f patients treated with Mekinist; no chemotherapy-treated patient in Trial 1 developed cardiomyopathy. The median time to onset of cardiomyopathy in patients treated with Mekinist was 63 days (range: 16 to 156 days); cardiomyopathy was identified within the first month of treatment with Mekinist in five of these 14 patients. Four percent of patients in Trial 1 required discontinuation (4/211) and/or dose reduction (7/211) of Mekinist. Cardiomyopathy resolved in 10 of these 14 (71%) patients.
Across clinical trials of Mekinist at the recommended dose (N = 329), 11% of patients developed evidence of cardiomyopathy (decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF ≥10% below baseline) and 5% demonstrated a decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF of ≥20% below baseline.
Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of Mekinist, one month after initiation of Mekinist, and then at 2- to 3-month intervals while on treatment. Withhold treatment if absolute LVEF value decreases by 10% from pre-treatment values and is less than the lower limit of normal. Permanently discontinue Mekinist for symptomatic cardiomyopathy or persistent, asymptomatic LVEF dysfunction that does not resolve within 4 weeks [see Dosage and Administration (2.3)].
Retinal Pigment Epithelial Detachment (RPED)
Retinal pigment epithelial detachments (RPED) can occur during treatment with Mekinist. In Trial 1, where ophthalmologic examinations including retinal eva luation were performed pretreatment and at regular intervals during treatment, one patient (0.5%) receiving Mekinist developed RPED and no cases of RPED were identified in chemotherapy-treated patients. Across all clinical trials of Mekinist, the incidence of RPED was 0.8% (14/1749).
Retinal detachments were often bilateral and multifocal, occurring in the macular region of the retina. RPED led to reduction in visual acuity that resolved after a median of 11.5 days (range: 3 to 71 days) following the interruption of dosing with Mekinist, although Ocular Coherence Tomography (OCT) abnormalities persisted beyond a month in at least several cases.
Perform ophthalmological eva luation at any time a patient reports visual disturbances and compare to baseline, if available. Withhold Mekinist if RPED is diagnosed. If resolution of the RPED is documented on repeat ophthalmological eva luation within 3 weeks, resume Mekinist at a reduced dose [see Dosage and Administration (2.3)].
Retinal Vein Occlusion (RVO)
Across all clinical trials of Mekinist, the incidence of RVO was 0.2% (4/1749). An RVO may lead to macular edema, decreased visual function, neovascularization, and glaucoma.
Urgently (within 24 hours) perform ophthalmological eva luation for patient-reported loss of vision or other visual disturbances. Permanently discontinue Mekinist in patients with documented retinal vein occlusion [see Dosage and Administration (2.3)].
Interstitial Lung Disease
In clinical trials of Mekinist at the recommended dose (N = 329), interstitial lung disease (ILD) or pneumonitis occurred in 1.8% of patients. In Trial 1, 2.4% (5/211) of patients treated with Mekinist developed ILD or pneumonitis; all five patients required hospitalization. The median time to first presentation of ILD or pneumonitis was 160 days (range: 60 to 172 days).
Withhold Mekinist in patients present |
