gher incidence in patients aged > 65 years compared to patients aged < 65 years included diarrhoea, pruritus, GGT and blood phosphatase alkaline elevation. In the small group of patients aged ≥ 75 years (n=15), patients were more likely to experience serious adverse events and adverse events leading to discontinuation of treatment.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via United Kingdom: Yellow Card Scheme; website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store. Ireland: HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2, Tel: +353 1 6764971, Fax: +353 1 6762517, website: www.hpra.ie, e-mail: medsafety@hpra.ie.
4.9 Overdose
The highest dose of binimetinib eva luated as single agent in clinical studies was 80 mg administered orally twice daily and was associated with ocular (chorioretinopathy) and skin toxicities (dermatitis acneiform).
There is no specific treatment of overdose. If overdose occurs, the patient should be treated supportively with appropriate monitoring as necessary.
Since binimetinib is highly bound to plasma proteins, haemodialysis is likely to be ineffective in the treatment of overdose with binimetinib.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: antineoplastic agent, protein kinase inhibitor, ATC code: L01XE41
Mechanism of action
Binimetinib is an ATP-uncompetitive, reversible inhibitor of the kinase activity of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2. In cell free system, binimetinib inhibits MEK1 and MEK2 with the half maximal inhibitory concentration (IC50)'s in the 12-46 nM. MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway, which promotes cellular proliferation. In melanoma and other cancers, this pathway is often activated by mutated forms of BRAF which activates MEK. Binimetinib inhibits activation of MEK by BRAF and inhibits MEK kinase activity. Binimetinib inhibits growth of BRAF V600 mutant melanoma cell lines and demonstrates anti-tumour effects in BRAF V600 mutant melanoma animal models.
Combination with encorafenib
Binimetinib and encorafenib (a BRAF inhibitor, see section 5.1 of encorafenib SmPC) both inhibit the MAPK pathway resulting in higher anti-tumour activity.
Additionally, the combination of encorafenib and binimetinib prevented the emergence of treatment resistance in BRAF V600E mutant human melanoma xenografts in vivo.
Clinical efficacy and safety
BRAF V600 mutant unresectable or metastatic melanoma
The safety and efficacy of binimetinib in combination with encorafenib were eva luated in a 2-part Phase III, randomised (1:1:1) active-controlled, open-label, multicenter study in patients with unresectable or metastatic BRAF V600 E or K mutant melanoma (Study CMEK162B2301), as detected using a BRAF assay. Patients had histologically confirmed cutaneous or unknown primary melanoma but those with uveal or mucosal melanoma were excluded. Patients were permitted to receive prior adjuvant therapy and one prior line of immunotherapy for unresec
