductive potential to use an effective, non-hormonal method of contraception during treatment and for 2 weeks after the final dose of encorafenib. Encorafenib can cause fetal harm when administered during pregnancy.
    Drospirenone; Ethinyl Estradiol: (Major) Avoid coadministration of encorafenib and hormonal contraceptives due to the potential for loss of contraceptive efficacy. Advise females of reproductive potential to use an effective, non-hormonal method of contraception during treatment and for 2 weeks after the final dose of encorafenib. Encorafenib can cause fetal harm when administered during pregnancy.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Major) Avoid coadministration of encorafenib and hormonal contraceptives due to the potential for loss of contraceptive efficacy. Advise females of reproductive potential to use an effective, non-hormonal method of contraception during treatment and for 2 weeks after the final dose of encorafenib. Encorafenib can cause fetal harm when administered during pregnancy.
    Duvelisib: (Major) Avoid coadministration of encorafenib and duvelisib due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-half of the dose used prior to the addition of duvelisib. If duvelisib is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of duvelisib. Encorafenib is a CYP3A4 substrate; duvelisib is a moderate CYP3A4 inhibitor. Coadministration of a moderate CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 2-fold and 45%, respectively.
    Efavirenz: (Major) Avoid coadministration of encorafenib and efavirenz due to decreased encorafenib exposure and potential loss of efficacy. Additive risk of QT prolongation is also possible. Encorafenib is a CYP3A4 substrate that is associated with dose-dependent prolongation of the QT interval; efavirenz is a moderate CYP3A4 inducer that has been associated with QT prolongation. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
    Efavirenz; Emtricitabine; Tenofovir: (Major) Avoid coadministration of encorafenib and efavirenz due to decreased encorafenib exposure and potential loss of efficacy. Additive risk of QT prolongation is also possible. Encorafenib is a CYP3A4 substrate that is associated with dose-dependent prolongation of the QT interval; efavirenz is a moderate CYP3A4 inducer that has been associated with QT prolongation. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of encorafenib and efavirenz due to decreased encorafenib exposure and potential loss of efficacy. Additive risk of QT prolongation is also possible. Encorafenib is a CYP3A4 substrate that is associated with dose-dependent prolongation of the QT interval; efavirenz is a moderate CYP3A4 inducer that has been associated with QT prolongation. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
    Elagolix: (Major) Avoid coadministration of encorafenib and elagolix due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; elagolix is a weak to moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
    Elagolix; Estradiol; Norethindrone acetate: (Major) Avoid coadministration of encorafenib and elagolix due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; elagolix is a weak to moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction. (Major) Avoid coadministration of encorafenib and hormonal contraceptives due to the potential for loss of contraceptive efficacy. Advise females of reproductive potential to use an effective, non-hormonal method of contraception during treatment and for 2 weeks after the final dose of encorafenib. Encorafenib can cause fetal harm when administered during pregnancy.
    Eletriptan: (Moderate) Coadministration of encorafenib with eletriptan may result in increased toxicity or decreased efficacy of eletriptan. Eletriptan is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
    Elexacaftor; tezacaftor; ivacaftor: (Major) Coadministration of encorafenib with ivacaftor may result in increased toxicity or decreased efficacy of ivacaftor. Ivacaftor is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
    Eliglustat: (Major) Avoid coadministration of encorafenib and eliglustat due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Eliglustat is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid coadministration of encorafenib and cobicistat due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of cobicistat. If cobicistat is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of cobicistat. Encorafenib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of encorafenib and cobicistat due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of cobicistat. If cobicistat is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of cobicistat. Encorafenib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) Avoid coadministration of encorafenib and rilpivirine due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Major) Avoid coadministration of encorafenib and rilpivirine due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Enalapril; Felodipine: (Moderate) Coadministration of encorafenib with felodipine may result in increased toxicity or decreased efficacy of felodipine. Felodipine is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
    Enflurane: (Major) Avoid coadministration of encorafenib and halogenated anesthetics due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Halogenated anesthetics can also prolong the QT interval.
    Entrectinib: (Major) Avoid coadministration of encorafenib and entrectinib due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib has been associated with dose-dependent QT prolongation. Entrectinib has also been associated with QT prolongation.
    Enzalutamide: (Major) Avoid coadministration of encorafenib and enzalutamide due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; enzalutamide is a strong CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
    Eplerenone: (Moderate) Coadministration of encorafenib with eplerenone may result in increased toxicity or decreased efficacy of eplerenone. Eplerenone is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
    Eribulin: (Major) Avoid coadministration of encorafenib and eliglustat due to QT prolongation. If eribulin and encorafenib must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Eribulin has been associated with QT prolongation.
    Erythromycin: (Major) Avoid coadministration of encorafenib and erythromycin due to increased encorafenib exposure and QT prolongation. If concurrent use cannot be avoided, reduce the encorafenib dose to one-half of the dose used prior to the addition of erythromycin. Monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. If erythromycin is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of erythromycin. Encorafenib is a CYP3A4 substrate that has been associated with dose-dependent QT prolongation; erythromycin is a moderate CYP3A4 inhibitor that is associated with QT prolongation and torsade de pointes (TdP). Coadministration of a moderate CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 2-fold and 45%, respectively.
    Erythromycin; Sulfisoxazole: (Major) Avoid coadministration of encorafenib and erythromycin due to increased encorafenib exposure and QT prolongation. If concurrent use cannot be avoided, reduce the encorafenib dose to one-half of the dose used prior to the addition of erythromycin. Monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. If erythromycin is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of erythromycin. Encorafenib is a CYP3A4 substrate that has been associated with dose-dependent QT prolongation; erythromycin is a moderate CYP3A4 inhibitor that is associated with QT prolongation and torsade de pointes (TdP). Coadministration of a moderate CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 2-fold and 45%, respectively.
    Escitalopram: (Major) Avoid coadministration of encorafenib and escitalopram due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Escitalopram has been associated with a risk of QT prolongation and torsade de pointes (TdP).
    Eslicarbazepine: (Major) Avoid coadministration of encorafenib and eslicarbazepine due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; eslicarbazepine is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
    Estradiol; Levonorgestrel: (Major) Avoid coadministration of encorafenib and hormonal contraceptives due to the potential for loss of contraceptive efficacy. Advise females of reproductive potential to use an effective, non-hormonal method of contraception during treatment and for 2 weeks after the final dose of encorafenib. Encorafenib can cause fetal harm when administered during pregnancy.
    Estradiol; Norethindrone: (Major) Avoid coadministration of encorafenib and hormonal contraceptives due to the potential for loss of contraceptive efficacy. Advise females of reproductive potential to use an effective, non-hormonal method of contraception during treatment and for 2 weeks after the final dose of encorafenib. Encorafenib can cause fetal harm when administered during pregnancy.
    Estradiol; Norgestimate: (Major) Avoid coadministration of encorafenib and hormonal contraceptives due to the potential for loss of contraceptive efficacy. Advise females of reproductive potential to use an effective, non-hormonal method of contraception during treatment and for 2 weeks after the final dose of encorafenib. Encorafenib can cause fetal harm when administered during pregnancy.
    Ethinyl Estradiol: (Major) Avoid coadministration of encorafenib and hormonal contraceptives due to the potential for loss of contraceptive efficacy. Advise females of reproductive potential to use an effective, non-hormonal method of contraception during treatment and for 2 weeks after the final dose of encorafenib. Encorafenib can cause fetal harm when administered during pregnancy.
    Ethinyl Estradiol; Desogestrel: (Major) Avoid coadministration of encorafenib and hormonal contraceptives due to the potential for loss of contraceptive efficacy. Advise females of reproductive potential to use an effective, non-hormonal method of contraception during treatment and for 2 weeks after the final dose of encorafenib. Encorafenib can cause fetal harm when administered during pregnancy.
    Ethinyl Estradiol; Ethynodiol Diacetate: (Major) Avoid coadministration of encorafenib and hormonal contraceptives due to the potential for loss of contraceptive efficacy. Advise females of reproductive potential to use an effective, non-hormonal method of contraception during treatment and for 2 weeks after the final dose of encorafenib. Encorafenib can cause fetal harm when administered during pregnancy.
    Ethinyl Estradiol; Etonogestrel: (Major) Avoid coadministration of encorafenib and hormonal contraceptives due to the potential for loss of contraceptive efficacy. Advise females of reproductive potential to use an effective, non-hormonal method of contraception during treatment and for 2 weeks after the final dose of encorafenib. Encorafenib can cause fetal harm when administered during pregnancy.
    Ethinyl Estradiol; Levonorgestrel: (Major) Avoid coadministration of encorafenib and hormonal contraceptives due to the potential for loss of contraceptive efficacy. Advise females of reproductive potential to use an effective, non-hormonal method of contraception during treatment and for 2 weeks after the final dose of encorafenib. Encorafenib can cause fetal harm when administered during pregnancy.
    Ethinyl Estradiol; Levonorgestrel; Ferrous bisglycinate: (Major) Avoid coadministration of encorafenib and hormonal contraceptives due to the potential for loss of contraceptive efficacy. Advise females of reproductive potential to use an effective, non-hormonal method of contraception during treatment and for 2 weeks after the final dose of encorafenib. Encorafenib can cause fetal harm when administered during pregnancy.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Major) Avoid coadministration of encorafenib and hormonal contraceptives due to the potential for loss of contraceptive efficacy. Advise females of reproductive potential to use an effective, non-hormonal method of contraception during treatment and for 2 weeks after the final dose of encorafenib. Encorafenib can cause fetal harm when administered during pregnancy.
    Ethinyl Estradiol; Norelgestromin: (Major) Avoid coadministration of encorafenib and hormonal contraceptives due to the potential for loss of contraceptive efficacy. Advise females of reproductive potential to use an effective, non-hormonal method of contraception during treatment and for 2 weeks after the final dose of encorafenib. Encorafenib can cause fetal harm when administered during pregnancy.
    Ethinyl Estradiol; Norethindrone Acetate: (Major) Avoid coadministration of encorafenib and hormonal contraceptives due to the potential for loss of contraceptive efficacy. Advise females of reproductive potential to use an effective, non-hormonal method of contraception during treatment and for 2 weeks after the final dose of encorafenib. Encorafenib can cause fetal harm when administered during pregnancy.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Major) Avoid coadministration of encorafenib and hormonal contraceptives due to the potential for loss of contraceptive efficacy. Advise females of reproductive potential to use an effective, non-hormonal method of contraception during treatment and for 2 weeks after the final dose of encorafenib. Encorafenib can cause fetal harm when administered during pregnancy.
    Ethinyl Estradiol; Norethindrone: (Major) Avoid coadministration of encorafenib and hormonal contraceptives due to the potential for loss of contraceptive efficacy. Advise females of reproductive potential to use an effective, non-hormonal method of contraception during treatment and for 2 weeks after the final dose of encorafenib. Encorafenib can cause fetal harm when administered during pregnancy.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Major) Avoid coadministration of encorafenib and hormonal contraceptives due to the potential for loss of contraceptive efficacy. Advise females of reproductive potential to use an effective, non-hormonal method of contraception during treatment and for 2 weeks after the final dose of encorafenib. Encorafenib can cause fetal harm when administered during pregnancy.
    Ethinyl Estradiol; Norgestimate: (Major) Avoid coadministration of encorafenib and hormonal contraceptives due to the potential for loss of contraceptive efficacy. Advise females of reproductive potential to use an effective, non-hormonal method of contraception during treatment and for 2 weeks after the final dose of encorafenib. Encorafenib can cause fetal harm when administered during pregnancy.
    Ethinyl Estradiol; Norgestrel: (Major) Avoid coadministration of encorafenib and hormonal contraceptives due to the potential for loss of contraceptive efficacy. Advise females of reproductive potential to use an effective, non-hormonal method of contraception during treatment and for 2 weeks after the final dose of encorafenib. Encorafenib can cause fetal harm when administered during pregnancy.
    Etonogestrel: (Major) Avoid coadministration of encorafenib and hormonal contraceptives due to the potential for loss of contraceptive efficacy. Advise females of reproductive potential to use an effective, non-hormonal method of contraception during treatment and for 2 weeks after the final dose of encorafenib. Encorafenib can cause fetal harm when administered during pregnancy.
    Etravirine: (Major) Avoid coadministration of encorafenib and etravirine due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; etravirine is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
    Everolimus: (Moderate) Coadministration of encorafenib with everolimus may result in increased toxicity or decreased efficacy of everolimus. Everolimus is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
    Ezetimibe; Simvastatin: (Moderate) Coadministration of encorafenib with simvastatin may result in increased toxicity or decreased efficacy of simvastatin. Simvastatin is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
    Ezogabine: (Major) Avoid coadministration of encorafenib and ezogabine due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Ezogabine has also been associated with QT prolongation.
    Fedratinib: (Major) Avoid coadministration of encorafenib and fedratinib due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-half of the dose used prior to the addition of fedratinib. If fedratinib is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of fedratinib. Encorafenib is a CYP3A4 substrate; fedratinib is a moderate CYP3A4 inhibitor. Coadministration of a moderate CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 2-fold and 45%, respectively.
    Felodipine: (Moderate) Coadministration of encorafenib with felodipine may result in increased toxicity or decreased efficacy of felodipine. Felodipine is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
    Fingolimod: (Major) Avoid coadministration of encorafenib and fingolimod due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
    Flecainide: (Major) Avoid coadministration of encorafenib and flecainide due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Flecainide is a Class IC antiarrhythmic associated with a possible risk for QT prolongation and/or torsade de pointes (TdP); flecainide increases the QT interval, but largely due to prolongation of the QRS interval. Although causality for TdP has not been established for flecainide, patients receiving concurrent drugs that have the potential for QT prolongation may have an increased risk of developing proarrhythmias.
    Fluconazole: (Severe) The concurrent use of fluconazole with drugs that are associated with QT prolongation and are also CYP3A4 substrates, such as encorafenib, is contraindicated. Fluconazole has been associated with QT prolongation.
    Fluoxetine: (Major) Avoid coadministration of encorafenib and fluoxetine due to increased encorafenib exposure and QT prolongation. If concurrent use cannot be avoided, reduce the encorafenib dose to one-half of the dose used prior to the addition of fluoxetine. Monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. If fluoxetine is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of fluoxetine. Encorafenib is a CYP3A4 substrate that has been associated with dose-dependent QT prolongation. Fluoxetine is a weak CYP3A4 inhibitor, but the norfluoxetine metabolite is a moderate CYP3A4 inhibitor; QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine. Coadministration of a moderate CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 2-fold and 45%, respectively.
    Fluoxetine; Olanzapine: (Major) Avoid coadministration of encorafenib and fluoxetine due to increased encorafenib exposure and QT prolongation. If concurrent use cannot be avoided, reduce the encorafenib dose to one-half of the dose used prior to the addition of fluoxetine. Monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. If fluoxetine is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of fluoxetine. Encorafenib is a CYP3A4 substrate that has been associated with dose-dependent QT prolongation. Fluoxetine is a weak CYP3A4 inhibitor, but the norfluoxetine metabolite is a moderate CYP3A4 inhibitor; QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine. Coadministration of a moderate CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 2-fold and 45%, respectively. (Major) Avoid coadministration of encorafenib and olanzapine due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Fluphenazine: (Minor) Use caution if fluphenazine is administered with encorafenib. Encorafenib is associated with dose-dependent prolongation of the QT interval. Fluphenazine is associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
    Fluticasone; Salmeterol: (Moderate) If encorafenib is coadministered with a long-acting beta-agonist, consider monitoring ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib has been associated with dose-dependent QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) If encorafenib is coadministered with a long-acting beta-agonist, consider monitoring ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib has been associated with dose-dependent QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Fluticasone; Vilanterol: (Moderate) If encorafenib is coadministered with a long-acting beta-agonist, consider monitoring ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib has been associated with dose-dependent QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Fluvoxamine: (Major) Avoid coadministration of encorafenib and fluvoxamine due to increased encorafenib exposure and QT prolongation. If concurrent use cannot be avoided, reduce the encorafenib dose to one-half of the dose used prior to the addition of fluvoxamine. Monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. If fluvoxamine is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of fluvoxamine. Encorafenib is a CYP3A4 substrate that has been associated with dose-dependent QT prolongation; fluvoxamine is a moderate CYP3A4 inhibitor that has been associated with QT prolongation and torsade de pointes (TdP) during postmarketing use. Coadministration of a moderate CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 2-fold and 45%, respectively.
    Formoterol: (Moderate) If encorafenib is coadministered with a long-acting beta-agonist, consider monitoring ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib has been associated with dose-dependent QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Formoterol; Mometasone: (Moderate) If encorafenib is coadministered with a long-acting beta-agonist, consider monitoring ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib has been associated with dose-dependent QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Fosamprenavir: (Major) Avoid coadministration of encorafenib and fosamprenavir due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of fosamprenavir. If fosamprenavir is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of fosamprenavir. Encorafenib is a CYP3A4 substrate; fosamprenavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
    Foscarnet: (Major) Avoid coadministration of encorafenib and foscarnet due to QT prolongation. Encorafenib is associated with dose-dependent prolongation of the QT interval. Both QT prolongation and torsade de pointes (TdP) have been reported during postmarketing use of foscarnet.
    Fosphenytoin: (Major) Avoid coadministration of encorafenib and fosphenytoin due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; fosphenytoin is a strong CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
    Fostemsavir: (Major) Avoid coadministration of encorafenib and fostemsavir due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib has been associated with dose-dependent QT prolongation. Supratherapeutic doses of fostemsavir (2,400 mg twice daily, 4 times the recommended daily dose) have been shown to cause QT prolongation. Fostemsavir causes dose-dependent QT prolongation.
    Gemifloxacin: (Major) Avoid coadministration of encorafenib and gemifloxacin due to QT prolongation. Encorafenib is associated with dose-dependent prolongation of the QT interval. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Gemifloxacin may prolong the QT interval in some patients. The maximal change in the QTc interval occurs approximately 5 to 10 hours following oral administration of gemifloxacin. The likelihood of QTc prolongation may increase with increasing dose of the drug; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher.
    Gemtuzumab Ozogamicin: (Major) Avoid coadministration of encorafenib and gemtuzumab due to QT prolongation. If these agents must be used together, obtain an ECG and serum electrolytes prior to the start of gemtuzumab and as needed during treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Although QT interval prolongation has not been reported with gemtuzumab, it has been reported with other drugs that contain calicheamicin.
    Gilteritinib: (Major) Avoid coadministration of encorafenib and gilteritinib due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib has been associated with dose-dependent QT prolongation. Gilteritinib has been associated with QT prolongation.
    Glasdegib: (Major) Avoid coadministration of glasdegib with encorafenib due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with a dose-dependent prolongation of the QT interval. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia.
    Glycopyrrolate; Formoterol: (Moderate) If encorafenib is coadministered with a long-acting beta-agonist, consider monitoring ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib has been associated with dose-dependent QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Goserelin: (Major) Avoid coadministration of encorafenib and goserelin due to the risk of QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib has been associated with dose-dependent QT prolongation. Androgen deprivation therapy (i.e., goserelin) may also prolong the QT/QTc interval.
    Granisetron: (Major) Avoid coadministration of encorafenib and granisetron due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Granisetron has also been associated with QT prolongation.
    Grapefruit juice: (Major) Advise patients to avoid grapefruit juice while taking encorafenib due to increased encorafenib exposure. Encorafenib is a CYP3A4 substrate; grapefruit juice is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
    Halogenated Anesthetics: (Major) Avoid coadministration of encorafenib and halogenated anesthetics due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Halogenated anesthetics can also prolong the QT interval.
    Haloperidol: (Major) Avoid coadministration of encorafenib and haloperidol due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. QT prolongation and torsade de pointes (TdP) have been observed during haloperidol treatment. Excessive doses (particularly in the overdose setting) or IV administration of haloperidol may be associated with a higher risk of QT prolongation.
    Halothane: (Major) Avoid coadministration of encorafenib and halogenated anesthetics due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Halogenated anesthetics can also prolong the QT interval.
    Histrelin: (Major) Avoid coadministration of encorafenib and histrelin due to the risk of QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib has been associated with dose-dependent QT prolongation. Androgen deprivation therapy (i.e., histrelin) may also prolong the QT/QTc interval.
    Hydroxychloroquine: (Major) Avoid coadministration of encorafenib and hydroxychloroquine due to the risk of increased QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Hydroxychloroquine prolongs the QT interval. Encorafenib is associated with dose-dependent prolongation of the QT interval.
    Hydroxyzine: (Major) Avoid coadministration of encorafenib and hydroxyzine due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Postmarketing data indicate that hydroxyzine causes QT prolongation and torsade de pointes (TdP).
    Ibrutinib: (Moderate) Coadministration of encorafenib with ibrutinib may result in increased toxicity or decreased efficacy of ibrutinib. Ibrutinib is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
    Ibutilide: (Major) Avoid coadministration of encorafenib and ibutilide due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Ibutilide administration can cause QT prolongation and torsade de pointes (TdP); proarrhythmic events should be anticipated. The potential for proarrhythmic events with ibutilide increases with the coadministration of other drugs that prolong the QT interval.
    Idelalisib: (Major) Avoid coadministration of encorafenib and idelalisib due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of idelalisib. If idelalisib is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of idelalisib. Encorafenib is a CYP3A4 substrate; idelalisib is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
    Iloperidone: (Major) Avoid coadministration of encorafenib and iloperidone due to QT prolongation. Encorafenib is associated with dose-dependent prolongation of the QT interval. Iloperidone has also been associated with QT prolongation.
    Imatinib: (Major) Avoid coadministration of encorafenib and imatinib due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-half of the dose used prior to the addition of imatinib. If imatinib is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of imatinib. Encorafenib is a CYP3A4 substrate; imatinib is a moderate CYP3A4 inhibitor. Coadministration of a moderate CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 2-fold and 45%, respectively.
    Imipramine: (Major) Avoid coadministration of encorafenib and tricyclic antidepressants due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Tricyclic antidepressants share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Indacaterol: (Moderate) If encorafenib is coadministered with a long-acting beta-agonist, consider monitoring ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib has been associated with dose-dependent QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Indacaterol; Glycopyrrolate: (Moderate) If encorafenib is coadministered with a long-acting beta-agonist, consider monitoring ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib has been associated with dose-dependent QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Indinavir: (Major) Avoid coadministration of encorafenib and indinavir due to increased encorafenib exposure. Increased or decreased indinavir exposure is also possible. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of indinavir. If indinavir is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of indinavir. Encorafenib is a CYP3A4 substrate; in vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. Indinavir is a strong CYP3A4 inhibitor and sensitive CYP3A4 substrate. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
    Inotuzumab Ozogamicin: (Major) Avoid coadministration of encorafenib and inotuzumab due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Inotuzumab has also been associated with QT interval prolongation.
    Isavuconazonium: (Major) Avoid coadministration of encorafenib and isavuconazonium due to increased encorafenib exposure. Concurrent use may also result in increased toxicity or decreased efficacy of isavuconazonium. If concurrent use cannot be avoided, reduce the encorafenib dose to one-half of the dose used prior to the addition of isavuconazonium. If isavuconazonium is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of isavuconazonium. Encorafenib is a CYP3A4 substrate; in vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established. Isavuconazonium is a moderate CYP3A4 inhibitor and sensitive CYP3A4 substrate. Coadministration of a moderate CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 2-fold and 45%, respectively.
    Isoflurane: (Major) Avoid coadministration of encorafenib and halogenated anesthetics due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Halogenated anesthetics can also prolong the QT interval.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid coadministration of encorafenib and rifampin due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; rifampin is a strong CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
    Isoniazid, INH; Rifampin: (Major) Avoid coadministration of encorafenib and rifampin due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; rifampin is a strong CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
    Itraconazole: (Major) Avoid coadministration of encorafenib and itraconazole due to increased encorafenib exposure and QT prolongation. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of itraconazole. Monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. If itraconazole is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of itraconazole. Encorafenib is a CYP3A4 substrate that has been associated with dose-dependent QT prolongation; itraconazole is a strong CYP3A4 inhibitor that has been associated with prolongation of the QT interval. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
    Ivacaftor: (Major) Coadministration of encorafenib with ivacaftor may result in increased toxicity or decreased efficacy of ivacaftor. Ivacaftor is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
    Ivosidenib: (Major) Avoid coadministration of ivosidenib with encorafenib if possible due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Encorafenib has been associated with dose-dependent QT prolongation.
    Ketoconazole: (Major) Avoid coadministration of encorafenib and ketoconazole due to increased encorafenib exposure and QT prolongation. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of ketoconazole. Monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. If ketoconazole is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of ketoconazole. Encorafenib is a CYP3A4 substrate that has been associated with dose-dependent QT prolongation; ketoconazole is a strong CYP3A4 inhibitor that has been associated with prolongation of the QT interval. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
    Lapatinib: (Major) Avoid coadministration of encorafenib and lapatinib due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience.
    Lefamulin: (Major) Avoid coadministration of lefamulin with encorafenib as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG and electrolytes during treatment; correct hypokalemia and hypomagnesemia prior to treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Encorafenib has been associated with dose-dependent QT prolongation.
    Lenvatinib: (Major) Avoid coadministration of encorafenib and lenvatinib due to QT prolongation. Encorafenib is associated with dose-dependent prolongation of the QT interval. QT prolongation was reported during clinical trials of lenvatinib.
    Letermovir: (Major) Avoid coadministration of encorafenib and letermovir due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-half of the dose used prior to the addition of letermovir. If letermovir is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of letermovir. Encorafenib is a CYP3A4 substrate; letermovir is a moderate CYP3A4 inhibitor. Coadministration of a moderate CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 2-fold and 45%, respectively.
    Leuprolide: (Major) Avoid coadministration of encorafenib and leuprolide due to the risk of QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib has been associated with dose-dependent QT prolongation. Androgen deprivation therapy (i.e., leuprolide) may also prolong the QT/QTc interval.
    Leuprolide; Norethindrone: (Major) Avoid coadministration of encorafenib and hormonal contraceptives due to the potential for loss of contraceptive efficacy. Advise females of reproductive potential to use an effective, non-hormonal method of contraception during treatment and for 2 weeks after the final dose of encorafenib. Encorafenib can cause fetal harm when administered during pregnancy. (Major) Avoid coadministration of encorafenib and leuprolide due to the risk of QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib has been associated with dose-dependent QT prolongation. Androgen deprivation therapy (i.e., leuprolide) may also prolong the QT/QTc interval.
    Levalbuterol: (Minor) If encorafenib is coadministered with a short-acting beta-agonist, consider monitoring ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Levofloxacin: (Major) Avoid coadministration of encorafenib and levofloxacin due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Levofloxacin has been associated with a risk of QT prolongation. Although extremely rare, torsade de pointes has been reported during postmarketing surveillance of levofloxacin.
    Levonorgestrel: (Major) Avoid coadministration of encorafenib and hormonal contraceptives due to the potential for loss of contraceptive efficacy. Advise females of reproductive potential to use an effective, non-hormonal method of contraception during treatment and for 2 weeks after the final dose of encorafenib. Encorafenib can cause fetal harm when administered during pregnancy.
    Lithium: (Major) Avoid coadministration of encorafenib and lithium due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Lithium has also been associated with QT prolongation.
    Lofexidine: (Major) Avoid coadministration of encorafenib and lofexidine due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Lofexidine has also been associated with QT prolongation.
    Lomitapide: (Moderate) Coadministration of encorafenib with lomitapide may result in increased toxicity or decreased efficacy of lomitapide. Lomitapide is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
    Long-acting beta-agonists: (Moderate) If encorafenib is coadministered with a long-acting beta-agonist, consider monitoring ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib has been associated with dose-dependent QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Loperamide: (Major) Avoid coadministration of encorafenib and loperamide due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest.
    Loperamide; Simethicone: (Major) Avoid coadministration of encorafenib and loperamide due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest.
    Lopinavir; Ritonavir: (Major) Avoid coadministration of encorafenib and ritonavir due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of ritonavir. If ritonavir is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of ritonavir. Encorafenib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively. (Major) Avoid coadministration of lopinavir with encorafenib due to the potential for additive QT prolongation. If use together is necessary, obtain a baseline ECG to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Lopinavir is associated with QT prolongation. Encorafenib has been associated with dose-dependent QT prolongation.
    Lorlatinib: (Major) Avoid coadministration of encorafenib and lorlatinib due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; lorlatinib is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
    Lovastatin: (Moderate) Coadministration of encorafenib with lovastatin may result in increased toxicity or decreased efficacy of lovastatin. Lovastatin is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
    Lovastatin; Niacin: (Moderate) Coadministration of encorafenib with lovastatin may result in increased toxicity or decreased efficacy of lovastatin. Lovastatin is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
    Lumacaftor; Ivacaftor: (Major) Avoid coadministration of encorafenib and lumacaftor; ivacaftor due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; lumacaftor is a strong CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction. (Major) Coadministration of encorafenib with ivacaftor may result in increased toxicity or decreased efficacy of ivacaftor. Ivacaftor is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
    Lumacaftor; Ivacaftor: (Major) Avoid coadministration of encorafenib and lumacaftor; ivacaftor due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; lumacaftor is a strong CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
    Lurasidone: (Moderate) Coadministration of encorafenib with lurasidone may result in increased toxicity or decreased efficacy of lurasidone. Lurasidone is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
    Macimorelin: (Major) Avoid concurrent administration of macimorelin with encorafenib. Use of these drugs together may increase the risk of developing torsade de pointes-type ventricular tachycardia. Sufficient washout time encorafenib prior to administration of macimorelin is recommended. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval. Encorafenib has been associated with dose-dependent QT prolongation.
    Maprotiline: (Major) Avoid coadministration of encorafenib and maprotiline due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation.
    Maraviroc: (Moderate) Coadministration of encorafenib with maraviroc may result in increased toxicity or decreased efficacy of maraviroc. Maraviroc is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
    Mefloquine: (Major) Avoid coadministration of encorafenib and mefloquine due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. There is evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation.
    Meperidine; Promethazine: (Major) Avoid coadministration of encorafenib and promethazine due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Mestranol; Norethindrone: (Major) Avoid coadministration of encorafenib and hormonal contraceptives due to the potential for loss of contraceptive efficacy. Advise females of reproductive potential to use an effective, non-hormonal method of contraception during treatment and for 2 weeks after the final dose of encorafenib. Encorafenib can cause fetal harm when administered during pregnancy.
    Metaproterenol: (Minor) If encorafenib is coadministered with a short-acting beta-agonist, consider monitoring ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Methadone: (Major) Avoid coadministration of encorafenib and methadone due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Methadone is considered to be associated with an increased risk for QT prolongation and torsade de pointes (TdP), especially at higher doses (more than 200 mg/day but averaging approximately 400 mg/day in adult patients). Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction.
    Metronidazole: (Major) Avoid coadministration of encorafenib and metronidazole due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Potential QT prolongation has been reported in limited case reports with metronidazole.
    Midazolam: (Moderate) Coadministration of encorafenib with midazolam may result in increased toxicity or decreased efficacy of midazolam. Midazolam is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
    Midostaurin: (Major) Avoid coadministration of encorafenib and midostaurin due to the potential for additive QT prolongation. Concurrent use may also result in increased toxicity or decreased efficacy of midostaurin. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established. QT prolongation was reported in patients who received midostaurin, a sensitive CYP3A4 substrate, in clinical trials.
    Mifepristone: (Major) Avoid coadministration of encorafenib and mifepristone due to increased encorafenib exposure and QT prolongation. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of mifepristone. Monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Use the lowest effective dose of mifepristone. If mifepristone is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of mifepristone. Encorafenib is a CYP3A4 substrate that has been associated with dose-dependent QT prolongation. When administered chronically, mifepristone is a strong CYP3A4 inhibitor that has been associated with dose-dependent QT prolongation. The clinical significance of mifepristone inhibition of CYP3A4 when used for pregnancy termination is not established. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
    Mirtazapine: (Major) Avoid coadministration of encorafenib and mirtazapine due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation.
    Mitotane: (Major) Avoid coadministration of encorafenib and mitotane due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; mitotane is a strong CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
    Modafinil: (Major) Avoid coadministration of encorafenib and modafinil due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; modafinil is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
    Moxifloxacin: (Major) Avoid coadministration of encorafenib and moxifloxacin due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Quinolones have been associated with a risk of QT prolongation. Although extremely rare, TdP has been reported during postmarketing surveillance of moxifloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Nafcillin: (Major) Avoid coadministration of encorafenib and nafcillin due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; nafcillin is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
    Naloxegol: (Moderate) Coadministration of encorafenib with naloxegol may result in increased toxicity or decreased efficacy of naloxegol. Naloxegol is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
    Nefazodone: (Major) Avoid coadministration of encorafenib and nefazodone due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of nefazodone. If nefazodone is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of nefazodone. Encorafenib is a CYP3A4 substrate; nefazodone is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
    Nelfinavir: (Major) Avoid coadministration of encorafenib and nelfinavir due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of nelfinavir. If nelfinavir is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of nelfinavir. Encorafenib is a CYP3A4 substrate; nelfinavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
    Netupitant, Fosnetupitant; Palonosetron: (Major) Avoid coadministration of encorafenib and netupitant due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-half of the dose used prior to the addition of netupitant. If netupitant is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of netupitant. Encorafenib is a CYP3A4 substrate; netupitant is a moderate CYP3A4 inhibitor. Coadministration of a moderate CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 2-fold and 45%, respectively.
    Nevirapine: (Major) Avoid coadministration of encorafenib and nevirapine due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; nevirapine is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
    Niacin; Simvastatin: (Moderate) Coadministration of encorafenib with simvastatin may result in increased toxicity or decreased efficacy of simvastatin. Simvastatin is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
    Nilotinib: (Major) Avoid coadministration of encorafenib and nilotinib due to increased encorafenib exposure and QT prolongation. If concurrent use cannot be avoided, reduce the encorafenib dose to one-half of the dose used prior to the addition of nilotinib. Monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. If nilotinib is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of nilotinib. Encorafenib is a CYP3A4 substrate that has been associated with dose-dependent QT prolongation. Nilotinib is a moderate CYP3A4 inhibitor; sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy. Coadministration of a moderate CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 2-fold and 45%, respectively.
    Nisoldipine: (Moderate) Coadministration of encorafenib with nisoldipine may result in increased toxicity or decreased efficacy of nisoldipine. Nisoldipine is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
    Non-oral combination contraceptives: (Major) Avoid coadministration of encorafenib and hormonal contraceptives due to the potential for loss of contraceptive efficacy. Advise females of reproductive potential to use an effective, non-hormonal method of contraception during treatment and for 2 weeks after the final dose of encorafenib. Encorafenib can cause fetal harm when administered during pregnancy.
    Norethindrone: (Major) Avoid coadministration of encorafenib and hormonal contraceptives due to the potential for loss of contraceptive efficacy. Advise females of reproductive potential to use an effective, non-hormonal method of contraception during treatment and for 2 weeks after the final dose of encorafenib. Encorafenib can cause fetal harm when administered during pregnancy.
    Norfloxacin: (Major) Avoid coadministration of encorafenib and norfloxacin due to the potential for additive QT prolongation. Encorafenib is associated with dose-dependent prolongation of the QT interval. Quinolones have been associated with a risk of QT prolongation. Although extremely rare, torsade de pointes has been reported during postmarketing surveillance of norfloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Norgestrel: (Major) Avoid coadministration of encorafenib and hormonal contraceptives due to the potential for loss of contraceptive efficacy. Advise females of reproductive potential to use an effective, non-hormonal method of contraception during treatment and for 2 weeks after the final dose of encorafenib. Encorafenib can cause fetal harm when administered during pregnancy.
    Nortriptyline: (Major) Avoid coadministration of encorafenib and tricyclic antidepressants due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Tricyclic antidepressants share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Octreotide: (Major) Avoid coadministration of encorafenib and octreotide due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Arrhythmias, sinus bradycardia, and conduction disturbances have occurred during octreotide therapy. Since bradycardia is a risk factor for development of torsade de pointes (TdP), the potential occurrence of bradycardia during octreotide administration could theoretically increase the risk of TdP in patients receiving drugs that prolong the QT interval.
    Ofloxacin: (Major) Avoid coadministration of encorafenib and ofloxacin due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Quinolones have been associated with a risk of QT prolongation. Although extremely rare, torsade de pointes has been reported during postmarketing surveillance of ofloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Olanzapine: (Major) Avoid coadministration of encorafenib and olanzapine due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Olodaterol: (Moderate) If encorafenib is coadministered with a long-acting beta-agonist, consider monitoring ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib has been associated with dose-dependent QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid coadministration of encorafenib and ritonavir due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of ritonavir. If ritonavir is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of ritonavir. Encorafenib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
    Omeprazole; Amoxicillin; Rifabutin: (Major) Avoid coadministration of encorafenib and rifabutin due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; rifabutin is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
    Ondansetron: (Major) Avoid coadministration of encorafenib and ondansetron due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP).
    Oral Contraceptives: (Major) Avoid coadministration of encorafenib and hormonal contraceptives due to the potential for loss of contraceptive efficacy. Advise females of reproductive potential to use an effective, non-hormonal method of contraception during treatment and for 2 weeks after the final dose of encorafenib. Encorafenib can cause fetal harm when administered during pregnancy.
    Osilodrostat: (Major) Avoid coadministration of encorafenib and osilodrostat due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib has been associated with dose-dependent QT prolongation. Osilodrostat is associated with dose-dependent QT prolongation.
    Osimertinib: (Major) Avoid coadministration of encorafenib and osimertinib due to the potential for additive QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation may be necessary if QT prolongation occurs. Encorafenib is associated with dose-dependent prolongation of the QT interval. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib.
    Oxaliplatin: (Major) Avoid coadministration of encorafenib and oxaliplatin due to the potential for additive QT prolongation. If coadministration is necessary, monitor ECG and electrolytes; correct electrolyte abnormalities prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. QT prolongation and ventricular arrhythmias including fatal torsade de pointes have also been reported with oxaliplatin use in postmarketing experience.
    Ozanimod: (Major) Avoid coadministration of encorafenib and ozanimod due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib has been associated with dose-dependent QT prolongation. Ozanimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ozanimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with torsade de pointes in patients with bradycardia.
    Paliperidone: (Major) Avoid coadministration of encorafenib and paliperidone if possible due to the potential for additive QT prolongation. If coadministration is necessary, close monitoring of ECGs and electrolytes essential, particularly in patients with known risk factors for cardiac disease or arrhythmias. Correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose.
    Panobinostat: (Major) Avoid coadministration of encorafenib and panobinostat due to the potential for additive QT prolongation. Encorafenib is associated with dose-dependent prolongation of the QT interval. QT prolongation has been reported with panobinostat.
    Pasireotide: (Major) Avoid coadministration of encorafenib and pasireotide due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. QT prolongation has occurred with pasireotide at therapeutic and supra-therapeutic doses.
    Pazopanib: (Major) Avoid coadministration of encorafenib and pazopanib due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Pazopanib has been reported to prolong the QT interval.
    Pentamidine: (Major) Avoid coadministration of encorafenib and pentamidine due to the potential for additive QT prolongation. If unavoidable, monitor ECGs and electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Systemic pentamidine has been associated with QT prolongation.
    Perphenazine: (Minor) Consider monitoring ECGs for QT prolongation and electrolytes if encorafenib and perphenazine are coadministered due to the potential for additive QT prolongation. Correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Perphenazine is associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
    Perphenazine; Amitriptyline: (Major) Avoid coadministration of encorafenib and tricyclic antidepressants due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Tricyclic antidepressants share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). (Minor) Consider monitoring ECGs for QT prolongation and electrolytes if encorafenib and perphenazine are coadministered due to the potential for additive QT prolongation. Correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Perphenazine is associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
    Pexidartinib: (Major) Avoid coadministration of encorafenib and pexidartinib due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; pexidartinib is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
    Phenobarbital: (Major) Avoid coadministration of encorafenib and phenobarbital due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; phenobarbital is a strong CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
    Phenylephrine; Promethazine: (Major) Avoid coadministration of encorafenib and promethazine due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Phenytoin: (Major) Avoid coadministration of encorafenib and phenytoin due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; phenytoin is a strong CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
    Pimavanserin: (Major) Avoid coadministration of encorafenib and pimavanserin due to the potential for additive QT prolongation. Encorafenib is associated with dose-dependent prolongation of the QT interval. Pimavanserin may also cause QT prolongation.
    Pimozide: (Severe) Coadministration of encorafenib with pimozide is contraindicated due to the potential for QT prolongation. Pimozide is associated with a well-established risk of QT prolongation and torsade de pointes (TdP).
    Pirbuterol: (Minor) If encorafenib is coadministered with a short-acting beta-agonist, consider monitoring ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Pitolisant: (Major) Avoid coadministration of pitolisant with encorafenib as concurrent use may increase the risk of QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib has been associated with dose-dependent QT prolongation. Pitolisant also prolongs the QT interval.
    Posaconazole: (Major) Avoid coadministration of encorafenib and posaconazole due to increased encorafenib exposure and QT prolongation. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of posaconazole. Monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. If posaconazole is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of posaconazole. Encorafenib is a CYP3A4 substrate that has been associated with dose-dependent QT prolongation; posaconazole is a strong CYP3A4 inhibitor that has been associated with prolongation of the QT interval as well as rare cases of torsade de pointes. Coadministration of posaconazole with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
    Primaquine: (Major) Avoid coadministration of encorafenib and primaquine due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Primaquine has also been associated with QT interval prolongation.
    Primidone: (Major) Avoid coadministration of encorafenib and primidone due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; primidone is a strong CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
    Procainamide: (Major) Avoid coadministration of encorafenib and procainamide due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Procainamide is associated with a well-established risk of QT prolongation and torsade de pointes (TdP).
    Prochlorperazine: (Minor) Consider monitoring ECGs for QT prolongation and electrolytes if encorafenib and prochlorperazine are coadministered due to the potential for additive QT prolongation. Correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Prochlorperazine is associated with a possible risk for QT prolongation.
    Promethazine: (Major) Avoid coadministration of encorafenib and promethazine due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Propafenone: (Major) Avoid coadministration of encorafenib and propafenone due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval.
    Protriptyline: (Major) Avoid coadministration of encorafenib and tricyclic antidepressants due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Tricyclic antidepressants share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Quetiapine: (Major) Avoid coadministration of encorafenib and quetiapine due to the potential for additive QT prolongation. Concurrent use may also result in increased toxicity or decreased efficacy of quetiapine. Encorafenib is associated with dose-dependent prolongation of the QT interval. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established. Limited data, including some case reports, suggest that quetiapine, a sensitive CYP3A4 substrate, may be associated with a significant prolongation of the QTc interval in rare instances.
    Quinidine: (Major) Avoid coadministration of encorafenib and quinidine due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Quinidine administration is associated with QT prolongation and torsade de pointes (TdP).
    Quinine: (Major) Avoid coadministration of encorafenib and quinine due to increased encorafenib exposure and QT prolongation. If concurrent use cannot be avoided, reduce the encorafenib dose to one-half of the dose used prior to the addition of quinine. Monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. If quinine is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of quinine. Encorafenib is a CYP3A4 substrate that has been associated with dose-dependent QT prolongation; quinine is a moderate CYP3A4 inhibitor that has been associated with QT prolongation and rare cases of torsade de pointes (TdP). Coadministration of a moderate CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 2-fold and 45%, respectively.
    Ranolazine: (Major) Avoid coadministration of encorafenib and ranolazine due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval.
    Ribociclib: (Major) Avoid coadministration of encorafenib and ribociclib due to increased encorafenib exposure and QT prolongation. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of ribociclib. If unavoidable, monitor ECGs and electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. If ribociclib is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of ribociclib. Encorafenib is a CYP3A4 substrate that has been associated with dose-dependent QT prolongation; ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
    Ribociclib; Letrozole: (Major) Avoid coadministration of encorafenib and ribociclib due to increased encorafenib exposure and QT prolongation. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of ribociclib. If unavoidable, monitor ECGs and electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. If ribociclib is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of ribociclib. Encorafenib is a CYP3A4 substrate that has been associated with dose-dependent QT prolongation; ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
    Rifabutin: (Major) Avoid coadministration of encorafenib and rifabutin due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; rifabutin is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
    Rifampin: (Major) Avoid coadministration of encorafenib and rifampin due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; rifampin is a strong CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
    Rifapentine: (Major) Avoid coadministration of encorafenib and rifapentine due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; rifapentine is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
    Rifaximin: (Major) Avoid coadministration of encorafenib and rifaximin due to decreased encorafenib exposure and potential loss of efficacy. Although not observed in patients with normal hepatic function, in patients with reduced liver function rifaximin may induce metabolism of CYP3A4 substrates, such as encorafenib. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
    Rilpivirine: (Major) Avoid coadministration of encorafenib and rilpivirine due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Risperidone: (Major) Avoid coadministration of encorafenib and risperidone due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Risperidone has been associated with a possible risk for QT prolongation and/or torsade de pointes. Reports of QT prolongation and torsade de pointes during risperidone therapy have been reported, primarily in the overdosage setting.
    Ritonavir: (Major) Avoid coadministration of encorafenib and ritonavir due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of ritonavir. If ritonavir is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of ritonavir. Encorafenib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
    Romidepsin: (Major) Avoid coadministration of encorafenib and romidepsin due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Romidepsin has been reported to prolong the QT interval.
    Salmeterol: (Moderate) If encorafenib is coadministered with a long-acting beta-agonist, consider monitoring ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib has been associated with dose-dependent QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Saquinavir: (Major) Avoid coadministration of encorafenib and saquinavir due to increased encorafenib exposure and QT prolongation. Increased or decreased saquinavir exposure is also possible. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of saquinavir. Monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. If saquinavir is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of saquinavir. Encorafenib is a CYP3A4 substrate that has been associated with dose-dependent QT prolongation. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. Saquinavir is a strong CYP3A4 inhibitor and sensitive CYP3A4 substrate that increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsade de pointes (TdP). Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
    Secobarbital: (Major) Avoid coadministration of encorafenib and secobarbital due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; secobarbital is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
    Segesterone Acetate; Ethinyl Estradiol: (Major) Avoid coadministration of encorafenib and hormonal contraceptives due to the potential for loss of contraceptive efficacy. Advise females of reproductive potential to use an effective, non-hormonal method of contraception during treatment and for 2 weeks after the final dose of encorafenib. Encorafenib can cause fetal harm when administered during pregnancy.
    Selpercatinib: (Major) Avoid coadministration of encorafenib and selpercatinib due to the risk of additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib has been associated with dose-dependent QT prolongation. Concentration-dependent QT prolongation has been observed with selpercatinib therapy.
    Sertraline: (Major) Avoid coadministration of encorafenib and sertraline due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. QTc prolongation and torsade de pointes (TdP) have been reported during postmarketing use of sertraline; most cases had confounding risk factors. The risk of sertraline-induced QT prolongation is generally considered to be low in clinical practice. Its effect on QTc interval is minimal (typically less than 5 msec), and the drug has been used safely in patients with cardiac disease (e.g., recent myocardial infarction, unstable angina, chronic heart failure).
    Sevoflurane: (Major) Avoid coadministration of encorafenib and halogenated anesthetics due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Halogenated anesthetics can also prolong the QT interval.
    Short-acting beta-agonists: (Minor) If encorafenib is coadministered with a short-acting beta-agonist, consider monitoring ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Sildenafil: (Moderate) Coadministration of encorafenib with sildenafil may result in increased toxicity or decreased efficacy of sildenafil. Sildenafil is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
    Simvastatin: (Moderate) Coadministration of encorafenib with simvastatin may result in increased toxicity or decreased efficacy of simvastatin. Simvastatin is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
    Simvastatin; Sitagliptin: (Moderate) Coadministration of encorafenib with simvastatin may result in increased toxicity or decreased efficacy of simvastatin. Simvastatin is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
    Siponimod: (Major) Avoid coadministration of encorafenib and siponimod due to the potential for additive QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Encorafenib has been associated with dose-dependent QT prolongation.
    Sirolimus: (Moderate) Coadministration of encorafenib with sirolimus may result in increased toxicity or decreased efficacy of sirolimus. sirolimus is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
    Solifenacin: (Major) Avoid coadministration of encorafenib and solifenacin due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Solifenacin has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported with postmarketing use, although causality was not determined.
    Sorafenib: (Major) Avoid coadministration of sorafenib with encorafenib due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Encorafenib has been associated with dose-dependent QT prolongation. Sorafenib is also associated with QTc prolongation.
    Sotalol: (Major) Avoid coadministration of encorafenib and sotalol due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Sotalol administration is associated with QT prolongation and torsade de pointes (TdP). Proarrhythmic events should be anticipated after initiation of therapy and after each upward dosage adjustment.
    St. John's Wort, Hypericum perforatum: (Major) Avoid coadministration of encorafenib and St. John's Wort due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; St. John's Wort is a strong CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
    Sunitinib: (Major) Avoid coadministration of encorafenib and sunitinib due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Sunitinib can also prolong the QT interval.
    Tacrolimus: (Major) Avoid coadministration of encorafenib and tacrolimus due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Coadministration may also result in increased toxicity or decreased efficacy of tacrolimus. Encorafenib is associated with dose-dependent prolongation of the QT interval. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established. Tacrolimus causes QT prolongation and is a sensitive CYP3A4 substrate.
    Tamoxifen: (Major) Avoid coadministration of encorafenib and tamoxifen due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib has been associated with dose-dependent QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses.
    Telavancin: (Major) Avoid coadministration of encorafenib and telavancin due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Telavancin has been associated with QT prolongation.
    Telithromycin: (Major) Avoid coadministration of encorafenib and telithromycin due to increased encorafenib exposure and QT prolongation. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of telithromycin. Monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. If telithromycin is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of telithromycin. Encorafenib is a CYP3A4 substrate that has been associated with dose-dependent QT prolongation; telithromycin is a strong CYP3A4 inhibitor that is associated with QT prolongation and torsade de pointes (TdP). Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
    Terbutaline: (Minor) If encorafenib is coadministered with a short-acting beta-agonist, consider monitoring ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Tetrabenazine: (Major) Avoid coadministration of encorafenib and tetrabenazine due to the potential for additive QT prolongation. Encorafenib is associated with dose-dependent prolongation of the QT interval. Tetrabenazine causes a small increase in the corrected QT interval (QTc).
    Tezacaftor; Ivacaftor: (Major) Coadministration of encorafenib with ivacaftor may result in increased toxicity or decreased efficacy of ivacaftor. Ivacaftor is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
    Thioridazine: (Severe) Coadministration of encorafenib with thioridazine is contraindicated due to the potential for QT prolongation. Thioridazine is associated with a well-established risk of QT prolongation and torsade de pointes (TdP).
    Ticagrelor: (Moderate) Coadministration of encorafenib with ticagrelor may result in increased toxicity or decreased efficacy of ticagrelor. Ticagrelor is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
    Tiotropium; Olodaterol: (Moderate) If encorafenib is coadministered with a long-acting beta-agonist, consider monitoring ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib has been associated with dose-dependent QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Tipranavir: (Major) Avoid coadministration of encorafenib and tipranavir/ritonavir due to increased encorafenib exposure. Increased or decreased tipranavir exposure is also possible. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of tipranavir/ritonavir. If tipranavir/ritonavir is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of tipranavir/ritonavir. Encorafenib is a CYP3A4 substrate; in vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. Tipranavir boosted with ritonavir is a strong CYP3A4 inhibitor; tipranavir is a sensitive CYP3A4 substrate. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
    Tolterodine: (Major) Avoid coadministration of encorafenib and tolterodine due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
    Tolvaptan: (Moderate) Coadministration of encorafenib with tolvaptan may result in increased toxicity or decreased efficacy of tolvaptan. Tolvaptan is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
    Toremifene: (Major) Avoid coadministration of encorafenib and toremifene due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Trandolapril; Verapamil: (Major) Avoid coadministration of encorafenib and verapamil due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-half of the dose used prior to the addition of verapamil. If verapamil is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of verapamil. Encorafenib is a CYP3A4 substrate; verapamil is a moderate CYP3A4 inhibitor. Coadministration of a moderate CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 2-fold and 45%, respectively.
    Trazodone: (Major) Avoid coadministration of encorafenib and trazodone due to the potential for additive QT prolongation. Encorafenib is associated with dose-dependent prolongation of the QT interval. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are postmarketing reports of torsade de pointes (TdP).l
    Triazolam: (Moderate) Coadministration of encorafenib with triazolam may result in increased toxicity or decreased efficacy of triazolam. Triazolam is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
    Triclabendazole: (Major) Avoid coadministration of encorafenib and triclabendazole due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib has been associated with dose-dependent QT prolongation. Transient prolongation of the mean QTc interval was noted on the ECG recordings in dogs administered triclabendazole.
    Tricyclic antidepressants: (Major) Avoid coadministration of encorafenib and tricyclic antidepressants due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Tricyclic antidepressants share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Trifluoperazine: (Minor) Consider monitoring ECGs for QT prolongation and electrolytes if encorafenib and trifluoperazine are coadministered due to the potential for additive QT prolongation. Correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Trifluoperazine is associated with a possible risk for QT prolongation.
    Trimipramine: (Major) Avoid coadministration of encorafenib and tricyclic antidepressants due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Tricyclic antidepressants share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Triptorelin: (Major) Avoid coadministration of encorafenib and triptorelin due to the risk of QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib has been associated with dose-dependent QT prolongation. Androgen deprivation therapy (i.e., triptorelin) may also prolong the QT/QTc interval.
    Tucatinib: (Major) Avoid coadministration of encorafenib and tucatinib due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of tucatinib. If tucatinib is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of tucatinib. Encorafenib is a CYP3A4 substrate; tucatinib is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
    Umeclidinium; Vilanterol: (Moderate) If encorafenib is coadministered with a long-acting beta-agonist, consider monitoring ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib has been associated with dose-dependent QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Vandetanib: (Major) Avoid coadministration of vandetanib with encorafenib due to an increased risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes; correct hypocalcemia, hypomagnesemia, and/or hypomagnesemia prior to vandetanib administration. An interruption of vandetanib therapy or dose reduction may be necessary for QT prolongation. Both drugs can prolong the QT interval in a concentration-dependent manner; TdP and sudden death have been reported in patients receiving vandetanib.
    Vardenafil: (Major) Avoid coadministration of encorafenib and vardenafil due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib has been associated with dose-dependent QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil can produce an increase in QTc interval.
    Vemurafenib: (Major) Avoid coadministration of encorafenib and vemurafenib due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. If coadministration necessary, monitor ECG for QT interval prolongation. Encorafenib is associated with dose-dependent prolongation of the QT interval. Vemurafenib has been associated with QT prolongation.
    Venetoclax: (Moderate) Coadministration of encorafenib with venetoclax may result in increased toxicity or decreased efficacy of venetoclax. Venetoclax is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
    Venlafaxine: (Major) Avoid coadministration of encorafenib and venlafaxine due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use.
    Verapamil: (Major) Avoid coadministration of encorafenib and verapamil due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-half of the dose used prior to the addition of verapamil. If verapamil is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of verapamil. Encorafenib is a CYP3A4 substrate; verapamil is a moderate CYP3A4 inhibitor. Coadministration of a moderate CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 2-fold and 45%, respectively.
    Voriconazole: (Severe) Coadministration of voriconazole with drugs that are associated with QT prolongation and are also CYP3A4 substrates, such as encorafenib, is contraindicated. Voriconazole has been associated with QT prolongation and rare cases of torsade de pointes.
    Vorinostat: (Major) Avoid coadministration of encorafenib and vorinostat due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Vorinostat therapy is associated with a risk of QT prolongation.
    Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with encorafenib is necessary as concurrent use may increase or decrease the exposure of warfarin leading to increased bleeding risk or reduced efficacy. Encorafenib is a weak CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate which can lead to increased warfarin exposure and increased bleeding risk. Encorafenib is also a weak CYP3A4 inducer which can lead to decreased warfarin exposure and reduced efficacy.
    Ziprasidone: (Major) Avoid coadministration of encorafenib and ziprasidone due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors.

    PREGNANCY AND LACTATION

    Pregnancy

    Encorafenib may cause fetal harm when administered to a pregnant woman, based on its mechanism of action. Advise females of reproductive potential to avoid pregnancy while taking encorafenib. Discuss the potential hazard to the fetus if encorafenib is used during pregnancy or if a patient becomes pregnant while taking this drug. Embryo-fetal toxicities including decreased fetal weights and increased rate of skeletal variations were observed in pregnant rats and rabbits who received encorafenib doses that resulted in drug exposures that were about 26-times and 178-times the recommended human exposure, respectively. However, no clear embryo-fetal toxicity was reported at lower doses.

    It is not known if encorafenib or its metabolites are secreted in human milk or if it has effects on the breast-fed infant or on milk production. Due to the risk of serious adverse reactions in nursing infants, women should discontinue breast-feeding during encorafenib therapy and for 2 weeks after the last dose.

    MECHANISM OF ACTION

    Encorafenib is a protein kinase inhibitor that targets BRAF and CRAF kinases. BRAF mutated genes activate BRAF kinases resulting in stimulation of tumor cell growth. In vitro, encorafenib inhibits tumor cells expressing BRAF V600E, V600K, and V600D mutations; it also reduces ligand binding for JNK1, JNK2, JNK3, LIMK1, LIMK2, MEK4, and STK36 kinases at concentrations achieved with typical encorafenib dosing. In animal studies in mice implanted with BRAF V600E-expressing tumors, encorafenib induced tumor regressions by suppressing the RAF/MEK/ERK pathway. Combination therapy with encorafenib and binimetinib, a MEK inhibitor, led to greater anti-tumor activity and delayed resistance in BRAF V600-mutant human melanoma xenografts in mice compared with either drug alone. Coadministration of encorafenib and cetuximab, an EGFR inhibitor, in patients with BRAF V600E-mutated colorectal cancer was able to overcome induction of EGFR-mediated MAPK pathway activation in nonclinical models, which has been identified as a mechanism of resistance to BRAF inhibitors. Concomitant use of these drugs had an anti-tumor effect greater than either drug alone in a mouse model of colorectal cancer with mutated BRAF V600E.

    PHARMACOKINETICS

    Encorafenib is administered orally. It is 86% bound to plasma proteins (in vitro) and has an apparent volume of distribution of 164 L (coefficient of variation (CV), 70%). Encorafenib is metabolized by CYP3A4 (83%), CYP2C19 (16%), and CYP2D6 (1%) isoenzymes. The mean terminal half-life is 3.5 hours (CV, 17%). The apparent clearance is 14 L/hour (CV, 54%) on day 1 and 32 L/hour (59%) at steady-state. Following a radioactive encorafenib 100-mg dose, 45% of the dose was recovered in the feces and 47% of the total reactivity was recovered in the urine; unchanged drug excretion was 5% and 2%, respectively.
     
    Affected cytochrome P450 isoenzymes and transporters: CYP3A4
    Encorafenib is primarily metabolized by CYP3A4 (83%) and to a lesser extent by CYP2C19 (16%) and CYP2D6 (1%). Avoid concomitant use with strong or moderate CYP3A4 inhibitors or inducers. If coadministration with strong or moderate CYP3A4 inhibitors is necessary, reduce the encorafenib dose as recommended. Concomitant use with sensitive CYP3A4 substrates may result in increased toxicity or decreased efficacy of these drugs. In vitro, encorafenib inhibits UGT1A1, CYP1A2, CYP2B6, CYP2C8/9, CYP2D6, CYP3A, P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic cation transporter (OCT)-2, organic anion transporter (OAT)-1, OAT3, OATP1B1, and OATP1B3; induces CYP2B6, CYP2C9, and CYP3A4; and is a substrate of P-gp.

    Oral Route

    Following oral administration, 86% or more of the dose is absorbed and the median time to peak plasma concentration (Tmax) is 2 hours. Encorafenib exhibits dose proportional exposure over a dosage range of 50 mg to 700 mg following a single dose; exposure was less than proportional over the dose range of 50 mg to 800 mg following once daily dosing. Steady-state is achieved within 15 days; exposure is 50% lower at steady-state compared with day 1 dosing. The AUC intersubject variability (CV%) ranged from 12% to 69%.
    Effects of Food: Administering encorafenib 100 mg orally with a high-fat (500 calories from fat), high-calorie (150 calories from protein; 350 calories from carbohydrates) meal decreased the Cmax by 36% but had no effect on the AUC when compared to the fasted state. Encorafenib may be taken with or without food.