a, reticular opacities or pulmonary infiltrates (see Table 1 in section 4.2). Binimetinib should be permanently discontinued in patients diagnosed with treatment related pneumonitis or ILD.
New primary malignancies
New primary malignancies, cutaneous and non-cutaneous, have been observed in patients treated with BRAF inhibitors and can occur when binimetinib is administered in combination with encorafenib (see section 4.8).
Cutaneous malignancies
Cutaneous malignancies such as cutaneous squamous cell carcinoma (cuSCC) including kerathoacanthoma has been observed in patients treated with binimetinib when used in combination with encorafenib.
Dermatologic eva luations should be performed prior to initiation of therapy with binimetinib in combination with encorafenib, every 2 months while on therapy and for up to 6 months following discontinuation of the combination. Suspicious skin lesions should be managed with dermatological excision and dermatopathologic eva luation. Patients should be instructed to immediately inform their physicians if new skin lesions develop. Binimetinib and encorafenib should be continued without any dose modifications.
Non-cutaneous malignancies
Based on its mechanism of action, encorafenib may promote malignancies associated with activation of RAS through mutation or other mechanisms. Patients receiving binimetinib in combination with encorafenib should undergo a head and neck examination, chest/abdomen computerised tomography (CT) scan, anal and pelvic examinations (for women) and complete blood cell counts prior to initiation, during and at the end of treatment as clinically appropriate.
Permanent discontinuation of binimetinib and encorafenib should be considered in patients who develops RAS mutation-positive non-cutaneous malignancies. Benefits and risks should be carefully considered before administering binimetinib in combination with encorafenib to patients with a prior or concurrent cancer associated with RAS mutation.
Liver laboratory abnormalities
Liver laboratory abnormalities including AST and ALT elevations can occur with binimetinib (see section 4.8). Liver laboratory values should be monitored before initiation of binimetinib and encorafenib and at least monthly during the 6 first months of treatment, and then as clinically indicated. Liver laboratory abnormalities should be managed with dose interruption, reduction or treatment discontinuation (see Table 1 in section 4.2).
Hepatic impairment
Liver metabolism mainly via glucuronidation is the primary route of elimination of binimetinib (see section 5.2). As encorafenib is not recommended in patients with moderate (Child Pugh B) and severe hepatic impairment (Child Pugh C), administration of binimetinib is not recommended in these patients (see sections 4.2 and 5.2).
Lactose intolerance
Mektovi contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
4.5 Interaction with other medicinal products and other forms of interaction
Effects of other medicinal products on binimetinib
Binimetinib is primarily metabolised through UGT1A1 mediated glucuronidation. The extent of drug interactions mediated by UGT1A1 is unlikely to be clinically relevant (see section 5.2); however, as this has not been eva luate
