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Vemurafenib

Pronunciation

(vem ue RAF e nib)

Index Terms

  • BRAF(V600E) Kinase Inhibitor RO5185426
  • PLX4032
  • RG7204
  • RO5185426

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Zelboraf: 240 mg

Brand Names: U.S.

  • Zelboraf

Pharmacologic Category

  • Antineoplastic Agent, BRAF Kinase Inhibitor

Pharmacology

BRAF kinase inhibitor (potent) which inhibits tumor growth in melanomas by inhibiting kinase activity of certain mutated forms of BRAF, including BRAF with V600E mutation, thereby blocking cellular proliferation in melanoma cells with the mutation. Does not have activity against cells with wild-type BRAF. BRAFV600E activating mutations are present in ~50% of melanomas; V600E mutation involves the substitution of glutamic acid for valine at amino acid 600. The cobas 4800 BRAF V600 mutation test is approved to detect BRAFV600E mutation.

Distribution

Vd: ~106 L

Excretion

Feces (~94%); urine (~1%)

Time to Peak

~3 hours

Half-Life Elimination

57 hours (range: 30 to 120 hours)

Protein Binding

>99%, to albumin and α1-acid glycoprotein

Use: Labeled Indications

Melanoma, unresectable or metastatic:

US labeling: Treatment of unresectable or metastatic melanoma in patients with a BRAFV600E mutation (as detected by an approved test).

Canadian labeling: Treatment of unresectable or metastatic melanoma in patients with a BRAFV600 mutation (as identified by a validated test).

Limitations of use: Vemurafenib is not indicated in patients with wild-type BRAF melanoma.

Use: Unlabeled

Treatment of metastatic melanoma in patients with a BRAFV600K mutation

Contraindications

There are no contraindications listed in the manufacturer’s labeling.

Canadian labeling: Hypersensitivity to vemurafenib or any component of the formulation.

Dosing: Adult

US labeling: Melanoma, metastatic or unresectable (with BRAFV600E mutation): Oral: 960 mg every 12 hours; continue until disease progression or unacceptable toxicity.

Canadian labeling: Melanoma, metastatic or unresectable (with BRAFV600 mutation): Oral: 960 mg twice daily; continue until disease progression or unacceptable toxicity.

Missed doses: A missed dose may be taken up to 4 hours prior to the next scheduled dose. If it is within 4 hours of the next scheduled dose, administer the next dose at the regular schedule. If vomiting occurs after a dose is taken, do not take an additional dose; continue with the next scheduled dose.

Melanoma, metastatic or unresectable (with BRAFV600K mutation; off-label use): Oral: 960 mg every 12 hours; continue until disease progression or unacceptable toxicity (Sossman 2012).

Melanoma, metastatic or unresectable (with BRAFV600E or V600K mutations; off-label combination): Oral: 960 mg every 12 hours (in combination with cobimetinib); continue until disease progression or unacceptable toxicity (Larkin 2014).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

US labeling:

Mild to moderate impairment (preexisting): No dosage adjustment necessary.

Severe impairment (preexisting): There are no dosage adjustments provided in the manufacturer’s labeling (data are insufficient to determine if dosage adjustment is necessary); use with caution.

Canadian labeling: There are no dosage adjustments provided in the manufacturer’s labeling.

Dosing: Hepatic Impairment

Mild to moderate impairment (preexisting): No dosage adjustment necessary.

Severe impairment (preexisting): There are no dosage adjustments provided in manufacturer’s labeling (data are insufficient to determine if dosage adjustment is necessary); use with caution.

Hepatotoxicity/lab abnormalities during treatment: Refer to dosage adjustment for toxicity and manage with dose reduction, treatment interruption, or discontinuation.

Dosing: Adjustment for Toxicity

Note: Do not dose reduce below 480 mg twice daily. NCI Common Terminology Criteria for Adverse Events (CTC-AE) version 4.0 used for adverse event grades.

Grade 1 or grade 2 (tolerable) toxicity: No dosage adjustment recommended.

Grade 2 (intolerable) or grade 3 toxicity:

US labeling:

First incident: Interrupt treatment until toxicity returns to grade 0 or 1, then resume at 720 mg twice daily

Second incident: Interrupt treatment until toxicity returns to grade 0 or 1, then resume at 480 mg twice daily

Third incident: Discontinue permanently.

Canadian labeling:

First incident: Interrupt treatment until toxicity returns to grade 0 or 1, then resume at 720 mg twice daily or 480 mg twice daily if dose previously reduced.

Second incident: Interrupt treatment until toxicity returns to grade 0 or 1, then resume at 480 mg twice daily or discontinue permanently if dose previously reduced to 480 mg twice daily.

Third incident: Discontinue permanently.

Grade 4 toxicity:

First incident: Interrupt treatment until toxicity returns to grade 0 or 1, then resume at 480 mg twice daily or discontinue permanently

Second incident: Discontinue permanently.

Specific toxicities:

Severe hypersensitivity or severe dermatologic toxicity: Discontinue permanently.

QTc interval changes:

US labeling:

QTc >500 msec (grade ≥3): Temporarily withhold treatment, correct electrolytes and control risk factors for QT prolongation; may reinitiate with a dose reduction once QTc ≤500 msec.

QTc persistently >500 msec and >60 msec above baseline: Discontinue permanently.

Canadian labeling:

QTc >500 msec during treatment and ≤60 msec change from baseline:

First incident: Interrupt treatment until QTc <500 msec, then resume at 720 mg twice daily or 480 mg twice daily if dose previously reduced.

Second incident: Interrupt treatment until QTc <500 msec, then resume at 480 mg twice daily or discontinue permanently if dose previously reduced to 480 mg twice daily.

Third incident: Discontinue permanently.

QTc >500 msec during treatment and >60 msec above baseline: Discontinue permanently.

Administration

Doses should be administered orally in the morning and evening, ~12 hours apart. May be taken with or without a meal. If vomiting occurs after a dose is taken, do not take an additional dose; continue with the next scheduled dose.

Swallow whole with a glass of water; do not crush or chew. There are case reports of vemurafenib administration after crushing (Janson 2013; Khimani 2014), however vemurafenib is nearly insoluble in water and is manufactured as a microprecipitated bulk powder core (to improve solubility/bioavailability) within a film coated tablet (Shah 2013). Pharmacokinetics and efficacy of administration other than swallowing tablets whole have not been determined.

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]). NIOSH recommends single gloving for administration of intact tablets (NIOSH 2014). Although crushing of the tablets is not recommended, if it is necessary to manipulate tablets, it is recommended to double glove, wear a protective gown, and prepare in a controlled device (NIOSH 2014).

Dietary Considerations

Avoid grapefruit and grapefruit juice.

Storage

Store at room temperature of 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C and 30°C (59°F and 86°F). Store in the original container with the lid tightly closed.

Drug Interactions

Afatinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib. Management: Per US labeling: reduce afatinib by 10mg if not tolerated. Per Canadian labeling: avoid combination if possible; if used, administer the P-gp inhibitor simultaneously with or after the dose of afatinib. Consider therapy modification

Aprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

ARIPiprazole: CYP3A4 Inducers may decrease the serum concentration of ARIPiprazole. Management: Double the oral aripiprazole dose and closely monitor response. Reduce oral aripiprazole dose to 10-15 mg/day (for adults) if the inducer is discontinued. Avoid use of CYP3A4 inducers for more than 14 days with extended-release injectable aripiprazole. Consider therapy modification

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Bosutinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Bosutinib. Avoid combination

Brentuximab Vedotin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be increased. Monitor therapy

Colchicine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Colchicine. Colchicine distribution into certain tissues (e.g., brain) may also be increased. Management: Colchicine is contraindicated in patients with impaired renal or hepatic function who are also receiving a p-glycoprotein inhibitor. In those with normal renal and hepatic function, reduce colchicine dose as directed. Consider therapy modification

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

CYP1A2 Substrates: Vemurafenib may increase the serum concentration of CYP1A2 Substrates. Management: Consider alternatives to such combinations whenever possible, particularly if the CYP1A2 substrate has a relatively narrow therapeutic index. Consider therapy modification

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Vemurafenib. Avoid combination

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Vemurafenib. Avoid combination

Dabigatran Etexilate: P-glycoprotein/ABCB1 Inhibitors may increase serum concentrations of the active metabolite(s) of Dabigatran Etexilate. Management: Dabigatran dose reductions may be needed. Specific recommendations vary considerably according to US vs Canadian labeling, specific P-gp inhibitor, renal function, and indication for dabigatran treatment. Refer to full monograph or dabigatran labeling. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Digoxin: Vemurafenib may increase the serum concentration of Digoxin. Management: Avoid coadministration of vemurafenib and digoxin when possible. If concomitant use cannot be avoided, consider digoxin dose reduction. Consider therapy modification

DOXOrubicin (Conventional): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to P-glycoprotein inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification

Edoxaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban. Management: See full monograph for details. Reduced doses are recommended for patients receiving edoxaban for venous thromboembolism in combination with certain inhibitors. Similar dose adjustment is not recommended for edoxaban use in atrial fibrillation. Consider therapy modification

Everolimus: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Everolimus. Management: Everolimus dose reductions are required for patients being treated for subependymal giant cell astrocytoma or renal cell carcinoma. See prescribing information for specific dose adjustment and monitoring recommendations. Consider therapy modification

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Highest Risk QTc-Prolonging Agents: May enhance the QTc-prolonging effect of other Highest Risk QTc-Prolonging Agents. Avoid combination

Hydrocodone: CYP3A4 Inducers (Weak) may decrease the serum concentration of Hydrocodone. Monitor therapy

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Ipilimumab: May enhance the hepatotoxic effect of Vemurafenib. Management: Consider alternatives to this combination when possible. Use of this combination should only be undertaken with extra close monitoring of liver function (hepatic transaminases and bilirubin) and signs/symptoms of hepatotoxicity. Consider therapy modification

Ivabradine: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Ledipasvir: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Ledipasvir. Monitor therapy

Luliconazole: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Mifepristone: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Moderate Risk QTc-Prolonging Agents: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Naloxegol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naloxegol. Monitor therapy

Netupitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

NiMODipine: CYP3A4 Inducers (Weak) may decrease the serum concentration of NiMODipine. Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

PAZOPanib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of PAZOPanib. Avoid combination

P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

P-glycoprotein/ABCB1 Substrates: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

Pirfenidone: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Pirfenidone. Management: Use any such combination with caution and close monitoring for pirfenidone toxicity. Avoid the use of pirfenidone with moderate CYP1A2 inhibitors whenever CYP2C9, 2C19, 2C6, or 2E1 is also inhibited (either by the CYP1A2 inhibitor or by a third drug). Consider therapy modification

Porfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer. Monitor therapy

Prucalopride: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Prucalopride. Monitor therapy

QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying): May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

Rifaximin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Rifaximin. Monitor therapy

Saxagliptin: CYP3A4 Inducers may decrease the serum concentration of Saxagliptin. Monitor therapy

Silodosin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Silodosin. Avoid combination

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

St John's Wort: May decrease the serum concentration of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

TiZANidine: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of TiZANidine. Management: If combined use cannot be avoided, initiate tizanidine in adults at 2 mg and increase in 2-4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Avoid combination

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Topotecan: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Topotecan. Avoid combination

Verteporfin: Photosensitizing Agents may enhance the photosensitizing effect of Verteporfin. Monitor therapy

VinCRIStine (Liposomal): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of VinCRIStine (Liposomal). Avoid combination

Warfarin: Vemurafenib may increase the serum concentration of Warfarin. Monitor therapy

Adverse Reactions

>10%:

Cardiovascular: Peripheral edema (17% to 23%)

Central nervous system: Fatigue (38% to 54%; grade 3: 2% to 4%), headache (23% to 27%)

Dermatologic: Skin rash (37% to 52%; grade 3: 7% to 8%), skin photosensitivity (33% to 49%; grade 3: 3%), alopecia (36% to 45%), pruritus (23% to 30%; grade 3: 2%), hyperkeratosis (24% to 28%; actinic: 8% to 17%; seborrheic: 10% to 14%; pilaris: ≤10%), maculopapular rash (9% to 21%; grade 3: 2% to 6%), xeroderma (16% to 19%), sunburn (10% to 14%), erythema (8% to 14%), papular rash (5% to 13%)

Gastrointestinal: Nausea (35% to 37%; grade 3: 2%), diarrhea (28% to 29%; grade 3: <1%), vomiting (18% to 26%; grade 3: 1% to 2%), decreased appetite (18% to 21%), constipation (12% to 16%), dysgeusia (11% to 14%)

Hematologic & oncologic: Cutaneous papilloma (21% to 30%), squamous cell carcinoma of skin (24%; grade 3: 22% to 24%)

Hepatic: Increased gamma-glutamyl transferase (5% to 15%)

Neuromuscular & skeletal: Arthralgia (53% to 67%; grade 3: 4% to 8%), myalgia (13% to 24%; grade 3: <1%), limb pain (9% to 18%), back pain (8% to 11%; grade 3: <1%), musculoskeletal pain (8% to 11%), weakness (2% to 11%)

Respiratory: Cough (8% to 12%)

Miscellaneous: Fever (17% to 19%)

1% to 10%:

Cardiovascular: Atrial fibrillation, hypotension, prolonged Q-T interval on ECG, retinal vein occlusion, vasculitis

Central nervous system: Cranial nerve palsy (facial), dizziness, peripheral neuropathy

Dermatologic: Erythema nodosum, folliculitis, palmar-plantar erythrodysesthesia, Stevens-Johnson syndrome, toxic epidermal necrolysis

Endocrine & metabolic: Weight loss

Hematologic & oncologic: Basal cell carcinoma, malignant melanoma (new primary), squamous cell carcinoma (oropharyngeal)

Hepatic: Increased serum alkaline phosphatase, increased serum ALT, increased serum AST, increased serum bilirubin

Hypersensitivity: Anaphylaxis, hypersensitivity

Neuromuscular & skeletal: Arthritis

Ophthalmic: Blurred vision, iritis, photophobia, uveitis

Renal: Increased serum creatinine

<1% (Limited to important or life-threatening): Chronic myelomonocytic leukemia with NRAS mutation (progression of preexisting condition), drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), febrile neutropenia, hepatic failure, neutropenia, pancreatitis, panniculitis, recall skin sensitization

Warnings/Precautions

Concerns related to adverse effects:

• Dermatologic toxicity: Dermatologic reactions have been observed, including case reports of Stevens-Johnson syndrome and toxic epidermal necrolysis. Discontinue (permanently) for severe dermatologic toxicity.

• Hepatotoxicity: Liver injury has been reported with use, and may cause functional impairment such as coagulopathy or other organ dysfunction. Monitor transaminases, alkaline phosphatase, and bilirubin at baseline and monthly during therapy, or as clinically necessary. May require dosage reduction, therapy interruption, or discontinuation.

• Hypersensitivity: Anaphylaxis and severe hypersensitivity may occur during treatment or upon reinitiation. Serious reactions have included generalized rash, erythema, hypotension, and drug rash with eosinophilia and systemic symptoms (DRESS syndrome). Discontinue (permanently) with severe hypersensitivity reaction.

• Malignancies: Cutaneous squamous cell carcinomas (cuSCC), keratoacanthomas, and melanoma have been reported (at a higher rate in patients receiving vemurafenib compared to control). Cutaneous SCC generally occurs early in the treatment course (median onset: 7 to 8 weeks) and is managed with excision (while continuing vemurafenib treatment). Approximately one-third of patients experienced >1 cuSCC occurrence and the median time between occurrences was 6 weeks. Potential risk factors for cuSCC include age ≥65 years, history of skin cancer, or chronic sun exposure. Monitor for skin lesions (with dermatology evaluation) at baseline and every 2 months during treatment; consider continued monitoring for 6 months after treatment. Noncutaneous squamous cell carcinomas (SCC) of the head and neck have also been observed; monitor closely for signs/symptoms. Vemurafenib may promote malignancies correlated with RAS activation; monitor for signs/symptoms of other malignancies.

• Ocular toxicity: Uveitis (including iritis), blurred vision, and photophobia may occur; monitor for signs and symptoms. Uveitis may be managed with corticosteroid and mydriatic eye drops. Retinal vein occlusion has been reported in clinical trials.

• Pancreatitis: Pancreatitis has been reported (case reports), with onset generally occurring within 2 weeks after initiation (Muluneh 2013; Zelboraf Canadian product monograph 2015). Exacerbation of pancreatitis has also occurred upon rechallenge. Patients with unexplained abdominal pain should be promptly evaluated for pancreatitis (eg, serum lipase and amylase; abdominal CT) as clinically indicated.

• Photosensitivity: Photosensitivity ranging from mild to severe has been reported. Advise patients to avoid sun exposure and wear protective clothing and use effective UVA/UVB sunscreen and lip balm (SPF ≥30) when outdoors. Dosage modifications are recommended for intolerable photosensitivity consisting of erythema ≥10% to 30% of body surface area.

• QT prolongation: QT prolongation (dose-dependent) has been observed; may lead to increased risk for ventricular arrhythmia, including torsade de pointes. Monitor electrolytes (calcium, magnesium and potassium) at baseline and with dosage adjustments. Monitor ECG at baseline, 15 days after initiation, then monthly for 3 months, then every 3 months thereafter (more frequently if clinically appropriate); also monitor with dosage adjustments. Do not initiate treatment if baseline QTc >500 msec. During treatment, if QTc >500 msec, temporarily interrupt treatment; correct electrolytes and control other risk factors for QT prolongation. May reinitiate with a dose reduction once QTc falls to <500 msec. Discontinue (permanently), if after correction of risk factors, both the QTc continues to increase >500 msec and there is >60 msec change above baseline. Do not initiate treatment in patients with electrolyte abnormalities which are not correctable, long QT syndrome, or taking concomitant medication known to prolong the QT interval.

• Radiation sensitization/recall: Radiation sensitization and recall (some cases may be severe or involve cutaneous and visceral organs) have been reported in patients treated with radiation prior to, during, or after treatment with vemurafenib. Monitor closely when vemurafenib is administered concomitantly or sequentially with radiation treatment.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: May be at increased risk for adverse effects; in clinical trials, there was an increased incidence of cuSCC and keratoacanthoma, atrial fibrillation, peripheral edema, and nausea/decreased appetite in patients ≥65 years of age.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Other warnings/precautions:

• BRAF genomics: Only patients with a BRAFV600 mutation-positive melanoma (including BRAFV600E) will benefit from treatment; mutation must be detected and confirmed by an approved test prior to treatment. The cobas 4800 BRAF V600 Mutation Test was used in clinical trials and is FDA-approved to detect BRAFV600E mutation.

Monitoring Parameters

Liver transaminases, alkaline phosphatase and bilirubin at baseline and monthly during treatment (or as clinically appropriate). Electrolytes (calcium, magnesium and potassium) at baseline and after dosage modification. ECG at baseline, 15 days after initiation, then monthly for 3 months, then every 3 months thereafter (more frequently if clinically appropriate) and with dosage adjustments. Dermatology evaluation (for new skin lesions) at baseline and every 2 months during treatment; also consider continued monitoring for 6 months after completion of treatment. Signs/symptoms of hypersensitivity reactions, uveitis, and malignancies; signs of radiation sensitization and recall.

Pregnancy Risk Factor

D

Pregnancy Considerations

Adverse effects were not demonstrated in animal reproduction studies. Based on the mechanism of action, vemurafenib may cause fetal harm if administered during pregnancy or in patients who become pregnant during treatment. Women of childbearing potential and men of reproductive potential should use adequate contraception methods during and for at least 2 months after treatment (Canadian labeling recommends during and for at least 6 months after treatment).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience alopecia, arthralgia, myalgia, back pain, headache, nausea, diarrhea, constipation, dysgeusia, asthenia, lack of appetite, or xeroderma. Have patient report immediately to prescriber signs of hepatic impairment, signs of pancreatitis, inability to eat, severe dizziness, syncope, tachycardia, arrhythmia, edema of extremities, mole changes, skin growths, eczema of hands or feet, skin changes, paresthesia, vision changes, ophthalmalgia, eye irritation, or signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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