MEKTOVI

). 1 Pregnancy There are no data from the use of binimetinib in pregnant women. Based on its mechanism of action and animal reproduction studies, MEKTOVI can cause fetal harm when administered to a pregnant woman (see 10 Clinical Pharmacology, Mechanism of Action and 16 Non-Clinical Toxicology).

MEKTOVI should not be used in pregnant women. If the patient becomes pregnant while taking MEKTOVI, the patient should be apprised of potential hazard to the fetus. Advise females of reproductive potential to use effective contraception during treatment with MEKTOVI and for at least 1 month after the final dose.

2 Breastfeeding There are no data on the presence of binimetinib or its active metabolite in human milk, or the effects of binimetinib on the breastfed infant, or on milk production. Because of the potential for serious adverse reactions from MEKTOVI in breastfed infants, advise women not to breastfeed during treatment with MEKTOVI and for 3 days after the final dose.

3 Pediatrics Pediatrics (<18 years): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use. 4 Geriatrics Of the 690 patients with BRAF mutation-positive melanoma who received MEKTOVI (45 mg twice daily) in combination with encorafenib at doses between 300 mg and 600 mg once daily across multiple clinical trials, 20% were aged 65 to 74 years and 8% were aged 75 years and older.

No overall differences in the safety or effectiveness of MEKTOVI plus encorafenib were observed in patients over 65 years of age compared to younger patients. The most common AEs reported with a higher incidence in patients aged ≥ 65 years compared to patients aged < 65 years included diarrhea, pruritus, GGT and blood phosphatase alkaline elevation.

1 Adverse Reaction Overview The safety of MEKTOVI in combination with encorafenib is described in 192 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma who received MEKTOVI (45 mg twice daily) in combination with encorafenib (450 mg once daily) in a randomized open-label, active-controlled trial (COLUMBUS).

MEKTOVI Binimetinib Page 14 of 36 Unclassified / Non classifié The most common (≥ 20%) adverse events in patients receiving MEKTOVI in combination with encorafenib were fatigue, nausea, diarrhea, vomiting, constipation, abdominal pain, headache, rash, hyperkeratosis, blood creatinine kinase (CK) increased, visual impairment, arthralgia, and myopathy.

4% of patients receiving vemurafenib. Adverse reactions leading to dose interruptions of MEKTOVI occurred in 33% of patients receiving MEKTOVI in combination with encorafenib; the most common were left ventricular dysfunction (6%) and serous retinopathy (5%).

Adverse reactions leading to dose reductions of MEKTOVI occurred in 19% of patients receiving MEKTOVI in combination with encorafenib; the most common were left ventricular dysfunction (3%), serous retinopathy (3%), and colitis (2%).

Five percent (5%) of patients receiving MEKTOVI in combination with encorafenib experienced an adverse reaction that resulted in permanent discontinuation of MEKTOVI. The most common adverse reactions resulting in permanent discontinuation of MEKTOVI were hemorrhage in 2% and headache in 1% of patients.

2 Clinical Trial Adverse Reactions Clinical trials are conducted under very specific conditions. Therefore, the frequencies of adverse reactions observed in the clinical trials may not reflect frequencies observed in clinical practice and should not be compared to frequencies reported in clinical trials of another drug.

The COLUMBUS trial (see 14 Clinical Trials) excluded patients with a history of Gilbert’s syndrome, abnormal left ventricular ejection fraction, prolonged QTc (>480 msec), uncontrolled hypertension, and history or current evidence of retinal vein occlusion.

2 months for patients treated with vemurafenib or, for rare events, exposure of 690 patients with BRAF V600 mutation- positive melanoma to MEKTOVI (45 mg twice daily) in combination with encorafenib at doses between 300 mg and 600 mg once daily across multiple clinical trials.

Error! Reference source not found. presents adverse drug reactions, identified in COLUMBUS. 03. b Grade 4 adverse reactions limited to diarrhea (n=1) and hemorrhage (n=3) in the MEKTOVI […]