Encorafenib is a kinase inhibitor that inhibits cell growth in BRAF V600 mutation-positive tumors. Using an FDA-approved test, confirm the presence of the BRAF V600 mutation in tumor or plasma specimens prior to initiation of treatment. Encorafenib is indicated in combination with binimetinib for the treatment of BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma, BRAF V600E-mutated metastatic NSCLC, and in combination with cetuximab for the treatement of BRAF V600 mutated metastatic colorectal cancer. It is not indicated for the treatment of BRAF wild-type melanoma or colorectal cancer. New primary cutaneous malignancies and QT prolongation have been reported with encorafenib use.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Emetic Risk
-Minimal/Low
-Administer prn antiemetics as necessary.
Route-Specific 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.
New primary malignancy has occurred in patients who received combination therapy with encorafenib and either binimetinib or cetuximab in clinical trials. Squamous cell carcinoma (cuSCC) including keratoacanthoma (KA) (2.6%) and basal cell carcinoma (BCC) (1.6%) were reported in patients with advanced melanoma who received combination therapy with encorafenib and binimetinib (n = 192) in a randomized trial. The median time to first cuSCC/KA occurrence was 5.8 months (range, 1 to 9 months). Additionally, cuSCC/KA (8%), BCC (1%), and new primary melanoma (5%) occurred with single-agent encorafenib in this trial. CuSCC and skin papilloma each occurred in 2% of patients with metastatic lung cancer who received this combination in an open-label, single arm clinical trial. In a clinical trial of patients with metastatic colorectal cancer, cuSCC/KA occurred in 1.4% of patients who received encorafenib in combination with cetuximab; and a new primary melanoma also occurred in 1.4% of patients receiving encorafenib with cetuximab. Perform regular dermatologic evaluations and monitor patients for signs and symptoms of cutaneous and non-cutaneous malignancies. 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 non-cutaneous malignancy.
Bleeding was reported in 12% to 19% of patients who received encorafenib plus binimetinib in 2 clinical trials (grade 3 or 4, 3.2% to 4.1%); bleeding was a combined term that included anal hemorrhage, hemothorax, GI bleeding, hematochezia, hematuria, hemoptysis, intracranial bleeding, hyphema, and vaginal bleeding. GI bleeding (e.g., rectal bleeding (4.2% or less), hematochezia (3.1% or less), anal hemorrhage (2% or less), and hemorrhoid bleeding (1% or less)) and hemothorax (2% or less) were the most frequently reported bleeding events in patients who received encorafenib with binimetinib; fatal intracranial bleeding occurred in 1% to 1.6% of these patients. The incidence of hemorrhage was similar in patients treated with encorafenib plus cetuximab in another randomized clinical trial (19%; grade 3 or higher, 1.9%); the most frequent bleeding events in this trial were epistaxis (6.9%), hematochezia (2.3%), and rectal bleeding (2.3%). Prolonged bleeding time (increased aPTT) was also reported in these patients (13%; grade 3 or higher, 1%). Therapy interruption, a dose reduction, or permanent discontinuation of therapy may be necessary for patients who develop bleeding.
Uveitis including iritis and iridocyclitis occurred in 1% to 4% of patients who received encorafenib plus binimetinib in 2 clinical trials. Visual impairment including blurred vision, vitreous floaters, photophobia, reduced visual acuity, and photopsia was also reported in 29% of patients treated with encorafenib and binimetinib in an open-label, single-arm trial. Monitor patients for signs and symptoms of visual impairment at each clinic visit. Perform an ophthalmologic evaluation regularly and in patients who experience new, worsening, or persistent visual disturbances. Therapy interruption, a dose reduction, or permanent discontinuation of therapy may be necessary in patients who develop persistent or severe ocular toxicity.
Encorafenib is associated with dose-dependent QT prolongation in some patients. QT prolongation (defined as a QTcF increase to greater than 500 milliseconds) was reported in 0.5% to 2.1% of patients who received encorafenib plus binimetinib in 2 clinical trials. Serious cases of arrhythmia exacerbation and myocardial infarction were each reported in 2% of patients treated with encorafenib and binimetinib in an open-label, single-arm trial.
Hyperkeratosis (23% or less; grade 3, 1% or less), rash (22% to 27%; grade 4, 1% to 3.1%), xerosis/dry skin (13% to 16%), pruritus (13% to 16%; grade 4, 1% or less), and hypersensitivity (less than 10%) were reported in patients who received encorafenib plus binimetinib in 2 clinical trials; in 1 trial, rash was a composite term that includes maculopapular rash, pustular rash, acneiform rash, palmar-plantar erythrodysesthesia syndrome (hand and foot syndrome), eczema, and exfoliative dermatitis. Panniculitis was reported in less than 10% of patients in 1 of these trials, and erythema in less than 10% of patients in the other trial. Palmar-plantar erythrodysesthesia (hand and foot syndrome) (51% vs. 7%), hyperkeratosis (57% vs. 23%), xerosis (38% vs. 16%), erythema (16% vs. 7%), rash (41% vs. 22%), alopecia (56% vs. 14%), pruritus (31% vs. 13%), and acneiform rash/dermatitis (8% vs. 3%) occurred at a higher rate in patients who received single-agent encorafenib compared with encorafenib plus binimetinib in this trial. Similar dermatologic adverse reactions were observed in patients with metastatic colorectal cancer treated with encorafenib plus cetuximab, including acneiform dermatitis (32%; grade 3 or 4, 1%), rash (26%), pruritus (14%), melanocytic nevus (14%), and dry skin (13%). Therapy interruption, a dose reduction, or permanent discontinuation of therapy may be necessary for patients who develop skin toxicity.
Anemia (34% to 47%; grade 3 or 4, 3.6% to 11%) and lymphopenia (13% to 24%; grade 3 or 4, 2.1% to 7%) occurred in patients treated with encorafenib in combination with either binimetinib or cetuximab in 3 clinical trials. Leukopenia (12% to 13%), neutropenia (12% to 13%; grade 3 or 4, 1.1% to 3.1%), and thrombocytopenia (20% or less; grade 3 or 4, 1.1%) were also reported patients who received encorafenib plus binimetinib in 2 clinical trials.
Fatigue was reported in 43% to 61% (grade 3 or 4, 3% to 8%) of patients who received encorafenib plus either binimetinib or cetuximab in 3 clinical trials; fatigue was a composite term that included asthenia in 1 of these trials.
Fever was reported in 17% to 22% of patients who received encorafenib plus either cetuximab or binimetinib in 2 clinical trials (grade 3, 4% or less). Serious cases of infection including pneumonia (3.1%) and device-related infections (2%) were reported with encorafenib plus binimetinib therapy in an open-label, single-arm clinical trial.
Nausea (41% to 58%; grade 3, 2% to 3.1%) and vomiting (30% to 37%; grade 3, 1% to 2%) were reported in patients who received encorafenib plus binimetinib in 2 clinical trials. The incidence was slightly lower in patients with metastatic colorectal cancer treated with encorafenib and cetuximab in a separate clinical trial, with nausea reported in 34% (grade 3 or 4, 1%) and vomiting in 21% (grade 3 or 4, 1%) of patients.
Arthralgia (26% to 27%; grade 3 or 4, 1%) and extremity pain (10% to 11%; grade 3, 1% or less) were reported in patients treated with encorafenib plus either binimetinib or cetuximab in 2 randomized clinical trials; arthralgia (44% vs. 26%) and back pain (15% vs. 9%) occurred at a higher rate in patients who received single-agent encorafenib compared with encorafenib plus binimetinib in 1 of these trials. Musculoskeletal pain, which was a composite term including back pain, arthralgia, extremity pain, myalgia, noncardiac chest pain, and neck pain, occurred in 48% (grade 3 or 4, 4.1%) of metastatic NSCLC patients treated with encorafenib plus binimetinib in an open-label, single-arm trial.
Headache was reported in 11% to 22% (grade 3, 2% or less) of patients who received encorafenib plus either binimetinib or cetuximab in 3 clinical trials. Dizziness occurred in 15% to 17% (grade 3, 1% to 3%) of patients treated with encorafenib plus binimetinib in 2 clinical trials.
Pancreatitis was reported in less than 10% of patients who received encorafenib plus either binimetinib or cetuximab 3 clinical trials. Hyperamylasemia (22%; grade 3 or 4, 1.1%) and increased serum lipase (40%; grade 3 or 4, 14%) were also reported in patients treated with encorafenib plus binimetinib in an open-label, single-arm trial.
Hepatotoxicity can occur when encorafenib is administered in combination with binimetinib. Monitor liver function tests at baseline, monthly during treatment, and as clinically indicated. An interruption of therapy, dose reduction, or permanent discontinuation of therapy may be necessary based on the severity of adverse reaction. Elevated hepatic enzymes including increased ALT (29% to 34%; grade 3 or 4, 6% to 9%), AST (27% to 31%; grade 3 or 4, 2.6% to 10%), alkaline phosphatase (21% to 31%; grade 3 or 4, 0.5% to 3.2%), and gamma glutamyl transferase (45% or less; grade 3 or 4, 11% or less) were reported in patients with advanced melanoma or NSCLC who received encorafenib and binimetinib in 2 clinical trials. Increased alkaline phosphatase (18%; grade 3 or 4, 4%), increased ALT (17%), and increased AST (15%) were slightly less common in patients with metastatic colorectal cancer treated with encorafenib plus cetuximab.
Nephrotoxicity, specifically increased serum creatinine level, was reported in 91% to 93% of patients who received encorafenib plus binimetinib in 2 clinical trials; grade 3 or 4 increased serum creatinine level occurred in 3.2% to 3.6% of patients.
Hyperglycemia was reported in 28% to 48% of patients who received encorafenib plus binimetinib in 2 clinical trials; grade 3 or 4 hyperglycemia occurred in 5% to 6% of patients.
Electrolyte abnormalities have been reported in patients treated with encorafenib. Hyponatremia occurred in 18% to 26% (grade 3 or 4, 3.6% to 11%) of patients who received encorafenib in combination with either binimetinib or cetuximab in 3 clinical trials. Hyperkalemia (31% or less; grade 3 or 4, 2.1% or less) and hypocalcemia (12%; grade 3 or 4, 2.1%) were reported in patients treated with encorafenib plus binimetinib in an open-label, single-agent trial while hypermagnesemia (10%; grade 3 or 4, 1%) occurred in patients receiving this combination in a separate randomized clinical trial. In another clinical trial, hypomagnesemia (19%), hypokalemia (12%; grade 3 or 4, 3%), occurred in patients with metastatic colorectal cancer treated with encorafenib plus cetuximab.
Abdominal pain (28% to 33%; grade 3, 4% or less) and constipation (15% to 27%) were reported in patients who received encorafenib plus either binimetinib or cetuximab in 3 clinical trials. Diarrhea was also reported in 52% (grade 3 or 4, 7%) of metastatic NSCLC patients treated with encorafenib plus binimetinib in an open-label, single-arm trial (including colitis), and in 33% (grade 3 or higher, 2%) of colorectal cancer patients who received encorafenib plus cetuximab in a randomized clinical trial.
Dysgeusia occurred at a higher rate in patients who received single-agent encorafenib (13%) compared with encorafenib plus binimetinib (6%) in patients with advanced melanoma in a randomized trial; it was also reported in fewer than 10% of metastatic NSCLC patients who received encorafenib plus binimetinib in an open-label, single-arm clinical trial. Decreased appetite/anorexia was reported in 14% to 27% (grade 3 or higher, 1%) of patients treated with encorafenib plus cetuximab in 2 clinical trials.
Myopathy was reported in 15% to 33% (grade 3 or 4, 1% or less) of patients who received encorafenib plus either binimetinib or cetuximab in 2 randomized trials; the incidence was higher in patients who received single-agent encorafenib (33%) compared with encorafenib plus binimetinib (15%) in 1 of those trials. Increased creatine kinase was reported in 41% (grade 3 or 4, 3.3%) of patients treated with encorafenib plus binimetinib in an open-label, single-arm trial.
Alopecia was reported in 12% to 14% of patients who received encorafenib plus binimetinib in 2 clinical trials, and occurred at a higher rate in patients who received single-agent encorafenib (56%) compared with those who received encorafenib plus binimetinib.
Peripheral neuropathy occurred in 12% or fewer patients treated with encorafenib in combination with either binimetinib or cetuximab in 3 clinical trials (grade 3 or 4, 1% or less). Facial paresis in less than 10% of patients who received encorafenib and binimetinib in 2 clinical trials.
Insomnia occurred in 10% to 13% of patients treated with encorafenib plus either binimetinib or cetuximab in 2 clinical trials.
Cardiomyopathy occurred in 7% to 11% of patients with metastatic NSCLC treated with encorafenib plus binimetinib in an open-label, single-arm clinical trial (grade 3, 1% to 1.6%), including left ventricular dysfunction, decreased ejection fraction below the institutional lower limit of normal (LLN) with an absolute decrease of 10% or more from baseline, and heart failure. The median time to onset of any grade of left ventricular dysfunction was 3.6 months (range, 0 to 21 months); resolution occurred in 82% to 87% of patients. Use encorafenib with caution in patients with a history of heart failure; the safety of encorafenib treatment in combination with binimetinib has not been established in patients with a baseline ejection fraction that is either below 50% or below the institutional lower limit of normal (LLN). Assess the ejection fraction by echocardiogram or MUGA scan at baseline, 1 month after initiating treatment, and every 2 to 3 months during treatment. Monitor the QT interval in patients with severe or uncontrolled heart failure. An interruption of therapy, dose reduction, or permanent discontinuation of therapy may be necessary based on the severity of the adverse reaction.
Edema occurred in 23% of patients treated with encorafenib plus binimetinib in an open-label, single-arm trial (grade 3 or 4, 1%), including peripheral edema, generalized edema, localized edema, and facial edema.
Hypertension occurred in 10% of patients treated with encorafenib plus binimetinib in an open-label, single-arm clinical trial (grade 3 or 4, 5%).
Weight gain occurred in 11% of patients treated with encorafenib plus binimetinib in an open-label, single-arm clinical trial (grade 3 or 4, 1%).
Pleural effusion occurred in 2% of patients treated with encorafenib plus binimetinib in an open-label, single-arm clinical trial.
Dyspnea (27%; grade 3 or 4, 8%) and cough (26%) were reported in patients treated with encorafenib plus binimetinib in an open-label, single-arm clinical trial.
Hypoalbuminemia occurred in 32% of patients treated with encorafenib plus binimetinib in an open-label, single-arm clinical trial.
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 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.
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.
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.
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.
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.
Use encorafenib with caution in patients with a history of heart failure; the safety of encorafenib treatment in combination with binimetinib has not been established in patients with a baseline ejection fraction that is either below 50% or below the institutional lower limit of normal (LLN). Additionally, dose-dependent QT prolongation has been reported in patients who received combination therapy with encorafenib and binimetinib. Closely monitor patients with cardiovascular risk factors. Cardiomyopathy (e.g., left ventricular dysfunction associated with symptomatic or asymptomatic decreases in ejection fraction) has been reported in patients treated with encorafenib in combination with binimetinib. Assess the ejection fraction by echocardiogram or MUGA scan at baseline, 1 month after initiating treatment, and every 2 to 3 months during treatment. Monitor the QT interval in patients with severe or uncontrolled heart failure. An interruption of therapy, dose reduction, or permanent discontinuation of therapy may be necessary based on the severity of the adverse reaction.
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.
Hepatotoxicity can occur when encorafenib is administered in combination with binimetinib; use this combination with caution in patients with a history of hepatic disease. Monitor liver function tests at baseline, monthly during treatment, and as clinically indicated. An interruption of therapy, dose reduction, or permanent discontinuation of therapy may be necessary based on the severity of adverse reaction.
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.
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 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. At a median follow-up time of 40.8 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, 0.4 to 0.67) 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 COLUMBUS 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 = 0.64; 95% CI, 0.5 to 0.81) at a median follow-up time of 70.4 months. At the time of analysis, the median PFS (14.9 months vs. 9.6 months; HR = 0.79; 95% CI, 0.61 to 1.02) and OS (33.6 months vs. 23.5 months; HR = 0.93; 95% CI, 0.72 to 1.19) times were not significantly longer in the combination therapy arm compared with single-agent encorafenib. The 5-year PFS rates were 23%, 10%, and 19% in the encorafenib plus binimetinib, single-agent vemurafenib, and single-agent encorafenib arms, respectively; the 5-year OS rates were 35%, 21%, and 35%, respectively. 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.
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 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 (9.3 months vs. 5.9 months), overall response rate (20% vs. 2%; complete response, 3% vs. 0%), and progression-free survival (4.3 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, phase 3 trial (BEACON); the median duration of response was 5.5 months in the encorafenib arm.
For the treatment of non-small cell lung cancer (NSCLC):
NOTE: Encorafenib is designated by the FDA as an orphan drug for the treatment of BRAF-mutant non-small cell lung cancer (NSCLC).
-for the treatment of metastatic non-small cell lung cancer (NSCLC) in patients with a BRAF V600E mutation, in combination with binimetinib:
NOTE: Confirm the presence of a BRAF V600E mutation in plasma specimens prior to starting therapy; if no BRAF V600E mutation is present in a plasma specimen, test tumor tissue. Information on FDA-approved tests for the detection of BRAF V600 mutations is available at www.fda.gov/CompanionDiagnostics.
NOTE: Encorafenib is not indicated in patients with wild-type BRAF NSCLC.
Oral dosage:
Adults: 450 mg PO once daily in combination with binimetinib (45 mg PO twice daily) until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Treatment with binimetinib plus encorafenib resulted in an objective response rate (ORR) of 75% (complete response [CR], 15%) for a median duration that was not estimable in treatment-naive patients with BRAF V600E metastatic NSCLC (n = 59) in a multicenter, open-label, noncomparative phase 2 trial (PHAROS); the ORR was 46% (CR, 10%) for a median duration of 16.7 months in patients with previously treated disease (n = 39). Prior use of BRAF inhibitors or MEK inhibitors was not allowed. Seventy-five percent (75%) of patients with treatment-naive disease and 67% of patients with previously treated disease had a duration of response of at least 6 months. The duration of response was 12 months or longer in 59% and 33% of patients, respectively.
Therapeutic Drug Monitoring:
Dosage Adjustments for Treatment-Related Toxicities:
Recommended dose reductions for patients with Melanoma or Non-Small Cell Lung Cancer:
NOTE: If binimetinib is withheld, reduce the encorafenib dose to 300 mg PO once daily until therapy with binimetinib is resumed.
-First dose reduction: 300 mg PO once daily.
-Second dose reduction: 225 mg PO once daily; permanently discontinue therapy in patients unable to tolerate 225 mg PO once daily.
Recommended dose reductions for patients with Colorectal Cancer:
NOTE: If cetuximab is discontinued, also discontinue encorafenib.
-First dose reduction: 225 mg PO once daily.
-Second dose reduction: 150 mg PO once daily; permanently discontinue therapy in patients unable to tolerate 150 mg PO once daily.
Cardiomyopathy
-Symptomatic congestive heart failure or absolute decrease in left ventricular ejection fraction (LVEF) of greater than 20% from baseline that is also below the lower limit of normal (LLN): Reduce the dose of encorafenib by 1 dose level. If the LVEF improves to at least the institutional LLN and the absolute decrease from baseline is less than or equal to 10%, continue encorafenib therapy at the reduced dose. If there is no improvement on the reduced dose, hold encorafenib therapy. When the LVEF improves to at least the institutional LLN and the absolute decrease from baseline is less than or equal to 10%, resume encorafenib therapy at the reduced dose or reduce the dose by 1 additional dose level.
Malignancy
-New Primary Cutaneous Malignancy: Dose adjustment not required.
-New Primary RAS-positive Non-Cutaneous Malignancy: Permanently discontinue encorafenib.
Ocular Toxicity (including iritis and iridocyclitis)
-Grade 1 or 2 uveitis that does not respond to specific ocular therapy or grade 3 uveitis: Hold encorafenib for up to 6 weeks; resume encorafenib at the same dose or at a reduced dose when symptoms improve. Permanently discontinue encorafenib if toxicity does not improve after 6 weeks.
-Grade 4 uveitis: Permanently discontinue encorafenib.
QT Prolongation
-QTcF greater than 500 milliseconds (msec) and 60 msec or less increase from baseline: Hold encorafenib therapy. When the QTcF interval is 500 msec or less, resume encorafenib at a reduced dose. If toxicity recurs, permanently discontinue encorafenib.
-QTcF greater than 500 msec and more than 60 msec increase from baseline: Permanently discontinue encorafenib.
Skin Toxicity (excluding palmar-plantar erythrodysesthesia (hand and foot syndrome))
-Grade 2 with no improvement within 2 weeks: Hold encorafenib. When the toxicity improves to grade 1 or less, resume encorafenib therapy at the same dose.
-Grade 3: Hold encorafenib. When the toxicity improves to grade 1 or less, resume encorafenib therapy at the same dose for the first occurrence and at a reduced dose for recurrent toxicity.
-Grade 4: Permanently discontinue encorafenib.
Other Adverse Reactions (including bleeding and hand and foot syndrome)
-Recurrent grade 2 or first occurrence of grade 3: 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: Consider permanently discontinuing encorafenib.
-Grade 4: Consider permanently discontinuing encorafenib; alternatively, 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.
Maximum Dosage Limits:
-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.
Patients with Hepatic Impairment Dosing
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.
Patients with Renal Impairment Dosing
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.
*non-FDA-approved indication
Abacavir; Dolutegravir; Lamivudine: (Moderate) Monitor for increased toxicity or decreased efficacy of dolutegravir if coadministered with encorafenib. Concurrent use may increase or decrease the plasma concentrations of dolutegravir. Dolutegravir is a CYP3A and BCRP substrate and encorafenib is a strong CYP3A inducer and BCRP inhibitor. The net effect on dolutegravir exposure is unknown.
Abemaciclib: (Major) Avoid coadministration of encorafenib with abemaciclib due to decreased exposure to abemaciclib and its active metabolites, which may lead to reduced efficacy. Abemaciclib is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by approximately 70% in healthy subjects.
Abiraterone: (Major) Avoid the concomitant use of abiraterone and encorafenib due to the risk of decreased abiraterone efficacy. If concomitant use is unavoidable, increase the abiraterone dosing frequency to twice daily. Resume the previous dose and frequency when encorafenib is discontinued. Abiraterone is a CYP3A4 substrate and encorafenib is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased abiraterone exposure by 55%.
Acalabrutinib: (Major) Avoid the concomitant use of acalabrutinib and encorafenib. If coadministration cannot be avoided, increase the acalabrutinib dose to 200 mg PO twice daily. Decreased acalabrutinib exposure occurred in a drug interaction study. Acalabrutinib is a CYP3A substrate; encorafenib is a strong CYP3A inducer. In healthy subjects, the AUC of acalabrutinib was decreased by 77% when acalabrutinib was coadministered with another strong inducer.
Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal if coadministration with encorafenib is necessary; consider increasing the dose of dihydrocodeine as needed. If encorafenib is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs of respiratory depression and sedation. Encorafenib is a strong inducer of CYP3A, an isoenzyme partially responsible for the metabolism of dihydrocodeine. Concomitant use of dihydrocodeine with encorafenib can decrease dihydrocodeine levels, resulting in less metabolism by CYP2D6 and decreased dihydromorphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with encorafenib can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If encorafenib is discontinued, consider a dose reduction of codeine and frequently monitor for signs of respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Encorafenib is a strong CYP3A inducer.
Acetaminophen; Hydrocodone: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with encorafenib is necessary; consider increasing the dose of hydrocodone as needed. It is recommended to avoid this combination when hydrocodone is being used for cough. If encorafenib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Concomitant use with CYP3A inducers can decrease hydrocodone concentration; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Acetaminophen; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with encorafenib is necessary; consider increasing the dose of oxycodone as needed. If encorafenib is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Concomitant use with CYP3A inducers can decrease oxycodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Adagrasib: (Major) Avoid coadministration of encorafenib and adagrasib due to the risk of decreased adagrasib exposure, increased encorafenib exposure, and increased risk of QT/QTc prolongation and torsade de pointes (TdP). If concomitant use is necessary, an encorafenib dosage reduction is required: reduce a daily dose of 450 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Adagrasib is a CYP3A substrate and strong CYP3A inhibitor, encorafenib is a CYP3A substrate and strong CYP3A inducer, and both medications may prolong the QT interval. Concomitant use with another strong CYP3A inducer reduced adagrasib exposure by more than 66%. Concomitant use with another strong CYP3A inhibitor increased encorafenib overall exposure by 3-fold.
Alfentanil: (Moderate) Consider an increased dose of alfentanil and monitor for evidence of opioid withdrawal if coadministration with encorafenib is necessary. If encorafenib is discontinued, consider reducing the alfentanil dosage and monitor for evidence of respiratory depression. Coadministration of a strong CYP3A inducer like encorafenib with alfentanil, a CYP3A substrate, may decrease exposure to alfentanil resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to alfentanil. Alfentanil plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
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.
Alpelisib: (Major) Avoid coadministration of alpelisib with encorafenib due to altered exposure to alpelisib, which may decrease its efficacy and/or increase the risk of alpelisib-related toxicity. Alpelisib is a CYP3A and BCRP substrate and encorafenib is a strong CYP3A inducer and BCRP inhibitor. The net effect on alpelisib exposure is unknown.
Alprazolam: (Moderate) Monitor for reduced efficacy of alprazolam and signs of benzodiazepine withdrawal if coadministration with encorafenib is necessary. Concomitant use can decrease alprazolam concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Alprazolam is a CYP3A substrate and encorafenib is a strong CYP3A inducer.
Amiodarone: (Major) Concomitant use of amiodarone and encorafenib may decrease amiodarone exposure and efficacy and increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Amiodarone is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Amisulpride: (Major) Avoid coadministration of encorafenib and amisulpride 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. Amisulpride causes dose- and concentration- dependent QT prolongation.
Amlodipine: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with encorafenib is necessary. Amlodipine is a CYP3A substrate and encorafenib is a strong CYP3A inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Amlodipine; Atorvastatin: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with encorafenib is necessary. Amlodipine is a CYP3A substrate and encorafenib is a strong CYP3A inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine. (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with encorafenib is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a substrate of OATP1B1/3 and BCRP; encorafenib is an OATP1B1/3 and BCRP inhibitor.
Amlodipine; Benazepril: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with encorafenib is necessary. Amlodipine is a CYP3A substrate and encorafenib is a strong CYP3A inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Amlodipine; Celecoxib: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with encorafenib is necessary. Amlodipine is a CYP3A substrate and encorafenib is a strong CYP3A inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Amlodipine; Olmesartan: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with encorafenib is necessary. Amlodipine is a CYP3A substrate and encorafenib is a strong CYP3A inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Amlodipine; Valsartan: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with encorafenib is necessary. Amlodipine is a CYP3A substrate and encorafenib is a strong CYP3A inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with encorafenib is necessary. Amlodipine is a CYP3A substrate and encorafenib is a strong CYP3A inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Amobarbital: (Major) Avoid concomitant use of encorafenib and barbiturates. Concurrent use may decrease encorafenib exposure which may reduce its efficacy. Encorafenib is a CYP3A substrate and barbiturates are strong CYP3A inducers.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid concomitant use of encorafenib and clarithromycin due to the risk for decreased clarithromycin exposure, increased encorafenib exposure, and increased risk of QT/QTc prolongation and torsade de pointes (TdP). If concomitant use is necessary, an encorafenib dosage reduction is required: reduce a daily dose of 450 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Clarithromycin is a CYP3A substrate and strong CYP3A inhibitor, encorafenib is a CYP3A substrate and strong CYP3A inducer, and both medications may prolong the QT interval. Concomitant use with another strong CYP3A inhibitor increased encorafenib overall exposure by 3-fold. There have been spontaneous or published reports of CYP3A-based interactions of clarithromycin with another CYP3A inducer. (Major) Avoid concomitant use of omeprazole and encorafenib as omeprazole exposure may be decreased, reducing its efficacy. Omeprazole is a CYP3A substrate and encorafenib is a strong CYP3A inducer.
Anagrelide: (Major) Concomitant use of encorafenib and anagrelide increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Apalutamide: (Major) Avoid concomitant use of encorafenib and apalutamide. Concurrent use may decrease encorafenib exposure which may reduce its efficacy. Encorafenib is a CYP3A substrate and apalutamide is a strong CYP3A inducer.
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.
Apremilast: (Major) Coadministration of apremilast with encorafenib is not recommended due to decreased plasma concentrations of apremilast. Apremilast is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased the single-dose apremilast AUC and Cmax by 72% and 43%, respectively.
Aprepitant, Fosaprepitant: (Major) Avoid concomitant use of encorafenib and aprepitant/fosaprepitant due to the risk for increased encorafenib exposure, which may increase the risk for adverse effects, and substantially decreased exposure of aprepitant, which may reduce its efficacy. If concomitant use is necessary, an encorafenib dosage reduction is required: reduce a daily dose of 450 mg to 225 mg, reduce a daily dose of 300 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Encorafenib is a CYP3A substrate and strong CYP3A inducer and aprepitant/fosaprepitant is a CYP3A substrate and moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased encorafenib overall exposure by 2-fold. Coadministration with another strong CYP3A inducer decreased the AUC of aprepitant by approximately 11-fold and decreased the mean terminal half-life by 3-fold.
Aripiprazole: (Major) Recommendations for managing aripiprazole and encorafenib vary by aripiprazole dosage form. For aripiprazole oral dosage forms, double the usual dose over 1 to 2 weeks. For extended-release aripiprazole injections administered monthly (Abilify Maintena) and every 2 months (Abilify Asimtufii), avoid concomitant use. Concomitant use may decrease aripiprazole exposure and reduce efficacy. Aripiprazole is CYP3A substrate; and encorafenib is a strong CYP3A inducer. (Major) Recommendations for managing aripiprazole and encorafenib vary by aripiprazole dosage form. For extended-release aripiprazole lauroxil injections (Aristada), increase the 441 mg dose to 662 mg; no adjustments are necessary for other dosages. For fixed dose extended-release aripiprazole lauroxil injections (Aristada Initio), avoid concomitant use because the dose cannot be modified. Concomitant use may decrease aripiprazole exposure and reduce efficacy. Aripiprazole is CYP3A substrate and encorafenib is a strong CYP3A inducer.
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: (Contraindicated) Concomitant use of encorafenib and artemether is contraindicated due to the risk of decreased artemether concentrations and possible reduction in antimalarial activity. Concomitant use also increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Artemether is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications may prolong the QT interval. Coadministration of another strong CYP3A inducer reduced the overall exposure of artemether and dihydroartemisinin (an active metabolite of artemether) by 89% and 85%, respectively. (Contraindicated) Concurrent use of lumefantrine with encorafenib is contraindicated due to decreased lumefantrine exposure which may impair efficacy. Concomitant use also increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Lumefantrine is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation. Coadministration of another strong CYP3A inducer reduced the overall exposure lumefantrine by 68%.
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 concomitant use of encorafenib and barbiturates. Concurrent use may decrease encorafenib exposure which may reduce its efficacy. Encorafenib is a CYP3A substrate and barbiturates are strong CYP3A inducers.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with encorafenib can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If encorafenib is discontinued, consider a dose reduction of codeine and frequently monitor for signs of respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Encorafenib is a strong CYP3A inducer.
Aspirin, ASA; Omeprazole: (Major) Avoid concomitant use of omeprazole and encorafenib as omeprazole exposure may be decreased, reducing its efficacy. Omeprazole is a CYP3A substrate and encorafenib is a strong CYP3A inducer.
Aspirin, ASA; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with encorafenib is necessary; consider increasing the dose of oxycodone as needed. If encorafenib is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Concomitant use with CYP3A inducers can decrease oxycodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Atazanavir: (Contraindicated) Concurrent use of atazanavir and encorafenib is contraindicated due to the risk of decreased atazanavir exposure which may increase the risk for virologic failure and drug resistance. Concomitant use may also increase encorafenib exposure which may increase the risk for adverse effects. If concomitant use is necessary, an encorafenib dosage reduction is required: reduce a daily dose of 450 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Atazanavir is a CYP3A substrate and strong CYP3A inhibitor and encorafenib is a CYP3A substrate and strong CYP3A inducer. Concomitant use with another strong CYP3A inhibitor increased encorafenib overall exposure by 3-fold.
Atazanavir; Cobicistat: (Contraindicated) Concurrent use of atazanavir and encorafenib is contraindicated due to the risk of decreased atazanavir exposure which may increase the risk for virologic failure and drug resistance. Concomitant use may also increase encorafenib exposure which may increase the risk for adverse effects. If concomitant use is necessary, an encorafenib dosage reduction is required: reduce a daily dose of 450 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Atazanavir is a CYP3A substrate and strong CYP3A inhibitor and encorafenib is a CYP3A substrate and strong CYP3A inducer. Concomitant use with another strong CYP3A inhibitor increased encorafenib overall exposure by 3-fold. (Major) Avoid coadministration of cobicistat and encorafenib due to the risk of decreased cobicistat exposure which may increase the risk for virologic failure and drug resistance and increased encorafenib exposure which may increase the risk for adverse effects. If concomitant use is necessary, an encorafenib dosage reduction is required: reduce a daily dose of 450 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Cobicistat is a CYP3A substrate and strong CYP3A inhibitor and encorafenib is a CYP3A substrate and strong CYP3A inducer. Concomitant use with another strong CYP3A inhibitor increased encorafenib overall exposure by 3-fold.
Atogepant: (Major) Avoid use of atogepant and encorafenib due to the risk for altered atogepant exposure. Concurrent use may decrease atogepant exposure and reduce efficacy or increase atogepant exposure and the risk of adverse effects. Atogepant is a substrate of CYP3A and OATP1B1/3 and encorafenib is a strong CYP3A inducer and OATP inhibitor. The net effect on atogepant exposure is unknown. Coadministration with a strong CYP3A inducer resulted in a 60% reduction in atogepant overall exposure and a 30% reduction in atogepant peak concentration. Coadministration with an OATP1B1/3 inhibitor resulted in a 2.85-fold increase in atogepant overall exposure and a 2.23-fold increase in atogepant peak concentration.
Atomoxetine: (Major) Concomitant use of encorafenib and atomoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Atorvastatin: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with encorafenib is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a substrate of OATP1B1/3 and BCRP; encorafenib is an OATP1B1/3 and BCRP inhibitor.
Avacopan: (Major) Avoid concomitant use of avacopan and encorafenib due to the risk of decreased avacopan exposure which may reduce its efficacy. Avacopan is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Concomitant use of another strong CYP3A inducer decreased avacopan overall exposure by 93%.
Avanafil: (Major) Coadministration of avanafil with encorafenib is not recommended by the manufacturer of avanafil due to the potential for decreased avanafil efficacy. Avanafil is a CYP3A substrate and encorafenib is a CYP3A inducer. Although the potential effect of CYP inducers on the pharmacokinetics of avanafil has not been evaluated, plasma concentrations may decrease.
Avapritinib: (Major) Avoid coadministration of avapritinib with encorafenib due to the risk of decreased avapritinib efficacy. Avapritinib is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased the overall exposure and peak of avapritinib by 92% and 74%, respectively.
Axitinib: (Major) Avoid coadministration of axitinib with encorafenib due to the risk of decreased efficacy of axitinib. Selection of a concomitant medication with no or minimal CYP3A induction potential is recommended. Axitinib is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
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.
Barbiturates: (Major) Avoid concomitant use of encorafenib and barbiturates. Concurrent use may decrease encorafenib exposure which may reduce its efficacy. Encorafenib is a CYP3A substrate and barbiturates are strong CYP3A inducers.
Bedaquiline: (Major) Avoid concurrent use of encorafenib with bedaquiline due to the risk for decreased bedaquiline exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Bedaquiline is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation. Coadministration with another strong CYP3A inducer decreased bedaquiline exposure by 52%.
Belumosudil: (Major) Increase the dosage of belumosudil to 200 mg PO twice daily when coadministered with encorafenib. Belumosudil is a CYP3A substrate and encorafenib is a strong CYP3A inducer; concomitant use may result in decreased belumosudil exposure and reduced belumosudil efficacy. Coadministration with another strong CYP3A inducer decreased belumosudil exposure by 72% in healthy subjects.
Benzhydrocodone; Acetaminophen: (Moderate) Monitor for reduced efficacy of benzhydrocodone and signs of opioid withdrawal if coadministration with encorafenib is necessary; consider increasing the dose of benzhydrocodone as needed. If encorafenib is discontinued, consider a dose reduction of benzhydrocodone and frequently monitor for signs of respiratory depression and sedation. Benzhydrocodone is a prodrug for hydrocodone. Hydrocodone is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Concomitant use with CYP3A inducers can decrease hydrocodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Berotralstat: (Major) Avoid concomitant use of encorafenib and berotralstat due to the risk for increased encorafenib exposure which may increase the risk for adverse effects. If concomitant use is necessary, an encorafenib dosage reduction is required: reduce a daily dose of 450 mg to 225 mg, reduce a daily dose of 300 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Encorafenib is a CYP3A substrate and berotralstat is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased encorafenib overall exposure by 2-fold.
Bictegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Coadministration of tenofovir alafenamide with encorafenib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp and BCRP substrate and encorafenib is a BCRP inhibitor.
Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Concomitant use of metronidazole and encorafenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Concomitant use of metronidazole and encorafenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Bortezomib: (Major) Coadministration of encorafenib with bortezomib is not recommended as concurrent use may decrease bortezomib exposure which may lead to decreased efficacy. Bortezomib is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with a strong CYP3A inducer is expected to decrease the exposure of bortezomib by at least 45%.
Bosutinib: (Major) Avoid coadministration of bosutinib with encorafenib as concurrent use may decrease bosutinib exposure which may lead to decreased efficacy. Bosutinib is a sensitive CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased bosutinib exposure by 94%.
Brentuximab vedotin: (Moderate) Monitor for decreased efficacy of brentuximab if coadministration with encorafenib is necessary. Monomethyl auristatin E (MMAE) is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased MMAE exposure by approximately 46%.
Brexpiprazole: (Major) Double the usual dose of brexpiprazole over one to two weeks if coadministration with encorafenib is necessary. If encorafenib is discontinued, reduce the brexpiprazole dose to the original level over one to two weeks. Brexpiprazole is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased brexpiprazole exposure by 73%.
Brigatinib: (Major) Avoid coadministration of brigatinib with encorafenib due to decreased plasma exposure to brigatinib which may result in decreased efficacy. Brigatinib is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased the AUC and Cmax of brigatinib by 80% and 60%, respectively.
Brincidofovir: (Moderate) Postpone the administration of encorafenib for at least three hours after brincidofovir administration and increase monitoring for brincidofovir-related adverse reactions (i.e., elevated hepatic enzymes and bilirubin, diarrhea, other gastrointestinal adverse events) if concomitant use of brincidofovir and encorafenib is necessary. Brincidofovir is an OATP1B1/3 substrate and encorafenib is an OATP1B1/3 inhibitor. In a drug interaction study, the mean AUC and Cmax of brincidofovir increased by 374% and 269%, respectively, when administered with another OATP1B1/3 inhibitor.
Bromocriptine: (Moderate) Caution and close monitoring are advised if bromocriptine and encorafenib are used together. Concurrent use may decrease the plasma concentrations of bromocriptine resulting in loss of efficacy. Bromocriptine is extensively metabolized by the liver via CYP3A; encorafenib is a strong inducer of CYP3A.
Bupivacaine; Lidocaine: (Moderate) Monitor for decreased efficacy of lidocaine if coadministration of systemic lidocaine with encorafenib is necessary; higher doses of lidocaine may be required. Lidocaine is a CYP3A substrate and encorafenib is a strong CYP3A inducer.
Buprenorphine: (Major) Concomitant use of encorafenib and buprenorphine increases the risk for QT/QTc prolongation and torsade de pointes (TdP) and may decrease buprenorphine exposure. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. If concomitant use is necessary, monitor for reduced efficacy of buprenorphine and signs of opioid withdrawal and consider increasing the dose of buprenorphine as needed. If encorafenib is discontinued, consider a dose reduction of buprenorphine and frequently monitor for signs of respiratory depression and sedation. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Buprenorphine is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation.
Buprenorphine; Naloxone: (Major) Concomitant use of encorafenib and buprenorphine increases the risk for QT/QTc prolongation and torsade de pointes (TdP) and may decrease buprenorphine exposure. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. If concomitant use is necessary, monitor for reduced efficacy of buprenorphine and signs of opioid withdrawal and consider increasing the dose of buprenorphine as needed. If encorafenib is discontinued, consider a dose reduction of buprenorphine and frequently monitor for signs of respiratory depression and sedation. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Buprenorphine is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation.
Buspirone: (Moderate) Monitor for decreased efficacy of buspirone if encorafenib is added to a patient on a stable dosage of buspirone; a dose increase of buspirone may be needed to maintain anxiolytic activity. Buspirone is a sensitive CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased buspirone exposure by 89.6%.
Butalbital; Acetaminophen: (Major) Avoid concomitant use of encorafenib and barbiturates. Concurrent use may decrease encorafenib exposure which may reduce its efficacy. Encorafenib is a CYP3A substrate and barbiturates are strong CYP3A inducers.
Butalbital; Acetaminophen; Caffeine: (Major) Avoid concomitant use of encorafenib and barbiturates. Concurrent use may decrease encorafenib exposure which may reduce its efficacy. Encorafenib is a CYP3A substrate and barbiturates are strong CYP3A inducers.
Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Avoid concomitant use of encorafenib and barbiturates. Concurrent use may decrease encorafenib exposure which may reduce its efficacy. Encorafenib is a CYP3A substrate and barbiturates are strong CYP3A inducers. (Moderate) Concomitant use of codeine with encorafenib can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If encorafenib is discontinued, consider a dose reduction of codeine and frequently monitor for signs of respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Encorafenib is a strong CYP3A inducer.
Butalbital; Aspirin; Caffeine; Codeine: (Major) Avoid concomitant use of encorafenib and barbiturates. Concurrent use may decrease encorafenib exposure which may reduce its efficacy. Encorafenib is a CYP3A substrate and barbiturates are strong CYP3A inducers. (Moderate) Concomitant use of codeine with encorafenib can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If encorafenib is discontinued, consider a dose reduction of codeine and frequently monitor for signs of respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Encorafenib is a strong CYP3A inducer.
Cabotegravir; Rilpivirine: (Major) Concomitant use of encorafenib and rilpivirine increases the risk of QT/QTc prolongation and torsade de pointes (TdP) and may decrease rilpivirine exposure and efficacy. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Monitor for altered response to rilpivirine and consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Rilpivirine is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation. Coadministration with another strong CYP3A inducer decreased rilpivirine exposure by approximately 80%. Although specific recommendations are unavailable for use with encorafenib, coadministration with other strong CYP3A inducers is contraindicated.
Cabozantinib: (Major) Avoid coadministration of cabozantinib with encorafenib due to the risk of decreased cabozantinib exposure which could affect efficacy. If concomitant use is unavoidable, increase the dose of cabozantinib. For patients taking cabozantinib tablets, increase the dose of cabozantinib by 20 mg (e.g., 60 mg/day to 80 mg/day; 40 mg/day to 60 mg/day); the daily dose should not exceed 80 mg. For patients taking cabozantinib capsules, increase the dose of cabozantinib by 40 mg (e.g., 140 mg/day to 180 mg/day or 100 mg/day to 140 mg/day); the daily dose should not exceed 180 mg. Resume the cabozantinib dose that was used prior to initiating treatment with encorafenib 2 to 3 days after discontinuation of encorafenib. Cabozantinib is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased single-dose cabozantinib exposure by 77%.
Cannabidiol: (Moderate) Consider a dose increase of cannabidiol if coadministered with encorafenib. Coadministration may decrease cannabidiol plasma concentrations resulting in a decrease in efficacy. Cannabidiol is metabolized by CYP3A; encorafenib is a strong inducer of CYP3A.
Capivasertib: (Major) Avoid coadministration of capivasertib with encorafenib due to decreased capivasertib exposure and risk of decreased efficacy. Capivasertib is a CYP3A substrate; encorafenib is a strong CYP3A inducer. Coadministration of another strong CYP3A inducer is predicted to decrease the capivasertib overall exposure by 70%.
Capmatinib: (Major) Avoid coadministration of capmatinib and encorafenib due to the risk of decreased capmatinib exposure which may reduce its efficacy. Capmatinib is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased capmatinib exposure by 67%.
Carbamazepine: (Major) Avoid concomitant use of encorafenib and carbamazepine. Concurrent use may decrease the exposure of both drugs, which may reduce their efficacy. Both drugs are CYP3A substrates and strong CYP3A inducers.
Cariprazine: (Major) Coadministration of cariprazine with encorafenib is not recommended as the net effect of CYP3A induction on cariprazine and its metabolites is unclear. Cariprazine is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with cariprazine with CYP3A inducers has not been evaluated.
Caspofungin: (Major) Consider a caspofungin dosage increase if concomitant use with encorafenib is necessary. Increase the caspofungin dose to 70 mg/day in adults and 70 mg/m2/day (up to 70 mg/day) in pediatric patients. Concomitant use may decrease caspofungin exposure which may reduce its efficacy. Caspofungin is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced caspofungin trough concentrations by 30%.
Celecoxib; Tramadol: (Moderate) Monitor for reduced efficacy of tramadol and signs of opioid withdrawal if coadministration with encorafenib is necessary; consider increasing the dose of tramadol as needed. If encorafenib is discontinued, consider a dose reduction of tramadol and frequently monitor for seizures, serotonin syndrome, and signs of respiratory depression and sedation. Tramadol is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Concomitant use with CYP3A inducers can decrease tramadol levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Ceritinib: (Major) Avoid concomitant use of encorafenib and ceritinib due to the risk for decreased ceritinib exposure, increased encorafenib exposure, and increased risk of QT/QTc prolongation and torsade de pointes (TdP). If concomitant use is necessary, an encorafenib dosage reduction is required: reduce a daily dose of 450 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Ceritinib is a CYP3A substrate and strong CYP3A inhibitor, encorafenib is a CYP3A substrate and strong CYP3A inducer, and both medications may prolong the QT interval. Concomitant use with another strong CYP3A inhibitor increased encorafenib overall exposure by 3-fold. Coadministration with a strong CYP3A inducer decreased ceritinib exposure by 70%.
Chloramphenicol: (Major) Avoid concomitant use of encorafenib and chloramphenicol due to the risk for increased encorafenib exposure which may increase the risk for adverse effects. If concomitant use is necessary, an encorafenib dosage reduction is required: reduce a daily dose of 450 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Encorafenib is a CYP3A substrate and chloramphenicol is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased encorafenib overall exposure by 3-fold.
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; Codeine: (Moderate) Concomitant use of codeine with encorafenib can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If encorafenib is discontinued, consider a dose reduction of codeine and frequently monitor for signs of respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Encorafenib is a strong CYP3A inducer.
Chlorpheniramine; Hydrocodone: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with encorafenib is necessary; consider increasing the dose of hydrocodone as needed. It is recommended to avoid this combination when hydrocodone is being used for cough. If encorafenib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Concomitant use with CYP3A inducers can decrease hydrocodone concentration; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
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).
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Ciprofloxacin: (Major) Avoid concomitant use of encorafenib with ciprofloxacin due to the risk for increased encorafenib exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If concomitant use is necessary, an encorafenib dosage reduction is required: reduce a daily dose of 450 mg to 225 mg, reduce a daily dose of 300 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Encorafenib is a CYP3A substrate, ciprofloxacin is a moderate CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Concomitant use with another moderate CYP3A inhibitor increased encorafenib overall exposure by 2-fold.
Cisapride: (Contraindicated) 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) Concomitant use of encorafenib and citalopram increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Clarithromycin: (Major) Avoid concomitant use of encorafenib and clarithromycin due to the risk for decreased clarithromycin exposure, increased encorafenib exposure, and increased risk of QT/QTc prolongation and torsade de pointes (TdP). If concomitant use is necessary, an encorafenib dosage reduction is required: reduce a daily dose of 450 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Clarithromycin is a CYP3A substrate and strong CYP3A inhibitor, encorafenib is a CYP3A substrate and strong CYP3A inducer, and both medications may prolong the QT interval. Concomitant use with another strong CYP3A inhibitor increased encorafenib overall exposure by 3-fold. There have been spontaneous or published reports of CYP3A-based interactions of clarithromycin with another CYP3A inducer.
Clindamycin: (Moderate) Monitor for loss of clindamycin efficacy with coadministration of encorafenib as concurrent use may decrease clindamycin exposure. Clindamycin is a CYP3A substrate; encorafenib is a strong inducer of CYP3A.
Clofazimine: (Major) Concomitant use of clofazimine and encorafenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Clonazepam: (Moderate) Monitor patients for decreased efficacy and a change in clonazepam dosage requirements when coadministered with encorafenib. Clonazepam is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Clonazepam concentration decreases of approximately 38% have been reported when clonazepam is used with other strong CYP3A inducers.
Clozapine: (Major) Avoid concurrent use of encorafenib with clozapine due to the risk for decreased clozapine exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If concomitant use is required, monitor for altered response to clozapine and increase the clozapine dose if necessary. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Clozapine is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation.
Cobicistat: (Major) Avoid coadministration of cobicistat and encorafenib due to the risk of decreased cobicistat exposure which may increase the risk for virologic failure and drug resistance and increased encorafenib exposure which may increase the risk for adverse effects. If concomitant use is necessary, an encorafenib dosage reduction is required: reduce a daily dose of 450 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Cobicistat is a CYP3A substrate and strong CYP3A inhibitor and encorafenib is a CYP3A substrate and strong CYP3A inducer. Concomitant use with another strong CYP3A inhibitor increased encorafenib overall exposure by 3-fold.
Cobimetinib: (Major) Avoid coadministration of cobimetinib with encorafenib as concurrent use may decrease cobimetinib exposure, which may reduce its efficacy. Cobimetinib is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Based on simulations, cobimetinib exposure may decrease by 83% when coadministered with a strong CYP3A inducer.
Codeine: (Moderate) Concomitant use of codeine with encorafenib can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If encorafenib is discontinued, consider a dose reduction of codeine and frequently monitor for signs of respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Encorafenib is a strong CYP3A inducer.
Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with encorafenib can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If encorafenib is discontinued, consider a dose reduction of codeine and frequently monitor for signs of respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Encorafenib is a strong CYP3A inducer.
Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of codeine with encorafenib can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If encorafenib is discontinued, consider a dose reduction of codeine and frequently monitor for signs of respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Encorafenib is a strong CYP3A inducer.
Codeine; Phenylephrine; Promethazine: (Major) Concomitant use of promethazine and encorafenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. (Moderate) Concomitant use of codeine with encorafenib can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If encorafenib is discontinued, consider a dose reduction of codeine and frequently monitor for signs of respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Encorafenib is a strong CYP3A inducer.
Codeine; Promethazine: (Major) Concomitant use of promethazine and encorafenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. (Moderate) Concomitant use of codeine with encorafenib can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If encorafenib is discontinued, consider a dose reduction of codeine and frequently monitor for signs of respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Encorafenib is a strong CYP3A inducer.
Conivaptan: (Major) Avoid concomitant use of encorafenib and conivaptan due to the risk for increased encorafenib exposure which may increase the risk for adverse effects. If concomitant use is necessary, an encorafenib dosage reduction is required: reduce a daily dose of 450 mg to 225 mg, reduce a daily dose of 300 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Encorafenib is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased encorafenib overall exposure by 2-fold.
Conjugated Estrogens; Medroxyprogesterone: (Major) Avoid coadministration of medroxyprogesterone with encorafenib as it is expected to decrease concentrations of medroxyprogesterone acetate. Formal drug interaction studies have not been conducted; however, medroxyprogesterone is a CYP3A substrate and encorafenib is a strong CYP3A inducer.
Copanlisib: (Major) Avoid the concomitant use of copanlisib and encorafenib; decreased copanlisib exposure and loss of efficacy may occur. Copanlisib is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased exposure after a single dose of copanlisib by 63%.
Crizotinib: (Major) Avoid concomitant use of encorafenib and crizotinib due to the risk for decreased crizotinib exposure, increased encorafenib exposure, and increased risk of QT/QTc prolongation and torsade de pointes (TdP). If concomitant use is necessary, an encorafenib dosage reduction is required: reduce a daily dose of 450 mg to 225 mg, reduce a daily dose of 300 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Crizotinib is a CYP3A substrate and moderate CYP3A inhibitor, encorafenib is a CYP3A substrate and strong CYP3A inducer, and both medications may prolong the QT interval. Concomitant use with another moderate CYP3A inhibitor increased encorafenib overall exposure by 2-fold. Coadministration with another strong CYP3A inducer decreased the crizotinib AUC at steady state by 84%.
Cyclosporine: (Major) Avoid concomitant use of encorafenib and cyclosporine due to the risk for increased encorafenib exposure which may increase the risk for adverse effects. The exposure of cyclosporine may also be decreased. If concomitant use is necessary, monitor for altered response to cyclosporine and decrease encorafenib dosage: reduce a daily dose of 450 mg to 225 mg, reduce a daily dose of 300 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Cyclosporine is a CYP3A substrate and moderate CYP3A inhibitor and encorafenib is a CYP3A substrate and strong CYP3A inducer. Concomitant use with another moderate CYP3A inhibitor increased encorafenib overall exposure by 2-fold.
Daclatasvir: (Contraindicated) Coadministration of daclatasvir and encorafenib is contraindicated due to decreased daclatasvir exposure resulting in potential loss of virologic control. Daclatasvir is a CYP3A substrate; encorafenib is a strong CYP3A inducer. Coadministration of a strong CYP3A inducer reduced the daclatasvir AUC by 79%.
Danazol: (Major) Avoid concomitant use of encorafenib and danazol due to the risk for increased encorafenib exposure which may increase the risk for adverse effects. If concomitant use is necessary, an encorafenib dosage reduction is required: reduce a daily dose of 450 mg to 225 mg, reduce a daily dose of 300 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Encorafenib is a CYP3A substrate and danazol is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased encorafenib overall exposure by 2-fold.
Dapsone: (Moderate) Monitor for an increase in hemolysis if coadministration of dapsone with encorafenib is necessary; dapsone efficacy may also be compromised. Dapsone is a CYP3A metabolite and encorafenib is a strong CYP3A inducer. Strong CYP3A inducers may increase the formation of dapsone hydroxylamine, a metabolite associated with hemolysis. Coadministration with another strong CYP3A inducer decreased dapsone levels by 7-fold to 10-fold; in leprosy, this reduction has not required a change in dosage.
Daridorexant: (Major) Avoid concomitant use of daridorexant and encorafenib. Coadministration may decrease daridorexant exposure which may reduce its efficacy. Daridorexant is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Concomitant use of another strong CYP3A inducer decreased daridorexant overall exposure by over 50%.
Darunavir: (Major) Avoid coadministration of darunavir and encorafenib due to the risk of decreased darunavir exposure which may increase the risk for virologic failure and drug resistance and increased encorafenib exposure which may increase the risk for adverse effects. If concomitant use is necessary, an encorafenib dosage reduction is required: reduce a daily dose of 450 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Darunavir is a CYP3A substrate and strong CYP3A inhibitor and encorafenib is a CYP3A substrate and strong CYP3A inducer. Concomitant use with another strong CYP3A inhibitor increased encorafenib overall exposure by 3-fold.
Darunavir; Cobicistat: (Major) Avoid coadministration of cobicistat and encorafenib due to the risk of decreased cobicistat exposure which may increase the risk for virologic failure and drug resistance and increased encorafenib exposure which may increase the risk for adverse effects. If concomitant use is necessary, an encorafenib dosage reduction is required: reduce a daily dose of 450 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Cobicistat is a CYP3A substrate and strong CYP3A inhibitor and encorafenib is a CYP3A substrate and strong CYP3A inducer. Concomitant use with another strong CYP3A inhibitor increased encorafenib overall exposure by 3-fold. (Major) Avoid coadministration of darunavir and encorafenib due to the risk of decreased darunavir exposure which may increase the risk for virologic failure and drug resistance and increased encorafenib exposure which may increase the risk for adverse effects. If concomitant use is necessary, an encorafenib dosage reduction is required: reduce a daily dose of 450 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Darunavir is a CYP3A substrate and strong CYP3A inhibitor and encorafenib is a CYP3A substrate and strong CYP3A inducer. Concomitant use with another strong CYP3A inhibitor increased encorafenib overall exposure by 3-fold.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid coadministration of cobicistat and encorafenib due to the risk of decreased cobicistat exposure which may increase the risk for virologic failure and drug resistance and increased encorafenib exposure which may increase the risk for adverse effects. If concomitant use is necessary, an encorafenib dosage reduction is required: reduce a daily dose of 450 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Cobicistat is a CYP3A substrate and strong CYP3A inhibitor and encorafenib is a CYP3A substrate and strong CYP3A inducer. Concomitant use with another strong CYP3A inhibitor increased encorafenib overall exposure by 3-fold. (Major) Avoid coadministration of darunavir and encorafenib due to the risk of decreased darunavir exposure which may increase the risk for virologic failure and drug resistance and increased encorafenib exposure which may increase the risk for adverse effects. If concomitant use is necessary, an encorafenib dosage reduction is required: reduce a daily dose of 450 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Darunavir is a CYP3A substrate and strong CYP3A inhibitor and encorafenib is a CYP3A substrate and strong CYP3A inducer. Concomitant use with another strong CYP3A inhibitor increased encorafenib overall exposure by 3-fold. (Moderate) Coadministration of tenofovir alafenamide with encorafenib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp and BCRP substrate and encorafenib is a BCRP inhibitor.
Dasatinib: (Major) Avoid concurrent use of encorafenib with dasatinib due to the risk for decreased dasatinib exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). Consider an increased dose of dasatinib if concomitant use is necessary. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Dasatinib is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation. Concurrent use of another strong CYP3A inducer decreased the mean AUC of dasatinib by 82%.
Deflazacort: (Major) Avoid concomitant use of deflazacort and encorafenib. Concurrent use may significantly decrease concentrations of 21-desDFZ , the active metabolite of deflazacort, resulting in loss of efficacy. Deflazacort is a CYP3A substrate; encorafenib is a strong CYP3A inducer. Administration of deflazacort with multiple doses of another strong CYP3A inducer resulted in geometric mean exposures that were approximately 95% lower compared to administration alone.
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 delavirdine and encorafenib due to the risk of decreased delavirdine exposure which may increase the risk for virologic failure and drug resistance and increased encorafenib exposure which may increase the risk for adverse effects. If concomitant use is necessary, an encorafenib dosage reduction is required: reduce a daily dose of 450 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Delavirdine is a CYP3A substrate and strong CYP3A inhibitor and encorafenib is a CYP3A substrate and strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased delavirdine exposure by 97%. Concomitant use with another strong CYP3A inhibitor increased encorafenib overall exposure by 3-fold.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
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.
Desogestrel; 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.
Dexamethasone: (Moderate) Monitor for decreased efficacy of dexamethasone if coadministration with encorafenib is necessary; consider increasing the dose of dexamethasone if clinically appropriate. Dexamethasone is a CYP3A substrate and encorafenib is a strong CYP3A inducer.
Dexlansoprazole: (Major) Avoid coadministration of dexlansoprazole with encorafenib due to the risk of decreased dexlansoprazole plasma concentrations which may decrease efficacy. Dexlansoprazole is a CYP3A substrate and encorafenib is a strong CYP3A inducer.
Dexmedetomidine: (Major) Concomitant use of dexmedetomidine and encorafenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Dextromethorphan; Quinidine: (Major) Concomitant use of encorafenib and quinidine increases the risk of QT/QTc prolongation and torsade de pointes (TdP) and may decrease quinidine exposure and efficacy. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Monitor for altered response to quinidine and consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Quinidine is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation.
Diazepam: (Moderate) Monitor patients for decreased efficacy of diazepam if coadministration with encorafenib is necessary. Concurrent use may decrease diazepam exposure. Diazepam is a CYP3A substrate and encorafenib is a CYP3A inducer.
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.
Diltiazem: (Major) Avoid coadministration of diltiazem and encorafenib due to the risk of decreased diltiazem exposure which may reduce its efficacy and increased encorafenib exposure which may increase the risk for adverse effects. If concomitant use is necessary, an encorafenib dosage reduction is required: reduce a daily dose of 450 mg to 225 mg, reduce a daily dose of 300 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Diltiazem is a CYP3A substrate and moderate CYP3A inhibitor and encorafenib is a CYP3A substrate and strong CYP3A inducer. Coadministration with another strong CYP3A inducer lowered diltiazem plasma concentrations to undetectable levels. Concomitant use has been observed to increase encorafenib overall exposure by 2-fold.
Disopyramide: (Major) Concomitant use of encorafenib and disopyramide increases the risk of QT/QTc prolongation and torsade de pointes (TdP) and may decrease disopyramide exposure. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Monitor for altered response to disopyramide and adjust disopyramide dose as needed if concomitant use is necessary. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Disopyramide is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation.
Docetaxel: (Major) Avoid coadministration of docetaxel with encorafenib due to decreased plasma concentrations of docetaxel. Docetaxel is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Concomitant use with other strong CYP3A inducers increased docetaxel metabolism by 2.6-fold to 32-fold.
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: (Moderate) Monitor for increased toxicity or decreased efficacy of dolutegravir if coadministered with encorafenib. Concurrent use may increase or decrease the plasma concentrations of dolutegravir. Dolutegravir is a CYP3A and BCRP substrate and encorafenib is a strong CYP3A inducer and BCRP inhibitor. The net effect on dolutegravir exposure is unknown.
Dolutegravir; Lamivudine: (Moderate) Monitor for increased toxicity or decreased efficacy of dolutegravir if coadministered with encorafenib. Concurrent use may increase or decrease the plasma concentrations of dolutegravir. Dolutegravir is a CYP3A and BCRP substrate and encorafenib is a strong CYP3A inducer and BCRP inhibitor. The net effect on dolutegravir exposure is unknown.
Dolutegravir; Rilpivirine: (Major) Concomitant use of encorafenib and rilpivirine increases the risk of QT/QTc prolongation and torsade de pointes (TdP) and may decrease rilpivirine exposure and efficacy. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Monitor for altered response to rilpivirine and consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Rilpivirine is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation. Coadministration with another strong CYP3A inducer decreased rilpivirine exposure by approximately 80%. Although specific recommendations are unavailable for use with encorafenib, coadministration with other strong CYP3A inducers is contraindicated. (Moderate) Monitor for increased toxicity or decreased efficacy of dolutegravir if coadministered with encorafenib. Concurrent use may increase or decrease the plasma concentrations of dolutegravir. Dolutegravir is a CYP3A and BCRP substrate and encorafenib is a strong CYP3A inducer and BCRP inhibitor. The net effect on dolutegravir exposure is unknown.
Donepezil: (Major) Concomitant use of encorafenib and donepezil increases the risk of QT/QTc prolongation and torsade de pointes (TdP) and may decrease donepezil exposure. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Monitor for altered response to donepezil and adjust donepezil dose as needed if concomitant use is necessary. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Donepezil is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation.
Donepezil; Memantine: (Major) Concomitant use of encorafenib and donepezil increases the risk of QT/QTc prolongation and torsade de pointes (TdP) and may decrease donepezil exposure. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Monitor for altered response to donepezil and adjust donepezil dose as needed if concomitant use is necessary. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Donepezil is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation.
Doravirine: (Contraindicated) Concurrent administration of doravirine and encorafenib is contraindicated due to decreased doravirine exposure, resulting in potential loss of virologic control. At least a 4-week cessation period is recommended before initiating treatment with doravirine. Doravirine is a CYP3A substrate; encorafenib is a strong CYP3A inducer.
Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Contraindicated) Concurrent administration of doravirine and encorafenib is contraindicated due to decreased doravirine exposure, resulting in potential loss of virologic control. At least a 4-week cessation period is recommended before initiating treatment with doravirine. Doravirine is a CYP3A substrate; encorafenib is a strong CYP3A inducer. (Moderate) Coadministration of tenofovir disoproxil fumarate with encorafenib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a BCRP substrate and encorafenib is a BCRP inhibitor.
Doxorubicin Liposomal: (Major) Avoid coadministration of doxorubicin with encorafenib due to the risk for decreased doxorubicin plasma concentrations which may compromise the efficacy of chemotherapy. Doxorubicin is a CYP3A substrate and encorafenib is a strong CYP3A inducer.
Doxorubicin: (Major) Avoid coadministration of doxorubicin with encorafenib due to the risk for decreased doxorubicin plasma concentrations which may compromise the efficacy of chemotherapy. Doxorubicin is a CYP3A substrate and encorafenib is a strong CYP3A inducer.
Dronabinol: (Moderate) Monitor for a decrease in dronabinol efficacy if coadministration with encorafenib is necessary. Coadministration may decrease the exposure of dronabinol. Dronabinol is a CYP3A substrate; encorafenib is a strong CYP3A inducer.
Dronedarone: (Contraindicated) Dronedarone use is contraindicated with other medications that may prolong the QT/QTc interval and increase the risk for torsade de pointes (TdP), such as encorafenib. Concomitant use may also decrease dronedarone exposure and efficacy and increase encorafenib exposure and the risk for encorafenib-related adverse effects. If concomitant use is necessary, an encorafenib dosage reduction is required: reduce a daily dose of 450 mg to 225 mg, reduce a daily dose of 300 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Dronedarone is a CYP3A substrate and moderate CYP3A inhibitor, encorafenib is a CYP3A substrate and strong CYP3A inducer, and both medications may prolong the QT interval. Concomitant use with another moderate CYP3A inhibitor increased encorafenib overall exposure by 2-fold. Coadministration with another strong CYP3A inducer significantly decreased dronedarone exposure.
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; Estetrol: (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 duvelisib and encorafenib due to the risk of decreased duvelisib exposure which may reduce its efficacy and increased encorafenib exposure which may increase the risk for adverse effects. If concomitant use is necessary, an encorafenib dosage reduction is required: reduce a daily dose of 450 mg to 225 mg, reduce a daily dose of 300 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Duvelisib is a CYP3A substrate and moderate CYP3A inhibitor and encorafenib is a CYP3A substrate and strong CYP3A inducer. Coadministration with another strong CYP3A inducer for 7 days decreased duvelisib AUC by 82%. Concomitant use with another moderate CYP3A inhibitor increased encorafenib overall exposure by 2-fold.
Efavirenz: (Major) Concomitant use of encorafenib and efavirenz increases the risk of QT/QTc prolongation and torsade de pointes (TdP) and may decrease efavirenz exposure and efficacy. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Monitor for altered response to efavirenz and consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. When efavirenz is coadministered with another strong CYP3A inducer, it is recommended to increase efavirenz from 600 mg to 800 mg (patients weighing 50 kg or more). Efavirenz is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Concomitant use of encorafenib and efavirenz increases the risk of QT/QTc prolongation and torsade de pointes (TdP) and may decrease efavirenz exposure and efficacy. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Monitor for altered response to efavirenz and consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. When efavirenz is coadministered with another strong CYP3A inducer, it is recommended to increase efavirenz from 600 mg to 800 mg (patients weighing 50 kg or more). Efavirenz is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation. (Moderate) Coadministration of tenofovir disoproxil fumarate with encorafenib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a BCRP substrate and encorafenib is a BCRP inhibitor.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Concomitant use of encorafenib and efavirenz increases the risk of QT/QTc prolongation and torsade de pointes (TdP) and may decrease efavirenz exposure and efficacy. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Monitor for altered response to efavirenz and consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. When efavirenz is coadministered with another strong CYP3A inducer, it is recommended to increase efavirenz from 600 mg to 800 mg (patients weighing 50 kg or more). Efavirenz is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation. (Moderate) Coadministration of tenofovir disoproxil fumarate with encorafenib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a BCRP substrate and encorafenib is a BCRP inhibitor.
Elacestrant: (Major) Avoid concurrent use of elacestrant and encorafenib due to the risk of decreased elacestrant exposure which may reduce its efficacy. Elacestrant is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced elacestrant overall exposure by 86%.
Elagolix: (Contraindicated) Coadministration of elagolix with encorafenib is contraindicated. Concurrent use may have an unpredictable effect on elagolix exposure which may reduce elagolix efficacy or increase the risk for elagolix-related adverse effects. Elagolix is a CYP3A and OATP1B1 substrate and encorafenib is a strong CYP3A inducer and OATP1B1 inhibitor. The net effect on elagolix exposure is unknown.
Elagolix; Estradiol; Norethindrone acetate: (Contraindicated) Coadministration of elagolix with encorafenib is contraindicated. Concurrent use may have an unpredictable effect on elagolix exposure which may reduce elagolix efficacy or increase the risk for elagolix-related adverse effects. Elagolix is a CYP3A and OATP1B1 substrate and encorafenib is a strong CYP3A inducer and OATP1B1 inhibitor. The net effect on elagolix exposure is unknown. (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.
Elbasvir; Grazoprevir: (Contraindicated) Concomitant use of grazoprevir and encorafenib is contraindicated due to the potential for altered grazoprevir exposure which may decrease grazoprevir efficacy or increase the risk for adverse effects. Grazoprevir is a substrate of CYP3A and OATP1B1/3 and encorafenib is a strong CYP3A inducer and OATP1B1/3 inhibitor. The net effect on grazoprevir exposure is unknown. (Contraindicated) Concurrent administration of encorafenib with elbasvir is contraindicated. Use of these drugs together is expected to significantly decrease the plasma concentrations of elbasvir, and may result in decreased virologic response. Encorafenib is a strong CYP3A inducer and elbasvir is a substrate of CYP3A.
Elexacaftor; tezacaftor; ivacaftor: (Major) Coadministration of elexacaftor; tezacaftor; ivacaftor with encorafenib is not recommended as concurrent use may decrease exposure of elexacaftor; tezacaftor; ivacaftor. Elexacaftor, tezacaftor, and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate); encorafenib is a strong CYP3A inducer. Coadministration of a strong CYP3A inducer significantly decreased ivacaftor exposure by 89%. Elexacaftor and tezacaftor exposures are expected to also decrease during coadministration of strong CYP3A inducers. (Major) Coadministration of ivacaftor with encorafenib is not recommended due to decreased plasma concentrations of ivacaftor. Ivacaftor is a sensitive CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer significantly decreased ivacaftor exposure by approximately 9-fold. (Major) Do not administer tezacaftor; ivacaftor and encorafenib together; coadministration may reduce the efficacy of tezacaftor; ivacaftor. Exposure to ivacaftor is significantly decreased and exposure to tezacaftor may be reduced by the concomitant use of encorafenib, a strong CYP3A inducer; both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate). Coadministration of ivacaftor with a strong CYP3A inducer decreased ivacaftor exposure 89%. Tezacaftor exposures can also be expected to decrease significantly during coadministration with strong CYP3A inducers.
Eliglustat: (Major) Avoid concurrent use of encorafenib with eliglustat due to the risk for decreased eliglustat exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Eliglustat is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation. During clinical trials, systemic exposures (Cmax and AUC) of eliglustat decreased by approximately 90% in extensive metabolizers and intermediate metabolizers after coadministration of eliglustat 127 mg PO twice daily with another strong CYP3A inducer. Additionally, systemic exposures decreased by approximately 95% after coadministration of eliglustat 84 mg PO twice daily with another strong CYP3A inducer in poor metabolizers.
Eluxadoline: (Major) Reduce the dose of eluxadoline to 75 mg twice daily and monitor for eluxadoline-related adverse effects including decreased mental and physical acuity if coadministered with encorafenib. Coadministration may increase exposure of eluxadoline. Eluxadoline is an OATP1B1 substrate and encorafenib is a an OATP1B1 inhibitor. Coadministration with another OATP1B1 inhibitor increased the exposure of eluxadoline by 4.4-fold.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid coadministration of cobicistat and encorafenib due to the risk of decreased cobicistat exposure which may increase the risk for virologic failure and drug resistance and increased encorafenib exposure which may increase the risk for adverse effects. If concomitant use is necessary, an encorafenib dosage reduction is required: reduce a daily dose of 450 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Cobicistat is a CYP3A substrate and strong CYP3A inhibitor and encorafenib is a CYP3A substrate and strong CYP3A inducer. Concomitant use with another strong CYP3A inhibitor increased encorafenib overall exposure by 3-fold. (Major) Coadministration of elvitegravir with encorafenib is not recommended as there is a potential for decreased elvitegravir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Elvitegravir is metabolized by CYP3A and encorafenib is a strong CYP3A inducer. (Moderate) Coadministration of tenofovir alafenamide with encorafenib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp and BCRP substrate and encorafenib is a BCRP inhibitor.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of cobicistat and encorafenib due to the risk of decreased cobicistat exposure which may increase the risk for virologic failure and drug resistance and increased encorafenib exposure which may increase the risk for adverse effects. If concomitant use is necessary, an encorafenib dosage reduction is required: reduce a daily dose of 450 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Cobicistat is a CYP3A substrate and strong CYP3A inhibitor and encorafenib is a CYP3A substrate and strong CYP3A inducer. Concomitant use with another strong CYP3A inhibitor increased encorafenib overall exposure by 3-fold. (Major) Coadministration of elvitegravir with encorafenib is not recommended as there is a potential for decreased elvitegravir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Elvitegravir is metabolized by CYP3A and encorafenib is a strong CYP3A inducer. (Moderate) Coadministration of tenofovir disoproxil fumarate with encorafenib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a BCRP substrate and encorafenib is a BCRP inhibitor.
Empagliflozin; Linagliptin: (Moderate) Monitor for a decrease in linagliptin efficacy during concomitant use of linagliptin and encorafenib if coadministration is required. Concomitant use may decrease linagliptin exposure. Linagliptin is a CYP3A and P-gp substrate and encorafenib is a strong CYP3A inducer. Concomitant use with a strong CYP3A and P-gp inducer reduced linagliptin overall exposure by 0.6-fold.
Empagliflozin; Linagliptin; Metformin: (Moderate) Monitor for a decrease in linagliptin efficacy during concomitant use of linagliptin and encorafenib if coadministration is required. Concomitant use may decrease linagliptin exposure. Linagliptin is a CYP3A and P-gp substrate and encorafenib is a strong CYP3A inducer. Concomitant use with a strong CYP3A and P-gp inducer reduced linagliptin overall exposure by 0.6-fold.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) Concomitant use of encorafenib and rilpivirine increases the risk of QT/QTc prolongation and torsade de pointes (TdP) and may decrease rilpivirine exposure and efficacy. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Monitor for altered response to rilpivirine and consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Rilpivirine is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation. Coadministration with another strong CYP3A inducer decreased rilpivirine exposure by approximately 80%. Although specific recommendations are unavailable for use with encorafenib, coadministration with other strong CYP3A inducers is contraindicated. (Moderate) Coadministration of tenofovir alafenamide with encorafenib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp and BCRP substrate and encorafenib is a BCRP inhibitor.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Major) Concomitant use of encorafenib and rilpivirine increases the risk of QT/QTc prolongation and torsade de pointes (TdP) and may decrease rilpivirine exposure and efficacy. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Monitor for altered response to rilpivirine and consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Rilpivirine is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation. Coadministration with another strong CYP3A inducer decreased rilpivirine exposure by approximately 80%. Although specific recommendations are unavailable for use with encorafenib, coadministration with other strong CYP3A inducers is contraindicated. (Moderate) Coadministration of tenofovir disoproxil fumarate with encorafenib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a BCRP substrate and encorafenib is a BCRP inhibitor.
Emtricitabine; Tenofovir alafenamide: (Moderate) Coadministration of tenofovir alafenamide with encorafenib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp and BCRP substrate and encorafenib is a BCRP inhibitor.
Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with encorafenib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a BCRP substrate and encorafenib is a BCRP inhibitor.
Entrectinib: (Major) Avoid concurrent use of encorafenib with entrectinib due to the risk for decreased entrectinib exposure and efficacy and additive risk for QT/QTc prolongation and torsade de pointes (TdP). Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Entrectinib is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation. Coadministration of a strong CYP3A inducer decreased the entrectinib overall exposure by 77%.
Enzalutamide: (Major) Avoid coadministration of enzalutamide with encorafenib due to the risk of decreased exposure of both drugs and decreased efficacy. If concomitant use is unavoidable, increase the dose of enzalutamide from 160 mg to 240 mg PO once daily and monitor for altered response to both drugs. If encorafenib is discontinued, resume the dose of enzalutamide used prior to initiation of encorafenib. Both drugs are CYP3A substrates and strong CYP3A inducers. Coadministration with another strong CYP3A inducer decreased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 37%.
Eravacycline: (Major) Increase the dose of eravacycline to 1.5 mg/kg IV every 12 hours when coadministered with a strong CYP3A inducer, such as encorafenib. Concomitant use of strong CYP3A inducers decreases the exposure of eravacycline, which may reduce its efficacy. When eravacycline was administered with a strong CYP3A inducer, the eravacycline AUC was decreased by 35% and its clearance was increased by 54%.
Erdafitinib: (Major) Avoid coadministration of erdafitinib and encorafenib due to the risk of decreased plasma concentrations of erdafitinib resulting in decreased efficacy. Erdafitinib is a CYP3A substrate and encorafenib is a strong CYP3A inducer.
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.
Erlotinib: (Major) Avoid coadministration of erlotinib with encorafenib if possible due to the risk of decreased erlotinib efficacy. If concomitant use is unavoidable, increase the dose of erlotinib in 50 mg increments at 2-week intervals as tolerated (Max: 450 mg). Erlotinib is a CYP3A substrate, and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased erlotinib exposure by 58% to 80%.
Erythromycin: (Major) Avoid concomitant use of encorafenib with erythromycin due to the risk for increased encorafenib exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If concomitant use is necessary, an encorafenib dosage reduction is required: reduce a daily dose of 450 mg to 225 mg, reduce a daily dose of 300 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Additionally, onsider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Encorafenib is a CYP3A substrate, erythromycin is a moderate CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Concomitant use with another moderate CYP3A inhibitor increased encorafenib overall exposure by 2-fold.
Escitalopram: (Major) Concomitant use of encorafenib and escitalopram increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Esomeprazole: (Major) Avoid concomitant use of esomeprazole and encorafenib as esomeprazole exposure may be decreased, reducing its efficacy. Esomeprazole is a CYP3A substrate and encorafenib is a strong CYP3A inducer.
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.
Eszopiclone: (Moderate) Monitor for decreased efficacy of eszopiclone if coadministration with encorafenib is necessary. Eszopiclone is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased racemic zopiclone exposure by 80%; a similar effect would be expected with eszopiclone.
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; 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.
Ethynodiol Diacetate; 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.
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.
Etonogestrel; 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.
Etrasimod: (Major) Concomitant use of etrasimod and encorafenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Etrasimod has a limited effect on the QT/QTc interval at therapeutic doses but may cause bradycardia and atrioventricular conduction delays which may increase the risk for TdP in patients with a prolonged QT/QTc interval.
Etravirine: (Moderate) Concurrent use of etravirine and encorafenib may decrease plasma concentrations of etravirine, leading to a reduction of antiretroviral efficacy and the potential development of antiretroviral drug resistance. Although specific recommendations are unavailable for use with encorafenib, coadministration with other strong CYP3A inducers is not recommended. Etravirine is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Concurrent use of a moderate CYP3A inducer decreased etravirine exposure by approximately 35%; further reductions in etravirine plasma concentrations may occur with a strong inducer.
Everolimus: (Major) Avoid coadministration of everolimus with encorafenib due to the risk of decreased efficacy of everolimus. If concomitant use is unavoidable, coadministration requires a dose increase for some indications and close monitoring for others. For oncology indications and TSC-associated renal angiomyolipoma, double the daily dose using increments of 5 mg or less; multiple increments may be required. For patients with tuberous sclerosis complex (TSC)-associated SEGA and TSC-associated partial-onset seizures, assess the everolimus whole blood trough concentration 2 weeks after initiation of encorafenib and adjust the dose as necessary to remain in the recommended therapeutic range. Also closely monitor everolimus whole blood trough concentrations in patients receiving everolimus for either kidney or liver transplant and adjust the dose as necessary to remain in the recommended therapeutic range. Everolimus is a sensitive CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased the overall exposure of everolimus by 63%.
Exemestane: (Major) If coadministration of exemestane with encorafenib is necessary, increase the dose of exemestane to 50 mg once daily after a meal. Exemestane is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased exemestane exposure by 54%.
Ezetimibe; Simvastatin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with encorafenib is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is an OATP1B1 substrate and encorafenib is an OATP1B1 inhibitor.
Fedratinib: (Major) Avoid coadministration of fedratinib and encorafenib due to the risk of decreased fedratinib exposure which may reduce its efficacy and increased encorafenib exposure which may increase the risk for adverse effects. If concomitant use is necessary, an encorafenib dosage reduction is required: reduce a daily dose of 450 mg to 225 mg, reduce a daily dose of 300 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Fedratinib is a CYP3A substrate and moderate CYP3A inhibitor and encorafenib is a CYP3A substrate and strong CYP3A inducer. Coadministration of fedratinib with another strong CYP3A inducer decreased the overall exposure of fedratinib by 81%. Concomitant use with another moderate CYP3A inhibitor increased encorafenib overall exposure by 2-fold.
Fenfluramine: (Major) Avoid concurrent use of fenfluramine and encorafenib due to the risk of decreased fenfluramine plasma concentrations, which may reduce its efficacy. If concomitant use is necessary, monitor for decreased efficacy and consider increasing fenfluramine dose as needed. Fenfluramine is a CYP3A substrate and encorafenib is a strong CYP3A inducer.
Fentanyl: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if concurrent use of encorafenib is necessary. If encorafenib is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a CYP3A inducer like encorafenib with fentanyl, a CYP3A substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Fexinidazole: (Major) Avoid concomitant use of fexinidazole with encorafenib due to the risk for increased fexinidazole exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Fexinidazole is converted to its active metabolites via CYP3A, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation.
Finasteride; Tadalafil: (Major) Avoid coadministration of tadalafil with encorafenib in patients with pulmonary hypertension due to decreased plasma concentrations of tadalafil. In patients with erectile dysfunction and/or benign prostatic hyperplasia, consider the potential for loss of efficacy of tadalafil during concurrent administration of encorafenib due to reduced tadalafil exposure. Tadalafil is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased tadalafil exposure by 88%.
Finerenone: (Major) Avoid concurrent use of finerenone and encorafenib due to the risk for decreased finerenone exposure which may reduce its efficacy. Finerenone is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased overall exposure to finerenone by 90%.
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.
Flibanserin: (Major) Avoid concurrent use of flibanserin with encorafenib due to the potential for decreased plasma concentrations of flibanserin. Flibanserin is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased flibanserin exposure by 95%.
Fluconazole: (Contraindicated) Fluconazole use in contraindicated with other medications that may prolong the QT interval and are metabolized via CYP3A, such as encorafenib. Avoid concomitant use of encorafenib and fluconazole due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase encorafenib exposure and the risk for other encorafenib-related adverse effects. If concomitant use is necessary, an encorafenib dosage reduction is required: reduce a daily dose of 450 mg to 225 mg, reduce a daily dose of 300 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Encorafenib is a CYP3A substrate, fluconazole is a moderate CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Concomitant use with another moderate CYP3A inhibitor increased encorafenib overall exposure by 2-fold.
Fluoxetine: (Major) Concomitant use of encorafenib and fluoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
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.
Flurazepam: (Moderate) Monitor patients for decreased efficacy of flurazepam if coadministration with encorafenib is necessary. Concurrent use may decrease flurazepam exposure. Flurazepam is a CYP3A substrate and encorafenib is a strong CYP3A inducer.
Fluvastatin: (Moderate) Monitor for an increase in fluvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with encorafenib is necessary. Concomitant use may increase fluvastatin exposure. Fluvastatin is a substrate of OATP1B3; encorafenib is an inhibitor of OATP1B3.
Fluvoxamine: (Major) Avoid concomitant use of encorafenib with fluvoxamine due to the risk for increased encorafenib exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If concomitant use is necessary, an encorafenib dosage reduction is required: reduce a daily dose of 450 mg to 225 mg, reduce a daily dose of 300 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Encorafenib is a CYP3A substrate, fluvoxamine is a moderate CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Concomitant use with another moderate CYP3A inhibitor increased encorafenib overall exposure by 2-fold.
Food: (Major) Advise patients to avoid cannabis use during encorafenib treatment. Concomitant use may decrease the concentration of some cannabinoids and alter their effects. The cannabinoids delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are CYP3A substrates and encorafenib is a strong CYP3A inducer. Concomitant use of a cannabinoid product containing THC and CBD at an approximate 1:1 ratio with another strong CYP3A inducer decreased THC, 11-OH-THC, and CBD peak exposure by 36%, 87%, and 52% respectively.
Fosamprenavir: (Major) Avoid concomitant use of encorafenib and fosamprenavir due to the risk for increased encorafenib exposure which may increase the risk for adverse effects. The exposure of fosamprenavir may also be decreased leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. If concomitant use is necessary, monitor for altered response to fosamprenavir and decrease the encorafenib dosage: reduce a daily dose of 450 mg to 225 mg, reduce a daily dose of 300 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Fosamprenavir is a CYP3A substrate and moderate CYP3A inhibitor and encorafenib is a CYP3A substrate and strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased the fosamprenavir overall exposure 82%. Concomitant use with another moderate CYP3A inhibitor increased encorafenib overall exposure by 2-fold.
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 concomitant use of encorafenib and phenytoin/fosphenytoin. Concurrent use may decrease encorafenib exposure which may reduce its efficacy. Encorafenib is a CYP3A substrate and phenytoin/fosphenytoin is a strong CYP3A inducer.
Fostamatinib: (Major) Avoid the concomitant use of fostamatinib with encorafenib. Concurrent use of fostamatinib with encorafenib may decrease exposure to the major active metabolite, R406. R406 is extensively metabolized by CYP3A; encorafenib is a strong CYP3A inducer. Concomitant use of fostamatinib with another strong CYP3A inducer decreased R406 AUC by 75% and Cmax by 59%.
Fostemsavir: (Contraindicated) Concurrent use of fostemsavir with encorafenib is contraindicated due to decreased exposure of temsavir, the active moiety of fostemsavir, which may impair efficacy and increase the risk for HIV treatment failure or development of viral resistance. Concomitant use also increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Temsavir is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation.
Fruquintinib: (Major) Avoid coadministration of fruquintinib with encorafenib due to decreased fruquintinib exposure and risk of decreased efficacy. Fruquintinib is a CYP3A substrate; encorafenib is a strong CYP3A inducer. Coadministration of a strong CYP3A inducer decreased fruquintinib exposure by 65%.
Ganaxolone: (Major) Avoid concurrent use of ganaxolone and encorafenib due to the risk of decreased ganaxolone efficacy. If concomitant use is unavoidable, consider increasing ganaxolone dose without exceeding the maximum daily dose. Ganaxolone is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased ganaxolone overall exposure by 68%.
Gefitinib: (Major) Increase the dose of gefitinib to 500 mg PO once daily if coadministration with encorafenib is necessary. If encorafenib is discontinued, gefitinib at a dose of 250 mg once daily may be resumed seven days later. Gefitinib is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer reduced gefitinib exposure by 83%.
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 concurrent use of encorafenib with glasdegib due to the risk for decreased glasdegib exposure and efficacy and additive risk for QT/QTc prolongation and torsade de pointes (TdP). Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Glasdegib is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation. Coadministration of a strong CYP3A inducer decreased the glasdegib AUC by 70%.
Glecaprevir; Pibrentasvir: (Moderate) Monitor for an increase in glecaprevir-related adverse reactions or decreased efficacy if coadministration with encorafenib is necessary. Glecaprevir is a CYP3A, BRCP, and OATP1B1/3 substrate and encorafenib is a strong CYP3A inducer, BCRP inhibitor, and OATP1B1/3 inhibitor. The net effect on glecaprevir exposure is unknown. (Moderate) Monitor for an increase in pibrentasvir-related adverse effects if concomitant use of encorafenib is necessary. Concomitant use may increase pibrentasvir exposure. Pibrentasvir is a substrate of BCRP and encorafenib is a BCRP inhibitor.
Glyburide: (Moderate) Monitor for an increase in glyburide-related adverse reactions, such as hypoglycemia, if coadministration with encorafenib is necessary. Concomitant use may increase glyburide exposure. Glyburide is a substrate of OATP1B1/3; encorafenib is an OATP1B1/3 inhibitor.
Glyburide; Metformin: (Moderate) Monitor for an increase in glyburide-related adverse reactions, such as hypoglycemia, if coadministration with encorafenib is necessary. Concomitant use may increase glyburide exposure. Glyburide is a substrate of OATP1B1/3; encorafenib is an OATP1B1/3 inhibitor.
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) Concomitant use of encorafenib and granisetron increases the risk of QT/QTc prolongation and torsade de pointes (TdP) and may decrease granisetron exposure and efficacy. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Monitor for altered response to granisetron and consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Granisetron is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation. Coadministration with another strong CYP3A inducer increased the total plasma clearance of granisetron by 25%.
Grapefruit juice: (Major) Advise patients to avoid grapefruit and grapefruit juice during encorafenib treatment due to the risk of increased encorafenib exposure and adverse reactions. Encorafenib is a CYP3A substrate and grapefruit juice is a CYP3A inhibitor.
Guanfacine: (Major) A dose increase of extended-release (ER) guanfacine should be considered if coadministration with encorafenib is necessary. Consider doubling the recommended dose of guanfacine if therapy is added to a patient already taking encorafenib; increase the dose of guanfacine over 1 to 2 weeks if encorafenib therapy is added to a patient already taking guanfacine. Specific recommendations for immediate-release (IR) guanfacine are not available. Guanfacine is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased guanfacine exposure by 70%.
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) Concomitant use of encorafenib and haloperidol increases the risk of QT/QTc prolongation and torsade de pointes (TdP) and may decrease haloperidol exposure and efficacy. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Monitor for altered response to haloperidol; adjust haloperidol dose as needed, and consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The intravenous route may carry a higher risk for haloperidol-induced QT/QTc prolongation than other routes of administration. Haloperidol is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation. Coadministration with another strong CYP3A inducer decreased haloperidol plasma concentrations by a mean of 70% and increased mean scores on the Brief Psychiatric Rating Scale from baseline.
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.
Homatropine; Hydrocodone: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with encorafenib is necessary; consider increasing the dose of hydrocodone as needed. It is recommended to avoid this combination when hydrocodone is being used for cough. If encorafenib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Concomitant use with CYP3A inducers can decrease hydrocodone concentration; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Hydrocodone: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with encorafenib is necessary; consider increasing the dose of hydrocodone as needed. It is recommended to avoid this combination when hydrocodone is being used for cough. If encorafenib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Concomitant use with CYP3A inducers can decrease hydrocodone concentration; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Hydrocodone; Ibuprofen: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with encorafenib is necessary; consider increasing the dose of hydrocodone as needed. It is recommended to avoid this combination when hydrocodone is being used for cough. If encorafenib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Concomitant use with CYP3A inducers can decrease hydrocodone concentration; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Hydrocortisone: (Moderate) Monitor for decreased corticosteroid efficacy if hydrocortisone is used with encorafenib; a dosage increase may be necessary. Concurrent use may decrease hydrocortisone exposure. Hydrocortisone is a CYP3A substrate and encorafenib is a strong CYP3A inducer.
Hydroxychloroquine: (Major) Concomitant use of hydroxychloroquine and encorafenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Hydroxyzine: (Major) Concomitant use of hydroxyzine and encorafenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Ibrexafungerp: (Major) Avoid concurrent administration of ibrexafungerp with encorafenib. Use of these drugs together is expected to significantly decrease ibrexafungerp exposure, which may reduce its efficacy. Ibrexafungerp is a CYP3A substrate and encorafenib is a strong CYP3A inducer.
Ibrutinib: (Major) Avoid concurrent use of ibrutinib with encorafenib due to decreased plasma concentrations of ibrutinib. Ibrutinib is a sensitive CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased ibrutinib exposure by more than 10-fold.
Ibuprofen; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with encorafenib is necessary; consider increasing the dose of oxycodone as needed. If encorafenib is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Concomitant use with CYP3A inducers can decrease oxycodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
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 idelalisib and encorafenib due to the risk of decreased idelalisib exposure which may reduce its efficacy and increased encorafenib exposure which may increase the risk for adverse effects. If concomitant use is necessary, an encorafenib dosage reduction is required: reduce a daily dose of 450 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Idelalisib is a CYP3A substrate and strong CYP3A inhibitor and encorafenib is a CYP3A substrate and strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased idelalisib exposure by 75%. Concomitant use with another strong CYP3A inhibitor increased encorafenib overall exposure by 3-fold.
Ifosfamide: (Moderate) Closely monitor for increased ifosfamide-related toxicities (e.g., neurotoxicity, nephrotoxicity) if coadministration with encorafenib is necessary; consider adjusting the dose of ifosfamide as clinically appropriate. Ifosfamide is metabolized to its active alkylating metabolites by CYP3A; encorafenib is a strong CYP3A inducer. Concomitant use may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde.
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 imatinib and encorafenib due to the risk of decreased imatinib exposure which may reduce its efficacy and increased encorafenib exposure which may increase the risk for adverse effects. If coadministration is unavoidable, dosage adjustments are recommended for both drugs. For imatinib, increase the dose by at least 50%, carefully monitoring clinical response; imatinib doses up to 1,200 mg per day (600 mg twice daily) have been given to patients receiving concomitant strong CYP3A inducers. For encorafenib, reduce a daily dose of 450 mg to 225 mg, reduce a daily dose of 300 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Imatinib is a CYP3A substrate and moderate CYP3A inhibitor and encorafenib is a CYP3A substrate and strong CYP3A inducer. Coadministration with another strong CYP3A inducer increased imatinib clearance by 3.8-fold, which significantly decreased the mean Cmax and AUC of imatinib. Concomitant use with another moderate CYP3A inhibitor increased encorafenib overall exposure by 2-fold.
Indinavir: (Major) Avoid coadministration of indinavir and encorafenib due to the risk of decreased indinavir exposure which may increase the risk for virologic failure and drug resistance and increased encorafenib exposure which may increase the risk for adverse effects. If concomitant use is necessary, monitor for altered response to indinavir and decrease encorafenib dosage: reduce a daily dose of 450 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Although specific recommendations are unavailable for use with encorafenib, coadministration of indinavir with other strong CYP3A inducers is not recommended. Indinavir is a CYP3A substrate and strong CYP3A inhibitor and encorafenib is a CYP3A substrate and strong CYP3A inducer. Coadministration with another strong inducer decreased indinavir exposure by approximately 90%. Concomitant use with another strong CYP3A inhibitor increased encorafenib overall exposure by 3-fold.
Infigratinib: (Major) Avoid concurrent use of infigratinib and encorafenib. Coadministration may decrease infigratinib exposure resulting in decreased efficacy. Infigratinib is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased the overall exposure of infigratinib by 56%.
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.
Irinotecan Liposomal: (Major) Avoid administration of encorafenib during treatment with irinotecan and for at least two weeks prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A substrates and encorafenib is a strong CYP3A inducer. Coadministration with other strong CYP3A inducers substantially reduced exposure to irinotecan or SN-38 in both adult and pediatric patients. An appropriate starting dose for patients taking irinotecan with strong CYP3A inducers has not been defined.
Irinotecan: (Major) Avoid administration of encorafenib during treatment with irinotecan and for at least two weeks prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A substrates and encorafenib is a strong CYP3A inducer. Coadministration with other strong CYP3A inducers substantially reduced exposure to irinotecan or SN-38 in both adult and pediatric patients. An appropriate starting dose for patients taking irinotecan with strong CYP3A inducers has not been defined.
Isavuconazonium: (Contraindicated) Concurrent use of isavuconazonium and encorafenib is contraindicated due to the risk of decreased isavuconazonium exposure and treatment failure. Concomitant use may also increase encorafenib exposure and the risk for adverse effects. If concomitant use is necessary, an encorafenib dosage reduction is required: reduce a daily dose of 450 mg to 225 mg, reduce a daily dose of 300 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Isavuconazonium is a CYP3A substrate and moderate CYP3A inhibitor and encorafenib is a CYP3A substrate and strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased isavuconazole serum concentrations by 97%. Concomitant use with another moderate CYP3A inhibitor increased encorafenib overall exposure by 2-fold.
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 concomitant use of encorafenib and rifampin. Concurrent use may decrease encorafenib exposure which may reduce its efficacy. Encorafenib is a CYP3A substrate and rifampin is a strong CYP3A inducer.
Isoniazid, INH; Rifampin: (Major) Avoid concomitant use of encorafenib and rifampin. Concurrent use may decrease encorafenib exposure which may reduce its efficacy. Encorafenib is a CYP3A substrate and rifampin is a strong CYP3A inducer.
Isradipine: (Moderate) Monitor for decreased efficacy of isradipine if coadministration with encorafenib is necessary. Concomitant use may decrease isradipine exposure. Isradipine is a CYP3A substrate and encorafenib is a strong CYP3A inducer.
Istradefylline: (Major) Avoid coadministration of istradefylline with encorafenib as istradefylline exposure and efficacy may be reduced. Istradefylline is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Istradefylline exposure was decreased by 81% when administered with a strong CYP3A inducer in a drug interaction study.
Itraconazole: (Major) Avoid using encorafenib within 2 weeks of itraconazole therapy due to the risk for decreased itraconazole exposure, increased encorafenib exposure, and torsade de pointes (TdP) and QT/QTc prolongation, especially in patients with additional risk factors for TdP. If concurrent use cannot be avoided, monitor for decreased efficacy of itraconazole and reduce encorafenib daily dose of 450 mg to 150 mg and to for all other dosages to 75 mg. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Itraconazole is a CYP3A substrate and strong CYP3A inhibitor and encorafenib is a CYP3A substrate and strong CYP3A inducer; both medications may prolong the QT interval. Concomitant use with another strong CYP3A inhibitor increased encorafenib overall exposure by 3-fold.
Ivabradine: (Major) Avoid coadministration of ivabradine and encorafenib due to decreased plasma concentrations of ivabradine. Ivabradine is a CYP3A substrate and encorafenib is a CYP3A inducer. Coadministration with another strong CYP3A inducer decreased ivabradine exposure by approximately half.
Ivacaftor: (Major) Coadministration of ivacaftor with encorafenib is not recommended due to decreased plasma concentrations of ivacaftor. Ivacaftor is a sensitive CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer significantly decreased ivacaftor exposure by approximately 9-fold.
Ivosidenib: (Major) Avoid concurrent use of encorafenib with ivosidenib due to the risk for decreased ivosidenib exposure and efficacy and additive risk for QT/QTc prolongation and torsade de pointes (TdP). Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Ivosidenib is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation. Concurrent use of a strong CYP3A inducer is predicted to decrease ivosidenib exposure by 33%.
Ixabepilone: (Major) Avoid concurrent use of ixabepilone and encorafenib due to decreased plasma concentrations of ixabepilone, which may reduce its efficacy. If concomitant use is unavoidable, gradually increase the dose of ixabepilone as tolerated from 40 mg/m2 to 60 mg/m2 and increase the infusion time to 4 hours; monitor carefully for ixabepilone-related toxicities. Ixabepilone is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased ixabepilone exposure by 43%.
Ixazomib: (Major) Avoid the concurrent use of ixazomib and encorafenib; ixazomib exposure may be significantly decreased and its efficacy reduced. Ixazomib is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Concurrent use of another strong CYP3A inducer decreased overall ixazomib exposure by 74%.
Ketoconazole: (Contraindicated) Ketoconazole use is contraindicated with other medications that may prolong the QT interval, such as encorafenib. Avoid concomitant use of encorafenib and ketoconazole due to the risk for decreased ketoconazole exposure, increased encorafenib exposure, and increased risk of QT/QTc prolongation and torsade de pointes (TdP). If concomitant use is necessary, monitor for altered response to ketoconazole and increase dose if needed. An encorafenib dosage decrease is also required: reduce a daily dose of 450 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Ketoconazole is a CYP3A substrate and strong CYP3A inhibitor, encorafenib is a CYP3A substrate and strong CYP3A inducer, and both medications may prolong the QT interval. Concomitant use with another strong CYP3A inhibitor increased encorafenib overall exposure by 3-fold.
Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with encorafenib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a BCRP substrate and encorafenib is a BCRP inhibitor.
Lansoprazole: (Major) Avoid concomitant use of lansoprazole and encorafenib as lansoprazole exposure may be decreased, reducing its efficacy. Lansoprazole is a CYP3A substrate and encorafenib is a strong CYP3A inducer.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Avoid concomitant use of encorafenib and clarithromycin due to the risk for decreased clarithromycin exposure, increased encorafenib exposure, and increased risk of QT/QTc prolongation and torsade de pointes (TdP). If concomitant use is necessary, an encorafenib dosage reduction is required: reduce a daily dose of 450 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Clarithromycin is a CYP3A substrate and strong CYP3A inhibitor, encorafenib is a CYP3A substrate and strong CYP3A inducer, and both medications may prolong the QT interval. Concomitant use with another strong CYP3A inhibitor increased encorafenib overall exposure by 3-fold. There have been spontaneous or published reports of CYP3A-based interactions of clarithromycin with another CYP3A inducer. (Major) Avoid concomitant use of lansoprazole and encorafenib as lansoprazole exposure may be decreased, reducing its efficacy. Lansoprazole is a CYP3A substrate and encorafenib is a strong CYP3A inducer.
Lapatinib: (Major) Avoid concurrent use of encorafenib with lapatinib due to the risk for decreased lapatinib exposure and efficacy and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If concomitant use is necessary, gradually titrate the dose of lapatinib from 1,250 mg per day to 4,500 mg per day in patients receiving concomitant capecitabine (HER2-positive metastatic breast cancer), and from 1,500 mg per day to 5,500 mg per day in patients receiving concomitant aromatase inhibitor therapy (HR-positive, HER2-positive breast cancer) based on tolerability. If encorafenib is discontinued, reduce lapatinib to the indicated dose. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Lapatinib is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation. Concomitant use with another strong CYP3A inducer decreased lapatinib exposure by 72%.
Larotrectinib: (Major) Avoid coadministration of encorafenib with larotrectinib due to the risk of decreased larotrectinib exposure which may reduce its efficacy. If concomitant use is unavoidable, double the dose of larotrectinib. After encorafenib has been discontinued for 3 to 5 elimination half-lives, resume the larotrectinib dose taken prior to initiating encorafenib. Larotrectinib is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased the larotrectinib AUC by 81%.
Lefamulin: (Major) Avoid concomitant use of encorafenib and lefamulin due to the risk for decreased lefamulin exposure and efficacy, increased encorafenib exposure, and increased risk of QT/QTc prolongation and torsade de pointes (TdP). If concomitant use of oral lefamulin is necessary, an encorafenib dosage reduction is required: reduce a daily dose of 450 mg to 225 mg, reduce a daily dose of 300 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. An encorafenib dosage reduction is not required with intravenous lefamulin. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Lefamulin is a CYP3A substrate, oral lefamulin is a moderate CYP3A inhibitor, encorafenib is a CYP3A substrate and strong CYP3A inducer, and both medications may prolong the QT interval. Concomitant use with another moderate CYP3A inhibitor increased encorafenib overall exposure by 2-fold. Coadministration of a strong CYP3A inducer decreased the mean AUC of lefamulin oral tablets by 72% and the mean AUC of lefamulin injection by 28%.
Lemborexant: (Major) Avoid coadministration of lemborexant and encorafenib as concurrent use may decrease lemborexant exposure which may reduce efficacy. Lemborexant is a CYP3A substrate; encorafenib is a strong CYP3A inducer.
Lenacapavir: (Contraindicated) Concurrent use of lenacapavir and encorafenib is contraindicated due to the risk of decreased lenacapavir exposure which may result in loss of therapeutic effect and development of resistance. Concomitant use may also increase encorafenib exposure and the risk for adverse effects. If concomitant use is necessary, an encorafenib dosage reduction is required: reduce a daily dose of 450 mg to 225 mg, reduce a daily dose of 300 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Lenacapavir is a CYP3A substrate and moderate CYP3A inhibitor and encorafenib is a CYP3A substrate and strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced lenacapavir overall exposure by 84%. Concomitant use with another moderate CYP3A inhibitor increased encorafenib overall exposure by 2-fold.
Leniolisib: (Major) Avoid concomitant use of leniolisib and encorafenib. Concomitant use may decrease leniolisib exposure which may reduce its efficacy. Leniolisib is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced leniolisib overall exposure by 78%.
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 concomitant use of encorafenib and letermovir due to the risk for increased encorafenib exposure which may increase the risk for adverse effects. The exposure of letermovir may also be increased. If concomitant use is necessary, an encorafenib dosage reduction is required: reduce a daily dose of 450 mg to 225 mg, reduce a daily dose of 300 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. If combination letermovir plus cyclosporine is used, reduce a daily dose of 450 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Encorafenib is a CYP3A substrate and OATP1B1/3 inhibitor; letermovir is a substrate of OATP1B1/3 and moderate CYP3A inhibitor; combination letermovir plus cyclosporine is a strong CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased encorafenib overall exposure by 2-fold and concomitant use with another strong CYP3A inhibitor increased encorafenib overall exposure by 3-fold.
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.
Levamlodipine: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with encorafenib is necessary. Amlodipine is a CYP3A substrate and encorafenib is a strong CYP3A inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Levofloxacin: (Major) Concomitant use of levofloxacin and encorafenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Levoketoconazole: (Contraindicated) Ketoconazole use is contraindicated with other medications that may prolong the QT interval, such as encorafenib. Avoid concomitant use of encorafenib and ketoconazole due to the risk for decreased ketoconazole exposure, increased encorafenib exposure, and increased risk of QT/QTc prolongation and torsade de pointes (TdP). If concomitant use is necessary, monitor for altered response to ketoconazole and increase dose if needed. An encorafenib dosage decrease is also required: reduce a daily dose of 450 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Ketoconazole is a CYP3A substrate and strong CYP3A inhibitor, encorafenib is a CYP3A substrate and strong CYP3A inducer, and both medications may prolong the QT interval. Concomitant use with another strong CYP3A inhibitor increased encorafenib overall exposure by 3-fold.
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.
Levonorgestrel; 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.
Levonorgestrel; Ethinyl Estradiol; 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.
Levonorgestrel; Ethinyl Estradiol; 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.
Lidocaine: (Moderate) Monitor for decreased efficacy of lidocaine if coadministration of systemic lidocaine with encorafenib is necessary; higher doses of lidocaine may be required. Lidocaine is a CYP3A substrate and encorafenib is a strong CYP3A inducer.
Lidocaine; Epinephrine: (Moderate) Monitor for decreased efficacy of lidocaine if coadministration of systemic lidocaine with encorafenib is necessary; higher doses of lidocaine may be required. Lidocaine is a CYP3A substrate and encorafenib is a strong CYP3A inducer.
Lidocaine; Prilocaine: (Moderate) Monitor for decreased efficacy of lidocaine if coadministration of systemic lidocaine with encorafenib is necessary; higher doses of lidocaine may be required. Lidocaine is a CYP3A substrate and encorafenib is a strong CYP3A inducer.
Linagliptin: (Moderate) Monitor for a decrease in linagliptin efficacy during concomitant use of linagliptin and encorafenib if coadministration is required. Concomitant use may decrease linagliptin exposure. Linagliptin is a CYP3A and P-gp substrate and encorafenib is a strong CYP3A inducer. Concomitant use with a strong CYP3A and P-gp inducer reduced linagliptin overall exposure by 0.6-fold.
Linagliptin; Metformin: (Moderate) Monitor for a decrease in linagliptin efficacy during concomitant use of linagliptin and encorafenib if coadministration is required. Concomitant use may decrease linagliptin exposure. Linagliptin is a CYP3A and P-gp substrate and encorafenib is a strong CYP3A inducer. Concomitant use with a strong CYP3A and P-gp inducer reduced linagliptin overall exposure by 0.6-fold.
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.
Lonafarnib: (Contraindicated) Coadministration of lonafarnib and encorafenib is contraindicated due to the risk of decreased lonafarnib exposure, which may reduce its efficacy. Concomitant use may also increase encorafenib exposure which may increase the risk for adverse effects. If concomitant use is necessary, an encorafenib dosage reduction is required: reduce a daily dose of 450 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Lonafarnib is a sensitive CYP3A substrate and strong CYP3A inhibitor and encorafenib is a CYP3A substrate and strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased the exposure of lonafarnib by 98%. Concomitant use with another strong CYP3A inhibitor increased encorafenib overall exposure by 3-fold.
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: (Contraindicated) Concurrent use of lopinavir and encorafenib is contraindicated. Concurrent use may decrease lopinavir exposure and increase the risk for virologic failure and drug resistance. Concomitant use may also increase the risk for torsade de pointes (TdP) and QT/QTc prolongation. Lopinavir is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications may prolong the QT interval. (Contraindicated) Concurrent use of ritonavir and encorafenib is contraindicated due to the risk of decreased ritonavir exposure which may result in loss of virologic control and drug resistance. Concomitant use may also increase encorafenib exposure which may increase the risk for adverse effects. If concomitant use is necessary, an encorafenib dosage reduction is required: reduce a daily dose of 450 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Ritonavir is a CYP3A substrate and strong CYP3A inhibitor and encorafenib is a CYP3A substrate and strong CYP3A inducer. Concomitant use with another strong CYP3A inhibitor increased encorafenib overall exposure by 3-fold.
Lorlatinib: (Contraindicated) Coadministration of lorlatinib with encorafenib is contraindicated due to the risk severe hepatotoxicity as well as decreased lorlatinib exposure which may reduce its efficacy. Discontinue encorafenib for 3 plasma half-lives prior to initiating therapy with lorlatinib. Lorlatinib is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased lorlatinib exposure by 85% and caused severe (grade 3 or 4) hepatotoxicity in 83% of patients.
Lumacaftor; Ivacaftor: (Major) Avoid concomitant use of lumacaftor; ivacaftor and encorafenib. Concurrent use may decrease the exposure of both drugs, which may reduce their efficacy. Ivacaftor is a substrate of CYP3A and lumacaftor; ivacaftor is a strong CYP3A inducer; encorafenib is a CYP3A substrate and strong CYP3A inducer. In a pharmacokinetic study, coadministration of lumacaftor; ivacaftor with another strong CYP3A inducer decreased ivacaftor exposure by 57%, with minimal effect on the exposure of lumacaftor. (Major) Coadministration of ivacaftor with encorafenib is not recommended due to decreased plasma concentrations of ivacaftor. Ivacaftor is a sensitive CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer significantly decreased ivacaftor exposure by approximately 9-fold.
Lumacaftor; Ivacaftor: (Major) Avoid concomitant use of lumacaftor; ivacaftor and encorafenib. Concurrent use may decrease the exposure of both drugs, which may reduce their efficacy. Ivacaftor is a substrate of CYP3A and lumacaftor; ivacaftor is a strong CYP3A inducer; encorafenib is a CYP3A substrate and strong CYP3A inducer. In a pharmacokinetic study, coadministration of lumacaftor; ivacaftor with another strong CYP3A inducer decreased ivacaftor exposure by 57%, with minimal effect on the exposure of lumacaftor.
Lumateperone: (Major) Avoid coadministration of lumateperone and encorafenib as concurrent use may decrease lumateperone exposure which may reduce efficacy. Lumateperone is a CYP3A substrate; encorafenib is a strong CYP3A inducer. Coadministration of lumateperone with another strong CYP3A inducer decreased lumateperone overall exposure by over 97%.
Lurasidone: (Contraindicated) Coadministration of lurasidone with encorafenib is contraindicated due to decreased plasma concentrations of lurasidone. Lurasidone is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased lurasidone exposure by 83%.
Lurbinectedin: (Major) Avoid coadministration of lurbinectedin and encorafenib due to the risk of decreased lurbinectedin exposure which may reduce its efficacy. Lurbinectedin is a CYP3A substrate and encorafenib is a strong CYP3A inducer.
Macimorelin: (Major) Discontinue encorafenib and allow a sufficient washout period to pass before administering macimorelin. Use of these drugs together can significantly decrease macimorelin plasma concentrations and may result in a false positive test for growth hormone deficiency. Concomitant use also increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Macimorelin is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation.
Macitentan: (Major) Avoid coadministration of macitentan with encorafenib due to the risk of decreased macitentan exposure which may lead to reduced efficacy. Macitentan is a CYP3A substrate and encorafenib is a strong CYP3A inducer.
Macitentan; Tadalafil: (Major) Avoid coadministration of macitentan with encorafenib due to the risk of decreased macitentan exposure which may lead to reduced efficacy. Macitentan is a CYP3A substrate and encorafenib is a strong CYP3A inducer. (Major) Avoid coadministration of tadalafil with encorafenib in patients with pulmonary hypertension due to decreased plasma concentrations of tadalafil. In patients with erectile dysfunction and/or benign prostatic hyperplasia, consider the potential for loss of efficacy of tadalafil during concurrent administration of encorafenib due to reduced tadalafil exposure. Tadalafil is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased tadalafil exposure by 88%.
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: (Major) Coadministration of maraviroc with encorafenib may result in decreased maraviroc efficacy or an increased risk of maraviroc-related adverse reactions; a dose adjustment may be needed. Maraviroc is a sensitive CYP3A and OATP1B1 substrate and encorafenib is both a strong CYP3A inducer and OATP1B1 inhibitor. The net effect on maraviroc exposure is unknown. When administered with a strong CYP3A inducer, without a concomitant strong CYP3A inhibitor, it is recommended to increase the adult dose of maraviroc to 600 mg PO twice daily. Coadministration of maraviroc and encorafenib is contraindicated in patients with CrCl less than 30 mL/min. For pediatric patients, the concomitant use of maraviroc with encorafenib without also taking a strong CYP3A inhibitor is not recommended. If the adult or pediatric patient's medication regimen also contains a strong CYP3A inhibitor, the CYP3A inhibitor's actions are expected to exceed that of encorafenib; overall, increased maraviroc concentrations are expected (see recommended dose adjustments for use of maraviroc with the strong inhibitor).
Maribavir: (Major) Avoid concomitant use of maribavir and encorafenib. Coadministration may decrease maribavir exposure resulting in reduced virologic response. Maribavir is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased the exposure of maribavir by 60%.
Mavacamten: (Contraindicated) Mavacamten is contraindicated for use with encorafenib due to risk for reduced mavacamten efficacy. Concomitant use decreases mavacamten exposure. Mavacamten is a CYP3A substrate and encorafenib is a strong CYP3A inducer. The impact that a CYP3A inducer may have on mavacamten overall exposure varies based on the patient's CYP2C19 metabolizer status. Concomitant use of a strong CYP3A inducer is predicted to decrease mavacamten overall exposure by 69% and 87% in poor and normal CYP2C19 metabolizers, respectively.
Medroxyprogesterone: (Major) Avoid coadministration of medroxyprogesterone with encorafenib as it is expected to decrease concentrations of medroxyprogesterone acetate. Formal drug interaction studies have not been conducted; however, medroxyprogesterone is a CYP3A substrate and encorafenib is a strong CYP3A inducer.
Mefloquine: (Major) Concomitant use of encorafenib and mefloquine increases the risk of QT/QTc prolongation and torsade de pointes (TdP) and may decrease mefloquine exposure and efficacy. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Monitor for altered response to mefloquine, and consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Mefloquine is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation. Coadministration with another strong CYP3A inducer decreased mefloquine exposure by 68%.
Meperidine: (Moderate) Monitor for reduced efficacy of meperidine and signs of opioid withdrawal if coadministration with encorafenib is necessary. Consider increasing the dose of meperidine as needed. If encorafenib is discontinued, consider a dose reduction of meperidine and frequently monitor for signs of respiratory depression and sedation. Meperidine is a substrate of CYP3A; encorafenib is a strong CYP3A inducer. Concomitant use can decrease meperidine exposure resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Metformin; Repaglinide: (Moderate) The dose of repaglinide and frequency of blood glucose monitoring may need to be increased if coadministration with encorafenib is necessary. Repaglinide is a CYP3A substrate and encorafenib is a strong CYP3A inducer.
Methadone: (Major) Concomitant use of encorafenib and methadone increases the risk of QT/QTc prolongation and torsade de pointes (TdP) and may decrease methadone exposure and efficacy. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. If concomitant use is necessary, monitor for reduced efficacy of methadone and signs of opioid withdrawal and consider increasing the dose of methadone as needed. If encorafenib is discontinued, consider a dose reduction of methadone and frequently monitor for signs of respiratory depression and sedation. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Methadone is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation.
Methohexital: (Major) Avoid concomitant use of encorafenib and barbiturates. Concurrent use may decrease encorafenib exposure which may reduce its efficacy. Encorafenib is a CYP3A substrate and barbiturates are strong CYP3A inducers.
Methylergonovine: (Moderate) Monitor for a decrease in methylergonovine efficacy during concomitant use of methylergonovine and encorafenib. Concomitant use may decrease methylergonovine exposure. Methylergonovine is a CYP3A substrate and encorafenib is a strong CYP3A inducer.
Methylprednisolone: (Moderate) Monitor for decreased corticosteroid efficacy if methylprednisolone is used with encorafenib; a dosage increase may be necessary. Concurrent use may decrease the exposure of methylprednisolone. Methylprednisolone is a CYP3A substrate and encorafenib is a strong CYP3A inducer.
Metronidazole: (Major) Concomitant use of metronidazole and encorafenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Midostaurin: (Major) Avoid concurrent use of encorafenib with midostaurin due to the risk for decreased midostaurin exposure and efficacy and additive risk for QT/QTc prolongation and torsade de pointes (TdP). Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Midostaurin is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation. The AUC values of midostaurin and its metabolites CGP62221 and CGP52421 decreased by 96%, 92%, and 59%, respectively, when midostaurin was administered with another strong CYP3A inducer.
Mifepristone: (Major) Avoid concomitant use of encorafenib and mifepristone due to the risk for decreased mifepristone exposure and efficacy, increased encorafenib exposure, and increased risk of QT/QTc prolongation and torsade de pointes (TdP). If concomitant use is necessary, monitor for reduced response to mifepristone and decrease the encorafenib dosage: reduce a daily dose of 450 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Mifepristone is a CYP3A substrate and strong CYP3A inhibitor, encorafenib is a CYP3A substrate and strong CYP3A inducer, and both medications may prolong the QT interval. Concomitant use with another strong CYP3A inhibitor increased encorafenib overall exposure by 3-fold.
Mirtazapine: (Major) Concomitant use of encorafenib and mirtazapine increases the risk of QT/QTc prolongation and torsade de pointes (TdP) and may decrease mirtazapine exposure and efficacy. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. If concomitant use is necessary, monitor for altered response to mirtazapine and adjust mirtazapine dose as needed based on response. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Mirtazapine is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation. Coadministration with other strong CYP3A inducers increased mirtazapine clearance by approximately 2-fold, decreasing average mirtazapine plasma concentrations by 45% to 60%.
Mitapivat: (Major) Avoid coadministration of mitapivat with encorafenib due to decreased mitapivat efficacy. Coadministration decreases mitapivat concentrations. Mitapivat is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased mitapivat overall exposure by 91% to 95%.
Mitotane: (Major) Avoid concomitant use of encorafenib and mitotane. Concurrent use may decrease encorafenib exposure which may reduce its efficacy. Encorafenib is a CYP3A substrate and mitotane is a strong CYP3A inducer.
Mobocertinib: (Major) Avoid concurrent use of encorafenib with mobocertinib due to the risk for decreased mobocertinib exposure and efficacy and additive risk for QT/QTc prolongation and torsade de pointes (TdP). Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Mobocertinib is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation. Use of a strong CYP3A inducer is predicted to decrease the overall exposure of mobocertinib and its active metabolites by 92%.
Modafinil: (Moderate) Monitor for decreased efficacy of modafinil if coadministration with encorafenib is necessary. Modafinil is a CYP3A substrate and encorafenib is a strong CYP3A inducer. The probability of effect of encorafenib on modafinil exposure is low due to the existence of multiple pathways for modafinil metabolism, as well as the fact that a non-CYP-related pathway is the most rapid in metabolizing modafinil; however, plasma concentrations of modafinil may be impacted by strong CYP3A inducers.
Momelotinib: (Moderate) Monitor for an increase in momelotinib-related adverse reactions if coadministration with encorafenib is necessary. Concomitant use may increase momelotinib exposure. Momelotinib is an OATP1B1/3 substrate; encorafenib is an OATP1B1/3 inhibitor. Coadministration with another OATP1B1/1B3 inhibitor increased momelotinib exposure by 57%; exposure of its active M21 metabolite increased by 12%.
Montelukast: (Minor) Monitor for decreased montelukast efficacy if coadministered with encorafenib. The systemic exposure of montelukast may be reduced; however, dosage adjustments are not likely to be needed. Montelukast is a CYP3A substrate; encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased the exposure of montelukast by approximately 40%.
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.
Naldemedine: (Major) Avoid coadministration of naldemedine with encorafenib due the risk for a significant decrease in naldemedine plasma concentrations which may reduce efficacy. Naldemedine is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased naldemedine exposure by 83%.
Naloxegol: (Major) Coadministration of naloxegol with encorafenib is not recommended due to the potential for decreased naloxegol efficacy. Naloxegol is a CYP3A substrate; encorafenib is a strong CYP3A inducer. Coadministration of another strong CYP3A inducer decreased naloxegol exposure by 89%.
Nanoparticle Albumin-Bound Paclitaxel: (Moderate) Monitor for decreased efficacy of nab-paclitaxel if coadministration with encorafenib is necessary due to the risk of decreased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP3A substrate and encorafenib is a strong CYP3A inducer.
Nanoparticle Albumin-Bound Sirolimus: (Major) Avoid concomitant use of sirolimus and encorafenib as use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A substrate and encorafenib is a strong CYP3A inducer.
Naproxen; Esomeprazole: (Major) Avoid concomitant use of esomeprazole and encorafenib as esomeprazole exposure may be decreased, reducing its efficacy. Esomeprazole is a CYP3A substrate and encorafenib is a strong CYP3A inducer.
Nefazodone: (Major) Avoid concomitant use of encorafenib and nefazodone due to the risk for increased encorafenib exposure which may increase the risk for adverse effects. The exposure of nefazodone may also be decreased. If concomitant use is necessary, monitor for altered response to nefazodone and decrease encorafenib dosage: reduce a daily dose of 450 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Encorafenib is a CYP3A substrate and strong CYP3A inducer and nefazodone is a CYP3A substrate and strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased encorafenib overall exposure by 3-fold. Coadministration with another strong CYP3A inducer decreased nefazodone and hydroxynefazodone exposure by almost 95%.
Nelfinavir: (Major) Avoid concomitant use of encorafenib and nelfinavir due to the risk for increased encorafenib exposure which may increase the risk for adverse effects. The exposure of nelfinavir may also be decreased. If concomitant use is necessary, monitor for altered response to nelfinavir and decrease encorafenib dosage: reduce a daily dose of 450 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Encorafenib is a CYP3A substrate and strong CYP3A inducer and nelfinavir is a CYP3A substrate and strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased encorafenib overall exposure by 3-fold. Coadministration with another strong CYP3A inducer decreased the exposure of nelfinavir by 83%.
Neratinib: (Major) Avoid concomitant use of encorafenib with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased neratinib exposure by 87%, while exposure to active metabolites M6 and M7 were reduced by 37% to 49%. Concomitant use with other strong inducers of CYP3A may also decrease neratinib concentrations.
Netupitant, Fosnetupitant; Palonosetron: (Major) Avoid coadministration of netupitant and encorafenib due to the risk of decreased netupitant exposure which may reduce its efficacy and increased encorafenib exposure which may increase the risk for adverse effects. If concomitant use is necessary, an encorafenib dosage reduction is required: reduce a daily dose of 450 mg to 225 mg, reduce a daily dose of 300 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Netupitant is a CYP3A substrate and moderate CYP3A inhibitor and encorafenib is a CYP3A substrate and strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased netupitant exposure by 62%. Concomitant use with another moderate CYP3A inhibitor increased encorafenib overall exposure by 2-fold.
Nevirapine: (Moderate) Use caution and monitor for decreased efficacy of nevirapine if coadministered with encorafenib. Concurrent use may decrease the plasma concentrations of nevirapine leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Nevirapine is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased nevirapine exposure by greater than 50%.
NIFEdipine: (Major) Avoid coadministration of nifedipine with encorafenib and consider alternative therapy if possible. If coadministration is necessary, monitor the patient closely for desired cardiovascular effects on heart rate, blood pressure, or chest pain. The FDA-approved labeling for some nifedipine products contraindicates coadministration with strong CYP3A inducers, while other manufacturers classify the recommendation as a warning. Nifedipine is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration of nifedipine with another strong CYP3A inducer reduced the AUC and Cmax of nifedipine by approximately 70%.
Nilotinib: (Major) Avoid concomitant use of encorafenib and nilotinib due to the risk for decreased nilotinib exposure and efficacy, increased encorafenib exposure and adverse effects, and increased risk of QT/QTc prolongation and torsade de pointes (TdP). If concomitant use is necessary, an encorafenib dosage reduction is required: reduce a daily dose of 450 mg to 225 mg, reduce a daily dose of 300 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Nilotinib is a CYP3A substrate and moderate CYP3A inhibitor, encorafenib is a CYP3A substrate and strong CYP3A inducer, and both medications may prolong the QT interval. In a drug interaction study, coadministration with another strong CYP3A inducer decreased nilotinib exposure by approximately 80%. Concomitant use with another strong CYP3A inhibitor increased encorafenib overall exposure by 3-fold.
Nimodipine: (Major) Avoid coadministration of nimodipine and encorafenib due to the risk of decreased nimodipine exposure which may reduce its efficacy. Nimodipine is a CYP3A substrate and encorafenib is a strong CYP3A inducer.
Niraparib; Abiraterone: (Major) Avoid the concomitant use of abiraterone and encorafenib due to the risk of decreased abiraterone efficacy. If concomitant use is unavoidable, increase the abiraterone dosing frequency to twice daily. Resume the previous dose and frequency when encorafenib is discontinued. Abiraterone is a CYP3A4 substrate and encorafenib is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased abiraterone exposure by 55%.
Nirmatrelvir; Ritonavir: (Contraindicated) Concurrent use of ritonavir and encorafenib is contraindicated due to the risk of decreased ritonavir exposure which may result in loss of virologic control and drug resistance. Concomitant use may also increase encorafenib exposure which may increase the risk for adverse effects. If concomitant use is necessary, an encorafenib dosage reduction is required: reduce a daily dose of 450 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Ritonavir is a CYP3A substrate and strong CYP3A inhibitor and encorafenib is a CYP3A substrate and strong CYP3A inducer. Concomitant use with another strong CYP3A inhibitor increased encorafenib overall exposure by 3-fold. (Moderate) Monitor for a diminished response to nirmatrelvir if concomitant use of encorafenib is necessary. Concomitant use of nirmatrelvir and encorafenib may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and encorafenib is a CYP3A inducer.
Nirogacestat: (Major) Avoid concomitant use of nirogacestat and encorafenib. Concurrent use may decrease nirogacestat exposure and efficacy and increase encorafenib exposure and the risk for encorafenib-related adverse effects. While concomitant use is not recommended, if coadministration is necessary, an encorafenib dosage reduction is required: reduce a daily dose of 450 mg to 225 mg, reduce a daily dose of 300 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Nirogacestat is a CYP3A substrate and moderate CYP3A inhibitor; encorafenib is a CYP3A substrate and strong CYP3A inducer. Concomitant with another strong CYP3A inducer is predicted to reduce nirogacestat overall exposure by 85%. Concomitant use with another moderate CYP3A inhibitor increased encorafenib overall exposure by 2-fold.
Nisoldipine: (Major) Avoid coadministration of nisoldipine with encorafenib as concurrent use may decrease nisoldipine exposure and efficacy. Alternative antihypertensive therapy should be considered. Nisoldipine is a CYP3A substrate and encorafenib is a CYP3A inducer. Coadministration with a strong CYP3A inducer lowered nisoldipine plasma concentrations to undetectable levels.
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 Acetate; Ethinyl Estradiol; 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.
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.
Norethindrone; 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.
Norethindrone; Ethinyl Estradiol; 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.
Norgestimate; 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.
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.
Ofloxacin: (Major) Concomitant use of ofloxacin and encorafenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
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.
Olanzapine; Fluoxetine: (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. (Major) Concomitant use of encorafenib and fluoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Olanzapine; Samidorphan: (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. (Major) Avoid the concurrent use of samidorphan and encorafenib; decreased samidorphan exposure and loss of efficacy may occur. Samidorphan is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Concomitant use of another strong CYP3A inducer reduced samidorphan exposure by 73%.
Olaparib: (Major) Avoid coadministration of olaparib with encorafenib due to the risk of decreasing the efficacy of olaparib. Olaparib is a CYP3A substrate and encorafenib is a strong CYP3A inducer; concomitant use may decrease olaparib exposure. Coadministration with another strong CYP3A inducer decreased the olaparib Cmax by 71% and the AUC by 87%.
Oliceridine: (Moderate) Monitor for reduced efficacy of oliceridine and signs of opioid withdrawal if coadministration with encorafenib is necessary; consider increasing the dose of oliceridine as needed. If encorafenib is discontinued, consider a dose reduction of oliceridine and frequently monitor for signs of respiratory depression and sedation. Oliceridine is a CYP3A substrate and encorafenib is a CYP3A inducer. Concomitant use with CYP3A inducers can decrease the plasma concentrations of oliceridine; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with encorafenib is necessary. Amlodipine is a CYP3A substrate and encorafenib is a strong CYP3A inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Olutasidenib: (Major) Avoid concurrent use of olutasidenib and encorafenib due to the risk of decreased olutasidenib exposure which may reduce its efficacy. Olutasidenib is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced olutasidenib exposure by approximately 80%.
Omaveloxolone: (Major) Avoid concurrent use of omaveloxolone and encorafenib. Concurrent use may decrease omaveloxolone exposure which may reduce its efficacy. Omaveloxolone is a CYP3A substrate and encorafenib is a strong CYP3A inducer.
Omeprazole: (Major) Avoid concomitant use of omeprazole and encorafenib as omeprazole exposure may be decreased, reducing its efficacy. Omeprazole is a CYP3A substrate and encorafenib is a strong CYP3A inducer.
Omeprazole; Amoxicillin; Rifabutin: (Major) Avoid concomitant use of omeprazole and encorafenib as omeprazole exposure may be decreased, reducing its efficacy. Omeprazole is a CYP3A substrate and encorafenib is a strong CYP3A inducer.
Omeprazole; Sodium Bicarbonate: (Major) Avoid concomitant use of omeprazole and encorafenib as omeprazole exposure may be decreased, reducing its efficacy. Omeprazole is a CYP3A substrate and encorafenib is a strong CYP3A inducer.
Ondansetron: (Major) Concomitant use of ondansetron and encorafenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Do not exceed 16 mg of IV ondansetron in a single dose; the degree of QT prolongation associated with ondansetron significantly increases above this dose.
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) Concomitant use of encorafenib and osilodrostat increases the risk of QT/QTc prolongation and torsade de pointes (TdP) and may decrease osilodrostat exposure and efficacy. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Additionally, monitor cortisol concentration and patient's signs and symptoms after initiation and discontinuation of encorafenib; an adjustment in osilodrostat dose may be needed. Osilodrostat is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation.
Osimertinib: (Major) Avoid concurrent use of encorafenib with osimertinib due to the risk for decreased osimertinib exposure and efficacy and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, increase the dose of osimertinib to 160 mg once daily. If encorafenib is discontinued, reduce the dose of osimertinib to 80 mg once daily after a washout period of 3 weeks. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Osimertinib is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation. Coadministration with another strong CYP3A inducer decreased osimertinib exposure by 78%.
Ospemifene: (Moderate) Monitor for decreased efficacy of ospemifene if coadministration with encorafenib is necessary. Ospemifene is a CYP3A substrate; encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased ospemifene exposure by 58%.
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.
Oxcarbazepine: (Moderate) Monitor for decreased plasma levels of MHD, the active metabolite of oxcarbazepine, if coadministered with encorafenib. The oxcarbazepine dose may require adjustment after initiation, dosage modification, or discontinuation of encorafenib. Strong CYP3A inducers like encorafenib have been shown to decrease MHD exposure by 25 to 49%.
Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with encorafenib is necessary; consider increasing the dose of oxycodone as needed. If encorafenib is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Concomitant use with CYP3A inducers can decrease oxycodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
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.
Paclitaxel: (Moderate) Monitor for decreased efficacy of paclitaxel if coadministration with encorafenib is necessary due to the risk of decreased plasma concentrations of paclitaxel. Paclitaxel is a CYP3A substrate and encorafenib is a strong CYP3A inducer.
Pacritinib: (Contraindicated) Concurrent use of pacritinib with encorafenib is contraindicated due to decreased pacritinib exposure which may impair efficacy. Concomitant use also increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Pacritinib is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation. Coadministration with another strong CYP3A inducer decreased pacritinib exposure by 87%.
Palbociclib: (Major) Avoid coadministration of palbociclib with encorafenib due to the risk of decreased palbociclib exposure and reduced efficacy. Palbociclib is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration of another strong CYP3A inducer decreased the plasma exposure of palbociclib 85%.
Paliperidone: (Major) Avoid concurrent use of encorafenib with paliperidone due to the risk for decreased paliperidone exposure and efficacy and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If use of encorafenib is required in patients receiving injectable paliperidone, consider management with oral paliperidone; however, a dosage increase may be necessary. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Paliperidone is a P-gp substrate, with minor contributions in metabolism by CYP3A, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation.
Palovarotene: (Major) Avoid concomitant use of palovarotene and encorafenib. Concurrent use may decrease palovarotene exposure which may reduce its efficacy. Palovarotene is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced palovarotene overall exposure by 11%.
Panobinostat: (Major) Avoid concurrent use of encorafenib with panobinostat due to the risk for decreased panobinostat exposure and efficacy and additive risk for QT/QTc prolongation and torsade de pointes (TdP). Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Panobinostat is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation. Using a physiologically-based pharmacokinetic model, the systemic exposure of panobinostat was estimated to be decreased by 70% when a strong CYP3A inducer was co-administered.
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 pazopanib and encorafenib due to the potential for alterations in pazopanib exposure and increased risk of QT/QTc prolongation and torsade de pointes (TdP). Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Pazopanib is a CYP3A and BCRP substrate, encorafenib is a strong CYP3A inducer and BCRP inhibitor, and both medications may prolong the QT interval. Concomitant use may decrease pazopanib exposure and efficacy or increase exposure and the risk for pazopanib-related adverse effects. The net effect on pazopanib exposure is unknown.
Pemigatinib: (Major) Avoid coadministration of pemigatinib and encorafenib due to the risk of decreased pemigatinib exposure which may reduce its efficacy. Pemigatinib is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased pemigatinib exposure by 85%.
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.
Pentobarbital: (Major) Avoid concomitant use of encorafenib and barbiturates. Concurrent use may decrease encorafenib exposure which may reduce its efficacy. Encorafenib is a CYP3A substrate and barbiturates are strong CYP3A inducers.
Perampanel: (Major) Start perampanel at a higher initial dose of 4 mg once daily at bedtime if perampanel is added to encorafenib therapy; increase the dose as tolerated in 2 mg increments no more than weekly, based on clinical response. If encorafenib is added or withdrawn from perampanel therapy, closely monitor patient response; a dosage adjustment may be necessary. Perampanel is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with other strong CYP3A inducers decreased perampanel exposure by 50% to 67%.
Perindopril; Amlodipine: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with encorafenib is necessary. Amlodipine is a CYP3A substrate and encorafenib is a strong CYP3A inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
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: (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 pexidartinib with encorafenib as concurrent use may decrease pexidartinib exposure which may result in decreased therapeutic response. Pexidartinib is a CYP3A substrate; encorafenib is a strong CYP3A inducer. Coadministration of another strong CYP3A inducer decreased pexidartinib exposure by 65%.
Phenobarbital: (Major) Avoid concomitant use of encorafenib and barbiturates. Concurrent use may decrease encorafenib exposure which may reduce its efficacy. Encorafenib is a CYP3A substrate and barbiturates are strong CYP3A inducers.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid concomitant use of encorafenib and barbiturates. Concurrent use may decrease encorafenib exposure which may reduce its efficacy. Encorafenib is a CYP3A substrate and barbiturates are strong CYP3A inducers.
Phenytoin: (Major) Avoid concomitant use of encorafenib and phenytoin/fosphenytoin. Concurrent use may decrease encorafenib exposure which may reduce its efficacy. Encorafenib is a CYP3A substrate and phenytoin/fosphenytoin is a strong CYP3A inducer.
Pimavanserin: (Major) Avoid concurrent use of encorafenib with pimavanserin due to the risk for decreased pimavanserin exposure and efficacy and additive risk for QT/QTc prolongation and torsade de pointes (TdP). Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Pimavanserin is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation. Coadministration with another strong inducer decreased pimavanserin exposure by 91%.
Pimozide: (Contraindicated) 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).
Pirtobrutinib: (Major) Avoid concurrent use of pirtobrutinib and encorafenib due to the risk of decreased pirtobrutinib exposure which may reduce its efficacy. Pirtobrutinib is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced pirtobrutinib overall exposure by 71%.
Pitavastatin: (Moderate) Monitor for an increase in pitavastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with encorafenib is necessary. Concomitant use may increase pitavastatin exposure. Pitavastatin is an OATP1B1 substrate; encorafenib is an OATP1B1 inhibitor.
Pitolisant: (Major) Avoid concurrent use of encorafenib with pitolisant due to the risk for decreased pitolisant exposure and efficacy and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If concomitant use is necessary, monitor for loss of pitolisant efficacy after initiation of encorafenib and increase pitolisant to double its original daily dose over seven days in patients stable on 8.9 mg or 17.8 mg once daily (i.e., 17.8 mg or 35.6 mg, respectively). Decrease the pitolisant dose by one-half if encorafenib is discontinued. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Pitolisant is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation. Coadministration of strong CYP3A inducers decreases pitolisant exposure by 50%.
Polatuzumab Vedotin: (Moderate) Monitor for decreased polatuzumab vedotin efficacy during coadministration of encorafenib due to the risk of decreased exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A and encorafenib is a strong CYP3A inducer. Strong CYP3A inducers are predicted to decrease the exposure of MMAE by 63%.
Ponatinib: (Major) Avoid coadministration of ponatinib with encorafenib due to decreased plasma concentrations of ponatinib. If concomitant use is unavoidable, monitor for reduced efficacy of ponatinib. Ponatinib is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased ponatinib exposure by 62%.
Ponesimod: (Major) Avoid concurrent use of encorafenib with ponesimod due to the risk for decreased ponesimod exposure and efficacy and additive risk for QT/QTc prolongation and torsade de pointes (TdP). Monitor for altered response to ponesimod and consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Ponesimod is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation. Ponesimod has a limited effect on the QT/QTc interval at therapeutic doses but may cause bradycardia and atrioventricular conduction delays which may increase the risk for TdP in patients with a prolonged QT/QTc interval.
Posaconazole: (Contraindicated) Posaconazole use is contraindicated with CYP3A substrates that may prolong the QT interval, such as encorafenib. Avoid concomitant use of encorafenib and posaconazole due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase encorafenib exposure and the risk for other encorafenib-related adverse effects. If concomitant use is necessary, an encorafenib dosage reduction is required: reduce a daily dose of 450 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Encorafenib is a CYP3A substrate, posaconazole is a strong CYP3A inhibitor, and both medications may prolong the QT interval. Concomitant use increased encorafenib overall exposure by 3-fold.
Pralsetinib: (Major) Avoid concurrent use of encorafenib and pralsetinib due to the risk of decreased pralsetinib exposure which may reduce its efficacy. If concomitant use is necessary, double the current dose of pralsetinib starting on day 7 of coadministration. After encorafenib has been discontinued for at least 14 days, resume the pralsetinib dose taken prior to initiating encorafenib. Pralsetinib is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased the pralsetinib AUC by 68%.
Pravastatin: (Moderate) Monitor for an increase in pravastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with encorafenib is necessary. Concomitant use may increase pravastatin exposure. Pravastatin is an OATP1B1/3 substrate; encorafenib is an OATP1B1/3 inhibitor.
Praziquantel: (Contraindicated) Concomitant use of praziquantel and encorafenib is contraindicated due to the risk of decreased praziquantel exposure which may reduce its efficacy. Praziquantel is a CYP3A substrate and encorafenib is a strong CYP3A inducer. In a crossover study with a 2-week washout period, administration of praziquantel followed by another strong CYP3A inducer resulted in undetectable plasma concentrations of praziquantel in 7 out of 10 subjects. When praziquantel was administered 2 weeks after discontinuation of the strong inducer, the mean praziquantel AUC was 23% lower than when praziquantel was given alone.
Prednisolone: (Moderate) Monitor for decreased corticosteroid efficacy if prednisolone is used with encorafenib; a dosage increase may be necessary. Concurrent use may decrease the exposure of prednisolone. Prednisolone is a CYP3A substrate and encorafenib is a strong CYP3A inducer.
Prednisone: (Moderate) Monitor for decreased corticosteroid efficacy if prednisone is used with encorafenib; a dosage increase may be necessary. Concurrent use may decrease the exposure of prednisone. Prednisone is a CYP3A substrate and encorafenib is a strong CYP3A inducer.
Pretomanid: (Major) Avoid coadministration of pretomanid with encorafenib as concurrent use may decrease pretomanid exposure which may lead to decreased efficacy. Pretomanid is a CYP3A substrate; encorafenib is a strong CYP3A inducer.
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 concomitant use of encorafenib and barbiturates. Concurrent use may decrease encorafenib exposure which may reduce its efficacy. Encorafenib is a CYP3A substrate and barbiturates are strong CYP3A inducers.
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) Concomitant use of promethazine and encorafenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Promethazine; Dextromethorphan: (Major) Concomitant use of promethazine and encorafenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Promethazine; Phenylephrine: (Major) Concomitant use of promethazine and encorafenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Propafenone: (Major) Concomitant use of propafenone and encorafenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Quazepam: (Moderate) Monitor for withdrawal symptoms or lack of quazepam efficacy if coadministration with encorafenib is necessary. Concurrent use may decrease the concentrations of quazepam. Quazepam is a CYP3A substrate and encorafenib is a strong CYP3A inducer.
Quetiapine: (Major) Avoid concurrent use of encorafenib with quetiapine due to the risk for decreased quetiapine exposure and efficacy and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If concomitant use is necessary, increase the dose of quetiapine by up to 5-fold. If encorafenib is discontinued, reduce the quetiapine dose to the original level in 7 to 14 days. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Quetiapine is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation. Coadministration with another strong CYP3A inducer increased the mean oral clearance of quetiapine by 5-fold.
Quinidine: (Major) Concomitant use of encorafenib and quinidine increases the risk of QT/QTc prolongation and torsade de pointes (TdP) and may decrease quinidine exposure and efficacy. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Monitor for altered response to quinidine and consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Quinidine is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation.
Quinine: (Major) Concomitant use of encorafenib and quinine increases the risk of QT/QTc prolongation and torsade de pointes (TdP) and may decrease quinine exposure and efficacy. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Monitor for altered response to quinine and consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Quinine is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation. Coadministration with another strong CYP3A inducer decreased the exposure of quinine by 75%.
Quizartinib: (Major) Avoid concurrent use of encorafenib with quizartinib due to the risk for decreased quizartinib exposure and efficacy and additive risk for QT/QTc prolongation and torsade de pointes (TdP). Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Quizartinib is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation.
Ramelteon: (Moderate) Monitor for a decrease in the efficacy of ramelteon if coadministration with encorafenib is necessary. Ramelteon is a CYP3A substrate; encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased total exposure to ramelteon and metabolite M-II by approximately 80%.
Ranolazine: (Contraindicated) Coadministration of ranolazine with encorafenib is contraindicated due to the risk for decreased ranolazine exposure and efficacy. Concomitant use also increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Ranolazine is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation. Coadministration of another strong CYP3A inducer decreased the plasma concentrations of ranolazine by approximately 95%.
Regorafenib: (Major) Avoid coadministration of regorafenib with encorafenib due to decreased plasma concentrations of regorafenib and increased plasma concentrations of the M-5 active metabolite, which may lead to decreased efficacy. Regorafenib is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased the mean AUC of regorafenib by 50% and increased the mean AUC of M-5 by 264%; no change in the mean AUC of M-2 was observed.
Relugolix: (Major) Avoid coadministration of encorafenib and relugolix 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. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval.
Relugolix; 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. (Major) Avoid coadministration of encorafenib and relugolix 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. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval.
Repaglinide: (Moderate) The dose of repaglinide and frequency of blood glucose monitoring may need to be increased if coadministration with encorafenib is necessary. Repaglinide is a CYP3A substrate and encorafenib is a strong CYP3A inducer.
Repotrectinib: (Major) Avoid coadministration of repotrectinib with encorafenib due to decreased repotrectinib exposure and risk of decreased efficacy. Repotrectinib is a CYP3A substrate; encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased repotrectinib overall exposure by 92%.
Resmetirom: (Major) Avoid concomitant use of resmetirom and encorafenib due to the risk for increased resmetirom exposure which may increase the risk for resmetirom-related adverse effects. Resmetirom is an OATP1B1/3 substrate and encorafenib is an OATP1B1/3 inhibitor.
Revefenacin: (Major) Avoid concomitant use of revefenacin and encorafenib. Concomitant use may increase exposure to the active metabolite of revefenacin and the risk for anticholinergic adverse effects. The active metabolite of revefenacin is a substrate of OATP1B1/3; encorafenib is an inhibitor of OATP1B1/3.
Ribociclib: (Major) Avoid concomitant use of encorafenib and ribociclib due to the risk for decreased ribociclib exposure and efficacy, increased encorafenib exposure and adverse effects, and increased risk of QT/QTc prolongation and torsade de pointes (TdP). If concomitant use is necessary, an encorafenib dosage reduction is required: reduce a daily dose of 450 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Ribociclib is a CYP3A substrate and strong CYP3A inhibitor, encorafenib is a CYP3A substrate and strong CYP3A inducer, and both medications may prolong the QT interval. Coadministration with a strong inducer decreased ribociclib exposure in healthy subjects by 89%. Concomitant use with another strong CYP3A inhibitor increased encorafenib overall exposure by 3-fold.
Ribociclib; Letrozole: (Major) Avoid concomitant use of encorafenib and ribociclib due to the risk for decreased ribociclib exposure and efficacy, increased encorafenib exposure and adverse effects, and increased risk of QT/QTc prolongation and torsade de pointes (TdP). If concomitant use is necessary, an encorafenib dosage reduction is required: reduce a daily dose of 450 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Ribociclib is a CYP3A substrate and strong CYP3A inhibitor, encorafenib is a CYP3A substrate and strong CYP3A inducer, and both medications may prolong the QT interval. Coadministration with a strong inducer decreased ribociclib exposure in healthy subjects by 89%. Concomitant use with another strong CYP3A inhibitor increased encorafenib overall exposure by 3-fold.
Rifampin: (Major) Avoid concomitant use of encorafenib and rifampin. Concurrent use may decrease encorafenib exposure which may reduce its efficacy. Encorafenib is a CYP3A substrate and rifampin is a strong CYP3A inducer.
Rifapentine: (Major) Avoid concomitant use of encorafenib and rifapentine. Concurrent use may decrease encorafenib exposure which may reduce its efficacy. Encorafenib is a CYP3A substrate and rifapentine is a strong CYP3A inducer.
Rilpivirine: (Major) Concomitant use of encorafenib and rilpivirine increases the risk of QT/QTc prolongation and torsade de pointes (TdP) and may decrease rilpivirine exposure and efficacy. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Monitor for altered response to rilpivirine and consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Rilpivirine is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation. Coadministration with another strong CYP3A inducer decreased rilpivirine exposure by approximately 80%. Although specific recommendations are unavailable for use with encorafenib, coadministration with other strong CYP3A inducers is contraindicated.
Rimegepant: (Major) Avoid coadministration of rimegepant with encorafenib; concurrent use may significantly decrease rimegepant exposure which may result in loss of efficacy. Rimegepant is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration of rimegepant with another strong CYP3A inducer decreased rimegepant exposure by 80%.
Riociguat: (Moderate) Coadministration of riociguat with encorafenib may significantly reduce riociguat exposure; however, riociguat dosage adjustment recommendations are not available. Riociguat is a CYP3A substrate and encorafenib is a strong CYP3A inducer.
Ripretinib: (Major) Avoid coadministration of ripretinib with encorafenib. Coadministration may decrease the exposure of ripretinib and its active metabolite (DP-5439), which may decrease ripretinib anti-tumor activity. Ripretinib and DP-5439 are metabolized by CYP3A and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased ripretinib exposure by 61% and decreased DP-5439 exposure by 57%.
Risperidone: (Major) Concomitant use of encorafenib and risperidone increases the risk of QT/QTc prolongation and torsade de pointes (TdP) and may decrease risperidone exposure and efficacy. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Monitor for altered response to risperidone and consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Risperidone is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation. Concomitant use with another strong CYP3A inducer reduced risperidone overall exposure by 50%.
Ritlecitinib: (Major) Avoid concomitant use of encorafenib and ritlecitinib due to the risk for increased encorafenib exposure which may increase the risk for adverse effects. The exposure of ritlecitinib may also be decreased. If concomitant use is necessary, monitor for altered response to ritlecitinib and decrease encorafenib dosage: reduce a daily dose of 450 mg to 225 mg, reduce a daily dose of 300 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Ritlecitinib is a CYP3A substrate and moderate CYP3A inhibitor and encorafenib is a CYP3A substrate and strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced ritlecitinib overall exposure by 0.56-fold. Concomitant use with another moderate CYP3A inhibitor increased encorafenib overall exposure by 2-fold.
Ritonavir: (Contraindicated) Concurrent use of ritonavir and encorafenib is contraindicated due to the risk of decreased ritonavir exposure which may result in loss of virologic control and drug resistance. Concomitant use may also increase encorafenib exposure which may increase the risk for adverse effects. If concomitant use is necessary, an encorafenib dosage reduction is required: reduce a daily dose of 450 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Ritonavir is a CYP3A substrate and strong CYP3A inhibitor and encorafenib is a CYP3A substrate and strong CYP3A inducer. Concomitant use with another strong CYP3A inhibitor increased encorafenib overall exposure by 3-fold.
Roflumilast: (Major) Concomitant use of roflumilast and encorafenib is not recommended. Concurrent use may decrease the systemic exposure to roflumilast which may reduce its efficacy. Roflumilast is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased roflumilast exposure by 80%; exposure to roflumilast N-oxide was decreased by 56%.
Rolapitant: (Major) Avoid coadministration of rolapitant with encorafenib due to decreased plasma concentrations of rolapitant. Rolapitant is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased rolapitant exposure by 85%; the mean half-life of rolapitant decreased from 176 hours to 41 hours.
Romidepsin: (Major) Avoid concurrent use of encorafenib with romidepsin due to the risk for decreased romidepsin exposure and efficacy and additive risk for QT/QTc prolongation and torsade de pointes (TdP). Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Romidepsin is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation. The effect of strong CYP3A inducers on the exposure of romidepsin is unknown.
Rosuvastatin: (Moderate) Monitor for an increase in rosuvastatin-related adverse reactions, including myopathy and rhabdomyolysis, during concomitant use with encorafenib. Concurrent use may increase rosuvastatin exposure. Rosuvastatin is a substrate of OATP1B1/3 and BCRP; encorafenib is an OATP1B1/3 and BCRP inhibitor.
Rosuvastatin; Ezetimibe: (Moderate) Monitor for an increase in rosuvastatin-related adverse reactions, including myopathy and rhabdomyolysis, during concomitant use with encorafenib. Concurrent use may increase rosuvastatin exposure. Rosuvastatin is a substrate of OATP1B1/3 and BCRP; encorafenib is an OATP1B1/3 and BCRP inhibitor.
Ruxolitinib: (Moderate) Monitor patients frequently and adjust the ruxolitinib dose based on safety and efficacy if coadministered with encorafenib; decreased ruxolitinib exposure is possible. Ruxolitinib is a CYP3A substrate; encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased ruxolitinib exposure by 61%. The relative exposure to ruxolitinib's active metabolites increased approximately 100%.
Saquinavir: (Major) Avoid concomitant use of encorafenib and saquinavir due to the risk for decreased saquinavir exposure and efficacy, increased encorafenib exposure and adverse effects, and increased risk of QT/QTc prolongation and torsade de pointes (TdP). If concomitant use is necessary, monitor for altered response to saquinavir and decrease the encorafenib dosage: reduce a daily dose of 450 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Saquinavir is a CYP3A substrate and strong CYP3A inhibitor, encorafenib is a CYP3A substrate and strong CYP3A inducer, and both medications may prolong the QT interval. Concomitant use with another strong CYP3A inhibitor increased encorafenib overall exposure by 3-fold.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Secobarbital: (Major) Avoid concomitant use of encorafenib and barbiturates. Concurrent use may decrease encorafenib exposure which may reduce its efficacy. Encorafenib is a CYP3A substrate and barbiturates are strong CYP3A inducers.
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.
Selegiline: (Moderate) Monitor for a decrease in selegiline efficacy if coadministered with encorafenib. Although adequate studies have not been conducted, concurrent use may decrease selegiline exposure. Selegiline is a CYP3A substrate and encorafenib is a strong CYP3A inducer.
Selpercatinib: (Major) Avoid concurrent use of encorafenib with selpercatinib due to the risk for decreased selpercatinib exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Selpercatinib is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation. Coadministration with another strong CYP3A inducer decreased selpercatinib exposure by 87%
Selumetinib: (Major) Avoid coadministration of selumetinib and encorafenib due to the risk of decreased selumetinib exposure which may reduce its efficacy. Selumetinib is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased selumetinib exposure by 51%.
Sertraline: (Major) Concomitant use of sertraline and encorafenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with sertraline is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 2 times the maximum recommended dose.
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.
Sildenafil: (Moderate) Monitor for decreased efficacy of sildenafil if coadministration with encorafenib is necessary as concurrent use may decrease sildenafil exposure. Sildenafil is a sensitive CYP3A substrate and encorafenib is a strong CYP3A inducer. Concomitant administration of strong CYP3A inducers is expected to substantially decrease plasma concentrations of sildenafil.
Simvastatin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with encorafenib is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is an OATP1B1 substrate and encorafenib is an OATP1B1 inhibitor.
Siponimod: (Major) Concomitant use of encorafenib and siponimod increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Additionally, concomitant use of siponimod and encorafenib is not recommended for patients with CYP2C9*1/*3 and *2/*3 genotypes due to a significant decrease in siponimod exposure. Use of siponimod with encorafenib is also not recommended in any patient if they are also receiving a moderate CYP2C9 inducer. Siponimod is a CYP2C9 and CYP3A substrate; encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation. Coadministration with a moderate CYP2C9/strong CYP3A dual inducer decreased siponimod exposure by 57%.
Sirolimus: (Major) Avoid concomitant use of sirolimus and encorafenib as use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A substrate and encorafenib is a strong CYP3A inducer.
Sodium Phenylbutyrate; Taurursodiol: (Major) Avoid coadministration of sodium phenylbutyrate; taurursodiol and encorafenib. Concomitant use may increase plasma concentrations of sodium phenylbutyrate; taurursodiol. Sodium phenylbutyrate; taurursodiol is an OATP1B3 substrate and encorafenib is an OATP1B3 inhibitor.
Sodium Stibogluconate: (Major) Concomitant use of sodium stibogluconate and encorafenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Sofosbuvir; Velpatasvir: (Major) Concomitant use of velpatasvir with encorafenib is not recommended due to the risk of decreased plasma concentrations of velpatasvir, which may result in loss of antiviral efficacy. Velpatasvir is a CYP3A substrate and encorafenib is a strong CYP3A inducer.
Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Avoid concomitant use of voxilaprevir and encorafenib due to altered voxilaprevir exposure. Concomitant use may decrease plasma concentrations of voxilaprevir, which may result in loss of antiviral efficacy, or increase voxilaprevir exposure and the risk of voxilaprevir-related adverse reactions. Voxilaprevir is a CYP3A and OATP1B1/3 substrate and encorafenib is a strong CYP3A inducer and OATP1B1/3 inhibitor. The net effect on voxilaprevir exposure is unknown. (Major) Concomitant use of velpatasvir with encorafenib is not recommended due to the risk of decreased plasma concentrations of velpatasvir, which may result in loss of antiviral efficacy. Velpatasvir is a CYP3A substrate and encorafenib is a strong CYP3A inducer.
Solifenacin: (Major) Concomitant use of encorafenib and solifenacin increases the risk of QT/QTc prolongation and torsade de pointes (TdP) and may decrease solifenacin exposure and efficacy. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Monitor for altered response to solifenacin and consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Solifenacin is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation.
Sonidegib: (Major) Avoid the concomitant use of sonidegib and encorafenib; sonidegib exposure may be significantly decreased and its efficacy reduced. Sonidegib is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration of a strong CYP3A inducer decreased the geometric mean Cmax and AUC of sonidegib by 54% and 72%, respectively.
Sorafenib: (Major) Avoid concurrent use of encorafenib with sorafenib due to the risk for decreased sorafenib exposure and efficacy and additive risk for QT/QTc prolongation and torsade de pointes (TdP). Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Sorafenib is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation. Concomitant use with another strong CYP3A inducer decreased sorafenib exposure by 37%.
Sotalol: (Major) Concomitant use of sotalol and encorafenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Sotorasib: (Major) Avoid concurrent use of sotorasib and encorafenib. Coadministration may decrease sotorasib exposure resulting in decreased efficacy. Sotorasib is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased the overall exposure of sotorasib by 51%.
Sparsentan: (Major) Avoid concomitant use of sparsentan and encorafenib due to the risk for decreased sparsentan exposure which may reduce its efficacy. Sparsentan is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer is predicted to decrease sparsentan overall exposure by 47%.
St. John's Wort, Hypericum perforatum: (Major) Avoid concomitant use of encorafenib and St. John's wort. Concurrent use may decrease encorafenib exposure which may reduce its efficacy. Encorafenib is a CYP3A substrate and St. John's wort is a strong CYP3A inducer.
Stiripentol: (Major) Avoid coadministration of stiripentol with encorafenib. If concurrent use is necessary, consider a dose increase of stiripentol. Coadministration may decrease stiripentol plasma concentrations resulting in a decrease in efficacy. Stiripentol is a CYP3A substrate and encorafenib is a strong CYP3A inducer.
Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if encorafenib must be administered. Monitor for reduced efficacy of sufentanil injection and signs of opioid withdrawal if coadministration with encorafenib is necessary; consider increasing the dose of sufentanil injection as needed. If encorafenib is discontinued, consider a dose reduction of sufentanil injection and frequently monitor for signs of respiratory depression and sedation. Sufentanil is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Concomitant use with CYP3A inducers can decrease sufentanil concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Sunitinib: (Major) Avoid concurrent use of encorafenib with sunitinib due to the risk for decreased sunitinib exposure and efficacy and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, consider increasing the daily dose of sunitinib to a maximum of 87.5 mg for patients with GIST or RCC, and to a maximum of 62.5 mg for patients with pNET; monitor carefully for toxicity. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Sunitinib is a CYP3A substrate; encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation. Coadministration with another strong CYP3A inducer decreased exposure to sunitinib and its primary active metabolite by 46%.
Suvorexant: (Moderate) Monitor for decreased efficacy of suvorexant if coadministration with encorafenib is necessary. Suvorexant is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased suvorexant exposure by 77% to 88%.
Tacrolimus: (Major) Avoid concurrent use of encorafenib with tacrolimus due to the risk for decreased tacrolimus exposure and efficacy and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If concomitant use is necessary, monitor tacrolimus serum concentrations and increase tacrolimus dose as appropriate. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Tacrolimus is a sensitive CYP3A substrate; encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation.
Tadalafil: (Major) Avoid coadministration of tadalafil with encorafenib in patients with pulmonary hypertension due to decreased plasma concentrations of tadalafil. In patients with erectile dysfunction and/or benign prostatic hyperplasia, consider the potential for loss of efficacy of tadalafil during concurrent administration of encorafenib due to reduced tadalafil exposure. Tadalafil is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased tadalafil exposure by 88%.
Talazoparib: (Moderate) Monitor for an increase in talazoparib-related adverse reactions if concomitant use of encorafenib is necessary. Concomitant use may increase talazoparib exposure. Talazoparib is a BCRP substrate and encorafenib is a BCRP inhibitor.
Tamoxifen: (Major) Avoid concurrent use of encorafenib with tamoxifen due to the risk for decreased tamoxifen exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Tamoxifen is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation. Coadministration with another strong CYP3A inducer decreased the AUC of tamoxifen by 86%.
Tasimelteon: (Major) Avoid coadministration of tasimelteon with encorafenib due to the potential for a large decrease in tasimelteon exposure resulting in reduced efficacy. Tasimelteon is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased tasimelteon exposure by about 90%.
Tazemetostat: (Major) Avoid coadministration of tazemetostat with encorafenib as concurrent use may decrease tazemetostat exposure, which may reduce its efficacy. Tazemetostat is a CYP3A substrate and encorafenib is a strong CYP3A inducer.
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.
Telmisartan; Amlodipine: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with encorafenib is necessary. Amlodipine is a CYP3A substrate and encorafenib is a strong CYP3A inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Temsirolimus: (Major) Avoid coadministration of temsirolimus and encorafenib due to the risk of decreased temsirolimus exposure which may reduce its efficacy. If concomitant use is unavoidable, consider increasing the dose of temsirolimus from 25 mg per week up to 50 mg per week. If encorafenib is discontinued, resume the original temsirolimus dose. Temsirolimus is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer did not have a significant effect on temsirolimus exposure but decreased the exposure of sirolimus (the primary and active metabolite) by 56%.
Tenofovir Alafenamide: (Moderate) Coadministration of tenofovir alafenamide with encorafenib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp and BCRP substrate and encorafenib is a BCRP inhibitor.
Tenofovir Alafenamide: (Moderate) Coadministration of tenofovir alafenamide with encorafenib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp and BCRP substrate and encorafenib is a BCRP inhibitor.
Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with encorafenib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a BCRP substrate and encorafenib is a BCRP inhibitor.
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 ivacaftor with encorafenib is not recommended due to decreased plasma concentrations of ivacaftor. Ivacaftor is a sensitive CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer significantly decreased ivacaftor exposure by approximately 9-fold. (Major) Do not administer tezacaftor; ivacaftor and encorafenib together; coadministration may reduce the efficacy of tezacaftor; ivacaftor. Exposure to ivacaftor is significantly decreased and exposure to tezacaftor may be reduced by the concomitant use of encorafenib, a strong CYP3A inducer; both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate). Coadministration of ivacaftor with a strong CYP3A inducer decreased ivacaftor exposure 89%. Tezacaftor exposures can also be expected to decrease significantly during coadministration with strong CYP3A inducers.
Thioridazine: (Contraindicated) 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).
Thiotepa: (Major) Avoid the concomitant use of thiotepa and encorafenib if possible; increased metabolism to the active thiotepa metabolite may result in increased thiotepa toxicity (e.g., infection, bleeding, skin toxicity). Consider an alternative agent with no or minimal potential to induce CYP3A. If coadministration is necessary, monitor patients for signs and symptoms of thiotepa toxicity. In vitro, thiotepa is metabolized via CYP3A to the active metabolite, TEPA; encorafenib is a strong CYP3A inducer.
Tiagabine: (Moderate) Monitor for decreased efficacy of tiagabine if coadministration with encorafenib is necessary. Tiagabine is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Population pharmacokinetic analyses indicate that tiagabine clearance is 60% greater in patients taking another strong CYP3A inducer.
Ticagrelor: (Major) Avoid coadministration of ticagrelor with encorafenib due to decreased plasma concentrations of ticagrelor. Ticagrelor is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased ticagrelor exposure by 86%.
Tinidazole: (Moderate) Monitor for decreased efficacy of tinidazole if coadministration with encorafenib is necessary. Concomitant use may accelerate the elimination of tinidazole, decreasing plasma concentrations. Tinidazole is a CYP3A substrate and encorafenib is a strong CYP3A inducer.
Tipranavir: (Contraindicated) Concurrent use of tipranavir and encorafenib is contraindicated due to the risk of decreased tipranavir exposure which may result in loss of virologic control and drug resistance. Concomitant use may also increase encorafenib exposure which may increase the risk for adverse effects. If concomitant use is necessary, an encorafenib dosage reduction is required: reduce a daily dose of 450 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Tipranavir is a CYP3A substrate and strong CYP3A inhibitor and encorafenib is a CYP3A substrate and strong CYP3A inducer. Concomitant use with another strong CYP3A inhibitor increased encorafenib overall exposure by 3-fold.
Tivozanib: (Major) Avoid concomitant use of tivozanib with encorafenib due to decreased plasma concentrations of tivozanib, which may reduce its efficacy. Tivozanib is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased the overall exposure of tivozanib by 52%.
Tofacitinib: (Major) Coadministration of tofacitinib and encorafenib is not recommended due to the potential for a loss of response or reduced clinical response to tofacitinib. Tofacitinib is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased the mean overall exposure and peak of tofacitinib by 84% and 74%, 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: (Major) Avoid concurrent use of tolvaptan and encorafenib due to the risk for decreased tolvaptan plasma concentrations and reduced efficacy. Tolvaptan is a sensitive CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased tolvaptan exposure by 85%.
Topotecan: (Major) Avoid coadministration of encorafenib with oral topotecan due to increased topotecan exposure; encorafenib may be administered with intravenous topotecan. Oral topotecan is a substrate of the BCRP and encorafenib is a BCRP inhibitor. Coadministration increases the risk of topotecan-related adverse reactions.
Toremifene: (Major) Avoid concurrent use of encorafenib with toremifene due to the risk for decreased toremifene exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Toremifene is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation.
Trabectedin: (Major) Avoid the concomitant use of trabectedin with encorafenib due to the risk of decreased trabectedin exposure. Trabectedin is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased the systemic exposure of a single dose of trabectedin by 31% compared to a single dose of trabectedin given alone.
Tramadol: (Moderate) Monitor for reduced efficacy of tramadol and signs of opioid withdrawal if coadministration with encorafenib is necessary; consider increasing the dose of tramadol as needed. If encorafenib is discontinued, consider a dose reduction of tramadol and frequently monitor for seizures, serotonin syndrome, and signs of respiratory depression and sedation. Tramadol is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Concomitant use with CYP3A inducers can decrease tramadol levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Tramadol; Acetaminophen: (Moderate) Monitor for reduced efficacy of tramadol and signs of opioid withdrawal if coadministration with encorafenib is necessary; consider increasing the dose of tramadol as needed. If encorafenib is discontinued, consider a dose reduction of tramadol and frequently monitor for seizures, serotonin syndrome, and signs of respiratory depression and sedation. Tramadol is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Concomitant use with CYP3A inducers can decrease tramadol levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Trandolapril; Verapamil: (Major) Avoid concomitant use of encorafenib and verapamil due to the risk for increased encorafenib exposure which may increase the risk for adverse effects. The exposure of verapamil may also be decreased. If concomitant use is necessary, monitor for altered response to verapamil and decrease encorafenib dosage: reduce a daily dose of 450 mg to 225 mg, reduce a daily dose of 300 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Verapamil is a CYP3A substrate and moderate CYP3A inhibitor and encorafenib is a CYP3A substrate and strong CYP3A inducer. Concomitant use with another moderate CYP3A inhibitor increased encorafenib overall exposure by 2-fold.
Trazodone: (Major) Concomitant use of encorafenib and trazodone increases the risk of QT/QTc prolongation and torsade de pointes (TdP) and may decrease trazodone exposure and efficacy. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. If concomitant use is necessary, monitor for altered response to trazodone and increase the trazodone dose as needed based on therapeutic response. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Trazodone is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation. Coadministration with other strong CYP3A inducers decreased the exposure of trazodone compared to the use of trazodone alone.
Triazolam: (Moderate) Monitor for withdrawal symptoms or lack of triazolam efficacy if coadministration with encorafenib is necessary. Triazolam is a CYP3A substrate and encorafenib is a strong CYP3A inducer.
Triclabendazole: (Major) Concomitant use of triclabendazole and encorafenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
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.
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 tucatinib and encorafenib due to the risk of decreased tucatinib exposure which may reduce its efficacy and increased encorafenib exposure which may increase the risk for adverse effects. If concomitant use is necessary, an encorafenib dosage reduction is required: reduce a daily dose of 450 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Tucatinib is a CYP3A substrate and strong CYP3A inhibitor and encorafenib is a CYP3A substrate and strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased tucatinib exposure by 50%. Concomitant use with another strong CYP3A inhibitor increased encorafenib overall exposure by 3-fold.
Ubrogepant: (Major) Avoid coadministration of ubrogepant and encorafenib due to altered ubrogepant exposure. Concurrent use may decrease ubrogepant exposure and reduce efficacy or increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a CYP3A and BCRP substrate and encorafenib is a strong CYP3A inducer and BCRP inhibitor. The net effect on ubrogepant exposure is unknown. Coadministration with another strong CYP3A inducer resulted in an 80% reduction in ubrogepant exposure.
Ulipristal: (Major) Avoid coadministration of ulipristal with encorafenib. Concomitant use may decrease the plasma concentration and effectiveness of ulipristal. Ulipristal is a substrate of CYP3A and encorafenib is a CYP3A inducer.
Upadacitinib: (Major) Coadministration of upadacitinib with encorafenib is not recommended as upadacitinib exposure may be decreased leading to reduced therapeutic effect. Upadacitinib is CYP3A substrate; encorafenib is a strong CYP3A inducer. Concurrent use of a strong CYP3A inducer decreased upadacitinib exposure by 61%.
Valbenazine: (Major) Coadministration of valbenazine with encorafenib is not recommended as plasma concentrations of valbenazine and its active metabolite may be decreased. Reduced exposure of valbenazine and its active metabolite may reduce efficacy. Valbenazine is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased exposure to valbenazine and NBI-98782 by 70% and 80%, respectively.
Vandetanib: (Major) Avoid concurrent use of encorafenib with vandenatib due to the risk for decreased vandenatib exposure and efficacy and additive risk for QT/QTc prolongation and torsade de pointes (TdP). Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Vandenatib is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation. Concomitant use with another strong CYP3A inducer decreased the AUC of vandetanib by 40%.
Vardenafil: (Major) Concomitant use of vardenafil and encorafenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Vemurafenib: (Major) Avoid concurrent use of encorafenib with vemurafenib due to the risk for decreased vemurafenib exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If use with encorafenib cannot be avoided, increase the vemurafenib dose by 240 mg (as tolerated). The original dose of vemurafenib may be resumed 2 weeks after encorafenib is discontinued. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Vemurafenib is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation. Coadministration with another strong CYP3A inducer decreased the exposure of vemurafenib by 40%.
Venetoclax: (Major) Avoid coadministration of venetoclax with encorafenib as concurrent use may decrease venetoclax exposure and lead to reduced efficacy. Venetoclax is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased venetoclax exposure by 71%.
Venlafaxine: (Major) Concomitant use of venlafaxine and encorafenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Verapamil: (Major) Avoid concomitant use of encorafenib and verapamil due to the risk for increased encorafenib exposure which may increase the risk for adverse effects. The exposure of verapamil may also be decreased. If concomitant use is necessary, monitor for altered response to verapamil and decrease encorafenib dosage: reduce a daily dose of 450 mg to 225 mg, reduce a daily dose of 300 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Verapamil is a CYP3A substrate and moderate CYP3A inhibitor and encorafenib is a CYP3A substrate and strong CYP3A inducer. Concomitant use with another moderate CYP3A inhibitor increased encorafenib overall exposure by 2-fold.
Vilazodone: (Moderate) Consider increasing the dose of vilazodone up to 2-fold over 1 to 2 weeks (maximum, 80 mg per day) based on clinical response if coadministration with encorafenib is necessary for more than 14 days. After discontinuation of encorafenib, resume the previous vilazodone dose over 1 to 2 weeks. Vilazodone is primarily metabolized by CYP3A and encorafenib is a strong CYP3A inducer. Decreased plasma concentrations of vilazodone are expected if vilazodone is used concomitantly with strong CYP3A inducers.
Vincristine Liposomal: (Major) Avoid coadministration of vincristine and encorafenib due to the risk of decreased vincristine exposure which may reduce its efficacy. Vincristine is a CYP3A substrate and encorafenib is a strong CYP3A inducer.
Vincristine: (Major) Avoid coadministration of vincristine and encorafenib due to the risk of decreased vincristine exposure which may reduce its efficacy. Vincristine is a CYP3A substrate and encorafenib is a strong CYP3A inducer.
Voclosporin: (Major) Avoid concurrent use of encorafenib with voclosporin due to the risk for decreased voclosporin exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Voclosporin is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation. Coadministration with another strong CYP3A inducer decreased voclosporin exposure by 87%. The degree of QT prolongation associated with voclosporin is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Vonoprazan: (Major) Avoid concomitant use of vonoprazan and encorafenib due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A inducer.
Vonoprazan; Amoxicillin: (Major) Avoid concomitant use of vonoprazan and encorafenib due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A inducer.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Avoid concomitant use of encorafenib and clarithromycin due to the risk for decreased clarithromycin exposure, increased encorafenib exposure, and increased risk of QT/QTc prolongation and torsade de pointes (TdP). If concomitant use is necessary, an encorafenib dosage reduction is required: reduce a daily dose of 450 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Clarithromycin is a CYP3A substrate and strong CYP3A inhibitor, encorafenib is a CYP3A substrate and strong CYP3A inducer, and both medications may prolong the QT interval. Concomitant use with another strong CYP3A inhibitor increased encorafenib overall exposure by 3-fold. There have been spontaneous or published reports of CYP3A-based interactions of clarithromycin with another CYP3A inducer. (Major) Avoid concomitant use of vonoprazan and encorafenib due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A inducer.
Vorapaxar: (Major) Avoid coadministration of vorapaxar and encorafenib due to decreased serum concentrations of vorapaxar. Vorapaxar is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased vorapaxar exposure by 55%; the impact on efficacy for a change in exposure of this magnitude is not known.
Voriconazole: (Major) Avoid concomitant use of encorafenib and voriconazole due to the risk for decreased voriconazole exposure, increased encorafenib exposure, and torsade de pointes (TdP) and QT/QTc prolongation, especially in patients with additional risk factors for TdP. If concurrent use cannot be avoided, monitor for decreased efficacy of voriconazole and reduce encorafenib daily dose of 450 mg to 150 mg and to for all other dosages to 75 mg. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Voriconazole is a CYP3A substrate and strong CYP3A inhibitor and encorafenib is a CYP3A substrate and strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased voriconazole exposure by 96%. Concomitant use with another strong CYP3A inhibitor increased encorafenib overall exposure by 3-fold.
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.
Vortioxetine: (Major) Consider increasing the dose of vortioxetine (maximum, 3 times the original dose) if coadministration with encorafenib for longer than 14 days is necessary. Reduce the dose of vortioxetine to the original level within 14 days when encorafenib is discontinued. Vortioxetine is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer significantly reduced the exposure of vortioxetine.
Voxelotor: (Major) Avoid coadministration of voxelotor and encorafenib due to the risk of decreased voxelotor exposure which may reduce its efficacy and increased encorafenib exposure which may increase the risk for adverse effects. If coadministration is unavoidable, dosage adjustments are recommended for both drugs. Increase voxelotor dosage to 2,500 mg PO once daily in patients 12 years and older. In patients 4 to 11 years old, weight-based dosage adjustments are recommended; consult product labeling for specific recommendations. For encorafenib, a dosage reduction is also required: reduce a daily dose of 450 mg to 225 mg, reduce a daily dose of 300 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Voxelotor is a CYP3A substrate and moderate CYP3A inhibitor and encorafenib is a CYP3A substrate and strong CYP3A inducer. Coadministration of voxelotor with a strong CYP3A inducer is predicted to decrease voxelotor exposure by up to 40%. Concomitant use with another moderate CYP3A inhibitor increased encorafenib overall exposure by 2-fold.
Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with encorafenib is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. The R-enantiomer of warfarin is a CYP3A substrate and encorafenib is a CYP3A inducer. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Zaleplon: (Moderate) Monitor for decreased efficacy when zaleplon is coadministered with encorafenib due to decreased zaleplon exposure. Zaleplon is partially metabolized by CYP3A; encorafenib is a strong CYP3A inducer. Consider using an alternative non-CYP3A substrate hypnotic in patients taking strong CYP3A inducers. Coadministration with another strong CYP3A inducer reduced zaleplon exposure by approximately 80%.
Zanubrutinib: (Major) Avoid the concomitant use of zanubrutinib and encorafenib. Coadministration may result in decreased zanubrutinib exposure and reduced efficacy. Zanubrutinib is a CYP3A substrate; encorafenib is a strong CYP3A inducer. The AUC of zanubrutinib was decreased by 93% when coadministered with another strong CYP3A inducer.
Zavegepant: (Major) Avoid concomitant use of zavegepant and encorafenib. Concomitant use may increase zavegepant exposure and the risk for zavegepant-related adverse effects. Zavegepant is an OATP1B3 substrate and encorafenib is an OATP1B3 inhibitor. Concomitant use with another OATP1B3 inhibitor increased zavegepant overall exposure by 2.3-fold.
Ziprasidone: (Major) Concomitant use of encorafenib and ziprasidone increases the risk of QT/QTc prolongation and torsade de pointes (TdP) and may decrease ziprasidone exposure and efficacy. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Monitor for altered response to ziprasidone and consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Ziprasidone is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation. Coadministration with another strong CYP3A inducer decreased the exposure of ziprasidone by approximately 35%.
Zolpidem: (Major) Coadministration of zolpidem with encorafenib is not recommended as concurrent use may decrease plasma concentrations of zolpidem. Zolpidem is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased zolpidem exposure by 73% and significantly reduced the pharmacodynamic effects of zolpidem.
Zonisamide: (Moderate) Monitor for decreased efficacy of zonisamide when coadministered with encorafenib; adjust the dose of zonisamide as clinically appropriate. Zonisamide is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with other strong CYP3A inducers decreased the zonisamide half-life by 8 to 19 hours. These effects are unlikely to be of clinical significance when zonisamide is added to apalutamide therapy; however, changes in zonisamide concentrations may occur if encorafenib is added, dose adjusted, or withdrawn from zonisamide therapy.
Zuranolone: (Major) Avoid concomitant use of zuranolone and encorafenib. Concurrent use may decrease zuranolone exposure which may reduce its efficacy. Zuranolone is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced zuranolone overall exposure by 85%.
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.
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, OATP1B1, OATP1B3, BCRP
Encorafenib is primarily metabolized by CYP3A4 (83%) and to a lesser extent by CYP2C19 (16%) and CYP2D6 (1%). It is also an inhibitor of organic anion transport protein (OATP)-1B1, OATP1B3, and breast cancer resistance protein (BCRP). In vitro, encorafenib inhibits UGT1A1, CYP1A2, CYP2B6, CYP2C8/9, CYP2D6, CYP3A, P-glycoprotein (P-gp), 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.
-Route-Specific Pharmacokinetics
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.
-Special Populations
Hepatic Impairment
Mild hepatic impairment (Child-Pugh class A) did not have a clinically significant impact on the pharmacokinetic (PK) parameters of encorafenib in a population PK analysis. Encorafenib has not been evaluated in patients with moderate (Child-Pugh class B) or severe (Child-Pugh class C) hepatic impairment.
Renal Impairment
Mild or moderate renal impairment (creatinine clearance (CrCl) of 30 to less than 90 mL/min) did not have a clinically significant impact on the pharmacokinetic (PK) parameters of encorafenib in a population PK analysis. Encorafenib has not been evaluated in patients with severe renal impairment (CrCl less than 30 mL/min).
Geriatric
Age (range, 19 to 94 years) did not have a clinically significant impact on the pharmacokinetic (PK) parameters of encorafenib in a population PK analysis.
Gender Differences
Gender did not have a clinically significant impact on the pharmacokinetic (PK) parameters of encorafenib in a population PK analysis.
Obesity
Body weight (34 to 168 kg) did not have a clinically significant impact on the pharmacokinetic (PK) parameters of encorafenib in a population PK analysis