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IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

New Primary Malignancies: New primary malignancies, cutaneous and non-cutaneous, can occur. In the PHAROS trial, cutaneous squamous cell carcinoma (cuSCC) and skin papilloma (SP), each occurred in 2% of patients. Perform dermatologic evaluations prior to initiating treatment, every 2 months during treatment, and for up to 6 months following discontinuation of treatment. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Dose modification is not recommended for new primary cutaneous malignancies. Based on its mechanism of action, BRAFTOVI may promote malignancies associated with activation of RAS through mutation or other mechanisms. Monitor patients receiving BRAFTOVI for signs and symptoms of non-cutaneous malignancies. Discontinue BRAFTOVI for RAS mutation-positive non-cutaneous malignancies. Monitor patients for new malignancies prior to initiation of treatment, while on treatment, and after discontinuation of treatment.

Tumor Promotion in BRAF Wild-Type Tumors: In vitro experiments have demonstrated paradoxical activation of MAP- kinase signaling and increased cell proliferation in BRAF wild-type cells exposed to BRAF inhibitors. Confirm evidence of BRAF V600E or V600K mutation using an FDA-approved test prior to initiating BRAFTOVI.

Cardiomyopathy: Cardiomyopathy manifesting as left ventricular dysfunction associated with symptomatic or asymptomatic decreases in ejection fraction, has been reported in patients. In the PHAROS trial, evidence of cardiomyopathy occurred in 11% and Grade 3 left ventricular dysfunction occurred in 1% of patients. Cardiomyopathy resolved in 82% of patients. Assess left ventricular ejection fraction (LVEF) by echocardiogram or multi-gated acquisition (MUGA) scan prior to initiating treatment, 1 month after initiating treatment, and then every 2 to 3 months during treatment. The safety has not been established in patients with a baseline ejection fraction that is either below 50% or below the institutional lower limit of normal (LLN). Patients with cardiovascular risk factors should be monitored closely. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction.

Hepatotoxicity: Hepatotoxicity can occur when MEKTOVI is administered in combination with BRAFTOVI. In the PHAROS trial, the incidence of Grade 3 or 4 increases in liver function laboratory tests was 10% for aspartate aminotransferase (AST), 9% for alanine aminotransferase (ALT), and 3.2% for alkaline phosphatase. Monitor liver laboratory tests before initiation of BRAFTOVI and MEKTOVI, monthly during treatment, and as clinically indicated. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction.

Rhabdomyolysis: Rhabdomyolysis can occur when MEKTOVI is administered in combination with BRAFTOVI. In the PHAROS trial, elevation of laboratory values of serum creatine kinase (CK) occurred in 41% of patients. No patient experienced rhabdomyolysis. Monitor CPK and creatinine levels prior to initiating MEKTOVI, periodically during treatment, and as clinically indicated. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction.

Hemorrhage: Hemorrhage can occur when BRAFTOVI is administered in combination with MEKTOVI. In the PHAROS trial, hemorrhage occurred in 12% of patients, including fatal intracranial hemorrhage (1%); Grade 3 or 4 hemorrhage occurred in 4.1% of patients. The most frequent hemorrhagic events were anal hemorrhage and hemothorax (2% each). Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction.

Venous Thromboembolism (VTE): In the PHAROS trial, VTE occurred in 7% of patients, including 1% of patients who developed pulmonary embolism. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction.

Ocular Toxicities: In the PHAROS trial, serous retinopathy (retinal detachment) occurred in 2% of patients with no cases of blindness. Retinal vein occlusion (RVO) is a known class-related adverse reaction of MEK inhibitors and may occur in patients treated with MEKTOVI in combination with BRAFTOVI. The safety of MEKTOVI has not been established in patients with a history of RVO or current risk factors for RVO including uncontrolled glaucoma or a history of hyperviscosity or hypercoagulability syndromes. Perform ophthalmological evaluation for patient-reported acute vision loss or other visual disturbance within 24 hours. Permanently discontinue MEKTOVI in patients with documented RVO. Uveitis, including iritis and iridocyclitis, was reported in patients treated with MEKTOVI in combination with BRAFTOVI. In PHAROS, uveitis occurred in 1% of patients. Assess for visual symptoms at each visit. Perform an ophthalmological evaluation at regular intervals and for new or worsening visual disturbances, and to follow new or persistent ophthalmologic findings. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction.

QT Prolongation: BRAFTOVI is associated with dose-dependent QTc interval prolongation in some patients. In the PHAROS trial, an increase in QTcF to >500 ms was measured in 2.1% (2/95) of patients who received BRAFTOVI with MEKTOVI. Monitor patients who already have or who are at significant risk of developing QTc prolongation, including patients with known long QT syndromes, clinically significant bradyarrhythmias, severe or uncontrolled heart failure and those taking other medicinal products associated with QT prolongation. Correct hypokalemia and hypomagnesemia prior to and during BRAFTOVI administration. Withhold, reduce dose, or permanently discontinue for QTc >500 ms.

Interstitial Lung Disease (ILD): In the PHAROS trial, 1 patient (1%) receiving MEKTOVI with BRAFTOVI developed pneumonitis. Assess new or progressive unexplained pulmonary symptoms or findings for possible ILD. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction.

Embryo-Fetal Toxicity: BRAFTOVI and MEKTOVI can cause fetal harm when administered to pregnant women. BRAFTOVI can render hormonal contraceptives ineffective. Effective, non-hormonal contraceptives should be used during treatment and for at least 30 days after the final dose for patients taking BRAFTOVI with MEKTOVI.

Risks Associated with BRAFTOVI as a Single Agent: There is an increased risk of certain adverse reactions compared to when BRAFTOVI is used in combination with MEKTOVI. If MEKTOVI is temporarily interrupted or permanently discontinued, reduce the dose of BRAFTOVI as recommended.

Risks Associated with Combination Treatment: BRAFTOVI is indicated for use as part of a regimen in combination with MEKTOVI. Refer to the prescribing information for BRAFTOVI and MEKTOVI for additional risk information.

Lactation: Advise women not to breastfeed during treatment with BRAFTOVI and MEKTOVI and for 2 weeks after the final dose.

Infertility: Advise males of reproductive potential that BRAFTOVI may impair fertility.

ADVERSE REACTIONS

The most common adverse reactions (≥25%, all grades, in the PHAROS trial) for BRAFTOVI with MEKTOVI were: fatigue (61%), nausea (58%), diarrhea (52%), musculoskeletal pain (48%), vomiting (37%), abdominal pain (32%), visual impairment (29%), constipation (27%), dyspnea (27%), rash (27%), and cough (26%).

Serious adverse reactions occurred in 38% of patients receiving BRAFTOVI with MEKTOVI. Serious adverse reactions (≥2% of patients in the PHAROS trial) were hemorrhage (6%), diarrhea (4.1%), anemia (3.1%), dyspnea (3.1%), pneumonia (3.1%), arrhythmia (2%), device related infection (2%), edema (2%), myocardial infarction (2%), and pleural effusion (2%). Fatal adverse reactions occurred in 2% of patients, including intracranial hemorrhage (1%) and myocardial infarction (1%).

Other clinically important adverse reactions occurring in <10% of patients who received BRAFTOVI with MEKTOVI in the PHAROS trial were peripheral neuropathy, dysgeusia, facial paresis, pancreatitis, hyperkeratosis, erythema, photosensitivity, and drug hypersensitivity.

In the PHAROS trial, the most common laboratory abnormalities (all grades) (≥20%) for BRAFTOVI and MEKTOVI included increased creatinine (91%), hyperglycemia (48%), anemia (47%), increased creatine kinase (41%), lipase increased (40%), increased ALT (34%), hypoalbuminemia (32%), increased alkaline phosphatase (31%), increased AST (31%), hyperkalemia (31%), hyponatremia (26%), lymphopenia (24%), serum amylase increased (22%), and thrombocytopenia (20%).

DRUG INTERACTIONS

Strong or moderate CYP3A4 inhibitors: Avoid coadministration of BRAFTOVI with strong or moderate CYP3A4 inhibitors, including grapefruit juice. If coadministration is unavoidable, reduce the BRAFTOVI dose.

Strong CYP3A4 inducers: Avoid coadministration of BRAFTOVI with strong CYP3A4 inducers.

Sensitive CYP3A4 substrates: Avoid the coadministration of BRAFTOVI with CYP3A4 substrates (including hormonal contraceptives) for which a decrease in plasma concentration may lead to reduced efficacy of the substrate. If the coadministration cannot be avoided, see the CYP3A4 substrate product labeling for recommendations.

Dose reductions of drugs that are substrates of OATP1B1, OATP1B3, or BCRP may be required when used concomitantly with BRAFTOVI.

Avoid coadministration of BRAFTOVI with drugs known to prolong QT/QTc interval.

The information above applies to the safety of the combination of BRAFTOVI and MEKTOVI unless otherwise noted. See full Prescribing Information for BRAFTOVI and for MEKTOVI for dose modifications for adverse reactions.

Please see full Prescribing Information for BRAFTOVI and full Prescribing Information for MEKTOVI for additional information.

INDICATIONS AND USAGE

BRAFTOVI and MEKTOVI are kinase inhibitors indicated for use in combination for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) with a BRAF V600E mutation, as detected by an FDA-approved test.

Limitations of Use: BRAFTOVI is not indicated for treatment of patients with wild-type BRAF NSCLC.