n 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 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 administered. Uveitis including iridocyclitis and iritis have been reported in patients treated with binimetinib in combination with encorafenib (see section 4.8).
Binimetinib is not recommended in patients with a history of RVO. The safety of binimetinib has not been established in patients with predisposing factors for RVO including uncontrolled glaucoma, ocular hypertension, uncontrolled diabetes mellitus or a history of hyperviscosity or hypercoagulability syndromes. Therefore, binimetinib should be used with caution in these patients.
Patients should be assessed at each visit for symptoms of new or worsening visual disturbances. If symptoms of new or worsening visual disturbances including diminished central vision, blurred vision or loss of vision are identified, a prompt ophthalmologic examination is recommended.
The occurrence of symptomatic RPED can be managed with treatment interruption, dose reduction or with treatment discontinuation (see Table 1 in section 4.2).
Binimetinib should be permanently discontinued with the occurrence of RVO (see Table 1 in section 4.2).
If during treatment patient develops uveitis, see section 4.2 of encorafenib SmPC for guidance.
CK elevation and rhabdomyolysis
Asymptomatic CK elevations are seen in patients treated with binimetinib (see section 4.8), and, rhabdomyolysis was uncommonly reported. Special attention should be paid to patients with neuromuscular conditions associated with CK elevation and rhabdomyolysis.
CK and creatinine levels should be monitored monthly during the first 6 months of treatment and as clinically indicated. The patient should be advised to maintain an adequate fluid intake during treatment. Depending on the severity of symptoms, degree of CK elevation or creatinine elevation, dose reduction, dose interruption or permanent discontinuation of binimetinib may be required (see Table 1 in section 4.2).
Hypertension
Hypertension, or worsening of pre-existing hypertension, can occur with the use of binimetinib. Blood pressure should be measured at baseline and monitored during treatment, with control of hypertension by standard therapy as appropriate. In case of severe hypertension, temporary interruption of binimetinib is recommended until hypertension is controlled (see Table 2 in section 4.2).
Venous thromboembolism (VTE)
VTE can occur when binimetinib is administered (see section 4.8). Binimetinib should be used with caution in patients who are at risk for, or who have a history of VTE.
If during treatment patient develops VTE or pulmonary embolism, it should be managed with dose interruption, reduction or treatment discontinuation (see Table 1 in section 4.2).
Pneumonitis/Interstitial lung disease
Pneumonitis/ILD can occur with binimetinib. Treatment with binimetinib should be withheld in patients with suspected pneumonitis or ILD, including patients presenting new or progressive pulmonary symptoms or findings such as cough, dyspnoea, hypoxi
