EZMEKLY

Treatment with Ezmekly should be initiated by a physician experienced in the diagnosis and the treatment of patients with NF1 related tumours. Posology The recommended dose of Ezmekly is 2 mg/m2 of body surface area (BSA), twice daily (approximately every 12 hours) for the first 21 days of each 28-day cycle.

The maximum dose is 4 mg twice daily (see Table 1). For paediatric patients 2 to <6 years of age and for patients who are unable to swallow capsules whole, Ezmekly is also available as a 1 mg dispersible tablet formulation that can be dispersed in water.

40 m2 has not been established. 50 m2 4 mg twice daily Duration of treatment Treatment with Ezmekly should continue until PN progression or the development of unacceptable toxicity. Missed dose If a dose of Ezmekly is missed, an additional dose is not to be taken.

The patient should continue with the next scheduled dose. Vomiting If vomiting occurs after Ezmekly is administered, an additional dose is not to be taken. The patient should continue with the next scheduled dose. Manage events of vomiting as clinically indicated, including use of anti-emetics.

8). Recommended dose reductions are given in Table 2. Permanently discontinue treatment in patients unable to tolerate Ezmekly after one dose reduction. 50 m2 3 mg 3 mg Management of patients according to the adverse reactions associated with this medicinal product are presented in Table 3.

8) Grade ≤ 2 Continue treatment. Consider ophthalmologic examinations every 2 to 4 weeks until improvement. Grade ≥ 3 Interrupt treatment until improvement. If recovery occurs ≤14 days, resume at reduced dose (see Table 2). If recovery occurs in >14 days, consider discontinuation.

Asymptomatic retinal pigment epithelium detachment (RPED) Continue treatment. Ophthalmic assessment should be conducted every 3 weeks until resolution. Symptomatic RPED Interrupt treatment until resolution. Resume at reduced dose (see Table 2).

Retinal vein occlusion (RVO) Discontinue treatment permanently. 8) Asymptomatic, absolute decrease in LVEF less than 20% from baseline and is greater than the lower limit of normal Continue treatment. Asymptomatic, absolute decrease in LVEF of 10 % or greater from baseline and is less than the lower limit of Interrupt treatment until improvement.

Summary of the safety profile In the adult pool of NF1 patients, the most common adverse reactions of any grade were dermatitis acneiform (83%), diarrhoea (55%), nausea (55%), blood creatine phosphokinase increased (47%), musculoskeletal pain (41%), vomiting (37%), and fatigue (36%).

Adverse reactions leading to discontinuation in >1 adult patient were dermatitis acneiform, diarrhoea, nausea, rash, and vomiting. 3%). In the paediatric pool of NF1 patients, the most common adverse reaction of any grade were blood creatine phosphokinase increased (59%), diarrhoea (53%), dermatitis acneiform (43%), musculoskeletal pain (41%), abdominal pain (40%), vomiting (40%), and headache (36%).

7%). Tabulated list of adverse reactions The safety profile of mirdametinib has been determined following evaluation of a combined safety population of 75 adult and 58 paediatric patients dosed at 2 mg/m2 twice daily for the first 21 days of each 28-day cycle.

This pool of patients comprised 114 patients (58 adult, 56 paediatric) in ReNeu (the pivotal dataset), and 19 patients (17 adult, 2 paediatric) in NF-106. 6 months). 1 months). Table 4 presents the adverse reactions identified in the safety population.

Adverse reactions are classified by MedDRA system organ class (SOC). Within each SOC, preferred terms are arranged by decreasing frequency and then by decreasing seriousness. Frequencies of occurrence of adverse reactions are defined as: 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).

Table 4:

Adverse reactions reported in the safety population MedDRA SOC MedDRA term Adult pool (N=75) Paediatric pool (N=58) Overall frequency (All CTCAE grades) Frequency of CTCAE grade 3 and above Overall frequency (All CTCAE grades) Frequency of CTCAE grade 3 and above Infections and Infestations Paronychia Common (3%) - Very Common (33%) - Nervous system disorders Headache Very common (16%) Common (1%) Very common (36%) Common (2%) Blurred vision Common (9%) - Common (7%) - Retinal vein occlusion Common (3%) Common (1%) - - Eye disorders RPED (retinal pigment epithelial detachment) Common (1%) - - - Diarrhoea Very common (55%) - Very common (53%) Common (5%) Nausea Very common (55%) - Very common (29%) - Vomiting Very common (37%) - Very common (40%) - Abdominal paina Very common (20%) Common (4%) Very common (40%) Common (3%) Gastrointestin al disorders Constipation Very common - Very common - MedDRA SOC MedDRA term Adult pool (N=75) Paediatric pool (N=58) Overall frequency (All CTCAE grades) Frequency of CTCAE grade 3 and above Overall frequency (All CTCAE grades) Frequency of CTCAE grade 3 and above (19%) (10%) Dry mouth Common (7%) - - - Stomatitisb Common (5%) - Very Common (19%) - Dermatitis acneiform Very common (83%) Common (7%) Very common (43%) Common (2%) Rashc Very common (17%) Common (1%) Very common (33%) Common (2%) Dry skin Very common (13%) - Very common (17%) - Alopecia Very common (12%) - Very common (14%) - Pruritus Very common (13%) - Very common (12%) - Eczema Common (3%) - Very common (14%) - Hair colour changes Common (1%) - Very common (12%) - Skin and subcutaneous tissue disorders Hair texture abnormal Common (1%) - Common (5%) - Musculoskelet al and connective tissue disorders Musculoskele tal pain d Very common (41%) Common (7%) Very common (41%) Common (2%) General Fatigue Very Common Very - MedDRA SOC MedDRA term Adult pool (N=75) Paediatric pool (N=58) Overall frequency (All CTCAE grades) Frequency of CTCAE grade 3 and above Overall frequency (All CTCAE grades) Frequency of CTCAE grade 3 and above common (36%) (1%) common (12%)disorders and administation site conditions Oedema peripherale Very common (12%) - Common (5%) - Blood creatine phosphokinas e increased Very common (47%) Common (3%) Very common (59%) Common (5%) AST increased Very common (16%) - Common (9%) - Blood alkaline phosphatase increased Very common (14%) - Very common (24%) - Ejection fraction decreased Very common (12%) - Very common (26%) Common (2%) Neutrophil count decreased Common (8%) Common (1%) Very common (30%) Very common (11%) Leukocyte count decreased Common (7%) - Very common (39%) - Investigations ALT increased Common (7%) - Very common (21%) - a Abdominal pain includes abdominal pain and abdominal pain upper.

Ocular toxicity Patients should be advised to report any new visual disturbances. 8). A comprehensive ophthalmological evaluation prior to treatment initiation, at regular intervals during treatment, and at any time a patient reports new or worsening visual changes such as blurred vision is necessary in children, adolescents and adults.

For ocular adverse reactions, mirdametinib therapy should be interrupted and then dose reduced or treatment permanently discontinued based on severity of the adverse reaction. If RVO is diagnosed, treatment with mirdametinib should be permanently discontinued.

If symptomatic RPED is diagnosed, treatment with mirdametinib should be interrupted until resolution and the dose reduced when treatment is resumed. 2). Decreased left ventricular ejection fraction (LVEF) Asymptomatic decrease in LVEF ≥ 10% from baseline occurred in 16% of adult patients and 27% of paediatric patients in the ReNeu study.

8). Patients with a history of impaired LVEF or a baseline ejection fraction that is below the institutional lower limit of normal (LLN) have not been studied. LVEF should be evaluated by echocardiogram before initiation of treatment to establish baseline values, every 3 months during the first year, then as clinically indicated thereafter.

Prior to starting treatment, patients should have an ejection fraction above the institutional LLN. 2). 8). Patients should contact their doctor or nurse if they experience any skin reactions. g. the use of emollient creams, should be initiated at first signs of skin toxicity.

2). 3). 6). Both male and female patients (of reproductive potential) should be advised to use effective contraception. Excipients with known effect Each dispersible tablet contains less than 1 mmol sodium (23 mg) per dose which means it is essentially ‘sodium-free’.

1.