While encorafenib is a relatively potent reversible inhibitor of UGT1A1, no differences in binimetinib exposure have been observed clinically when binimetinib is co-administered with encorafenib (see section 5.2).

Inducers of CYP1A2 enzymes (such as carbamazepine and rifampicin) and inducers of Pgp transport (such as Saint John's wort or phenytoin) may decrease binimetinib exposure, which could result in a decrease of efficacy.

Effects of binimetinib on other medicinal products

Binimetinib is a potential inducer of CYP1A2, and caution should be taken when it is used with sensitive substrates (such as duloxetine or theophylline).

Binimetinib is a weak inhibitor of OAT3, and caution should be taken when it is used with sensitive substrates (such as pravastatin or ciprofloxacin).

4.6 Fertility, pregnancy and lactation

Women of childbearing potential/Contraception in females

Women of childbearing potential must use effective contraception during treatment with binimetinib and for at least 1 month following the last dose.

Pregnancy

There are no data from the use of binimetinb in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Binimetinib is not recommended during pregnancy and in women of childbearing potential not using contraception. If binimetinib is used during pregnancy, or if the patient becomes pregnant while taking binimetinib, the patient should be informed of the potential hazard to the foetus.

Breast-feeding

It is unknown whether binimetinib or its metabolite are excreted in human. A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue Mektovi therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the mother.

Fertility

There are no data on the effect on fertility in humans for binimetinib.

4.7 Effects on ability to drive and use machines

Binimetinib has minor influence on the ability to drive or use machines. Visual disturbances have been reported in patients treated with binimetinib during clinical studies. Patients should be advised not to drive or use machines if they experience visual disturbances or any other adverse reaction that may affect their ability to drive and use machines (see sections 4.4 and 4.8).

4.8 Undesirable effects

Summary of safety profile

The safety of binimetinib (45 mg orally twice daily) in combination with encorafenib (450 mg orally once daily) (hereafter referred to as Combo 450) was eva luated in 274 patients with BRAF V600 mutant unresectable or metastatic melanoma, based on two Phase II studies (CMEK162X2110 and CLGX818X2109) and one Phase III study (CMEK162B2301, Part 1) (hereafter referred to as the pooled Combo 450 population). At the recommended dose (n = 274) in patients with unresectable or metastatic melanoma, the most common adverse reactions (> 25 %) occurring in patients treated with binimetinib administered with encorafenib were fatigue, nausea, diarrhoea, vomiting, retinal detachment, abdominal pain, arthralgia, blood CK increased and myalgia.