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Zelboraf
Classes
Small Molecule Antineoplastic BRAF kinase Inhibitors
Administration
Hazardous Drugs Classification
NIOSH 2016 List: Group 1
NIOSH (Draft) 2020 List: Table 2
Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure.
Emetic Risk
Minimal/Low
Administer prn antiemetics as necessary.
Take doses approximately 12 hours apart.
May be taken orally with or without a meal.
Have patient swallow tablet whole with a full glass of water. Do not crush or chew.
If vomiting occurs after administration, do not take an additional dose; take the next dose at the scheduled time.
If a dose is missed, it can be taken up to 4 hours before the next dose is due to maintain the twice daily regimen. Do not take both doses at the same time.
Adverse Reactions
new primary malignancy / Delayed / 0-55.0
skin cancer / Delayed / 0-40.9
hypertension / Early / 23.0-23.0
maculopapular rash / Early / 2.0-18.0
elevated hepatic enzymes / Delayed / 0-16.0
arthralgia / Delayed / 4.0-14.0
atrial fibrillation / Early / 0-10.0
toxic epidermal necrolysis / Delayed / 0-10.0
erythema nodosum / Delayed / 0-10.0
Stevens-Johnson syndrome / Delayed / 0-10.0
retinal thrombosis / Delayed / 0-10.0
nephrotoxicity / Delayed / 0-9.1
rash / Early / 0-8.0
QT prolongation / Rapid / 0-5.0
hyperkeratosis / Delayed / 0-5.0
fatigue / Early / 0-5.0
photosensitivity / Delayed / 0-3.0
uveitis / Delayed / 0-2.1
pruritus / Rapid / 0-2.0
diarrhea / Early / 0-2.0
vomiting / Early / 0-2.0
nausea / Early / 0-2.0
fever / Early / 2.0-2.0
hyperbilirubinemia / Delayed / 0-1.9
alopecia / Delayed / 0-1.0
back pain / Delayed / 0-1.0
myalgia / Early / 0-1.0
asthenia / Delayed / 0-1.0
constipation / Delayed / 0-1.0
headache / Early / 0-1.0
peripheral edema / Delayed / 0-1.0
vasculitis / Delayed / 10.0
coagulopathy / Delayed / Incidence not known
cranial nerve palsies / Delayed / Incidence not known
anaphylactoid reactions / Rapid / Incidence not known
myocarditis / Delayed / Incidence not known
pleural effusion / Delayed / Incidence not known
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
pancreatitis / Delayed / Incidence not known
renal failure (unspecified) / Delayed / Incidence not known
interstitial nephritis / Delayed / Incidence not known
renal tubular necrosis / Delayed / Incidence not known
palmar-plantar erythrodysesthesia (hand and foot syndrome) / Delayed / 0-41.0
peripheral neuropathy / Delayed / 0-36.0
erythema / Early / 0-14.0
neutropenia / Delayed / 0-10.0
iritis / Delayed / 0-2.1
plantar fibromatosis / Delayed / 0-1.0
Dupuytren's contracture / Delayed / 0-1.0
photophobia / Early / Incidence not known
blurred vision / Early / Incidence not known
eosinophilia / Delayed / Incidence not known
hypotension / Rapid / Incidence not known
lymphadenopathy / Delayed / Incidence not known
radiation recall reaction / Delayed / Incidence not known
xerosis / Delayed / 0-45.0
cough / Delayed / 8.0-36.0
anorexia / Delayed / 0-21.0
dysgeusia / Early / 0-14.0
musculoskeletal pain / Early / 0-11.0
panniculitis / Delayed / 0-10.0
folliculitis / Delayed / 0-10.0
Common Brand Names
Zelboraf
Dea Class
Rx
Description
BRAF serine threonine kinase inhibitor
Used for the treatment of unresectable or metastatic melanoma and for the treatment of Erdheim-Chester disease in patients with V600E mutations of the BRAF gene
Secondary malignancies have been reported
Dosage And Indications
NOTE: Vemurafenib has been designated an orphan drug by the FDA for the treatment of BRAF V600E mutation-positive stage IIB to IV melanoma.
NOTE: Confirm the BRAF V600E mutation prior to starting therapy using an FDA-approved test available at www.fda.gov/CompanionDiagnostics; vemurafenib is not indicated in patients with wild-type BRAF melanoma. For the treatment of unresectable or metastatic melanoma in patients with the BRAF V600E mutation. Oral dosage Adults
960 mg orally every 12 hours until disease progression. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Interruption of vemurafenib therapy and/or a dosage reduction may be necessary in patients who develop toxicity or intolerable side effects. The overall survival (OS) time (13.6 months vs. 9.7 months) and progression-free survival (PFS) time (6.9 months vs. 1.6 months) were significantly improved in patients with previously untreated BRAF V600-mutated unresectable stage IIIC or metastatic melanoma who received twice-daily oral vemurafenib (n = 337; median follow-up, 12.5 months) compared with dacarbazine 1,000 mg/m2 IV every 3 weeks (n = 338; median follow-up, 9.5 months) in a multinational, randomized, phase 3 study (the BRIM-3 trial). Some patients (n = 83; 25%) in the dacarbazine arm crossed over to vemurafenib therapy; data were censored at crossover. The 12-month OS rates were 56% and 44% in the vemurafenib and dacarbazine arms, respectively. In a multicenter, phase 2 trial (median follow-up time of 12.9 months; range, 0.6 to 20.1 months), treatment with single-agent vemurafenib resulted in an overall response rate (ORR) of 53% (complete response rate, 6%) in 132 patients with previously treated BRAF V600-mutant metastatic melanoma (1 prior therapy, 51%; 2 prior therapies, 27%; 3 or more prior therapies, 22%). The median response duration was 6.7 months. The median OS and PFS times were 15.9 and 6.8 months, respectively. The 12- and 18-month OS rates were 58% and 43%, respectively. In a multicenter, 2-cohort trial (the MO25743 trial) in patients with BRAF V600E mutation-positive melanoma and brain metastases, treatment with vemurafenib resulted in a best overall response rate of 18% in patients who had no prior local therapy for brain metastases (cohort A; n = 90) and 18% in patients who had CNS progression after at least 1 prior local therapy for brain metastases (i.e., surgical resection, whole brain radiotherapy, or stereotactic radiotherapy) (cohort B; n = 56). The median duration of response was 4.6 months (range, 2.9 to 6.2 months) in cohort A and 6.6 months (2.8 to 10.7 months) in cohort B. Eligible patients in this study had no prior treatment with a BRAF or MEK inhibitor, at least 1 measurable brain lesion of 0.5 cm or greater (on contrast-enhanced MRI), and a stable or decreasing corticosteroid dose.
Dosage not established. The disease-free survival time was not significantly improved with up to 1 year of adjuvant vemurafenib 960 mg orally twice daily compared with placebo in a cohort of patients with stage IIIC melanoma in a randomized, double-blind, placebo-controlled, phase 3 trial (n = 498; the BRIM8 trial); there is not sufficient evidence to support the use of this drug for this indication.
NOTE: Cobimetinib in combination with vemurafenib is FDA-approved for this indication.
Oral dosage Adults
960 mg orally twice daily in combination with cobimetinib 60 mg orally once daily for 21 days; repeat cycle every 28 days until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Interruption of vemurafenib therapy and/or a dosage reduction may be necessary in patients who develop toxicity or intolerable side effects. At a median follow-up of 14.2 months, the median investigator-assessed progression-free survival (PFS) time was significantly improved with cobimetinib plus vemurafenib compared with placebo plus vemurafenib (12.3 months vs. 7.2 months; hazard ratio (HR) = 0.58; 95% CI, 0.46 to 0.72) in patients with previously untreated unresectable locally advanced or metastatic BRAF V600 mutation-positive melanoma in a multinational, randomized, double-blind, phase 3 trial (n = 495; the CoBRIM trial). Additionally, the median PFS (12.6 months vs. 7.2 months) and median overall survival (OS) (22.5 months vs. 17.4 months; HR = 0.8; 95% CI, 0.64 to 0.99) times were significantly improved with cobimetinib plus vemurafenib compared with placebo plus vemurafenib at a median follow-up of 21.2 months. The 5-year PFS rates were 14% and 10% in the cobimetinib plus vemurafenib and placebo plus vemurafenib arms, respectively; the 5-year OS rates were 31% and 26%, respectively.
NOTE: Atezolizumab in combination with cobimetinib and vemurafenib is FDA-approved for this indication.
Oral dosage Adults
Cycle 1, 960 mg orally twice daily on days 1 to 21 then 720 mg orally twice daily on days 22 to 28; cycle 2 and beyond, 720 mg orally twice daily. Give in combination with atezolizumab (840 mg IV repeated every 2 weeks; OR 1,200 mg IV every 3 weeks; OR 1,680 mg IV every 4 weeks starting on cycle 2) and cobimetinib 60 mg orally once daily for 21 days (on days 1 to 21). Cycle 1 consists of cobimetinib and vemurafenib only. Treatment cycles are repeated every 28 days. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Interruption of vemurafenib therapy and/or a dosage reduction may be necessary in patients who develop toxicity or intolerable side effects. At a median follow-up time of 18.9 months, the investigator-assessed median progression-free survival (PFS) time was significantly longer in patients who received atezolizumab, vemurafenib, and cobimetinib compared with placebo, vemurafenib, and cobimetinib (15.1 months vs. 10.6 months; hazard ratio (HR) = 0.78; 95% CI, 0.63 to 0.97) in an international, randomized, double-blind, placebo-controlled, phase 3 trial (n = 514; IMspire150 trial). When PFS was assessed by an independent review committee, the median PFS time was not significantly improved in the atezolizumab arm (16.1 months vs. 12.3 months; HR = 0.85; 95% CI, 0.67 to 1.07). Additionally, the median overall survival (OS) time was not significantly improved in patients who received atezolizumab compared with placebo (39 months vs. 25.8 months; HR = 0.84; 95% CI, 0.66 to 1.06) in an interim OS analysis of the IMspire150 trial performed at median follow-up times of 29.1 and 22.8 months, respectively. Patients (median age 54 years; range, 43 to 64 years) in this trial had BRAF V600 mutation-positive unresectable stage IIIc or stage IV melanoma and had not received previous systemic therapy for metastatic disease.
NOTE: Vemurafenib has been designated an orphan drug by the FDA for the treatment of ECD.
Oral dosage Adults
960 mg orally every 12 hours until disease progression. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Interruption of vemurafenib therapy and/or a dosage reduction may be necessary in patients who develop toxicity or intolerable side effects. The overall response rate was 54.5% in patients with BRAF V600 mutation-positive ECD who received vemurafenib (n = 22; age range, 34 to 77 years) in a multicenter, single-arm, cohort trial; 1 patient (4.5%) achieved a complete response. At a median follow-up time of 26.6 months (range, 3 to 44.3 months), the median time to response was 11 months and the median duration of response was not estimable. In this trial, 68.2% of patients had received prior therapy for ECD.
960 mg by mouth twice daily, in combination with irinotecan (180 mg/m2 IV) and cetuximab (500 mg/m2 IV) on day 1, every 14 days until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In a multicenter, randomized, open-label phase 2 clinical trial, treatment with vemurafenib, cetuximab and irinotecan significantly improved the median progression-free survival (PFS) over treatment with cetuximab plus irinotecan, without vemurafenib (4.4 months vs. 2 months) in patients with BRAF V600E mutation-positive, RAS wild-type, metastatic colorectal cancer (mCRC) received treatment with cetuximab and irinotecan, with or without vemurafenib (a BRAF inhibitor). Approximately 50% of patients in the control arm crossed over to receive vemurafenib after progression; the rate of disease control was also significantly improved in the vemurafenib arm (67% vs. 22%).
960 mg orally twice daily for 8 or 12 weeks (up to 24 weeks in patients with residual disease) was evaluated in 2 nonrandomized trials.[63823] Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Interruption of vemurafenib therapy and/or a dosage reduction may be necessary in patients who develop toxicity or intolerable side effects.[45335]
†Indicates off-label use
Dosing Considerations
No initial vemurafenib dosage adjustment is necessary in patients with mild to moderate hepatic impairment (total bilirubin levels of 1—3X the upper limit of normal) based on a population pharmacokinetic analysis. The appropriate dosage of vemurafenib in patients with severe hepatic impairment has not been established.
Renal ImpairmentNo initial vemurafenib dosage adjustment is necessary in patients with mild to moderate renal impairment (creatinine clearance of 30—89 ml/min) based on a population pharmacokinetic analysis. The appropriate dosage of vemurafenib in patients with severe renal impairment has not been established.
Drug Interactions
Acetaminophen: (Moderate) Concomitant use of vemurafenib and acetaminophen may result in altered concentrations of acetaminophen. Vemurafenib is an inhibitor of CYP1A2 and CYP2A6, and an inducer of CYP3A4. Acetaminophen is a substrate of CYP1A2, CYP2A6, and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Concomitant use of vemurafenib and acetaminophen may result in altered concentrations of acetaminophen. Vemurafenib is an inhibitor of CYP1A2 and CYP2A6, and an inducer of CYP3A4. Acetaminophen is a substrate of CYP1A2, CYP2A6, and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
Acetaminophen; Aspirin: (Moderate) Concomitant use of vemurafenib and acetaminophen may result in altered concentrations of acetaminophen. Vemurafenib is an inhibitor of CYP1A2 and CYP2A6, and an inducer of CYP3A4. Acetaminophen is a substrate of CYP1A2, CYP2A6, and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
Acetaminophen; Aspirin; Diphenhydramine: (Moderate) Concomitant use of vemurafenib and acetaminophen may result in altered concentrations of acetaminophen. Vemurafenib is an inhibitor of CYP1A2 and CYP2A6, and an inducer of CYP3A4. Acetaminophen is a substrate of CYP1A2, CYP2A6, and CYP3A4. Use caution and monitor patients for toxicity and efficacy. (Moderate) Concomitant use of vemurafenib and diphenhydramine may result in increased diphenhydramine concentrations. Vemurafenib is a CYP1A2, CYP2C9, and CYP2D6 inhibitor and diphenhydramine is a substrate of these isoenzymes. Patients should be monitored for toxicity and sedation.
Acetaminophen; Caffeine: (Moderate) Concomitant use of vemurafenib and acetaminophen may result in altered concentrations of acetaminophen. Vemurafenib is an inhibitor of CYP1A2 and CYP2A6, and an inducer of CYP3A4. Acetaminophen is a substrate of CYP1A2, CYP2A6, and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of vemurafenib and acetaminophen may result in altered concentrations of acetaminophen. Vemurafenib is an inhibitor of CYP1A2 and CYP2A6, and an inducer of CYP3A4. Acetaminophen is a substrate of CYP1A2, CYP2A6, and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
Acetaminophen; Caffeine; Pyrilamine: (Moderate) Concomitant use of vemurafenib and acetaminophen may result in altered concentrations of acetaminophen. Vemurafenib is an inhibitor of CYP1A2 and CYP2A6, and an inducer of CYP3A4. Acetaminophen is a substrate of CYP1A2, CYP2A6, and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
Acetaminophen; Chlorpheniramine: (Moderate) Concomitant use of vemurafenib and acetaminophen may result in altered concentrations of acetaminophen. Vemurafenib is an inhibitor of CYP1A2 and CYP2A6, and an inducer of CYP3A4. Acetaminophen is a substrate of CYP1A2, CYP2A6, and CYP3A4. Use caution and monitor patients for toxicity and efficacy. (Moderate) Concomitant use of vemurafenib and chlorpheniramine may result in increased chlorpheniramine concentrations. Chlorpheniramine is metabolized by CYP2D6 and vemurafenib is a weak CYP2D6 inhibitor. Monitor patients for toxicity.
Acetaminophen; Chlorpheniramine; Dextromethorphan: (Moderate) Concomitant use of vemurafenib and acetaminophen may result in altered concentrations of acetaminophen. Vemurafenib is an inhibitor of CYP1A2 and CYP2A6, and an inducer of CYP3A4. Acetaminophen is a substrate of CYP1A2, CYP2A6, and CYP3A4. Use caution and monitor patients for toxicity and efficacy. (Moderate) Concomitant use of vemurafenib and chlorpheniramine may result in increased chlorpheniramine concentrations. Chlorpheniramine is metabolized by CYP2D6 and vemurafenib is a weak CYP2D6 inhibitor. Monitor patients for toxicity. (Minor) Use of dextromethorphan with vemurafenib increases dextromethorphan exposure. Vemurafenib is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Coadministration of vemurafenib and dextromethorphan increased the AUC of dextromethorphan by 47% and the dextromethorphan Cmax by 36%.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Concomitant use of vemurafenib and acetaminophen may result in altered concentrations of acetaminophen. Vemurafenib is an inhibitor of CYP1A2 and CYP2A6, and an inducer of CYP3A4. Acetaminophen is a substrate of CYP1A2, CYP2A6, and CYP3A4. Use caution and monitor patients for toxicity and efficacy. (Moderate) Concomitant use of vemurafenib and chlorpheniramine may result in increased chlorpheniramine concentrations. Chlorpheniramine is metabolized by CYP2D6 and vemurafenib is a weak CYP2D6 inhibitor. Monitor patients for toxicity. (Minor) Use of dextromethorphan with vemurafenib increases dextromethorphan exposure. Vemurafenib is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Coadministration of vemurafenib and dextromethorphan increased the AUC of dextromethorphan by 47% and the dextromethorphan Cmax by 36%.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Concomitant use of vemurafenib and acetaminophen may result in altered concentrations of acetaminophen. Vemurafenib is an inhibitor of CYP1A2 and CYP2A6, and an inducer of CYP3A4. Acetaminophen is a substrate of CYP1A2, CYP2A6, and CYP3A4. Use caution and monitor patients for toxicity and efficacy. (Moderate) Concomitant use of vemurafenib and chlorpheniramine may result in increased chlorpheniramine concentrations. Chlorpheniramine is metabolized by CYP2D6 and vemurafenib is a weak CYP2D6 inhibitor. Monitor patients for toxicity. (Minor) Use of dextromethorphan with vemurafenib increases dextromethorphan exposure. Vemurafenib is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Coadministration of vemurafenib and dextromethorphan increased the AUC of dextromethorphan by 47% and the dextromethorphan Cmax by 36%.
Acetaminophen; Chlorpheniramine; Phenylephrine : (Moderate) Concomitant use of vemurafenib and acetaminophen may result in altered concentrations of acetaminophen. Vemurafenib is an inhibitor of CYP1A2 and CYP2A6, and an inducer of CYP3A4. Acetaminophen is a substrate of CYP1A2, CYP2A6, and CYP3A4. Use caution and monitor patients for toxicity and efficacy. (Moderate) Concomitant use of vemurafenib and chlorpheniramine may result in increased chlorpheniramine concentrations. Chlorpheniramine is metabolized by CYP2D6 and vemurafenib is a weak CYP2D6 inhibitor. Monitor patients for toxicity.
Acetaminophen; Codeine: (Moderate) Concomitant use of vemurafenib and acetaminophen may result in altered concentrations of acetaminophen. Vemurafenib is an inhibitor of CYP1A2 and CYP2A6, and an inducer of CYP3A4. Acetaminophen is a substrate of CYP1A2, CYP2A6, and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
Acetaminophen; Dextromethorphan: (Moderate) Concomitant use of vemurafenib and acetaminophen may result in altered concentrations of acetaminophen. Vemurafenib is an inhibitor of CYP1A2 and CYP2A6, and an inducer of CYP3A4. Acetaminophen is a substrate of CYP1A2, CYP2A6, and CYP3A4. Use caution and monitor patients for toxicity and efficacy. (Minor) Use of dextromethorphan with vemurafenib increases dextromethorphan exposure. Vemurafenib is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Coadministration of vemurafenib and dextromethorphan increased the AUC of dextromethorphan by 47% and the dextromethorphan Cmax by 36%.
Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Concomitant use of vemurafenib and acetaminophen may result in altered concentrations of acetaminophen. Vemurafenib is an inhibitor of CYP1A2 and CYP2A6, and an inducer of CYP3A4. Acetaminophen is a substrate of CYP1A2, CYP2A6, and CYP3A4. Use caution and monitor patients for toxicity and efficacy. (Minor) Use of dextromethorphan with vemurafenib increases dextromethorphan exposure. Vemurafenib is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Coadministration of vemurafenib and dextromethorphan increased the AUC of dextromethorphan by 47% and the dextromethorphan Cmax by 36%.
Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Concomitant use of vemurafenib and acetaminophen may result in altered concentrations of acetaminophen. Vemurafenib is an inhibitor of CYP1A2 and CYP2A6, and an inducer of CYP3A4. Acetaminophen is a substrate of CYP1A2, CYP2A6, and CYP3A4. Use caution and monitor patients for toxicity and efficacy. (Minor) Use of dextromethorphan with vemurafenib increases dextromethorphan exposure. Vemurafenib is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Coadministration of vemurafenib and dextromethorphan increased the AUC of dextromethorphan by 47% and the dextromethorphan Cmax by 36%.
Acetaminophen; Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of vemurafenib and acetaminophen may result in altered concentrations of acetaminophen. Vemurafenib is an inhibitor of CYP1A2 and CYP2A6, and an inducer of CYP3A4. Acetaminophen is a substrate of CYP1A2, CYP2A6, and CYP3A4. Use caution and monitor patients for toxicity and efficacy. (Minor) Use of dextromethorphan with vemurafenib increases dextromethorphan exposure. Vemurafenib is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Coadministration of vemurafenib and dextromethorphan increased the AUC of dextromethorphan by 47% and the dextromethorphan Cmax by 36%.
Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) Concomitant use of vemurafenib and acetaminophen may result in altered concentrations of acetaminophen. Vemurafenib is an inhibitor of CYP1A2 and CYP2A6, and an inducer of CYP3A4. Acetaminophen is a substrate of CYP1A2, CYP2A6, and CYP3A4. Use caution and monitor patients for toxicity and efficacy. (Minor) Use of dextromethorphan with vemurafenib increases dextromethorphan exposure. Vemurafenib is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Coadministration of vemurafenib and dextromethorphan increased the AUC of dextromethorphan by 47% and the dextromethorphan Cmax by 36%.
Acetaminophen; Dextromethorphan; Pseudoephedrine: (Moderate) Concomitant use of vemurafenib and acetaminophen may result in altered concentrations of acetaminophen. Vemurafenib is an inhibitor of CYP1A2 and CYP2A6, and an inducer of CYP3A4. Acetaminophen is a substrate of CYP1A2, CYP2A6, and CYP3A4. Use caution and monitor patients for toxicity and efficacy. (Minor) Use of dextromethorphan with vemurafenib increases dextromethorphan exposure. Vemurafenib is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Coadministration of vemurafenib and dextromethorphan increased the AUC of dextromethorphan by 47% and the dextromethorphan Cmax by 36%.
Acetaminophen; Dichloralphenazone; Isometheptene: (Moderate) Concomitant use of vemurafenib and acetaminophen may result in altered concentrations of acetaminophen. Vemurafenib is an inhibitor of CYP1A2 and CYP2A6, and an inducer of CYP3A4. Acetaminophen is a substrate of CYP1A2, CYP2A6, and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
Acetaminophen; Diphenhydramine: (Moderate) Concomitant use of vemurafenib and acetaminophen may result in altered concentrations of acetaminophen. Vemurafenib is an inhibitor of CYP1A2 and CYP2A6, and an inducer of CYP3A4. Acetaminophen is a substrate of CYP1A2, CYP2A6, and CYP3A4. Use caution and monitor patients for toxicity and efficacy. (Moderate) Concomitant use of vemurafenib and diphenhydramine may result in increased diphenhydramine concentrations. Vemurafenib is a CYP1A2, CYP2C9, and CYP2D6 inhibitor and diphenhydramine is a substrate of these isoenzymes. Patients should be monitored for toxicity and sedation.
Acetaminophen; Guaifenesin; Phenylephrine: (Moderate) Concomitant use of vemurafenib and acetaminophen may result in altered concentrations of acetaminophen. Vemurafenib is an inhibitor of CYP1A2 and CYP2A6, and an inducer of CYP3A4. Acetaminophen is a substrate of CYP1A2, CYP2A6, and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
Acetaminophen; Hydrocodone: (Moderate) Concomitant use of vemurafenib and acetaminophen may result in altered concentrations of acetaminophen. Vemurafenib is an inhibitor of CYP1A2 and CYP2A6, and an inducer of CYP3A4. Acetaminophen is a substrate of CYP1A2, CYP2A6, and CYP3A4. Use caution and monitor patients for toxicity and efficacy. (Moderate) Hydrocodone is metabolized by CYP3A4. Vemurafenib, an inducer of CYP3A4, may cause increased clearance of hydrocodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone. Monitor the patient for reduced efficacy of hydrocodone. A higher hydrocodone dose may be needed if used with vemurafenib.
Acetaminophen; Ibuprofen: (Major) Concomitant use of vemurafenib and ibuprofen may result in increased ibuprofen concentrations. Vemurafenib is a CYP2C9 inhibitor and ibuprofen is a CYP2C9 substrate. Patients should be monitored for toxicity. (Moderate) Concomitant use of vemurafenib and acetaminophen may result in altered concentrations of acetaminophen. Vemurafenib is an inhibitor of CYP1A2 and CYP2A6, and an inducer of CYP3A4. Acetaminophen is a substrate of CYP1A2, CYP2A6, and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
Acetaminophen; Oxycodone: (Moderate) Concomitant use of vemurafenib and acetaminophen may result in altered concentrations of acetaminophen. Vemurafenib is an inhibitor of CYP1A2 and CYP2A6, and an inducer of CYP3A4. Acetaminophen is a substrate of CYP1A2, CYP2A6, and CYP3A4. Use caution and monitor patients for toxicity and efficacy. (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with vemurafenib is necessary; consider increasing the dose of oxycodone as needed. If vemurafenib is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and vemurafenib is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Acetaminophen; Pamabrom; Pyrilamine: (Moderate) Concomitant use of vemurafenib and acetaminophen may result in altered concentrations of acetaminophen. Vemurafenib is an inhibitor of CYP1A2 and CYP2A6, and an inducer of CYP3A4. Acetaminophen is a substrate of CYP1A2, CYP2A6, and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
Acetaminophen; Phenylephrine: (Moderate) Concomitant use of vemurafenib and acetaminophen may result in altered concentrations of acetaminophen. Vemurafenib is an inhibitor of CYP1A2 and CYP2A6, and an inducer of CYP3A4. Acetaminophen is a substrate of CYP1A2, CYP2A6, and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
Acetaminophen; Pseudoephedrine: (Moderate) Concomitant use of vemurafenib and acetaminophen may result in altered concentrations of acetaminophen. Vemurafenib is an inhibitor of CYP1A2 and CYP2A6, and an inducer of CYP3A4. Acetaminophen is a substrate of CYP1A2, CYP2A6, and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
Adagrasib: (Major) Avoid concomitant use of adagrasib and vemurafenib due to the potential for increased vemurafenib exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If use is necessary, consider a vemurafenib dose reduction; monitor patients closely for the development of adverse events and dose reduce or discontinue therapy based on manufacturer guidance. Additionally, consider taking steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Vemurafenib is a CYP3A substrate, adagrasib is a strong CYP3A inhibitor, and both medications have been associated with QT interval prolongation. Coadministration with another strong CYP3A inhibitor increased the exposure of vemurafenib by 40%.
Afatinib: (Moderate) If the concomitant use of vemurafenib and afatinib is necessary, consider reducing the afatinib dose by 10 mg per day if the original dose is not tolerated; resume the previous dose of afatinib as tolerated after discontinuation of vemurafenib. Afatinib is a P-glycoprotein (P-gp) substrate and inhibitor in vitro, and vemurafenib is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Coadministration of vemurafenib (960 mg twice daily for 22 days) with digoxin (single dose, 0.25 mg), a sensitive P-gp substrate, to 22 cancer patients increased the digoxin AUC and Cmax by 1.8-fold and 1.5-fold, respectively. Administration of another P-gp inhibitor, ritonavir (200 mg twice daily for 3 days), 1 hour before afatinib (single dose) increased the afatinib AUC and Cmax by 48% and 39%, respectively; there was no change in the afatinib AUC when ritonavir was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with ritonavir, and 111% and 105% when ritonavir was administered 6 hours after afatinib. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise.
Albuterol; Budesonide: (Moderate) Concomitant use of vemurafenib and budesonide may result in altered concentrations of budesonide and increased concentrations vemurafenib. Vemurafenib is a substrate/inducer of CYP3A4 and a substrate/inhibitor of P-glycoprotein (PGP). Budesonide is a substrate of CYP3A4 and a substrate/inhibitor of PGP. Use caution and monitor patients for toxicity and efficacy.
Aldesleukin, IL-2: (Moderate) Concomitant use of vemurafenib and aldesleukin, IL-2 may result in increased vemurafenib concentrations. Vemurafenib is CYP3A4 substrate and aldesleukin, IL-2 is a CYP3A4 inhibitor. Use caution and monitor patients for increased side effects.
Alfentanil: (Moderate) Vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as alfentanil, could be expected with concurrent use. Use caution, and monitor therapeutic effects of alfentanil when coadministered with vemurafenib.
Alfuzosin: (Major) Vemurafenib has been associated with QT prolongation. If vemurafenib and another drug, such as alfuzosin, that is associated with a possible risk for QT prolongation and torsade de pointes (TdP) must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. In addition to avoiding concurrent drug interactions, the potential for TdP can be reduced by avoiding the use of QT prolonging drugs in patients at substantial risk for TdP. Examples of general risk factors for TdP include congenital long QT syndrome, female sex, elderly patients, significant bradycardia, hypokalemia, hypomagnesemia, and underlying cardiac disease (e.g., arrhythmias, cardiomyopathy, acute myocardial ischemia). Also, alfuzosin is a CYP3A4 substrate, while vemurafenib is a CYP3A4 substrate and inducer; therefore, concentrations of alfuzosin may be decreased.
Alosetron: (Moderate) Concomitant use of vemurafenib and alosetron may result in altered concentrations of alosetron. Vemurafenib is an inhibitor of CYP1A2 and CYP2C9 and an inducer of CYP3A4. Alosetron is a substrate of CYP1A2, CYP2C9, and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
Alpelisib: (Major) Avoid coadministration of alpelisib with vemurafenib 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 vemurafenib is a BCRP inhibitor.
Amiodarone: (Major) Vemurafenib has been associated with QT prolongation. If vemurafenib and another drug, such as amiodarone, that is associated with a possible risk for QT prolongation and torsade de pointes (TdP) must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Amiodarone, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and TdP. Although the frequency of TdP is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. Also, amiodarone is a CYP3A4 substrate/inhibitor and a P-glycoprotein (P-gp) inhibitor, while vemurafenib is CYP3A4 substrate/inducer and a P-gp substrate/inhibitor. Decreased amiodarone and increased vemurafenib concentrations may occur with concomitant use.
Amisulpride: (Major) Monitor ECGs for QT prolongation when amisulpride is administered with vemurafenib. Amisulpride causes dose- and concentration- dependent QT prolongation. Vemurafenib has been associated with QT prolongation and TdP.
Amlodipine: (Moderate) Vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as amlodipine, could be expected with concurrent use. Use caution, and monitor therapeutic effects of amlodipine when coadministered with vemurafenib.
Amlodipine; Atorvastatin: (Moderate) Concomitant use of vemurafenib and atorvastatin may result in altered concentrations of atorvastatin and increased concentrations of vemurafenib. Vemurafenib is a substrate/inhibitor of P-glycoprotein (P-gp) and an inducer of CYP3A4. Atorvastatin is a substrate of P-gp and CYP3A4 and an inhibitor of P-gp. Use caution and monitor patients for toxicity and efficacy. (Moderate) Vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as amlodipine, could be expected with concurrent use. Use caution, and monitor therapeutic effects of amlodipine when coadministered with vemurafenib.
Amlodipine; Benazepril: (Moderate) Vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as amlodipine, could be expected with concurrent use. Use caution, and monitor therapeutic effects of amlodipine when coadministered with vemurafenib.
Amlodipine; Celecoxib: (Moderate) Vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as amlodipine, could be expected with concurrent use. Use caution, and monitor therapeutic effects of amlodipine when coadministered with vemurafenib.
Amlodipine; Olmesartan: (Moderate) Vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as amlodipine, could be expected with concurrent use. Use caution, and monitor therapeutic effects of amlodipine when coadministered with vemurafenib.
Amlodipine; Valsartan: (Moderate) Vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as amlodipine, could be expected with concurrent use. Use caution, and monitor therapeutic effects of amlodipine when coadministered with vemurafenib.
Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as amlodipine, could be expected with concurrent use. Use caution, and monitor therapeutic effects of amlodipine when coadministered with vemurafenib.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid vemurafenib in patients receiving medications known to prolong the QT interval such as clarithromycin. Vemurafenib has been shown to prolong the QT interval in a concentration-dependent manner. The ECG changes occurred within the first month of treatment. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP). Additionally, coadministration may result in increased vemurafenib exposure and an increased risk of adverse events, including QT prolongation. Vemurafenib is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of vemurafenib by 40%.
Anagrelide: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Vemurafenib is associated with a possible risk for QT prolongation and TdP and should be used cautiously and with close monitoring with anagrelide. In addition, concomitant use of vemurafenib and anagrelide may result in increased anagrelide concentrations. Vemurafenib is a CYP1A2 inhibitor and anagrelide is a CYP1A2 substrate. Anagrelide inhibits platelet aggregation at high doses. Patients should be monitored for toxicity. Patients with thrombocytopenia are at increased risk of bleeding complications. An increased risk of bleeding may occur when anagrelide is used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
Apalutamide: (Major) Avoid coadministration of vemurafenib with apalutamide due to decreased plasma concentrations of vemurafenib. If unavoidable, increase to dose of vemurafenib by 240 mg as tolerated. The original dose of vemurafenib may be resumed 2 weeks after apalutamide is discontinued. Vemurafenib is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased exposure to vemurafenib by 40%.
Apomorphine: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering vemurafenib with apomorphine. If these drugs must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Vemurafenib has been associated with QT prolongation. Dose-related QTc prolongation is associated with therapeutic apomorphine exposure.
Aprepitant, Fosaprepitant: (Major) Use caution if vemurafenib and aprepitant, fosaprepitant are used concurrently and monitor for a possible decrease in the efficacy of aprepitant as well as an increase in vemurafenib-related adverse effects for several days after administration of a multi-day aprepitant regimen. Vemurafenib is a CYP3A4 substrate in vitro. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of vemurafenib. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important. Additionally, vemurafenib is a weak CYP3A4 inducer and aprepitant is a CYP3A4 substrate. When a single dose of aprepitant (375 mg, or 3 times the maximum recommended dose) was administered on day 9 of a 14-day rifampin regimen (a strong CYP3A4 inducer), the AUC of aprepitant decreased approximately 11-fold and the mean terminal half-life decreased by 3-fold. The manufacturer of aprepitant recommends avoidance of administration with strong CYP3A4 inducers, but does not provide guidance for weak-to-moderate inducers.
Aripiprazole: (Major) Because both vemurafenib and aripiprazole are associated with a possible risk for QT prolongation and torsade de pointes (TdP), the combination should be used cautiously and with close monitoring. In addition, concomitant use of vemurafenib and aripiprazole may result in altered concentrations of aripiprazole. Vemurafenib is a weak inhibitor of CYP2D6 and an inducer of CYP3A4. Aripiprazole is a substrate of CYP2D6 and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
Arsenic Trioxide: (Major) If possible, drugs that are known to prolong the QT interval should be discontinued prior to initiating arsenic trioxide therapy. QT prolongation should be expected with the administration of arsenic trioxide. Torsade de pointes (TdP) and complete atrioventricular block have been reported. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with arsenic trioxide include vemurafenib.
Artemether; Lumefantrine: (Major) Vemurafenib has been associated with QT prolongation. If vemurafenib and another drug, such as artemether; lumefantrine, that is associated with a possible risk for QT prolongation and torsade de pointes (TdP) must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Also, artemether is a substrate of CYP2C9 and 3A4, while lumefantrine is a substrate of CYP3A4. Vemurafenib is a CYP2C9 inhibitor and CYP3A4 substrate/inducer. Altered concentrations of artemether; lumefantrine may increase side effects or decrease the potency of the antimicrobial effect. Caution is warranted with coadministration.
Asenapine: (Major) Vemurafenib has been associated with QT prolongation. Asenapine is associated with a possible risk for QT prolongation and torsade de pointes. According to the manufacturer of asenapine, the drug should be avoided in combination with other agents also known to have this effect. The manufacturer of vemurafenib recommends ECG monitoring if the drug must be coadministered with another QT prolonging drug; closely monitor the patient for QT interval prolongation.
Aspirin, ASA; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with vemurafenib is necessary; consider increasing the dose of oxycodone as needed. If vemurafenib is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and vemurafenib is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Atazanavir: (Major) Avoid the concomitant use of vemurafenib and atazanavir; vemurafenib exposure may be increased resulting in an increased risk of adverse events, including QT prolongation. If use with atazanavir cannot be avoided, consider a vemurafenib dose reduction; monitor patients closely for the development of adverse events and dose reduce or discontinue therapy based on manufacturer guidance. Vemurafenib is a CYP3A4 substrate; atazanavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of vemurafenib by 40%.
Atazanavir; Cobicistat: (Major) Avoid the concomitant use of vemurafenib and atazanavir; vemurafenib exposure may be increased resulting in an increased risk of adverse events, including QT prolongation. If use with atazanavir cannot be avoided, consider a vemurafenib dose reduction; monitor patients closely for the development of adverse events and dose reduce or discontinue therapy based on manufacturer guidance. Vemurafenib is a CYP3A4 substrate; atazanavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of vemurafenib by 40%. (Major) Avoid the concomitant use of vemurafenib and cobicistat; vemurafenib exposure may be increased resulting in an increased risk of adverse events, including QT prolongation. If use with cobicistat cannot be avoided, consider a vemurafenib dose reduction; monitor patients closely for the development of adverse events and dose reduce or discontinue therapy based on manufacturer guidance. Vemurafenib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of vemurafenib by 40%.
Atomoxetine: (Major) QT prolongation has occurred during therapeutic use of atomoxetine and following overdose. Both atomoxetine and vemurafenib are considered drugs with a possible risk of torsade de pointes (TdP); therefore, the combination should be used cautiously and with close monitoring. In addition, because atomoxetine is primarily metabolized by CYP2D6, concurrent use of CYP2D6 inhibitors such as vemurafenib may theoretically increase the risk of atomoxetine-induced adverse effects. Monitor for adverse effects, such as dizziness, drowsiness, nervousness, insomnia, and cardiac effects (e.g., hypertension, increased pulse rate, QT prolongation).
Atorvastatin: (Moderate) Concomitant use of vemurafenib and atorvastatin may result in altered concentrations of atorvastatin and increased concentrations of vemurafenib. Vemurafenib is a substrate/inhibitor of P-glycoprotein (P-gp) and an inducer of CYP3A4. Atorvastatin is a substrate of P-gp and CYP3A4 and an inhibitor of P-gp. Use caution and monitor patients for toxicity and efficacy.
Atorvastatin; Ezetimibe: (Moderate) Concomitant use of vemurafenib and atorvastatin may result in altered concentrations of atorvastatin and increased concentrations of vemurafenib. Vemurafenib is a substrate/inhibitor of P-glycoprotein (P-gp) and an inducer of CYP3A4. Atorvastatin is a substrate of P-gp and CYP3A4 and an inhibitor of P-gp. Use caution and monitor patients for toxicity and efficacy.
Azithromycin: (Major) Avoid coadministration of azithromycin with vemurafenib 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. QT prolongation and torsade de pointes (TdP) have been spontaneously reported during azithromycin postmarketing surveillance. Vemurafenib has been associated with QT prolongation.
Bedaquiline: (Major) Avoid concurrent use of bedaquiline with vemurafenib. Vemurafenib may induce CYP3A4 metabolism resulting in decreased bedaquiline systemic exposure (AUC) and possibly reduced therapeutic effect. Furthermore, since both drugs are associated with QT prolongation, coadministration may result in additive prolongation of the QT. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy.
Bendamustine: (Major) Avoid the use of vemurafenib with bendamustine. Vemurafenib may increase bendamustine exposure, which may increase the risk of adverse reactions (e.g., myelosuppression, infection, hepatotoxicity). Bendamustine is a CYP1A2 substrate and vemurafenib is a CYP1A2 inhibitor.
Benzhydrocodone; Acetaminophen: (Moderate) Concomitant use of vemurafenib and acetaminophen may result in altered concentrations of acetaminophen. Vemurafenib is an inhibitor of CYP1A2 and CYP2A6, and an inducer of CYP3A4. Acetaminophen is a substrate of CYP1A2, CYP2A6, and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
Berotralstat: (Major) Reduce the berotralstat dose to 110 mg PO once daily in patients chronically taking vemurafenib. Concurrent use may increase berotralstat exposure and the risk of adverse effects. Berotralstat is a P-gp and BCRP substrate and vemurafenib is a P-gp and BCRP inhibitor. Coadministration with another P-gp and BCRP inhibitor increased berotralstat exposure by 69%.
Betrixaban: (Major) Avoid betrixaban use in patients with severe renal impairment receiving vemurafenib. Reduce betrixaban dosage to 80 mg PO once followed by 40 mg PO once daily in all other patients receiving vemurafenib. Bleeding risk may be increased; monitor patients closely for signs and symptoms of bleeding. Betrixaban is a substrate of P-gp; vemurafenib inhibits P-gp.
Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Concomitant use of metronidazole and vemurafenib 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 vemurafenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Bortezomib: (Moderate) Vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as bortezomib, could be expected with concurrent use. Use caution, and monitor therapeutic effects of bortezomib when coadministered with vemurafenib.
Brimonidine; Timolol: (Moderate) Concomitant use of vemurafenib and timolol may result in increased timolol concentrations. Vemurafenib is a weak CYP2D6 inhibitor and timolol is a CYP2D6 substrate. Patients should be monitored for toxicity.
Brompheniramine; Dextromethorphan; Phenylephrine: (Minor) Use of dextromethorphan with vemurafenib increases dextromethorphan exposure. Vemurafenib is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Coadministration of vemurafenib and dextromethorphan increased the AUC of dextromethorphan by 47% and the dextromethorphan Cmax by 36%.
Brompheniramine; Pseudoephedrine; Dextromethorphan: (Minor) Use of dextromethorphan with vemurafenib increases dextromethorphan exposure. Vemurafenib is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Coadministration of vemurafenib and dextromethorphan increased the AUC of dextromethorphan by 47% and the dextromethorphan Cmax by 36%.
Budesonide: (Moderate) Concomitant use of vemurafenib and budesonide may result in altered concentrations of budesonide and increased concentrations vemurafenib. Vemurafenib is a substrate/inducer of CYP3A4 and a substrate/inhibitor of P-glycoprotein (PGP). Budesonide is a substrate of CYP3A4 and a substrate/inhibitor of PGP. Use caution and monitor patients for toxicity and efficacy.
Budesonide; Formoterol: (Moderate) Concomitant use of vemurafenib and budesonide may result in altered concentrations of budesonide and increased concentrations vemurafenib. Vemurafenib is a substrate/inducer of CYP3A4 and a substrate/inhibitor of P-glycoprotein (PGP). Budesonide is a substrate of CYP3A4 and a substrate/inhibitor of PGP. Use caution and monitor patients for toxicity and efficacy.
Budesonide; Glycopyrrolate; Formoterol: (Moderate) Concomitant use of vemurafenib and budesonide may result in altered concentrations of budesonide and increased concentrations vemurafenib. Vemurafenib is a substrate/inducer of CYP3A4 and a substrate/inhibitor of P-glycoprotein (PGP). Budesonide is a substrate of CYP3A4 and a substrate/inhibitor of PGP. Use caution and monitor patients for toxicity and efficacy.
Buprenorphine: (Major) Due to the potential for QT prolongation, cautious use and close monitoring are advisable if concurrent use of vemurafenib and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Vemurafenib also has a possible risk for QT prolongation and TdP. Some buprenorphine labels recommend avoiding use with any drug that has the potential to prolong the QT interval. If buprenorphine and vemurafenib must be coadministered, must be coadministered, ECG monitoring is recommended. In addition, vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as buprenorphine, could be expected with concurrent use. Decreased buprenorphine efficacy or buprenorphine withdrawal symptoms are possible. Use caution, and monitor therapeutic effects of buprenorphine when co-administered with vemurafenib. The effect of CYP3A4 inducers on buprenorphine implants has not been studied.
Buprenorphine; Naloxone: (Major) Due to the potential for QT prolongation, cautious use and close monitoring are advisable if concurrent use of vemurafenib and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Vemurafenib also has a possible risk for QT prolongation and TdP. Some buprenorphine labels recommend avoiding use with any drug that has the potential to prolong the QT interval. If buprenorphine and vemurafenib must be coadministered, must be coadministered, ECG monitoring is recommended. In addition, vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as buprenorphine, could be expected with concurrent use. Decreased buprenorphine efficacy or buprenorphine withdrawal symptoms are possible. Use caution, and monitor therapeutic effects of buprenorphine when co-administered with vemurafenib. The effect of CYP3A4 inducers on buprenorphine implants has not been studied.
Buspirone: (Moderate) Vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as buspirone, could be expected with concurrent use. Use caution, and monitor therapeutic effects of buspirone when coadministered with vemurafenib.
Butalbital; Acetaminophen: (Moderate) Concomitant use of vemurafenib and acetaminophen may result in altered concentrations of acetaminophen. Vemurafenib is an inhibitor of CYP1A2 and CYP2A6, and an inducer of CYP3A4. Acetaminophen is a substrate of CYP1A2, CYP2A6, and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
Butalbital; Acetaminophen; Caffeine: (Moderate) Concomitant use of vemurafenib and acetaminophen may result in altered concentrations of acetaminophen. Vemurafenib is an inhibitor of CYP1A2 and CYP2A6, and an inducer of CYP3A4. Acetaminophen is a substrate of CYP1A2, CYP2A6, and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Concomitant use of vemurafenib and acetaminophen may result in altered concentrations of acetaminophen. Vemurafenib is an inhibitor of CYP1A2 and CYP2A6, and an inducer of CYP3A4. Acetaminophen is a substrate of CYP1A2, CYP2A6, and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
Cabotegravir; Rilpivirine: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with vemurafenib. If these drugs must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Both vemurafenib and supratherapeutic doses of rilpivirine (75 to 300 mg/day) have been associated with QT prolongation. Also, rilpivirine is a CYP3A4 substrate, while vemurafenib is a CYP3A4 substrate and inducer. Therefore, decreased concentrations of rilpivirine and potential loss of virologic response may occur with concomitant use.
Caffeine: (Minor) Coadministration of vemurafenib and caffeine increased the caffeine AUC by 2.6-fold. Vemurafenib is a CYP1A2 inhibitor and caffeine is a CYP1A2 substrate. The manufacturer of vemurafenib suggests that concomitant use with agents with narrow therapeutic windows that are metabolized by CYP1A2 is not recommended. Theophylline (or aminophylline), another methylxanthine, is also primarily a CYP1A2 substrate with a narrow therapeutic index. If coadministration cannot be avoided, the manufacturer recommends considering a dose reduction of the concomitant drug; it may also be prudent to monitor for signs and symptoms of theophylline toxicity during coadministration. Some patients may need to reduce intake of caffeine from non-drug sources (e.g., beverages) during treatment to avoid caffeine-related side effects.
Carbamazepine: (Major) Avoid the concomitant use of vemurafenib and carbamazepine; significantly decreased vemurafenib exposure may occur resulting in reduced vemurafenib efficacy. Consider the use of an alternative agent. If use with carbamazepine cannot be avoided, increase the vemurafenib dose by 240 mg (as tolerated). If carbamazepine is discontinued, the previous (lower) vemurafenib dose may be resumed 2 weeks after the last carbamazepine dose. Vemurafenib is a CYP3A4 substrate; carbamazepine is a strong CYP3A4 inducer. In a drug interaction study, the vemurafenib AUC value decreased by 40% (90% CI, 24% to 53%) when a single 960-mg vemurafenib dose was administered with another strong CYP3A4 inducer; the vemurafenib Cmax was not changed.
Carvedilol: (Moderate) Altered concentrations of vemurafenib and/or carvedilol may occur during coadministration. Carvedilol and vemurafenib are both substrates and inhibitors of P-glycoprotein (P-gp). Use caution if concomitant use is necessary and monitor for increased side effects.
Celecoxib; Tramadol: (Moderate) Concomitant use of vemurafenib and tramadol may result in altered concentrations of tramadol. Vemurafenib is a weak inhibitor of CYP2D6 and an inducer of CYP3A4. Tramadol is a substrate of CYP2D6 and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
Ceritinib: (Major) Avoid vemurafenib in patients receiving medications known to prolong the QT interval such as ceritinib. Vemurafenib has been shown to prolong the QT interval in a concentration-dependent manner. The ECG changes occurred within the first month of treatment. Ceritinib causes concentration-dependent QT prolongation. Additionally, coadministration may result in increased vemurafenib exposure and an increased risk of adverse events, including QT prolongation. Vemurafenib is a CYP3A4 substrate; ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of vemurafenib by 40%.
Chloramphenicol: (Major) Avoid the concomitant use of vemurafenib and chloramphenicol; vemurafenib exposure may be increased resulting in an increased risk of adverse events, including QT prolongation. If use with chloramphenicol cannot be avoided, consider a vemurafenib dose reduction; monitor patients closely for the development of adverse events and dose reduce or discontinue therapy based on manufacturer guidance. Vemurafenib is a CYP3A4 substrate; chloramphenicol is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of vemurafenib by 40%.
Chloroquine: (Major) Avoid coadministration of chloroquine with vemurafenib 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. Vemurafenib has also been associated with QT prolongation.
Chlorpheniramine: (Moderate) Concomitant use of vemurafenib and chlorpheniramine may result in increased chlorpheniramine concentrations. Chlorpheniramine is metabolized by CYP2D6 and vemurafenib is a weak CYP2D6 inhibitor. Monitor patients for toxicity.
Chlorpheniramine; Codeine: (Moderate) Concomitant use of vemurafenib and chlorpheniramine may result in increased chlorpheniramine concentrations. Chlorpheniramine is metabolized by CYP2D6 and vemurafenib is a weak CYP2D6 inhibitor. Monitor patients for toxicity.
Chlorpheniramine; Dextromethorphan: (Moderate) Concomitant use of vemurafenib and chlorpheniramine may result in increased chlorpheniramine concentrations. Chlorpheniramine is metabolized by CYP2D6 and vemurafenib is a weak CYP2D6 inhibitor. Monitor patients for toxicity. (Minor) Use of dextromethorphan with vemurafenib increases dextromethorphan exposure. Vemurafenib is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Coadministration of vemurafenib and dextromethorphan increased the AUC of dextromethorphan by 47% and the dextromethorphan Cmax by 36%.
Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Concomitant use of vemurafenib and chlorpheniramine may result in increased chlorpheniramine concentrations. Chlorpheniramine is metabolized by CYP2D6 and vemurafenib is a weak CYP2D6 inhibitor. Monitor patients for toxicity. (Minor) Use of dextromethorphan with vemurafenib increases dextromethorphan exposure. Vemurafenib is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Coadministration of vemurafenib and dextromethorphan increased the AUC of dextromethorphan by 47% and the dextromethorphan Cmax by 36%.
Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Concomitant use of vemurafenib and chlorpheniramine may result in increased chlorpheniramine concentrations. Chlorpheniramine is metabolized by CYP2D6 and vemurafenib is a weak CYP2D6 inhibitor. Monitor patients for toxicity. (Minor) Use of dextromethorphan with vemurafenib increases dextromethorphan exposure. Vemurafenib is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Coadministration of vemurafenib and dextromethorphan increased the AUC of dextromethorphan by 47% and the dextromethorphan Cmax by 36%.
Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Concomitant use of vemurafenib and chlorpheniramine may result in increased chlorpheniramine concentrations. Chlorpheniramine is metabolized by CYP2D6 and vemurafenib is a weak CYP2D6 inhibitor. Monitor patients for toxicity.
Chlorpheniramine; Hydrocodone: (Moderate) Concomitant use of vemurafenib and chlorpheniramine may result in increased chlorpheniramine concentrations. Chlorpheniramine is metabolized by CYP2D6 and vemurafenib is a weak CYP2D6 inhibitor. Monitor patients for toxicity. (Moderate) Hydrocodone is metabolized by CYP3A4. Vemurafenib, an inducer of CYP3A4, may cause increased clearance of hydrocodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone. Monitor the patient for reduced efficacy of hydrocodone. A higher hydrocodone dose may be needed if used with vemurafenib.
Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Major) Concomitant use of vemurafenib and ibuprofen may result in increased ibuprofen concentrations. Vemurafenib is a CYP2C9 inhibitor and ibuprofen is a CYP2C9 substrate. Patients should be monitored for toxicity. (Moderate) Concomitant use of vemurafenib and chlorpheniramine may result in increased chlorpheniramine concentrations. Chlorpheniramine is metabolized by CYP2D6 and vemurafenib is a weak CYP2D6 inhibitor. Monitor patients for toxicity.
Chlorpheniramine; Phenylephrine: (Moderate) Concomitant use of vemurafenib and chlorpheniramine may result in increased chlorpheniramine concentrations. Chlorpheniramine is metabolized by CYP2D6 and vemurafenib is a weak CYP2D6 inhibitor. Monitor patients for toxicity.
Chlorpheniramine; Pseudoephedrine: (Moderate) Concomitant use of vemurafenib and chlorpheniramine may result in increased chlorpheniramine concentrations. Chlorpheniramine is metabolized by CYP2D6 and vemurafenib is a weak CYP2D6 inhibitor. Monitor patients for toxicity.
Chlorpromazine: (Major) Vemurafenib has been associated with QT prolongation. Coadministration of vemurafenib and another drug, such as chlorpromazine, that is associated with a possible risk for QT prolongation and torsade de pointes (TdP) are generally not recommended for combined use. If coadministration is necessary, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Also, chlorpromazine is a CYP2D6 substrate, while vemurafenib is a weak CYP2D6 inhibitor; therefore, increased concentrations of chlorpromazine may occur with concomitant use.
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.
Cilostazol: (Moderate) Vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as cilostazol, could be expected with concurrent use. Use caution, and monitor therapeutic effects of cilostazol when coadministered with vemurafenib.
Cimetidine: (Moderate) Concomitant use of vemurafenib and cimetidine may result in increased vemurafenib concentrations. Vemurafenib is CYP3A4 substrate and cimetidine is a CYP3A4 inhibitor. Use caution and monitor patients for increased side effects.
Ciprofloxacin: (Major) Concomitant use of vemurafenib and ciprofloxacin 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.
Cisapride: (Contraindicated) Vemurafenib has been associated with QT prolongation. Because of the potential for torsade de pointes (TdP), use of cisapride with vemurafenib is contraindicated.
Citalopram: (Major) Citalopram causes dose-dependent QT interval prolongation. According to the manufacturer, concurrent use of citalopram with other drugs that prolong the QT interval is not recommended. If concurrent therapy is considered essential, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with citalopram include vemurafenib. In addition, vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as citalopram, could be expected with concurrent use. Use caution, and monitor therapeutic effects of citalopram when coadministered with vemurafenib.
Clarithromycin: (Major) Avoid vemurafenib in patients receiving medications known to prolong the QT interval such as clarithromycin. Vemurafenib has been shown to prolong the QT interval in a concentration-dependent manner. The ECG changes occurred within the first month of treatment. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP). Additionally, coadministration may result in increased vemurafenib exposure and an increased risk of adverse events, including QT prolongation. Vemurafenib is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of vemurafenib by 40%.
Clofazimine: (Major) Concomitant use of clofazimine and vemurafenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Clonazepam: (Moderate) Vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as clonazepam, could be expected with concurrent use. Use caution, and monitor therapeutic effects of clonazepam when coadministered with vemurafenib.
Clozapine: (Major) Vemurafenib is a moderate CYP1A2 inhibitor and the manufacturer of vemurafenib recommends avoiding use with medications that are CYP1A2 substrates and that have a narrow therapeutic index. In addition, vemurafenib is a weak inhibitor of CYP2D6 and a substrate/inducer of CYP3A4 while clozapine is a substrate of CYP1A2, 2D6, and 3A4. Elevated plasma concentrations of clozapine may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. Vemurafenib is also associated with a possible risk for QT prolongation and torsade de pointes (TdP), It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. If concurrent use of vemurafenib and clozapine is necessary, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist. When initiating clozapine or adding a mild or moderate CYP1A2 inhibitor, CYP2D6 inhibitor, or CYP3A4 inhibitor to clozapine treatment, the manufacturer of clozapine recommends monitoring for adverse reactions and reducing the clozapine dose if necessary. If the inhibitor is discontinued, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
Cobicistat: (Major) Avoid the concomitant use of vemurafenib and cobicistat; vemurafenib exposure may be increased resulting in an increased risk of adverse events, including QT prolongation. If use with cobicistat cannot be avoided, consider a vemurafenib dose reduction; monitor patients closely for the development of adverse events and dose reduce or discontinue therapy based on manufacturer guidance. Vemurafenib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of vemurafenib by 40%.
Cobimetinib: (Minor) Cobimetinib is indicated for the treatment of unresectable or metastatic melanoma in combination with vemurafenib. Cobimetinib is a P-glycoprotein (P-gp) substrate, and vemurafenib is a P-gp inhibitor; theoretically, coadministration may result in increased cobimetinib exposure. However, coadministration of cobimetinib with vemurafenib (960 mg twice daily), did not result in clinically relevant pharmacokinetic drug interactions when studied.
Codeine; Phenylephrine; Promethazine: (Major) Vemurafenib has been associated with QT prolongation. If vemurafenib and another drug that is associated with a possible risk for QT prolongation and torsade de pointes (TdP) must be coadministered, ECG monitoring is recommended; closely monitor the patient. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with vemurafenib include promethazine. Concomitant use of vemurafenib and promethazine may also theoretically result in increased promethazine concentrations. Promethazine is metabolized by CYP2D6 and vemurafenib is a weak CYP2D6 inhibitor. Monitor patients for toxicity if co-use cannot be avoided.
Codeine; Promethazine: (Major) Vemurafenib has b
Colchicine: (Major) Avoid concomitant use of colchicine and vemurafenib due to the risk for increased colchicine exposure which may increase the risk for adverse effects. Concomitant use is contraindicated in patients with renal or hepatic impairment. Additionally, this combination is contraindicated if colchicine is being used for cardiovascular risk reduction. If concomitant use is necessary outside of these scenarios, consider a colchicine dosage reduction. Specific dosage reduction recommendations are available for colchicine tablets for some indications; it is unclear if these dosage recommendations are appropriate for other products or indications. For colchicine tablets being used for gout prophylaxis, reduce the dose from 0.6 mg twice daily to 0.3 mg once daily or from 0.6 mg once daily to 0.3 mg once every other day. For colchicine tablets being used for gout treatment, reduce the dose from 1.2 mg followed by 0.6 mg to 0.6 mg without an additional dose. For colchicine tablets being used for Familial Mediterranean Fever, the maximum daily dose is 0.6 mg. Colchicine is a P-gp substrate and vemurafenib is a P-gp inhibitor.
Crizotinib: (Major) Avoid coadministration of crizotinib with vemurafenib due to the risk of QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Vemurafenib has also been associated with QT prolongation.
Cyclosporine: (Moderate) Concomitant use of vemurafenib and cyclosporine may result in altered concentrations of cyclosporine and increased concentrations vemurafenib. Vemurafenib is a substrate/inducer of CYP3A4 and a substrate/inhibitor of P-glycoprotein (PGP). Budesonide is a substrate of CYP3A4 and a substrate/inhibitor of PGP. Use caution and monitor patients for toxicity and efficacy.
Dabigatran: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with vemurafenib, a mild P-gp inhibitor. Patients should be monitored for increased adverse effects of dabigatran. When dabigatran is administered for treatment or reduction in risk of recurrence of deep venous thrombosis (DVT) or pulmonary embolism (PE) or prophylaxis of DVT or PE following hip replacement surgery, avoid coadministration with P-gp inhibitors like vemurafenib in patients with CrCl less than 50 mL/minute. When dabigatran is used in patients with non-valvular atrial fibrillation and severe renal impairment (CrCl less than 30 mL/minute), avoid coadministration with vemurafenib, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
Daclatasvir: (Major) The dose of daclatasvir, a CYP3A4 substrate, must be increased to 90 mg PO once daily when administered in combination with moderate CYP3A4 inducers, such as vemurafenib. Taking these drugs together may decrease daclatasvir serum concentrations, potentially resulting in reduced antiviral efficacy and antimicrobial resistance. Conversely, the therapeutic effects of vemurafenib, a substrate of P-glycoprotein (P-gp), may be increased by daclatasvir, a P-gp inhibitor.
Danazol: (Moderate) Concomitant use of vemurafenib and danazol may result in increased vemurafenib concentrations. Vemurafenib is CYP3A4 substrate and danazol is a CYP3A4 inhibitor. Use caution and monitor patients for increased side effects.
Dapsone: (Moderate) The metabolism of dapsone may be accelerated when administered concurrently with vemurafenib, a known inducer of CYP3A4. Coadministration is expected to decrease the plasma concentration of dapsone and increase the formation of dapsone hydroxylamine (a metabolite associated with hemolysis). If these drugs must be administered together, closely monitor for a reduction in dapsone efficacy and signs of hemolytic anemia.
Darifenacin: (Moderate) Concomitant use of vemurafenib and darifenacin may result in altered concentrations of darifenacin. Vemurafenib is a weak inhibitor of CYP2D6 and an inducer of CYP3A4. Darifenacin is a substrate of CYP2D6 and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
Darunavir: (Major) Avoid the concomitant use of vemurafenib and darunavir; vemurafenib exposure may be increased resulting in an increased risk of adverse events, including QT prolongation. If use with darunavir cannot be avoided, consider a vemurafenib dose reduction; monitor patients closely for the development of adverse events and dose reduce or discontinue therapy based on manufacturer guidance. Vemurafenib is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of vemurafenib by 40%.
Darunavir; Cobicistat: (Major) Avoid the concomitant use of vemurafenib and cobicistat; vemurafenib exposure may be increased resulting in an increased risk of adverse events, including QT prolongation. If use with cobicistat cannot be avoided, consider a vemurafenib dose reduction; monitor patients closely for the development of adverse events and dose reduce or discontinue therapy based on manufacturer guidance. Vemurafenib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of vemurafenib by 40%. (Major) Avoid the concomitant use of vemurafenib and darunavir; vemurafenib exposure may be increased resulting in an increased risk of adverse events, including QT prolongation. If use with darunavir cannot be avoided, consider a vemurafenib dose reduction; monitor patients closely for the development of adverse events and dose reduce or discontinue therapy based on manufacturer guidance. Vemurafenib is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of vemurafenib by 40%.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid the concomitant use of vemurafenib and cobicistat; vemurafenib exposure may be increased resulting in an increased risk of adverse events, including QT prolongation. If use with cobicistat cannot be avoided, consider a vemurafenib dose reduction; monitor patients closely for the development of adverse events and dose reduce or discontinue therapy based on manufacturer guidance. Vemurafenib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of vemurafenib by 40%. (Major) Avoid the concomitant use of vemurafenib and darunavir; vemurafenib exposure may be increased resulting in an increased risk of adverse events, including QT prolongation. If use with darunavir cannot be avoided, consider a vemurafenib dose reduction; monitor patients closely for the development of adverse events and dose reduce or discontinue therapy based on manufacturer guidance. Vemurafenib is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of vemurafenib by 40%.
Degarelix: (Major) Avoid vemurafenib in patients receiving medications known to prolong the QT interval such as degarelix. Vemurafenib has been shown to prolong the QT interval in a concentration-dependent manner; the ECG changes occurred within the first month of treatment. Androgen deprivation therapy (i.e., degarelix) may also prolong the QT/QTc interval.
Delavirdine: (Major) Avoid the concomitant use of vemurafenib and delavirdine; vemurafenib exposure may be increased resulting in an increased risk of adverse events, including QT prolongation. If use with delavirdine cannot be avoided, consider a vemurafenib dose reduction; monitor patients closely for the development of adverse events and dose reduce or discontinue therapy based on manufacturer guidance. Vemurafenib is a CYP3A4 substrate; delavirdine is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of vemurafenib by 40%.
Deutetrabenazine: (Major) Avoid vemurafenib in patients receiving medications known to prolong the QT interval such as deutetrabenazine. Vemurafenib has been shown to prolong the QT interval in a concentration-dependent manner. The ECG changes occurred within the first month of treatment. 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.
Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Minor) Use of dextromethorphan with vemurafenib increases dextromethorphan exposure. Vemurafenib is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Coadministration of vemurafenib and dextromethorphan increased the AUC of dextromethorphan by 47% and the dextromethorphan Cmax by 36%.
Dexmedetomidine: (Major) Concomitant use of dexmedetomidine and vemurafenib 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: (Minor) Use of dextromethorphan with vemurafenib increases dextromethorphan exposure. Vemurafenib is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Coadministration of vemurafenib and dextromethorphan increased the AUC of dextromethorphan by 47% and the dextromethorphan Cmax by 36%.
Dextromethorphan; Bupropion: (Minor) Use of dextromethorphan with vemurafenib increases dextromethorphan exposure. Vemurafenib is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Coadministration of vemurafenib and dextromethorphan increased the AUC of dextromethorphan by 47% and the dextromethorphan Cmax by 36%.
Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Concomitant use of vemurafenib and diphenhydramine may result in increased diphenhydramine concentrations. Vemurafenib is a CYP1A2, CYP2C9, and CYP2D6 inhibitor and diphenhydramine is a substrate of these isoenzymes. Patients should be monitored for toxicity and sedation. (Minor) Use of dextromethorphan with vemurafenib increases dextromethorphan exposure. Vemurafenib is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Coadministration of vemurafenib and dextromethorphan increased the AUC of dextromethorphan by 47% and the dextromethorphan Cmax by 36%.
Dextromethorphan; Guaifenesin: (Minor) Use of dextromethorphan with vemurafenib increases dextromethorphan exposure. Vemurafenib is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Coadministration of vemurafenib and dextromethorphan increased the AUC of dextromethorphan by 47% and the dextromethorphan Cmax by 36%.
Dextromethorphan; Guaifenesin; Phenylephrine: (Minor) Use of dextromethorphan with vemurafenib increases dextromethorphan exposure. Vemurafenib is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Coadministration of vemurafenib and dextromethorphan increased the AUC of dextromethorphan by 47% and the dextromethorphan Cmax by 36%.
Dextromethorphan; Guaifenesin; Potassium Guaiacolsulfonate: (Minor) Use of dextromethorphan with vemurafenib increases dextromethorphan exposure. Vemurafenib is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Coadministration of vemurafenib and dextromethorphan increased the AUC of dextromethorphan by 47% and the dextromethorphan Cmax by 36%.
Dextromethorphan; Guaifenesin; Pseudoephedrine: (Minor) Use of dextromethorphan with vemurafenib increases dextromethorphan exposure. Vemurafenib is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Coadministration of vemurafenib and dextromethorphan increased the AUC of dextromethorphan by 47% and the dextromethorphan Cmax by 36%.
Dextromethorphan; Quinidine: (Major) Vemurafenib has been associated with QT prolongation. Quinidine administration is associated with QT prolongation and torsades de pointes (TdP). If vemurafenib and quinidine must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Also, quinidine is also a CYP3A4 substrate and a P-glycoprotein (P-gp) substrate/inhibitor. Vemurafenib is a CYP3A4 substrate/inducer, and a P-gp substrate/inhibitor. Quinidine concentrations may be increased or decreased and vemurafenib concentrations may be increased during concurrent use. (Minor) Use of dextromethorphan with vemurafenib increases dextromethorphan exposure. Vemurafenib is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Coadministration of vemurafenib and dextromethorphan increased the AUC of dextromethorphan by 47% and the dextromethorphan Cmax by 36%.
Diazepam: (Moderate) Vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as diazepam, could be expected with concurrent use. Use caution, and monitor therapeutic effects of diazepam when coadministered with vemurafenib.
Diclofenac: (Minor) Concomitant use of vemurafenib and diclofenac may result in altered concentrations of diclofenac. Vemurafenib is an inhibitor of CYP2C9 and an inducer of CYP3A4. Diclofenac is a substrate of CYP2C9 and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
Diclofenac; Misoprostol: (Minor) Concomitant use of vemurafenib and diclofenac may result in altered concentrations of diclofenac. Vemurafenib is an inhibitor of CYP2C9 and an inducer of CYP3A4. Diclofenac is a substrate of CYP2C9 and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
Digoxin: (Major) Avoid the concomitant use of vemurafenib and digoxin; increased digoxin exposure has been reported. If coadministration is unavoidable, consider a digoxin dose reduction and monitor patients carefully for signs and symptoms of digoxin toxicity (e.g., arrhythmias, heart block). Vemurafenib is a substrate and inhibitor P-glycoprotein (P-gp) and digoxin is a sensitive P-gp substrate with a narrow therapeutic index. The digoxin AUC and Cmax values were increased by 1.8-fold (90% CI, 1.6 to 2) and 1.5-fold (90% CI, 1.3 to 1.7), respectively, in 26 cancer patients who received vemurafenib 960 mg PO twice daily for 22 days and a single 0.25 mg-dose of digoxin.
Diphenhydramine: (Moderate) Concomitant use of vemurafenib and diphenhydramine may result in increased diphenhydramine concentrations. Vemurafenib is a CYP1A2, CYP2C9, and CYP2D6 inhibitor and diphenhydramine is a substrate of these isoenzymes. Patients should be monitored for toxicity and sedation.
Diphenhydramine; Ibuprofen: (Major) Concomitant use of vemurafenib and ibuprofen may result in increased ibuprofen concentrations. Vemurafenib is a CYP2C9 inhibitor and ibuprofen is a CYP2C9 substrate. Patients should be monitored for toxicity. (Moderate) Concomitant use of vemurafenib and diphenhydramine may result in increased diphenhydramine concentrations. Vemurafenib is a CYP1A2, CYP2C9, and CYP2D6 inhibitor and diphenhydramine is a substrate of these isoenzymes. Patients should be monitored for toxicity and sedation.
Diphenhydramine; Naproxen: (Moderate) Concomitant use of vemurafenib and diphenhydramine may result in increased diphenhydramine concentrations. Vemurafenib is a CYP1A2, CYP2C9, and CYP2D6 inhibitor and diphenhydramine is a substrate of these isoenzymes. Patients should be monitored for toxicity and sedation. (Minor) Concomitant use of vemurafenib and naproxen may result in increased naproxen concentrations. Vemurafenib is a CYP2C9 and CYP1A2 inhibitor and naproxen is a CYP2C9 and CYP1A2 substrate. Patients should be monitored for toxicity.
Diphenhydramine; Phenylephrine: (Moderate) Concomitant use of vemurafenib and diphenhydramine may result in increased diphenhydramine concentrations. Vemurafenib is a CYP1A2, CYP2C9, and CYP2D6 inhibitor and diphenhydramine is a substrate of these isoenzymes. Patients should be monitored for toxicity and sedation.
Disopyramide: (Major) Vemurafenib has been associated with QT prolongation. If vemurafenib and another drug, such as disopyramide, that is associated with a possible risk for QT prolongation and torsade de pointes (TdP) must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Also, disopyramide is a CYP3A4 substrate, while vemurafenib is a CYP3A4 substrate and inducer; therefore, decreased concentrations of disopyramide may occur.
Disulfiram: (Minor) Concomitant use of vemurafenib and disulfiram may result in altered concentrations of disulfiram. Vemurafenib is an inhibitor of CYP1A2 and an inducer of CYP3A4. Disulfiram is a substrate of CYP1A2 and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
Docetaxel: (Moderate) Concomitant use of vemurafenib and docetaxel may result in altered concentrations of docetaxel. Vemurafenib is an inhibitor of P-glycoprotein (PGP) and an inducer of CYP3A4. Docetaxel is a substrate of PGP and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
Dofetilide: (Major) Coadministration of dofetilide and vemurafenib is not recommended as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Vemurafenib has been associated with QT prolongation.
Dolasetron: (Major) If vemurafenib and dolasetron must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Vemurafenib has been associated with QT prolongation. Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram. Concurrent use may increase the risk of QT prolongation.
Dolutegravir; Rilpivirine: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with vemurafenib. If these drugs must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Both vemurafenib and supratherapeutic doses of rilpivirine (75 to 300 mg/day) have been associated with QT prolongation. Also, rilpivirine is a CYP3A4 substrate, while vemurafenib is a CYP3A4 substrate and inducer. Therefore, decreased concentrations of rilpivirine and potential loss of virologic response may occur with concomitant use.
Donepezil: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Vemurafenib has a possible risk for QT prolongation and TdP and should be used cautiously and with close monitoring with donepezil. In addition, concomitant use of vemurafenib and donepezil may result in altered concentrations of donepezil. Vemurafenib is a weak inhibitor of CYP2D6 and an inducer of CYP3A4. Donepezil is a substrate of CYP2D6 and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
Donepezil; Memantine: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Vemurafenib has a possible risk for QT prolongation and TdP and should be used cautiously and with close monitoring with donepezil. In addition, concomitant use of vemurafenib and donepezil may result in altered concentrations of donepezil. Vemurafenib is a weak inhibitor of CYP2D6 and an inducer of CYP3A4. Donepezil is a substrate of CYP2D6 and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as vemurafenib. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
Dorzolamide; Timolol: (Moderate) Concomitant use of vemurafenib and timolol may result in increased timolol concentrations. Vemurafenib is a weak CYP2D6 inhibitor and timolol is a CYP2D6 substrate. Patients should be monitored for toxicity.
Doxorubicin Liposomal: (Major) Avoid coadministration of vemurafenib with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Vemurafenib is a P-glycoprotein (P-gp) inhibitor, and doxorubicin is a major substrate of P-gp. Concurrent use of P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
Doxorubicin: (Major) Avoid coadministration of vemurafenib with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Vemurafenib is a P-glycoprotein (P-gp) inhibitor, and doxorubicin is a major substrate of P-gp. Concurrent use of P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
Dronabinol: (Moderate) Vemurafenib is an inhibitor of CYP2C9 and may increase concentrations of dronabinol, THC, a CYP2C9 substrate. Use caution if these drugs are coadministered, as severe dronabinol, THC related adverse reactions may occur. A decreased dose of dronabinol may be needed if these drugs are coadministered.
Dronedarone: (Contraindicated) Concurrent use of vemurafenib and dronedarone is contraindicated. Vemurafenib has been associated with QT 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) Vemurafenib has been associated with QT prolongation. If vemurafenib and another drug, such as droperidol, that is associated with a possible risk for QT prolongation and torsade de pointes (TdP) must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Also, droperidol is a CYP3A4 and P-glycoprotein (P-gp) substrate, while vemurafenib is a CYP3A4 substrate/inducer and a P-gp substrate/inhibitor; therefore, alterations in droperidol concentrations may occur with concomitant use.
Duloxetine: (Moderate) Concomitant use of vemurafenib and duloxetine may result in increased duloxetine concentrations. Vemurafenib is a CYP1A2 and CYP2D6 inhibitor and duloxetine is a substrate of these isoenzymes. Monitor the patient for signs of excessive serotonin activity.
Dutasteride; Tamsulosin: (Moderate) Vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as tamsulosin, could be expected with concurrent use. Use caution, and monitor therapeutic effects of tamsulosin when coadministered with vemurafenib.
Edoxaban: (Moderate) Coadministration of edoxaban and vemurafenib may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and in vitro data indicate vemurafenib is a mild P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of vemurafenib; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
Efavirenz: (Major) Vemurafenib has been associated with QT prolongation. ECG monitoring is recommended if vemurafenib and another QT prolonging drug, such as efavirenz, must be coadministered; closely monitor the patient for QT interval prolongation. In addition, concomitant use may result in decreased vemurafenib and efavirenz concentrations. Both drugs are substrates and inducers of CYP3A4.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Vemurafenib has been associated with QT prolongation. ECG monitoring is recommended if vemurafenib and another QT prolonging drug, such as efavirenz, must be coadministered; closely monitor the patient for QT interval prolongation. In addition, concomitant use may result in decreased vemurafenib and efavirenz concentrations. Both drugs are substrates and inducers of CYP3A4. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as vemurafenib. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Vemurafenib has been associated with QT prolongation. ECG monitoring is recommended if vemurafenib and another QT prolonging drug, such as efavirenz, must be coadministered; closely monitor the patient for QT interval prolongation. In addition, concomitant use may result in decreased vemurafenib and efavirenz concentrations. Both drugs are substrates and inducers of CYP3A4. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as vemurafenib. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
Elbasvir; Grazoprevir: (Moderate) Caution is advised when administering elbasvir; grazoprevir with vemurafenib. Use of these drugs together may cause the plasma concentration of vemurafenib to increase. Elbasvir and grazoprevir are inhibitors of the breast cancer resistance protein (BCRP), while grazoprevir is also a weak inhibitor of CYP3A. Vemurafenib is a substrate for both BCRP and CYP3A. If these drugs are administered concurrently, closely monitor for adverse reactions.
Eletriptan: (Major) Concomitant use of vemurafenib and eletriptan may result in altered concentrations of eletriptan. Vemurafenib is an inhibitor of P-glycoprotein (PGP) and an inducer of CYP3A4. Eletriptan is a substrate of PGP and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
Eliglustat: (Major) Eliglustat is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously and with close monitoring with eliglustat include vemurafenib.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid the concomitant use of vemurafenib and cobicistat; vemurafenib exposure may be increased resulting in an increased risk of adverse events, including QT prolongation. If use with cobicistat cannot be avoided, consider a vemurafenib dose reduction; monitor patients closely for the development of adverse events and dose reduce or discontinue therapy based on manufacturer guidance. Vemurafenib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of vemurafenib by 40%. (Major) Coadministration of with vemurafenib is not recommended as there is a potential for decreased elvitegravir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Vemurafenib is a CYP3A4 inducer, while elvitegravir is a substrate of CYP3A4.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid the concomitant use of vemurafenib and cobicistat; vemurafenib exposure may be increased resulting in an increased risk of adverse events, including QT prolongation. If use with cobicistat cannot be avoided, consider a vemurafenib dose reduction; monitor patients closely for the development of adverse events and dose reduce or discontinue therapy based on manufacturer guidance. Vemurafenib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of vemurafenib by 40%. (Major) Coadministration of with vemurafenib is not recommended as there is a potential for decreased elvitegravir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Vemurafenib is a CYP3A4 inducer, while elvitegravir is a substrate of CYP3A4. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as vemurafenib. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with vemurafenib. If these drugs must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Both vemurafenib and supratherapeutic doses of rilpivirine (75 to 300 mg/day) have been associated with QT prolongation. Also, rilpivirine is a CYP3A4 substrate, while vemurafenib is a CYP3A4 substrate and inducer. Therefore, decreased concentrations of rilpivirine and potential loss of virologic response may occur with concomitant use.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with vemurafenib. If these drugs must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Both vemurafenib and supratherapeutic doses of rilpivirine (75 to 300 mg/day) have been associated with QT prolongation. Also, rilpivirine is a CYP3A4 substrate, while vemurafenib is a CYP3A4 substrate and inducer. Therefore, decreased concentrations of rilpivirine and potential loss of virologic response may occur with concomitant use. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as vemurafenib. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as vemurafenib. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
Encorafenib: (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.
Entrectinib: (Major) Avoid coadministration of entrectinib with vemurafenib due to the risk of QT prolongation. If concomitant use is unavoidable, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Both entrectinib and vemurafenib have been associated with QT prolongation.
Enzalutamide: (Major) Avoid coadministration of vemurafenib with enzalutamide due to decreased plasma concentrations of vemurafenib. If unavoidable, increase to dose of vemurafenib by 240 mg as tolerated. The original dose of vemurafenib may be resumed 2 weeks after enzalutamide is discontinued. Vemurafenib is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased exposure to vemurafenib by 40%.
Eplerenone: (Moderate) Vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as eplerenone, could be expected with concurrent use. Use caution, and monitor therapeutic effects of eplerenone when coadministered with vemurafenib.
Eribulin: (Major) Vemurafenib has been associated with QT prolongation. Eribulin has been associated with QT prolongation. If vemurafenib and another drug that potentially prolongs the QT interval must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation.
Erythromycin: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering erythromycin with vemurafenib. If these drugs must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Both erythromycin and vemurafenib have been associated with QT prolongation. Also, erythromycin is a CYP3A4 inhibitor and a P-glycoprotein (P-gp) substrate/inhibitor, while vemurafenib is a CYP3A4 substrate and a P-gp substrate/inhibitor. Concentrations of both erythromycin and vemurafenib may be altered with concomitant use.
Escitalopram: (Major) Because both vemurafenib and escitalopram are associated with a possible risk for QT prolongation and torsade de pointes (TdP), the combination should be used cautiously and with close monitoring. In addition, concomitant use of vemurafenib and escitalopram may result in altered concentrations of escitalopram. Vemurafenib is a weak inhibitor of CYP2D6 and an inducer of CYP3A4. Escitalopram is a substrate of CYP3A4. Use caution and monitor patients for toxicity and efficacy.
Esomeprazole: (Moderate) Coadministration of vemurafenib and esomeprazole could lead to decreased esomeprazole concentrations and efficacy. Vemurafenib is a CYP3A4 inducer and esomeprazole is a CYP3A4 substrate. Monitor patients for efficacy.
Estazolam: (Moderate) Vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as estazolam, could be expected with concurrent use. Use caution, and monitor therapeutic effects of estazolam when coadministered with vemurafenib.
Ethosuximide: (Moderate) Vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as ethosuximide, could be expected with concurrent use. Use caution, and monitor therapeutic effects of ethosuximide when coadministered with vemurafenib.
Etravirine: (Major) Concomitant use of vemurafenib and etravirine may result in altered concentrations of both drugs. Use caution and monitor patients for toxicity and efficacy. Vemurafenib is a substrate/inducer of CYP3A4, an inhibitor of CYP2C9, and a substrate/inhibitor of P-glycoprotein (P-gp). Etravirine is a substrate/inducer of CYP3A4, a substrate/inhibitor of CYP2C9, and an inhibitor of P-gp.
Everolimus: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with vemurafenib is necessary. The dose of everolimus may need to be reduced. Everolimus is a P-glycoprotein (P-gp) substrate and vemurafenib is a P-gp inhibitor. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations.
Felodipine: (Moderate) Vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as felodipine, could be expected with concurrent use. Use caution, and monitor therapeutic effects of felodipine when coadministered with vemurafenib.
Fezolinetant: (Contraindicated) Concomitant use of fezolinetant and vemurafenib is contraindicated due to the risk of increased fezolinetant exposure which may increase the risk of fezolinetant-related adverse effects. Fezolinetant is a CYP1A2 substrate; vemurafenib is a moderate CYP1A2 inhibitor. Concomitant use with another moderate CYP1A2 inhibitor increased fezolinetant overall exposure by 360%.
Finasteride; Tadalafil: (Minor) Vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as tadalafil, could be expected with concurrent use. Use caution, and monitor therapeutic effects of tadalafil when coadministered with vemurafenib.
Fingolimod: (Major) If vemurafenib and another drug that is associated with a possible risk for QT prolongation and torsade de pointes (TdP), such as fingolimod, must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Vemurafenib has been associated with QT prolongation. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of TdP. 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) Vemurafenib has been associated with QT prolongation. If vemurafenib and another drug, such as flecainide, that is associated with a possible risk for QT prolongation and torsade de pointes (TdP) must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Also, flecainide is a CYP2D6 substrate, while vemurafenib is a weak CYP2D6 inhibitor; therefore concentrations of flecainide may be increased with concomitant use. Caution is warranted and patients should be monitored for increased side effects.
Fluconazole: (Contraindicated) Concurrent use of fluconazole and vemurafenib is contraindicated due to the risk of life threatening arrhythmias such as torsade de pointes (TdP). Fluconazole is an inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of vemurafenib. These drugs used in combination may result in elevated vemurafenib plasma concentrations, causing an increased risk for vemurafenib-related adverse events, such as QT prolongation. Additionally, fluconazole has been associated with prolongation of the QT interval; do not use with other drugs that may prolong the QT interval and are metabolized through CYP3A4, such as vemurafenib.
Fluoxetine: (Major) Vemurafenib has been associated with QT prolongation. If vemurafenib and another drug that is associated with a possible risk for QT prolongation and torsade de pointes (TdP) must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine. In addition, concomitant use of vemurafenib and fluoxetine may result in increased concentrations of fluoxetine and vemurafenib. Vemurafenib is a substrate of CYP3A4 and an inhibitor of CYP2C9 and CYP2D6. Fluoxetine is an inhibitor of CYP3A4 and a substrate of CYP2C9 and CYP2D6. Use caution and monitor patients for toxicity and efficacy.
Fluphenazine: (Minor) Vemurafenib has been associated with QT prolongation. If vemurafenib and another drug that is associated with a possible risk for QT prolongation must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Drugs with a possible risk for QT prolongation that should be used cautiously with vemurafenib include fluphenazine.
Flurazepam: (Moderate) Vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as flurazepam, could be expected with concurrent use. Use caution, and monitor therapeutic effects of flurazepam when coadministered with vemurafenib.
Flurbiprofen: (Minor) Concomitant use of vemurafenib and flurbiprofen may result in increased flurbiprofen concentrations. Vemurafenib is a CYP2C9 inhibitor and flurbiprofen is a CYP2C9 substrate. Patients should be monitored for toxicity.
Flutamide: (Major) Concomitant use of vemurafenib and flutamide may result in altered concentrations of flutamide and decreased concentrations vemurafenib. Vemurafenib is a substrate/inducer of CYP3A4 and an inhibitor of CYP1A2. Flutamide is a substrate/inducer of CYP3A4 and substrate of CYP1A2. Use caution and monitor patients for toxicity and efficacy.
Fluvastatin: (Moderate) Concomitant use of vemurafenib and fluvastatin may result in increased fluvastatin concentrations. Vemurafenib is a CYP2C9 inhibitor and fluvastatin is a CYP2C9 substrate. Patients should be monitored for toxicity.
Fluvoxamine: (Major) There may be an increased risk for QT prolongation, torsade de pointes (TdP), or elevated vemurafenib concentrations during concurrent use of fluvoxamine and vemurafenib. If vemurafenib and another drug that is associated with a possible risk for QT prolongation and TdP must be coadministered, ECG monitoring is recommended. In addition, concomitant use of vemurafenib and fluvoxamine may result in increased concentrations of fluvoxamine and vemurafenib. Vemurafenib is a substrate of CYP3A4 and an inhibitor of CYP1A2 and CYP2D6. Fluvoxamine is an inhibitor of CYP3A4 and a substrate of CYP1A2 and CYP2D6. Use caution and monitor patients for toxicity and efficacy.
Fosamprenavir: (Major) Concomitant use of vemurafenib and fosamprenavir may result in altered concentrations of amprenavir and vemurafenib. Fosamprenavir is metabolized to the active drug amprenavir. Vemurafenib is an inhibitor of CYP2C9, CYP2D6, and P-glycoprotein (P-gp) and a substrate/inducer of CYP3A4. Amprenavir is a substrate of CYP2C9 and CYP2D6, a substrate/inducer of P-gp, and is a substrate/potent inhibitor/moderate inducer of CYP3A4. Avoid using these agents together if possible.
Foscarnet: (Major) When possible, avoid concurrent use of foscarnet with other drugs known to prolong the QT interval, such as vemurafenib. Foscarnet has been associated with postmarketing reports of both QT prolongation and torsade de pointes (TdP). Vemurafenib has also been associated with QT prolongation. If these drugs are administered together, obtain an electrocardiogram and electrolyte concentrations before and periodically during treatment.
Fosphenytoin: (Major) Avoid the concomitant use of vemurafenib and fosphenytoin; significantly decreased vemurafenib exposure may occur resulting in reduced vemurafenib efficacy. Consider the use of an alternative agent. If use with fosphenytoin cannot be avoided, increase the vemurafenib dose by 240 mg (as tolerated). If fosphenytoin is discontinued, the previous (lower) vemurafenib dose may be resumed 2 weeks after the last fosphenytoin dose. Vemurafenib is a CYP3A4 substrate; fosphenytoin is a strong CYP3A4 inducer. In a drug interaction study, the vemurafenib AUC value decreased by 40% (90% CI, 24% to 53%) when a single 960-mg vemurafenib dose was administered with another strong CYP3A4 inducer; the vemurafenib Cmax was not changed.
Fostemsavir: (Major) Avoid vemurafenib in patients receiving medications known to prolong the QT interval such as fostemsavir. Vemurafenib has been shown to prolong the QT interval in a dose-dependent manner. The ECG changes occurred within the first month of treatment. Supratherapeutic doses of fostemsavir (2,400 mg twice daily, four times the recommended daily dose) have been shown to cause QT prolongation. Fostemsavir causes dose-dependent QT prolongation.
Gemifloxacin: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering vemurafenib with gemifloxacin. If these drugs must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Vemurafenib has been associated with QT prolongation. Gemifloxacin may also prolong the QT interval in some patients, with the maximal change in the QTc interval occurring approximately 5 to 10 hours following oral administration. The likelihood of QTc prolongation may increase with increasing dose of gemifloxacin; 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) Use gemtuzumab ozogamicin and vemurafenib together with caution due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If these agents are used together, obtain an ECG and serum electrolytes prior to the start of gemtuzumab and as needed during treatment. Although QT interval prolongation has not been reported with gemtuzumab, it has been reported with other drugs that contain calicheamicin. Vemurafenib has been associated with QT prolongation.
Gilteritinib: (Major) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and vemurafenib is necessary. ECG monitoring is recommended. Both drugs have been associated with QT prolongation.
Glasdegib: (Major) Avoid coadministration of glasdegib with vemurafenib due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Vemurafenib has also been associated with QT prolongation.
Glimepiride: (Moderate) Concomitant use of vemurafenib and glimepiride may result in increased glimepiride concentrations. Vemurafenib is a CYP2C9 inhibitor and glimepiride is a CYP2C9 substrate. Monitor serum glucose concentrations if glimepiride is coadministered with CYP2C9 inhibitors. Dosage adjustments may be necessary.
Glipizide: (Moderate) Concomitant use of vemurafenib and glipizide may result in increased glipizide concentrations. Vemurafenib is a CYP2C9 inhibitor and glipizide is a CYP2C9 substrate. Monitor serum glucose concentrations if glipizide is coadministered with CYP2C9 inhibitors. Dosage adjustments may be necessary.
Glipizide; Metformin: (Moderate) Concomitant use of vemurafenib and glipizide may result in increased glipizide concentrations. Vemurafenib is a CYP2C9 inhibitor and glipizide is a CYP2C9 substrate. Monitor serum glucose concentrations if glipizide is coadministered with CYP2C9 inhibitors. Dosage adjustments may be necessary.
Glyburide: (Moderate) Concomitant use of vemurafenib and glyburide may result in increased glyburide concentrations. Vemurafenib is a CYP2C9 and P-glycoprotein (PGP) inhibitor and glimepiride is a CYP2C9 and PGP substrate. Monitor serum glucose concentrations if glyburide is coadministered with CYP2C9 inhibitors. Dosage adjustments may be necessary.
Glyburide; Metformin: (Moderate) Concomitant use of vemurafenib and glyburide may result in increased glyburide concentrations. Vemurafenib is a CYP2C9 and P-glycoprotein (PGP) inhibitor and glimepiride is a CYP2C9 and PGP substrate. Monitor serum glucose concentrations if glyburide is coadministered with CYP2C9 inhibitors. Dosage adjustments may be necessary.
Goserelin: (Major) Closely monitor ECGs for QT prolongation if coadministration of vemurafenib with goserelin is necessary. Vemurafenib has been associated with QT prolongation. Androgen deprivation therapy (i.e., goserelin) may prolong the QT/QTc interval.
Granisetron: (Major) Vemurafenib has been associated with QT prolongation. If vemurafenib and another drug, such as granisetron, that is associated with a possible risk for QT prolongation and torsade de pointes (TdP) must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Also, vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as granisetron, could be expected with concurrent use. Use caution, and monitor therapeutic effects of granisetron when coadministered with vemurafenib.
Grapefruit juice: (Major) Avoid the concomitant use of vemurafenib and grapefruit juice; vemurafenib exposure may be increased resulting in an increased risk of adverse events, including QT prolongation.
Guaifenesin; Hydrocodone: (Moderate) Hydrocodone is metabolized by CYP3A4. Vemurafenib, an inducer of CYP3A4, may cause increased clearance of hydrocodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone. Monitor the patient for reduced efficacy of hydrocodone. A higher hydrocodone dose may be needed if used with vemurafenib.
Halogenated Anesthetics: (Major) Vemurafenib has been associated with QT prolongation. If vemurafenib and another drug that is associated with a possible risk for QT prolongation and torsade de pointes (TdP) must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with vemurafenib include halogenated anesthetics.
Haloperidol: (Major) Vemurafenib has been associated with QT prolongation. If vemurafenib and another drug, such as haloperidol, that is associated with a possible risk for QT prolongation and torsade de pointes (TdP) must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Also, haloperidol is a CYP2D6 and 3A4 substrate, while vemurafenib is a weak CYP2D6 inhibitor and a CYP3A4 substrate/inducer; therefore, altered concentrations of haloperidol may occur with concomitant use. Elevated haloperidol concentrations occurring through inhibition of CYP2D6 or CYP3A4 may increase the risk of adverse effects, including QT prolongation.
Histrelin: (Major) Closely monitor ECGs for QT prolongation if coadministration of vemurafenib with histrelin is necessary. Vemurafenib has been associated with QT prolongation. Androgen deprivation therapy (i.e., histrelin) may prolong the QT/QTc interval.
Homatropine; Hydrocodone: (Moderate) Hydrocodone is metabolized by CYP3A4. Vemurafenib, an inducer of CYP3A4, may cause increased clearance of hydrocodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone. Monitor the patient for reduced efficacy of hydrocodone. A higher hydrocodone dose may be needed if used with vemurafenib.
Hydrocodone: (Moderate) Hydrocodone is metabolized by CYP3A4. Vemurafenib, an inducer of CYP3A4, may cause increased clearance of hydrocodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone. Monitor the patient for reduced efficacy of hydrocodone. A higher hydrocodone dose may be needed if used with vemurafenib.
Hydrocodone; Ibuprofen: (Major) Concomitant use of vemurafenib and ibuprofen may result in increased ibuprofen concentrations. Vemurafenib is a CYP2C9 inhibitor and ibuprofen is a CYP2C9 substrate. Patients should be monitored for toxicity. (Moderate) Hydrocodone is metabolized by CYP3A4. Vemurafenib, an inducer of CYP3A4, may cause increased clearance of hydrocodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone. Monitor the patient for reduced efficacy of hydrocodone. A higher hydrocodone dose may be needed if used with vemurafenib.
Hydrocodone; Pseudoephedrine: (Moderate) Hydrocodone is metabolized by CYP3A4. Vemurafenib, an inducer of CYP3A4, may cause increased clearance of hydrocodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone. Monitor the patient for reduced efficacy of hydrocodone. A higher hydrocodone dose may be needed if used with vemurafenib.
Hydroxychloroquine: (Major) Concomitant use of vemurafenib and hydroxychloroquine 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 vemurafenib and hydroxyzine 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.
Ibuprofen: (Major) Concomitant use of vemurafenib and ibuprofen may result in increased ibuprofen concentrations. Vemurafenib is a CYP2C9 inhibitor and ibuprofen is a CYP2C9 substrate. Patients should be monitored for toxicity.
Ibuprofen; Famotidine: (Major) Concomitant use of vemurafenib and ibuprofen may result in increased ibuprofen concentrations. Vemurafenib is a CYP2C9 inhibitor and ibuprofen is a CYP2C9 substrate. Patients should be monitored for toxicity.
Ibuprofen; Oxycodone: (Major) Concomitant use of vemurafenib and ibuprofen may result in increased ibuprofen concentrations. Vemurafenib is a CYP2C9 inhibitor and ibuprofen is a CYP2C9 substrate. Patients should be monitored for toxicity. (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with vemurafenib is necessary; consider increasing the dose of oxycodone as needed. If vemurafenib is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and vemurafenib is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Ibuprofen; Pseudoephedrine: (Major) Concomitant use of vemurafenib and ibuprofen may result in increased ibuprofen concentrations. Vemurafenib is a CYP2C9 inhibitor and ibuprofen is a CYP2C9 substrate. Patients should be monitored for toxicity.
Ibutilide: (Major) Vemurafenib has been associated with QT prolongation. Ibutilide administration can cause QT prolongation and torsades de pointes (TdP); proarrhythmic events should be anticipated. The potential for proarrhythmic events with ibutilide increases with the coadministration of vemurafenib. If vemurafenib and ibutilide must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation.
Idelalisib: (Major) Avoid the concomitant use of vemurafenib and idelalisib; vemurafenib exposure may be increased resulting in an increased risk of adverse events, including QT prolongation. If use with idelalisib cannot be avoided, consider a vemurafenib dose reduction; monitor patients closely for the development of adverse events and dose reduce or discontinue therapy based on manufacturer guidance. Vemurafenib is a CYP3A4 substrate; idelalisib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of vemurafenib by 40%.
Iloperidone: (Major) Avoid coadministration of iloperidone and vemurafenib due to the potential for QT prolongation. If coadministration cannot be avoided, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Both iloperidone and vemurafenib have been associated with QT prolongation.
Indinavir: (Major) Avoid the concomitant use of vemurafenib and indinavir; vemurafenib exposure may be increased resulting in an increased risk of adverse events, including QT prolongation. If use with indinavir cannot be avoided, consider a vemurafenib dose reduction; monitor patients closely for the development of adverse events and dose reduce or discontinue therapy based on manufacturer guidance. Vemurafenib is a CYP3A4 substrate; indinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of vemurafenib by 40%.
Indomethacin: (Major) Concomitant use of vemurafenib and indomethacin may result in increased indomethacin concentrations. Vemurafenib is a CYP2C9 inhibitor and indomethacin is a CYP2C9 substrate. Patients should be monitored for toxicity.
Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab ozogamicin with vemurafenib due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Both inotuzumab and vemurafenib have been associated with QT interval prolongation.
Ipilimumab: (Moderate) Concurrent use of vemurafenib and ipilimumab led to elevated transaminase levels in the majority of patients with BRAF V600-mutation positive melanoma in a small dose finding study; this study was closed due to adverse hepatic effects. Grade 3 elevated transaminase levels occurred in 6 of 10 patients who received combination therapy with vemurafenib (960 mg or 720 mg PO twice daily) plus ipilimumab (3 mg/kg IV every 3 weeks) in a phase I dose finding study; grade 2 or 3 elevated total bilirubin levels were reported in 2 patients in this study.
Isavuconazonium: (Major) Concomitant use of isavuconazonium with vemurafenib may result in increased serum concentrations of vemurafenib and decreased concentrations of isavuconazonium. Decreased isavuconazonium concentrations may lead to a reduction of antifungal efficacy and the potential for treatment failure. Vemurafenib is a substrate and inducer of the hepatic isoenzyme CYP3A4 and a substrate of the drug transporter P-glycoprotein (P-gp); isavuconazole, the active moiety of isavuconazonium, is a sensitive substrate and moderate inhibitor of CYP3A4 and an inhibitor of P-gp. Caution and close monitoring are advised if these drugs are used together.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid the concomitant use of vemurafenib and rifampin; significantly decreased vemurafenib exposure has been reported. Consider the use of an alternative agent. If use with rifampin cannot be avoided, increase the vemurafenib dose by 240 mg (as tolerated). If rifampin is discontinued, the previous (lower) vemurafenib dose may be resumed 2 weeks after the last rifampin dose. Vemurafenib is a CYP3A4 substrate; rifampin is a strong CYP3A4 inducer. In a drug interaction study, the vemurafenib AUC value decreased by 40% (90% CI, 24% to 53%) when a single 960-mg vemurafenib dose was administered with rifampin 600 mg/day; the vemurafenib Cmax was not changed.
Isoniazid, INH; Rifampin: (Major) Avoid the concomitant use of vemurafenib and rifampin; significantly decreased vemurafenib exposure has been reported. Consider the use of an alternative agent. If use with rifampin cannot be avoided, increase the vemurafenib dose by 240 mg (as tolerated). If rifampin is discontinued, the previous (lower) vemurafenib dose may be resumed 2 weeks after the last rifampin dose. Vemurafenib is a CYP3A4 substrate; rifampin is a strong CYP3A4 inducer. In a drug interaction study, the vemurafe nib AUC value decreased by 40% (90% CI, 24% to 53%) when a single 960-mg vemurafenib dose was administered with rifampin 600 mg/day; the vemurafenib Cmax was not changed.
Isradipine: (Moderate) Vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as isradipine, could be expected with concurrent use. Use caution, and monitor therapeutic effects of isradipine when coadministered with vemurafenib.
Itraconazole: (Major) Avoid vemurafenib in patients receiving medications known to prolong the QT interval such as itraconazole. Vemurafenib has been shown to prolong the QT interval in a concentration-dependent manner. The ECG changes occurred within the first month of treatment. Itraconazole has been associated with prolongation of the QT interval. Additionally, coadministration may result in increased vemurafenib exposure and an increased risk of adverse events, including QT prolongation. Vemurafenib is a CYP3A4 substrate; itraconazole is a strong CYP3A4 inhibitor. In a drug interaction study, the steady-state AUC value of vemurafenib was increased by 40% when vemurafenib 960 mg twice daily was administered with itraconazole 200 mg once daily. If itraconazole therapy is stopped, it may be prudent to continue close monitoring for up to 2 weeks after discontinuing itraconazole. Once discontinued, the plasma concentration of itraconazole decreases to almost undetectable concentrations within 7 to 14 days. The decline in plasma concentrations may be even more gradual in patients with hepatic cirrhosis or who are receiving concurrent CYP3A4 inhibitors.
Ivosidenib: (Major) Avoid coadministration of ivosidenib with vemurafenib 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 and/or vandetanib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Vemurafenib has also been associated with QT prolongation.
Ketoconazole: (Contraindicated) Avoid concomitant use of ketoconazole and vemurafenib due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of vemurafenib, further increasing the risk for adverse effects. Vemurafenib is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of vemurafenib by 40%.
Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as vemurafenib. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Avoid vemurafenib in patients receiving medications known to prolong the QT interval such as clarithromycin. Vemurafenib has been shown to prolong the QT interval in a concentration-dependent manner. The ECG changes occurred within the first month of treatment. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP). Additionally, coadministration may result in increased vemurafenib exposure and an increased risk of adverse events, including QT prolongation. Vemurafenib is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of vemurafenib by 40%.
Lapatinib: (Major) Monitor for an increase in lapatinib-related adverse reactions if coadministration with vemurafenib is necessary; also monitor ECGs for QT prolongation and monitor electrolytes. Correct any electrolyte abnormalities prior to treatment. Lapatinib is a P-glycoprotein (P-gp) substrate that has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have also been reported in postmarketing experience. Vemurafenib is a P-gp inhibitor that has been associated with QT prolongation. Increased plasma concentrations of lapatinib are likely when administered with P-gp inhibitors.
Ledipasvir; Sofosbuvir: (Moderate) Caution and close monitoring of adverse reactions is advised with concomitant administration of vemurafenib and ledipasvir; sofosbuvir. Both ledipasvir and vemurafenib are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp); sofosbuvir is a P-gp substrate. Taking these drugs together may increase plasma concentrations of all three drugs. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp inhibitors.
Lefamulin: (Major) Avoid coadministration of lefamulin with vemurafenib as concurrent use may increase the risk of QT prolongation; concurrent use may also increase exposure from lefamulin tablets which may increase the risk of adverse effects. If coadministration cannot be avoided, monitor ECG during treatment; additionally, monitor for lefamulin-related adverse effects if oral lefamulin is administered. Lefamulin is a CYP3A4 and P-gp substrate that 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. Vemurafenib is a P-gp inhibitor that has been associated with QT prolongation.
Lenvatinib: (Major) Avoid coadministration of lenvatinib with vemurafenib due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Vemurafenib has also been associated with QT prolongation.
Letermovir: (Moderate) Caution is advised when administering vemurafenib with letermovir. If the patient is also receiving cyclosporine, use of vemurafenib should be avoided. Administering letermovir with vemurafenib may increase vemurafenib concentration and risk for adverse events. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. Vemurafenib is a substrate of CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Leuprolide: (Major) Closely monitor ECGs for QT prolongation if coadministration of vemurafenib with leuprolide is necessary. Vemurafenib has been associated with QT prolongation. Androgen deprivation therapy (i.e., leuprolide) may prolong the QT/QTc interval.
Leuprolide; Norethindrone: (Major) Closely monitor ECGs for QT prolongation if coadministration of vemurafenib with leuprolide is necessary. Vemurafenib has been associated with QT prolongation. Androgen deprivation therapy (i.e., leuprolide) may prolong the QT/QTc interval.
Levamlodipine: (Moderate) Vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as amlodipine, could be expected with concurrent use. Use caution, and monitor therapeutic effects of amlodipine when coadministered with vemurafenib.
Levofloxacin: (Major) Concomitant use of vemurafenib and levofloxacin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Levoketoconazole: (Contraindicated) Avoid concomitant use of ketoconazole and vemurafenib due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of vemurafenib, further increasing the risk for adverse effects. Vemurafenib is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of vemurafenib by 40%.
Lithium: (Major) Concomitant use of vemurafenib and lithium 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.
Lofexidine: (Major) Monitor ECG if lofexidine is coadministered with vemurafenib due to the potential for additive QT prolongation and torsade de pointes (TdP). Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of TdP. Vemurafenib has been associated with QT prolongation and TdP.
Lonafarnib: (Major) Avoid the concomitant use of vemurafenib and lonafarnib; vemurafenib exposure may be increased resulting in an increased risk of adverse events, including QT prolongation. If use with lonafarnib cannot be avoided, consider a vemurafenib dose reduction; monitor patients closely for the development of adverse events and dose reduce or discontinue therapy based on manufacturer guidance. Vemurafenib is a CYP3A4 substrate; lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of vemurafenib by 40%.
Loperamide: (Major) Concomitant use of loperamide and vemurafenib 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. Concomitant use may also increase loperamide exposure and the risk for other loperamide-related adverse effects; loperamide is a P-gp substrate and vemurafenib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased loperamide plasma concentrations by 2- to 3-fold.
Loperamide; Simethicone: (Major) Concomitant use of loperamide and vemurafenib 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. Concomitant use may also increase loperamide exposure and the risk for other loperamide-related adverse effects; loperamide is a P-gp substrate and vemurafenib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased loperamide plasma concentrations by 2- to 3-fold.
Lopinavir; Ritonavir: (Major) Avoid coadministration of lopinavir with vemurafenib 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. Both drugs have been associated with QT prolongation. (Major) Avoid the concomitant use of vemurafenib and ritonavir; vemurafenib exposure may be increased resulting in an increased risk of adverse events, including QT prolongation. If use with ritonavir cannot be avoided, consider a vemurafenib dose reduction; monitor patients closely for the development of adverse events and dose reduce or discontinue therapy based on manufacturer guidance. Vemurafenib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of vemurafenib by 40%.
Losartan: (Moderate) Concomitant use of vemurafenib and losartan may result in altered concentrations of losartan. Vemurafenib is an inhibitor of CYP2C9 and an inducer of CYP3A4. Losartan is a substrate of CYP2C9 and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
Losartan; Hydrochlorothiazide, HCTZ: (Moderate) Concomitant use of vemurafenib and losartan may result in altered concentrations of losartan. Vemurafenib is an inhibitor of CYP2C9 and an inducer of CYP3A4. Losartan is a substrate of CYP2C9 and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
Lumacaftor; Ivacaftor: (Major) Avoid the concomitant use of vemurafenib and lumacaftor; ivacaftor as significantly decreased vemurafenib exposure may occur resulting in reduced vemurafenib efficacy. Consider the use of an alternative agent. If use with lumacaftor; ivacaftor cannot be avoided, increase the vemurafenib dose by 240 mg (as tolerated). If lumacaftor; ivacaftor is discontinued, the previous (lower) vemurafenib dose may be resumed 2 weeks after the last lumacaftor; ivacaftor dose. Vemurafenib is a CYP3A4 substrate; lumacaftor is a strong CYP3A4 inducer. In a drug interaction study, the vemurafenib AUC value decreased by 40% (90% CI, 24% to 53%) when a single 960-mg vemurafenib dose was administered with another strong CYP3A4 inducer; the vemurafenib Cmax was not changed.
Lumacaftor; Ivacaftor: (Major) Avoid the concomitant use of vemurafenib and lumacaftor; ivacaftor as significantly decreased vemurafenib exposure may occur resulting in reduced vemurafenib efficacy. Consider the use of an alternative agent. If use with lumacaftor; ivacaftor cannot be avoided, increase the vemurafenib dose by 240 mg (as tolerated). If lumacaftor; ivacaftor is discontinued, the previous (lower) vemurafenib dose may be resumed 2 weeks after the last lumacaftor; ivacaftor dose. Vemurafenib is a CYP3A4 substrate; lumacaftor is a strong CYP3A4 inducer. In a drug interaction study, the vemurafenib AUC value decreased by 40% (90% CI, 24% to 53%) when a single 960-mg vemurafenib dose was administered with another strong CYP3A4 inducer; the vemurafenib Cmax was not changed.
Lurasidone: (Moderate) Vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as lurasidone, could be expected with concurrent use. Use caution, and monitor therapeutic effects of lurasidone when coadministered with vemurafenib.
Macimorelin: (Major) Avoid concurrent administration of macimorelin with drugs that prolong the QT interval, such as vemurafenib. Use of these drugs together may increase the risk of developing torsade de pointes-type ventricular tachycardia. Sufficient washout time of drugs that are known to prolong the QT interval prior to administration of macimorelin is recommended. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval. Vemurafenib has been associated with QT prolongation.
Maprotiline: (Major) Vemurafenib has been associated with QT prolongation. If vemurafenib and another drug, such as maprotiline, that is associated with a possible risk for QT prolongation and torsade de pointes (TdP) must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Also, maprotiline is a CYP2D6 substrate, while vemurafenib is a CYP2D6 inhibitor; therefore, increased concentrations of maprotiline may occur.
Maraviroc: (Moderate) Concomitant use of vemurafenib and maraviroc may result in altered concentrations of maraviroc. Vemurafenib is an inhibitor of P-glycoprotein (P-gp) and a weak inducer of CYP3A4. Maraviroc is a substrate of P-gp and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
Meclofenamate Sodium: (Major) In increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia. Notable interactions may occur with myelosuppressive antineoplastic agents, antithymocyte globulin and strontium-89 chloride. Patients receiving meclofenamate concurrently with antineoplastic agents, antithymocyte globulin, or strontium-89 chloride should be monitored closely for bleeding.
Mefenamic Acid: (Major) In increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia. Notable interactions may occur with myelosuppressive antineoplastic agents, antithymocyte globulin and strontium-89 chloride. Patients receiving meclofenamate concurrently with antineoplastic agents, antithymocyte globulin, or strontium-89 chloride should be monitored closely for bleeding.
Mefloquine: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering vemurafenib with mefloquine. If these drugs must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. There is evidence that the use of halofantrine after mefloquine causes significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation; however due to the lack of clinical data, mefloquine should be used with caution in patients receiving drugs that prolong the QT interval, such as vemurafenib. Also, mefloquine is a CYP3A4 substrate and P-glycoprotein (P-gp) substrate/inhibitor, while vemurafenib is a CYP3A4 substrate/inducer and a P-gp substrate/inhibitor. Concomitant use may increase vemurafenib concentrations and may alter mefloquine concentrations. Monitor patients for toxicity and efficacy.
Metformin; Repaglinide: (Moderate) Vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as repaglinide, could be expected with concurrent use. Use caution, and monitor therapeutic effects of repaglinide when coadministered with vemurafenib.
Metformin; Rosiglitazone: (Moderate) Rosiglitazone is metabolized by CYP2C9 (minor pathway) and it is possible for serum concentrations of rosiglitazone to rise when coadministered with drugs that inhibit CYP2C9, including vemurafenib. Monitor serum glucose concentrations if rosiglitazone and vemurafenib are coadministered. Dosage adjustments may be necessary.
Methadone: (Major) The need to coadminister methadone with drugs known to prolong the QT interval, such as vemurafenib, should be done with extreme caution and a careful assessment of treatment risks versus benefits. Methadone is considered to be associated with an increased risk for QT prolongation and torsades de pointes (TdP), especially at higher doses (> 200 mg/day but averaging approximately 400 mg/day in adult patients). Also, methadone is a substrate of CYP2C9, 2D6, 3A4, and P-glycoprotein (P-gp), while vemurafenib is a CYP2C9 inhibitor, a weak CYP2D6 inhibitor, a CYP3A4 substrate/inducer, and a P-gp substrate/inhibitor. Therefore, altered concentrations of methadone may occur with concomitant use. If coadministration is necessary, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation.
Metoprolol: (Moderate) Concomitant use of vemurafenib and metoprolol may result in increased metoprolol concentrations. Metoprolol is significantly metabolized by CYP2D6 and vemurafenib is a weak CYP2D6 inhibitor. Potent CYP2D6 inhibitors may increase the plasma concentrations of metoprolol, resulting in similar pharmacokinetics of a patient who is a poor metabolizer of CYP2D6 isoenzymes (see Pharmacokinetics). Caution should be exercised when coadministering CYP2D6 inhibitors with metoprolol to avoid exaggerated beta-blocking effects.
Metoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Concomitant use of vemurafenib and metoprolol may result in increased metoprolol concentrations. Metoprolol is significantly metabolized by CYP2D6 and vemurafenib is a weak CYP2D6 inhibitor. Potent CYP2D6 inhibitors may increase the plasma concentrations of metoprolol, resulting in similar pharmacokinetics of a patient who is a poor metabolizer of CYP2D6 isoenzymes (see Pharmacokinetics). Caution should be exercised when coadministering CYP2D6 inhibitors with metoprolol to avoid exaggerated beta-blocking effects.
Metronidazole: (Major) Concomitant use of metronidazole and vemurafenib 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.
Mexiletine: (Major) Concomitant use of vemurafenib and mexiletine may result in increased mexiletine concentrations. Mexiletine is primarily metabolized by CYP2D6 isoenzymes, with a secondary pathway by CYP1A2, while vemurafenib is a CYP1A2 inhibitor and a weak CYP2D6 inhibitor. Monitor patients for toxicity. Caution is recommended when administering CYP2D6 inhibitors with mexiletine, which has a narrow therapeutic index.
Midazolam: (Moderate) The concomitant use of vemurafenib, a CYP3A4 substrate and inducer, and oral midazolam, a CYP3A4 substrate, resulted in decreased concentrations of midazolam in a drug interaction study performed in cancer patients. In this study, the mean midazolam AUC value was decreased by 39% when a single dose of midazolam was administered after 15 days of vemurafenib 960 mg PO twice daily.
Midostaurin: (Major) The concomitant use of midostaurin and vemurafenib may lead to additive QT interval prolongation. Monitor ECG and serum electrolytes prior to and during vemurafenib therapy. If the QTc interval exceeds 500 milliseconds (msec) during therapy, hold vemurafenib; resume at a lower dose once the QTc is below 500 msec. Permanently discontinue vemurafenib if the QTc increases to greater than 500 msec and to greater than 60 msec from baseline after the correction of associated risk factors. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. QTc prolongation was reported in patients who received vemurafenib in a multicenter, open-label, single-arm trial.
Mifepristone: (Major) Avoid vemurafenib in patients receiving medications known to prolong the QT interval such as mifepristone. Vemurafenib has been shown to prolong the QT interval in a concentration-dependent manner. The ECG changes occurred within the first month of treatment. Mifepristone has also been associated with dose-dependent prolongation of the QT interval. Additionally, coadministration may result in increased vemurafenib exposure and an increased risk of adverse events, including QT prolongation. Vemurafenib is a CYP3A4 substrate; mifepristone is a strong CYP3A4 inhibitor. Because of the prolonged action of mifepristone, the effects on CYP3A may be prolonged. Coadministration with another strong CYP3A4 inhibitor increased the exposure of vemurafenib by 40%.
Mirtazapine: (Major) Concomitant use of vemurafenib 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 the concomitant use of vemurafenib and mitotane; significantly decreased vemurafenib exposure may occur resulting in reduced vemurafenib efficacy. Consider the use of an alternative agent. If use with mitotane cannot be avoided, increase the vemurafenib dose by 240 mg (as tolerated). If mitotane is discontinued, the previous (lower) vemurafenib dose may be resumed 2 weeks after the last mitotane dose. Vemurafenib is a CYP3A4 substrate; mitotane is a strong CYP3A4 inducer. In a drug interaction study, the vemurafenib AUC value decreased by 40% (90% CI, 24% to 53%) when a single 960-mg vemurafenib dose was administered with another strong CYP3A4 inducer; the vemurafenib Cmax was not changed.
Mobocertinib: (Major) Concomitant use of mobocertinib and vemurafenib 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) Concomitant use of vemurafenib and modafinil may result in decreased concentrations of both agents. Both are CYP3A4 substrates and inducers. Use caution and monitor patients for therapeutic effects.
Morphine: (Moderate) Concomitant use of vemurafenib and morphine may result in increased morphine concentrations. Vemurafenib is a P-glycoprotein (P-gp) inhibitor and morphine is a P-gp substrate. Monitor patients for increased side effects, including CNS or respiratory depression.
Morphine; Naltrexone: (Moderate) Concomitant use of vemurafenib and morphine may result in increased morphine concentrations. Vemurafenib is a P-glycoprotein (P-gp) inhibitor and morphine is a P-gp substrate. Monitor patients for increased side effects, including CNS or respiratory depression.
Moxifloxacin: (Major) Concurrent use of vemurafenib and moxifloxacin should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). If these drugs must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Vemurafenib has been associated with QT prolongation. Moxifloxacin has also been associated with prolongation of the QT interval. Additionally, post-marketing surveillance has identified very rare cases of ventricular arrhythmias including TdP, usually in patients with severe underlying proarrhythmic conditions. The likelihood of QT prolongation may increase with increasing concentrations of moxifloxacin, therefore the recommended dose or infusion rate should not be exceeded.
Nanoparticle Albumin-Bound Sirolimus: (Major) Avoid concomitant use of sirolimus and vemurafenib. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a P-gp substrate and vemurafenib is a P-gp inhibitor.
Naproxen: (Minor) Concomitant use of vemurafenib and naproxen may result in increased naproxen concentrations. Vemurafenib is a CYP2C9 and CYP1A2 inhibitor and naproxen is a CYP2C9 and CYP1A2 substrate. Patients should be monitored for toxicity.
Naproxen; Esomeprazole: (Moderate) Coadministration of vemurafenib and esomeprazole could lead to decreased esomeprazole concentrations and efficacy. Vemurafenib is a CYP3A4 inducer and esomeprazole is a CYP3A4 substrate. Monitor patients for efficacy. (Minor) Concomitant use of vemurafenib and naproxen may result in increased naproxen concentrations. Vemurafenib is a CYP2C9 and CYP1A2 inhibitor and naproxen is a CYP2C9 and CYP1A2 substrate. Patients should be monitored for toxicity.
Naproxen; Pseudoephedrine: (Minor) Concomitant use of vemurafenib and naproxen may result in increased naproxen concentrations. Vemurafenib is a CYP2C9 and CYP1A2 inhibitor and naproxen is a CYP2C9 and CYP1A2 substrate. Patients should be monitored for toxicity.
Nateglinide: (Moderate) Monitor blood sugar and for changes in glycemic control. Concomitant use of vemurafenib and nateglinide may result in altered concentrations of nateglinide. Vemurafenib is an inhibitor of CYP2C9. Nateglinide is primarily a substrate of CYP2C9.
Nebivolol: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with vemurafenib. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as vemurafenib, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
Nebivolol; Valsartan: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with vemurafenib. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as vemurafenib, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
Nefazodone: (Major) Avoid the concomitant use of vemurafenib and nefazodone; vemurafenib exposure may be increased resulting in an increased risk of adverse events, including QT prolongation. If use with nefazodone cannot be avoided, consider a vemurafenib dose reduction; monitor patients closely for the development of adverse events and dose reduce or discontinue therapy based on manufacturer guidance. Vemurafenib is a CYP3A4 substrate; nefazodone is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of vemurafenib by 40%.
Nelfinavir: (Major) Avoid the concomitant use of vemurafenib and nelfinavir; vemurafenib exposure may be increased resulting in an increased risk of adverse events, including QT prolongation. If use with nelfinavir cannot be avoided, consider a vemurafenib dose reduction; monitor patients closely for the development of adverse events and dose reduce or discontinue therapy based on manufacturer guidance. Vemurafenib is a CYP3A4 substrate; nelfinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of vemurafenib by 40%.
Nicotine: (Moderate) Concomitant use of vemurafenib and nicotine may result in increased nicotine concentrations. Vemurafenib is a CYP2A6 inhibitor and nicotine is a CYP2A6 substrate. Pharmacologically, the effects of nicotine on the cardiovascular system mimic those of sympathetic stimulation; agonism of nicotinic receptors on adrenal medullary cells causes the release of epinephrine and norepinephrine. Nicotine raises systolic and diastolic blood pressure and can increase the inotropic and chronotropic actions of the heart. The degree to which these reactions occur is a function of the nicotine blood concentration. Symptoms of excessive nicotine can include nausea/vomiting, abdominal pain, diarrhea, headache, and hypertension.
Nilotinib: (Major) Avoid coadministration of vemurafenib with nilotinib with vemurafenib due to the risk of QT prolongation. Sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy. Vemurafenib has also been associated with QT prolongation. Additive QT prolongation may occur.
Nimodipine: (Moderate) Vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as nimodipine, could be expected with concurrent use. Use caution, and monitor therapeutic effects of nimodipine when coadministered with vemurafenib.
Nirmatrelvir; Ritonavir: (Major) Avoid the concomitant use of vemurafenib and ritonavir; vemurafenib exposure may be increased resulting in an increased risk of adverse events, including QT prolongation. If use with ritonavir cannot be avoided, consider a vemurafenib dose reduction; monitor patients closely for the development of adverse events and dose reduce or discontinue therapy based on manufacturer guidance. Vemurafenib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of vemurafenib by 40%.
Nisoldipine: (Moderate) Vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as nisoldipine, could be expected with concurrent use. Use caution, and monitor therapeutic effects of nisoldipine when coadministered with vemurafenib.
Ofloxacin: (Major) Concomitant use of vemurafenib and ofloxacin 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) Vemurafenib has been associated with QT prolongation. If vemurafenib and another drug, such as olanzapine, that is associated with a possible risk for QT prolongation and torsade de pointes (TdP) must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Also, olanzapine is a substrate of CYP1A2 and 2D6, while vemurafenib is an inhibitor of both of these enzymes. Therefore, concentrations of olanzapine could be increased with concomitant use. Monitor the patient for increase side effects.
Olanzapine; Fluoxetine: (Major) Vemurafenib has been associated with QT prolongation. If vemurafenib and another drug that is associated with a possible risk for QT prolongation and torsade de pointes (TdP) must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine. In addition, concomitant use of vemurafenib and fluoxetine may result in increased concentrations of fluoxetine and vemurafenib. Vemurafenib is a substrate of CYP3A4 and an inhibitor of CYP2C9 and CYP2D6. Fluoxetine is an inhibitor of CYP3A4 and a substrate of CYP2C9 and CYP2D6. Use caution and monitor patients for toxicity and efficacy. (Major) Vemurafenib has been associated with QT prolongation. If vemurafenib and another drug, such as olanzapine, that is associated with a possible risk for QT prolongation and torsade de pointes (TdP) must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Also, olanzapine is a substrate of CYP1A2 and 2D6, while vemurafenib is an inhibitor of both of these enzymes. Therefore, concentrations of olanzapine could be increased with concomitant use. Monitor the patient for increase side effects.
Olanzapine; Samidorphan: (Major) Vemurafenib has been associated with QT prolongation. If vemurafenib and another drug, such as olanzapine, that is associated with a possible risk for QT prolongation and torsade de pointes (TdP) must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Also, olanzapine is a substrate of CYP1A2 and 2D6, while vemurafenib is an inhibitor of both of these enzymes. Therefore, concentrations of olanzapine could be increased with concomitant use. Monitor the patient for increase side effects.
Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as amlodipine, could be expected with concurrent use. Use caution, and monitor therapeutic effects of amlodipine when coadministered with vemurafenib.
Omeprazole; Amoxicillin; Rifabutin: (Major) Concomitant administration of rifabutin and vemurafenib may decrease concentrations of both agents. Both rifabutin and vemurafenib are CYP3A4 substrates and inducers. Avoid using these agents together if possible.
Ondansetron: (Major) Concomitant use of vemurafenib and ondansetron 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.
Oritavancin: (Moderate) Vemurafenib is metabolized by CYP3A4; oritavancin is a weak CYP3A4 inducer. Plasma concentrations and efficacy of vemurafenib may be reduced if these drugs are administered concurrently.
Osilodrostat: (Major) Monitor ECGs in patients receiving osilodrostat with vemurafenib. Osilodrostat is associated with dose-dependent QT prolongation. Vemurafenib has been associated with QT prolongation and torsade de pointes.
Osimertinib: (Major) Avoid coadministration of vemurafenib with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Vemurafenib has also been associated with QT prolongation.
Oxaliplatin: (Major) Closely monitor electrolytes and ECGs for QT prolongation if coadministration of vemurafenib with oxaliplatin is necessary; correct electrolyte abnormalities prior to administration of oxaliplatin. Vemurafenib has been associated with QT prolongation. QT prolongation and ventricular arrhythmias including fatal torsade de pointes have also been reported with oxaliplatin use in postmarketing experience.
Oxybutynin: (Moderate) Vemuraifenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as oxybutynin, could be expected with concurrent use. Use caution, and monitor therapeutic effects of oxybutynin when coadministered with vemurafenib.
Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with vemurafenib is necessary; consider increasing the dose of oxycodone as needed. If vemurafenib is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and vemurafenib is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Ozanimod: (Major) Concomitant use of ozanimod and vemurafenib 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. Ozanimod has a limited effect on the QT/QTc interval at therapeutic doses but may cause bradycardia and atrioventricular conduction delays which may increase the risk for TdP in patients with a prolonged QT/QTc interval.
Paclitaxel: (Major) Avoid the concomitant use of vemurafenib and paclitaxel; increased paclitaxel exposure may occur. If co-administration is unavoidable, consider a paclitaxel dose reduction and monitor patients carefully for signs and symptoms of paclitaxel toxicity (e.g., neutropenia, peripheral neuropathy). Vemurafenib is a substrate and weak inducer of CYP3A4 and a substrate and inhibitor of P-glycoprotein (P-gp); paclitaxel is a CYP3A4 and P-gp substrate with a narrow therapeutic index.
Pacritinib: (Major) Concomitant use of pacritinib and vemurafenib 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) Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer of paliperidone, since the drug may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect. Vemurafenib has been associated with QT prolongation. If vemurafenib and paliperidone must be coadministered, ECG monitoring is recommended; closely monitor patients with known risk factors for cardiac disease or arrhythmias.
Panobinostat: (Major) The co-administration of panobinostat with vemurafenib is not recommended; QT prolongation has been reported with both agents. Additionally, vemurafenib is a CYP3A4 inducer and panobinostat is a CYP3A4 substrate; panobinostat levels may be significantly decreased and its efficacy reduced. Using a physiologically-based pharmacokinetic model, the systemic exposure was estimated to be decreased by 70% when a strong CYP3A inducer was co-administered with panobinostat.
Paricalcitol: (Moderate) Vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as paricalcitol, could be expected with concurrent use. Use caution, and monitor therapeutic effects of paricalcitol when coadministered with vemurafenib.
Paroxetine: (Moderate) Concomitant use of vemurafenib and paroxetine may result in increased paroxetine concentrations. Paroxetine is metabolized by CYP2D6 and vemurafenib is a weak CYP2D6 inhibitor. Monitor patients for toxicity.
Pasireotide: (Major) Vemurafenib has been associated with QT prolongation. If vemurafenib and pasireotide must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation as coadministration may have additive effects on the prolongation of the QT interval.
Pazopanib: (Major) Coadministration of pazopanib and other drugs that prolong the QT interval is not advised; pazopanib and vemurafenib have been reported to prolong the QT interval. If pazopanib and vemurafenib must be continued, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. In addition, pazopanib is a weak inhibitor of CYP3A4 and a substrate for P-glycoprotein (P-gp). Vemurafenib is a substrate for CYP3A4 and an inhibitor of P-gp. Concurrent administration of vemurafenib and pazopanib may result in increased pazopanib and/or vemurafenib concentrations. Use caution when concurrent administration is necessary.
Pentamidine: (Major) Vemurafenib has been associated with QT prolongation. If vemurafenib and another drug that is associated with a possible risk for QT prolongation and torsade de pointes (TdP) must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Pentamidine has been associated with QT prolongation. Pentamidine is a CYP2D6 substrate and vemurafenib is a weak CYP2D6 inhibitor; therefore, increased pentamidine concentrations may occur.
Perindopril; Amlodipine: (Moderate) Vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as amlodipine, could be expected with concurrent use. Use caution, and monitor therapeutic effects of amlodipine when coadministered with vemurafenib.
Perphenazine: (Minor) Vemurafenib has been associated with QT prolongation. If vemurafenib and another drug, such as perphenazine, that is associated with a possible risk for QT prolongation must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Also, perphenazine is a CYP2D6 substrate, while vemurafenib is a weak CYP2D6 inhibitor; therefore, increased concentrations of perphenazine may occur with concomitant use. Monitor patients for toxicity.
Perphenazine; Amitriptyline: (Minor) Vemurafenib has been associated with QT prolongation. If vemurafenib and another drug, such as perphenazine, that is associated with a possible risk for QT prolongation must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Also, perphenazine is a CYP2D6 substrate, while vemurafenib is a weak CYP2D6 inhibitor; therefore, increased concentrations of perphenazine may occur with concomitant use. Monitor patients for toxicity.
Phenobarbital: (Major) Avoid the concomitant use of vemurafenib and phenobarbital; significantly decreased vemurafenib exposure may occur resulting in reduced vemurafenib efficacy. Consider the use of an alternative agent. If use with phenobarbital cannot be avoided, increase the vemurafenib dose by 240 mg (as tolerated). If phenobarbital is discontinued, the previous (lower) vemurafenib dose may be resumed 2 weeks after the last phenobarbital dose. Vemurafenib is a CYP3A4 substrate; phenobarbital is a strong CYP3A4 inducer. In a drug interaction study, the vemurafenib AUC value decreased by 40% (90% CI, 24% to 53%) when a single 960-mg vemurafenib dose was administered with another strong CYP3A4 inducer; the vemurafenib Cmax was not changed.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid the concomitant use of vemurafenib and phenobarbital; significantly decreased vemurafenib exposure may occur resulting in reduced vemurafenib efficacy. Consider the use of an alternative agent. If use with phenobarbital cannot be avoided, increase the vemurafenib dose by 240 mg (as tolerated). If phenobarbital is discontinued, the previous (lower) vemurafenib dose may be resumed 2 weeks after the last phenobarbital dose. Vemurafenib is a CYP3A4 substrate; phenobarbital is a strong CYP3A4 inducer. In a drug interaction study, the vemurafenib AUC value decreased by 40% (90% CI, 24% to 53%) when a single 960-mg vemurafenib dose was administered with another strong CYP3A4 inducer; the vemurafenib Cmax was not changed.
Phentermine; Topiramate: (Major) Concomitant use of vemurafenib and topiramate may result in decreased concentrations of vemurafenib. Vemurafenib is a CYP3A4 substrate and topiramate is a weak CYP3A4 inducer. Use caution and monitor patients for therapeutic effects.
Phenytoin: (Major) Avoid the concomitant use of vemurafenib and phenytoin; significantly decreased vemurafenib exposure may occur resulting in reduced vemurafenib efficacy. Consider the use of an alternative agent. If use with phenytoin cannot be avoided, increase the vemurafenib dose by 240 mg (as tolerated). If phenytoin is discontinued, the previous (lower) vemurafenib dose may be resumed 2 weeks after the last phenytoin dose. Vemurafenib is a CYP3A4 substrate; phenytoin is a strong CYP3A4 inducer. In a drug interaction study, the vemurafenib AUC value decreased by 40% (90% CI, 24% to 53%) when a single 960-mg vemurafenib dose was administered with another strong CYP3A4 inducer; the vemurafenib Cmax was not changed.
Pimavanserin: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval. Vemurafenib has been associated with QT prolongation. Coadministration may increase the risk for QT prolongation. If vemurafenib and another drug that is associated with a possible risk for QT prolongation and torsade de pointes (TdP) must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation.
Pimozide: (Contraindicated) Pimozide is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Because of the potential for TdP, use of vemurafenib with pimozide is contraindicated.
Pioglitazone; Glimepiride: (Moderate) Concomitant use of vemurafenib and glimepiride may result in increased glimepiride concentrations. Vemurafenib is a CYP2C9 inhibitor and glimepiride is a CYP2C9 substrate. Monitor serum glucose concentrations if glimepiride is coadministered with CYP2C9 inhibitors. Dosage adjustments may be necessary.
Pirfenidone: (Major) Discontinue vemurafenib prior to beginning pirfenidone because it may increase exposure to pirfenidone. Vemurafenib is a moderate inhibitor of CYP1A2, CYP2C9, and to a lesser extent CYP2D6. Pirfenidone is primarily metabolized by CYP1A2 with minor contributions from CYP2C9, CYP2C19, CYP2D6, and CYP2E1.
Piroxicam: (Minor) Concomitant use of vemurafenib and piroxicam may result in increased piroxicam concentrations. Vemurafenib is a CYP2C9 inhibitor and piroxicam is a CYP2C9 substrate. Patients should be monitored for toxicity.
Pitolisant: (Major) Avoid coadministration of pitolisant with vemurafenib as concurrent use may increase the risk of QT prolongation. If coadministration is necessary, monitor ECG. Pitolisant prolongs the QT interval. Vemurafenib has also been associated with QT prolongation.
Ponesimod: (Major) In general, do not initiate ponesimod in patients taking vemurafenib 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 treatment initiation is considered, seek advice from a cardiologist and monitor for signs and symptoms of infection. 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. Vemurafenib has been shown to prolong the QT interval in a concentration-dependent manner; the ECG changes occurred within the first month of treatment.
Porfimer: (Major) Avoid coadministration of porfimer with vemurafenib due to the risk of increased photosensitivity. All patients treated with porfimer will be photosensitive. Concomitant use of other photosensitizing agents like vemurafenib may increase the risk of a photosensitivity reaction.
Posaconazole: (Contraindicated) Concurrent use of posaconazole and vemurafenib is contraindicated due to the risk of life threatening arrhythmias such as torsade de pointes (TdP). Vemurafenib has been shown to prolong the QT interval in a concentration-dependent manner. The ECG changes occurred within the first month of treatment. Posaconazole has been associated with QT prolongation and torsade de pointes. Additionally, coadministration may result in increased vemurafenib exposure and an increased risk of adverse events, including QT prolongation. Vemurafenib is a CYP3A4 substrate; posaconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of vemurafenib by 40%.
Pralsetinib: (Major) Avoid concomitant use of vemurafenib with pralsetinib due to the risk of increased pralsetinib exposure which may increase the risk of adverse reactions. If concomitant use is necessary, reduce the daily dose of pralsetinib by 100 mg. Pralsetinib is a P-gp substrate and vemurafenib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased the overall exposure of pralsetinib by 81%.
Praziquantel: (Moderate) Vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as praziquantel, could be expected with concurrent use. Use caution, and monitor therapeutic effects of praziquantel when coadministered with vemurafenib.
Prednisolone: (Minor) Vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as prednisolone, could be expected with concurrent use. Use caution, and monitor therapeutic effects of prednisolone when coadministered with vemurafenib.
Prednisone: (Minor) Concomitant use of vemurafenib and prednisone may result in altered concentrations of prednisone or its active metabolite, prednisolone. Vemurafenib is an inhibitor of P-glycoprotein (PGP) and an inducer of CYP3A4. Prednisone is a substrate of PGP and its active metabolite, prednisolone, is a CYP3A4 substrate. Use caution and monitor patients for toxicity and efficacy.
Primaquine: (Major) Due to the potential for QT interval prolongation with primaquine, caution is advised with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with primaquine include vemurafenib.
Primidone: (Major) Avoid the concomitant use of vemurafenib and primidone; significantly decreased vemurafenib exposure may occur resulting in reduced vemurafenib efficacy. Consider the use of an alternative agent. If use with primidone cannot be avoided, increase the vemurafenib dose by 240 mg (as tolerated). If primidone is discontinued, the previous (lower) vemurafenib dose may be resumed 2 weeks after the last primidone dose. Vemurafenib is a CYP3A4 substrate; primidone is metabolized to phenobarbital and is a strong CYP3A4 inducer. In a drug interaction study, the vemurafenib AUC value decreased by 40% (90% CI, 24% to 53%) when a single 960-mg vemurafenib dose was administered with another strong CYP3A4 inducer; the vemurafenib Cmax was not changed.
Probenecid; Colchicine: (Major) Avoid concomitant use of colchicine and vemurafenib due to the risk for increased colchicine exposure which may increase the risk for adverse effects. Concomitant use is contraindicated in patients with renal or hepatic impairment. Additionally, this combination is contraindicated if colchicine is being used for cardiovascular risk reduction. If concomitant use is necessary outside of these scenarios, consider a colchicine dosage reduction. Specific dosage reduction recommendations are available for colchicine tablets for some indications; it is unclear if these dosage recommendations are appropriate for other products or indications. For colchicine tablets being used for gout prophylaxis, reduce the dose from 0.6 mg twice daily to 0.3 mg once daily or from 0.6 mg once daily to 0.3 mg once every other day. For colchicine tablets being used for gout treatment, reduce the dose from 1.2 mg followed by 0.6 mg to 0.6 mg without an additional dose. For colchicine tablets being used for Familial Mediterranean Fever, the maximum daily dose is 0.6 mg. Colchicine is a P-gp substrate and vemurafenib is a P-gp inhibitor.
Procainamide: (Major) Vemurafenib has been associated with QT prolongation. If vemurafenib and another drug that is associated with a possible risk for QT prolongation and torsade de pointes (TdP) must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with vemurafenib include procainamide.
Prochlorperazine: (Minor) Vemurafenib has been associated with QT prolongation. If vemurafenib and another drug that is associated with a possible risk for QT prolongation and torsade de pointes (TdP) must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Drugs with a possible risk for QT prolongation that should be used cautiously with vemurafenib include prochlorperazine.
Promethazine: (Major) Vemurafenib has been associated with QT prolongation. If vemurafenib and another drug that is associated with a possible risk for QT prolongation and torsade de pointes (TdP) must be coadministered, ECG monitoring is recommended; closely monitor the patient. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with vemurafenib include promethazine. Concomitant use of vemurafenib and promethazine may also theoretically result in increased promethazine concentrations. Promethazine is metabolized by CYP2D6 and vemurafenib is a weak CYP2D6 inhibitor. Monitor patients for toxicity if co-use cannot be avoided.
Promethazine; Dextromethorphan: (Major) Vemurafenib has been associated with QT prolongation. If vemurafenib and another drug that is associated with a possible risk for QT prolongation and torsade de pointes (TdP) must be coadministered, ECG monitoring is recommended; closely monitor the patient. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with vemurafenib include promethazine. Concomitant use of vemurafenib and promethazine may also theoretically result in increased promethazine concentrations. Promethazine is metabolized by CYP2D6 and vemurafenib is a weak CYP2D6 inhibitor. Monitor patients for toxicity if co-use cannot be avoided. (Minor) Use of dextromethorphan with vemurafenib increases dextromethorphan exposure. Vemurafenib is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Coadministration of vemurafenib and dextromethorphan increased the AUC of dextromethorphan by 47% and the dextromethorphan Cmax by 36%.
Promethazine; Phenylephrine: (Major) Vemurafenib has been associated with QT prolongation. If vemurafenib and another drug that is associated with a possible risk for QT prolongation and torsade de pointes (TdP) must be coadministered, ECG monitoring is recommended; closely monitor the patient. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with vemurafenib include promethazine. Concomitant use of vemurafenib and promethazine may also theoretically result in increased promethazine concentrations. Promethazine is metabolized by CYP2D6 and vemurafenib is a weak CYP2D6 inhibitor. Monitor patients for toxicity if co-use cannot be avoided.
Propafenone: (Major) Vemurafenib has been associated with QT prolongation. If vemurafenib and another drug, such as propafenone, that is associated with a possible risk for QT prolongation and torsade de pointes (TdP) must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Also, propafenone is a substrate of CYP 1A2, 2D6, and 3A4 and is an inhibitor of P-glycoprotein (P-gp). Vemurafenib is an inhibitor of CYP1A2, a weak inhibitor of CYP2D6, a substrate/inducer of CYP3A4, and a substrate/inhibitor of P-glycoprotein (P-gp) . Concentrations of both propafenone and vemurafenib may be altered with concomitant use.
Propranolol: (Moderate) Propranolol is significantly metabolized by CYP2D6 and secondarily by the CYP1A2 isoenzymes. CYP2D6 and CYP1A2 inhibitors, such as vemurafenib, could theoretically impair propranolol metabolism. The clinical significance of such interactions is unknown.
Propranolol; Hydrochlorothiazide, HCTZ: (Moderate) Propranolol is significantly metabolized by CYP2D6 and secondarily by the CYP1A2 isoenzymes. CYP2D6 and CYP1A2 inhibitors, such as vemurafenib, could theoretically impair propranolol metabolism. The clinical significance of such interactions is unknown.
Quazepam: (Moderate) Vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as quazepam, could be expected with concurrent use. Use caution, and monitor therapeutic effects of quazepam when coadministered with vemurafenib.
Quetiapine: (Major) Concomitant use of vemurafenib and quetiapine 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.
Quinidine: (Major) Vemurafenib has been associated with QT prolongation. Quinidine administration is associated with QT prolongation and torsades de pointes (TdP). If vemurafenib and quinidine must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Also, quinidine is also a CYP3A4 substrate and a P-glycoprotein (P-gp) substrate/inhibitor. Vemurafenib is a CYP3A4 substrate/inducer, and a P-gp substrate/inhibitor. Quinidine concentrations may be increased or decreased and vemurafenib concentrations may be increased during concurrent use.
Quinine: (Major) Concurrent use of quinine and vemurafenib should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). If these drugs must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Both drugs have been associated with prolongation of the QT interval. In addition, both drugs are substrates of CYP3A4, quinine is a CYP3A4 inhibitor, and vemurafenib is a CYP3A4 inducer; coadministration may increase concentrations of vemurafenib and reduce concentrations of quinine.
Quizartinib: (Major) Concomitant use of quizartinib and vemurafenib 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.
Ramelteon: (Moderate) Concomitant use of vemurafenib and ramelteon may result in altered concentrations of ramelteon. Vemurafenib is an inhibitor of CYP2C9 and CYP1A2 and an inducer of CYP3A4. Ramelteon is a substrate of CYP2C9, CYP1A2, and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
Ranolazine: (Major) Vemurafenib has been associated with QT prolongation. If vemurafenib and another drug, such as ranolazine, that is associated with a possible risk for QT prolongation and torsade de pointes (TdP) must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Also, ranolazine is a CYP2D6 substrate, a CYP3A4 substrate/inhibitor, and P-glycoprotein (PGP) substrate/inhibitor. Vemurafenib is a weak CYP2D6 inhibitor, a CYP3A4 substrate/inducer, and a PGP substrate/inhibitor. Alt ered concentrations of both drugs may occur with concomitant use; therefore, monitor the patient for toxicity and efficacy.
Rasagiline: (Major) Do not exceed a rasagiline dose of 0.5 mg once daily when coadministered with vemurafenib. Coadministration may result in increased rasagiline concentrations. Rasagiline is primarily metabolized by CYP1A2; vemurafenib is a moderate CYP1A2 inhibitor. When rasagiline was administered with a strong CYP1A2 inhibitor, the AUC of rasagiline increased by 83%.
Relugolix: (Major) Avoid vemurafenib in patients receiving medications known to prolong the QT interval such as relugolix. Concomitant use may also increase relugolix exposure and the risk of relugolix-related adverse effects. If concomitant oral use is necessary, administer vemurafenib at least six hours after relugolix and monitor for adverse reactions. Vemurafenib is a P-glycoprotein (P-gp) inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. The ECG changes occurred within the first month of treatment. Relugolix is a P-gp substrate that may also prolong the QT/QTc interval.
Relugolix; Estradiol; Norethindrone acetate: (Major) Avoid vemurafenib in patients receiving medications known to prolong the QT interval such as relugolix. Concomitant use may also increase relugolix exposure and the risk of relugolix-related adverse effects. If concomitant oral use is necessary, administer vemurafenib at least six hours after relugolix and monitor for adverse reactions. Vemurafenib is a P-glycoprotein (P-gp) inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. The ECG changes occurred within the first month of treatment. Relugolix is a P-gp substrate that may also prolong the QT/QTc interval.
Repaglinide: (Moderate) Vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as repaglinide, could be expected with concurrent use. Use caution, and monitor therapeutic effects of repaglinide when coadministered with vemurafenib.
Ribociclib: (Major) Avoid vemurafenib in patients receiving medications known to prolong the QT interval such as ribociclib. Vemurafenib has been shown to prolong the QT interval in a concentration-dependent manner. The ECG changes occurred within the first month of treatment. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. The ECG changes occurred within the first four weeks of treatment and were reversible with dose interruption. Additionally, coadministration may result in increased vemurafenib exposure and an increased risk of adverse events, including QT prolongation. Vemurafenib is a CYP3A4 substrate; ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of vemurafenib by 40%. Ribociclib is a strong CYP3A4 inhibitor that has been associated with concentration-dependent QT prolongation. Vemurafenib is a CYP3A4 substrate that has also been associated with QT prolongation. Additive QT prolongation may occur.
Ribociclib; Letrozole: (Major) Avoid vemurafenib in patients receiving medications known to prolong the QT interval such as ribociclib. Vemurafenib has been shown to prolong the QT interval in a concentration-dependent manner. The ECG changes occurred within the first month of treatment. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. The ECG changes occurred within the first four weeks of treatment and were reversible with dose interruption. Additionally, coadministration may result in increased vemurafenib exposure and an increased risk of adverse events, including QT prolongation. Vemurafenib is a CYP3A4 substrate; ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of vemurafenib by 40%. Ribociclib is a strong CYP3A4 inhibitor that has been associated with concentration-dependent QT prolongation. Vemurafenib is a CYP3A4 substrate that has also been associated with QT prolongation. Additive QT prolongation may occur.
Rifabutin: (Major) Concomitant administration of rifabutin and vemurafenib may decrease concentrations of both agents. Both rifabutin and vemurafenib are CYP3A4 substrates and inducers. Avoid using these agents together if possible.
Rifampin: (Major) Avoid the concomitant use of vemurafenib and rifampin; significantly decreased vemurafenib exposure has been reported. Consider the use of an alternative agent. If use with rifampin cannot be avoided, increase the vemurafenib dose by 240 mg (as tolerated). If rifampin is discontinued, the previous (lower) vemurafenib dose may be resumed 2 weeks after the last rifampin dose. Vemurafenib is a CYP3A4 substrate; rifampin is a strong CYP3A4 inducer. In a drug interaction study, the vemurafenib AUC value decreased by 40% (90% CI, 24% to 53%) when a single 960-mg vemurafenib dose was administered with rifampin 600 mg/day; the vemurafenib Cmax was not changed.
Rifapentine: (Major) Avoid coadministration of vemurafenib with rifapentine due to the potential for decreased vemurafenib exposure and reduced efficacy. Consider the use of an alternative agent. If use with rifapentine cannot be avoided, increase the vemurafenib dose by 240 mg (as tolerated). The original dose of vemurafenib may be resumed 2 weeks after rifapentine is discontinued. Vemurafenib is a CYP3A4 substrate; rifapentine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the exposure of vemurafenib by 40%.
Rifaximin: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with vemurafenib is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and vemurafenib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.
Rilpivirine: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with vemurafenib. If these drugs must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Both vemurafenib and supratherapeutic doses of rilpivirine (75 to 300 mg/day) have been associated with QT prolongation. Also, rilpivirine is a CYP3A4 substrate, while vemurafenib is a CYP3A4 substrate and inducer. Therefore, decreased concentrations of rilpivirine and potential loss of virologic response may occur with concomitant use.
Riluzole: (Moderate) Coadministration of riluzole with vemurafenib may increase the risk for riluzole-related adverse reactions, such as gastrointestinal symptoms and elevated hepatic enzymes. In vitro findings suggest an increase in riluzole exposure is likely; riluzole is a CYP1A2 substrate and vemurafenib is a CYP1A2 inhibitor.
Rimegepant: (Major) Avoid a second dose of rimegepant within 48 hours if coadministered with vemurafenib; concurrent use may increase rimegepant exposure. Rimegepant is a P-gp substrate and vemurafenib is a P-gp inhibitor.
Risperidone: (Major) Vemurafenib and risperidone have been associated with a possible risk for QT prolongation and/or torsade de pointes (TdP). Additionally, coadministration of risperidone, a CYP2D6 substrate, with CYP2D6 inhibitors may increase plasma concentrations of risperidone; however, a clinically significant kinetic interaction with vemurafenib is unlikely because vemurafenib is only a mild inhibitor of CYP2D6.
Ritonavir: (Major) Avoid the concomitant use of vemurafenib and ritonavir; vemurafenib exposure may be increased resulting in an increased risk of adverse events, including QT prolongation. If use with ritonavir cannot be avoided, consider a vemurafenib dose reduction; monitor patients closely for the development of adverse events and dose reduce or discontinue therapy based on manufacturer guidance. Vemurafenib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of vemurafenib by 40%.
Rivaroxaban: (Minor) Coadministration of rivaroxaban and vemurafenib may result in increases or decreases in rivaroxaban exposure and may increase bleeding risk or decrease efficacy of rivaroxaban. Vemurafenib is an inducer of CYP3A4 and a mild inhibitor of P-gp. Rivaroxaban is a substrate of CYP3A4 and P-gp. If these drugs are administered concurrently, monitor the patient for signs and symptoms of bleeding and lack of efficacy.
Rolapitant: (Moderate) Use caution if vemurafenib and rolapitant are used concurrently, and monitor for vemurafenib-related adverse effects. Vemurafenib is a substrate of the Breast Cancer Resistance Protein (BCRP) and P-glycoprotein (P-gp), where an increase in exposure may significantly increase adverse effects; rolapitant is a BCRP and P-gp inhibitor. The Cmax and AUC of another BCRP substrate, sulfasalazine, were increased by 140% and 130%, respectively, on day 1 with rolapitant, and by 17% and 32%, respectively, on day 8 after rolapitant administration. When rolapitant was administered with digoxin, a P-gp substrate, the day 1 Cmax and AUC were increased by 70% and 30%, respectively; the Cmax and AUC on day 8 were not studied.
Romidepsin: (Major) Vemurafenib has been associated with QT prolongation. If vemurafenib and another drug, such as romidepsin, that is associated with a possible risk for QT prolongation and torsade de pointes (TdP) must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Also, romidepsin is a CYP3A4 substrate, while vemurafenib is CYP3A4 inducer. Decreased romidepsin concentrations may occur with concomitant use.
Ropinirole: (Moderate) Vemurafenib inhibits CYP1A2, which can potentially lead to increased plasma concentrations of ropinirole, a CYP1A2 substrate. If these drugs are coadministered, adjustment of ropinirole dose may be required.
Rosiglitazone: (Moderate) Rosiglitazone is metabolized by CYP2C9 (minor pathway) and it is possible for serum concentrations of rosiglitazone to rise when coadministered with drugs that inhibit CYP2C9, including vemurafenib. Monitor serum glucose concentrations if rosiglitazone and vemurafenib are coadministered. Dosage adjustments may be necessary.
Saquinavir: (Contraindicated) Concurrent use of vemurafenib and saquinavir boosted with ritonavir is contraindicated due to the risk of life threatening cardiac arrhythmias such as torsade de pointes. Vemurafenib has been shown to prolong the QT interval in a concentration-dependent manner. The ECG changes occurred within the first month of treatment. Saquinavir boosted with ritonavir also increases the QT interval in a dose-dependent fashion. Additionally, coadministration may result in increased vemurafenib exposure and an increased risk of adverse events, including QT prolongation. Vemurafenib is a CYP3A4 substrate; saquinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of vemurafenib by 40%.
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.
Selpercatinib: (Major) Monitor ECGs more frequently for QT prolongation if coadministration of selpercatinib with vemurafenib is necessary due to the risk of additive QT prolongation. Concentration-dependent QT prolongation has been observed with selpercatinib therapy. Vemurafenib has been associated with QT prolongation.
Sertraline: (Major) Concomitant use of vemurafenib and sertraline 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.
Sildenafil: (Moderate) Concomitant use of vemurafenib with sildenafil may increase sildenafil exposure. In vitro studies suggest vemurafenib inhibits CYP3A and CYP2C9. Sildenafil is cleared predominantly by CYP3A (major route) and CYP2C9 (minor route). Use caution and monitor patients for potential sildenafil-related side effects.
Silodosin: (Moderate) Concomitant use of vemurafenib and silodosin may result in altered concentrations of silodosin. Vemurafenib is an inhibitor of P-glycoprotein (PGP) and an inducer of CYP3A4. Silodosin is a substrate of PGP and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
Siponimod: (Major) In general, do not initiate treatment with siponimod in patients receiving vemurafenib due to the potential for 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. Vemurafenib has been associated with QT prolongation.
Sirolimus: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of vemurafenib. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a P-gp substrate and vemurafenib is a P-gp inhibitor.
Sodium Stibogluconate: (Major) Concomitant use of sodium stibogluconate and vemurafenib 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: (Moderate) Use caution when administering velpatasvir with vemurafenib. Taking these medications together may increase the plasma concentrations of both drugs, potentially resulting in adverse events. Both drugs are substrates and inhibitors of the drug transporters P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP).
Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Avoid concurrent administration of voxilaprevir with vemurafenib. Taking these medications together may increase vemurafenib plasma concentrations, potentially increasing the risk for adverse events. Vemurafenib is a substrate for the drug transporters P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP). Voxilaprevir is a P-gp and BCRP inhibitor. (Moderate) Use caution when administering velpatasvir with vemurafenib. Taking these medications together may increase the plasma concentrations of both drugs, potentially resulting in adverse events. Both drugs are substrates and inhibitors of the drug transporters P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP).
Solifenacin: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering solifenacin with vemurafenib. If these drugs must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Solifenacin has been associated with dose-dependent prolongation of the QT interval; TdP has been reported during post-marketing use, although causality was not determined. Vemurafenib has also been associated with QT prolongation. In addition, solifenacin is a CYP3A4 substrate, while vemurafenib is CYP3A4 inducer. Decreased solifenacin concentrations may occur with concomitant use. Use caution, and monitor therapeutic effects of solifenacin when coadministered with vemurafenib.
Sorafenib: (Major) Avoid vemurafenib in patients receiving medications known to prolong the QT interval such as sorafenib. Vemurafenib has been shown to prolong the QT interval in a concentration-dependent manner; these ECG changes occurred within the first month of treatment. Sorafenib is also associated with QTc prolongation.
Sotalol: (Major) Concomitant use of vemurafenib and sotalol 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.
St. John's Wort, Hypericum perforatum: (Major) Avoid the concomitant use of vemurafenib and St. John's Wort; significantly decreased vemurafenib exposure may occur resulting in reduced vemurafenib efficacy. Consider the use of an alternative agent. If use with St. John's Wort cannot be avoided, increase the vemurafenib dose by 240 mg (as tolerated). If St. John's Wort is discontinued, the previous (lower) vemurafenib dose may be resumed 2 weeks after the last St. John's Wort dose. Vemurafenib is a CYP3A4 substrate; St. John's Wort is a strong CYP3A4 inducer. In a drug interaction study, the vemurafenib AUC value decreased by 40% (90% CI, 24% to 53%) when a single 960-mg vemurafenib dose was administered with another strong CYP3A4 inducer; the vemurafenib Cmax was not changed.
Sufentanil: (Moderate) Vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as sufentanil, could be expected with concurrent use. Use caution, and monitor therapeutic effects of sufentanil when coadministered with vemurafenib.
Sumatriptan; Naproxen: (Minor) Concomitant use of vemurafenib and naproxen may result in increased naproxen concentrations. Vemurafenib is a CYP2C9 and CYP1A2 inhibitor and naproxen is a CYP2C9 and CYP1A2 substrate. Patients should be monitored for toxicity.
Sunitinib: (Major) Avoid vemurafenib in patients receiving medications known to prolong the QT interval such as sunitinib. Vemurafenib has been shown to prolong the QT interval in a concentration-dependent manner. The ECG changes occurred within the first month of treatment. Sunitinib can also prolong the QT interval.
Tacrolimus: (Major) Tacrolimus causes QT prolongation. Vemurafenib has also been associated with QT prolongation. Reducing the tacrolimus dose, close monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation (including ECG monitoring) is recommended when coadministrating tacrolimus with other substrates and/or inhibitors of CYP3A4 that also have the potential to prolong the QT interval such as vemurafenib.
Tadalafil: (Minor) Vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as tadalafil, could be expected with concurrent use. Use caution, and monitor therapeutic effects of tadalafil when coadministered with vemurafenib.
Tafamidis: (Moderate) Caution is advised with the coadministration of tafamidis and vemurafenib due to the potential for increased plasma concentrations of vemurafenib increasing the risk of adverse effects. Vemurafenib dose adjustment may be needed with coadministration. Vemurafenib is a substrate of breast cancer resistance protein (BCRP) and tafamidis is a BCRP inhibitor.
Talazoparib: (Moderate) Monitor for an increase in talazoparib-related adverse reactions if concomitant use of vemurafenib is necessary. Concomitant use may increase talazoparib exposure. Talazoparib is a P-gp and BCRP substrate; vemurafenib is a P-gp and BCRP inhibitor.
Tamoxifen: (Major) Concomitant use of vemurafenib and tamoxifen 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.
Tamsulosin: (Moderate) Vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as tamsulosin, could be expected with concurrent use. Use caution, and monitor therapeutic effects of tamsulosin when coadministered with vemurafenib.
Tasimelteon: (Moderate) Caution is recommended during concurrent use of tasimelteon and vemurafenib. Concurrent use of these agents may have variable effects on tasimelteon exposure. Vemurafenib has inhibitory effects on CYP1A2 and inducing effects on CYP3A4, which are two metabolic pathways of tasimelteon.
Tedizolid: (Moderate) If possible, stop use of vemurafenib temporarily during treatment with oral tedizolid. If coadministration cannot be avoided, closely monitor for vemurafenib-associated adverse events. Vemurafenib plasma concentrations may be increased when administered concurrently with oral tedizolid. Vemurafenib is an in vitro substrate of the Breast Cancer Resistance Protein (BCRP); oral tedizolid inhibits BCRP in the intestine.
Telavancin: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering telavancin with vemurafenib. If these drugs must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Both telavancin and vemurafenib have been associated with QT prolongation.
Telmisartan; Amlodipine: (Moderate) Vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as amlodipine, could be expected with concurrent use. Use caution, and monitor therapeutic effects of amlodipine when coadministered with vemurafenib.
Temsirolimus: (Moderate) Monitor for an increase in temsirolimus-related adverse reactions if coadministration with vemurafenib is necessary. Temsirolimus is a P-glycoprotein (P-gp) substrate and vemurafenib is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of temsirolimus.
Teniposide: (Major) Concomitant use of vemurafenib and teniposide may result in altered concentrations of teniposide. Vemurafenib is an inhibitor of P-glycoprotein (PGP) and an inducer of CYP3A4. Teniposide is a substrate of PGP and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
Tenofovir Alafenamide: (Moderate) Coadministration of vemurafenib and tenofovir alafenamide may result in elevated tenofovir concentrations. Vemurafenib is an inhibitor of the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Tenofovir alafenamide is a P-gp and BCRP substrate. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
Tenofovir Disoproxil Fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as vemurafenib. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
Terbinafine: (Moderate) Caution is advised when administering terbinafine with vemurafenib. Although this interaction has not been studied by the manufacturer, and published literature suggests the potential for interactions to be low, taking these drugs together may alter the systemic exposure of terbinafine. Predictions about the interaction can be made based on the metabolic pathways of both drugs. Terbinafine is metabolized by at least 7 CYP isoenyzmes, with major contributions coming from CYP1A2, CYP2C9 and CYP3A4; vemurafenib is an inducer of CYP3A4 and an inhibitor of CYP1A2 and CYP2C9. Monitor patients for adverse reactions and breakthrough fungal infections if these drugs are coadministered.
Tetrabenazine: (Major) Vemurafenib has been associated with QT prolongation. Tetrabenazine causes a small increase in the corrected QT interval (QTc). The manufacturer recommends avoiding concurrent use of tetrabenazine with other drugs known to prolong QTc. If vemurafenib and tetrabenazine must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Also, the active metabolites for tetrabenazine are substrates for CYP1A2 and 2D6, while vemurafenib is an inhibitor of both enzymes. Therefore increased concentrations of the tetrabenazine metabolites may occur with concomitant use. Monitor patients for increased side effect.
Theophylline, Aminophylline: (Major) Coadministration of vemurafenib and caffeine increased the caffeine AUC by 2.6-fold. Vemurafenib is a CYP1A2 inhibitor and caffeine is a CYP1A2 substrate. The manufacturer of vemurafenib suggests that concomitant use with agents with narrow therapeutic windows that are metabolized by CYP1A2 is not recommended. Theophylline (or aminophylline), another methylxanthine, is also primarily a CYP1A2 substrate with a narrow therapeutic index. If coadministration cannot be avoided, the manufacturer recommends considering a dose reduction of the concomitant drug; it may also be prudent to monitor for signs and symptoms of theophylline toxicity during coadministration. Some patients may need to reduce intake of caffeine from non-drug sources (e.g., beverages) during treatment to avoid caffeine-related side effects.
Thioridazine: (Contraindicated) Vemurafenib has been associated with QT prolongation. Because of the potential for torsade de pointes (TdP), use of thioridazine with vemurafenib is contraindicated.
Tiagabine: (Moderate) Vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as tiagabine, could be expected with concurrent use. Use caution, and monitor therapeutic effects of tiagabine when coadministered with vemurafenib.
Ticagrelor: (Minor) Coadministration of ticagrelor and vemurafenib may result in increased exposure to ticagrelor which may increase the bleeding risk. Ticagrelor is a P-glycoprotein (P-gp) substrate and vemurafenib is a mild P-gp inhibitor. Based on drug information data with cyclosporine, no dose adjustment is recommended by the manufacturer of ticagrelor. Use combination with caution and monitor for evidence of bleeding.
Timolol: (Moderate) Concomitant use of vemurafenib and timolol may result in increased timolol concentrations. Vemurafenib is a weak CYP2D6 inhibitor and timolol is a CYP2D6 substrate. Patients should be monitored for toxicity.
Tinidazole: (Minor) Vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as tinidazole, could be expected with concurrent use. Use caution, and monitor therapeutic effects of tinidazole when coadministered with vemurafenib.
Tipranavir: (Major) Avoid the concomitant use of vemurafenib and tipranavir; vemurafenib exposure may be increased resulting in an increased risk of adverse events, including QT prolongation. If use with tipranavir cannot be avoided, consider a vemurafenib dose reduction; monitor patients closely for the development of adverse events and dose reduce or discontinue therapy based on manufacturer guidance. Vemurafenib is a CYP3A4 substrate; tipranavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of vemurafenib by 40%.
Tizanidine: (Major) Avoid the use of vemurafenib with tizanidine; the tizanidine Cmax and AUC values were significantly increased when these agents were coadministered in a drug interaction study. If concomitant use of these drugs is required, initiate tizanidine at the 2-mg dose and increase in 2- to 4-mg increments daily based on the patient response. Monitor patients closely for tizanidine toxicity; if adverse reactions such as hypotension, bradycardia, or excessive drowsiness occur, reduce or discontinue tizanidine therapy. Vemurafenib is a moderate CYP1A2 inhibitor and tizanidine is a CYP1A2 substrate with a narrow therapeutic index. In a drug interaction study (n = 16), the tizanidine Cmax increased 2.2-fold and the tizanidine AUC value increased 4.7-fold when a single 2-mg PO dose of tizanidine was given following 21 days of vemurafenib 960 mg PO twice daily in cancer patients.
Tolbutamide: (Moderate) Concomitant use of vemurafenib and tolbutamide may result in increased tolbutamide concentrations. Vemurafenib is a CYP2C9 inhibitor and tolbutamide is a CYP2C9 substrate. Monitor serum glucose concentrations if tolbutamide is coadministered with CYP2C9 inhibitors. Dosage adjustments may be necessary.
Tolterodine: (Major) Vemurafenib has been associated with QT prolongation. If vemurafenib and another drug, such as tolterodine, that is associated with a possible risk for QT prolongation and torsade de pointes (TdP) must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Also, concomitant use of vemurafenib and tolterodine may result in altered concentrations of tolterodine. Vemurafenib is a weak inhibitor of CYP2D6 and an inducer of CYP3A4. Tolterodine is metabolized primarily by CYP2D6 and alternatively, CYP3A4 in those patients who are poor metabolizers of tolterodine via CYP2D6. Use caution and monitor patients for toxicity and efficacy.
Topiramate: (Major) Concomitant use of vemurafenib and topiramate may result in decreased concentrations of vemurafenib. Vemurafenib is a CYP3A4 substrate and topiramate is a weak CYP3A4 inducer. Use caution and monitor patients for therapeutic effects.
Topotecan: (Major) Avoid coadministration of vemurafenib with oral topotecan due to increased topotecan exposure; vemurafenib may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP); vemurafenib is a P-gp and BCRP inhibitor. Following escalating doses of a dual inhibitor of BCRP and P-gp, the AUC of topotecan lactone and total topotecan increased by approximately 2.5-fold compared to topotecan alone. Coadministration of a dual P-gp/BCRP inhibitor with intravenous topotecan increased total topotecan exposure by 1.2-fold and exposure to topotecan lactone by 1.1-fold.
Toremifene: (Major) Avoid coadministration of vemurafenib with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Vemurafenib has also been associated with QT prolongation.
Torsemide: (Moderate) Concomitant use of vemurafenib and torsemide may result in increased torsemide concentrations. Vemurafenib is a CYP2C9 inhibitor and torsemide is a CYP2C9 substrate. Patients should be monitored for toxicity.
Tramadol: (Moderate) Concomitant use of vemurafenib and tramadol may result in altered concentrations of tramadol. Vemurafenib is a weak inhibitor of CYP2D6 and an inducer of CYP3A4. Tramadol is a substrate of CYP2D6 and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
Tramadol; Acetaminophen: (Moderate) Concomitant use of vemurafenib and acetaminophen may result in altered concentrations of acetaminophen. Vemurafenib is an inhibitor of CYP1A2 and CYP2A6, and an inducer of CYP3A4. Acetaminophen is a substrate of CYP1A2, CYP2A6, and CYP3A4. Use caution and monitor patients for toxicity and efficacy. (Moderate) Concomitant use of vemurafenib and tramadol may result in altered concentrations of tramadol. Vemurafenib is a weak inhibitor of CYP2D6 and an inducer of CYP3A4. Tramadol is a substrate of CYP2D6 and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
Trandolapril; Verapamil: (Moderate) Concomitant use of vemurafenib and verapamil may result in altered concentrations of verapamil and increased concentrations of vemurafenib. Vemurafenib is a substrate/inducer of CYP3A4, a substrate/inhibitor of P-glycoprotein (PGP), and an inhibitor of CYP1A2 and CYP2C9. Verapamil is a substrate/inhibitor of CYP3A4 and PGP and a substrate of CYP1A2 and CYP2C9. Use caution and monitor patients for toxicity and efficacy.
Trazodone: (Major) Concomitant use of vemurafenib and trazodone 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.
Triamterene: (Minor) Concomitant use of vemurafenib and triamterene may result in increased triamterene concentrations. Vemurafenib is a CYP1A2 inhibitor and triamterene is a CYP1A2 substrate. Monitor patients for increased toxicity and hypotension.
Triamterene; Hydrochlorothiazide, HCTZ: (Minor) Concomitant use of vemurafenib and triamterene may result in increased triamterene concentrations. Vemurafenib is a CYP1A2 inhibitor and triamterene is a CYP1A2 substrate. Monitor patients for increased toxicity and hypotension.
Triclabendazole: (Major) Concomitant use of triclabendazole and vemurafenib 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) Vemurafenib has been associated with QT prolongation. If vemurafenib and another drug that is associated with a possible risk for QT prolongation and torsade de pointes (TdP) must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Drugs with a possible risk for QT prolongation that should be used cautiously with vemurafenib include trifluoperazine.
Triptorelin: (Major) Closely monitor ECGs for QT prolongation if coadministration of vemurafenib with triptorelin is necessary. Vemurafenib has been associated with QT prolongation. Androgen deprivation therapy (i.e., triptorelin) may prolong the QT/QTc interval.
Tucatinib: (Major) Avoid the concomitant use of vemurafenib and tucatinib; vemurafenib exposure may be increased resulting in an increased risk of adverse events, including QT prolongation. If use with tucatinib cannot be avoided, consider a vemurafenib dose reduction; monitor patients closely for the development of adverse events and dose reduce or discontinue therapy based on manufacturer guidance. Vemurafenib is a CYP3A4 substrate; tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of vemurafenib by 40%.
Ubrogepant: (Major) Limit the initial and second dose of ubrogepant to 50 mg if coadministered with vemurafenib. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a substrate of the BCRP and P-gp drug transporters; vemurafenib is a BCRP and P-gp inhibitor.
Vandetanib: (Major) Avoid coadministration of vandetanib with vemurafenib due to an increased risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, closely 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. Vandetanib can prolong the QT interval in a concentration-dependent manner; TdP and sudden death have been reported in patients receiving vandetanib. Vemurafenib has also been associated with QT prolongation.
Vardenafil: (Major) Concomitant use of vemurafenib and vardenafil 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.
Venetoclax: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with vemurafenib due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of vemurafenib. Venetoclax is a P-glycoprotein (P-gp) substrate; vemurafenib is a P-gp inhibitor. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
Venlafaxine: (Major) Vemurafenib has been associated with QT prolongation. If vemurafenib and another drug, such as venlafaxine, that is associated with a possible risk for QT prolongation and torsade de pointes must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Also, venlafaxine is a substrate of CYP2D6 and 3A4, while vemurafenib is a weak CYP2D6 inhibitor and CYP3A4 substrate/inducer. Therefore, altered concentrations of venlafaxine may occur. Monitor the patient for toxicity and efficacy.
Verapamil: (Moderate) Concomitant use of vemurafenib and verapamil may result in altered concentrations of verapamil and increased concentrations of vemurafenib. Vemurafenib is a substrate/inducer of CYP3A4, a substrate/inhibitor of P-glycoprotein (PGP), and an inhibitor of CYP1A2 and CYP2C9. Verapamil is a substrate/inhibitor of CYP3A4 and PGP and a substrate of CYP1A2 and CYP2C9. Use caution and monitor patients for toxicity and efficacy.
Verteporfin: (Moderate) Use caution if coadministration of verteporfin with vemurafenib is necessary due to the risk of increased photosensitivity. Verteporfin is a light-activated drug used in photodynamic therapy; all patients treated with verteporfin will be photosensitive. Concomitant use of other photosensitizing agents like vemurafenib may increase the risk of a photosensitivity reaction.
Vincristine Liposomal: (Moderate) Concomitant use of vemurafenib and vincristine may result in altered concentrations of vincristine. Vemurafenib is an inhibitor of P-glycoprotein (PGP) and an inducer of CYP3A4. Vincristine is a substrate of PGP and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
Vincristine: (Moderate) Concomitant use of vemurafenib and vincristine may result in altered concentrations of vincristine. Vemurafenib is an inhibitor of P-glycoprotein (PGP) and an inducer of CYP3A4. Vincristine is a substrate of PGP and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
Voclosporin: (Major) Avoid concomitant use of vemurafenib and voclosporin due to the risk of additive QT prolongation. Vemurafenib has been shown to prolong the QT interval in a concentration-dependent manner. The ECG changes occurred within the first month of treatment. Voclosporin has been associated with QT prolongation at supratherapeutic doses.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Avoid vemurafenib in patients receiving medications known to prolong the QT interval such as clarithromycin. Vemurafenib has been shown to prolong the QT interval in a concentration-dependent manner. The ECG changes occurred within the first month of treatment. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP). Additionally, coadministration may result in increased vemurafenib exposure and an increased risk of adverse events, including QT prolongation. Vemurafenib is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of vemurafenib by 40%.
Vorapaxar: (Moderate) Use caution during concurrent use of vorapaxar and vemurafenib. Decreased serum concentrations of vorapaxar and thus decreased efficacy are possible when vorapaxar, a CYP3A4 substrate, is coadministered with vemurafenib, a CYP3A inducer.
Voriconazole: (Major) Avoid vemurafenib in patients receiving medications known to prolong the QT interval such as ceritinib. Vemurafenib has been shown to prolong the QT interval in a concentration-dependent manner. The ECG changes occurred within the first month of treatment. Voriconazole may cause additive QT prolongation; it has also been associated with rare cases of torsade de pointes, cardiac arrest, and sudden death. Additionally, coadministration may result in increased vemurafenib exposure and an increased risk of adverse events, including QT prolongation. Vemurafenib is a CYP3A4 substrate; voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of vemurafenib by 40%.
Vorinostat: (Major) Vemurafenib has been associated with QT prolongation. If vemurafenib and another drug that is associated with a possible risk for QT prolongation and torsade de pointes (TdP), such as vorinostat, must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation.
Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with vemurafenib is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Vemurafenib is a CYP1A2 and CYP2C9 inhibitor; warfarin is a CYP1A2 and CYP2C9 substrate. Coadministration of vemurafenib and S-warfarin increased the AUC of S-warfarin by 18%.
Ziprasidone: (Major) Concomitant use of ziprasidone and vemurafenib should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Vemurafenib has been associated with QT prolongation. If vemurafenib and another drug that is associated with a possible risk for QT prolongation and TdP must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation.
Zolpidem: (Moderate) Vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as zolpidem, could be expected with concurrent use. Use caution, and monitor therapeutic effects of zolpidem when coadministered with vemurafenib.
How Supplied
Zelboraf Oral Tab: 240mg
Maximum Dosage
1920 mg/day PO.
Geriatric1920 mg/day PO.
AdolescentsSafety and efficacy have not been established.
ChildrenSafety and efficacy have not been established.
InfantsSafety and efficacy have not been established.
NeonatesSafety and efficacy have not been established.
Mechanism Of Action
Vemurafenib is a low molecular weight inhibitor of some mutated forms of BRAF serine threonine kinase, including BRAFV600E. It also inhibits other kinases in vitro including CRAF, ARAF, wild-type BRAF, SRMS, ACK1, MAP4K5, and FGR at similar concentrations. It is a potent adenosine triphosphate-competitive inhibitor of RAFs, with a modest preference in vitro for mutant BRAF and CRAF as compared with wild-type BRAF. Some BRAF gene mutations, including the V600E mutation, result in constitutively activated BRAF proteins, which can cause cell proliferation in the absence of growth factors that would normally be required for cell proliferation. Approximately 40% to 60% of cutaneous melanomas carry mutations in BRAF that lead to downstream signaling through the MAPK pathway and approximately 90% of these mutations are V600E mutations. Vemurafenib has anti-tumor effects in cellular and animal models of melanoma with the V600E mutation of the BRAF gene, but not against cells with wild-type BRAF.
Potential mechanisms may exist for resistance to vemurafenib and other RAF inhibitors. These may include reactivation of RAF-MEK signaling, alterations in ERK 1/2-regulated cell cycle events, activation of alternative signaling pathways, and chromatin-regulating events.
Pharmacokinetics
Vemurafenib is administered orally. At steady state, it exhibits linear pharmacokinetics. Vemurafenib is greater than 99% protein bound to human albumin and alpha-1 acid glycoprotein and has an apparent volume of distribution of 106 L (66% inter-patient variability). Vemurafenib is metabolized by cytochrome P450 isoenzymes, primarily via CYP3A4. Forty-eight hours after dose administration, mean data showed that vemurafenib and its metabolites represented 95% and 5% of the components in plasma, respectively. Approximately 94% of the dose is eliminated in the feces and approximately 1% is eliminated in the urine with an apparent clearance of 31 L/day (32% inter-patient variability). The median half-life is 57 hours (range 30 to 120 hours).
Affected cytochrome P450 isoenzymes and drug transporters: CYP1A2, CYP3A4, P-gp
Vemurafenib is a CYP3A4 substrate and an inhibitor of CYP1A2 and P-glycoprotein (P-gp) as demonstrated in drug interactions studies. Additionally, vemurafenib was a weak CYP2D6 inhibitor (mean dextromethorphan AUC increased by 47%), and a weak CYP3A4 inducer (mean midazolam AUC decreased by 39%) in a drug interaction study performed in cancer patients. Concomitant use with S-warfarin, a CYP2C9 substrate, resulted in a mean S-warfarin AUC increase of 18%; concomitant use with omeprazole, a CYP2C19 substrate, did not result in altered omeprazole exposure. In vitro, vemurafenib is both a substrate and an inhibitor of the efflux transporters P-gp and Breast Cancer Resistance Protein (BCRP).
The mean steady-state bioavailability of orally administered vemurafenib was 64% (coefficient of variance, 56%). After oral administration for 15 days, the median Tmax was approximately 3 hours, the mean Cmax was 62 mcg/mL (+/- 17 mcg/mL), and the mean 12 hour AUC was 601 mcg x hour/mL (+/- 170 mcg x hour/mL). The mean accumulation ratio is 7.4 with a steady state achieved at approximately 15 to 22 days after the dose. In a food effect study, administering vemurafenib with a high-fat meal resulted in a 2.5-fold increase in Cmax, approximately 5-fold increase in AUC, and a delayed Tmax by 4 hours when compared to the fasted state. However, vemurafenib may be taken with or without food according to the manufacturer.
Pregnancy And Lactation
Fetal harm may occur if vemurafenib is administered to a woman during pregnancy, based on its mechanism of action. Females of reproductive potential should be advised to avoid pregnancy. If vemurafenib is used during pregnancy, the patient should be informed of the potential hazard to the fetus. Placental transfer of vemurafenib to a fetus has been reported. Fetal drug levels were 3% to 5% of maternal levels in animal studies. There was no evidence of teratogenicity following vemurafenib administration in pregnant rats or rabbits; however, there are no well-controlled studies in pregnant women.
According to the manufacturer, women should discontinue breast-feeding during vemurafenib therapy and for 2 weeks after the last dose because of the potential for serious adverse reactions in nursing infants including malignancy, severe dermatologic reactions, QT prolongation, hepatotoxicity, photosensitivity, and ophthalmologic toxicity. It is not known if vemurafenib is secreted in human milk or if it affects milk production or the breast fed infant.