Mektovi · 4.4 Special warnings and precautions for use · 1

HOS-098443 · has-adverse-reaction-information · PDF-Seite 11

Summary of safety profile The safety of binimetinib (45 mg orally twice daily) in combination with encorafenib (450 mg orally once daily) has been evaluated in the integrated safety population (ISP) of 372 patients including patients with BRAF V600 mutant unresectable or metastatic melanoma and BRAF V600E mutant advanced NSCLC (hereafter referred to as Combo 450 ISP). In Combo 450 ISP, 274 patients received the combination for the treatment of BRAF V600 mutant unresectable or metastatic melanoma (in two Phase II studies (CMEK162X2110 and CLGX818X2109) and one Phase III study (CMEK162B2301, Part 1), and 98 received the combination for the treatment of BRAF V600E mutant advanced NSCLC (in one non-randomized Phase II study (ARRAY-818-202)) (see section 5.1). The most common adverse reactions (> 25 %) occurring in patients treated with binimetinib administered with encorafenib were fatigue, nausea, diarrhoea, vomiting, abdominal pain, myopathy/muscular disorders and arthralgia. The safety of encorafenib (300 mg orally once daily) in combination with binimetinib (45 mg orally twice daily) was evaluated in 257 patients with BRAF V600 mutant unresectable or metastatic melanoma (hereafter referred to as the Combo 300 population), based on the Phase III study (CMEK162B2301, Part 2). The most common adverse reactions (>25%) occurring in patients treated with encorafenib 300 mg administered with binimetinib were fatigue, nausea and diarrhoea. Tabulated list of adverse reactions Adverse reactions are listed below by MedDRA body system organ class and the following frequency convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1 000 to <1/100), rare (≥1/10 000 to <1/1 000), very rare (<1/10 000) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Table 3: Adverse reactions occurring in patients receiving binimetinib in combination with encorafenib at the recommended dose (n = 372) System Organ Class Adverse reaction Frequency (All grades) Cutaneous squamous cell carcinomaa Common Neoplasms benign, Skin papilloma* Common malignant and unspecified Basal cell carcinoma* Uncommon Blood and lymphatic Anaemia

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HOS-098439 · has-contraindication-information · PDF-Seite 7

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

HOS-098438 · has-indication-information · PDF-Seite 2

Melanoma Binimetinib in combination with encorafenib is indicated for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation. Non-small cell lung cancer (NSCLC) Binimetinib in combination with encorafenib is indicated for the treatment of adult patients with advanced non-small cell lung cancer with a BRAF V600E mutation.

HOS-098441 · has-interaction-information · PDF-Seite 10

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 evaluated in a formal clinical study, UGT1A1 inducers (such as rifampicin and phenobarbital) and inhibitors (such as indinavir, atazanavir, sorafenib) should be co-administered with caution. 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).

HOS-098442 · has-pregnancy-information · PDF-Seite 10

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 milk. A risk to the breastfed 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 10 There are no data on the effect on fertility in humans for binimetinib.

HOS-098440 · has-warning-information · PDF-Seite 7

Binimetinib is to be given in combination with encorafenib. For additional information on warnings and precautions associated with encorafenib treatment, see section 4.4 of encorafenib SmPC. Binimetinib in combination with encorafenib in patients who have progressed on a BRAF inhibitor There are limited data for use of the combination of binimetinib with encorafenib in patients who have progressed on a prior BRAF inhibitor given for the treatment of unresectable or metastatic melanoma with BRAF V600 mutation. These data show that the efficacy of the combination would be lower in these patients. Binimetinib in combination with encorafenib in patients with brain metastases There are limited efficacy data with the combination of binimetinib and encorafenib in patients with a BRAF V600 mutant melanoma or BRAF V600E mutant NSCLC which have metastasised to the brain (see section 5.1). Left ventricular dysfunction (LVD) LVD defined as symptomatic or asymptomatic decreases in ejection fraction can occur when binimetinib is administered. It is recommended that LVEF is assessed by echocardiogram or multi-gated acquisition (MUGA) scan before initiation of binimetinib, 1 month after initiation, and then at approximately 3-month intervals or more frequently as clinically indicated, while on treatment. The occurrence of LVEF decrease can be managed with treatment interruption, dose reduction or with treatment discontinuation (see section 4.2). The safety of binimetinib in combination with encorafenib has not been established in patients with a baseline LVEF that is either below 50 % or below the institutional LLN. Therefore, in these patients, binimetinib should be used with caution and for any symptomatic left ventricular dysfunction, Grade 3-4 LVEF, or absolute decrease of LVEF from baseline of ≥ 10 %, binimetinib should be discontinued and LVEF should be evaluated every 2 weeks until recovery. Haemorrhage Haemorrhages, including major haemorrhagic events, can occur when binimetinib is administered (see section 4.8). The risk of haemorrhage may be increased with concomitant use of anticoagulant and antiplatelet therapy. The occurrence of Grade ≥ 3 haemorrhagic events should be managed with dose 7 interruption, reduction or treatment discontinuation (see Table 2 in section 4.2) and as clinically indicated. Ocular toxicities Ocular toxicities including RPED and RVO can occur when binimetinib is adminis

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