Erdheim-Chester disease, with BRAF V600 mutation: Oral: 960 mg every 12 hours; continue until disease progression or unacceptable toxicity.
Melanoma, metastatic or unresectable:
With BRAF V600E mutation: Oral: 960 mg every 12 hours; continue until disease progression or unacceptable toxicity.
With BRAF V600K mutation (off-label use): Oral: 960 mg every 12 hours; continue until disease progression or unacceptable toxicity (Chapman 2011; Sosman 2012). Refer to protocol for dosage modification details.
With BRAF V600 mutations (off-label combinations): Oral:
In combination with cobimetinib: 960 mg every 12 hours; continue until disease progression or unacceptable toxicity (Larkin 2014). Refer to protocol for dosage modification details.
In combination with cobimetinib and atezolizumab:
Cycle 1 (with cobimetinib only): 960 mg every 12 hours on days 1 to 21 of a 28-day cycle, followed by 720 mg every 12 hours on days 22 to 28 of cycle 1 (Gutzmer 2020).
Cycle 2 and beyond (with cobimetinib and atezolizumab): 720 mg every 12 hours until disease progression or unacceptable toxicity (Gutzmer 2020). Refer to protocol for further information.
Non-small cell lung cancer, refractory, with BRAF V600 mutation (off-label use; based on limited data): Oral: 960 mg twice daily (Hyman 2015). Refer to protocol for dosage modification details.
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.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult Drug Interactions database for more information.
Mild to moderate impairment (preexisting): No dosage adjustment necessary.
Severe impairment (preexisting): There are no dosage adjustments provided in the manufacturer's labeling (data are insufficient to determine if dosage adjustment is necessary); use with caution.
Nephrotoxicity/creatinine abnormalities during treatment: Refer to dosage adjustment for toxicity and manage with dose reduction, treatment interruption, or discontinuation.
Mild to moderate impairment (preexisting): No dosage adjustment necessary.
Severe impairment (preexisting): There are no dosage adjustments provided in manufacturer's labeling (data are insufficient to determine if dosage adjustment is necessary); use with caution.
Hepatotoxicity/lab abnormalities during treatment: Refer to dosage adjustment for toxicity and manage with dose reduction, treatment interruption, or discontinuation.
Refer to adult dosing.
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.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Zelboraf: 240 mg
No
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Zelboraf: 240 mg
Available through specialty pharmacies. Further information may be obtained from the manufacturer, Genentech, at 1-888-249-4918, or at http://www.zelboraf.com.
An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/202429s016lbl.pdf#page=21, must be dispensed with this medication.
Oral: 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.
Hazardous agent (NIOSH 2016 [group 1]).
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).
Melanoma, unresectable or metastatic, with BRAF 600E mutation: Treatment of unresectable or metastatic melanoma in patients with a BRAF V600E mutation (as detected by an approved test)
Limitations of use: Not indicated for treatment of wild-type BRAF melanoma
Erdheim-Chester disease, with BRAF V600 mutation: Treatment of Erdheim-Chester disease (ECD) in patients with a BRAF V600 mutation
Melanoma, metastatic, with BRAF V600K mutation; Non-small cell lung cancer, refractory, with BRAF V600 mutation
Vemurafenib may be confused with axitinib, cabozantinib, cobimetinib, dabrafenib, encorafenib, ponatinib, regorafenib, SORAfenib, trametinib, vandetanib, venetoclax, vismodegib
This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%:
Cardiovascular: Prolonged QT 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, 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, retinal vein occlusion
There are no contraindications listed in the manufacturer's US labeling.
Canadian labeling: Hypersensitivity to vemurafenib or any component of the formulation.
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.
Special populations:
• Older adult: 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.
Substrate of BCRP/ABCG2, CYP3A4 (major), P-glycoprotein/ABCB1 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits CYP1A2 (moderate), CYP2D6 (weak), P-glycoprotein/ABCB1; Induces CYP3A4 (weak)
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Afatinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib. Management: If combined, administer the P-gp inhibitor simultaneously with, or after, the dose of afatinib. Monitor closely for signs and symptoms of afatinib toxicity and if the combination is not tolerated, reduce the afatinib dose by 10 mg. Risk D: Consider therapy modification
Agomelatine: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Agomelatine. Risk C: Monitor therapy
Aliskiren: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Aliskiren. Risk C: 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. Risk D: Consider therapy modification
Aminolevulinic Acid (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Systemic). Risk X: Avoid combination
Aminolevulinic Acid (Topical): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Topical). Risk C: Monitor therapy
Amisulpride (Oral): May enhance the QTc-prolonging effect of QT-prolonging Agents (Moderate Risk). Risk C: Monitor therapy
Anagrelide: CYP1A2 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Anagrelide. CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Anagrelide. Risk C: Monitor therapy
Androgens: Hypertension-Associated Agents may enhance the hypertensive effect of Androgens. Risk C: Monitor therapy
Azithromycin (Systemic): QT-prolonging Kinase Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Azithromycin (Systemic). 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. Risk C: 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. Risk D: Consider therapy modification
Berotralstat: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Berotralstat. Management: Decrease the berotralstat dose to 110 mg daily when combined with P-glycoprotein (P-gp) inhibitors. Risk D: Consider therapy modification
Bilastine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Bilastine. Risk X: Avoid combination
Bromazepam: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Bromazepam. Risk C: Monitor therapy
Caffeine and Caffeine Containing Products: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Caffeine and Caffeine Containing Products. Risk C: Monitor therapy
Celiprolol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Celiprolol. Risk C: Monitor therapy
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
ClomiPRAMINE: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of ClomiPRAMINE. Risk C: Monitor therapy
CloZAPine: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of CloZAPine. Risk C: Monitor therapy
CloZAPine: CYP3A4 Inducers (Weak) may decrease the serum concentration of CloZAPine. Risk C: 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-gp inhibitor. In those with normal renal and hepatic function, reduce colchicine dose as directed. See interaction monograph for details. Risk D: Consider therapy modification
CycloSPORINE (Systemic): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy
CYP3A4 Inducers (Moderate): May decrease the serum concentration of Vemurafenib. Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May decrease the serum concentration of Vemurafenib. Management: Avoid coadministration of vemurafenib and strong CYP3A4 inducers if possible. If coadministration is unavoidable, increase the vemurafenib dose by 240 mg as tolerated. Resume prior vemurafenib dose 2 weeks after discontinuation of strong CYP3A4 inducer. Risk D: Consider therapy modification
CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Vemurafenib. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Vemurafenib. Management: Avoid concurrent use of vemurafenib with strong CYP3A4 inhibitors when possible. If concomitant use is unavoidable, consider a vemurafenib dose reduction if clinically indicated. Risk D: Consider therapy modification
Dabigatran Etexilate: P-glycoprotein/ABCB1 Inhibitors may increase serum concentrations of the active metabolite(s) of Dabigatran Etexilate. Risk C: Monitor therapy
Dabrafenib: May enhance the QTc-prolonging effect of Vemurafenib. Dabrafenib may decrease the serum concentration of Vemurafenib. Management: Monitor for decreased vemurafenib efficacy, QTc interval prolongation and ventricular arrhythmias, including torsades de pointes when these agents are combined. Risk C: Monitor therapy
Digoxin: Vemurafenib may increase the serum concentration of Digoxin. Management: Avoid coadministration of vemurafenib and digoxin when possible. If combined, measure digoxin levels and reduce digoxin concentrations by either reducing the digoxin dose by 30% to 50% or by modifying the dosing frequency. Risk D: 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. Risk D: Consider therapy modification
DOXOrubicin (Conventional): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of DOXOrubicin (Conventional). Risk X: Avoid combination
DOXOrubicin (Liposomal): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of DOXOrubicin (Liposomal). Risk C: Monitor therapy
DULoxetine: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of DULoxetine. Risk C: Monitor therapy
Edoxaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban. Risk C: Monitor therapy
Etoposide: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Etoposide. Risk C: Monitor therapy
Etoposide Phosphate: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Etoposide Phosphate. Risk C: Monitor therapy
Everolimus: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Everolimus. Risk C: Monitor therapy
Fexinidazole: QT-prolonging Kinase Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Fexinidazole. 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. Risk C: Monitor therapy
Fluorouracil Products: 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. Risk C: Monitor therapy
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Glecaprevir and Pibrentasvir: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Glecaprevir and Pibrentasvir. Risk C: Monitor therapy
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. Risk C: Monitor therapy
Hormonal Contraceptives: CYP3A4 Inducers (Weak) may decrease the serum concentration of Hormonal Contraceptives. Management: Advise patients to use an alternative method of contraception or a back-up method during coadministration, and to continue back-up contraception for 28 days after discontinuing a weak CYP3A4 inducer to ensure contraceptive reliability. Risk D: Consider therapy modification
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. Risk D: Consider therapy modification
Lapatinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Lapatinib. Risk C: Monitor therapy
Larotrectinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Larotrectinib. Risk C: Monitor therapy
Lefamulin: May enhance the QTc-prolonging effect of QT-prolonging CYP3A4 Substrates. Management: Do not use lefamulin tablets with QT-prolonging CYP3A4 substrates. Lefamulin prescribing information lists this combination as contraindicated. Risk X: Avoid combination
Levoketoconazole: QT-prolonging CYP3A4 Substrates may enhance the QTc-prolonging effect of Levoketoconazole. Levoketoconazole may increase the serum concentration of QT-prolonging CYP3A4 Substrates. Risk X: Avoid combination
Melatonin: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Melatonin. Risk C: Monitor therapy
Methoxsalen (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Methoxsalen (Systemic). Risk C: Monitor therapy
Midostaurin: 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. Risk C: Monitor therapy
Morphine (Systemic): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Morphine (Systemic). Risk C: Monitor therapy
Nadolol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Nadolol. Risk C: Monitor therapy
Naldemedine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naldemedine. Risk C: Monitor therapy
Naloxegol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naloxegol. Risk C: Monitor therapy
NiMODipine: CYP3A4 Inducers (Weak) may decrease the serum concentration of NiMODipine. Risk C: Monitor therapy
OLANZapine: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of OLANZapine. Risk C: 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. Risk C: Monitor therapy
PAZOPanib: Vemurafenib may enhance the QTc-prolonging effect of PAZOPanib. Vemurafenib may increase the serum concentration of PAZOPanib. Risk X: 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. Risk C: Monitor therapy
Pentoxifylline: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Pentoxifylline. Risk C: Monitor therapy
Pimozide: May enhance the QTc-prolonging effect of QT-prolonging Agents (Moderate Risk). Risk X: 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. Risk D: Consider therapy modification
Pomalidomide: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Pomalidomide. Risk C: Monitor therapy
Porfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer. Risk C: Monitor therapy
Posaconazole: May increase the serum concentration of QT-prolonging CYP3A4 Substrates. Such increases may lead to a greater risk for proarrhythmic effects and other similar toxicities. Risk X: Avoid combination
Propranolol: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Propranolol. Risk C: 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. Risk D: 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. Risk C: 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. Risk C: 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. Risk C: Monitor therapy
QT-Prolonging Inhalational Anesthetics (Moderate Risk): QT-prolonging Kinase Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of QT-Prolonging Inhalational Anesthetics (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. Risk C: 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. Risk C: 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. Risk C: 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). Risk C: 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. Risk C: Monitor therapy
QT-prolonging Strong CYP3A4 Inhibitors (Highest Risk): May enhance the QTc-prolonging effect of Vemurafenib. QT-prolonging Strong CYP3A4 Inhibitors (Highest 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, and consider a vemurafenib dose reduction. Risk D: Consider therapy modification
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, and consider a vemurafenib dose reduction. Risk D: Consider therapy modification
Ramelteon: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Ramelteon. Risk C: Monitor therapy
Ramosetron: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Ramosetron. Risk C: Monitor therapy
Ranolazine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Ranolazine. Risk C: 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. Risk D: Consider therapy modification
Relugolix: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Relugolix. Management: Avoid coadministration of relugolix with oral P-gp inhibitors whenever possible. If combined, take relugolix at least 6 hours prior to the P-gp inhibitor and monitor patients more frequently for adverse reactions. Risk D: Consider therapy modification
Relugolix, Estradiol, and Norethindrone: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Relugolix, Estradiol, and Norethindrone. Management: Avoid use of relugolix/estradiol/norethindrone with P-glycoprotein (P-gp) inhibitors. If concomitant use is unavoidable, relugolix/estradiol/norethindrone should be administered at least 6 hours before the P-gp inhibitor. Risk D: Consider therapy modification
RifAXIMin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of RifAXIMin. Risk C: Monitor therapy
Rimegepant: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Rimegepant. Management: Avoid administration of another dose of rimegepant within 48 hours if given concomitantly with a P-glycoprotein (P-gp) inhibitor. Risk D: Consider therapy modification
RisperiDONE: May enhance the QTc-prolonging effect of Vemurafenib. Vemurafenib may increase the serum concentration of RisperiDONE. Management: Monitor for increased risperidone toxicities, including 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. Risk C: Monitor therapy
RomiDEPsin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of RomiDEPsin. Risk C: Monitor therapy
ROPINIRole: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of ROPINIRole. Risk C: Monitor therapy
Ropivacaine: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Ropivacaine. Risk C: Monitor therapy
Sertindole: May enhance the QTc-prolonging effect of QT-prolonging Agents (Moderate Risk). Risk X: Avoid combination
Silodosin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Silodosin. Risk C: Monitor therapy
Sirolimus (Conventional): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Sirolimus (Conventional). Management: Avoid concurrent use of sirolimus with P-glycoprotein (P-gp) inhibitors when possible and alternative agents with lesser interaction potential with sirolimus should be considered. Monitor for increased sirolimus concentrations/toxicity if combined. Risk D: Consider therapy modification
Sirolimus (Protein Bound): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Sirolimus (Protein Bound). Risk X: Avoid combination
Solriamfetol: May enhance the hypertensive effect of Hypertension-Associated Agents. Risk C: Monitor therapy
Tacrolimus (Systemic): CYP3A4 Inducers (Weak) may decrease the serum concentration of Tacrolimus (Systemic). Risk C: Monitor therapy
Tacrolimus (Systemic): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Tacrolimus (Systemic). Risk C: Monitor therapy
Talazoparib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Talazoparib. Risk C: Monitor therapy
Tasimelteon: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Tasimelteon. Risk C: Monitor therapy
Tegaserod: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Tegaserod. Risk C: Monitor therapy
Teniposide: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Teniposide. Risk C: Monitor therapy
Tenofovir Disoproxil Fumarate: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Tenofovir Disoproxil Fumarate. Risk C: 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. Risk D: 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. Risk D: Consider therapy modification
Topotecan: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Topotecan. Risk X: 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. Risk D: 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 (at least 2 hours later if needed) of 50 mg when used with a P-gp inhibitor. Risk D: Consider therapy modification
Venetoclax: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Venetoclax. Management: Reduce the venetoclax dose by at least 50% in patients requiring concomitant treatment with P-glycoprotein (P-gp) inhibitors. Resume the previous venetoclax dose 2 to 3 days after discontinuation of a P-gp inhibitor. Risk D: Consider therapy modification
Verteporfin: Photosensitizing Agents may enhance the photosensitizing effect of Verteporfin. Risk C: Monitor therapy
VinCRIStine (Liposomal): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of VinCRIStine (Liposomal). Risk X: Avoid combination
Warfarin: Vemurafenib may increase the serum concentration of Warfarin. Risk C: Monitor therapy
Grapefruit and grapefruit juice may inhibit CYP3A4-mediated metabolism of vemurafenib. Management: Monitor for increased effects/toxicity with concomitant use.
Women of reproductive potential should use effective contraception during treatment and for at least 2 weeks after the last dose.
Vemurafenib crosses the placenta. Based on the mechanism of action, vemurafenib may cause fetal harm if administered during pregnancy.
It is not known if vemurafenib is present in breast milk. Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer during treatment and for 2 weeks after the last dose.
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.
The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.
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.
Distribution: Vd: ~106 L.
Protein binding: >99%, to albumin and α1-acid glycoprotein.
Bioavailability: Mean: 64% at steady state.
Half-life, elimination: 57 hours (range: 30 to 120 hours).
Time to peak: 3 hours.
Excretion: Feces (~94%); urine (~1%).
Tablets (Zelboraf Oral)
240 mg (per each): $56.97
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