vemurafenib (Rx)

Brand and Other Names:Zelboraf
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Dosing & Uses

AdultPediatricGeriatric

Dosage Forms & Strengths

film-coated tablet

  • 240mg
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Malignant Melanoma

Indicated for treatment of unresectable or metastatic melanoma with BRAF-V600E mutation as detected by an FDA-approved test

Limitation of use: Not recommended for use with wild-type BRAF melanoma

960 mg (4 x 240 mg tablets) PO q12hr (administer approximately 12 hr apart)

Dosage Modifications

Management of symptomatic adverse events or QT prolongation may require dose reduction, treatment interruption, or discontinuation

Dose modifications or interruptions are not recommended for cutaneous squamous cell carcinoma adverse reactions

Dose reductions resulting in a dose below 480 mg q12hr are not recommended

Recommended dosage modifications for adverse events (AE)

  • The intensity of clinical adverse events graded by the Common Terminology Criteria for Adverse Events v4.0 (CTC-AE)
  • Grade1 or 2 AE [tolerable]: Maintain dose of 960 mg PO q12hr
  • Grade 2 or 3 AE [intolerable] (1st appearance): Interrupt treatment until grade 0-1, then resume at 720 mg PO q12hr
  • Grade 2 or 3 AE [intolerable] (2nd appearance): Interrupt treatment until grade 0-1, then resume at 480 mg PO q12hr
  • Grade 2 or 3 AE [intolerable] (3rd appearance): Discontinue permanently
  • Grade 4 (1st appearance): Discontinue permanently or interrupt treatment until grade 0-1, then resume at 480 mg PO q12hr
  • Grade 4 (2nd appearance): Discontinue permanently
  • QTc prolongation >500 ms and increased by >60 ms from pretreatment values: Discontinue permanently

Renal & Hepatic Impairment

No adjustment to starting dose needed with pre-existing mild-to-moderate renal or hepatic impairment

Use caution in patients with pre-existing severe renal or hepatic impairment (data limited for severe renal or hepatic impairment)

Orphan Designations

Thyroid cancer: Treatment of anaplastic thyroid carcinoma and advanced papillary thyroid cancer whose tumors harbor a BRAF V600 mutation

Non-small cell lung cancer (NSCLC) with BRAF V600E mutation

Erdheim-Chester Disease

Sponsor

  • Genentech, Inc; 1 DNA Way, M/S 241B; South San Francisco, CA 94080-4990

<18 years: Safety and efficacy not established

No dosage adjustments are required for geriatric patients

During clinical trials, 28% of patients were aged 65 yr or older

Elderly patients may be more likely to experience some adverse reactions, including cutaneous squamous cell carcinoma, nausea, decreased appetite, peripheral edema, keratoacanthoma and atrial fibrillation

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Interactions

Interaction Checker

and vemurafenib

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            Adverse Effects

            >10%

            Arthralgia (53-67%)

            Fatigue (38-54%)

            Rash (37-52%)

            Photosensitivity (33-49%)

            Alopecia (36-45%)

            Nausea (35-37%)

            Pruritus (23-30%)

            Skin papilloma (21-30%)

            Diarrhea (28-29%)

            Hyperkeratosis (24-28%)

            Headache (23-27%)

            Vomiting (18-26%)

            Cutaneous squamous cell carcinoma (24%)

            Myalgia (13-24%)

            Peripheral edema (17-23%)

            Decreased appetite (18-21%)

            Maculopapular rash (9-21%)

            Pyrexia (17-19%)

            Dry skin (16-19%)

            Pain in extremity (9-18%)

            Actinic keratosis (8-17%)

            Constipation (12-16%)

            Increased gamma-glutamyltrasferase [GGT] (5-15%)

            Dysgeusia (11-14%)

            Sunburn (10-14%)

            Erythema (8-14%)

            Papular rash (5-13%)

            Cough (8-12%)

            Musculoskeletal and back pain (8-11%)

            Asthenia (2-11%)

            Postmarketing Reports

            Neoplasms benign, malignant and unspecified (including cysts and polyps): Progression of pre-existing chronic myelomonocytic leukemia with NRAS mutation

            Skin and subcutaneous tissue disorders: Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome)

            Hematologic: Panniculitis and neutropenia

            Radiation sensitization and recall

            Pancreatitis

            Renal failure

            Acute interstitial nephritis

            Acute tubular necrosis

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            Warnings

            Contraindications

            None

            Cautions

            Cutaneous squamous cell carcinomas (cuSCC) occurred in 24% of patients; perform dermatologic evaluations prior to treatment initiation and q2Months while on therapy; manage with excision and continue treatment without dose adjustment

            Anaphylaxis and other serious hypersensitivity reactions reported during treatment and upon reinitiation, including generalized rash and erythema, hypotension, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome); permanently discontinue

            Severe dermatologic reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis reported; discontinue treatment

            Elevated liver enzymes may occur; monitor liver enzymes and bilirubin before treatment initiation and then monthly or as clinically indicated

            Liver injury leading to functional hepatic impairment, including coagulopathy or other organ dysfunction, can occur with vemurafenib

            Mild-to-moderate photosensitivity reported; advise patients to avoid sun exposure and wear protective clothing and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF >30) when outdoors

            Serious ophthalmologic reactions, including uveitis, iritis, blurry vision, photophobia, and retinal vein occlusion reported

            New primary malignant melanomas reported; manage with excision, and continue treatment without dose modification

            Avoid in pregnancy; based on mechanism of action, therapy can cause fetal harm when administered to pregnant woman; advise females of reproductive potential to use effective contraception during treatment and for 2 weeks after the final dose

            Severe cases of radiation sensitization and recall reported

            Renal failure, including acute interstitial nephritis and acute tubular necrosis reported

            BRAF mutation test required to confirm eligibility for treatment; has not been studied with wild-type BRAF melanoma

            QT prolongation

            • QT prolongation reported
            • Monitor ECG and electrolytes before treatment initiation and after dose modification
            • Monitor ECGs at day 15, monthly during the first 3 months of treatment, and then q3Months thereafter, or more often as clinically indicated
            • If the QTc exceeds 500 ms, temporarily interrupt treatment, correct electrolyte abnormalities, and control for cardiac risk factors for QT prolongation (see Dosage Modifications)
            • Permanently discontinue if QTc interval remains >500 ms and increased >60 ms from pretreatment values after controlling cardiac risk factors for QT prolongation (eg, electrolyte abnormalities, congestive heart failure, and bradyarrhythmias)
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            Pregnancy & Lactation

            Pregnancy: Based on mechanism of action, therapy can cause fetal harm when administered to pregnant women; advise females of reproductive potential to use effective contraception during treatment and for 2 weeks after the final dose

            Lactation: There is no information available regarding presence of vemurafenib in human milk, effects on breastfed infant, or effects on milk production; because of potential for serious adverse reactions in breastfed infant, including malignancy, severe dermatologic reactions, QT prolongation, hepatotoxicity, photosensitivity, and ophthalmologic toxicity, advise women not to breastfeed during treatment and for 2 weeks after final dose

            Pregnancy Categories

            A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA:Information not available.

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            Pharmacology

            Mechanism of Action

            Inhibitor of some mutated forms of BRAF serine-threonine kinase, including BRAF-V600E

            Also inhibits other kinases in vitro (eg, CRAF, ARAF, wild-type BRAF, SRMS, ACK1, MAP4K5, FGR) at similar concentrations

            Some mutations in the BRAF gene including V600E result in constitutively activated BRAF proteins, which can cause cell proliferation in the absence of growth factors that would normally be required for proliferation

            Absorption

            Bioavailability: Not determined

            Peak Plasma Time: 3 hr

            Peak Plasma Concentration: 62 mcg/mL

            AUC: 610 mcg•h/mL

            Distribution

            Protein Bound: >99% to human albumin and alpha-1 acid glycoprotein plasma proteins

            Vd: 106 L (66% inter-patient variability

            Metabolism

            Mean data showed that vemurafenib and its metabolites represented 95% and 5% of the components in plasma, respectively

            Metabolized by CYP3A4

            Moderate CYP1A2 inhibitor, weak CYP2D6 inhibitor, and a CYP3A4 inducer

            Substrate and an inhibitor of the efflux transporter P-glycoprotein

            Elimination

            Half-life: 57 hr (range 30-120 hr)

            Total body clearance: 31 L/day (32% inter-patient variability)

            Excretion: Feces (94%), urine (1%)

            Pharmacogenomics

            Vemurafenib is indicated only for patients with melanoma who have the V600E mutation of the BRAF gene (50% of patients with melanoma have this type of BRAF mutation, which does not occur in normal cells)

            Genetic test

            • Vemurafenib approved with companion diagnostic test known as the cobas 4800 BRAF V600 Mutation Test (Roche Molecular Systems)
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            Administration

            Oral Administration

            Take in morning and evening approximately 12 hr apart

            May take with or without food

            Swallow whole with a glass of water; do not chew or crush

            If a dose is missed, it can be taken up to 4 hr prior to the next dose to maintain the twice daily regimen; do not take both doses at the same time

            Do not take an additional dose if vomiting occurs after administration, but continue with the next scheduled dose

            Duration of treatment is until disease progression occurs or unacceptable toxicity occurs

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            Formulary

            FormularyPatient Discounts

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            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
            QL Quantity Limits
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            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
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