5.6 Embryofetal Toxicity
Based on its mechanism of action, MEKINIST can cause fetal harm when administered to a pregnant woman. MEKINIST was embryotoxic and abortifacient in rabbits at doses greater than or equal to those resulting in exposures approximately 0.3 times the human exposure at the recommended clinical dose. 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 (8.1).]

Advise female patients of reproductive potential to use highly effective contraception during treatment with MEKINIST and for 4 months after treatment. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking MEKINIST. [See Use in Specific Populations (8.1, 8.6).]

6 ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in another section of the label:

•
Cardiomyopathy [see Warnings and Precautions (5.1)]
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Retinal pigment epithelial detachment [see Warnings and Precautions (5.2)]
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Retinal vein occlusion [see Warnings and Precautions (5.3)]
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Interstitial lung disease [see Warnings and Precautions (5.4)]
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Serious skin toxicity [see Warnings and Precautions (5.5)]
 

6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described in the Warnings and Precautions section and below reflect exposure to MEKINIST in 329 patients including 107 (33%) exposed for greater than or equal to 6 months and 30 (9%) exposed for greater than or equal to one year. MEKINIST was studied in open-label, single-arm trials (N = 118) or in an open-label, randomized, active-controlled trial (N = 211). The median age was 54, 60% were male, >99% were white, and all patients had metastatic melanoma. All patients received 2 mg once-daily doses of MEKINIST. The incidence of RPED and RVO are obtained from the 1,749 patients from all clinical trials with MEKINIST.

Table 2 presents adverse reactions identified from analyses of Trial 1, [see Clinical Studies (14.1)] a randomized, open-label trial of patients with BRAF V600E or V600K mutation-positive melanoma receiving MEKINIST (N = 211) 2 mg orally once daily or chemotherapy (N = 99) [either dacarbazine 1,000 mg/m2 every 3 weeks or paclitaxel 175 mg/m2 every 3 weeks]. Patients with abnormal LVEF, history of acute coronary syndrome within 6 months, or current evidence of Class II or greater congestive heart failure (New York Heart Association) were excluded from Trial 1. The median duration of treatment with MEKINIST was 4.3 months. In Trial 1, 9% of patients receiving MEKINIST experienced adverse reactions resulting in permanent discontinuation of trial medication. The most common adverse reactions resulting in permanent discontinuation of MEKINIST were decreased left ventricular ejection fraction (LVEF), pneumonitis, renal failure, diarrhea, and rash. Adverse reactions led to dose reductions in 27% of patients treated with MEKINIST. Rash and decreased LVEF were the most common reasons cited for dose reductions of MEKINIST.

Table 2. Selected Adverse Reactions Occu