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Zelboraf (Vemurafenib) - Warnings and Precautions

 
 



WARNINGS AND PRECAUTIONS

Cutaneous Squamous Cell Carcinoma (cuSCC)

Cases of cuSCC, including both SCCs of the skin and keratoacanthomas, have been reported in patients treated with ZELBORAF [see Adverse Reactions]. The incidence of cuSCC in ZELBORAF-treated patients in Trial 1 was 24%. CuSCC usually occurred early in the course of treatment with a median time to the first appearance of 7 to 8 weeks. Of the patients who experienced cuSCC, approximately 33% experienced > 1 occurrence with median time between occurrences of 6 weeks. Potential risk factors associated with cuSCC in ZELBORAF clinical studies included age (≥ 65 years), prior skin cancer, and chronic sun exposure. In the clinical trials, cases of cuSCC were managed with excision, and patients were able to continue treatment without dose adjustment.

It is recommended that all patients receive a dermatologic evaluation prior to initiation of therapy and every two months while on therapy. Any suspicious skin lesions should be excised, sent for dermatopathologic evaluation and treated as per standard of care. Monitoring should be considered for 6 months following discontinuation of ZELBORAF.

Hypersensitivity Reactions

Serious hypersensitivity reactions, including anaphylaxis, have been reported in association with ZELBORAF and upon re-initiation of treatment. Severe hypersensitivity reactions included generalized rash and erythema or hypotension. In patients who experience a severe hypersensitivity reaction, ZELBORAF treatment should be permanently discontinued.

Dermatologic Reactions

Severe dermatologic reactions have been reported in patients receiving ZELBORAF, including one case of Stevens-Johnson syndrome and one case of toxic epidermal necrolysis in Trial 1. In patients who experience a severe dermatologic reaction, ZELBORAF treatment should be permanently discontinued.

QT Prolongation

Exposure-dependent QT prolongation was observed in an uncontrolled, open-label Phase 2 QT sub-study in previously treated patients with BRAFV600E mutation-positive metastatic melanoma [see Clinical Pharmacology]. QT prolongation may lead to an increased risk of ventricular arrhythmias, including Torsade de Pointes. Treatment with ZELBORAF is not recommended in patients with uncorrectable electrolyte abnormalities, long QT syndrome, or who are taking medicinal products known to prolong the QT interval.

ECG and electrolytes, including potassium, magnesium, and calcium, should be monitored before treatment with ZELBORAF and after dose modification. Monitoring of ECGs should occur 15 days after treatment initiation and then monthly during the first 3 months of treatment, followed by every 3 months thereafter or more often as clinically indicated. Initiation of treatment with ZELBORAF is not recommended in patients with QTc > 500 ms. If during treatment the QTc exceeds 500 ms (CTC-AE ≥ Grade 3), ZELBORAF treatment should be temporarily interrupted, electrolyte abnormalities should be corrected, and cardiac risk factors for QT prolongation (e.g., congestive heart failure, bradyarrhythmias) should be controlled. Re-initiation of treatment should occur at a lower dose once the QTc decreases below 500 ms [see Dosage and Administration]. Permanent discontinuation of ZELBORAF treatment is recommended if after correction of associated risk factors, the QTc increase meets values of both > 500 ms and > 60 ms change from pre-treatment values.

Liver Laboratory Abnormalities

Liver laboratory abnormalities have occurred with ZELBORAF (Table 3) [see Adverse Reactions]. Liver enzymes (transaminases and alkaline phosphatase) and bilirubin should be monitored before initiation of treatment and monthly during treatment, or as clinically indicated. Laboratory abnormalities should be managed with dose reduction, treatment interruption, or treatment discontinuation [see Dosage and Administration].

Photosensitivity

Mild to severe photosensitivity was reported in patients treated with ZELBORAF in clinical trials [see Adverse Reactions]. All patients should be advised to avoid sun exposure while taking ZELBORAF. While taking the drug, patients should be advised to wear protective clothing and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥ 30) when outdoors to help protect against sunburn.

For intolerable grade 2 (tender erythema covering 10 - 30% body surface area) or greater photosensitivity, dose modifications are recommended [see Dosage and Administration].

Ophthalmologic Reactions

In Trial 1, five cases of uveitis have been reported in patients treated with ZELBORAF. Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Patients should be routinely monitored for signs and symptoms of uveitis. Additionally, there were five patients with blurry vision, five patients with iritis and six patients with photophobia. There was one case of retinal vein occlusion in Trial 2.

New Primary Malignant Melanoma

There were eight skin lesions in seven patients reported as new primary malignant melanoma in Trial 1. Cases were managed with excision, and patients continued treatment without dose adjustment. Monitoring for skin lesions should occur as outlined above [see Warnings and Precautions].

Use in Pregnancy

Pregnancy Category D

ZELBORAF may cause fetal harm when administered to a pregnant woman based on its mechanism of action. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations].

BRAFV600E Testing

Confirmation of BRAFV600E mutation-positive melanoma as detected by an FDA-approved test is required for selection of patients for ZELBORAF therapy because these are the only patients studied and for whom benefit has been shown. For patients in ZELBORAF clinical studies, including Trial 1 and Trial 2, all enrolled patients tested positive when their tumor tissue was assessed with the cobas 4800 BRAF V600 Mutation Test [see Clinical Studies]. This test is designed to detect BRAFV600E mutations in DNA isolated from formalin-fixed, paraffin-embedded human melanoma tissue. The safety and efficacy of ZELBORAF have not been evaluated in patients whose melanoma tested negative by the cobas 4800 BRAF V600 Mutation Test. Refer to the package inserts of FDA approved test kits, for detailed information.

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category D [see Warnings and Precautions].

ZELBORAF may cause fetal harm when administered to a pregnant woman based on its mechanism of action.

Vemurafenib revealed no evidence of teratogenicity in rat embryo/fetuses at doses up to 250 mg/kg/day (approximately 1.3 times the human clinical exposure based on AUC) or rabbit embryo/fetuses at doses up to 450 mg/kg/day (approximately 0.6 times the human clinical exposure based on AUC). Fetal drug levels were 3-5% of maternal levels, indicating that vemurafenib has the potential to be transmitted from the mother to the developing fetus. There are no adequate and well controlled studies in pregnant women. Women of childbearing potential and men should be advised to use appropriate contraceptive measures during ZELBORAF therapy and for at least 2 months after discontinuation of ZELBORAF. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

Nursing Mothers

It is not known whether vemurafenib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from ZELBORAF in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and efficacy in pediatric patients below the age of 18 have not been established.

Geriatric Use

Ninety-four (28%) of 336 patients with unresectable or metastatic melanoma treated with ZELBORAF in Trial 1 were ≥ 65 years. Elderly patients (≥ 65 years) may be more likely to experience some adverse reactions, including cutaneous squamous cell carcinoma, nausea, decreased appetite, peripheral edema, keratoacanthoma and atrial fibrillation. The effects of ZELBORAF on overall survival, progression-free survival and best overall response rate were similar in the elderly as compared to younger patients.

Gender

The Grade 3 adverse events reported more frequently in females than males were rash, arthralgia, photosensitivity and increased creatinine. The Grade 3 adverse events reported more frequently in males than females were keratoacanthoma, increased alkaline phosphatase and increased total bilirubin.

Hepatic Impairment

No adjustment to the starting dose is needed for patients with pre-existing mild and moderate hepatic impairment. In the population pharmacokinetic analysis using data from clinical trials in patients with metastatic melanoma, pre-existing mild and moderate hepatic impairment did not influence the apparent clearance of vemurafenib. Clinical and pharmacokinetic data from only three patients with pre-existing severe hepatic impairment are available from clinical trials, and based on the limited data, the potential need for starting dose adjustment cannot be determined. ZELBORAF should be used with caution in patients with pre-existing severe hepatic impairment [see Clinical Pharmacology].

Renal Impairment

No adjustment to the starting dose is needed for patients with pre-existing mild and moderate renal impairment. In the population pharmacokinetic analysis using data from clinical trials in patients with metastatic melanoma, pre-existing mild and moderate renal impairment did not influence the apparent clearance of vemurafenib. Clinical and pharmacokinetic data from one patient with pre-existing severe renal impairment are available from clinical trials, and based on the limited data, the potential need for starting dose adjustment cannot be determined. ZELBORAF should be used with caution in patients with pre-existing severe renal impairment [see Clinical Pharmacology].

Page last updated: 2011-08-01

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