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Vemurafenib

Pronunciation: VEM-ue-RAF-e-nib
Class: BRAF inhibitor

Trade Names

Zelboraf
- Tablets, oral 240 mg

Pharmacology

Inhibits the activity of some mutated forms of BRAF serine-threonine kinase, including BRAF V600E .

Slideshow: Flashback: FDA Drug Approvals 2013

Pharmacokinetics

Absorption

T max is approximately 3 h. Mean C max is 62 mcg/mL. Steady state is achieved in 15 to 22 days.

Distribution

Albumin and alpha-1 acid glycoprotein protein binding is more than 99%; Vd is approximately 106 L.

Metabolism

Vemurafenib and metabolites represented 95% and 5% of the components of the plasma, respectively.

Elimination

Half-life is 57 h and Cl is approximately 31 L/d. Eliminated primarily in the feces (94%) and the urine (1%).

Special Populations

Renal Function Impairment

Apparent Cl was similar in patients with mild and moderate renal impairment compared with patients with healthy renal function. Pharmacokinetic data are only available for 1 patient with severe renal impairment; the need for dosage adjustment in this patient population cannot be determined.

Hepatic Function Impairment

Apparent Cl was similar in patients with mild and moderate hepatic impairment compared with patients with healthy hepatic function. Pharmacokinetic data are only available for 3 patients with severe hepatic impairment; the need for dosage adjustment in this patient population cannot be determined.

Elderly

Age has no statistically significant effect on vemurafenib pharmacokinetics.

Children

The pharmacokinetics have not been evaluated in children.

Gender

No clinically relevant effect of gender on vemurafenib pharmacokinetics.

Race

Insufficient data are available to evaluate potential differences in the pharmacokinetics of vemurafenib by race.

Indications and Usage

For the treatment of unresectable or metastatic melanoma with BRAF V600E mutation.

Contraindications

None well documented.

Dosage and Administration

Adults

PO 960 mg twice daily. Continue treatment until disease progression or unacceptable toxicity occurs.

Dosage adjustment Grade 2 (intolerable) or grade 3

For the first appearance, interrupt treatment until adverse reaction is grade 0 to 1; resume dosing at 720 mg twice daily. For the second appearance, interrupt treatment until reaction is grade 0 to 1; resume dosing at 480 mg twice daily. For the third appearance, permanently discontinue vemurafenib.

Grade 4

For the first appearance, permanently discontinue vemurafenib or interrupt treatment until adverse reaction is grade 0 to 1; resume dosing at 480 mg twice daily. For the second appearance, permanently discontinue vemurafenib.

General Advice

  • Administer without regard to meals. The first dose should be taken in the morning and the second dose should be taken in the evening approximately 12 h later.
  • Tablets should be swallowed whole with a glass of water and should not be chewed or crushed.
  • If a patient misses a dose, the missed dose can be taken up to 4 h prior to the next dose to maintain the twice-daily regimen. Both doses should not be taken at the same time.

Storage/Stability

Store between 59° and 86°F in the original container.

Drug Interactions

CYP1A2 substrates (eg, caffeine)

Plasma concentrations of the CYP1A2 substrate may be increased. Concurrent use of vemurafenib with agents with a narrow therapeutic index that are metabolized by CYP1A2 is not recommended. If coadministration cannot be avoided, use with caution and consider reducing the dose of the CYP1A2 substrate.

CYP2D6 substrates (eg, dextromethorphan)

Plasma concentrations of the CYP2D6 substrate may be increased. Concurrent use of vemurafenib with agents with a narrow therapeutic index that are metabolized by CYP2D6 is not recommended. If coadministration cannot be avoided, use with caution and consider reducing the dose of the CYP2D6 substrate.

CYP3A4 strong inducers (eg, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine)

Vemurafenib plasma concentrations may be reduced, decreasing the therapeutic effect. Coadminister with caution.

CYP3A4 strong inhibitors (eg, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole)

Vemurafenib plasma concentrations may be elevated, increasing the pharmacologic effect and risk of adverse reactions. Coadminister with caution. Close clinical and laboratory monitoring is warranted.

CYP3A4 substrates (eg, midazolam)

Plasma concentrations of the CYP3A4 substrate may be decreased. Concurrent use of vemurafenib with agents with a narrow therapeutic index that are metabolized by CYP3A4 is not recommended.

QT prolonging drugs (eg, antiarrhythmic agents [eg, amiodarone, bretylium, disopyramide, dofetilide, procainamide, quinidine, sotalol], arsenic trioxide, chlorpromazine, cisapride, dolasetron, droperidol, gatifloxacin, halofantrine, levomethadyl, mefloquine, mesoridazine, moxifloxacin, pentamidine, pimozide, probucol, sparfloxacin, thioridazine, ziprasidone)

The risk of life-threatening cardiac arrhythmias, including torsades de pointes, may be increased. Treatment with vemurafenib is not recommended in patients taking drugs known to prolong the QT interval.

Warfarin

Coadministration of vemurafenib increased the AUC of S-warfarin, a CYP2C9 substrate. Use with caution and consider additional INR monitoring.

Adverse Reactions

Cardiovascular

Atrial fibrillation, vasculitis (less than 10%).

CNS

Fatigue (54%); headache (27%); dysgeusia (14%); asthenia (11%); dizziness, peripheral neuropathy, VII th nerve paralysis (less than 10%).

Dermatologic

Rash (52%); photosensitivity reaction (49%); alopecia (45%); pruritus, skin papilloma (30%); hyperkeratosis (28%); cutaneous squamous cell cancer (24%); maculopapular rash (21%); dry skin (19%); actinic keratosis (17%); erythema, seborrheic keratosis, sunburn (14%); papular rash (13%); basal cell carcinoma, erythema nodosum, folliculitis, keratosis pilaris, palmar-plantar erythrodysesthesia syndrome, Stevens-Johnson syndrome (less than 10%).

EENT

Retinal vein occlusion, uveitis (less than 10%).

GI

Nausea (37%); diarrhea (29%); vomiting (26%); constipation (16%).

Lab Tests

GGT increased (15%); increased alkaline phosphatase, ALT (3%); increased bilirubin (2%); increased AST (1%).

Metabolic-Nutritional

Peripheral edema (23%); decreased appetite (21%); weight decreased (less than 10%).

Musculoskeletal

Arthralgia (67%); myalgia (24%); pain in extremity (18%); back pain, musculoskeletal pain (11%); arthritis (less than 10%).

Respiratory

Cough (12%).

Miscellaneous

Pyrexia (19%).

Precautions

Monitor

All patients should receive a dermatologic evaluation prior to initiation of therapy and every 2 mo while on therapy; consider monitoring for 6 mo following discontinuation of therapy. ECG and electrolytes (potassium, magnesium, calcium) should be monitored before treatment and after dose modification. Monitor ECG 15 days after treatment initiation and then monthly during the first 3 mo of therapy, and every 3 mo thereafter or more often if clinically indicated. Monitor liver transaminases, alkaline phosphatase, and bilirubin before initiation of treatment and monthly during treatment, or as clinically indicated. Routinely monitor patients for signs and symptoms of uveitis.


Pregnancy

Category D . May cause fetal harm. Women of childbearing potential and men should be advised to use appropriate contraceptive measures during therapy and for at least 2 mo after discontinuation of therapy.

Lactation

Undetermined.

Children

Safety and efficacy have not been established.

Elderly

More likely to experience some adverse reactions, including cutaneous squamous cell carcinoma, nausea, decreased appetite, peripheral edema, keratoacanthoma, and atrial fibrillation.

Hypersensitivity

Serious hypersensitivity reactions, including anaphylaxis, have been reported.

Renal Function

Use with caution in patients with severe renal impairment.

Hepatic Function

Use with caution in patients with severe hepatic impairment.

Photosensitivity

Photosensitivity reactions are increased and may require dose modification.

BRAF V600E testing

Confirmation of BRAF V600E mutation–positive melanoma as detected by an FDA-approved test is required for selection of patients for vemurafenib therapy.

Cutaneous squamous cell carcinoma

Cases have been reported, including both squamous cell carcinomas of the skin and keratoacanthomas. Risk factors include age (65 y and older), prior skin cancer, and long-term sun exposure. Cases were managed in clinical trials with excision and continuation of vemurafenib treatment without dose adjustment.

Dermatologic effects

Severe skin reactions, including Stevens-Johnson syndrome and TEN, have been reported. If severe skin reactions occur, permanently discontinue treatment.

Hepatic effects

Liver laboratory abnormalities have occurred. Manage with dose reduction, treatment interruption, or treatment discontinuation.

New primary malignant melanoma

May occur during treatment. In clinical trials, cases were managed with excision and continuation of vemurafenib treatment without dose adjustment.

Ophthalmic effects

Cases of uveitis have been reported; uveitis may require management with steroid and mydriatic ophthalmic drops. Blurry vision, iritis, photophobia, and retinal vein occlusion were also reported.

QT prolongation

May occur and lead to an increased risk of ventricular arrhythmias, including torsades de pointes. Initiation of treatment with vemurafenib is not recommended in patients with QTc greater than 500 ms, uncorrectable electrolyte abnormalities, or long QT syndrome, or who are taking other drugs known to prolong the QT interval. Treatment interruption, dosage reduction, and/or permanent discontinuation may be necessary if QT prolongation occurs.

Overdosage

Symptoms

No data available.

Patient Information

  • Advise patients of the potential benefits and risks of therapy and instruct them to read the Medication Guide carefully before starting therapy, and to read and check for new information each time the medication is refilled.
  • Inform patients that cutaneous squamous cell carcinoma has been reported in patients treated with vemurafenib and that they should have regular skin checks during treatment and for up to 6 mo after treatment is discontinued. Advise patients to contact their health care provider immediately if they notice any changes in their skin.
  • Advise patients to avoid sun exposure during therapy and to wear protective clothing and use a broad spectrum UVA/UVB sunscreen and lip balm (at least sun protection factor 30) when outdoors.
  • Inform patients that commonly reported adverse reactions include arthralgia, rash, alopecia, fatigue, photosensitivity reactions, nausea, pruritus, and skin papilloma.
  • Instruct patients to take vemurafenib without regard to meals and to take the first dose in the morning and the second dose in the evening approximately 12 h later.
  • Advise patients that tablets should be swallowed whole with a glass of water and should not be chewed or crushed.
  • Instruct patients that if they miss a dose, the missed dose can be taken up to 4 h prior to the next dose to maintain the twice-daily regimen. Both doses should not be taken at the same time.
  • Advise women of childbearing potential and men to use appropriate contraceptive measures during therapy and for at least 2 mo after discontinuation of therapy.

Copyright © 2009 Wolters Kluwer Health.

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