Dosing and uses of Zelboraf (vemurafenib)
Adult dosage forms and strengths
film-coated tablet
- 240mg
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
Pediatric dosage forms and strengths
<18 years: Safety and efficacy not established
Geriatric dosage forms and strengths
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
Zelboraf (vemurafenib) adverse (side) 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
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
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)
Pregnancy and lactation
Pregnancy category: D; may cause fetal harm when administered to a pregnant woman based on its mechanism of action
Lactation: Unknown whether distributed in breast milk; breastfeeding not recommended during therapy
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.
Pharmacology of Zelboraf (vemurafenib)
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)
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
