Namuscla is indicated for the symptomatic treatment of myotonia in adult patients with non-dystrophic myotonic disorders.

Posology The recommended starting dose of mexiletine is 167 mg daily (1 capsule per day). After at least 1 week of treatment, based on the clinical response, the daily dose can be increased to 333 mg daily (2 capsules per day). After at least 1 further week of treatment, based on clinical response, dose can be further increased to 500 mg daily (3 capsules per day). Maintenance treatment is between 167 mg – 500 mg daily (1 to 3 capsules per day), according to the intensity of symptoms and the clinical response, taken regularly throughout the day. The dose should not exceed 500 mg/day. Regular reassessment should be implemented, not to continue long-term treatment in a patient not responding or not experiencing benefit of the treatment. Before starting mexiletine treatment, detailed and careful cardiac evaluation should be carried out; throughout treatment with mexiletine, cardiac monitoring needs to be continued and adapted as a function of the heart condition of the patient (see

in section 4.3 and warning in section 4.4). Patients with cardiac disorders In case of modification of the mexiletine dose, or if medicinal products susceptible to affect cardiac conduction are co-administered with mexiletine, patients should be closely monitored by ECG (especially patients with conduction anomalies) (see sections 4.3 and 4.4). Elderly Experience with mexiletine in patients with myotonic disorders aged > 65 years is limited. Based on the pharmacokinetic properties of mexiletine, no dosage adjustment is required in patients aged 65 years and over. Hepatic impairment Mexiletine should be used with caution in patients with mild or moderate hepatic impairment. In these patients, it is recommended that the dose should only be increased after at least 2 weeks of treatment. Mexiletine should not be used in patients with severe hepatic impairment (see section 4.4). Renal impairment No dosage adjustment is considered necessary in patients with mild or moderate renal impairment. The experience with mexiletine in patients with severe renal impairment is limited. Therefore, the use of mexiletine is not recommended in this patient population (see section 4.4). Paediatric population The safety and efficacy of mexiletine in children and adolescents aged 0 to 18 years have not been established. No data are available. Poor and extensive CYP2D6 metabolisers Patients who are CYP2D6 poor metabolisers may exhibit higher mexiletine blood levels (see section 5.2). A period of at least 7 days before dose increase must be respected to ensure that steady-state levels are reached, irrespective of the patient’s CYP450 polymorphism. Method of administration Oral use. The capsules should be swallowed with water, avoiding the supine position. In case of digestive intolerance, capsules should be taken during a meal. • Hypersensitivity to the active substance, or to any of the excipients listed in section 6.1 • Hypersensitivity to any local anaesthetic • Ventricular tachyarrhythmia • Complete heart block (i.e. third-degree atrioventricular block) or any heart block susceptible to evolve to complete heart block (first-degree atrioventricular block with markedly prolonged PR interval (= 240 ms) and/or wide QRS complex (= 120 ms), second-degree atrioventricular block, bundle branch block, bifascicular and trifascicular block), • Myocardial infarction (acute or past), or abnormal Q-waves • Symptomatic coronary artery disease • Heart failure with mid-range (40-49%) and reduced (<40%) ejection fraction • Atrial tachyarrhythmia, fibrillation or flutter • Sinus node dysfunction (including sinus rate < 50 bpm) • Co-administration with medicinal products inducing torsades de pointes (see section 4.5) • Co-administration with medicinal products with narrow therapeutic index (see section 4.5).

Cardiac arrhythmogenic effects Mexiletine may induce an arrhythmia or accentuate a pre-existing arrhythmia, either diagnosed or undiagnosed. See also sections 4.3 and 4.5 regarding association with other products with arrhythmogenic effects. Before starting mexiletine treatment, detailed and careful cardiac evaluation (ECG, 24-48-hour Holter-monitoring and echocardiography) should be carried out in all patients in order to determine the cardiac tolerability of mexiletine. A cardiac evaluation is recommended shortly after treatment start (e.g. within 48 hours). Throughout treatment with mexiletine, and in relation with dose changes, cardiac monitoring of patients needs to be adapted as a function of the heart condition of the patient: • In patients without cardiac abnormalities, periodic ECG monitoring is recommended (every 2 years or more frequently if considered necessary). • In patients with cardiac abnormalities, and in patients prone to such abnormalities, detailed cardiac evaluation, including ECG, should be carried out before and after any dose increase. During maintenance treatment, detailed cardiac evaluation, including ECG, 24-48 hour Holter-monitoring and echocardiography, is recommended at least annually, or more frequently if considered necessary as part of routine cardiac assessment. Patients should be informed about the presenting symptoms of arrhythmias (fainting, palpitation, chest pain, shortness of breath, light-headedness, lipothymia, and syncope) and should be advised to immediately contact an emergency centre if there are any symptoms of arrhythmias. For cardiac disorders not listed in section 4.3, the benefit of the antimyotonic effects of mexiletine needs to be balanced against the risk of cardiac complications on a case by case basis. Mexiletine should be stopped immediately in case any cardiac conduction abnormalities or any of the contraindications listed in the section 4.3 are detected. Electrolytic imbalance such as hypokalaemia, hyperkalaemia or hypomagnesaemia may increase the proarrhythmic effects of mexiletine. Therefore, electrolytic evaluation should be done prior to initiating therapy with mexiletine in every patient. Electrolyte imbalance needs to be corrected before administering mexiletine and to be monitored throughout treatment (with a periodicity to be adapted patient by patient). Drug reaction with eosinophilia and systemic symptoms (DRESS) DRESS refers to a syndrome which includes in its complete form severe cutaneous eruptions, fever, lymphadenopathy, hepatitis, haematological abnormalities with eosinophilia and atypical lymphocytes, and can involve other organs. Symptoms typically occur 1-8 weeks after exposure to the medicinal product. Severe systemic manifestations are responsible for a 10% mortality rate. Incidence of DRESS has been reported between 1:100 and 1:10.000 patients treated. Several medicinal products including anticonvulsants, antibiotics and also mexiletine have been identified as possible causes. Patients with known hypersensitivity to mexiletine or any other ingredients of this product or to any local anaesthetic are at high risk of developing DRESS and should not receive mexiletine. Hepatic impairment The experience with mexiletine in patients with severe hepatic impairment is limited. Therefore, mexiletine should not be used in this patient population (see section 4.2). Renal impairment The experience with mexiletine in patients with severe renal impairment is limited. Therefore, the use of mexiletine is not recommended in this patient population (see section 4.2). Epilepsy Epileptic patients need to be monitored because mexiletine can increase the frequency of seizure episodes. CYP2D6 polymorphism CYP2D6 polymorphism may affect mexiletine pharmacokinetics (see section 5.2). Higher systemic exposure is expected in patients who are CYP2D6 poor metabolisers or who take medicinal products that inhibit CYP2D6 (see section 4.5). A period of at least 7 days before dose increase must be respected to ensure that steady-state levels are reached and that mexiletine is well tolerated in all patients, irrespective of CYP450 polymorphism. Drug screening Mexiletine may cross-react in various amphetamine screening assays, which can lead to a false-positive urine test for amphetamines when Mexiletine is taken. Smoking Smoking affects mexiletine pharmacokinetics (see section 4.5). Mexiletine dose may need to be increased if a patient starts to smoke and decreased if a patient stops to smoke.

Pharmacodynamic

Pregnancy There are no or limited amount of data from the use of mexiletine in pregnant women. Limited clinical data of the use of mexiletine in pregnant women shows that mexiletine crosses the placenta and reaches the foetus. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of mexiletine during pregnancy. Breast-feeding Mexiletine is excreted in human milk. There is insufficient information on the effects of mexiletine in newborns/infants. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from mexiletine therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman. Fertility The effects of mexiletine on fertility in humans have not been studied. Animal studies with mexiletine do not indicate harmful effects with respect to fertility (see section 5.3).

Mexiletine may have minor influence on the ability to drive and use machines. Fatigue, confusion, blurred vision may occur following administration of mexiletine (see section 4.8).

Summary of the safety profile The most commonly reported adverse reactions in patients treated with mexiletine are abdominal pain (12%), vertigo (8%) and insomnia (12%). The most serious reported adverse reactions in patients treated with mexiletine are drug reaction with eosinophilia and systemic symptoms and arrhythmia (atrioventricular block, arrhythmia, ventricular fibrillation). Tabulated list of adverse reactions Frequency categories are derived according to the following conventions: 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), not known (cannot be estimated from the available data). Very common and common adverse reactions are derived from data from the MYOMEX study; less common adverse effects are derived from post-marketing data. Blood and lymphatic system disorders Not known: leukopenia, thrombocytopenia Immune system disorders Very rare: drug reaction with eosinophilia and systemic symptoms Not known: lupus-like syndrome, dermatitis exfoliative, Stevens-Johnson syndrome Psychiatric disorders Very common: insomnia Common: somnolence Not known: hallucinations, confusional state Nervous system disorders Common: headache, paraesthesia, vision blurred Uncommon: seizure, speech disorders Not known: diplopia, dysgeusia Ear and labyrinth disorders Common: vertigo Cardiac disorders Common: tachycardia Uncommon: bradycardia Not known: atrioventricular block Vascular disorders Common: flushing, hypotension Not known: circulatory collapse, hot flush Respiratory, thoracic and mediastinal disorders Not known: pulmonary fibrosis Gastrointestinal disorders Very common: abdominal pain Common: nausea Not known: diarrhoea, vomiting, oesophageal ulcers and perforation Hepatobiliary disorders Rare: hepatic function abnormal Very rare: drug-induced liver injury, liver disorder, hepatitis Skin and subcutaneous tissue disorders Common: acne Musculoskeletal and connective tissue disorders Common: pain in the extremities General disorders and administration site conditions Common: fatigue, asthenia, chest discomfort, malaise Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Symptoms Fatal outcomes have been reported for acute s at 4.4 g of mexiletine hydrochloride ingestion but survival has also been reported following acute of approximately 4 g of oral mexiletine hydrochloride. The symptoms of mexiletine include neurological disorders (paresthesia, confusion, hallucination, seizure) and cardiac disorders (sinusal bradycardia, hypotension, collapse, and in extreme cases, cardiac arrest). management The treatment is mainly symptomatic. The seriousness of the symptoms may require hospital supervision. In case of bradycardia with hypotension, intravenous atropine should be used. In case of seizure, benzodiazepines should be used.

Pharmacotherapeutic group: Cardiac therapy, antiarrhythmics, class Ib, ATC code: C01BB02. Mechanism of action Mexiletine blocks sodium channels with a stronger potency in situations of excessive burst of action potentials (use-dependent block) and/or prolonged depolarization (voltage-dependent block), as occurring in diseased tissues, rather than on physiological excitability (resting or tonic block). Mexiletine is, therefore, mostly active on muscle fibres subject to repeated discharges (such as skeletal muscles). It improves myotonic symptoms by decreasing muscle stiffness through reduction of the delay of muscle relaxation. Clinical efficacy and safety The efficacy and safety of mexiletine in non-dystrophic myotonia was evaluated in MYOMEX, a multi-centre, double-blind, placebo-controlled, cross-over (2 treatment periods of 18 days) study with a 4-day wash-out period in 13 patients with myotonia congenita (MC) and 12 patients with paramyotonia congenita (PC). Age of the overall study population ranged from 20 to 66 years old and about 2/3 of the patients were male. Patients who experienced myotonic symptoms that involved at least 2 segments and that had an impact on at least 3 daily activities were included into the study. The patients were randomized according to a cross-over design to a sequence including the 2 following treatments: a) mexiletine, started at 167 mg/day and titrated by increments of 167 mg every 3 days to reach a maximum dose of 500 mg/day in 1 week or b) placebo.1 The primary efficacy measure for both MC and PC was the score of stiffness severity as self-reported by the patients on a Visual Analogue Scale (VAS). The VAS is constructed as an absolute measure, with a 100 mm straight horizontal line having the endpoints “no stiffness at all” (0) and “worst possible stiffness” (100). The main secondary endpoints were changes in health–related quality of life as measured by individualised neuromuscular quality of life (INQoL) scale and the time needed to stand up from a chair, walk around the chair and sit down again (chair test). Results for the primary and key secondary endpoints are summarised in the table below. Mexiletine Placebo Primary Analysis Stiffness score (VAS) (mm) Number of subjects 25 25 Median VAS value at Baseline 71.0 81.0 Median VAS value at Day 18 16.0 78.0 Median VAS absolute change from baseline -42.0 2.0 Percentage of Patients with an Absolute VAS Change from Baseline = 50 mm at Day 18 12/21 (57.1%) 3/22 (13.6%) Effect of treatment (Mixed Effect Linear Model) p < 0.001 Secondary Analysis Chair test (s) Number of subjects 25 25 Mean (SD) value at Baseline 7.3 (3.5) Mean (SD) value at Day 18 5.2 (1.6) 7.5 (4.1) Mean (SD) absolute change from baseline -2.1 (2.9) 0.2 (1.6) Effect of treatment (Wilcoxon signed-rank test) p = 0.0007 Secondary Analysis Individualised neuromuscular quality of life – Overall quality of life Number of subjects 25 25 Median value at Baseline 51.1 Median value at Day 18 23.3 48.3 1 Clinical Study Report refers to 200 mg dose which is the amount of mexiletine hydrochloride (corresponding to 166.62mg mexiletine base) Median absolute change from baseline -25.0 1.1 Effect of treatment (linear mixed model) p < 0.001 Secondary Analysis Clinical Global Impression (CGI) Efficacy index Number of subjects 25 25 CGI as judged efficient by the investigators 22 (91.7%) 5 (20.0%) CGI as judged efficient by the patients 23 (92.0%) 6 (24.0%) Effect of treatment (Mc Nemar test) p < 0.001 Secondary Analysis Preference between the 2 treatment periods Number of subjects 25 25 Period preferred 20 (80.0%) 5 (20.0%) Effect of treatment (binomial test) p = 0.0041 Secondary Analysis Clinical Myotonia Scale – Severity Global Score Number of subjects 25 25 Mean (SD) value at Baseline 53.8 (10.0) Mean (SD) value at Day 18 24.0 (17.1) 47.6 (23.3) Mean (SD) absolute change from baseline -29.8 (16.0) -6.2 (19.0) Effect of treatment (linear mixed model) p < 0.001 Secondary Analysis Clinical Myotonia Scale – Disability Global Score Number of subjects 25 25 Mean (SD) value at Baseline 7.8 (2.8) Mean (SD) value at Day 18 2.7 (2.6) 7.0 (3.8) Mean (SD) absolute change from baseline -5.1 (3.1) -0.8 (3.4) Effect of treatment (linear mixed model) p < 0.001 Paediatric population The European Medicines Agency has deferred the obligation to submit the results of studies with Namuscla in all subsets of the paediatric population in the symptomatic treatment of myotonic disorders (see section 4.2 for information on paediatric use).

Absorption Mexiletine is rapidly and almost completely absorbed following oral administration with a bioavailability of about 90% in healthy subjects. Peak plasma concentrations following oral administration occur within 2 to 3 hours. No notable accumulation of mexiletine was observed after repeated administration. Food does not affect the rate or extent of absorption of mexiletine. Therefore, mexiletine can be taken with or without food. Distribution Mexiletine is rapidly distributed in the body; its volume of distribution is large and varies from 5 to 9 L/kg in healthy individuals. Mexiletine is weakly bound to plasma proteins (55%). Mexiletine crosses the placental barrier and diffuses into breast milk. Biotransformation Mexiletine is mainly (90%) metabolized in the liver, the primary pathway being CYP2D6 metabolism, although it is also a substrate for CYP1A2. The metabolic degradation proceeds via various pathways, including aromatic and aliphatic hydroxylation, dealkylation, deamination and N-oxidation. Several of the resulting metabolites are submitted to further conjugation with glucuronic acid (phase II metabolism); among these are the major metabolites p- hydroxymexiletine, hydroxy-methylmexiletine and N-hydroxymexiletine. The influence of CYP2D6 phenotype on mexiletine metabolism has been extensively investigated. Mexiletine pharmacokinetics are characterised by significantly lower total and renal clearance resulting in prolonged elimination half-life, higher exposure, and lower volume of distribution in poor metabolisers compared to extensive metabolisers. Approximately 10% is excreted unchanged by the kidney. Elimination Mexiletine is eliminated slowly in humans (with a mean elimination half-life of 10 hours, ranging from 5 to 15 hours). Excretion of mexiletine essentially occurs through the kidney (90% of the dose, including 10% as unchanged mexiletine). Mexiletine excretion may increase when the urinary pH is acidic, compared to normal or alkaline pH. In a clinical study, 51% of the mexiletine dose was excreted via the kidney at a urinary pH of 5, compared to 10% at normal pH. Changes in urinary pH are not expected to affect efficacy or safety. Linearity/non-linearity A linear relationship between mexiletine dose and plasma concentration has been observed in the dose range of 83 to 500 mg. Special populations CYP2D6 polymorphism CYP2D6 polymorphism affects mexiletine pharmacokinetics. Individuals who are CYP2D6 poor metabolisers (PM) exhibit higher mexiletine concentrations than CYP2D6 intermediate (IM), extensive (i.e. normal) or ultra-rapid (UM) metabolisers. The proportions of different ethnic populations across these various classes are tabulated below. Ethnicity Poor metabolisers (PM) Intermediate metabolisers (IM) Ultra-rapid metabolisers(UM) Caucasians Up to 10% 1-2% Up to 10% Africans Up to 10% - Up to 5% Asians Up to 5% More than 50% Up to 2% Weight In population pharmacokinetic analyses, weight was found to influence mexiletine pharmacokinetics. Age There is no clinically relevant effect of age on the exposure of mexiletine in adults.

Non-clinical data reveal no special hazard for humans based on studies of safety pharmacology, repeated dose toxicity, toxicity to reproduction and development. The main observed effects in rats and/or dogs were vomiting, diarrhoea, tremor, ataxia, convulsions and tachycardia. However, these studies were not performed in accordance with contemporary standards and are, hence, of unclear clinical relevance. The studies in rats on carcinogenic potential were negative, but not performed in accordance with current standards and therefore of unclear clinical relevance. The negative genotoxicity potential does not indicate an increased carcinogenic risk of treatment with mexiletine.

Capsule content Maize starch Colloidal anhydrous silica Magnesium stearate Capsule shell Iron (III) oxide (E 172) Titanium dioxide (E 171) Gelatin

Not applicable.

3 years.

Do not store above 30°C. Store in the original package in order to protect from moisture.

Capsules are packed in Aluminium/PVC/PVDC blisters containing 30, 50, 100 or 200 capsules. Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Feb. 16, 2026

spc-doc_PLGB 54289-0001.pdf

Bulk SPC upload Feb2026