Important Safety Information

WARNINGS AND PRECAUTIONS

New Primary Malignancies

Cutaneous Malignancies

• In Trial 1 in patients with unresectable or metastatic melanoma, cutaneous squamous cell carcinoma, keratoacanthoma, and melanoma occurred at a higher incidence in patients receiving ZELBORAF compared to those in the control arm. The incidence of cutaneous squamous cell carcinomas (cuSCC) and keratoacanthomas in the ZELBORAF arm was 24% compared to <1% in the dacarbazine arm. 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 1, new primary malignant melanoma occurred in 2.1% (7/336) of patients receiving ZELBORAF compared to none of the patients receiving dacarbazine.
• 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.
• Perform dermatologic evaluations prior to initiation of therapy and every 2 months while on therapy. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Consider dermatologic monitoring for 6 months following discontinuation of ZELBORAF.

Non-Cutaneous Squamous Cell Carcinoma

• Non-cutaneous squamous cell carcinomas (non-cuSCC) of the head and neck can occur in patients receiving ZELBORAF. Monitor patients receiving ZELBORAF closely for signs or symptoms of new non-cuSCC.

Other Malignancies

• Based on its mechanism of action, ZELBORAF may promote malignancies associated with activation of RAS through mutation or other mechanisms. Monitor patients receiving ZELBORAF closely for signs or symptoms of other malignancies.
• Cases of myeloid neoplasms amongst patients with ECD have been observed, including patients who have received ZELBORAF. Monitoring complete blood count in ECD patients with co-existing myeloid malignancies is recommended.

Tumor Promotion in BRAF Wild-Type Melanoma

• In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells that are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E mutation in tumor specimens prior to initiation of ZELBORAF.

Hypersensitivity Reactions

• Anaphylaxis and other serious hypersensitivity reactions can occur during treatment and upon re-initiation of treatment with ZELBORAF. Severe hypersensitivity reactions included generalized rash and erythema, hypotension, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome).
• Permanently discontinue ZELBORAF in patients who experience a severe hypersensitivity reaction.

Dermatologic Reactions

• Severe dermatologic reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, can occur in patients receiving ZELBORAF.
• Permanently discontinue ZELBORAF in patients who experience a severe dermatologic reaction.

QT Prolongation

• Concentration-dependent QT prolongation occurred in an uncontrolled, open-label QT substudy in previously treated patients with BRAF V600E mutation-positive metastatic melanoma. QT prolongation may lead to an increased risk of ventricular arrhythmias, including Torsade de Pointes.
• Do not start treatment in patients with uncorrectable electrolyte abnormalities, QTc >500 ms, or long QT syndrome, or in patients who are taking medicinal products known to prolong the QT interval. Prior to and following treatment initiation or after dose modification of ZELBORAF for QTc prolongation, evaluate ECG and electrolytes (including potassium, magnesium, and calcium) after 15 days, monthly during the first 3 months, and then every 3 months thereafter or more often as clinically indicated.
• Withhold ZELBORAF in patients who develop QTc >500 ms (Grade 3). Upon recovery to QTc ≤500 ms (Grade ≤2), restart at a reduced dose. Permanently discontinue ZELBORAF treatment if the QTc interval remains >500 ms and increased >60 ms from pretreatment values after controlling cardiac risk factors for QT prolongation (eg, electrolyte abnormalities, congestive heart failure, and bradyarrhythmias).

Hepatotoxicity

• Liver injury leading to functional hepatic impairment, including coagulopathy or other organ dysfunction, can occur with ZELBORAF.
• Monitor transaminases, alkaline phosphatase, and bilirubin before initiation of treatment and monthly during treatment, or as clinically indicated. Manage laboratory abnormalities with dose reduction, treatment interruption, or treatment discontinuation.

Concurrent Administration with Ipilimumab

• The safety and effectiveness of ZELBORAF in combination with ipilimumab have not been established.
• In a dose-finding trial, Grade 3 increases in transaminases and bilirubin occurred in a majority of patients who received concurrent ipilimumab (3 mg/kg) and vemurafenib (960 mg twice daily or 720 mg twice daily).

Photosensitivity

• Mild to severe photosensitivity can occur in patients treated with ZELBORAF. Advise patients to avoid sun exposure, wear protective clothing, and use a broad-spectrum UVA/UVB sunscreen and lip balm (SPF ≥30) when outdoors.

• Institute dose modifications for intolerable Grade 2 or greater photosensitivity.

Ophthalmologic Reactions

• Uveitis, blurry vision, and photophobia can occur in patients treated with ZELBORAF.
• In Trial 1, uveitis, including iritis, occurred in 2.1% (7/336) of patients receiving ZELBORAF compared to no patients in the dacarbazine arm.
• Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Monitor patients for signs and symptoms of uveitis.

Embryo-Fetal Toxicity

• Based on its mechanism of action, ZELBORAF can cause fetal harm when administered to a pregnant woman.
• Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with ZELBORAF and for 2 weeks after the final dose.

Radiation Sensitization and Radiation Recall

• Radiation sensitization and recall, in some cases severe, involving cutaneous and visceral organs have been reported in patients treated with radiation prior to, during, or subsequent to vemurafenib treatment. Fatal cases have been reported in patients with visceral organ involvement.
• Monitor patients closely when vemurafenib is administered concomitantly or sequentially with radiation treatment.

Renal Failure

• Renal failure, including acute interstitial nephritis and acute tubular necrosis, can occur with ZELBORAF. In patients with unresectable or metastatic melanoma, 26% of Zelboraf treated-patients and 5% of dacarbazine-treated patients experienced Grade 1-2 creatinine elevations (greater than 1 and up to 3 times upper limit of normal [ULN]); 1.2% of ZELBORAF-treated patients and 1.1% of dacarbazine-treated patients experienced Grade 3-4 creatinine elevations (greater than 3 times ULN).
• In patients with ECD, 86% (19/22) of patients experienced Grade 1/2 creatinine elevations and 9.1% (2/22) of patients experienced Grade 3 creatinine elevations.
• Measure serum creatinine before initiation of ZELBORAF and periodically during treatment.

Dupuytren’s Contracture and Plantar Fascial Fibromatosis

• Dupuytren’s contracture and plantar fascial fibromatosis have been reported with ZELBORAF. The majority of cases were mild to moderate, but severe, disabling cases have also been reported.
• Events should be managed with dose reduction, treatment interruption, or treatment discontinuation.

DRUG INTERACTIONS

• Avoid coadministration of ZELBORAF with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) or strong inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital), and replace these drugs with alternative drugs when possible.
• Avoid concomitant use of ZELBORAF with drugs having a narrow therapeutic window that are predominantly metabolized by CYP1A2. If coadministration cannot be avoided, monitor closely for toxicities and consider a dose reduction of concomitant CYP1A2 substrates.
• Avoid concurrent use of P-glycoprotein (P-gp) substrates known to have narrow therapeutic indices. If use of these medications is unavoidable, consider dose reduction of P-gp substrates with narrow therapeutic indices.

USE IN SPECIFIC POPULATIONS: Lactation

Because of the potential for serious adverse reactions in a breastfed infant, including malignancy, severe dermatologic reactions, QT prolongation, hepatotoxicity, photosensitivity, and ophthalmologic toxicity, advise women not to breastfeed during treatment with ZELBORAF and for 2 weeks after the final dose.

Most Common Adverse Reactions

Melanoma: Most common adverse reactions (≥ 30%) are arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus, and skin papilloma.

Erdheim-Chester Disease: Most common adverse reactions (>50%) are arthralgia, rash maculo-papular, alopecia, fatigue, electrocardiogram QT interval prolonged, and skin papilloma.

You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at (888) 835-2555.

Please see accompanying Full Prescribing Information for additional Important Safety Information.