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  • CLASSES

    Protein Kinase Inhibitors

    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

    COMMON BRAND NAMES

    Zelboraf

    HOW SUPPLIED

    Zelboraf Oral Tab: 240mg

    DOSAGE & INDICATIONS

    For the treatment of unresectable or metastatic malignant melanoma in patients with the BRAF V600E mutation.
    NOTE: Confirm the BRAF V600E mutation prior to starting therapy using a FDA-approved test; vemurafenib is not indicated in patients with wild-type BRAF melanoma.
    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; hazard ratio [HR] = 0.7; 95% CI, 0.57 to 0.87; p < 0.0008) and progression-free survival (PFS) time (6.9 months vs. 1.6 months; HR = 0.38; 95% CI, 0.32 to 0.46; p < 0.0001) 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 III 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 II 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.

    For the treatment of Erdheim-Chester Disease (ECD) in patients with the BRAF V600E mutation.
    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.

    MAXIMUM DOSAGE

    Adults

    1920 mg/day PO.

    Geriatric

    1920 mg/day PO.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    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 Impairment

    No 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.

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    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.

    STORAGE

    Zelboraf:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    - Store in original container

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

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

    Alcoholism, bradycardia, cardiac arrhythmias, cardiac disease, coronary artery disease, diabetes mellitus, females, geriatric, heart failure, hypertension, hypocalcemia, hypokalemia, hypomagnesemia, long QT syndrome, malnutrition, myocardial infarction, QT prolongation, thyroid disease

    Vemurafenib carries a risk for QT prolongation and resultant torsade de pointes (TdP). Exposure-dependent QT prolongation was observed with vemurafenib in an uncontrolled, open-label Phase 2 QT sub-study. QT prolongation may lead to an increased risk of ventricular arrhythmias, including TdP. No large change in mean QTc interval (> 20 ms) was noted in the clinical trail. In the first month, the largest mean change from baseline of 12.8 ms was observed at 2 hours after the dose on Day 15. In the first 6 months, the largest observed mean change from baseline of 15.1 ms was detected at a pre-dose time point. Vemurafenib is not recommended for use in patients with uncorrectable electrolyte imbalance (particularly hypokalemia or hypomagnesemia), long QT syndrome (QT > 500 ms), or who are taking concurrent medications that increase the QT interval. Use vemurafenib with caution in patients with cardiac disease or other conditions that may increase the risk of QT prolongation including cardiac arrhythmias, heart failure, bradycardia, myocardial infarction, hypertension, coronary artery disease, hypocalcemia, or in patients receiving medications known to cause electrolyte imbalances. Females, geriatric patients, patients with diabetes mellitus, thyroid disease, malnutrition, alcoholism, or hepatic dysfunction may also be at increased risk for QT prolongation. Monitor ECG and electrolytes (i.e., potassium, magnesium, calcium) before treatment, 15 days after treatment initiation or dose modification, and then monthly for 3 months for QTc prolongation. Continued ECG and electrolyte monitoring should occur every 3 months thereafter or more often as clinically indicated. If the QTc exceeds 500 ms (Grade 3) during therapy with vemurafenib, treatment should be discontinued temporarily, electrolyte abnormalities should be corrected, and cardiac risk factors (e.g., congestive heart failure, bradyarrhythmias) should be controlled. Treatment may resume at a lower dose once the QTc is below 500 ms. Permanent discontinuation is recommended if the QTc increase meets values of both > 500 ms and > 60 ms change from pretreatment values after the correction of associated risk factors.

    Secondary malignancy, skin cancer, sunburn

    Secondary malignancy has been reported with vemurafenib therapy, specifically cutaneous squamous cell carcinoma, basal cell carcinoma, keratoacanthoma, new primary malignant melanomas, and oropharyngeal squamous cell carcinoma. Myeloid neoplasms have been reported in patients with Erdheim-Chester Disease (ECD) who received vemurafenib. Perform a dermatologic evaluation before starting vemurafenib therapy, every 2 months on therapy, and for up to 6 months after therapy discontinuation. Also monitor patients for signs and symptoms of other noncutaneous malignancies. Evaluate complete blood counts in ECD patients with concomitant myeloid malignancies. No vemurafenib dose modifications are recommended in patients who develop a new primary cutaneous malignancy. Patients 65 years and older and patients with prior skin cancer or a history of chronic sun exposure/sunburn may have an increased risk of developing cuSCC. Additionally, vemurafenib may cause progression of other cancers associated with RAS mutations; use vemurafenib with caution in patients with prior or concurrent cancers associated with RAS mutations.

    Sunlight (UV) exposure

    Vermurafenib is associated with mild to severe photosensitivity. Patients should be advised to avoid sunlight (UV) exposure, and to wear protective clothing and use a broad spectrum UVA/UVB sunscreen (SPF >=30) and protective lip balm when outdoors while on treatment.

    Coagulopathy, hepatic disease

    Hepatotoxicity such as functional hepatic impairment (e.g., coagulopathy or other organ dysfunction), elevated hepatic enzymes, and hyperbilirubinemia have been reported with vemurafenib therapy; use vemurafenib with caution in patients with severe hepatic disease. Obtain liver function tests (LFTs) including bilirubin levels prior to starting vemurafenib and then monthly during treatment or as clinically indicated. Interruption of therapy, a dose reduction, or permanent therapy discontinuation may be necessary in patients who develop laboratory evidence of hepatotoxicity. Grade 3 elevated transaminase levels occurred in 6 of 10 patients with BRAF V600-mutation positive melanoma 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. Therefore, the safety and effectiveness of this combination has not been established.

    Iritis

    Uveitis (including iritis), blurred vision, and photophobia have been reported with vemurafenib therapy. Steroid and mydriatic ophthalmic drops may provide symptomatic relief for these eye conditions. Monitor patients for signs and symptoms of uveitis.

    Fever, hypotension

    Serious hypersensitivity reactions including anaphylaxis and symptoms of hypotension, generalized rash, and erythema have been reported with vemurafenib use. Permanently discontinue therapy in patients who develop a severe hypersensitivity reaction. Additionally, drug rash with eosinophilia and systemic symptoms (DRESS syndrome) has occurred with vemurafenib use, typically occurring 7 to 25 days after starting therapy. This syndrome may involve the liver, lung, heart, or kidney; symptoms include fever, skin rash, lymphadenopathy, and eosinophilia. Permanently discontinue therapy in patients who develop DRESS syndrome.

    Serious rash

    Serious rash including Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported with vemurafenib use. Permanently discontinue therapy in patients who develop a severe dermatologic reaction.

    Radiation therapy

    Radiation recall reaction (radiation sensitization) has been reported in patients who received vemurafenib; some cases were severe. Cutaneous and visceral organ reactions have occurred in patients who received radiation therapy prior to, during, or after vemurafenib therapy; fatalities have been reported in patients with visceral organ involvement. Monitor patients for signs of radiation recall reaction if vemurafenib is given concomitantly or sequentially with radiation.

    Renal failure

    Renal dysfunction including renal failure, acute interstitial nephritis, and acute tubular necrosis have been reported with vemurafenib treatment. Monitor serum creatinine levels prior to and periodically during vemurafenib therapy. No initial dosage adjustment is necessary in patients with mild to moderate renal impairment (creatinine clearance of 30 to 89 mL/min).

    Dupuytren's contracture, plantar fibromatosis

    Use vemurafenib with caution in patients with pre-existing Dupuytren's contracture or plantar fibromatosis; new onset or worsening Dupuytren's contracture and plantar fascial fibromatosis have been reported. Interruption of therapy or vemurafenib discontinuation may be necessary in patients who develop Dupuytren's contracture or plantar fibromatosis.

    Pregnancy

    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.

    Contraception requirements, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during vemurafenib treatment. Females should avoid pregnancy and use effective contraception during and 2 weeks after treatment with vemurafenib. Women who become pregnant while receiving vemurafenib should be apprised of the potential hazard to the fetus.

    Breast-feeding

    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.

    ADVERSE REACTIONS

    Severe

    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
    erythema nodosum / Delayed / 0-10.0
    Stevens-Johnson syndrome / Delayed / 0-10.0
    toxic epidermal necrolysis / Delayed / 0-10.0
    retinal thrombosis / Delayed / 0-10.0
    nephrotoxicity / Delayed / 0-9.1
    rash (unspecified) / 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
    bleeding / Early / 0-0.8
    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

    Moderate

    secondary malignancy / Delayed / 0-55.0
    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

    Mild

    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
    folliculitis / Delayed / 0-10.0

    DRUG INTERACTIONS

    Abacavir; Dolutegravir; Lamivudine: (Major) Avoid concurrent use of dolutegravir with vemurafenib, as coadministration may result in decreased dolutegravir plasma concentrations. Vemurafenib is an inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme.
    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; Butalbital: (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; Butalbital; 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; Butalbital; 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.
    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; Magnesium Salicylate; Phenyltoloxamine: (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; Phenyltoloxamine; Salicylamide: (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; 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) Coadministration of vemurafenib and dextromethorphan increased the AUC of dextromethorphan by 47% and the dextromethorphan Cmax by 36%. Vemurafenib is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate. The manufacturer of vemurafenib suggests that concomitant use with agents with narrow therapeutic windows that are metabolized by CYP2D6 is not recommended. If coadministration cannot be avoided, the manufacturer recommends considering a dose reduction of the concomitant drug.
    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) Coadministration of vemurafenib and dextromethorphan increased the AUC of dextromethorphan by 47% and the dextromethorphan Cmax by 36%. Vemurafenib is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate. The manufacturer of vemurafenib suggests that concomitant use with agents with narrow therapeutic windows that are metabolized by CYP2D6 is not recommended. If coadministration cannot be avoided, the manufacturer recommends considering a dose reduction of the concomitant drug.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (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) Coadministration of vemurafenib and dextromethorphan increased the AUC of dextromethorphan by 47% and the dextromethorphan Cmax by 36%. Vemurafenib is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate. The manufacturer of vemurafenib suggests that concomitant use with agents with narrow therapeutic windows that are metabolized by CYP2D6 is not recommended. If coadministration cannot be avoided, the manufacturer recommends considering a dose reduction of the concomitant drug.
    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) Coadministration of vemurafenib and dextromethorphan increased the AUC of dextromethorphan by 47% and the dextromethorphan Cmax by 36%. Vemurafenib is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate. The manufacturer of vemurafenib suggests that concomitant use with agents with narrow therapeutic windows that are metabolized by CYP2D6 is not recommended. If coadministration cannot be avoided, the manufacturer recommends considering a dose reduction of the concomitant drug.
    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) Coadministration of vemurafenib and dextromethorphan increased the AUC of dextromethorphan by 47% and the dextromethorphan Cmax by 36%. Vemurafenib is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate. The manufacturer of vemurafenib suggests that concomitant use with agents with narrow therapeutic windows that are metabolized by CYP2D6 is not recommended. If coadministration cannot be avoided, the manufacturer recommends considering a dose reduction of the concomitant drug.
    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) Coadministration of vemurafenib and dextromethorphan increased the AUC of dextromethorphan by 47% and the dextromethorphan Cmax by 36%. Vemurafenib is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate. The manufacturer of vemurafenib suggests that concomitant use with agents with narrow therapeutic windows that are metabolized by CYP2D6 is not recommended. If coadministration cannot be avoided, the manufacturer recommends considering a dose reduction of the concomitant drug.
    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) Coadministration of vemurafenib and dextromethorphan increased the AUC of dextromethorphan by 47% and the dextromethorphan Cmax by 36%. Vemurafenib is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate. The manufacturer of vemurafenib suggests that concomitant use with agents with narrow therapeutic windows that are metabolized by CYP2D6 is not recommended. If coadministration cannot be avoided, the manufacturer recommends considering a dose reduction of the concomitant drug.
    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; 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) Concomitant use of vemurafenib and oxycodone may result in altered concentrations of oxycodone. Vemurafenib is a weak inhibitor of CYP2D6 and an inducer of CYP3A4. Oxycodone is a substrate of CYP2D6 and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
    Acetaminophen; Pentazocine: (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; Propoxyphene: (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.
    Acetaminophen; Tramadol: (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.
    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: (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 the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Albuterol; Ipratropium: (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 the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    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.
    Aliskiren; 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.
    Aliskiren; 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.
    Alogliptin; Pioglitazone: (Major) Concomitant use of vemurafenib and pioglitazone may result in decreased concentrations of both agents. Both are CYP3A4 substrates and inducers. Use caution and monitor patients for therapeutic effects.
    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.
    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.
    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 concenrations of vemurafenib. Vemurafenib is a substrate/inhibitor of P-glycoprotein (PGP) and an inducer of CYP3A4. Atorvastatin is a substrate of PGP and CYP3A4 and an inhibitor of PGP. 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; Hydrochlorothiazide, HCTZ; 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; Hydrochlorothiazide, HCTZ; 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; 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; Telmisartan: (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.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with vemurafenib. If coadministration is considered necessary, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Both vemurafenib and clarithromycin are associated with prolongation of the QT interval, while clarithromycin is also associated with an established risk for TdP. Additionally, clarithromycin is a CYP3A4 substrate/inhibitor and P-glycoprotein (P-gp) inhibitor, while vemurafenib is a CYP3A4 substrate/inducer and P-gp substrate/inhibitor. Decreased clarithromycin and increased vemurafenib concentrations may occur with concomitant use (Moderate) Consider an alternative to lansoprazole in patients who are receiving vemurafenib. Coadministration could lead to increased vemurafenib concentrations and, thus, adverse reactions and toxicities. Altered lansoprazole concentrations could also occur. Vemurafenib is a P-glycoprotein (P-gp) substrate/inhibitor and is a CYP3A4 inducer. Lansoprazole is a CYP3A4 substrate and a P-gp substrate/inhibitor.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with vemurafenib. If coadministration is considered necessary, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Both vemurafenib and clarithromycin are associated with prolongation of the QT interval, while clarithromycin is also associated with an established risk for TdP. Additionally, clarithromycin is a CYP3A4 substrate/inhibitor and P-glycoprotein (P-gp) inhibitor, while vemurafenib is a CYP3A4 substrate/inducer and P-gp substrate/inhibitor. Decreased clarithromycin and increased vemurafenib concentrations may occur with concomitant use
    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.
    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. Limited data indicate that QT prolongation is also possible with apomorphine administration. The change in QTc interval is not significant in most patients receiving dosages within the manufacturer's guidelines; however, large increases (> 60 msecs from pre-dose) have occurred in two patients receiving 6 mg doses. Doses <= 6 mg SC are associated with minimal increases in QTc; doses > 6 mg SC do not provide additional clinical benefit and are not recommended.
    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.
    Arformoterol: (Moderate) 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 the long-acting beta-agonists (LABAs). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    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) Concomitant use of vemurafenib and oxycodone may result in altered concentrations of oxycodone. Vemurafenib is a weak inhibitor of CYP2D6 and an inducer of CYP3A4. Oxycodone is a substrate of CYP2D6 and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
    Atazanavir: (Major) Concomitant administration of atazanavir and vemurafenib may increase vemurafenib concentrations and decrease atazanavir concentrations. Atazanavir is a CYP3A4 substrate and inhibitor and vemurafenib is a CYP3A4 substrate and inducer. The manufacturer suggests that strong CYP3A4 inhibitors should be used with caution with vemurafenib.
    Atazanavir; Cobicistat: (Major) Coadministration of cobicistat with vemurafenib is not recommended as there is a potential for elevated vemurafenib concentrations and decreased cobicistat. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Vemurafenib is a CYP3A4 substrate/inducer and a P-glycoprotein (P-gp) substrate. Cobicistat is an inhibitor/substrate of CYP3A4 and P-gp. (Major) Concomitant administration of atazanavir and vemurafenib may increase vemurafenib concentrations and decrease atazanavir concentrations. Atazanavir is a CYP3A4 substrate and inhibitor and vemurafenib is a CYP3A4 substrate and inducer. The manufacturer suggests that strong CYP3A4 inhibitors should be used with caution with vemurafenib.
    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 concenrations of vemurafenib. Vemurafenib is a substrate/inhibitor of P-glycoprotein (PGP) and an inducer of CYP3A4. Atorvastatin is a substrate of PGP and CYP3A4 and an inhibitor of PGP. 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 concenrations of vemurafenib. Vemurafenib is a substrate/inhibitor of P-glycoprotein (PGP) and an inducer of CYP3A4. Atorvastatin is a substrate of PGP and CYP3A4 and an inhibitor of PGP. Use caution and monitor patients for toxicity and efficacy.
    Atropine; Hyoscyamine; Phenobarbital; 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.
    Axitinib: (Moderate) Use caution if coadministration of axitinib with vemurafenib is necessary, due to the risk of decreased efficacy of axitinib. Axitinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2, CYP2C19, and UGT1A1. Vemurafenib is a weak CYP3A4 inducer. Vemurafenib decreased the mean AUC of another CYP3A4 substrate, midazolam, by 39%. Coadministration with a strong CYP3A4/5 inducer, rifampin, significantly decreased the plasma exposure of axitinib in healthy volunteers. Vemurafenib is also a CYP1A2 inhibitor, resulting in 2.6-fold to 4.7-fold increases in the AUC of caffeine and tizanidine, respectively, both primary CYP1A2 substrates. Theoretically exposure to axitinib could increase; however, the effects of vemurafenib on CYP1A2 are not expected to overcome its effects on CYP3A4, as CYP3A4 is the major route of metabolism for axitinib.
    Azithromycin: (Major) Vemurafenib has been associated with QT prolongation. If vemurafenib and another drug, such as azithromycin, 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 may result in increased concentrations of azithromycin and vemurafenib. Both vemurafenib and azithromycin are substrates/inhibitors of P-glycoprotein (P-gp). Use caution and monitor patients for toxicity.
    Basiliximab: (Moderate) Concomitant use of vemurafenib and basiliximab may result in increased vemurafenib concentrations. Vemurafenib is CYP3A4 substrate and basiliximab is a CYP3A4 inhibitor. Use caution and monitor patients for increased side effects.
    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.
    Belladonna Alkaloids; Ergotamine; 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. (Moderate) Vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as ergotamine could be expected with concurrent use. Use caution, and monitor therapeutic effects of ergotamine when coadministered with vemurafenib.
    Bendamustine: (Major) Concomitant use of vemurafenib and bendamustine may result in increased bendamustine concentrations. Vemurafenib is a CYP1A2 inhibitor and bendamustine is a CYP1A2 substrate. Caution should be exercised, or alternative treatments considered, when coadministering bendamustine with a CYP1A2 inhibitor.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include vemurafenib.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include vemurafenib.
    Boceprevir: (Major) The concomitant use of vemurafenib, a CYP3A4 substrate and a P-glycoprotein (P-gp) substrate and inhibitor, and boceprevir, a strong CYP3A4 inhibitor and a P-gp substrate and inhibitor, may result in altered vemurafenib or boceprevir concentrations. Avoid using vemurafenib in combination with potent CYP3A4 inhibitors if possible.
    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.
    Bosentan: (Moderate) Concomitant use of vemurafenib and bosentan may result in altered concentrations of bosentan and decreased concentrations vemurafenib. Vemurafenib is a substrate/inducer of CYP3A4 and an inhibitor of CYP2C9. Bosentan is a substrate/inducer of CYP3A4 and a substrate of CYP2C9. Use caution and monitor patients for toxicity and efficacy.
    Brigatinib: (Moderate) Monitor for decreased efficacy of vemurafenib if coadministration with brigatinib is necessary. Vemurafenib is a CYP3A substrate and brigatinib induces CYP3A in vitro; plasma concentrations of vemurafenib may decrease.
    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; Guaifenesin: (Minor) Coadministration of vemurafenib and dextromethorphan increased the AUC of dextromethorphan by 47% and the dextromethorphan Cmax by 36%. Vemurafenib is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate. The manufacturer of vemurafenib suggests that concomitant use with agents with narrow therapeutic windows that are metabolized by CYP2D6 is not recommended. If coadministration cannot be avoided, the manufacturer recommends considering a dose reduction of the concomitant drug.
    Brompheniramine; 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.
    Brompheniramine; 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.
    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. (Moderate) 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 the long-acting beta-agonists (LABAs). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    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.
    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.
    Caffeine; Ergotamine: (Moderate) Vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as ergotamine could be expected with concurrent use. Use caution, and monitor therapeutic effects of ergotamine when coadministered with vemurafenib.
    Canagliflozin: (Moderate) Canagliflozin is a substrate/weak inhibitor of drug transporter P glycoprotein (P-gp). Vemurafenib is a mild PGP inhibitor and PGP substrate in vitro. Theoretically, concentrations of either drug may be increased. Patients should be monitored for changes in glycemic control and possible adverse reactions.
    Canagliflozin; Metformin: (Moderate) Canagliflozin is a substrate/weak inhibitor of drug transporter P glycoprotein (P-gp). Vemurafenib is a mild PGP inhibitor and PGP substrate in vitro. Theoretically, concentrations of either drug may be increased. Patients should be monitored for changes in glycemic control and possible adverse reactions.
    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.
    Carbetapentane; 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.
    Carbetapentane; 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.
    Carbetapentane; 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.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Minor) Coadministration of vemurafenib and dextromethorphan increased the AUC of dextromethorphan by 47% and the dextromethorphan Cmax by 36%. Vemurafenib is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate. The manufacturer of vemurafenib suggests that concomitant use with agents with narrow therapeutic windows that are metabolized by CYP2D6 is not recommended. If coadministration cannot be avoided, the manufacturer recommends considering a dose reduction of the concomitant drug.
    Carbinoxamine; Hydrocodone; Phenylephrine: (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.
    Carbinoxamine; 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.
    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.
    Ceritinib: (Major) Avoid coadministration of ceritinib with vemurafenib due to increased vemurafenib exposure; additive QT prolongation may also occur. If coadministration is unavoidable, monitor for vemurafenib-related adverse reactions. Closely monitor electrolytes and ECGs; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib is a CYP3A4 inhibitor that causes concentration-dependent prolongation of the QT interval. Vemurafenib is primarily metabolized by CYP3A4 and is also associated with QT prolongation.
    Cevimeline: (Moderate) Concomitant use of vemurafenib and cevimeline may result in altered concentrations of cevimeline. Vemurafenib is a weak inhibitor of CYP2D6 and an inducer of CYP3A4. Cevimeline is a substrate of CYP2D6 and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
    Chloramphenicol: (Moderate) Concomitant use of vemurafenib and chloramphenicol may result in increased vemurafenib concentrations. Vemurafenib is CYP3A4 substrate and chloramphenicol is a CYP3A4 inhibitor. Use caution and monitor patients for increased side effects.
    Chloroquine: (Major) Chloroquine administration is associated with an increased risk of QT prolongation and torsades de pointes (TdP). The need to coadminister chloroquine with drugs known to prolong the QT interval should be done with a careful assessment of risks versus benefits and should be avoided when possible. Vemurafenib has been associated with QT prolongation. If coadministration is necessary, ECG monitoring is recommended; closely monitor the patient for QT interval 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) Coadministration of vemurafenib and dextromethorphan increased the AUC of dextromethorphan by 47% and the dextromethorphan Cmax by 36%. Vemurafenib is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate. The manufacturer of vemurafenib suggests that concomitant use with agents with narrow therapeutic windows that are metabolized by CYP2D6 is not recommended. If coadministration cannot be avoided, the manufacturer recommends considering a dose reduction of the concomitant drug.
    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) Coadministration of vemurafenib and dextromethorphan increased the AUC of dextromethorphan by 47% and the dextromethorphan Cmax by 36%. Vemurafenib is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate. The manufacturer of vemurafenib suggests that concomitant use with agents with narrow therapeutic windows that are metabolized by CYP2D6 is not recommended. If coadministration cannot be avoided, the manufacturer recommends considering a dose reduction of the concomitant drug.
    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; Dihydrocodeine; 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.
    Chlorpheniramine; Guaifenesin; Hydrocodone; 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. (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; 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; Hydrocodone; 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. (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; Hydrocodone; 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. (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; 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.
    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.
    Cinacalcet: (Moderate) Concomitant use of vemurafenib and cinacalcet may result in altered concentrations of cinacalcet. Vemurafenib is an inhibitor of CYP1A2 and CYP2D6 and an inducer of CYP3A4. Cinacalcet is a substrate of CYP1A2, CYP2D6, and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
    Ciprofloxacin: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering vemurafenib with ciprofloxacin. 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, and ciprofloxacin is associated with a possible risk for QT prolongation and TdP.
    Cisapride: (Severe) 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) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with vemurafenib. If coadministration is considered necessary, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Both vemurafenib and clarithromycin are associated with prolongation of the QT interval, while clarithromycin is also associated with an established risk for TdP. Additionally, clarithromycin is a CYP3A4 substrate/inhibitor and P-glycoprotein (P-gp) inhibitor, while vemurafenib is a CYP3A4 substrate/inducer and P-gp substrate/inhibitor. Decreased clarithromycin and increased vemurafenib concentrations may occur with concomitant use
    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) Coadministration of cobicistat with vemurafenib is not recommended as there is a potential for elevated vemurafenib concentrations and decreased cobicistat. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Vemurafenib is a CYP3A4 substrate/inducer and a P-glycoprotein (P-gp) substrate. Cobicistat is an inhibitor/substrate of CYP3A4 and P-gp.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Major) Coadministration of cobicistat with vemurafenib is not recommended as there is a potential for elevated vemurafenib concentrations and decreased cobicistat. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Vemurafenib is a CYP3A4 substrate/inducer and a P-glycoprotein (P-gp) substrate. Cobicistat is an inhibitor/substrate of CYP3A4 and P-gp. (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.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Coadministration of cobicistat with vemurafenib is not recommended as there is a potential for elevated vemurafenib concentrations and decreased cobicistat. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Vemurafenib is a CYP3A4 substrate/inducer and a P-glycoprotein (P-gp) substrate. Cobicistat is an inhibitor/substrate of CYP3A4 and P-gp. (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.
    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 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.
    Colchicine: (Moderate) Concomitant use of vemurafenib and colchicine may result in altered concentrations of colchicine. Vemurafenib is an inhibitor of P-glycoprotein (PGP) and an inducer of CYP3A4. Colchicine is a substrate of PGP and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
    Conivaptan: (Major) Concomitant use of vemurafenib and conivaptan may result in decreased conivaptan concentrations and increased vemurafenib concentrations. Vemurafenib is a CYP3A4 substrate/inducer and conivaptan is a CYP3A4 substrate an a strong CYP3A4 inhibitor. Avoid using these agents together if possible.
    Crizotinib: (Major) Closely monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with vemurafenib. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation; vemurafenib has also been associated with QT prolongation.
    Cyclobenzaprine: (Major) Vemurafenib has been associated with QT prolongation. If vemurafenib and another drug, such as cyclobenzaprine, 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, cyclobenzaprine is a substrate for CYP1A2 and CYP3A4, while vemurafenib is a CYP1A2 inhibitor and CYP3A4 substrate/inducer. Concentrations of cyclobenzaprine may be altered with concomitant use; therefore, patients should be monitored for increased side effects and for drug efficacy.
    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.
    Dalfopristin; Quinupristin: (Major) Concomitant use of vemurafenib and dalfopristin; quinupristin may result in increased vemurafenib concentrations. Vemurafenib is CYP3A4 substrate and quinupristin is a strong CYP3A4 inhibitor. Avoid using these agents together if possible.
    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) Concomitant use of vemurafenib and darunavir may result in decreased concentrations of darunavir and increased concentrations vemurafenib. Vemurafenib is a substrate/inducer of CYP3A4 and a substrate/inhibitor of P-glycoprotein (PGP). Darunavir is a substrate/inhibitor of CYP3A4 and an inhibitor of PGP. Use caution and monitor patients for toxicity and efficacy.
    Darunavir; Cobicistat: (Major) Coadministration of cobicistat with vemurafenib is not recommended as there is a potential for elevated vemurafenib concentrations and decreased cobicistat. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Vemurafenib is a CYP3A4 substrate/inducer and a P-glycoprotein (P-gp) substrate. Cobicistat is an inhibitor/substrate of CYP3A4 and P-gp. (Major) Concomitant use of vemurafenib and darunavir may result in decreased concentrations of darunavir and increased concentrations vemurafenib. Vemurafenib is a substrate/inducer of CYP3A4 and a substrate/inhibitor of P-glycoprotein (PGP). Darunavir is a substrate/inhibitor of CYP3A4 and an inhibitor of PGP. Use caution and monitor patients for toxicity and efficacy.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Severe) Concurrent administration of vemurafenib with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir is contraindicated. Taking these drugs together could result in elevated vemurafenib and ombitasvir plasma concentrations and decreased concentrations of paritaprevir, ritonavir, and dasabuvir, which may affect antiviral efficacy. Additionally, vemurafenib has been associated with QT prolongation, and while dasabuvir; ombitasvir; paritaprevir; ritonavir did not prolong the QT interval to a clinically relevant extent in healthy subjects, ritonavir has been associated with dose-related QT prolongation in other trials. Vemurafenib is a substrate/inducer of CYP3A4, a substrate/inhibitor of P-glycoprotein (P-gp), and an inhibitor of CYP2D6. Ritonavir is a potent inhibitor of CYP3A4 and is metabolized by both CYP3A4 and CYP2D6. Paritaprevir and dasabuvir (minor) are substrates of CYP3A4. Paritaprevir is also a P-gp inhibitor. In addition, dasabuvir, ombitasvir, paritaprevir, and ritonavir are all substrates of P-gp. (Major) Concomitant administration of ritonavir and vemurafenib may increase vemurafenib concentrations and may alter ritonavir concentrations. Ritonavir is a CYP3A4 substrate and strong inhibitor as well as a P-glycoprotein (P-gp) substrate/inhibitor, while vemurafenib is a CYP3A4 substrate/inducer and a P-gp substrate/inhibitor. In addition, both ritonavir and vemurafenib are associated with QT prolongation; concomitant use increases the risk of QT prolongation. Avoid using these agents together if possible.
    Dasatinib: (Major) Vemurafenib has been associated with QT prolongation. If vemurafenib and another drug, such as dasatinib, 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, dasatinib is a CYP3A4 substrate/inhibitor and vemurafenib is a CYP3A4 substrate/inducer. Decreased concentrations of dasatinib and increased concentrations of vemurafenib may occur. Monitor patients for dasatinib efficacy and vemurafenib adverse events.
    Daunorubicin: (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. Acute cardiotoxicity can occur during the administration of daunorubicin; although, the incidence is rare. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported. Concomitant use of vemurafenib and daunorubicin may also result in increased daunorubicin concentrations. Vemurafenib is a P-glycoprotein (P-gp) inhibitor and daunorubicin is a P-gp substrate. Monitor patients for increased side effects.
    Degarelix: (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 degarelix.
    Delavirdine: (Major) Concomitant use of vemurafenib and delavirdine may result in altered concentrations of delavirdine and increased concentrations vemurafenib. Vemurafenib is a substrate/inducer of CYP3A4 and a weak inhibitor of CYP2D6. Delavirdine is a substrate/inhibitor of CYP3A4 and substrate of CYP2D6. Avoid using these agents together if possible.
    Desloratadine: (Minor) Concomitant use of vemurafenib and desloratadine may result in increased desloratadine concentrations. Vemurafenib is a P-glycoprotein (PGP) inhibitor and desloratadine is a PGP substrate. Monitor patients for increased side effects.
    Desloratadine; Pseudoephedrine: (Minor) Concomitant use of vemurafenib and desloratadine may result in increased desloratadine concentrations. Vemurafenib is a P-glycoprotein (PGP) inhibitor and desloratadine is a PGP substrate. Monitor patients for increased side effects.
    Deutetrabenazine: (Major) 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. For patients taking a deutetrabenazine dosage more than 24 mg/day with vemurafenib, assess the QTc interval before and after increasing the dosage of either medication. Clinically relevant QTc prolongation may occur with deutetrabenazine. Vemurafenib has been associated with QT prolongation.
    Dexamethasone: (Major) Concomitant use of vemurafenib and dexamethasone may result in altered concentrations of dexamethasone and decreased concentrations vemurafenib. Vemurafenib is a substrate/inducer of CYP3A4 and a substrate/inhibitor of P-glycoprotein (P-gp). Dexamethasone is a substrate/inducer of CYP3A4 and a substrate of P-gp. Avoid using these agents together if possible.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Minor) Coadministration of vemurafenib and dextromethorphan increased the AUC of dextromethorphan by 47% and the dextromethorphan Cmax by 36%. Vemurafenib is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate. The manufacturer of vemurafenib suggests that concomitant use with agents with narrow therapeutic windows that are metabolized by CYP2D6 is not recommended. If coadministration cannot be avoided, the manufacturer recommends considering a dose reduction of the concomitant drug.
    Dextromethorphan: (Minor) Coadministration of vemurafenib and dextromethorphan increased the AUC of dextromethorphan by 47% and the dextromethorphan Cmax by 36%. Vemurafenib is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate. The manufacturer of vemurafenib suggests that concomitant use with agents with narrow therapeutic windows that are metabolized by CYP2D6 is not recommended. If coadministration cannot be avoided, the manufacturer recommends considering a dose reduction of the concomitant drug.
    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) Coadministration of vemurafenib and dextromethorphan increased the AUC of dextromethorphan by 47% and the dextromethorphan Cmax by 36%. Vemurafenib is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate. The manufacturer of vemurafenib suggests that concomitant use with agents with narrow therapeutic windows that are metabolized by CYP2D6 is not recommended. If coadministration cannot be avoided, the manufacturer recommends considering a dose reduction of the concomitant drug.
    Dextromethorphan; Guaifenesin: (Minor) Coadministration of vemurafenib and dextromethorphan increased the AUC of dextromethorphan by 47% and the dextromethorphan Cmax by 36%. Vemurafenib is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate. The manufacturer of vemurafenib suggests that concomitant use with agents with narrow therapeutic windows that are metabolized by CYP2D6 is not recommended. If coadministration cannot be avoided, the manufacturer recommends considering a dose reduction of the concomitant drug.
    Dextromethorphan; Guaifenesin; Phenylephrine: (Minor) Coadministration of vemurafenib and dextromethorphan increased the AUC of dextromethorphan by 47% and the dextromethorphan Cmax by 36%. Vemurafenib is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate. The manufacturer of vemurafenib suggests that concomitant use with agents with narrow therapeutic windows that are metabolized by CYP2D6 is not recommended. If coadministration cannot be avoided, the manufacturer recommends considering a dose reduction of the concomitant drug.
    Dextromethorphan; Guaifenesin; Potassium Guaiacolsulfonate: (Minor) Coadministration of vemurafenib and dextromethorphan increased the AUC of dextromethorphan by 47% and the dextromethorphan Cmax by 36%. Vemurafenib is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate. The manufacturer of vemurafenib suggests that concomitant use with agents with narrow therapeutic windows that are metabolized by CYP2D6 is not recommended. If coadministration cannot be avoided, the manufacturer recommends considering a dose reduction of the concomitant drug.
    Dextromethorphan; Guaifenesin; Pseudoephedrine: (Minor) Coadministration of vemurafenib and dextromethorphan increased the AUC of dextromethorphan by 47% and the dextromethorphan Cmax by 36%. Vemurafenib is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate. The manufacturer of vemurafenib suggests that concomitant use with agents with narrow therapeutic windows that are metabolized by CYP2D6 is not recommended. If coadministration cannot be avoided, the manufacturer recommends considering a dose reduction of the concomitant drug.
    Dextromethorphan; 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. (Minor) Coadministration of vemurafenib and dextromethorphan increased the AUC of dextromethorphan by 47% and the dextromethorphan Cmax by 36%. Vemurafenib is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate. The manufacturer of vemurafenib suggests that concomitant use with agents with narrow therapeutic windows that are metabolized by CYP2D6 is not recommended. If coadministration cannot be avoided, the manufacturer recommends considering a dose reduction of the concomitant drug.
    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) Coadministration of vemurafenib and dextromethorphan increased the AUC of dextromethorphan by 47% and the dextromethorphan Cmax by 36%. Vemurafenib is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate. The manufacturer of vemurafenib suggests that concomitant use with agents with narrow therapeutic windows that are metabolized by CYP2D6 is not recommended. If coadministration cannot be avoided, the manufacturer recommends considering a dose reduction of the concomitant drug.
    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.
    Dihydroergotamine: (Moderate) Vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as dihydroergotamine, could be expected with concurrent use. Use caution, and monitor therapeutic effects of dihydroergotamine when coadministered with vemurafenib.
    Diltiazem: (Moderate) Concomitant use of vemurafenib and diltiazem may result in altered concentrations of diltiazem and increased concentrations vemurafenib. Vemurafenib is a substrate/inducer of CYP3A4 and a substrate/inhibitor of P-glycoprotein (PGP). Diltiazem is a substrate/inhibitor of CYP3A4 and a substrate/inhibitor of PGP. Use caution and monitor patients for toxicity and efficacy.
    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; Hydrocodone; 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. (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.
    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: (Severe) Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Vemurafenib has been associated with QT prolongation. Because of the potential for TdP, use of vemurafenib with dofetilide is contraindicated.
    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: (Major) Avoid concurrent use of dolutegravir with vemurafenib, as coadministration may result in decreased dolutegravir plasma concentrations. Vemurafenib is an inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme.
    Dolutegravir; Rilpivirine: (Major) Avoid concurrent use of dolutegravir with vemurafenib, as coadministration may result in decreased dolutegravir plasma concentrations. Vemurafenib is an inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme. (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.
    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: (Major) Avoid coadministration of vemurafenib and doxorubicin if possible. If not possible, closely monitor for doxorubicin efficacy and increased side effects of doxorubicin, including myelosuppression and cardiotoxicity. Vemurafenib has a possible risk of causing QT prolongation and torsades de pointes (TdP). Vemurafenib is also a moderate inducer of CYP3A4 and a mild inhibitor of CYP2D6; in vitro, it is also a mild P-glycoprotein (P-gp) inhibitor. Doxorubicin is a major substrate of CYP2D6, CYP3A4, and P-gp. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP2D6 and/or P-gp, resulting in increased concentration and clinical effect of doxorubicin. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Additionally, acute cardiotoxicity can occur during the administration of doxorubicin; although, the incidence is rare. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported.
    Dronabinol, THC: (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: (Severe) 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: (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: (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.
    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.
    Enalapril; 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.
    Encainide: (Major) Caution is recommended when administering encainide with CYP2D6 inhibitors, such as vemurafenib (weak inhibitor), since encainide is a CYP2D6 substrate and exhibits a narrow therapeutic range. Large increases in serum concentrations may be associated with severe adverse reactions. Coadminister these drugs with caution, monitoring clinical response and adjusting encainide dosage if necessary.
    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%.
    Epirubicin: (Major) Acute cardiotoxicity can occur during the administration of epirubicin; although, the incidence is rare. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported. Drugs with a possible risk for QT prolongation and torsades de pointes (TdP) that should be used cautiously with epirubicin include vemurafenib.
    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.
    Ergotamine: (Moderate) Vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as ergotamine could be expected with concurrent use. Use caution, and monitor therapeutic effects of ergotamine 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.
    Erlotinib: (Moderate) Concomitant use of vemurafenib and erlotinib may result in altered concentrations of erlotinib. Vemurafenib is an inhibitor of CYP1A2 and an inducer of CYP3A4. Erlotinib is a substrate of CYP1A2 and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
    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 substrate/inhibitor and a P-glycoprotein (P-gp) substrate/inhibitor, while vemurafenib is a CYP3A4 substrate/inducer and a P-gp substrate/inhibitor. Concentrations of both erythromycin and vemurafenib may be altered with concomitant use.
    Erythromycin; Sulfisoxazole: (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 substrate/inhibitor and a P-glycoprotein (P-gp) substrate/inhibitor, while vemurafenib is a CYP3A4 substrate/inducer 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.
    Esomeprazole; Naproxen: (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.
    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.
    Ester local anesthetics: (Major) Vemurafenib has been associated with QT prolongation. Local anesthetics are agents associated with a possible risk for QT prolongation and torsade de pointes based on varying levels of documentation. 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.
    Eszopiclone: (Moderate) Vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as eszopiclone, could be expected with concurrent use. Use caution, and monitor therapeutic effects of eszopiclone when coadministered with vemurafenib.
    Ethanol: (Major) Concomitant use of vemurafenib and ethanol may result in decreased vemurafenib concentrations. Vemurafenib is a CYP3A4 substrate and ethanol is a CYP3A4 inducer. Use caution and monitor therapeutic effects of 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.
    Etodolac: (Minor) An increased risk of bleeding may occur when NSAIDs, such as etodolac, 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 etodolac concurrently with antineoplastic agents, antithymocyte globulin, or strontium-89 chloride should be monitored closely for bleeding.
    Etoposide, VP-16: (Major) Monitor for clinical efficacy of etoposide as well as an increased incidence of etoposide-related adverse effects if used concomitantly with vemurafenib. Vemurafenib is a CYP3A4 inducer as well as a weak in vitro P-glycoprotein (P-gp) inhibitor; etoposide, VP-16 is a CYP3A4 and P-gp substrate. Coadministration may either increase or decrease etoposide concentrations.
    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.
    Exemestane: (Major) Vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as exemestane, could be expected with concurrent use. Use caution, and monitor therapeutic effects of exemestane when coadministered with vemurafenib.
    Ezetimibe; Simvastatin: (Moderate) Concomitant use of vemurafenib and simvastatin may result in altered concentrations of simvastatin and increased concentrations of vemurafenib. Vemurafenib is a substrate/inducer of CYP3A4, a substrate/inhibitor of P-glycoprotein (PGP), and a weak inhibitor of CYP2D6. Simvastatin is a substrate of CYP3A4 and CYP2D6 and a substrate/inhibitor of PGP. Use caution and monitor patients for toxicity and efficacy.
    Ezogabine: (Major) Vemurafenib has been associated with QT prolongation. Ezogabine is associated with a possible risk for QT prolongation and torsade de pointes based on varying levels of documentation. 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.
    Famotidine; 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.
    Febuxostat: (Major) Coadministration of febuxostat and cytotoxic antineoplastic agents has not been studied. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and calculi.
    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.
    Fenoprofen: (Major) An increased risk of bleeding may occur when NSAIDs, such as fenoprofen, 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 fenoprofen concurrently with antineoplastic agents, antithymocyte globulin, or strontium-89 chloride should be monitored closely for bleeding.
    Fentanyl: (Major) Avoid the concomitant use of vemurafenib and fentanyl; increased fentanyl exposure may occur. If co-administration is unavoidable, consider a fentanyl dose reduction and monitor patients carefully for signs and symptoms of fentanyl toxicity (e.g., respiratory depression, constipation, somnolence). Vemurafenib is a substrate and weak inducer of CYP3A4 and a substrate and inhibitor of P-glycoprotein (P-gp); fentanyl is a CYP3A4 and P-gp substrate with a narrow therapeutic index.
    Fexofenadine: (Minor) Concomitant use of vemurafenib and fexofenadine may result in increased fexofenadine concentrations. Vemurafenib is a P-glycoprotein (P-gp) inhibitor and fexofenadine is a P-gp substrate. Monitor patients for increased side effects.
    Fexofenadine; Pseudoephedrine: (Minor) Concomitant use of vemurafenib and fexofenadine may result in increased fexofenadine concentrations. Vemurafenib is a P-glycoprotein (P-gp) inhibitor and fexofenadine is a P-gp substrate. Monitor patients for increased side effects.
    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: (Severe) 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.
    Fluoxetine; Olanzapine: (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.
    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.
    Fluticasone; Salmeterol: (Moderate) 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 the long-acting beta-agonists (LABAs). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) 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 the long-acting beta-agonists (LABAs). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Fluticasone; Vilanterol: (Moderate) 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 the long-acting beta-agonists (LABAs). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    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.
    Formoterol: (Moderate) 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 the long-acting beta-agonists (LABAs). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Formoterol; Mometasone: (Moderate) 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 the long-acting beta-agonists (LABAs). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    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.
    Gefitinib: (Major) Monitor for clinical response of gefitinib if used concomitantly with vemurafenib. Gefitinib is metabolized significantly by CYP3A4 and vemurafenib is a CYP3A4 inducer; coadministration may increase gefitinib metabolism and decrease gefitinib concentrations. While the manufacturer has provided no guidance regarding the use of gefitinib with mild or moderate CYP3A4 inducers, administration of a single 500 mg gefitinib dose with a concurrent strong CYP3A4 inducer (rifampin) resulted in reduced mean AUC of gefitinib by 83%.
    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.
    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.
    Glimepiride; Pioglitazone: (Major) Concomitant use of vemurafenib and pioglitazone may result in decreased concentrations of both agents. Both are CYP3A4 substrates and inducers. Use caution and monitor patients for therapeutic effects. (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.
    Glimepiride; Rosiglitazone: (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. (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.
    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.
    Glycopyrrolate; Formoterol: (Moderate) 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 the long-acting beta-agonists (LABAs). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Goserelin: (Major) Vemurafenib should be used cautiously and with close monitoring with goserelin. 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 goserelin, must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Androgen deprivation therapy (e.g., goserelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT 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) Concomitant use of vemurafenib and grapefruit juice may result in increased vemurafenib concentrations. Vemurafenib is CYP3A4 and P-glycoprotein (P-gp) substrate and grapefruit juice is a strong CYP3A4 and P-gp inhibitor. Avoid using these agents together.
    Griseofulvin: (Major) Concomitant use of vemurafenib and griseofulvin may result in decreased vemurafenib concentrations. Vemurafenib is a CYP3A4 substrate and griseofulvin is a CYP3A4 inducer. Use caution and monitor therapeutic effects of vemurafenib.
    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.
    Guaifenesin; 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.
    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.
    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.
    Hydrochlorothiazide, HCTZ; 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.
    Hydrochlorothiazide, HCTZ; 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.
    Hydrochlorothiazide, HCTZ; 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.
    Hydrochlorothiazide, HCTZ; 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.
    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; Phenylephrine: (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; Potassium Guaiacolsulfonate: (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; Potassium Guaiacolsulfonate; 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.
    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) Avoid coadministration of hydroxychloroquine and vemurafenib. Hydroxychloroquine increases the QT interval and should not be administered with other drugs known to prolong the QT interval. Ventricular arrhythmias and torsade de pointes (TdP) have been reported with the use of hydroxychloroquine. 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.
    Hydroxyprogesterone: (Major) Vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as hydroxyprogesterone, could be expected with concurrent use. Use caution, and monitor therapeutic effects of hydroxyprogesterone when coadministered with vemurafenib.
    Hydroxyzine: (Major) Post-marketing data indicate that hydroxyzine causes QT prolongation and Torsade de Pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with hydroxyzine include vemurafenib.
    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; 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) Concomitant use of vemurafenib and oxycodone may result in altered concentrations of oxycodone. Vemurafenib is a weak inhibitor of CYP2D6 and an inducer of CYP3A4. Oxycodone is a substrate of CYP2D6 and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
    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.
    Idarubicin: (Major) Acute cardiotoxicity can occur during the administration of idarubicin; although, the incidence is rare. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported. Drugs with a possible risk for QT prolongation and torsades de pointes (TdP) that should be used cautiously with idarubicin include vemurafenib.
    Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with vemurafenib, a CYP3A substrate, as vemurafenib toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
    Ifosfamide: (Minor) Ifosfamide is metabolized in the liver to its active form via CYP3A4 and 2B6; therefore, CYP3A4 inducers, such as vemurafenib, may accelerate the conversion of ifosfamide to its active alkylating metabolites, perhaps increasing the clinical and/or toxic effects of ifosfamide. Use caution, and monitor therapeutic and toxic effects of ifosfamide when coadministered with vemurafenib.
    Iloperidone: (Major) Iloperidone has been associated with QT prolongation; however, torsade de pointes (TdP) has not been reported. According to the manufacturer, since iloperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect, such as vemurafenib. If coadministration is necessary, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Also, iloperidone is a CYP3A4 and CYP2D6 substrate and a P-glycoprotein (P-gp) inhibitor, while vemurafenib is CYP3A4 substrate/inducer, CYP2D6 inhibitor and a P-gp substrate/inhibitor. Concentrations of iloperidone may be increased or decreased and vemurafenib concentrations may be increased with concomitant use.
    Imatinib: (Moderate) Concomitant use of vemurafenib and imatinib, STI-571 may result in altered concentrations of imatinib and increased concentrations of vemurafenib. Vemurafenib is a substrate/inducer of CYP3A4, an inhibitor of CYP2C9, and a substrate/inhibitor P-glycoprotein (PGP). Imatinib is a substrate/inhibitor of CYP3A4 and a substrate of CYP2C9 and PGP. Use caution and monitor patients for toxicity and efficacy.
    Indacaterol: (Moderate) 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 the long-acting beta-agonists (LABAs). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Indacaterol; Glycopyrrolate: (Moderate) 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 the long-acting beta-agonists (LABAs). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Indinavir: (Major) Concomitant administration of indinavir and vemurafenib may increase vemurafenib concentrations and alter indinavir concentrations. Indinavir is a CYP3A4 substrate and strong inhibitor as well as a P-glycoprotein (P-gp) substrate, while vemurafenib is a CYP3A4 substrate/inducer and a P-gp substrate/inhibitor. Avoid using these agents together if possible.
    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.
    Irinotecan: (Major) Vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as irinotecan, could be expected with concurrent use. The manufacturer of irinotecan suggests that CYP3A4 inducers should be stopped 2 weeks prior to the initiation of irinotecan.
    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: (Major) Concomitant use of vemurafenib and isoniazid, INH may result in increased vemurafenib concentrations. Vemurafenib is CYP3A4 substrate and isoniazid is a strong CYP3A4 inhibitor. Avoid using these agents 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. (Major) Concomitant use of vemurafenib and isoniazid, INH may result in increased vemurafenib concentrations. Vemurafenib is CYP3A4 substrate and isoniazid is a strong CYP3A4 inhibitor. Avoid using these agents together.
    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 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. (Major) Concomitant use of vemurafenib and isoniazid, INH may result in increased vemurafenib concentrations. Vemurafenib is CYP3A4 substrate and isoniazid is a strong CYP3A4 inhibitor. Avoid using these agents together.
    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 concurrent administration of itraconazole and vemurafenib due to the potential for additive effects on the QT interval and increased exposure to vemurafenib; consider use of an alternative medication when possible. Both vemurafenib and itraconazole are associated with QT prolongation; coadministration may increase this risk. ECG monitoring is recommended if coadminsitration cannot be avoided. In addition, coadministration of itraconazole (a potent CYP3A4 inhibitor) with vemurafenib (a CYP3A4 substrate) may result in elevated vemurafenib plasma concentrations and an increased risk for adverse events, including QT prolongation. 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.
    Ivabradine: (Major) Avoid coadministration of ivabradine and vemurafenib. Ivabradine is primarily metabolized by CYP3A4; vemurafenib is a weak inducer of CYP3A4. Coadministration may decrease the plasma concentrations of ivabradine resulting in the potential for treatment failure.
    Ivacaftor: (Moderate) Use caution when administering ivacaftor and vemurafenib concurrently; the clinical impact of this interaction has not yet been determined. Administration of ivacaftor with strong CYP3A inducers is not recommended because sub-therapeutic ivacaftor exposure could result. Ivacaftor is a CYP3A substrate and vemurafenib is a CYP3A inducer. Co-administration with rifampin, a strong CYP3A inducer, decreased the ivacaftor exposure by approximately 9-fold. Ivacaftor is also an inhibitor of CYP3A and P-glycoprotein (Pgp); vemurafenib is metabolized by CYP3A and is a substrate of Pgp. Co-administration may increase vemurafenib exposure leading to increased or prolonged therapeutic effects and adverse events.
    Ketoconazole: (Major) Avoid concurrent administration of ketoconazole and vemurafenib due to the potential for additive effects on the QT interval, increased exposure to vemurafenib, and altered ketoconazole concentrations; an alternate drug therapy should be used when possible. Both vemurafenib and ketoconazole are associated with QT prolongation; coadministration may increase this risk. ECG monitoring is recommended if coadminsitration cannot be avoided. In addition, ketoconazole is a strong CYP3A4 inhibitor and substrate as well as a P-glycoprotein (P-gp) inhibitor and substrate, while vemurafenib is a CYP3A4 substrate and inducer and a P-gp substrate and inhibitor. Concomitant administration may increase vemurafenib concentrations and alter ketoconazole concentrations, and result in an increased risk for adverse events.
    Ketoprofen: (Major) An 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 ketoprofen concurrently with antineoplastic agents, antithymocyte globulin, or strontium-89 chloride should be monitored closely for bleeding.
    Ketorolac: (Major) An increased risk of bleeding may also 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 ketorolac concurrently with antineoplastic agents, antithymocyte globulin, or strontium-89 chloride should be monitored closely for bleeding.
    Lansoprazole: (Moderate) Consider an alternative to lansoprazole in patients who are receiving vemurafenib. Coadministration could lead to increased vemurafenib concentrations and, thus, adverse reactions and toxicities. Altered lansoprazole concentrations could also occur. Vemurafenib is a P-glycoprotein (P-gp) substrate/inhibitor and is a CYP3A4 inducer. Lansoprazole is a CYP3A4 substrate and a P-gp substrate/inhibitor.
    Lansoprazole; Naproxen: (Moderate) Consider an alternative to lansoprazole in patients who are receiving vemurafenib. Coadministration could lead to increased vemurafenib concentrations and, thus, adverse reactions and toxicities. Altered lansoprazole concentrations could also occur. Vemurafenib is a P-glycoprotein (P-gp) substrate/inhibitor and is a CYP3A4 inducer. Lansoprazole is a CYP3A4 substrate and a P-gp substrate/inhibitor. (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.
    Lapatinib: (Major) Lapatinib is a CYP3A4 inhibitor at clinically relevant concentrations in vitro. Also, lapatinib is a substrate and inhibitor of the efflux transporter P-glycoprotein (P-gp, ABCB1). Vemurafenib is a CYP3A4 substrate and a P-gp inhibitor. If lapatinib will be coadministered with a CYP3A4 substrate, such as vemurafenib, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Consider dose reduction of vemurafenib. Concurrent administration of lapatinib with a P-gp inhibitor, such as vemurafenib, is likely to cause elevated serum lapatinib concentrations, and caution is recommended. In addition to pharmacokinetic interactions, both lapatinib and vemurafenib can prolong the QT interval; therefore coadministration may further increase the risk for QT prolongation.
    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.
    Lenvatinib: (Major) Vemurafenib should be used cautiously and with close monitoring with lenvatinib. 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. QT prolongation was reported in patients with radioactive iodine-refractory differentiated thyroid cancer (RAI-refractory DTC) in a double-blind, randomized, placebo-controlled clinical trial after receiving lenvatinib daily at the recommended dose; the QT/QTc interval was not prolonged, however, after a single 32 mg dose (1.3 times the recommended daily dose) in healthy subjects.
    Leuprolide: (Major) Vemurafenib has been associated with QT prolongation. If vemurafenib and another drug 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. Androgen deprivation therapy (e.g., leuprolide) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Leuprolide; Norethindrone: (Major) Vemurafenib has been associated with QT prolongation. If vemurafenib and another drug 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. Androgen deprivation therapy (e.g., leuprolide) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Levalbuterol: (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 the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Levofloxacin: (Major) Concurrent use of vemurafenib and levofloxacin 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 Levofloxacin has been associated with prolongation of the QT interval and infrequent cases of arrhythmia. Additionally, rare cases of TdP have been spontaneously reported during postmarketing surveillance in patients receiving levofloxacin. Vemurafenib has also been associated with QT prolongation.
    Lithium: (Major) Lithium should be used cautiously with vemurafenib. Lithium has been associated with QT prolongation. 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.
    Long-acting beta-agonists: (Moderate) 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 the long-acting beta-agonists (LABAs). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Loperamide: (Major) Loperamide should be used cautiously and with close monitoring with vemurafenib. Vemurafenib has been associated with QT prolongation. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. If vemurafenib and loperamide must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. In addition, the plasma concentrations of loperamide, a CYP2D6 and P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with vemurafenib, a CYP2D6 and P-gp inhibitor, further increasing the risk of toxicity. If these drugs are used together, monitor for cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, TdP, cardiac arrest) and other loperamide-associated adverse reactions, such as CNS effects.
    Loperamide; Simethicone: (Major) Loperamide should be used cautiously and with close monitoring with vemurafenib. Vemurafenib has been associated with QT prolongation. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. If vemurafenib and loperamide must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. In addition, the plasma concentrations of loperamide, a CYP2D6 and P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with vemurafenib, a CYP2D6 and P-gp inhibitor, further increasing the risk of toxicity. If these drugs are used together, monitor for cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, TdP, cardiac arrest) and other loperamide-associated adverse reactions, such as CNS effects.
    Lopinavir; Ritonavir: (Major) Concomitant administration of ritonavir and vemurafenib may increase vemurafenib concentrations and may alter ritonavir concentrations. Ritonavir is a CYP3A4 substrate and strong inhibitor as well as a P-glycoprotein (P-gp) substrate/inhibitor, while vemurafenib is a CYP3A4 substrate/inducer and a P-gp substrate/inhibitor. In addition, both ritonavir and vemurafenib are associated with QT prolongation; concomitant use increases the risk of QT prolongation. Avoid using these agents together if possible. (Major) Vemurafenib has been associated with QT prolongation. If vemurafenib and another drug, such as lopinavir; ritonavir, 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, lopinavir is a CYP3A4 substrate and P-glycoprotein (P-gp) inhibitor; ritonavir is a CYP3A4 substrate and potent inhibitor, as well as a P-gp substrate and inhibitor. Vemurafenib is a CYP3A4 substrate/inducer and a P-gp substrate/inhibitor. Concentrations of vemurafenib could be increased and concentrations of lopinavir; ritonavir could be altered. Monitor patients for toxicity and efficacy.
    Loratadine: (Minor) Concomitant use of vemurafenib and loratadine may result in altered concentrations of loratadine. Vemurafenib is an inhibitor of CYP2D6 and P-glycoprotein (PGP) and an inducer of CYP3A4. Loratadine is a substrate of CYP2D6, PGP, and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
    Loratadine; Pseudoephedrine: (Minor) Concomitant use of vemurafenib and loratadine may result in altered concentrations of loratadine. Vemurafenib is an inhibitor of CYP2D6 and P-glycoprotein (PGP) and an inducer of CYP3A4. Loratadine is a substrate of CYP2D6, PGP, and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
    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.
    Lovastatin: (Moderate) Concomitant use of vemurafenib and lovastatin may result in altered concentrations of lovastatin and increased concentrations of vemurafenib. Vemurafenib is a substrate/inducer of CYP3A4 and a substrate/inhibitor of P-glycoprotein (PGP). Lovastatin is a substrate of CYP3A4 and a substrate/inhibitor of PGP. Use caution and monitor patients for toxicity and efficacy.
    Lovastatin; Niacin: (Moderate) Concomitant use of vemurafenib and lovastatin may result in altered concentrations of lovastatin and increased concentrations of vemurafenib. Vemurafenib is a substrate/inducer of CYP3A4 and a substrate/inhibitor of P-glycoprotein (PGP). Lovastatin is a substrate of CYP3A4 and a substrate/inhibitor of PGP. 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. (Moderate) Use caution when administering ivacaftor and vemurafenib concurrently; the clinical impact of this interaction has not yet been determined. Administration of ivacaftor with strong CYP3A inducers is not recommended because sub-therapeutic ivacaftor exposure could result. Ivacaftor is a CYP3A substrate and vemurafenib is a CYP3A inducer. Co-administration with rifampin, a strong CYP3A inducer, decreased the ivacaftor exposure by approximately 9-fold. Ivacaftor is also an inhibitor of CYP3A and P-glycoprotein (Pgp); vemurafenib is metabolized by CYP3A and is a substrate of Pgp. Co-administration may increase vemurafenib exposure leading to increased or prolonged therapeutic effects and adverse events.
    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.
    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
    Meperidine; 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.
    Mesoridazine: (Severe) Vemurafenib has been associated with QT prolongation. Mesoridazine has been specifically established to have a causal association with QT prolongation and torsade de pointes and is contraindicated for use with vemurafenib include.
    Metaproterenol: (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 the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Metformin; Pioglitazone: (Major) Concomitant use of vemurafenib and pioglitazone may result in decreased concentrations of both agents. Both are CYP3A4 substrates and inducers. Use caution and monitor patients for therapeutic effects.
    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.
    Metoclopramide: (Moderate) Concomitant use of vemurafenib and metoclopramide may result in increased metoclopramide concentrations. Metoclopramide is metabolized by CYP2D6 and vemurafenib is a weak CYP2D6 inhibitor. Monitor patients for toxicity.
    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.
    Metronidazole: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include vemurafenib.
    Metyrapone: (Major) Concomitant use of vemurafenib and metyrapone may result in decreased vemurafenib concentrations. Vemurafenib is a CYP3A4 substrate and metyrapone is a CYP3A4 inducer. Use caution and monitor therapeutic effects of vemurafenib.
    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, RU-486: (Major) Avoid co-administration if possible. If vemurafenib and mifepristone must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Vemurafenib has been associated with QT prolongation. Mifepristone has been associated with dose-dependent prolongation of the QT interval. To minimize the risk of QT prolongation, the lowest effective dose of mifepristone should always be used. In addition, vemurafenib is a substrate/weak inducer of CYP3A4 and substrate/inhibitor of P-glycoprotein (P-gp).Mifepristone is a substrate of, and also inhibits CYP3A4 and inhibits P-gp. Altered concentrations of either drug may occur; monitor for vemurafenib toxicity. Because of the prolonged action of mifepristone, the effects on CYP3A and P-gp may be prolonged.
    Mirtazapine: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine 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. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation.
    Mitomycin: (Moderate) Concomitant use of vemurafenib and mitomycin may result in increased mitomycin concentrations. Vemurafenib is a P-glycoprotein (PGP) inhibitor and mitomycin is a PGP substrate. Monitor patients for increased side effects.
    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.
    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.
    Montelukast: (Moderate) Concomitant use of vemurafenib and montelukast may result in altered concentrations of montelukast. Vemurafenib is an inhibitor of CYP2C9 and an inducer of CYP3A4. Montelukast is a substrate of CYP2C9 and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
    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.
    Nabumetone: (Minor) An 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. However, nabumetone may be associated with less risk than other NSAIDs due to its relative minimal platelet inhibitory effects and gastric ulceration or hemorrhagic potential. Patients receiving nabumetone concurrently with antineoplastic agents, antithymocyte globulin, or strontium-89 chloride should be monitored closely for bleeding.
    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; 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.
    Naproxen; Sumatriptan: (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) Concomitant use of vemurafenib and nateglinide may result in altered concentrations of nateglinide. Vemurafenib is an inhibitor of CYP2C9 and an inducer of CYP3A4. Nateglinide is a substrate of CYP2C9 and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
    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) Concomitant administration of nefazodone and vemurafenib may increase vemurafenib concentrations and may decrease nefazodone concentrations. Nefazodone is a CYP3A4 substrate and inhibitor and vemurafenib is a CYP3A4 substrate and inducer. Avoid using these agents together.
    Nelfinavir: (Major) Concomitant administration of nelfinavir and vemurafenib may increase vemurafenib concentrations and may alter nelfinavir concentrations. Nelfinavir is a CYP3A4 substrate/inhibitor and a P-glycoprotein (P-gp) substrate/inhibitor, while vemurafenib is a CYP3A4 substrate/inducer and a P-gp substrate/inhibitor. Avoid using these agents together if possible.
    Niacin; Simvastatin: (Moderate) Concomitant use of vemurafenib and simvastatin may result in altered concentrations of simvastatin and increased concentrations of vemurafenib. Vemurafenib is a substrate/inducer of CYP3A4, a substrate/inhibitor of P-glycoprotein (PGP), and a weak inhibitor of CYP2D6. Simvastatin is a substrate of CYP3A4 and CYP2D6 and a substrate/inhibitor of PGP. Use caution and monitor patients for toxicity and efficacy.
    Nicardipine: (Moderate) Concomitant use of vemurafenib and nicardipine may result in increased vemurafenib concentrations. Vemurafenib is CYP3A4 and P-glycoprotein (PGP) substrate and nicardipine is a CYP3A4 and PGP inhibitor. Use caution and monitor patients for increased side effects.
    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.
    Nifedipine: (Moderate) Concomitant use of vemurafenib and nifedipine may result in decreased concentrations of nifedipine and increased concentrations of vemurafenib. Vemurafenib is a substrate/inducer of CYP3A4 and a substrate/inhibitor of P-glycoprotein (PGP). Nifedipine is a substrate of CYP3A4 and an inhibitor of PGP. Use caution and monitor patients for toxicity and efficacy.
    Nilotinib: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval such as vemurafenib. Nilotinib is a substrate and inhibitor of CYP3A4 and P-glycoprotein (P-gp) and vemurafenib is a CYP3A4 substrate and an inhibitor and substrate of P-gp; nilotinib and/or vemurafenib levels may increase. If the use of vemurafenib is necessary, hold nilotinib therapy. Monitor patients for toxicity (e.g., QT interval prolongation) if these drugs are used together.
    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.
    Nintedanib: (Major) Vemurafenib is a CYP3A4 inducer and, in vitro, a mild P-glycoprotein (P-gp) inducer; nintedanib is a P-gp substrate as well as a minor substrate of CYP3A4. Coadministration of nintedanib with CYP3A4 inducers such as vemurafenib should be avoided as these drugs may decrease exposure to nintedanib and compromise its efficacy.
    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.
    Norfloxacin: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering vemurafenib with norfloxacin. 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. Quinolones have also been associated with QT prolongation and TdP. For norfloxacin specifically, extremely rare cases of TdP were reported during post-marketing surveillance. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Octreotide: (Major) ECG monitoring is recommended if vemurafenib and octreotide must be coadministered; closely monitor the patient for QT interval prolongation. Vemurafenib has been associated with QT prolongation. Arrhythmias, sinus bradycardia, and conduction disturbances have occurred during octreotide therapy. Since bradycardia is a risk factor for development of torsade de pointes (TdP), the potential occurrence of bradycardia during octreotide administration could theoretically increase the risk of TdP in patients receiving drugs that prolong the QT interval.
    Ofloxacin: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering vemurafenib with ofloxacin. 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. Some quinolones, including ofloxacin, have also been associated with QT prolongation. Additionally, post-marketing surveillance for ofloxacin has identified very rare cases of TdP.
    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.
    Olodaterol: (Moderate) 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 the long-acting beta-agonists (LABAs). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Ombitasvir; Paritaprevir; Ritonavir: (Severe) Concurrent administration of vemurafenib with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir is contraindicated. Taking these drugs together could result in elevated vemurafenib and ombitasvir plasma concentrations and decreased concentrations of paritaprevir, ritonavir, and dasabuvir, which may affect antiviral efficacy. Additionally, vemurafenib has been associated with QT prolongation, and while dasabuvir; ombitasvir; paritaprevir; ritonavir did not prolong the QT interval to a clinically relevant extent in healthy subjects, ritonavir has been associated with dose-related QT prolongation in other trials. Vemurafenib is a substrate/inducer of CYP3A4, a substrate/inhibitor of P-glycoprotein (P-gp), and an inhibitor of CYP2D6. Ritonavir is a potent inhibitor of CYP3A4 and is metabolized by both CYP3A4 and CYP2D6. Paritaprevir and dasabuvir (minor) are substrates of CYP3A4. Paritaprevir is also a P-gp inhibitor. In addition, dasabuvir, ombitasvir, paritaprevir, and ritonavir are all substrates of P-gp. (Major) Concomitant administration of ritonavir and vemurafenib may increase vemurafenib concentrations and may alter ritonavir concentrations. Ritonavir is a CYP3A4 substrate and strong inhibitor as well as a P-glycoprotein (P-gp) substrate/inhibitor, while vemurafenib is a CYP3A4 substrate/inducer and a P-gp substrate/inhibitor. In addition, both ritonavir and vemurafenib are associated with QT prolongation; concomitant use increases the risk of QT prolongation. Avoid using these agents together if possible.
    Ondansetron: (Major) Monitor ECG for evidence of QT prolongation if coadministration of ondansetron and vemurafenib is necessary. Vemurafenib has been associated with QT prolongation. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP).
    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.
    Osimertinib: (Major) Closely monitor electrolytes and ECGs for QT prolongation if coadministration of vemurafenib with osimertinib is necessary; an interruption of osimertinib therapy and dose reduction may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib, and vemurafenib has 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.
    Oxaprozin: (Minor) An 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 oxaprozin concurrently with antineoplastic agents, antithymocyte globulin, or strontium-89 chloride should be monitored closely for bleeding.
    Oxcarbazepine: (Major) Concomitant use of vemurafenib and oxcarbazepine may result in decreased vemurafenib concentrations. Vemurafenib is a CYP3A4 substrate and oxcarbazepine is a CYP3A4 inducer. Use caution and monitor therapeutic effects of vemurafenib.
    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) Concomitant use of vemurafenib and oxycodone may result in altered concentrations of oxycodone. Vemurafenib is a weak inhibitor of CYP2D6 and an inducer of CYP3A4. Oxycodone is a substrate of CYP2D6 and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
    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.
    Palbociclib: (Major) Use caution and monitor patients for decreased palbociclib efficacy if vemurafenib is used concomitantly with palbociclib. Palbociclib is a primary substrate of CYP3A and vemurafenib is a moderate CYP3A inducer. In a drug interaction study, coadministration of multiple daily doses of a moderate CYP3A inducer, modafinil, decreased the plasma exposure of a single dose of palbociclib in healthy patients by 32% and the Cmax by 11% (n = 14).
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Paliperidone: (Major) Paliperidone has been associated with QT prolongation; however, torsade de pointes (TdP) has not been reported. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect, such as vemurafenib. However, if coadministration is considered necessary by the practitioner, and the patient has known risk factors for cardiac disease or arrhythmia, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Also, paliperidone is a CYP3A4 substrate and a P-glycoprotein (P-gp) substrate/inhibitor, while vemurafenib is CYP3A4 substrate/inducer and a P-gp substrate/inhibitor. Concentrations of paliperidone may be increased or decreased and vemurafenib concentrations may be increased with concomitant use.
    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.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    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.
    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.
    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.
    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: (Severe) 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: (Major) Concomitant use of vemurafenib and pioglitazone may result in decreased concentrations of both agents. Both are CYP3A4 substrates and inducers. Use caution and monitor patients for therapeutic effects.
    Pirbuterol: (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 the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    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.
    Pomalidomide: (Major) Avoid the concomitant use of pomalidomide and vemurafenib; significantly increased pomalidomide exposure may occur increasing the risk of pomalidomide adverse events. If concomitant use is unavoidable, decrease the pomalidomide dose by 50% and monitor for pomalidomide adverse events. Pomalidomide is a CYP1A2 substrate and vemurafenib is a strong CYP1A2 inhibitor. In healthy volunteers, the Cmax and AUC values for pomalidomide were increased by 24% and 125%, respectively, when pomalidomide was co-administered with a strong CYP1A2 inhibitor.
    Posaconazole: (Severe) Concurrent use of posaconazole and vemurafenib is contraindicated due to the risk of life threatening arrhythmias such as torsade de pointes (TdP). Posaconazole is a CYP3A4 inhibitor and a P-glycoprotein (P-gp) substrate/inhibitor, while vemurafenib is a CYP3A4 substrate/inducer and a P-gp substrate/inhibitor; therefore, increased concentrations of posaconazole and vemurafenib may occur, causing an increased risk for adverse events, such as QT prolongation.
    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.
    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.
    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.
    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) Concurrent use of quetiapine 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. Limited data, including some case reports, suggest that quetiapine may be associated with a significant prolongation of the QTc interval in rare instances. Vemurafenib has also been associated with QT prolongation.
    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.
    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. Altered concentrations of both drugs may occur with concomitant use; therefore, monitor the patient for toxicity and efficacy.
    Rasagiline: (Major) Rasagiline plasma concentrations may increase up to 2 fold in patients using concomitant CYP1A2 inhibitors, such as vemurafenib resulting in the potential for increased adverse events from rasagiline. Dosage adjustments of rasagiline are required when CYP1A2 inhibitors are started in combination with rasagiline (recommended rasagiline dose is 0.5 mg PO once daily). Rasagiline does not have an alternate metabolic pathway other than CYP1A2 and thus these drug interactions may be of clinical significance; closely monitor for increased adverse effects including postural hypotension, hallucinations, dyskinesias, weight loss or xerostomia. If therapy with a CYP1A2 inhibitor is halted, the rasagiline dosage may require adjustment to attain appropriate clinical outcomes.
    Regadenoson: (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 regadenoson.
    Regorafenib: (Moderate) Use caution if coadministration of regorafenib with vemurafenib is necessary, and monitor for an increase in vemurafenib-related adverse reactions or a possible decrease in the efficacy of regorafenib. Vemurafenib is a BCRP substrate and regorafenib is a BCRP inhibitor. Regorafenib-mediated BCRP inhibition may increase exposure to vemurafenib. Additionally, vemurafenib is a weak inducer of CYP3A4 and regorafenib is a CYP3A4 substrate. Information is not available for coadministration of regorafenib with weak CYP3A4 inducers such as vemurafenib, but regorafenib exposure may decrease.
    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 coadministration of ribociclib with vemurafenib due to an increased risk for QT prolongation. If vemurafenib and ribociclib must be coadministered, ECG monitoring is recommended. Systemic exposure of vemurafenib may also be increased resulting in increase in treatment-related adverse reactions. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Vemurafenib has also been associated with QT prolongation. Concomitant use may increase the risk for QT prolongation. Ribociclib is also a moderate CYP3A4 inhibitor and vemurafenib is a CYP3A4 substrate.
    Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with vemurafenib due to an increased risk for QT prolongation. If vemurafenib and ribociclib must be coadministered, ECG monitoring is recommended. Systemic exposure of vemurafenib may also be increased resulting in increase in treatment-related adverse reactions. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Vemurafenib has also been associated with QT prolongation. Concomitant use may increase the risk for QT prolongation. Ribociclib is also a moderate CYP3A4 inhibitor and vemurafenib is a CYP3A4 substrate.
    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) Concomitant administration of rifapentine and vemurafenib may decrease vemurafenib concentrations. Rifapentine is a CYP3A4 inducer and vemurafenib is a CYP3A4 substrate. Avoid using these agents together.
    Rifaximin: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and vemurafenib, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    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.
    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) Concomitant administration of ritonavir and vemurafenib may increase vemurafenib concentrations and may alter ritonavir concentrations. Ritonavir is a CYP3A4 substrate and strong inhibitor as well as a P-glycoprotein (P-gp) substrate/inhibitor, while vemurafenib is a CYP3A4 substrate/inducer and a P-gp substrate/inhibitor. In addition, both ritonavir and vemurafenib are associated with QT prolongation; concomitant use increases the risk of QT prolongation. Avoid using these agents together if possible.
    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.
    Salmeterol: (Moderate) 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 the long-acting beta-agonists (LABAs). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Sapropterin: (Moderate) Caution is advised with the concomitant use of sapropterin and vemurafenib as coadministration may result in increased systemic exposure of vemurafenib. Vemurafenib is a substrate for the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); in vitro data show that sapropterin may inhibit these transporters. If these drugs are used together, closely monitor for increased side effects of vemurafenib, such as QT prolongation.
    Saquinavir: (Severe) 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 (TdP). Vemurafenib is a P-glycoprotein (P-gp) inhibitor, which may lead to increased serum concentrations of saquinavir when given concomitantly, thus increasing the risk of drug toxicity and proarrhythmic effects. Additionally, saquinavir boosted with ritonavir causes dose-dependent QT and PR prolongation; avoid use with other drugs that may prolong the QT or PR interval, such as vemurafenib
    Sertraline: (Major) Concomitant use of vemurafenib and sertraline may result in altered concentrations of sertraline. Vemurafenib is an inhibitor of CYP2C9 and CYP2D6 and an inducer of CYP3A4. Sertraline is a substrate of CYP2C9, CYP2D6, and CYP3A4. Use caution and monitor patients for toxicity and efficacy. There have been post-marketing reports of QT prolongation and Torsade de Pointes (TdP) during treatment with sertraline; therefore, caution is advisable when using sertraline in patients with risk factors for QT prolongation, including concurrent use of other drugs that prolong the QTc interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with sertraline include vemurafenib.
    Short-acting beta-agonists: (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 the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Sildenafil: (Moderate) Concomitant use of vemurafenib and sildenafil may result in altered concentrations of sildenafil. Vemurafenib is an inhibitor of CYP2C9 and an inducer of CYP3A4. Sildenafil is a substrate of CYP2C9 and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
    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.
    Simeprevir: (Major) Avoid concurrent use of simeprevir and vemurafenib as the interaction is complex. Induction of CYP3A4 by vemurafenib may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure. However, vemurafenib is also a P-glycoprotein (P-gp) inhbitor, while simeprevir is P-gp substrate in vitro. Additionally, simeprevir, a mild intestinal CYP3A4 inhibitor and P-gp inhibitor, may increase the side effects of vemurafenib, which is a CYP3A4 and P-gp substrate. Monitor patients for adverse effects of vemurafenib, such as QT prolongation.
    Simvastatin: (Moderate) Concomitant use of vemurafenib and simvastatin may result in altered concentrations of simvastatin and increased concentrations of vemurafenib. Vemurafenib is a substrate/inducer of CYP3A4, a substrate/inhibitor of P-glycoprotein (PGP), and a weak inhibitor of CYP2D6. Simvastatin is a substrate of CYP3A4 and CYP2D6 and a substrate/inhibitor of PGP. Use caution and monitor patients for toxicity and efficacy.
    Simvastatin; Sitagliptin: (Moderate) Concomitant use of vemurafenib and simvastatin may result in altered concentrations of simvastatin and increased concentrations of vemurafenib. Vemurafenib is a substrate/inducer of CYP3A4, a substrate/inhibitor of P-glycoprotein (PGP), and a weak inhibitor of CYP2D6. Simvastatin is a substrate of CYP3A4 and CYP2D6 and a substrate/inhibitor of PGP. Use caution and monitor patients for toxicity and efficacy.
    Sipuleucel-T: (Major) Concomitant use of sipuleucel-T and antineoplastic agents should be avoided. Concurrent administration of antineoplastic agents with the leukapheresis procedure that occurs prior to sipuleucel-T infusion has not been studied. Sipuleucel-T stimulates the immune system and patients receiving antineoplastic agents may have a diminished response to sipuleucel-T. When appropriate, consider discontinuing or reducing the dose of antineoplastic agents prior to initiating therapy with sipuleucel-T.
    Sirolimus: (Major) Concomitant use of vemurafenib and sirolimus may result in altered concentrations of sirolimus. Vemurafenib is an inhibitor of P-glycoprotein (PGP) and an inducer of CYP3A4. Sirolimus is a substrate of PGP and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
    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) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering sorafenib with vemurafenib. If these drugs must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Both sorafenib and vemurafenib have been associated with QT prolongation. Additionally, vemurafenib is a P-glycoprotein (P-gp) substrate and sorafenib is a P-gp inhibitor in vitro; coadministration may increase vemurafenib concentrations.
    Sotalol: (Major) Vemurafenib has been associated with QT prolongation. Sotalol administration is associated with QT prolongation and torsades de pointes (TdP). Proarrhythmic events should be anticipated after initiation of therapy and after each upward dosage adjustment. If vemurafenib and sotalol must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation.
    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.
    Streptogramins: (Major) Concomitant use of vemurafenib and dalfopristin; quinupristin may result in increased vemurafenib concentrations. Vemurafenib is CYP3A4 substrate and quinupristin is a strong CYP3A4 inhibitor. Avoid using these agents together if possible.
    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.
    Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Major) QT prolongation resulting in ventricular tachycardia and torsade de pointes (TdP) have been reported during post-marketing use of sulfamethoxazole; trimethoprim. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with sulfamethoxazole; trimethoprim include vemurafenib.
    Sulindac: (Minor) An 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 sulindac concurrently with antineoplastic agents, antithymocyte globulin, or strontium-89 chloride should be monitored closely for bleeding.
    Sunitinib: (Major) Vemurafenib has been associated with QT prolongation. If vemurafenib and another drug, such as sunitinib, 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, sunitinib is a CYP3A4 substrate, while vemurafenib is a CYP3A4 substrate and inducer. Decreased concentrations of sunitinib may occur with concomitant use; therefore, patients should be monitored for efficacy.
    Suvorexant: (Major) Suvorexant is primarily metabolized by CYP3A, and decreased systemic exposure of suvorexant may occur during concurrent use with strong CYP3A inducers such as vemurafenib. Patients should be monitored for a reduction in efficacy if this combination is necessary.
    Tacrine: (Moderate) Vemurafenib may increase the bioavailability and peak plasma concentrations of tacrine secondary to inhibition of the CYP1A2 isoenzyme. Practitioners should monitor patients for signs of increased cholinergic-related side effects.
    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.
    Tamoxifen: (Major) Caution is advised with the concomitant use of tamoxifen and vemurafenib due to an increased risk of QT prolongation; increased vemurafenib and tamoxifen exposure and reduced tamoxifen efficacy are also possible. If coadministration is necessary, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation and decreased efficacy of tamoxifen. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Vemurafenib has been associated with QT prolongation. Vemurafenib may reduce the conversion of tamoxifen to other potent active metabolites via inhibition of CYP2D6. Tamoxifen may also increase exposure to vemurafenib via inhibition of P-glycoprotein (P-gp).
    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.
    Telaprevir: (Major) Concomitant use of vemurafenib and telaprevir may result in altered concentrations of telaprevir and increased concentrations of vemurafenib. Vemurafenib is a substrate/inducer of CYP3A4 and a substrate/inhibitor of P-glycoprotein (P-gp). Telaprevir is a substrate/inhibitor of CYP3A4 and P-gp. Avoid using these agents together if possible.
    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.
    Telithromycin: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering telithromycin with vemurafenib. If these drugs must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Telithromycin is associated with QT prolongation and TdP. Vemurafenib has also been associated with QT prolongation. Additionally, telithromycin is an inhibitor of CYP3A4 and P-glycoprotein (P-gp), while vemurafenib is a substrate of both enzymes. Therefore, increased concentrations of vemurafenib may occur.
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and vemurafenib is necessary, as the systemic exposure of vemurafenib may be decreased resulting in reduced efficacy; exposure to telotristat ethyl may also be increased. If these drugs are used together, monitor patients for suboptimal efficacy of vemurafenib as well as an increase in adverse reactions related to telotristat ethyl. Vemurafenib is a CYP3A4 substrate in vitro. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate. Additionally, the active metabolite of telotristat ethyl, telotristat, is a substrate of P-glycoprotein (P-gp) and vemurafenib is a P-gp inhibitor. Exposure to telotristat ethyl may increase.
    Temsirolimus: (Moderate) Use caution if coadministration of temsirolimus with vemurafenib is necessary, and monitor for an increase in temsirolimus- and vemurafenib-related adverse reactions. Temsirolimus is a P-glycoprotein (P-gp) substrate/inhibitor in vitro, while vemurafenib is also a P-gp substrate/inhibitor. Pharmacokinetic data are not available for concomitant use of temsirolimus with P-gp inhibitors or substrates, but exposure to both vemurafenib and temsirolimus (and active metabolite, sirolimus) is likely to increase. 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.
    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, PMPA: (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.
    Terbutaline: (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 the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Testosterone: (Moderate) Concomitant use of vemurafenib and testosterone may result in altered concentrations of testosterone and increased concentrations of vemurafenib. Vemurafenib is a substrate/inducer of CYP3A4 and a substrate/inhibitor of P-glycoprotein (PGP).Testosterone is a substrate of CYP3A4 and a substrate/inhibitor of PGP. Use caution and monitor patients for toxicity and efficacy.
    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.
    Thiabendazole: (Moderate) Concomitant use of vemurafenib and thiabendazole may result in increased thiabendazole concentrations. Vemurafenib is a CYP1A2 inhibitor and thiabendazole is a CYP1A2 substrate. Patients should be monitored for toxicity.
    Thioridazine: (Severe) 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.
    Tiotropium; Olodaterol: (Moderate) 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 the long-acting beta-agonists (LABAs). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Tipranavir: (Major) The concomitant use of vemurafenib, a CYP3A4 substrate and a P-glycoprotein (P-gp) substrate and inhibitor, and tipranavir, a strong CYP3A4 inhibitor and a P-gp substrate and inducer, may result in altered vemurafenib or tipranavir concentrations. Avoid using these agents together if possible.
    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.
    Tolmetin: (Minor) An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia due to decreases in platelet aggregation. Notable interactions may occur with myelosuppressive antineoplastic agents, antithymocyte globulin, and strontium-89 chloride. Patients receiving tolmetin concurrently with antineoplastic agents, antithymocyte globulin, or strontium-89 chloride should be monitored closely for bleeding.
    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.
    Tolvaptan: (Moderate) Concomitant use of vemurafenib and tolvaptan may result in altered concentrations of tolvaptan and increased concentrations of vemurafenib. Vemurafenib is a substrate/inducer of CYP3A4 and a substrate/inhibitor of P-glycoprotein (PGP). Tolvaptan is a substrate of CYP3A4 and a substrate/inhibitor of PGP. 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 the concomitant use of vemurafenib, a weak, in vitro P-glycoprotein (P-gp) inhibitor, with oral topotecan, a P-gp substrate; P-gp inhibitors have less of an effect on intravenous topotecan and these may be coadministered with caution. If coadministration of vemurafenib and oral topotecan is necessary, carefully monitor for increased toxicity of topotecan, including severe myelosuppression and diarrhea. In a pharmacokinetic cohort study, coadministration of oral topotecan with a potent P-gp inhibitor (n = 8) increased the Cmax and AUC of topotecan by 2 to 3 fold (p = 0.008); coadministration with intravenous topotecan (n = 8) increased total topotecan exposure by 1.2-fold (p = 0.02) and topotecan lactone by 1.1-fold (not significant).
    Toremifene: (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 toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
    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.
    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) Avoid coadministration of trazodone and vemurafenib. If vemurafenib and trazodone must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Vemurafenib has been associated with QT prolongation. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval. In addition, concomitant use of vemurafenib and trazodone may result in altered concentrations of trazodone. Vemurafenib is a weak inhibitor of CYP2D6 and an inducer of CYP3A4. Trazodone is a substrate of CYP2D6 and CYP3A4.
    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.
    Triazolam: (Moderate) Vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as triazolam, could be expected with concurrent use. Use caution, and monitor therapeutic effects of triazolam when coadministered with vemurafenib.
    Tricyclic antidepressants: (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 and TdP that should be used cautiously with vemurafenib include tricyclic antidepressants.
    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) Androgen deprivation therapy (e.g., triptorelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with triptorelin include vemurafenib.
    Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
    Ulipristal: (Minor) In vitro data indicate that ulipristal may be an inhibitor of P-glycoprotein (P-gp) at clinically relevant concentrations. Thus, co-administration of ulipristal and P-gp substrates such as vemurafenib may increase vemurafenib concentrations; use caution. In the absence of clinical data, co-administration of ulipristal (when given daily) and P-gp substrates is not recommended.
    Umeclidinium; Vilanterol: (Moderate) 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 the long-acting beta-agonists (LABAs). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Valdecoxib: (Minor) An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia due to decreases in platelet aggregation. Notable interactions may occur with myelosuppressive antineoplastic agents, antithymocyte globulin, and strontium-89 chloride. However, valdecoxib may be associated with less risk than other NSAIDs due to its lack of platelet inhibitory effects and minimal gastric ulceration or hemorrhagic potential.
    Vandetanib: (Major) The manufacturer of vandetanib recommends avoiding coadministration with other drugs that prolong the QT interval due to an increased risk of QT prolongation and torsade de pointes (TdP). Additionally, changes in the serum concentration of vandetanib as well as an increase in side effects from vemurafenib are possible if these drugs are coadministered. Vandetanib can prolong the QT interval in a concentration-dependent manner. TdP and sudden death have been reported in patients receiving vandetanib; vemurafenib also has a possible risk for QT prolongation. If coadministration is necessary, an ECG is needed, as well as more frequent monitoring of the QT interval. If QTcF is greater than 500 msec, interrupt vandetanib dosing until the QTcF is less than 450 msec; then, vandetanib may be resumed at a reduced dose. Vemurafenib is a weak inducer of CYP3A4. In a crossover study (n = 12), coadministration of vandetanib with a strong CYP3A4 inducer decreased the mean AUC of vandetanib by 40% (90% CI, 56% to 63%); a clinically meaningful change in the mean vandetanib Cmax was not observed. However, the AUC and Cmax of active metabolite, N-desmethyl-vandetanib, increased by 266% and 414%, respectively. Finally, vemurafenib is an in vitro substrate of P-glycoprotein (P-gp); coadministration with vandetanib increased the Cmax and AUC of another P-gp substrate by 29% and 23%, respectively.
    Vardenafil: (Major) Vemurafenib has been associated with QT prolongation. If vemurafenib and another drug, such as vardenafil, 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, vardenafil is a CYP3A4 substrate, while vemurafenib is a CYP3A4 substrate/inducer. Therefore concentrations of vardenafil may be decreased with concomitant use. Monitor patients for efficacy.
    Venetoclax: (Major) Avoid the concomitant use of venetoclax and vemurafenib. Venetoclax is a substrate of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) and may be a P-gp inhibitor at therapeutic dose levels in the gut; vemurafenib is an inhibitor of P-gp and BCRP and a P-gp substrate. Consider alternative agents. If concomitant use of these drugs is required, reduce the venetoclax dosage by at least 50% (maximum dose of 200 mg/day) and consider administering vemurafenib at least 6 hours before venetoclax. If vemurafenib is discontinued, wait 2 to 3 days and then resume the recommended venetoclax dosage (or prior dosage if less). Monitor patients for signs and symptoms of venetoclax toxicity such as hematologic toxicity, GI toxicity, and tumor lysis syndrome. In a drug interaction study (n = 11), the venetoclax Cmax and AUC values were increased by 106% and 78%, respectively, when a P-gp inhibitor was co-administered in healthy subjects.
    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.
    Vinblastine: (Moderate) Concomitant use of vemurafenib and vinblastine may result in altered concentrations of vinblastine. Vemurafenib is an inhibitor of P-glycoprotein (PGP) and an inducer of CYP3A4.Vinblastine is a substrate of PGP and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
    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.
    Vinorelbine: (Moderate) Caution is warranted when vemurafenib is administered with vinorelbine, as there is a potential for the metabolism of vinorelbine to be affected, decreasing drug efficacy. Patients receiving this drug concurrently with vinorelbine should be monitored for clinical effects. Vinorelbine is a substrate for cytochrome P450 (CYP) 3A4 and vemurafenib is a CYP3A4 inducer.
    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 concurrent administration of voriconazole and vemurafenib due to the potential for additive effects on the QT interval and increased exposure to vemurafenib; consider use of an alternative medication when possible. Both vemurafenib and voriconazole are associated with QT prolongation; coadministration may increase this risk. Voriconazole has also been associated with rare cases of torsades de pointes, cardiac arrest, and sudden death. ECG monitoring is recommended if coadminsitration cannot be avoided. In addition, coadministration of voriconazole (a CYP3A4 inhibitor) with vemurafenib (a CYP3A4 substrate) may result in elevated vemurafenib plasma concentrations and an increased risk for adverse events, including QT prolongation. Rigorous attempts to correct any electrolyte abnormalities (i.e., potassium, magnesium, calcium) should be made before initiating concurrent therapy.
    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: (Minor) Vemurafenib may alter warfarin concentrations. Coadministration of vemurafenib and S-warfarin increased the AUC of S-warfarin by 18%. Vemurafenib is a CYP2C9 inhibitor and S-warfarin is a CYP2C9 substrate. R-warfarin is a substrate of CYP1A2, 3A4, and 2D6. Vemurafenib is a an inhibitor of CYP1A2 and 2D6 as well as a substrate/induce of CYP3A4. Caution is warranted with concomitant use; frequent monitoring of the INR appears prudent.
    Zafirlukast: (Moderate) Concomitant use of vemurafenib and zafirlukast may result in increased concentrations of zafirlukast and vemurafenib. Vemurafenib is a substrate of CYP3A4 and an inhibitor of CYP2C9. Zafirlukast is an inhibitor of CYP3A4 and a substrate of CYP2C9. Use caution and monitor patients for toxicity.
    Zileuton: (Minor) Concomitant use of vemurafenib and zileuton may result in altered concentrations of zileuton. Vemurafenib is an inhibitor of CYP1A2 and an inducer of CYP3A4. Zileuton is a substrate of CYP1A2 and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
    Ziprasidone: (Severe) According to the manufacturer, ziprasidone is contraindicated with any drugs that list QT prolongation as a pharmacodynamic effect when this effect has been described within the contraindications or bolded or boxed warnings of the official labeling for such drugs. Ziprasidone has been associated with a possible risk for QT prolongation and/or torsades de pointes (TdP). Clinical trial data indicate that ziprasidone causes QT prolongation. In one study, ziprasidone increased the QT interval 10 msec more than placebo at the maximum recommended dosage. Comparative data with other antipsychotics have shown that the mean QTc interval prolongation occurring with ziprasidone exceeds that of haloperidol, quetiapine, olanzapine, and risperidone, but is less than that which occurs with thioridazine. Given the potential for QT prolongation, ziprasidone is contraindicated for use with drugs that are known to cause QT prolongation with potential for torsades de pointes including vemurafenib.
    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.
    Zonisamide: (Moderate) Coadministration of vemurafenib and zonisamide may result in decreased zonisamide concentrations and increased vemurafenib concentrations. Vemurafenib is an inducer of CYP3A4 and a substrate of P-glycoprotein (P-gp). Zonisamide is a weak inhibitor of P-glycoprotein (P-gp) and a substrate of CYP3A4. Caution and close monitoring are advised if these drugs are administered together.

    PREGNANCY AND LACTATION

    Pregnancy

    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.

    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 > 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, CYP2D6, CYP3A4, P-gp
    Vemurafenib is a CYP3A4 substrate. Avoid the concomitant use of vemurafenib with strong CYP3A4 inhibitors and inducers; increase the vemurafenib dose by 240 mg (as tolerated) if use with a strong CYP3A4 inducer cannot be avoided. In vitro, vemurafenib is both a substrate and an inhibitor of the efflux transporters P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP). In vivo, vemurafenib was a moderate CYP1A2 inhibitor (mean caffeine AUC increased 2.6-fold), 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. Additionally, coadministration of vemurafenib with digoxin, a P-gp substrate, led to a 1.8-fold increase in digoxin exposure. Avoid the concomitant use of vemurafenib with narrow therapeutic index drugs that are P-gp substrates or predominantly metabolized by CYP1A2; consider a dose reduction of these drugs and monitor patients closely for toxicity if coadministration is necessary. 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.

    Oral Route

    The bioavailability of orally administered vemurafenib has not been determined. 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.