Source: European Medicines Agency (EU) Revision Year: 2025 Publisher: SpringWorks Therapeutics Ireland Limited, Hamilton House, 28 Fitzwilliam Place, Dublin 2, D02 P283, Ireland
Ezmekly as monotherapy is indicated for the treatment of symptomatic, inoperable plexiform neurofibromas (PN) in paediatric and adult patients with neurofibromatosis type 1 (NF1) aged 2 years and above.
Treatment with Ezmekly should be initiated by a physician experienced in the diagnosis and the treatment of patients with NF1 related tumours.
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. The recommended dose for patients with a BSA less than 0.40 m² has not been established.
Table 1. Recommended dose based on body surface area:
| Body surface area (BSA) | Recommended dose |
|---|---|
| 0.40 to 0.69 m² | 1 mg twice daily |
| 0.70 to 1.04 m² | 2 mg twice daily |
| 1.05 to 1.49 m² | 3 mg twice daily |
| ≥1.50 m² | 4 mg twice daily |
Treatment with Ezmekly should continue until PN progression or the development of unacceptable toxicity.
If a dose of Ezmekly is missed, an additional dose is not to be taken. The patient should continue with the next scheduled dose.
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
Interruption and/or dose reduction or permanent discontinuation of Ezmekly may be required based on individual safety and tolerability (see sections 4.4 and 4.8). Recommended dose reductions are given in Table 2. Permanently discontinue treatment in patients unable to tolerate Ezmekly after one dose reduction.
Table 2. Recommended dose reductions:
| Body surface area (BSA) | Reduced dose | |
|---|---|---|
| Morning | Evening | |
| 0.40 to 0.69 m² | 1 mg once daily | |
| 0.70 to 1.04 m² | 2 mg | 1 mg |
| 1.05 to 1.49 m² | 2 mg | 2 mg |
| ≥1.50 m² | 3 mg | 3 mg |
Management of patients according to the adverse reactions associated with this medicinal product are presented in Table 3.
Table 3. Recommended dose modifications for adverse reactions:
| Severity of adverse reactiona | Recommended dose modification for Ezmekly |
|---|---|
| Ocular toxicity (see sections 4.4 and section 4.8) | |
| 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. |
| Decreased left ventricular ejection fraction (LVEF) (see sections 4.4 and section 4.8) | |
| 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 normal. | Interrupt treatment until improvement. Resume at reduced dose (see Table 2). |
| For any absolute decrease in LVEF 20% or greater from baseline. | Discontinue treatment permanently. |
| Skin toxicity (see sections 4.4 and section 4.8) | |
| Grade 1 or 2 dermatitis acneiform or non‑acneiform rash | Continue treatment. |
| Intolerable Grade 2 or Grade 3 dermatitis acneiform or non‑acneiform rash | Interrupt treatment until improvement. Resume at reduced dose (see Table 2). |
| Grade 3 or Grade 4 dermatitis acneiform or non‑acneiform rash | Interrupt treatment until improvement. Resume at reduced dose (see Table 2). |
| Other adverse reactions (see section 4.8) | |
| Intolerable Grade 2 or Grade 3 | Interrupt treatment until improvement. Resume at reduced dose (see Table 2). |
| Grade 4 | Interrupt treatment until improvement. Resume at reduced dose (see Table 2). Consider discontinuation. |
a National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0
No dose adjustment is recommended for patients who are aged 65 or over. Clinical data in patients aged 65 or over is limited (see section 5.1).
No dose adjustment is recommended in patients with mild or moderate renal impairment based on a population pharmacokinetic analysis. Ezmekly has not been studied in patients with severe renal impairment (CrCL ≥15 to <30 mL/min) or patients with end stage renal disease (ESRD), and therefore, no dose recommendations can be made (see section 5.2).
No dose adjustment is recommended in patients with mild hepatic impairment (total bilirubin > ULN to 1.5 x ULN or total bilirubin ≤ ULN and AST > ULN), based on a population pharmacokinetic analysis. Ezmekly has not been studied in patients with moderate or severe hepatic impairment, and therefore, no dose recommendation can be made (see section 5.2).
The safety and efficacy of Ezmekly in children below 2 years of age have not been established. No data are available.
Ezmekly is for oral use.
The capsules can be taken with or without food (see section 5.2).
Ezmekly capsules should be swallowed whole with drinking water. The capsules should not be chewed, broken or opened to ensure the full dose is administered.
For paediatric patients 2 to <6 years of age and for patients who are unable to swallow whole capsules, Ezmekly is also available as a 1 mg dispersible tablet formulation that can be dispersed in water. Refer to the SmPC for Ezmekly dispersible tablets for method of administration.
There is no specific treatment for overdose. If overdose occurs, patients should be closely monitored for signs and symptoms of adverse reactions and treated supportively with appropriate monitoring as necessary. Dialysis is ineffective in the treatment of overdose.
42 months.
Store below 30°C.
Store in the original package to protect from light.
High‑density polyethylene (HDPE) bottle, secured with child‑resistant closure and aluminium foil induction seal.
1 mg hard capsules are provided in a carton containing one bottle of 42 capsules.
2 mg hard capsules are provided in a carton containing one bottle of 42 or 84 capsules.
Not all pack sizes may be marketed.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
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