encorafenib

Small Molecule Antineoplastic BRAF kinase Inhibitors

Emetic Risk
Minimal/Low
Administer prn antiemetics as necessary.

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.

Severe

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

Moderate

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

Mild

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

BRAFTOVI

Rx

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

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.[63317] 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.[63319]

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.

Hepatic Impairment

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

Renal Impairment

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

Abacavir; Dolutegravir; Lamivudine: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with encorafenib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a BCRP substrate and encorafenib is a BCRP inhibitor.
Acalabrutinib: (Moderate) Coadministration of encorafenib with acalabrutinib may result in increased toxicity or decreased efficacy of acalabrutinib. Acalabrutinib is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with encorafenib may alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of dihydrocodeine until stable drug effects are achieved. Discontinuation of encorafenib could alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If encorafenib is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Encorafenib is a weak inhibitor and inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine. CYP3A4 inhibitors may increase dihydrocodeine-related adverse effects while CYP3A4 inducers may reduce efficacy.
Adagrasib: (Major) Avoid coadministration of encorafenib and adagrasib due to increased encorafenib exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of adagrasib. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. If adagrasib is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of adagrasib. Encorafenib is a CYP3A substrate, adagrasib is a strong CYP3A inhibitor, and both medications may prolong the QT interval. Coadministration of a strong CYP3A inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
Albuterol; Budesonide: (Moderate) Coadministration of encorafenib with budesonide may result in increased toxicity or decreased efficacy of budesonide. Budesonide is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
Alfentanil: (Moderate) Consider a dose adjustment of alfentanil with frequent monitoring for efficacy, respiratory depression and sedation if concurrent use of encorafenib is necessary. If encorafenib is discontinued, consider adjusting the alfentanil dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal or increased or prolonged therapeutic and adverse effects. Encorafenib may increase or decrease alfentanil exposure. Alfentanil is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
Alfuzosin: (Major) Avoid coadministration of encorafenib and alfuzosin due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Based on electrophysiology studies performed by the manufacturer, alfuzosin may prolong the QT interval in a dose-dependent manner.
Alpelisib: (Major) Avoid coadministration of alpelisib with encorafenib due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and encorafenib is a BCRP inhibitor.
Alprazolam: (Major) Avoid coadministration of alprazolam and encorafenib due to the potential for elevated alprazolam concentrations, which may cause prolonged sedation and respiratory depression. If coadministration is necessary, consider reducing the dose of alprazolam as clinically appropriate and monitor for an increase in alprazolam-related adverse reactions. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with encorafenib, as these benzodiazepines are not oxidatively metabolized. Alprazolam is a CYP3A4 substrate and encorafenib is a weak CYP3A4 inhibitor. Coadministration with another weak CYP3A4 inhibitor increased alprazolam maximum concentration by 82%, decreased clearance by 42%, and increased half-life by 16%.
Amiodarone: (Major) Avoid coadministration of encorafenib and amiodarone due to increased encorafenib exposure and QT prolongation. If concurrent use cannot be avoided, reduce the encorafenib dose to one-half of the dose used prior to the addition of amiodarone; monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. If amiodarone is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of amiodarone. Encorafenib is a CYP3A4 substrate that has been associated with dose-dependent QT prolongation; amiodarone is a moderate CYP3A4 inhibitor that is associated with a well established risk of QT prolongation and torsade de pointes (TdP). Coadministration of a moderate CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 2-fold and 45%, respectively. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
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; 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.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid coadministration of encorafenib and clarithromycin due to increased encorafenib exposure and QT prolongation. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of clarithromycin. Monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. If clarithromycin is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of clarithromycin. Encorafenib is a CYP3A4 substrate that has been associated with dose-dependent QT prolongation; clarithromycin is a strong CYP3A4 inhibitor that is associated with an established risk for QT prolongation and torsade de pointes (TdP). Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
Anagrelide: (Major) Avoid coadministration of encorafenib and anagrelide due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects.
Apalutamide: (Major) Avoid coadministration of encorafenib and apalutamide due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; apalutamide is a strong CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
Apomorphine: (Major) Avoid coadministration of encorafenib and apomorphine due to a possible increased risk of QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Dose-related QTc prolongation is associated with therapeutic apomorphine exposure.
Aprepitant, Fosaprepitant: (Major) Avoid coadministration of encorafenib and a 3-day oral regimen (125 mg/80 mg/80 mg) of aprepitant due to increased encorafenib exposure. Increased or decreased aprepitant exposure is also possible. If concurrent use of multi-day oral aprepitant cannot be avoided, reduce the encorafenib dose to one-half of the dose used prior to the addition of aprepitant. If aprepitant is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of aprepitant. Encorafenib is a CYP3A4 substrate; In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established. Aprepitant is a sensitive CYP3A4 substrate and when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor. Coadministration of a moderate CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 2-fold and 45%, respectively.
Aripiprazole: (Major) Avoid concomitant use of aripiprazole and encorafenib, if possible, especially in patients with risk factors for torsade de pointes (TdP). If use is necessary, patients receiving both a CYP2D6 inhibitor plus encorafenib may require an aripiprazole dosage adjustment. Dosing recommendations vary based on aripiprazole dosage form, CYP2D6 inhibitor strength, and CYP2D6 metabolizer status. See prescribing information for details. Additionally, monitor for aripiprazole-related adverse effects and consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Concomitant use may increase aripiprazole exposure and risk for QT prolongation and TdP. Aripiprazole is a CYP3A and CYP2D6 substrate, encorafenib is a weak CYP3A inhibitor, and both medications have been associated with QT prolongation.
Arsenic Trioxide: (Major) Avoid coadministration of encorafenib and arsenic trioxide due to QT prolongation. Discontinue or select an alternative drug that does not prolong the QT interval prior to starting arsenic trioxide therapy. If concomitant drug use is unavoidable, frequently monitor electrocardiograms. Monitor electrolytes and correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP), QT interval prolongation, and complete atrioventricular block have been reported with arsenic trioxide use.
Artemether; Lumefantrine: (Major) Avoid coadministration of encorafenib and artemether; lumefantrine due to QT prolongation. Consider ECG monitoring if encorafenib must be used after artemether; lumefantrine treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Artemether; lumefantrine is associated with prolongation of the QT interval. (Major) Avoid coadministration of encorafenib and artemether; lumefantrine due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Artemether; lumefantrine is associated with prolongation of the QT interval.
Asenapine: (Major) Avoid coadministration of encorafenib and asenapine due to QT prolongation. Encorafenib is associated with dose-dependent prolongation of the QT interval. Asenapine has also been associated with QT prolongation.
Aspirin, ASA; Butalbital; Caffeine: (Major) Avoid coadministration of encorafenib and butalbital due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; butalbital is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
Atazanavir: (Major) Avoid coadministration of encorafenib and atazanavir due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of atazanavir. If atazanavir is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of atazanavir. Encorafenib is a CYP3A4 substrate; atazanavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
Atazanavir; Cobicistat: (Major) Avoid coadministration of encorafenib and atazanavir due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of atazanavir. If atazanavir is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of atazanavir. Encorafenib is a CYP3A4 substrate; atazanavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively. (Major) Avoid coadministration of encorafenib and cobicistat due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of cobicistat. If cobicistat is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of cobicistat. Encorafenib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
Atogepant: (Major) Avoid use of atogepant and encorafenib when atogepant is used for chronic migraine. Limit the dose of atogepant to 10 or 30 mg once daily for episodic migraine if coadministered with encorafenib. 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, OATP1B1, and OATP1B3 and encorafenib is a weak CYP3A inducer and OATP inhibitor. Coadministration with a weak CYP3A inducer resulted in a 25% reduction in atogepant overall exposure and a 24% 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.
Atorvastatin; Ezetimibe: (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.
Avanafil: (Moderate) Coadministration of encorafenib with avanafil may result in increased avanafil toxicity or reduced efficacy. Avanafil is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
Azithromycin: (Major) Avoid coadministration of azithromycin with encorafenib due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Encorafenib is associated with dose-dependent prolongation of the QT interval. QT prolongation and torsade de pointes (TdP) have been spontaneously reported during azithromycin postmarketing surveillance.
Bedaquiline: (Major) Avoid coadministration of encorafenib and bedaquiline due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Bedaquiline has been reported to prolong the QT interval. Coadministration may result in additive or synergistic prolongation of the QT interval.
Berotralstat: (Major) Avoid coadministration of encorafenib and berotralstat due to increased encorafenib and/or berotralstat exposure and an increased risk of adverse effects. If concurrent use cannot be avoided, reduce the encorafenib dose to one-half of the dose used prior to the addition of berotralstat. If berotralstat is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of berotralstat. Additionally, reduce the berotralstat dose to 110 mg PO once daily in patients chronically taking encorafenib. Encorafenib is a CYP3A4 substrate and a BCRP inhibitor; berotralstat is a moderate CYP3A4 inhibitor and a BCRP substrate. Coadministration of a moderate CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 2-fold and 45%, respectively. Coadministration with another BCRP inhibitor increased berotralstat exposure by 69%.
Bexarotene: (Major) Avoid coadministration of encorafenib and bexarotene due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; bexarotene is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) 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.
Bosentan: (Major) Avoid coadministration of encorafenib and bosentan due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; bosentan is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
Bosutinib: (Moderate) Coadministration of encorafenib with bosutinib may result in increased toxicity or decreased efficacy of bosutinib. Bosutinib is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
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.
Brodalumab: (Major) Avoid coadministration of encorafenib and brodalumab due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-half of the dose used prior to the addition of brodalumab. If brodalumab is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of brodalumab. Encorafenib is a CYP3A4 substrate; brodalumab is a moderate CYP3A4 inhibitor. Coadministration of a moderate CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 2-fold and 45%, respectively.
Budesonide: (Moderate) Coadministration of encorafenib with budesonide may result in increased toxicity or decreased efficacy of budesonide. Budesonide is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
Budesonide; Formoterol: (Moderate) Coadministration of encorafenib with budesonide may result in increased toxicity or decreased efficacy of budesonide. Budesonide is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
Budesonide; Glycopyrrolate; Formoterol: (Moderate) Coadministration of encorafenib with budesonide may result in increased toxicity or decreased efficacy of budesonide. Budesonide is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
Buprenorphine: (Major) Avoid coadministration of encorafenib and buprenorphine due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP).
Buprenorphine; Naloxone: (Major) Avoid coadministration of encorafenib and buprenorphine due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP).
Buspirone: (Moderate) Coadministration of encorafenib with buspirone may result in increased toxicity or decreased efficacy of buspirone. Buspirone is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
Butalbital; Acetaminophen: (Major) Avoid coadministration of encorafenib and butalbital due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; butalbital is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
Butalbital; Acetaminophen; Caffeine: (Major) Avoid coadministration of encorafenib and butalbital due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; butalbital is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Avoid coadministration of encorafenib and butalbital due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; butalbital is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
Butalbital; Aspirin; Caffeine; Codeine: (Major) Avoid coadministration of encorafenib and butalbital due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; butalbital is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
Cabotegravir; Rilpivirine: (Major) Avoid coadministration of encorafenib and rilpivirine due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Carbamazepine: (Major) Avoid coadministration of encorafenib and carbamazepine due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; carbamazepine is a strong CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
Cenobamate: (Major) Avoid coadministration of encorafenib and cenobamate due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; cenobamate is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
Ceritinib: (Major) Avoid coadministration of encorafenib and ceritinib due to increased encorafenib exposure and QT prolongation. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of ceritinib; monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. If ceritinib is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of ceritinib. Encorafenib is a CYP3A4 substrate that has been associated with dose-dependent QT prolongation; ceritinib is a strong CYP3A4 inhibitor that can also cause concentration-dependent QT prolongation. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
Chloramphenicol: (Major) Avoid coadministration of encorafenib and chloramphenicol due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of chloramphenicol. If chloramphenicol is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of chloramphenicol. Encorafenib is a CYP3A4 substrate; chloramphenicol is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
Chloroquine: (Major) Avoid coadministration of chloroquine with encorafenib due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); the risk of QT prolongation is increased with higher chloroquine doses. Encorafenib has been associated with dose-dependent QT prolongation.
Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Concomitant use of dihydrocodeine with encorafenib may alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of dihydrocodeine until stable drug effects are achieved. Discontinuation of encorafenib could alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If encorafenib is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Encorafenib is a weak inhibitor and inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine. CYP3A4 inhibitors may increase dihydrocodeine-related adverse effects while CYP3A4 inducers may reduce efficacy.
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 coadministration of encorafenib and ciprofloxacin due to increased encorafenib exposure and QT prolongation. If concurrent use cannot be avoided, reduce the encorafenib dose to one-half of the dose used prior to the addition of ciprofloxacin. Monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. If ciprofloxacin is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of ciprofloxacin. Encorafenib is a CYP3A4 substrate that has been associated with dose-dependent QT prolongation; ciprofloxacin is a moderate CYP3A4 inhibitor that has been associated with rare cases of QT prolongation and torsade de pointes (TdP) during postmarketing surveillance. Coadministration of a moderate CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 2-fold and 45%, respectively.
Cisapride: (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 coadministration of encorafenib and clarithromycin due to increased encorafenib exposure and QT prolongation. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of clarithromycin. Monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. If clarithromycin is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of clarithromycin. Encorafenib is a CYP3A4 substrate that has been associated with dose-dependent QT prolongation; clarithromycin is a strong CYP3A4 inhibitor that is associated with an established risk for QT prolongation and torsade de pointes (TdP). Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
Clofazimine: (Major) 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.
Clozapine: (Major) Avoid coadministration of encorafenib and clozapine due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death.
Cobicistat: (Major) Avoid coadministration of encorafenib and cobicistat due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of cobicistat. If cobicistat is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of cobicistat. Encorafenib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
Cobimetinib: (Moderate) Coadministration of encorafenib with cobimetinib may result in increased toxicity or decreased efficacy of cobimetinib. Cobimetinib is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.Coadministration may result in increased toxicity or decreased efficacy of cobimetinib.
Codeine; Phenylephrine; Promethazine: (Major) 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.
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.
Conivaptan: (Major) Avoid coadministration of encorafenib and conivaptan due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-half of the dose used prior to the addition of conivaptan. If conivaptan is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of conivaptan. Encorafenib is a CYP3A substrate; conivaptan is a moderate CYP3A inhibitor. Coadministration of a moderate CYP3A inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 2-fold and 45%, respectively.
Crizotinib: (Major) Avoid coadministration of encorafenib and crizotinib due to increased encorafenib exposure and QT prolongation. If concurrent use cannot be avoided, reduce the encorafenib dose to one-half of the dose used prior to the addition of crizotinib. Monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. If crizotinib is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of crizotinib. Encorafenib is a CYP3A4 substrate that has been associated with dose-dependent QT prolongation; crizotinib is a moderate CYP3A4 inhibitor that has also been associated with concentration-dependent QT prolongation. Coadministration of a moderate CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 2-fold and 45%, respectively.
Cyclosporine: (Major) Avoid coadministration of encorafenib and cyclosporine due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-half of the dose used prior to the addition of cyclosporine. If cyclosporine is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of cyclosporine. Encorafenib is a CYP3A4 substrate; cyclosporine is a moderate CYP3A4 inhibitor. Coadministration of a moderate CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 2-fold and 45%, respectively.
Dabrafenib: (Major) Avoid coadministration of encorafenib and dabrafenib due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; dabrafenib is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
Danazol: (Major) Avoid coadministration of encorafenib and danazol due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-half of the dose used prior to the addition of danazol. If danazol is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of danazol. Encorafenib is a CYP3A4 substrate; danazol is a moderate CYP3A4 inhibitor. Coadministration of a moderate CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 2-fold and 45%, respectively.
Darifenacin: (Moderate) Coadministration of encorafenib with darifenacin may result in increased toxicity or decreased efficacy of darifenacin. Darifenacin is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
Darunavir: (Major) Avoid coadministration of encorafenib and darunavir due to increased encorafenib exposure. Increased or decreased darunavir exposure is also possible. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of darunavir. If darunavir is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of darunavir. Encorafenib is a CYP3A4 substrate; in vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. Darunavir is a strong CYP3A4 inhibitor and sensitive CYP3A4 substrate. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
Darunavir; Cobicistat: (Major) Avoid coadministration of encorafenib and cobicistat due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of cobicistat. If cobicistat is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of cobicistat. Encorafenib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively. (Major) Avoid coadministration of encorafenib and darunavir due to increased encorafenib exposure. Increased or decreased darunavir exposure is also possible. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of darunavir. If darunavir is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of darunavir. Encorafenib is a CYP3A4 substrate; in vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. Darunavir is a strong CYP3A4 inhibitor and sensitive CYP3A4 substrate. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid coadministration of encorafenib and cobicistat due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of cobicistat. If cobicistat is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of cobicistat. Encorafenib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively. (Major) Avoid coadministration of encorafenib and darunavir due to increased encorafenib exposure. Increased or decreased darunavir exposure is also possible. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of darunavir. If darunavir is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of darunavir. Encorafenib is a CYP3A4 substrate; in vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. Darunavir is a strong CYP3A4 inhibitor and sensitive CYP3A4 substrate. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
Dasatinib: (Major) Avoid coadministration of encorafenib and dasatinib due to QT prolongation. Concurrent use may also result in increased toxicity or decreased efficacy of dasatinib. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established. Dasatinib is a sensitive CYP3A4 substrate. In vitro studies have shown that dasatinib has the potential to prolong the QT interval.
Degarelix: (Major) Avoid coadministration of encorafenib and degarelix due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Androgen deprivation therapy (i.e., degarelix) may also prolong the QT/QTc interval.
Delavirdine: (Major) Avoid coadministration of encorafenib and delavirdine due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of delavirdine. If delavirdine is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of delavirdine. Encorafenib is a CYP3A4 substrate; delavirdine is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
Desflurane: (Major) Avoid coadministration of encorafenib and halogenated anesthetics due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Halogenated anesthetics can also prolong the QT interval.
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.
Deutetrabenazine: (Major) Avoid coadministration of encorafenib and deutetrabenazine due to an 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 has been associated with dose-dependent QT prolongation. Deutetrabenazine may prolong the QT interval, but the degree of QT prolongation is not clinically significant when deutetrabenazine is administered within the recommended dosage range.
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) Avoid coadministration of encorafenib and quinidine due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Quinidine administration is associated with QT prolongation and torsade de pointes (TdP).
Dienogest; Estradiol valerate: (Major) Avoid coadministration of encorafenib and hormonal contraceptives due to the potential for loss of contraceptive efficacy. Advise females of reproductive potential to use an effective, non-hormonal method of contraception during treatment and for 2 weeks after the final dose of encorafenib. Encorafenib can cause fetal harm when administered during pregnancy.
Diltiazem: (Major) Avoid coadministration of encorafenib and diltiazem due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-half of the dose used prior to the addition of diltiazem. If diltiazem is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of diltiazem. Encorafenib is a CYP3A4 substrate; diltiazem is a moderate CYP3A4 inhibitor. Coadministration of diltiazem with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 2-fold and 45%, respectively.
Disopyramide: (Major) Avoid coadministration of encorafenib and disopyramide due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Disopyramide administration is associated with QT prolongation and torsade de pointes (TdP).
Dofetilide: (Major) Avoid coadministration of encorafenib and dofetilide due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib has been associated with dose-dependent QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP).
Dolasetron: (Major) Avoid coadministration of encorafenib and dolasetron due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram.
Dolutegravir: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with encorafenib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a BCRP substrate and encorafenib is a BCRP inhibitor.
Dolutegravir; Lamivudine: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with encorafenib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a BCRP substrate and encorafenib is a BCRP inhibitor.
Dolutegravir; Rilpivirine: (Major) Avoid coadministration of encorafenib and rilpivirine due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with encorafenib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a BCRP substrate and encorafenib is a BCRP inhibitor.
Donepezil: (Major) Avoid coadministration of encorafenib and donepezil due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
Donepezil; Memantine: (Major) Avoid coadministration of encorafenib and donepezil due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
Doravirine; 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.
Dronedarone: (Contraindicated) Coadministration of encorafenib with dronedarone is contraindicated due to QT prolongation. Encorafenib is associated with dose-dependent QT interval prolongation. Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
Droperidol: (Major) Avoid coadministration of encorafenib and droperidol due to QT prolongation. If coadministration cannot be avoided, use extreme caution; initiate droperidol at a low dose and increase the dose as needed to achieve the desired effect. Monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Droperidol administration is associated with an established risk for QT prolongation and torsade de pointes (TdP). Some cases have occurred in patients with no known risk factors for QT prolongation and some cases have been fatal. Encorafenib is associated with dose-dependent prolongation of the QT interval.
Drospirenone: (Major) Avoid coadministration of encorafenib and hormonal contraceptives due to the potential for loss of contraceptive efficacy. Advise females of reproductive potential to use an effective, non-hormonal method of contraception during treatment and for 2 weeks after the final dose of encorafenib. Encorafenib can cause fetal harm when administered during pregnancy.
Drospirenone; 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 encorafenib and duvelisib due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-half of the dose used prior to the addition of duvelisib. If duvelisib is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of duvelisib. Encorafenib is a CYP3A4 substrate; duvelisib is a moderate CYP3A4 inhibitor. Coadministration of a moderate CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 2-fold and 45%, respectively.
Efavirenz: (Major) Avoid coadministration of encorafenib and efavirenz due to decreased encorafenib exposure and potential loss of efficacy. Additive risk of QT prolongation is also possible. Encorafenib is a CYP3A4 substrate that is associated with dose-dependent prolongation of the QT interval; efavirenz is a moderate CYP3A4 inducer that has been associated with QT prolongation. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of encorafenib and efavirenz due to decreased encorafenib exposure and potential loss of efficacy. Additive risk of QT prolongation is also possible. Encorafenib is a CYP3A4 substrate that is associated with dose-dependent prolongation of the QT interval; efavirenz is a moderate CYP3A4 inducer that has been associated with QT prolongation. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction. (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) Avoid coadministration of encorafenib and efavirenz due to decreased encorafenib exposure and potential loss of efficacy. Additive risk of QT prolongation is also possible. Encorafenib is a CYP3A4 substrate that is associated with dose-dependent prolongation of the QT interval; efavirenz is a moderate CYP3A4 inducer that has been associated with QT prolongation. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction. (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.
Elagolix: (Contraindicated) Coadministration of elagolix with encorafenib is contraindicated as concurrent use may increase elagolix exposure. Elagolix is a substrate of OATP1B1 and encorafenib is a strong OATP1B1 inhibitor.
Elagolix; Estradiol; Norethindrone acetate: (Contraindicated) Coadministration of elagolix with encorafenib is contraindicated as concurrent use may increase elagolix exposure. Elagolix is a substrate of OATP1B1 and encorafenib is a strong OATP1B1 inhibitor. (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 enco

rafenib. 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 increased grazoprevir exposure. Grazoprevir is a substrate of OATP1B1/3; encorafenib is an inhibitor of OATP1B1/3.
Eletriptan: (Moderate) Coadministration of encorafenib with eletriptan may result in increased toxicity or decreased efficacy of eletriptan. Eletriptan is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
Elexacaftor; tezacaftor; ivacaftor: (Major) Coadministration of encorafenib with ivacaftor may result in increased toxicity or decreased efficacy of ivacaftor. Ivacaftor is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
Eliglustat: (Major) Avoid coadministration of encorafenib and eliglustat due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Eliglustat is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations.
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 encorafenib and cobicistat due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of cobicistat. If cobicistat is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of cobicistat. Encorafenib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of encorafenib and cobicistat due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of cobicistat. If cobicistat is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of cobicistat. Encorafenib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively. (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; Rilpivirine; Tenofovir alafenamide: (Major) Avoid coadministration of encorafenib and rilpivirine due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of encorafenib and rilpivirine due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. (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 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 coadministration of encorafenib and entrectinib due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib has been associated with dose-dependent QT prolongation. Entrectinib has also been associated with QT prolongation.
Enzalutamide: (Major) Avoid coadministration of encorafenib and enzalutamide due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; enzalutamide is a strong CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
Eplerenone: (Moderate) Coadministration of encorafenib with eplerenone may result in increased toxicity or decreased efficacy of eplerenone. Eplerenone is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
Eribulin: (Major) Avoid coadministration of encorafenib and eliglustat due to QT prolongation. If eribulin and encorafenib must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Eribulin has been associated with QT prolongation.
Erythromycin: (Major) Avoid coadministration of encorafenib and erythromycin due to increased encorafenib exposure and QT prolongation. If concurrent use cannot be avoided, reduce the encorafenib dose to one-half of the dose used prior to the addition of erythromycin. Monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. If erythromycin is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of erythromycin. Encorafenib is a CYP3A4 substrate that has been associated with dose-dependent QT prolongation; erythromycin is a moderate CYP3A4 inhibitor that is associated with QT prolongation and torsade de pointes (TdP). Coadministration of a moderate CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 2-fold and 45%, respectively.
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.
Eslicarbazepine: (Major) Avoid coadministration of encorafenib and eslicarbazepine due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; eslicarbazepine is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
Estradiol; Levonorgestrel: (Major) Avoid coadministration of encorafenib and hormonal contraceptives due to the potential for loss of contraceptive efficacy. Advise females of reproductive potential to use an effective, non-hormonal method of contraception during treatment and for 2 weeks after the final dose of encorafenib. Encorafenib can cause fetal harm when administered during pregnancy.
Estradiol; Norethindrone: (Major) Avoid coadministration of encorafenib and hormonal contraceptives due to the potential for loss of contraceptive efficacy. Advise females of reproductive potential to use an effective, non-hormonal method of contraception during treatment and for 2 weeks after the final dose of encorafenib. Encorafenib can cause fetal harm when administered during pregnancy.
Estradiol; Norgestimate: (Major) Avoid coadministration of encorafenib and hormonal contraceptives due to the potential for loss of contraceptive efficacy. Advise females of reproductive potential to use an effective, non-hormonal method of contraception during treatment and for 2 weeks after the final dose of encorafenib. Encorafenib can cause fetal harm when administered during pregnancy.
Ethinyl Estradiol; 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.
Etravirine: (Major) Avoid coadministration of encorafenib and etravirine due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; etravirine is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
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 encorafenib and fedratinib due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-half of the dose used prior to the addition of fedratinib. If fedratinib is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of fedratinib. Encorafenib is a CYP3A4 substrate; fedratinib is a moderate CYP3A4 inhibitor. Coadministration of a moderate CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 2-fold and 45%, respectively.
Felodipine: (Moderate) Coadministration of encorafenib with felodipine may result in increased toxicity or decreased efficacy of felodipine. Felodipine is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
Fingolimod: (Major) Avoid coadministration of encorafenib and fingolimod due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Flecainide: (Major) Avoid coadministration of encorafenib and flecainide due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Flecainide is a Class IC antiarrhythmic associated with a possible risk for QT prolongation and/or torsade de pointes (TdP); flecainide increases the QT interval, but largely due to prolongation of the QRS interval. Although causality for TdP has not been established for flecainide, patients receiving concurrent drugs that have the potential for QT prolongation may have an increased risk of developing proarrhythmias.
Fluconazole: (Contraindicated) The concurrent use of fluconazole with drugs that are associated with QT prolongation and are also CYP3A4 substrates, such as encorafenib, is contraindicated. Fluconazole has been associated with QT prolongation.
Fluoxetine: (Major) Avoid coadministration of encorafenib and fluoxetine due to increased encorafenib exposure and QT prolongation. If concurrent use cannot be avoided, reduce the encorafenib dose to one-half of the dose used prior to the addition of fluoxetine. Monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. If fluoxetine is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of fluoxetine. Encorafenib is a CYP3A4 substrate that has been associated with dose-dependent QT prolongation. Fluoxetine is a weak CYP3A4 inhibitor, but the norfluoxetine metabolite is a moderate CYP3A4 inhibitor; QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine. Coadministration of a moderate CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 2-fold and 45%, respectively.
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.
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 coadministration of encorafenib and fluvoxamine due to increased encorafenib exposure and QT prolongation. If concurrent use cannot be avoided, reduce the encorafenib dose to one-half of the dose used prior to the addition of fluvoxamine. Monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. If fluvoxamine is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of fluvoxamine. Encorafenib is a CYP3A4 substrate that has been associated with dose-dependent QT prolongation; fluvoxamine is a moderate CYP3A4 inhibitor that has been associated with QT prolongation and torsade de pointes (TdP) during postmarketing use. Coadministration of a moderate CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 2-fold and 45%, respectively.
Fosamprenavir: (Major) Avoid coadministration of encorafenib and fosamprenavir due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-half of the dose used prior to the addition of fosamprenavir. If fosamprenavir is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of fosamprenavir. Encorafenib is a CYP3A substrate; fosamprenavir is a moderate CYP3A inhibitor. Coadministration of a moderate CYP3A inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 2-fold and 45%, respectively.
Foscarnet: (Major) Avoid coadministration of encorafenib and foscarnet due to QT prolongation. Encorafenib is associated with dose-dependent prolongation of the QT interval. Both QT prolongation and torsade de pointes (TdP) have been reported during postmarketing use of foscarnet.
Fosphenytoin: (Major) Avoid coadministration of encorafenib and fosphenytoin due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; fosphenytoin is a strong CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
Fostemsavir: (Major) Avoid coadministration of encorafenib and fostemsavir due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib has been associated with dose-dependent QT prolongation. Supratherapeutic doses of fostemsavir (2,400 mg twice daily, 4 times the recommended daily dose) have been shown to cause QT prolongation. Fostemsavir causes dose-dependent QT prolongation.
Gemifloxacin: (Major) Avoid coadministration of encorafenib and gemifloxacin due to QT prolongation. Encorafenib is associated with dose-dependent prolongation of the QT interval. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Gemifloxacin may prolong the QT interval in some patients. The maximal change in the QTc interval occurs approximately 5 to 10 hours following oral administration of gemifloxacin. The likelihood of QTc prolongation may increase with increasing dose of the drug; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher.
Gemtuzumab Ozogamicin: (Major) Avoid coadministration of encorafenib and gemtuzumab due to QT prolongation. If these agents must be used together, obtain an ECG and serum electrolytes prior to the start of gemtuzumab and as needed during treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Although QT interval prolongation has not been reported with gemtuzumab, it has been reported with other drugs that contain calicheamicin.
Gilteritinib: (Major) Avoid coadministration of encorafenib and gilteritinib due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib has been associated with dose-dependent QT prolongation. Gilteritinib has been associated with QT prolongation.
Glasdegib: (Major) Avoid coadministration of glasdegib with encorafenib due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with a dose-dependent prolongation of the QT interval. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia.
Glecaprevir; Pibrentasvir: (Moderate) Monitor for an increase in glecaprevir-related adverse reactions if coadministration with encorafenib is necessary. Concomitant use may increase glecaprevir exposure and increase the risk of glecaprevir-related adverse events. Glecaprevir is substrate of P-gp, BCRP, and OATP1B1/3; encorafenib is a P-gp, BCRP, and OATP1B1/3 inhibitor. (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) Avoid coadministration of encorafenib and granisetron due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Granisetron has also been associated with QT prolongation.
Grapefruit juice: (Major) Advise patients to avoid grapefruit juice while taking encorafenib due to increased encorafenib exposure. Encorafenib is a CYP3A4 substrate; grapefruit juice is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
Halogenated Anesthetics: (Major) Avoid coadministration of encorafenib and halogenated anesthetics due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Halogenated anesthetics can also prolong the QT interval.
Haloperidol: (Major) Avoid coadministration of encorafenib and haloperidol due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. QT prolongation and torsade de pointes (TdP) have been observed during haloperidol treatment. Excessive doses (particularly in the overdose setting) or IV administration of haloperidol may be associated with a higher risk of QT prolongation.
Histrelin: (Major) Avoid coadministration of encorafenib and histrelin due to the risk of QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib has been associated with dose-dependent QT prolongation. Androgen deprivation therapy (i.e., histrelin) may also prolong the QT/QTc interval.
Hydroxychloroquine: (Major) 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.
Ibrutinib: (Moderate) Coadministration of encorafenib with ibrutinib may result in increased toxicity or decreased efficacy of ibrutinib. Ibrutinib is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
Ibutilide: (Major) Avoid coadministration of encorafenib and ibutilide due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Ibutilide administration can cause QT prolongation and torsade de pointes (TdP); proarrhythmic events should be anticipated. The potential for proarrhythmic events with ibutilide increases with the coadministration of other drugs that prolong the QT interval.
Idelalisib: (Major) Avoid coadministration of encorafenib and idelalisib due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of idelalisib. If idelalisib is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of idelalisib. Encorafenib is a CYP3A4 substrate; idelalisib is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
Iloperidone: (Major) Avoid coadministration of encorafenib and iloperidone due to QT prolongation. Encorafenib is associated with dose-dependent prolongation of the QT interval. Iloperidone has also been associated with QT prolongation.
Imatinib: (Major) Avoid coadministration of encorafenib and imatinib due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-half of the dose used prior to the addition of imatinib. If imatinib is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of imatinib. Encorafenib is a CYP3A4 substrate; imatinib is a moderate CYP3A4 inhibitor. Coadministration of a moderate CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 2-fold and 45%, respectively.
Indinavir: (Major) Avoid coadministration of encorafenib and indinavir due to increased encorafenib exposure. Increased or decreased indinavir exposure is also possible. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of indinavir. If indinavir is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of indinavir. Encorafenib is a CYP3A4 substrate; in vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. Indinavir is a strong CYP3A4 inhibitor and sensitive CYP3A4 substrate. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
Inotuzumab Ozogamicin: (Major) Avoid coadministration of encorafenib and inotuzumab due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Inotuzumab has also been associated with QT interval prolongation.
Isavuconazonium: (Major) Avoid coadministration of encorafenib and isavuconazonium due to increased encorafenib exposure. Concurrent use may also result in increased toxicity or decreased efficacy of isavuconazonium. If concurrent use cannot be avoided, reduce the encorafenib dose to one-half of the dose used prior to the addition of isavuconazonium. If isavuconazonium is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of isavuconazonium. Encorafenib is a CYP3A4 substrate; in vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established. Isavuconazonium is a moderate CYP3A4 inhibitor and sensitive CYP3A4 substrate. Coadministration of a moderate CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 2-fold and 45%, respectively.
Isoflurane: (Major) Avoid coadministration of encorafenib and halogenated anesthetics due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Halogenated anesthetics can also prolong the QT interval.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid coadministration of encorafenib and rifampin due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; rifampin is a strong CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
Isoniazid, INH; Rifampin: (Major) Avoid coadministration of encorafenib and rifampin due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; rifampin is a strong CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
Itraconazole: (Major) Avoid coadministration of encorafenib and itraconazole due to increased encorafenib exposure and QT prolongation. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of itraconazole. Monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. If itraconazole is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of itraconazole. Encorafenib is a CYP3A4 substrate that has been associated with dose-dependent QT prolongation; itraconazole is a strong CYP3A4 inhibitor that has been associated with prolongation of the QT interval. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
Ivacaftor: (Major) Coadministration of encorafenib with ivacaftor may result in increased toxicity or decreased efficacy of ivacaftor. Ivacaftor is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
Ivosidenib: (Major) Avoid coadministration of ivosidenib with encorafenib if possible due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Encorafenib has been associated with dose-dependent QT prolongation.
Ketoconazole: (Major) Avoid coadministration of encorafenib and ketoconazole due to increased encorafenib exposure and QT prolongation. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of ketoconazole. Monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. If ketoconazole is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of ketoconazole. Encorafenib is a CYP3A4 substrate that has been associated with dose-dependent QT prolongation; ketoconazole is a strong CYP3A4 inhibitor that has been associated with prolongation of the QT interval. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
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; Amoxicillin; Clarithromycin: (Major) Avoid coadministration of encorafenib and clarithromycin due to increased encorafenib exposure and QT prolongation. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of clarithromycin. Monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. If clarithromycin is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of clarithromycin. Encorafenib is a CYP3A4 substrate that has been associated with dose-dependent QT prolongation; clarithromycin is a strong CYP3A4 inhibitor that is associated with an established risk for QT prolongation and torsade de pointes (TdP). Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
Lapatinib: (Major) Avoid coadministration of encorafenib and lapatinib due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience.
Lefamulin: (Major) Avoid coadministration of lefamulin with encorafenib as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG and electrolytes during treatment; correct hypokalemia and hypomagnesemia prior to treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Encorafenib has been associated with dose-dependent QT prolongation.
Lenacapavir: (Major) Avoid coadministration of encorafenib and lenacapavir due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-half of the dose used prior to the addition of lenacapavir. If lenacapavir is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of lenacapavir. Encorafenib is a CYP3A substrate; lenacapavir is a moderate CYP3A inhibitor. Coadministration of a moderate CYP3A inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 2-fold and 45%, respectively.
Lenvatinib: (Major) Avoid coadministration of encorafenib and lenvatinib due to QT prolongation. Encorafenib is associated with dose-dependent prolongation of the QT interval. QT prolongation was reported during clinical trials of lenvatinib.
Letermovir: (Major) Avoid coadministration of encorafenib and letermovir due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-half of the dose used prior to the addition of letermovir. If letermovir is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of letermovir. Because concomitant use may also increase letermovir exposure, monitor for an increase in letermovir-related adverse reactions if coadministration with encorafenib is necessary. Encorafenib is a CYP3A4 substrate and an OATP1B1/3 inhibitor; letermovir is a moderate CYP3A4 inhibitor and a substrate of OATP1B1/3. Coadministration of a moderate CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 2-fold and 45%, respectively.
Leuprolide: (Major) Avoid coadministration of encorafenib and leuprolide due to the risk of QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib has been associated with dose-dependent QT prolongation. Androgen deprivation therapy (i.e., leuprolide) may also prolong the QT/QTc interval.
Leuprolide; Norethindrone: (Major) Avoid coadministration of encorafenib and hormonal contraceptives due to the potential for loss of contraceptive efficacy. Advise females of reproductive potential to use an effective, non-hormonal method of contraception during treatment and for 2 weeks after the final dose of encorafenib. Encorafenib can cause fetal harm when administered during pregnancy. (Major) Avoid coadministration of encorafenib and leuprolide due to the risk of QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib has been associated with dose-dependent QT prolongation. Androgen deprivation therapy (i.e., leuprolide) may also prolong the QT/QTc interval.
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: (Major) Avoid coadministration of encorafenib and ketoconazole due to increased encorafenib exposure and QT prolongation. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of ketoconazole. Monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. If ketoconazole is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of ketoconazole. Encorafenib is a CYP3A4 substrate that has been associated with dose-dependent QT prolongation; ketoconazole is a strong CYP3A4 inhibitor that has been associated with prolongation of the QT interval. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
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.
Lithium: (Major) Avoid coadministration of encorafenib and lithium due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Lithium has also been associated with QT prolongation.
Lofexidine: (Major) Avoid coadministration of encorafenib and lofexidine due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Lofexidine has also been associated with QT prolongation.
Lomitapide: (Moderate) Coadministration of encorafenib with lomitapide may result in increased toxicity or decreased efficacy of lomitapide. Lomitapide is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
Lonafarnib: (Major) Avoid coadministration of lonafarnib and encorafenib; concurrent use may increase the exposure of both drugs and the risk of adverse effects. If coadministration is unavoidable, reduce the encorafenib dose to one-third of the dose used prior to the addition of lonafarnib. If lonafarnib is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of lonafarnib. Additionally, reduce to or continue lonafarnib at a dosage of 115 mg/m2 and closely monitor patients for lonafarnib-related adverse reactions. Resume previous lonafarnib dosage 14 days after discontinuing encorafenib. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; encorafenib is a CYP3A4 substrate and weak CYP3A4 inhibitor. Coadministration with a strong CYP3A4 inhibitor increased encorafenib 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: (Major) Avoid coadministration of encorafenib and ritonavir due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of ritonavir. If ritonavir is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of ritonavir. Encorafenib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively. (Major) Avoid coadministration of lopinavir with encorafenib due to the potential for additive QT prolongation. If use together is necessary, obtain a baseline ECG to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Lopinavir is associated with QT prolongation. Encorafenib has been associated with dose-dependent QT prolongation.
Lorlatinib: (Major) Avoid coadministration of encorafenib and lorlatinib due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; lorlatinib is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
Lovastatin: (Moderate) Coadministration of encorafenib with lovastatin may result in increased toxicity or decreased efficacy of lovastatin. Lovastatin is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
Lumacaftor; Ivacaftor: (Major) Avoid coadministration of encorafenib and lumacaftor; ivacaftor due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; lumacaftor is a strong CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction. (Major) Coadministration of encorafenib with ivacaftor may result in increased toxicity or decreased efficacy of ivacaftor. Ivacaftor is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
Lumacaftor; Ivacaftor: (Major) Avoid coadministration of encorafenib and lumacaftor; ivacaftor due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; lumacaftor is a strong CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
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 weak CYP3A inducer.
Lurasidone: (Moderate) Coadministration of encorafenib with lurasidone may result in increased toxicity or decreased efficacy of lurasidone. Lurasidone is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
Macimorelin: (Major) Avoid concurrent administration of macimorelin with encorafenib. Use of these drugs together may increase the risk of developing torsade de pointes-type ventricular tachycardia. Sufficient washout time encorafenib prior to administration of macimorelin is recommended. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval. Encorafenib has been associated with dose-dependent QT prolongation.
Maprotiline: (Major) Avoid coadministration of encorafenib and maprotiline due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation.
Maraviroc: (Moderate) Coadministration of encorafenib with maraviroc may result in increased toxicity or decreased efficacy of maraviroc. Maraviroc is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established. Additionally, maraviroc is an OATP1B1 substrate and encorafenib is an OATP1B1 inhibitor. Monitor for an increase in maraviroc-related adverse reactions if these medications are used together.
Mavacamten: (Major) Avoid coadministration of encorafenib and mavacamten due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A substrate; mavacamten is a moderate CYP3A inducer. Coadministration with CYP3A inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A auto-induction.
Mefloquine: (Major) Avoid coadministration of encorafenib and mefloquine due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. There is evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation.
Methadone: (Major) Avoid coadministration of encorafenib and methadone due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Methadone is considered to be associated with an increased risk for QT prolongation and torsade de pointes (TdP), especially at higher doses (more than 200 mg/day but averaging approximately 400 mg/day in adult patients). Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction.
Metronidazole: (Major) 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.
Midazolam: (Moderate) Coadministration of encorafenib with midazolam may result in increased toxicity or decreased efficacy of midazolam. Midazolam is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
Midostaurin: (Major) Avoid coadministration of encorafenib and midostaurin due to the potential for additive QT prolongation. Concurrent use may also result in increased toxicity or decreased efficacy of midostaurin. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established. QT prolongation was reported in patients who received midostaurin, a sensitive CYP3A4 substrate, in clinical trials.
Mifepristone: (Major) Avoid coadministration of encorafenib and mifepristone due to increased encorafenib exposure and QT prolongation. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of mifepristone. Monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Use the lowest effective dose of mifepristone. If mifepristone is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of mifepristone. Encorafenib is a CYP3A4 substrate that has been associated with dose-dependent QT prolongation. When administered chronically, mifepristone is a strong CYP3A4 inhibitor that has been associated with dose-dependent QT prolongation. The clinical significance of mifepristone inhibition of CYP3A4 when used for pregnancy termination is not established. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
Mirtazapine: (Major) Concomitant use of encorafenib and mirtazapine 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.
Mitotane: (Major) Avoid coadministration of encorafenib and mitotane due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; mitotane is a strong CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
Mobocertinib: (Major) Concomitant use of mobocertinib 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.
Modafinil: (Major) Avoid coadministration of encorafenib and modafinil due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; modafinil is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
Moxifloxacin: (Major) Avoid coadministration of encorafenib and moxifloxacin due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Quinolones have been associated with a risk of QT prolongation. Although extremely rare, TdP has been reported during postmarketing surveillance of moxifloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
Nafcillin: (Major) Avoid coadministration of encorafenib and nafcillin due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; nafcillin is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
Naloxegol: (Moderate) Coadministration of encorafenib with naloxegol may result in increased toxicity or decreased efficacy of naloxegol. Naloxegol is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
Nanoparticle Albumin-Bound Sirolimus: (Moderate) Monitor response to sirolimus as appropriate during concomitant use of encorafenib. Concomitant use may alter sirolimus exposure resulting in decreased efficacy or increased risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and encorafenib is a weak CYP3A inducer and inhibitor.
Nefazodone: (Major) Avoid coadministration of encorafenib and nefazodone due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of nefazodone. If nefazodone is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of nefazodone. Encorafenib is a CYP3A4 substrate; nefazodone is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
Nelfinavir: (Major) Avoid coadministration of encorafenib and nelfinavir due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of nelfinavir. If nelfinavir is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of nelfinavir. Encorafenib is a CYP3A4 substrate; nelfinavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
Netupitant, Fosnetupitant; Palonosetron: (Major) Avoid coadministration of encorafenib and netupitant due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-half of the dose used prior to the addition of netupitant. If netupitant is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of netupitant. Encorafenib is a CYP3A4 substrate; netupitant is a moderate CYP3A4 inhibitor. Coadministration of a moderate CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 2-fold and 45%, respectively.
Niacin; 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.
Nilotinib: (Major) Avoid coadministration of encorafenib and nilotinib due to increased encorafenib exposure and QT prolongation. If concurrent use cannot be avoided, reduce the encorafenib dose to one-half of the dose used prior to the addition of nilotinib. Monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. If nilotinib is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of nilotinib. Encorafenib is a CYP3A4 substrate that has been associated with dose-dependent QT prolongation. Nilotinib is a moderate CYP3A4 inhibitor; sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy. Coadministration of a moderate CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 2-fold and 45%, respectively.
Nirmatrelvir; Ritonavir: (Major) Avoid coadministration of encorafenib and ritonavir due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of ritonavir. If ritonavir is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of ritonavir. Encorafenib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively. (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 and inhibitor; the net effect of encorafenib on CYP3A is unknown.
Nisoldipine: (Moderate) Coadministration of encorafenib with nisoldipine may result in increased toxicity or decreased efficacy of nisoldipine. Nisoldipine is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
Non-oral combination contraceptives: (Major) Avoid coadministration of encorafenib and hormonal contraceptives due to the potential for loss of contraceptive efficacy. Advise females of reproductive potential to use an effective, non-hormonal method of contraception during treatment and for 2 weeks after the final dose of encorafenib. Encorafenib can cause fetal harm when administered during pregnancy.
Norethindrone 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 fluoxetine due to increased encorafenib exposure and QT prolongation. If concurrent use cannot be avoided, reduce the encorafenib dose to one-half of the dose used prior to the addition of fluoxetine. Monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. If fluoxetine is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of fluoxetine. Encorafenib is a CYP3A4 substrate that has been associated with dose-dependent QT prolongation. Fluoxetine is a weak CYP3A4 inhibitor, but the norfluoxetine metabolite is a moderate CYP3A4 inhibitor; QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine. Coadministration of a moderate CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 2-fold and 45%, respectively. (Major) Avoid coadministration of encorafenib and olanzapine due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
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.
Omeprazole; Amoxicillin; Rifabutin: (Major) Avoid coadministration of encorafenib and rifabutin due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; rifabutin is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
Ondansetron: (Major) 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) Avoid coadministration of encorafenib and osilodrostat due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib has been associated with dose-dependent QT prolongation. Osilodrostat is associated with dose-dependent QT prolongation.
Osimertinib: (Major) Avoid coadministration of encorafenib and osimertinib due to the potential for additive QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation may be necessary if QT prolongation occurs. Encorafenib is associated with dose-dependent prolongation of the QT interval. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib.
Oxaliplatin: (Major) Avoid coadministration of encorafenib and oxaliplatin due to the potential for additive QT prolongation. If coadministration is necessary, monitor ECG and electrolytes; correct electrolyte abnormalities prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. QT prolongation and ventricular arrhythmias including fatal torsade de pointes have also been reported with oxaliplatin use in postmarketing experience.
Ozanimod: (Major) Avoid coadministration of encorafenib and ozanimod due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib has been associated with dose-dependent QT prolongation. Ozanimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ozanimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with torsade de pointes in patients with bradycardia.
Pacritinib: (Major) Concomitant use of pacritinib 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.
Paliperidone: (Major) Avoid coadministration of encorafenib and paliperidone if possible due to the potential for additive QT prolongation. If coadministration is necessary, close monitoring of ECGs and electrolytes essential, particularly in patients with known risk factors for cardiac disease or arrhythmias. Correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose.
Panobinostat: (Major) Avoid coadministration of encorafenib and panobinostat due to the potential for additive QT prolongation. Encorafenib is associated with dose-dependent prolongation of the QT interval. QT prolongation has been reported with panobinostat.
Pasireotide: (Major) Avoid coadministration of encorafenib and pasireotide due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. QT prolongation has occurred with pasireotide at therapeutic and supra-therapeutic doses.
Pazopanib: (Major) Avoid coadministration of encorafenib and pazopanib due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Pazopanib has been reported to prolong the QT interval. Additionally, coadministration of pazopanib and encorafenib may result in increased pazopanib exposure. Pazopanib is a BCRP substrate; encorafenib is a BCRP inhibitor. Consider selection of an alternative concomitant medication with no or minimal potential to inhibit BCRP.
Pentamidine: (Major) Avoid coadministration of encorafenib and pentamidine due to the potential for additive QT prolongation. If unavoidable, monitor ECGs and electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Systemic pentamidine has been associated with QT prolongation.
Perphenazine: (Minor) Consider monitoring ECGs for QT prolongation and electrolytes if encorafenib and perphenazine are coadministered due to the potential for additive QT prolongation. Correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Perphenazine is associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Perphenazine; Amitriptyline: (Minor) Consider monitoring ECGs for QT prolongation and electrolytes if encorafenib and perphenazine are coadministered due to the potential for additive QT prolongation. Correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Perphenazine is associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Pexidartinib: (Major) Avoid coadministration of encorafenib and pexidartinib due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; pexidartinib is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
Phenobarbital: (Major) Avoid coadministration of encorafenib and phenobarbital due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; phenobarbital is a strong CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid coadministration of encorafenib and phenobarbital due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; phenobarbital is a strong CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
Phenytoin: (Major) Avoid coadministration of encorafenib and phenytoin due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; phenytoin is a strong CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
Pimavanserin: (Major) Avoid coadministration of encorafenib and pimavanserin due to the potential for additive QT prolongation. Encorafenib is associated with dose-dependent prolongation of the QT interval. Pimavanserin may also cause QT prolongation.
Pimozide: (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).
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 coadministration of pitolisant with encorafenib as concurrent use may increase the risk of QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib has been associated with dose-dependent QT prolongation. Pitolisant also prolongs the QT interval.
Ponesimod: (Major) Avoid coadministration of encorafenib and ponesimod due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP); additive immunosuppression may also occur which may extend the duration or severity of immune suppression. If concurrent use cannot be avoided, monitor ECGs, electrolytes, and for signs and symptoms of infection; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib has been associated with dose-dependent QT prolongation. Ponesimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ponesimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia.
Posaconazole: (Major) Avoid coadministration of encorafenib and posaconazole due to increased encorafenib exposure and QT prolongation. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of posaconazole. Monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. If posaconazole is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of posaconazole. Encorafenib is a CYP3A4 substrate that has been associated with dose-dependent QT prolongation; posaconazole is a strong CYP3A4 inhibitor that has been associated with prolongation of the QT interval as well as rare cases of torsade de pointes. Coadministration of posaconazole with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
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.
Primaquine: (Major) Avoid coadministration of encorafenib and primaquine due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Primaquine has also been associated with QT interval prolongation.
Primidone: (Major) Avoid coadministration of encorafenib and primidone due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; primidone is a strong CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
Procainamide: (Major) Avoid coadministration of encorafenib and procainamide due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Procainamide is associated with a well-established risk of QT prolongation and torsade de pointes (TdP).
Prochlorperazine: (Minor) Consider monitoring ECGs for QT prolongation and electrolytes if encorafenib and prochlorperazine are coadministered due to the potential for additive QT prolongation. Correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Prochlorperazine is associated with a possible risk for QT prolongation.
Promethazine: (Major) 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.
Quetiapine: (Major) Avoid coadministration of encorafenib and quetiapine due to the potential for additive QT prolongation. Concurrent use may also result in increased toxicity or decreased efficacy of quetiapine. Encorafenib is associated with dose-dependent prolongation of the QT interval. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established. Limited data, including some case reports, suggest that quetiapine, a sensitive CYP3A4 substrate, may be associated with a significant prolongation of the QTc interval in rare instances.
Quinidine: (Major) Avoid coadministration of encorafenib and quinidine due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Quinidine administration is associated with QT prolongation and torsade de pointes (TdP).
Quinine: (Major) Avoid coadministration of encorafenib and quinine due to increased encorafenib exposure and QT prolongation. If concurrent use cannot be avoided, reduce the encorafenib dose to one-half of the dose used prior to the addition of quinine. Monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. If quinine is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of quinine. Encorafenib is a CYP3A4 substrate that has been associated with dose-dependent QT prolongation; quinine is a moderate CYP3A4 inhibitor that has been associated with QT prolongation and rare cases of torsade de pointes (TdP). Coadministration of a moderate CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 2-fold and 45%, respectively.
Quizartinib: (Major) Concomitant use of quizartinib 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.
Ranolazine: (Major) Avoid coadministration of encorafenib and ranolazine due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval.
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.
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 coadministration of encorafenib and ribociclib due to increased encorafenib exposure and QT prolongation. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of ribociclib. If unavoidable, monitor ECGs and electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. If ribociclib is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of ribociclib. Encorafenib is a CYP3A4 substrate that has been associated with dose-dependent QT prolongation; ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
Ribociclib; Letrozole: (Major) Avoid coadministration of encorafenib and ribociclib due to increased encorafenib exposure and QT prolongation. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of ribociclib. If unavoidable, monitor ECGs and electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. If ribociclib is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of ribociclib. Encorafenib is a CYP3A4 substrate that has been associated with dose-dependent QT prolongation; ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
Rifabutin: (Major) Avoid coadministration of encorafenib and rifabutin due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; rifabutin is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
Rifampin: (Major) Avoid coadministration of encorafenib and rifampin due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; rifampin is a strong CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
Rifapentine: (Major) Avoid coadministration of encorafenib and rifapentine due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; rifapentine is a strong CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
Rilpivirine: (Major) Avoid coadministration of encorafenib and rilpivirine due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Risperidone: (Major) Avoid coadministration of encorafenib and risperidone due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Risperidone has been associated with a possible risk for QT prolongation and/or torsade de pointes. Reports of QT prolongation and torsade de pointes during risperidone therapy have been reported, primarily in the overdosage setting.
Ritlecitinib: (Major) Avoid coadministration of encorafenib and ritlecitinib due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-half of the dose used prior to the addition of ritlecitinib. If ritlecitinib is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of ritlecitinib. Encorafenib is a CYP3A substrate; ritlecitinib is a moderate CYP3A inhibitor. Coadministration of a moderate CYP3A inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 2-fold and 45%, respectively.
Ritonavir: (Major) Avoid coadministration of encorafenib and ritonavir due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of ritonavir. If ritonavir is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of ritonavir. Encorafenib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
Romidepsin: (Major) Avoid coadministration of encorafenib and romidepsin due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Romidepsin has been reported to prolong the QT interval.
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.
Saquinavir: (Major) Avoid coadministration of encorafenib and saquinavir due to increased encorafenib exposure and QT prolongation. Increased or decreased saquinavir exposure is also possible. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of saquinavir. Monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. If saquinavir is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of saquinavir. Encorafenib is a CYP3A4 substrate that has been associated with dose-dependent QT prolongation. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. Saquinavir is a strong CYP3A4 inhibitor and sensitive CYP3A4 substrate that increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsade de pointes (TdP). Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Secobarbital: (Major) Avoid coadministration of encorafenib and secobarbital due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; secobarbital is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
Segesterone Acetate; Ethinyl Estradiol: (Major) Avoid coadministration of encorafenib and hormonal contraceptives due to the potential for loss of contraceptive efficacy. Advise females of reproductive potential to use an effective, non-hormonal method of contraception during treatment and for 2 weeks after the final dose of encorafenib. Encorafenib can cause fetal harm when administered during pregnancy.
Selpercatinib: (Major) Avoid coadministration of encorafenib and selpercatinib due to the risk of additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib has been associated with dose-dependent QT prolongation. Concentration-dependent QT prolongation has been observed with selpercatinib therapy.
Sertraline: (Major) 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) Coadministration of encorafenib with sildenafil may result in increased toxicity or decreased efficacy of sildenafil. Sildenafil is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
Simvastatin: (Moderate) 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) Avoid coadministration of encorafenib and siponimod due to the potential for additive QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Encorafenib has been associated with dose-dependent QT prolongation.
Sirolimus: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of encorafenib. Concomitant use may alter sirolimus exposure resulting in decreased efficacy or increased risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and encorafenib is a weak CYP3A inducer and inhibitor.
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; Voxilaprevir: (Major) Avoid concomitant use of voxilaprevir and encorafenib. Concomitant use may increase voxilaprevir exposure and the risk of voxilaprevir-related adverse reactions. Voxilaprevir is a substrate of OATP1B1/3; encorafenib is an OATP1B1/3 inhibitor.
Solifenacin: (Major) Avoid coadministration of encorafenib and solifenacin due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Solifenacin has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported with postmarketing use, although causality was not determined.
Sorafenib: (Major) Avoid coadministration of sorafenib with encorafenib due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Encorafenib has been associated with dose-dependent QT prolongation. Sorafenib is also associated with QTc prolongation.
Sotalol: (Major) 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 coadministration of encorafenib and sotorasib due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; sotorasib is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
St. John's Wort, Hypericum perforatum: (Major) Avoid coadministration of encorafenib and St. John's Wort due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; St. John's Wort is a strong CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
Sunitinib: (Major) Avoid coadministration of encorafenib and sunitinib due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Sunitinib can also prolong the QT interval.
Tacrolimus: (Major) Avoid coadministration of encorafenib and tacrolimus due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Coadministration may also result in increased toxicity or decreased efficacy of tacrolimus. Encorafenib is associated with dose-dependent prolongation of the QT interval. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established. Tacrolimus causes QT prolongation and is a sensitive CYP3A4 substrate.
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) Concomitant use of tamoxifen 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.
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.
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 encorafenib with ivacaftor may result in increased toxicity or decreased efficacy of ivacaftor. Ivacaftor is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
Thioridazine: (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).
Ticagrelor: (Moderate) Coadministration of encorafenib with ticagrelor may result in increased toxicity or decreased efficacy of ticagrelor. Ticagrelor is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
Tipranavir: (Major) Avoid coadministration of encorafenib and tipranavir/ritonavir due to increased encorafenib exposure. Increased or decreased tipranavir exposure is also possible. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of tipranavir/ritonavir. If tipranavir/ritonavir is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of tipranavir/ritonavir. Encorafenib is a CYP3A4 substrate; in vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. Tipranavir boosted with ritonavir is a strong CYP3A4 inhibitor; tipranavir is a sensitive CYP3A4 substrate. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
Tolterodine: (Major) Avoid coadministration of encorafenib and tolterodine due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
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 coadministration of encorafenib and toremifene due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
Trandolapril; Verapamil: (Major) Avoid coadministration of encorafenib and verapamil due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-half of the dose used prior to the addition of verapamil. If verapamil is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of verapamil. Encorafenib is a CYP3A4 substrate; verapamil is a moderate CYP3A4 inhibitor. Coadministration of a moderate CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 2-fold and 45%, respectively.
Trazodone: (Major) Concomitant use of trazodone 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.
Triazolam: (Moderate) Coadministration of encorafenib with triazolam may result in increased toxicity or decreased efficacy of triazolam. Triazolam is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
Triclabendazole: (Major) 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 encorafenib and tucatinib due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of tucatinib. If tucatinib is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of tucatinib. Encorafenib is a CYP3A4 substrate; tucatinib is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
Ubrogepant: (Major) Limit the initial and second dose of ubrogepant to 50 mg if coadministered with encorafenib. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a substrate of the BCRP and P-gp drug transporters; encorafenib is a BCRP inhibitor.
Vandetanib: (Major) Avoid coadministration of vandetanib with encorafenib due to an increased risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes; correct hypocalcemia, hypomagnesemia, and/or hypomagnesemia prior to vandetanib administration. An interruption of vandetanib therapy or dose reduction may be necessary for QT prolongation. Both drugs can prolong the QT interval in a concentration-dependent manner; TdP and sudden death have been reported in patients receiving vandetanib.
Vardenafil: (Major) 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 coadministration of encorafenib and vemurafenib due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. If coadministration necessary, monitor ECG for QT interval prolongation. Encorafenib is associated with dose-dependent prolongation of the QT interval. Vemurafenib has been associated with QT prolongation.
Venetoclax: (Moderate) Coadministration of encorafenib with venetoclax may result in increased toxicity or decreased efficacy of venetoclax. Venetoclax is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
Venlafaxine: (Major) 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 coadministration of encorafenib and verapamil due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-half of the dose used prior to the addition of verapamil. If verapamil is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of verapamil. Encorafenib is a CYP3A4 substrate; verapamil is a moderate CYP3A4 inhibitor. Coadministration of a moderate CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 2-fold and 45%, respectively.
Voclosporin: (Major) Avoid concomitant use of encorafenib and voclosporin due to the risk of additive QT prolongation. If concomitant use is necessary, monitor ECGs and electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib has been associated with dose-dependent QT prolongation. Voclosporin has been associated with QT prolongation at supratherapeutic doses.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Avoid coadministration of encorafenib and clarithromycin due to increased encorafenib exposure and QT prolongation. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of clarithromycin. Monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. If clarithromycin is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of clarithromycin. Encorafenib is a CYP3A4 substrate that has been associated with dose-dependent QT prolongation; clarithromycin is a strong CYP3A4 inhibitor that is associated with an established risk for QT prolongation and torsade de pointes (TdP). Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
Voriconazole: (Contraindicated) Coadministration of voriconazole with drugs that are associated with QT prolongation and are also CYP3A4 substrates, such as encorafenib, is contraindicated. Voriconazole has been associated with QT prolongation and rare cases of torsade de pointes.
Vorinostat: (Major) Avoid coadministration of encorafenib and vorinostat due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Vorinostat therapy is associated with a risk of QT prolongation.
Voxelotor: (Major) Avoid coadministration of encorafenib and voxelotor due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-half of the dose used prior to the addition of voxelotor. If voxelotor is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of voxelotor. Encorafenib is a CYP3A substrate; voxelotor is a moderate CYP3A inhibitor. Coadministration of a moderate CYP3A inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 2-fold and 45%, respectively.
Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with encorafenib is necessary as concurrent use may increase or decrease the exposure of warfarin leading to increased bleeding risk or reduced efficacy. Encorafenib is a weak CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate which can lead to increased warfarin exposure and increased bleeding risk. Encorafenib is also a weak CYP3A4 inducer which can lead to decreased warfarin exposure and reduced efficacy.
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) Avoid coadministration of encorafenib and ziprasidone due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors.

done due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors.

BRAFTOVI/Encorafenib Oral Cap: 50mg, 75mg

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.

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.

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.

Pregnancy

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

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