vemurafenib

Absorption: Some absorption follows oral administration; bioavailability is not known.

Distribution: Widely distributed to tissues.

Protein Binding: >99%.

Metabolism/Excretion: Mostly metabolized by the liver via the CYP3A4 isoenzyme system; primarily excreted in the feces, with 1% eliminated in urine.

Half-Life: 57 hr.

Time/Action Profile ⬆ ⬇

(plasma concentrations)

ROUTE	ONSET	PEAK	DURATION
PO	unknown	3 hr	12 hr

Contraind./Precautions ⬆ ⬇

Contraindicated in:

Underlying electrolyte abnormalities (↑ risk of serious arrhythmias; correct prior to administration);
Congenital or acquired prolonged QT syndromes;
Baseline QTc interval >500 msec;
Concurrent use of QT-interval prolonging drugs;
OB: Pregnancy;
Lactation: Lactation.

Use Cautiously in:

Severe renal impairment;
Severe hepatic impairment;
Receiving radiation therapy prior to, during, or after therapy (↑ risk of radiation sensitization/recall);
Rep: Women of reproductive potential;
Pedi: Safety and effectiveness not established in children;
Geri: risk of cutaneous squamous cell carcinoma, nausea, appetite, peripheral edema, keratoacanthoma, and atrial fibrillation in older adults.

Adv. Reactions/Side Effects ⬆ ⬇

CV: peripheral edema, QT interval prolongation, TORSADES DE POINTES

Derm: alopecia, dry skin, photosensitivity (↑ in females), pruritus, rash (↑ in females), skin cancer, skin papilloma, DRUG REACTION WITH EOSINOPHILIA AND SYSTEMIC SYMPTOMS (DRESS), keratocanthoma (↑ in males), STEVENS-JOHNSON SYNDROME (SJS), TOXIC EPIDERMAL NECROLYSIS (TEN)

EENT: iritis, retinal vein occlusion, uveitis

GI: ↓appetite, HEPATOTOXICITY, nausea

GU: ↑serum creatinine (↑ in females), acute interstitial nephritis, acute tubular necrosis

MS: arthralgia (↑ in females), myalgia, Dupuytren’s contracture, back pain, pain, plantar fascial fibromatosis

Neuro: fatigue, weakness, dysgeusia, headache

Resp: cough

Misc: fever, HYPERSENSITIVITY REACTIONS (INCLUDING ANAPHYLAXIS), radiation sensitization/recall

Interactions ⬆ ⬇

Drug-drug:

QT interval prolonging drugs may ↑ the risk of QT interval prolongation with arrhythmias; concurrent use contraindicated.
Concurrent use with CYP1A2 substrates with narrow therapeutic indices not recommended. Consider dose ↓ of substrates.
Strong CYP3A inhibitors, including atazanavir, clarithromycin, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, and voriconazole, may ↑ levels and the risk of toxicity; avoid concurrent use; if concurrent use is necessary, consider ↓ vemurafenib dose.
Strong CYP3A inducers, including carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, and rifapentine, may ↓ levels and effectiveness; avoid concurrent use; if concurrent use necessary, ↑ vemurafenib dose.
May ↑ risk of bleeding with warfarin.
Concurrent use with ipilimumab may ↑ risk of hepatotoxicity
May ↑ digoxin levels and the risk of toxicity

Route/Dosage ⬆ ⬇

PO (Adults ): 960 mg (4 tablets) twice daily until disease progression or unacceptable toxicity; Concurrent use of strong CYP3A4 inducers: 1200 mg (5 tablets) twice daily until disease progression or unacceptable toxicity.

Availability ⬆ ⬇

Assessment ⬆ ⬇

Perform dermatologic evaluation prior to initiation and every 2 mo during therapy. Excise any suspicious lesions, send for dermapathologic evaluation, and treat with standard care. Continue monitoring for 6 mo following discontinuation of therapy.
Monitor ECG 15 days after initiation of therapy, monthly during first 3 mo, every 3 mo thereafter, and more often if clinically indicated.
Monitor for hypersensitivity reactions (rash, erythema, hypotension). Permanently discontinue therapy if severe reaction occurs.
Monitor for signs and symptoms of uveitis periodically during therapy. May require treatment with steroid and mydriatic ophthalmic drops.
Assess patient for rash (mild to moderate rash usually occurs in the 2nd wk of therapy and resolves within 1–2 wk of continued therapy). If rash is severe (extensive erythematous or maculopapular rash with moist desquamation or angioedema) or accompanied by systemic symptoms (serum sickness-like reaction, SJS, TEN), therapy must be discontinued immediately.

Lab Test Considerations:

Information on FDA-approved tests for the detection of BRAF V600 mutations in melanoma is available at www.fda.gov/CompanionDiagnostics.
- Monitor serum potassium, magnesium, and calcium before starting therapy and after dose modification.
- Monitor AST, ALT, alkaline phosphatase, and bilirubin before starting therapy, monthly during therapy, and as clinically indicated. May require dose reduction, treatment interruption, or discontinuation.
- Monitor serum creatinine before starting and periodically during therapy.

Implementation ⬆ ⬇

PO: Administer (four 240-mg tablets) twice daily, without regard to food. Take first dose in the morning with 2nd dose about 12 hr later. DNC: Swallow tablets whole; do not crush or chew.
- Adverse reactions or QTc prolongation may occur requiring dose modification. If Grade 1 or 2 (tolerable) occur, maintain dose at 960 mg twice daily. If Grade 2 (Intolerable) or Grade 3, 1st appearance occurs, interrupt therapy until Grade 0–1. Resume dosing at 720 mg twice daily. If 2nd appearance, interrupt therapy until Grade 0–1. Resume dosing at 480 mg twice daily. If 3rd appearance, discontinue permanently. If Grade 4, 1st appearance occurs, discontinue permanently or interrupt therapy until Grade 0–1. Resume dosing at 480 twice daily. If 2nd appearance, discontinue permanently. Doses below 480 mg twice daily are not recommended.

Patient/Family Teaching ⬆ ⬇

Instruct patient to take vemurafenib as directed. If vomiting occurs, do not take an additional dose; take next dose as scheduled. Take missed doses as soon as remembered up to 4 hr before next dose; do not double dose.
Inform patient that assessment of BRAF mutation is required for selection of patients.
Instruct patient to stop taking vemurafenib and notify health care professional immediately if signs and symptoms of allergic reaction (rash or redness all over body; feeling faint; difficulty breathing or swallowing; throat tightness or hoarseness; fast heartbeat; swelling of face, lips, or tongue) or severe skin reactions (blisters on skin; blisters or sores in mouth; peeling of skin, fever, redness or swelling of face, hands, or soles of feet) occur.
Advise patient to wear broad spectrum UVA/UVB sunscreen, lip balm (SPF ≥30), and protective clothing, and to avoid sun exposure to prevent photosensitivity reactions. Severe photosensitivity reactions may require dose modifications.
Advise patient to notify health care professional if signs and symptoms of liver dysfunction (yellow skin or whites of eyes; feeling tired; urine turns dark or brown; nausea or vomiting; loss of appetite; pain on right side of stomach) or eye problems (eye pain, swelling, or redness; blurred vision; vision changes) occur.
Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and consult health care professional before taking any new medications.
Inform patient that regular assessments of skin and assessments for signs and symptoms of other malignancies must be done during and for up to 6 mo after therapy. Advise patient to notify health care professional immediately if any changes in skin occur.
Rep: Advise women of reproductive potential to use effective contraception during and for at least 2 wk after last dose of vemurafenib, and to avoid breastfeeding during and for 2 wk after last dose.

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Pronunciation ⬇

Classifications ⬆ ⬇

Indications ⬆ ⬇

Action ⬆ ⬇

Pharmacokinetics ⬆ ⬇