vemurafenib (Rx)

Brand and Other Names:Zelboraf
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Dosing & Uses

AdultPediatricGeriatric

Dosage Forms & Strengths

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

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

See also Administration

Erdheim-Chester Disease

Indicated for the treatment of Erdheim-Chester Disease (ECD) with BRAF V600 mutation

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

See also Administration

Dosage Modifications

New primary cutaneous malignancies: No dose modifications necessary

Do not dose reduce to below 480 mg q12hr

Recommended dosage modifications for other adverse events (AE)

  • Permanently discontinue treatment
    • Grade 4 AE, first appearance (if clinically appropriate) or second appearance
    • QTc prolongation >500 ms and increased by >60 ms from pretreatment values
  • Withhold treatment for intolerable Grade ≥2
    • First appearance of intolerable Grade 2 or Grade 3 AE: Restart and reduced dose to 720 mg PO q12hr upon recovery to Grade 0–1
    • Second appearance of Grade 2 (if intolerable) or Grade 3 adverse reactions or for first appearance of Grade 4 adverse reaction (if clinically appropriate): Restart and reduced dose to 480 mg PO q12hr upon recovery to Grade 0–1
  • Concomitant use of strong CYP3A4 inducers
    • Avoid concomitant use of strong CYP3A4 inducers with vemurafenib
    • If concomitant use of a strong CYP3A4 inducer is unavoidable, increase vemurafenib dose by 240 mg (one tablet) as tolerated
    • After discontinuation of a strong CYP3A4 inducer for 2 weeks, resume vemurafenib dose that was taken prior to initiating the strong CYP3A4 inducer

Renal Impairment

  • Mild-to-moderate: No dose adjustment required
  • Severe: Appropriate dose not established

Hepatic impairment

  • Mild-to-moderate: No dose adjustment required
  • Severe: Appropriate dose not established

Dosing Considerations

Limitation of use

  • Not recommended for use with wild-type BRAF melanoma

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

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% (All Grades)

            Arthralgia (82%)

            Maculopapular rash (59%)

            Alopecia (55%) Fatigue (55%)

            Skin papilloma (55%)

            QT prolongation (55%)

            Hyperkeratosis (50%)

            Diarrhea (50%)

            Dry skin (45%)

            Seborrheic keratosis (41%)

            Photosensitivity reaction (41%)

            Palmar-plantar erythrodysesthesia syndrome (41%)

            Pruritus (36%) SCC of skin (36%)

            Peripheral sensory neuropathy (36%)

            Cough (36%) Hypertension (36%)

            Nausea (32%)

            Actinic keratosis (32%)

            Keratosis pilaris (32%)

            Rash papular (23%)

            Vomiting (23%)

            Melanocytic nevus (23%)

            Sunburn (23%)

            Keratoacanthoma (<20%)

            Dupuytren’s contracture (<20%)

            >10% (Grade 3 or 4)

            SCC of skin (36%)

            Hypertension (23%)

            Arthralgia (14%)

            1-10% (Grades 3 or 4)

            Elevated AST (9.1%)

            Actinic keratosis (5%)

            Fatigue (5%)

            QT prolongation (5%)

            Elevated alkaline phosphatase (4.5%)

            Postmarketing Reports

            Neoplasms benign, malignant and unspecified (incl. 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)

            Blood and lymphatic systems disorder: Neutropenia

            Injury, poisoning and procedural complications: Radiation sensitization and recall

            Gastrointestinal disorders: Pancreatitis

            Renal and urinary disorders: Acute interstitial nephritis, acute tubular necrosis

            Musculoskeletal and connective tissue disorders: Dupuytren’s contracture and plantar fascial fibromatosis

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            Warnings

            Contraindications

            None

            Cautions

            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

            Based on mechanism of action, can cause fetal harm when administered to pregnant women; avoid use during pregnancy and use effective contraception (see Pregnancy

            Severe cases of radiation sensitization and recall reported

            Renal failure, including acute interstitial nephritis and acute tubular necrosis reported; measure serum creatinine before initiation of therapy and periodically during treatment

            Dupuytren’s contracture and plantar fascial fibromatosis reported; majority of cases, mild to moderate, but severe disabling cases of Dupuytren’s contracture also reported

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

            New primary malignancies

            • Cutaneous squamous cell carcinomas (cuSCC) and keratoacanthoma occurred in 24% of patients
            • Unresectable or metastatic melanoma, new primary malignant melanoma occurred in 2.1% of patients
            • Perform dermatologic evaluations prior to treatment initiation and q2Months while on therapy
            • Manage with excision and continue treatment without dose adjustment; consider monitoring for 6 months following discontinuation of treatment
            • Noncutaneous squamous cell carcinomas (non-cuSCC) of the head and neck can; monitor for signs or symptoms of new non-cuSCC
            • Based on mechanism of action, vemurafenib may promote malignancies associated with activation of RAS through mutation or other mechanisms; monitor for signs or symptoms of other malignancies
            • Cases of myeloid neoplasms amongst patients with Erdheim-Chester disease (ECD) reported, including in patients who have received therapy; monitoring complete blood count in ECD patients with co-existing myeloid malignancies recommended

            QT prolongation

            • Concentration-dependent QT prolongation reported
            • Do not start treatment in patients with uncorrectable electrolyte abnormalities, QTc >500 ms, or long QT syndrome, or in patients who are taking medication associated with QT prolongation
            • 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)

            Drug interactions overview

            • Vemurafenib is a CYP3A4 substrate and CYP1A2 inhibitor
            • Avoid coadministration of vemurafenib with strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, saquinavir, ritonavir, indinavir, nelfinavir, voriconazole) and replace and use alternative drugs when possible
            • Avoid coadministration with strong CYP3A4 inducers; if unavoidable, increase vemurafenib dose (see Dosage Modifications)
            • Avoid concomitant use of vemurafenib with drugs having a narrow therapeutic window that are predominantly metabolized by CYP1A2; coadministration of vemurafenib with tizanidine, a sensitive CYP1A2 substrate, increased tizanidine systemic exposure by 4.7-fold
            • Avoid concurrent use of P-gp substrates known to have narrow therapeutic window; if medication use is unavoidable, consider dose reduction of P-gp substrates with narrow therapeutic indices
            • Increases in transaminases and bilirubin occurred in a majority of patients who are concurrently using ipilimumab and vemurafenib
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            Pregnancy & Lactation

            Pregnancy

            There are no available data on the use of vemurafenib in pregnant women to determine the drug-associated risk

            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

            Steady state, twice daily regimen: 15-22 days

            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, following 960 mg dose: 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

            Storage

            Store at room temperature 20-25°C (68-77°F); excursions permitted between 15-30°C (59-86°F)

            Store in the original container with the lid tightly closes

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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.
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