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Vemurafenib

Generic name: vemurafenib systemic

Brand names: Zelboraf

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Zelboraf: 240 mg

Pharmacology

Mechanism of Action

Vemurafenib is a low molecular weight oral BRAF kinase inhibitor (potent) which inhibits tumor growth in melanomas by inhibiting kinase activity of certain mutated forms of BRAF, including BRAF with V600E mutation, thereby blocking cellular proliferation in melanoma cells with the mutation. Does not have activity against cells with wild-type BRAF. BRAF V600E activating mutations are present in ~50% of melanomas; V600E mutation involves the substitution of glutamic acid for valine at amino acid 600.

Pharmacokinetics/Pharmacodynamics

Distribution

Vd: ~106 L

Excretion

Feces (~94%); urine (~1%)

Time to Peak

~3 hours

Half-Life Elimination

57 hours (range: 30 to 120 hours)

Protein Binding

>99%, to albumin and α1-acid glycoprotein

Use: Labeled Indications

Melanoma, unresectable or metastatic: Treatment of unresectable or metastatic melanoma in patients with a BRAFV600E mutation (as detected by an approved test)

Limitations of use: Not indicated for treatment of wild-type BRAF melanoma

Erdheim-Chester disease: Treatment of Erdheim-Chester disease (ECD) in patients with a BRAF V600 mutation

Use: Off Label

Melanoma, metastatic (with BRAFV600K mutation)b

Data from a phase III, randomized study which included a subset of patients with BRAF V600K mutation supports the use of vemurafenib in the treatment of BRAF V600K mutated metastatic melanoma Chapman 2011. Data from a multicenter, phase II study also supports the use of vemurafenib in the setting of previously treated BRAF V600K mutated metastatic melanoma; partial responses and stable disease were observed among the subset of patients with a V600K mutation Sosman 2012.

Non-small cell lung cancer, refractory (with BRAF V600 mutation)c

Data from a phase II study in patients with various cancers with BRAF V600 mutations, including a small number of patients with BRAF V600-mutated non-small cell lung cancer (NSCLC) supports the use of vemurafenib in the management of NSCLC which is refractory to standard therapy or for which standard/curative therapy does not exist or is inappropriate Hyman 2015. In this study, the most common mutation observed was BRAF V600E. Additional data may be necessary to further define the role of vemurafenib in this condition.

Contraindications

There are no contraindications listed in the manufacturer's US labeling.

Canadian labeling: Hypersensitivity to vemurafenib or any component of the formulation.

Dosage and Administration

Dosing: Adult

Melanoma, metastatic or unresectable (with BRAF V600E mutation): Oral: 960 mg every 12 hours; continue until disease progression or unacceptable toxicity.

Erdheim-Chester disease (with BRAF V600 mutation): Oral: 960 mg every 12 hours; continue until disease progression or unacceptable toxicity.

Missed doses: A missed dose may be taken up to 4 hours prior to the next scheduled dose. If it is within 4 hours of the next scheduled dose, administer the next dose at the regular schedule. If vomiting occurs after a dose is taken, do not take an additional dose; continue with the next scheduled dose.

Melanoma, metastatic or unresectable (with BRAF V600K mutation) (off-label use): Oral: 960 mg every 12 hours; continue until disease progression or unacceptable toxicity (Chapman 2011; Sosman 2012).

Melanoma, metastatic or unresectable (with BRAF V600E or V600K mutations) (off-label combination): Oral: 960 mg every 12 hours (in combination with cobimetinib); continue until disease progression or unacceptable toxicity (Larkin 2014).

Non-small cell lung cancer, refractory (with BRAF V600 mutation) (off-label use): Oral: 960 mg twice daily (Hyman 2015). Additional data may be necessary to further define the role of vemurafenib in this condition.

Dosage adjustment for concomitant strong CYP3A4 inducers: Avoid concomitant use of strong CYP3A4 inducers. If concurrent use of a strong CYP3A4 inducer (eg, carbamazepine, phenytoin, rifampin) cannot be avoided, increase the vemurafenib dose by 240 mg as tolerated. After the strong CYP3A4 inducer has been discontinued for 2 weeks, resume the vemurafenib dose that was used prior to initiating the CYP3A4 inducer.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Adjustment for Toxicity

Note: Do not dose reduce below 480 mg twice daily. NCI Common Terminology Criteria for Adverse Events (CTC-AE) version 4.0 used for adverse event grades.

Grade 1 or grade 2 (tolerable) toxicity: No dosage adjustment recommended.

Grade 2 (intolerable) or grade 3 toxicity:

First incident: Interrupt treatment until toxicity returns to grade 0 or 1, then resume at 720 mg twice daily

Second incident: Interrupt treatment until toxicity returns to grade 0 or 1, then resume at 480 mg twice daily

Third incident: Discontinue permanently.

Grade 4 toxicity:

First incident: Interrupt treatment until toxicity returns to grade 0 or 1, then resume at 480 mg twice daily or discontinue permanently

Second incident: Discontinue permanently.

Specific toxicities:

New primary cutaneous malignancies: No dosage adjustment recommended.

Severe hypersensitivity or severe dermatologic toxicity: Discontinue permanently.

QTc interval changes:

QTc >500 msec (grade ≥3): Temporarily withhold treatment, correct electrolytes and control risk factors for QT prolongation; may reinitiate with a dose reduction once QTc ≤500 msec (≤ grade 2).

QTc persistently >500 msec and >60 msec above baseline: Discontinue permanently.

Administration

Doses should be administered orally in the morning and evening, ~12 hours apart. May be taken with or without a meal. If vomiting occurs after a dose is taken, do not take an additional dose; continue with the next scheduled dose.

Swallow whole with a glass of water; do not crush or chew. There are case reports of vemurafenib administration after crushing (Janson 2013; Khimani 2014), however vemurafenib is nearly insoluble in water and is manufactured as a microprecipitated bulk powder core (to improve solubility/bioavailability) within a film coated tablet (Shah 2013). Pharmacokinetics and efficacy of administration other than swallowing tablets whole have not been determined.

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C and 30°C (59°F and 86°F). Store in the original container with the lid tightly closed.

Drug Interactions

Afatinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib. Management: Reduce afatinib by 10 mg if not tolerated. Some non-US labeling recommends avoiding combination if possible. If used, administer the P-gp inhibitor simultaneously with or after the dose of afatinib. Consider therapy modification

Agomelatine: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Agomelatine. Monitor therapy

Alosetron: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Alosetron. Management: Avoid concomitant use of alosetron and moderate CYP1A2 inhibitors whenever possible. If combined use is necessary, monitor for increased alosetron effects/toxicities. Consider therapy modification

Aminolevulinic Acid (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Systemic). Avoid combination

Aminolevulinic Acid (Topical): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Topical). Monitor therapy

Aprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

ARIPiprazole: CYP2D6 Inhibitors (Weak) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult full interaction monograph for specific recommendations. Monitor therapy

Bendamustine: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Bendamustine. Management: Consider alternatives to moderate CYP1A2 inhibitors during therapy with bendamustine due to the potential for increased bendamustine plasma concentrations and increased bendamustine toxicity. Consider therapy modification

Betrixaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Betrixaban. Management: Decrease the adult betrixaban dose to an initial single dose of 80 mg followed by 40 mg once daily if combined with a P-glycoprotein inhibitor. Consider therapy modification

Bilastine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Bilastine. Management: Consider alternatives when possible; bilastine should be avoided in patients with moderate to severe renal insufficiency who are receiving p-glycoprotein inhibitors. Consider therapy modification

Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Brentuximab Vedotin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be increased. Monitor therapy

Bromazepam: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Bromazepam. Monitor therapy

Caffeine and Caffeine Containing Products: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Caffeine and Caffeine Containing Products. Monitor therapy

Celiprolol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Celiprolol. Monitor therapy

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

ClomiPRAMINE: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of ClomiPRAMINE. Monitor therapy

CloZAPine: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of CloZAPine. Monitor therapy

CloZAPine: CYP3A4 Inducers (Weak) may decrease the serum concentration of CloZAPine. Monitor therapy

Colchicine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Colchicine. Colchicine distribution into certain tissues (e.g., brain) may also be increased. Management: Colchicine is contraindicated in patients with impaired renal or hepatic function who are also receiving a p-glycoprotein inhibitor. In those with normal renal and hepatic function, reduce colchicine dose as directed. See full monograph for details. Consider therapy modification

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Vemurafenib. Management: Avoid concurrent use of vemurafenib with a strong CYP3A4 inducer and replace with another agent when possible. If a strong CYP3A4 inducer is indicated and unavoidable, the dose of vemurafenib may be increased by 240 mg (1 tablet) as tolerated. Consider therapy modification

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Vemurafenib. Management: Avoid concurrent use of vemurafenib with strong CYP3A4 inhibitors when possible. Consider use of an alternative that is not a strong inhibitor of CYP3A4 as clinically appropriate. Exceptions: Ceritinib; Clarithromycin; Saquinavir; Voriconazole. Consider therapy modification

Dabigatran Etexilate: P-glycoprotein/ABCB1 Inhibitors may increase serum concentrations of the active metabolite(s) of Dabigatran Etexilate. Monitor therapy

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Digoxin: Vemurafenib may increase the serum concentration of Digoxin. Management: Avoid coadministration of vemurafenib and digoxin when possible. If concomitant use cannot be avoided, consider digoxin dose reduction. Consider therapy modification

Domperidone: QT-prolonging Agents (Moderate Risk) may enhance the QTc-prolonging effect of Domperidone. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

DOXOrubicin (Conventional): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to P-glycoprotein inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification

DULoxetine: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of DULoxetine. Monitor therapy

Duvelisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Edoxaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban. Management: See full monograph for details. Reduced doses are recommended for patients receiving edoxaban for venous thromboembolism in combination with certain P-gp inhibitors. Similar dose adjustment is not recommended for edoxaban use in atrial fibrillation. Consider therapy modification

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Erdafitinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

Everolimus: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Everolimus. Monitor therapy

Fexinidazole [INT]: May enhance the QTc-prolonging effect of QT-prolonging Agents (Moderate Risk). Avoid combination

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fosnetupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Haloperidol: QT-prolonging Kinase Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Haloperidol. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Ipilimumab: May enhance the hepatotoxic effect of Vemurafenib. Management: Consider alternatives to this combination when possible. Use of this combination should only be undertaken with extra close monitoring of liver function (hepatic transaminases and bilirubin) and signs/symptoms of hepatotoxicity. Consider therapy modification

Larotrectinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Larotrectinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Larotrectinib. Monitor therapy

Lasmiditan: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Avoid combination

Lefamulin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Lefamulin. Management: Avoid concomitant use of lefamulin tablets with P-glycoprotein/ABCB1 inhibitors. If concomitant use is required, monitor for lefamulin adverse effects. Consider therapy modification

Lorlatinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences. Consider therapy modification

Melatonin: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Melatonin. Monitor therapy

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

Mitotane: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Naldemedine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naldemedine. Monitor therapy

Naloxegol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naloxegol. Monitor therapy

Netupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

NiMODipine: CYP3A4 Inducers (Weak) may decrease the serum concentration of NiMODipine. Monitor therapy

OLANZapine: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of OLANZapine. Monitor therapy

Ondansetron: May enhance the QTc-prolonging effect of QT-prolonging Kinase Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

PAZOPanib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of PAZOPanib. Avoid combination

Pentamidine (Systemic): May enhance the QTc-prolonging effect of QT-prolonging Kinase Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

Pentoxifylline: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Pentoxifylline. Monitor therapy

Perhexiline: CYP2D6 Inhibitors (Weak) may increase the serum concentration of Perhexiline. Monitor therapy

P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

P-glycoprotein/ABCB1 Substrates: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Exceptions: Loperamide. Monitor therapy

Pimozide: May enhance the QTc-prolonging effect of QT-prolonging Agents (Moderate Risk). Avoid combination

Pirfenidone: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Pirfenidone. Management: Avoid concomitant use of pirfenidone and moderate CYP1A2 inhibitors whenever possible. If combined, decrease the pirfenidone dose to 1,602 mg per day (534 mg three times daily) and monitor for increased pirfenidone toxicities. Consider therapy modification

Pomalidomide: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Pomalidomide. Monitor therapy

Porfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer. Monitor therapy

Propranolol: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Propranolol. Monitor therapy

Prucalopride: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Prucalopride. Monitor therapy

QT-prolonging Agents (Highest Risk): May enhance the QTc-prolonging effect of Vemurafenib. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Consider therapy modification

QT-prolonging Antidepressants (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Kinase Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

QT-prolonging Antipsychotics (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Kinase Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Exceptions: Pimozide. Monitor therapy

QT-prolonging Class IC Antiarrhythmics (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Kinase Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

QT-prolonging Kinase Inhibitors (Moderate Risk): May enhance the QTc-prolonging effect of other QT-prolonging Kinase Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

QT-prolonging Miscellaneous Agents (Moderate Risk): QT-prolonging Kinase Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Exceptions: Domperidone. Monitor therapy

QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Kinase Inhibitors (Moderate Risk). QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of QT-prolonging Kinase Inhibitors (Moderate Risk). Monitor therapy

QT-prolonging Quinolone Antibiotics (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Kinase Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk): Vemurafenib may enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Vemurafenib. Management: Avoid concomitant use of vemurafenib and strong CYP3A4 inhibitors that prolong the QTc interval whenever possible. If combined monitor patients for vemurafenib toxicities including QTc prolongation and TdP. Consider therapy modification

Ramelteon: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Ramelteon. Monitor therapy

Ramosetron: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Ramosetron. Monitor therapy

Ranolazine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Ranolazine. Monitor therapy

Ranolazine: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

Rasagiline: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Rasagiline. Management: Limit rasagiline dose to 0.5 mg once daily in patients taking moderate CYP1A2 inhibitors. Consider therapy modification

RifAXIMin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of RifAXIMin. Monitor therapy

ROPINIRole: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of ROPINIRole. Monitor therapy

Ropivacaine: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Ropivacaine. Monitor therapy

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Silodosin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Silodosin. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Talazoparib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Talazoparib. Management: These listed exceptions are discussed in detail in separate interaction monographs. Monitor therapy

Tasimelteon: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Tasimelteon. Monitor therapy

Tegaserod: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Tegaserod. Monitor therapy

Theophylline Derivatives: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Theophylline Derivatives. Management: Consider avoidance of this combination. If coadministration is necessary, monitor for increased theophylline serum concentrations and toxicities when combined. Theophylline dose reductions will likely be required. Exceptions: Dyphylline. Consider therapy modification

TiZANidine: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of TiZANidine. Management: If combined use cannot be avoided, initiate tizanidine in adults at 2 mg and increase in 2 to 4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Consider therapy modification

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Topotecan: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Topotecan. Avoid combination

Ubrogepant: CYP3A4 Inducers (Weak) may decrease the serum concentration of Ubrogepant. Management: Use an initial ubrogepant dose of 100 mg and second dose (if needed) of 100 mg when used with a weak CYP3A4 inducer. Consider therapy modification

Ubrogepant: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Ubrogepant. Management: Use an initial ubrogepant dose of 50 mg and second dose (if needed) of 50 mg when used with a P-gp inhibitor. Consider therapy modification

Venetoclax: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Venetoclax. Management: Consider a venetoclax dose reduction by at least 50% in patients requiring concomitant treatment with P-glycoprotein (P-gp) inhibitors. Consider therapy modification

Verteporfin: Photosensitizing Agents may enhance the photosensitizing effect of Verteporfin. Monitor therapy

VinCRIStine (Liposomal): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of VinCRIStine (Liposomal). Avoid combination

Warfarin: Vemurafenib may increase the serum concentration of Warfarin. Monitor therapy

Adverse Reactions

>10%:

Cardiovascular: Prolonged Q-T interval on ECG (≤55%), hypertension (≤36%), peripheral edema (17% to 23%)

Central nervous system: Fatigue (38% to ≤55%), peripheral sensory neuropathy (≤36%), headache (23% to 27%)

Dermatologic: Maculopapular rash (9% to ≤59%), alopecia (36% to ≤55%), skin rash (37% to 52%), hyperkeratosis (24% to ≤50%; seborrheic: 10% to ≤41%; pilaris: ≤32%; actinic: 8% to ≤32%), skin photosensitivity (33% to 49%), xeroderma (16% to ≤45%), palmar-plantar erythrodysesthesia (≤41%), pruritus (23% to ≤36%), nevus (≤23%), sunburn (10% to ≤23%), papular rash (5% to ≤23%), erythema (8% to 14%)

Gastrointestinal: Diarrhea (28% to ≤50%), nausea (≤32% to 37%), vomiting (18% to 26%), decreased appetite (18% to 21%), constipation (12% to 16%), dysgeusia (11% to 14%)

Hematologic & oncologic: Cutaneous papilloma (21% to ≤55%), keratoacanthoma (≤41%), squamous cell carcinoma of skin (≤41%; grade 3: 22% to ≤36%)

Hepatic: Increased gamma-glutamyl transferase (5% to 15%)

Neuromuscular & skeletal: Arthralgia (53% to ≤82%), myalgia (13% to 24%), limb pain (9% to 18%), back pain (8% to 11%), musculoskeletal pain (8% to 11%), weakness (2% to 11%)

Renal: Increased serum creatinine (up to 3x ULN: 26% to 86%; greater than 3x ULN: 1% to 9%)

Respiratory: Cough (8% to ≤36%)

Miscellaneous: Fibrosis (Dupuytren contracture) (<20%), fever (17% to 19%)

1% to 10%:

Cardiovascular: Atrial fibrillation, hypotension, vasculitis

Central nervous system: Cranial nerve palsy (facial), dizziness, peripheral neuropathy

Dermatologic: Erythema nodosum, folliculitis, Stevens-Johnson syndrome, toxic epidermal necrolysis

Endocrine & metabolic: Weight loss

Hematologic & oncologic: Basal cell carcinoma, malignant melanoma (new primary), squamous cell carcinoma (oropharyngeal)

Hepatic: Increased serum ALT (≥ grade 3: 3% to ≤9%), increased serum alkaline phosphatase (≥ grade 3: 3% to ≤5%), increased serum bilirubin (≥ grade 3: 2%)

Hypersensitivity: Anaphylaxis, hypersensitivity reaction

Neuromuscular & skeletal: Arthritis, panniculitis

Ophthalmic: Blurred vision, iritis, photophobia, retinal vein occlusion, uveitis

Frequency not defined: Hematologic & oncologic: Secondary acute myelocytic leukemia

<1%, postmarketing, and/or case reports: Acute interstitial nephritis, acute tubular necrosis, chronic myelomonocytic leukemia with NRAS mutation (progression of preexisting condition), DRESS syndrome, hepatic injury, increased serum AST, local acneiform eruptions (Ansai 2016), neutropenia, pancreatitis, plantar fasciitis, recall skin sensitization

Warnings/Precautions

Concerns related to adverse effects:

  • Dermatologic toxicity: Dermatologic reactions have been observed, including case reports of Stevens-Johnson syndrome and toxic epidermal necrolysis. Discontinue (permanently) for severe dermatologic toxicity.
  • Fibroproliferative disease: Cases of Dupuytren contracture and plantar fascial fibromatosis have been reported with vemurafenib use (Chan 2015; Perez 2017; Vandersleyen 2016). In June of 2017, the vemurafenib manufacturer issued a “Dear Healthcare Provider” letter stating that the majority of cases reported were mild to moderate, although disabling Dupuytren contracture cases have been observed. The median time to onset was 224 days from therapy initiation; the majority of patients experienced symptom resolution or improvement with interruption or discontinuation of vemurafenib (Perez 2017). Per the manufacturer, fibromatoses may require therapy interruption or treatment discontinuation.
  • Hepatotoxicity: Liver injury has been reported with use, and may cause functional impairment such as coagulopathy or other organ dysfunction. Monitor transaminases, alkaline phosphatase, and bilirubin at baseline and monthly during therapy, or as clinically necessary. May require dosage reduction, therapy interruption, or discontinuation.
  • Hypersensitivity: Anaphylaxis and severe hypersensitivity may occur during treatment or upon reinitiation. Serious reactions have included generalized rash, erythema, hypotension, and drug rash with eosinophilia and systemic symptoms (DRESS syndrome). Discontinue (permanently) with severe hypersensitivity reaction.
  • Malignancies: Cutaneous squamous cell carcinomas (cuSCC), keratoacanthomas, and melanoma have been reported (at a higher rate in patients receiving vemurafenib compared to control). Cutaneous SCC generally occurs early in the treatment course (median onset: 7 to 8 weeks in melanoma patients and ~12 weeks in Erdheim Chester disease [ECD] patients) and is managed with excision (while continuing vemurafenib treatment). Approximately one-third of melanoma patients experienced >1 cuSCC occurrence and the median time between occurrences was 6 weeks. Potential risk factors for cuSCC include age ≥65 years, history of skin cancer, or chronic sun exposure. Monitor for skin lesions (with dermatology evaluation) at baseline and every 2 months during treatment; consider continued monitoring for 6 months after treatment. In patients receiving vemurafenib for the treatment of melanoma, new primary malignant melanomas have been reported (rare). Noncutaneous squamous cell carcinomas (non-cuSCC) of the head and neck have also been observed; monitor closely for signs/symptoms. Vemurafenib may promote malignancies correlated with RAS activation; monitor for signs/symptoms of other malignancies. Myeloid malignancies in patients with ECD have been reported, including patients receiving vemurafenib; monitor CBC in patients with ECD and co-existing myeloid malignancies.
  • Nephrotoxicity: Acute kidney injury, including interstitial nephritis, acute tubular necrosis, and serum creatinine elevations (grades 1 to 4) have been reported. Monitor serum creatinine.
  • Ocular toxicity: Uveitis (including iritis), blurred vision, and photophobia may occur; monitor for signs and symptoms. Uveitis may be managed with corticosteroid and mydriatic eye drops. Retinal vein occlusion has been reported in clinical trials.
  • Pancreatitis: Pancreatitis has been reported (rare). Onset occurs within 2 weeks after initiation, with exacerbation occurring upon rechallenge at a reduced dose (Muluneh 2013). Consider evaluating unexplained abdominal pain for pancreatitis (eg, serum lipase and amylase; abdominal CT) as clinically indicated.
  • Photosensitivity: Photosensitivity ranging from mild to severe has been reported. Advise patients to avoid sun exposure and wear protective clothing and use effective UVA/UVB sunscreen and lip balm (SPF ≥30) when outdoors. Dosage modifications are recommended for intolerable photosensitivity consisting of erythema ≥10% to 30% of body surface area.
  • QT prolongation: QT prolongation (dose-dependent) has been observed; may lead to increased risk for ventricular arrhythmia, including torsade de pointes. Monitor electrolytes (calcium, magnesium and potassium) at baseline and with dosage adjustments. Monitor ECG at baseline, 15 days after initiation, then monthly for 3 months, then every 3 months thereafter (more frequently if clinically appropriate); also monitor with dosage adjustments. Do not initiate treatment if baseline QTc >500 msec. During treatment, if QTc >500 msec, temporarily interrupt treatment; correct electrolytes and control other risk factors for QT prolongation. May reinitiate with a dose reduction once QTc falls to <500 msec. Discontinue (permanently), if after correction of risk factors, both the QTc continues to increase >500 msec and there is >60 msec change above baseline. Do not initiate treatment in patients with electrolyte abnormalities which are not correctable, long QT syndrome, or taking concomitant medication known to prolong the QT interval.
  • Radiation sensitization/recall: Radiation sensitization and recall (some cases may be severe or involve cutaneous and visceral organs) have been reported in patients treated with radiation prior to, during, or after treatment with vemurafenib; fatal cases have been reported in patients with visceral organ involvement. Monitor closely when vemurafenib is administered concomitantly or sequentially with radiation treatment.

Concurrent drug therapy issues:

  • Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

  • Elderly: May be at increased risk for adverse effects; in clinical trials, there was an increased incidence of cuSCC and keratoacanthoma, atrial fibrillation, peripheral edema, and nausea/decreased appetite in patients ≥65 years.

Other warnings/precautions:

  • BRAF genomics: Only patients with a BRAF V600 mutation-positive melanoma (including BRAF V600E) will benefit from treatment; mutation must be detected and confirmed by an approved test prior to treatment. The cobas 4800 BRAF V600 Mutation Test was used in clinical trials and is FDA-approved to detect BRAF V600E mutation.

Monitoring Parameters

Confirm BRAF V600 mutation status (in patients with melanoma); liver transaminases, alkaline phosphatase and bilirubin at baseline and monthly during treatment (or as clinically appropriate). Serum creatinine at baseline and periodically during treatment. Electrolytes (calcium, magnesium and potassium) at baseline and after dosage modification. ECG at baseline, 15 days after initiation, then monthly for 3 months, then every 3 months thereafter (more frequently if clinically appropriate) and with dosage adjustments. Dermatology evaluation (for new skin lesions) at baseline and every 2 months during treatment; also consider continued monitoring for 6 months after completion of treatment. Signs/symptoms of hypersensitivity reactions, uveitis, and malignancies; signs of radiation sensitization and recall. Monitor adherence.

Pregnancy

Pregnancy Considerations

Vemurafenib crosses the placenta. Based on the mechanism of action, vemurafenib may cause fetal harm if administered during pregnancy. Women of reproductive potential should use effective contraception during treatment and for at least 2 weeks after the last dose.

Patient Education

What is this drug used for?

  • It is used to treat a type of skin cancer (melanoma).
  • It is used to treat a type of blood cell cancer called Erdheim-Chester disease (ECD).
  • It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

  • Hair loss
  • Joint pain
  • Muscle pain
  • Itching
  • Back pain
  • Nausea
  • Vomiting
  • Diarrhea
  • Constipation
  • Change in taste
  • Loss of strength and energy
  • Lack of appetite
  • Cough
  • Dry skin

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

  • Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain.
  • Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin.
  • Severe headache
  • Dizziness
  • Passing out
  • Fast heartbeat
  • Abnormal heartbeat
  • Swelling of arms or legs
  • Mole changes
  • Skin growths
  • Redness or irritation of palms of hands or soles of feet
  • Skin changes
  • Burning or numbness feeling
  • Vision changes
  • Eye pain
  • Severe eye irritation
  • Inward bending of fingers
  • Stevens-Johnson syndrome/toxic epidermal necrolysis like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in mouth, throat, nose, or eyes.
  • Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Source: Wolters Kluwer Health. Last updated February 8, 2020.