new primary cutaneous malignancies.
Noncutaneous Malignancies: In the NSCLC study, noncutaneous malignancies occurred in 1.1% of patients receiving TAFINLAR with MEKINIST. Monitor patients closely for signs or symptoms of noncutaneous malignancies. Permanently discontinue TAFINLAR for monomeric G protein (RAS)-mutation–positive noncutaneous malignancies. No dose modification of MEKINIST is required for patients who develop noncutaneous malignancies.
Tumor Promotion in BRAF Wild-type NSCLC. In vitro experiments have demonstrated paradoxical activation of mitogen-activated protein kinase (MAPK) signaling and increased cell proliferation in BRAF wild-type cells that are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E mutation status prior to initiation of therapy.
Hemorrhage. Hemorrhages, including major hemorrhages defined as symptomatic bleeding in a critical area or organ, can occur. In the COMBI-d study, the incidence of hemorrhagic events in patients treated with the combination was 19% compared with 15% of patients receiving single-agent TAFINLAR. Gastrointestinal hemorrhage occurred in 6% of patients treated with the combination compared with 3% of patients receiving single-agent TAFINLAR. In the NSCLC study, fatal hemorrhagic events occurred in 2.2% of patients receiving TAFINLAR with MEKINIST.
Permanently discontinue TAFINLAR and MEKINIST for all grade 4 hemorrhagic events and for any grade 3 hemorrhagic events that do not improve. Withhold TAFINLAR and MEKINIST for grade 3 hemorrhagic events; if improved, resume at the next lower dose level.
Colitis and Gastrointestinal Perforation. Colitis and gastrointestinal perforation, including fatal outcomes, can occur. Across clinical trials with MEKINIST, colitis occurred in 0.6% of patients and gastrointestinal perforation occurred in 0.3% of patients, respectively. Monitor patients closely for colitis and gastrointestinal perforations.
Venous Thromboembolism. In the NSCLC study, deep venous thrombosis (DVT) and pulmonary embolism (PE) occurred in 4.3% (4/93) of patients receiving TAFINLAR with MEKINIST.
Advise patients to immediately seek medical care if they develop symptoms of DVT or PE such as shortness of breath, chest pain, or arm or leg swelling. Permanently discontinue MEKINIST and TAFINLAR for life-threatening PE. Withhold MEKINIST for uncomplicated DVT or PE for up to 3 weeks; if improved, MEKINIST may be resumed at a lower dose.
Cardiomyopathy. Cardiomyopathy, including cardiac failure, can occur. In the NSCLC clinical trial, cardiomyopathy, defined as a decrease in left ventricular ejection fraction (LVEF) below the institutional lower limit of normal (LLN) with an absolute decrease in LVEF >10% below baseline, occurred in 9% of patients receiving TAFINLAR with MEKINIST and resulted in dose interruption and permanent discontinuation of MEKINIST in 5% and 2.2% of patients, respectively. Dose interruption and permanent discontinuation of TAFINLAR occurred in 3.2% and 2.2% of patients, respectively. Cardiomyopathy resolved in 4 of 8 patients receiving TAFINLAR with MEKINIST.
Assess LVEF by an echocardiogram or a multigated acquisition (MUGA) scan before initiation of therapy, 1 month after initiation then at 2- to 3-month intervals while on treatment. Withhold MEKINIST for up to 4 weeks, and continue TAFINLAR at the same dose if absolute LVEF value decreases by 10% from pretreatment values and is <LLN. For symptomatic cardio |
