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Pregnancy: Risk summary: Mekinist can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of Mekinist in pregnant women. Reproductive studies in animals (rats and rabbits) have demonstrated that trametinib induces maternal and developmental toxicity. In rats decreased fetal weight and increased incidences of post implantation loss were observed following maternal exposure to trametinib at concentrations 0.3 and 1.8 times the exposure in humans at the highest recommended dose of 2 mg once daily. In rabbits, decreased fetal weight and increased incidence of variations in ossification and post implantation loss were observed following maternal exposure to trametinib at concentrations 0.09 and 0.3 times the exposure in humans at the highest recommended dose of 2 mg once daily. Pregnant women should be advised of the potential risk to the fetus.
Animal data: In embryo-fetal development studies, rats and rabbits received oral doses of trametinib up to 0.125 mg/kg/day and 0.31 mg/kg/day, respectively, during the period of organogenesis. In rats at ≥0.031 mg/kg/day and 0.125 mg/kg/day, maternal systemic exposures (AUC) were 110 ng*h/mL and 684 ng*h/mL, respectively, corresponding to approximately 0.3 and 1.8 times the exposure in humans at the highest recommended dose of 2 mg once daily. At doses ≥0.031 mg/kg/day developmental toxicity consisted of decreased fetal weights. At a dose of 0.125 mg/kg/day there was maternal toxicity and increases in post implantation loss. In rabbits at ≥0.039 mg/kg/day and 0.15 mg/kg/day, maternal systemic exposures (AUC) were 31.9 ng*h/mL and 127 ng*h/mL, respectively corresponding to approximately 0.09 and 0.3 times the exposures in humans at the highest recommended dose of 2 mg once daily. At doses ≥0.039 mg/kg/day developmental toxicity consisted in decreased fetal body weight and increased incidence of variations in ossification. At doses 0.15 mg/kg/day there were increases in post-implantation loss, including total loss of pregnancy, compared with control animals.
Lactation: Risk summary: There are no data on the effect of Mekinist on the breast-fed child, or the effect of Mekinist on milk production. Because many drugs are transferred into human milk and because of the potential for adverse reactions in nursing infants from Mekinist, a nursing woman should be advised on the potential risks to the child. The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for Mekinist and any potential adverse effects on the breast-fed child from Mekinist or from the underlying maternal condition.
Females and males of reproductive potential: Contraception: Females: Females of reproductive potential should be advised that animal studies have been performed showing Mekinist to be harmful to the developing fetus. Sexually-active females of reproductive potential are recommended to use effective contraception (methods that result in less than 1% pregnancy rates) when taking Mekinist and for at least 16 weeks after stopping treatment with Mekinist.
Females of reproductive potential receiving Mekinist in combination with dabrafenib should be advised that dabrafenib may decrease the efficacy of oral or any other systemic hormonal contraceptives, and an effective alternative method of contraception should be used.
Males: Male patients (including those that have had a vasectomy) with sexual partners who are pregnant, possibly pregnant, or who could become pregnant should use condoms during sexual intercourse while taking Mekinist monotherapy or in combination with Dabrafenib and for at least 16 weeks after stopping treatment with Mekinist.
Infertility: There is no information on the effect of Mekinist on human fertility. In animals, no fertility studies have been performed, but adverse effects were seen on female reproductive organs (see Pharmacology: Toxicology: Non-Clinical Safety Data under Actions). Mekinist may impair fertility in humans.
