Common

*composite terms which included more than one preferred term

a includes keratoacanthoma, squamous cell carcinoma, lip squamous cell carcinoma and squamous cell carcinoma of skin

b includes angioedema, drug hypersensitivity, hypersensitivity, hypersensitivity vasculitis and urticaria

c includes facial nerve disorder, facial paralysis, facial paresis

d includes left ventricular dysfunction, ejection fraction decreased, cardiac failure and ejection fraction abnormal

e includes haemorrhage at various sites including cerebral haemorrhage

f includes pulmonary embolism, deep vein thrombosis, embolism, thrombophlebitis, thrombophlebitis superficial and thrombosis

g includes colitis, colitis ulcerative, enterocolitis and proctitis

h includes myalgia, muscular weakness, muscle spasm, muscle injury, myopathy, myositis

i includes fluid retention, peripheral oedema, localised oedema

When encorafenib was used at a dose of 300 mg once daily in combination with binimetinib 45 mg twice daily (Combo 300) in study CMEK162B2301-Part 2, the frequency category was lower compared to the pooled Combo 450 population for the following adverse reactions: anemia, peripheral neuropathy, haemorrhage, hypertension, pruritus (common) and colitis, increased amylase and increased lipase (uncommon).

Description of selected adverse reactions

Cutaneous malignancies

CuSCC was reported when binimetinib was used in combination with encorafenib (see section 4.8 of encorafenib SmPC).

Ocular events

In the pooled Combo 450 population, RPED was reported in 29.6 % (81/274) of patients. RPED was Grade 1 (asymptomatic) in 21.2 % (58/274) of patients, Grade 2 in 6.6 % (18/274) of patients and Grade 3 in 1.8 % (5/274) of patients. Most events were reported as retinopathy, retinal detachment, subretinal fluid, macular oedema, and chorioretinopathy and led to dose interruptions or dose modifications in 4.7 % (13/274) of patients. The median time to onset of the first event of RPED (all grades) was 1.5 month (range 0.03 to 17.5 months).

Visual impairment, including vision blurred and reduced visual acuity, occurred in 21.5 % (59/274) of patients. Visual impairment was generally reversible.

Uveitis was also reported when binimetinib was used in combination with encorafenib (see section 4.8 of encorafenib SmPC).

In Study CMEK162B2301-Part 2, in the Combo 300 arm, RPED was observed in 12.5% (32/257) of patients with 0.4% (1/257) Grade 4 event.

Left ventricular dysfunction

In the pooled Combo 450 population, LVD was reported in 8.4 % (23/274) of patients. Grade 3 events occurred in 1.1 % (3/274) of patients. LVD led to treatment discontinuation in 0.4% (1/274) of patients and led to dose interruptions or dose reductions in 6.6 % (18/274) of patients.

The median time to first occurrence of LVD (any grade) was 4.4 months (range 0.03 to 21.3 months) in patients who developed an LVEF below 50 %. The mean LVEF value dropped by 5.9 % in the pooled Combo 450 population, from a mean of 63.9 % at baseline to 58.1 %. LVD was generally reversible following dose reduction or dose interruption.

Haemorrhage