Vemurafenib - Warnings and Precautions

5 WARNINGS AND PRECAUTIONS New Primary Cutaneous Malignancies: Perform dermatologic evaluations prior to initiation of therapy, every 2 months while on therapy, and for up to 6 months following discontinuation of ZELBORAF.

Manage with excision and continue treatment without dose adjustment.

New Non-Cutaneous Squamous Cell Carcinoma: Evaluate for symptoms or clinical signs of new non-cutaneous SCC before initiation of treatment and periodically during treatment.

Other Malignancies: Monitor patients receiving ZELBORAF closely for signs or symptoms of other malignancies .

Tumor Promotion in BRAF Wild-Type Melanoma: Increased cell proliferation can occur with BRAF inhibitors .

Serious Hypersensitivity Reactions including anaphylaxis and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS Syndrome): Discontinue ZELBORAF for severe hypersensitivity reactions.

Severe Dermatologic Reactions, including Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: Discontinue ZELBORAF for severe dermatologic reactions.

QT Prolongation: Monitor ECG and electrolytes before and during treatment.

Withhold ZELBORAF for QTc of 500 ms or greater.

Correct electrolyte abnormalities and control for cardiac risk factors for QT prolongation.

Hepatotoxicity: Measure liver enzymes and bilirubin before initiating ZELBORAF and monitor monthly during treatment.

Photosensitivity: Advise patients to avoid sun exposure.

Serious Ophthalmologic Reactions: Monitor for signs and symptoms of uveitis.

Embryo-Fetal Toxicity: Can cause fetal harm.

Advise females of the potential risk to the fetus and to use effective contraception. ( 5.9 , 8.1 , 8.3 ) Radiation Sensitization and Radiation Recall: Severe cases have been reported. .

Renal Failure: Measure serum creatinine before initiating ZELBORAF and monitor periodically during treatment .

Dupuytren's Contracture and plantar fascial fibromatosis: Events should be managed with dose reduction, treatment interruption, or treatment discontinuation. .

5.1 New Primary Malignancies Cutaneous Malignancies Cutaneous squamous cell carcinoma, keratoacanthoma, and melanoma occurred at a higher incidence in patients receiving ZELBORAF compared to those in the control arm in Trial 1.

The incidence of cutaneous squamous cell carcinomas (cuSCC) and keratoacanthomas in the ZELBORAF arm was 24% compared to < 1% in the dacarbazine arm [see Adverse Reactions ] .

The median time to the first appearance of cuSCC was 7 to 8 weeks; approximately 33% of patients who developed a cuSCC while receiving ZELBORAF experienced at least one additional occurrence with median time between occurrences of 6 weeks.

Potential risk factors associated with cuSCC observed in clinical studies using ZELBORAF included age (≥ 65 years), prior skin cancer, and chronic sun exposure.

In Trial 4, in patients with ECD, the incidence of cuSCC and/or keratoacanthomas was 40.9% (9/22).

The median time to first appearance of cuSCC amongst patients with at least one occurrence was 12.1 weeks.

In Trial 1, in patients with unresectable or metastatic melanoma, new primary malignant melanoma occurred in 2.1% (7/336) of patients receiving ZELBORAF compared to none of the patients receiving dacarbazine.

Perform dermatologic evaluations prior to initiation of therapy and every 2 months while on therapy.